TW201536758A - Heterocyclic compound - Google Patents

Abstract

An object of the present invention is to provide a compound having a superior CH24H inhibitory action, which is useful as an agent for the prophylaxis or treatment of epilepsy, neurodegenerative disease and the like. The present invention relates to a compound represented by the formula: wherein each symbol is as defined in the specification, or a salt thereof.

Description

Heterocyclic compound

The present invention relates to a heterocyclic compound having a cholesterol 24-hydroxylase (in the present specification, sometimes abbreviated as "CH24H"), a pharmaceutical composition including the heterocyclic compound, and the like.

Alzheimer's disease is a progressive neurodegenerative disease characterized by the deposition of amyloid beta protein (Aβ), the accumulation of phospho-τ in nerve cells (neurofibrillary tangle), And nerve cell death. In recent years, the number of patients with Alzheimer's disease has gradually increased due to aging, but effective treatment methods have not yet been developed. The current medical treatment for Alzheimer's disease is mainly an acetylcholinesterase (AchE) inhibitor. While AchE inhibitors have been shown to provide some degree of effectiveness, but because their purpose is to supplement the reduced acetylcholine, treatment with AchE inhibitors is only symptomatic. Therefore, basic remedies and timely development of preventive drugs have been strongly expected.

Duality of apolipoprotein E (ApoE) regulating cholesterol metabolism has been elucidated The presence of allele ε 4 is a strong risk factor for Alzheimer's disease [Non-Patent Document 1: Science, vol. 261, 921-923, 1993]. After this discovery, it has been shown to be associated with the frequency of polymorphisms in the expression of proteins that regulate cholesterol metabolism and the frequency of Alzheimer's disease, suggesting a relationship between cholesterol metabolism and Alzheimer's disease. Relevance [Non-Patent Document 2: Neurobiol. Aging, vol. 24, 421-426, 2003, Non-Patent Document 3: Mol. Psychiatry, vol. 8, 635-638, 2003]. Furthermore, it has been reported that Cyp46 (same as "cholesterol 24-hydroxylase (CH24H)"), which is a cholesterol oxidase which is particularly expressed in the brain) is a risk factor for Alzheimer's disease [Non-Patent Document 4: Neurosci. Lett., vol. 328, pages 9-12, 2002]. In addition, it has been reported that Cyp46 (CH24H) is expressed around the amyloid-like protein deposited in Alzheimer's disease patients [Non-Patent Document 5: J. Biol. Chem., vol. 279, pages 34674-34681, 2004]. 24S-hydroxycholesterol (24-HC), a metabolite of Cyp46, is increased in the cerebral spinal fluid of patients with Alzheimer's disease [Non-Patent Document 6: Neurosci. Lett., vol. 324, pages 83-85, 2002 Non-Patent Document 7: Neurosci. Lett., vol. 397, pages 83-87, 2006], and 24-HC-induced death of SH-SY5Y cells (human neuroblasts) [Non-Patent Document 8: Brain Res. , vol. 818, pages 171-175, 1999], and rats injected with 24-HC into the lateral ventricle showed short-term memory of damage (usually observed in Alzheimer's disease), suggesting damage by 24-HC Hippocampal neurons [Non-Patent Document 9: Neuroscience, vol. 164, pages 398-403, 2009]. These findings suggest that Cyp46 (CH24H) is deeply involved in the pathology of Alzheimer's disease. Therefore, a compound that inhibits the activity of Cyp46 (CH24H) (ie, a Cyp46 (CH24H) inhibitor) by reducing the brain Intra-24-HC inhibits neuronal cell death, increased Aβ, inflammation in the brain, etc. observed in Alzheimer's disease, and is expected to be a therapeutic or preventive drug (which shows not only improvement of symptoms but also inhibition of disease duration). ). Furthermore, it has been reported that AchE inhibitors are clinically used as a therapeutic drug for Alzheimer's disease, which shows an improved effect of memory disorders caused by Aβ in mice [Non-Patent Document 10: British Journal] Of Pharmacology, vol. 149, pages 998-1012, 2006]. Therefore, Cyp46 (CH24H) inhibitors have shown an improved effect in animal models in which Aβ is overexpressed (APP gene-transforming mice, APP/PS1 double-gene transgenic mice, etc.), and are expected to be treated as Alzheimer's disease. drug.

As a concept of the preclinical stage of Alzheimer's disease, mild cognitive dysfunction has been proposed, and about half of those with this abnormality are described as developing Alzheimer's disease in the future. In recent years, it has been reported that the increase of 24-HC is not only in patients suffering from Alzheimer's disease but also in CSF patients with mild cognitive dysfunction [Non-Patent Document 7: Neurosci. Lett., vol. 397, Pages 83-87, 2006]. This finding suggests that Cyp46 (CH24H) is involved in the pathology of mild cognitive impairment. Therefore, Cyp46 (CH24H) inhibitors are expected to be a new therapeutic drug for Alzheimer's disease or a preventive drug for Alzheimer's disease. .

In addition, in recent years, in the autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis (one of the demyelinating diseases of the central nervous system), the blood has been reported before the symptoms. Increase in 24-HC [non- Patent Document 11: J. Neurosci. Res., vol. 85, pages 1499-1505, 2007]. Multiple sclerosis usually develops in young people around the age of 30, and almost no elderly people who are 60 years of age or older. It has also been reported that 24-HC is increased in patients with multiple sclerosis from the age of 21 to 50 [Non-Patent Document 12: Neurosci. Lett., vol. 331, pages 163-166, 2002]. These findings suggest that Cyp46 (CH24H) is involved in the pathology of multiple sclerosis, and therefore, Cyp46 (CH24H) inhibitors are promising as a new therapeutic or prophylactic agent for multiple sclerosis.

Traumatic brain injury (also referred to as TBI in this specification) is a state in which a very harmful effect is exerted on a healthy individual, and no effective treatment is established for this. In the repair process after TBI tissue damage, reconstruction of nerve cell membrane activated by growth of glial cells and cholesterol distribution in the brain are proposed [Non-Patent Document 13: Proc. Natl. Acad. Sci. USA, vol. 102, pages 8333-8338, 2005]. In the rat TBI mode, enhanced performance of post-traumatic Cyp46 (CH24H) has been reported [Non-Patent Document 14: J. Neurotrauma, vol. 25, pages 1087-1098, 2008]. Furthermore, 24-HC injury to nerve cells has been reported [Non-Patent Document 8: Brain Res., vol. 818, pages 171-175, 1999]. Therefore, Cyp46 (CH24H) inhibitors are expected as a new drug for the treatment or prevention of TBI.

The pathological significance of 24-HC as a neurodegenerative disease has been reported to enhance the inflammatory gene expression in nerve cells [Non-Patent Document 15: NeuroReport, vol. 16, pages 909-913, 2005]. In addition, it is also proposed Inflammatory response in the brain with activation of glial cells is a pathological change characteristic of neurodegenerative diseases [Non-Patent Document 16: Glia, vol. 50, pages 427-434, 2005]. In recent years, therapeutic effects by inhibiting inflammation in the brain have also been reported for neurodegenerative diseases (for example, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis) [Non-Patent Document 17] :Mol.Neurodegeneration, vol.4, pages 47-59, 2009]. Therefore, inhibition of 24-HC inhibition by Cyp46 (CH24H) inhibition of intracerebral inflammation is expected as a neurodegenerative disease (eg, Huntington's disease, Parkinson's disease, cerebral infarction, glaucoma, muscle) New treatment or preventive drugs for atrophic lateral sclerosis, etc.).

Glaucoma is the leading cause of blindness and is considered a serious social problem. However, normal intraocular pressure type stenosis (which is the main symptom of the disease) has no effective treatment. In recent years, the polymorphism of Cyp46 (CH24H) associated with the high value of 24HC in blood has also been reported to be associated with the pathogenesis of glaucoma [Non-Patent Document 18: Invest. Ophthalmol. Vis. Sci., vol. 50, pages 5712 -5717, 2009]. Therefore, Cyp46 (CH24H) inhibitors are expected to be used as drugs for the treatment or prevention of glaucoma.

Radon is a disease that occurs with the abnormal discharge of nerve cells in the brain.痉挛 is also one of the characteristics of clinical findings in Alzheimer's disease [Non-Patent Document 19: Epilepsia, vol. 47, pages 867-872, 2006], and the relationship between epilepsy and the onset of Alzheimer's disease has been pointed out. [Non-Patent Document 20: Epilepsia, vol. 52, Supplement 1, pages 39-46, 2011]. It has been reported that tick lines occur frequently in APP/PS1 double-gene transgenic mice (which is one of the Alzheimer's disease patterns due to excessive expression of A β) [Non-Patent Document 21: J. Neurosci., vol. 29, pages 3453-3462, 2012]. In addition, the relationship between the enzyme and the pathology of epilepsy was indicated by the relationship between Cyp46 (CH24H) and kainic acid-induced rat model (one of the epileptic patterns). Document 22: J. Neurol., vol. 65, pages 652-663, 2006]. It has also been reported that Carbamazepine, which is a therapeutic drug for sputum, shows a short-term memory improvement effect using the mouse sputum mode in the Y-maze test [Non-Patent Document 23: J. Neurol. Neurosurg. Psychiatry, vol. 48, pages 459-468, 1985]. Therefore, in an animal model having symptoms of sputum, a Cyp46 (CH2H) inhibitor exhibiting a short-term memory-improving effect is promising as a therapeutic or prophylactic agent for sputum.

Since schizophrenia shows various psychological symptoms (eg, hallucinations, delusions, excitement, depression, etc.), therapeutic drugs have been developed from various angles. In recent years, it has been pointed out that changes in cholesterol metabolism involve abnormalities in neurological activity seen in schizophrenia [Non-Patent Document 24: J. Psychiatry Neurosci., vol. 36, pages 47-55, 2011]. Since cytotoxic factors (for example, oxidative stress) also provide pathology of schizophrenia, neurocytotoxicity of 24-HC can exacerbate symptoms [Non-Patent Document 25: Psychoneuroendocrinology, vol. 28, pages 83-96, 2003]. Therefore, Cyp46 (CH24H) inhibitors that inhibit the metabolism of cholesterol in the brain to 24-HC are promising as new therapeutic or prophylactic agents for schizophrenia.

Examples of the compound having a structure similar to the compound of the present invention include the following compounds.

Patent Document 1 discloses the following compounds for use as an agent for treating HIV, AIDS, and the like.

Among them, the ring A system R ¹ is a hydrogen atom, a C _1-4 alkyl group or the like; R ² is a hydrogen atom; R ⁴ to R ⁷ are independently a hydrogen atom, a halogen atom or the like; X is N or CH; and Y is a 5- to 7-membered monocyclic aromatic group. a heterocyclic group or the like; a Z-based aryl group or an aromatic heterocyclic group; and R ⁹ to R ^{16 each} independently a hydrogen atom, a C _1-6 alkyl group or the like.

Patent Document 2 discloses a compound having a CH24H inhibitory action for use as a medicament for treating a neurodegenerative disease (for example, Alzheimer's disease, mild cognitive impairment, multiple sclerosis, etc.).

Wherein ring A ^{a is a} ring which is optionally substituted; R ^1a is a group of formula (1): -X ^1a -R ^6a wherein X ^1a is C _1-6 alkyl, C _2-6 alkylene Or a C _3-6 cycloalkyl group, and R ^6a are optionally substituted C _6-14 aryl, optionally substituted C _6-14 aryloxy or optionally substituted heterocyclic group, (2 a C _6-14 aryl group optionally substituted, (3) a C _6-14 aryloxy group optionally substituted, or (4) a heterocyclic group which may be optionally substituted; R ^2a is a hydrogen atom, optionally Substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl or optionally substituted hydroxy, R ^3a optionally substituted C _1-6 alkyl, optionally substituted a C _3-6 cycloalkyl group or an optionally substituted hydroxyl group, or R ^2a and R ^3a may be bonded as needed to form a pendant oxy group, a C _1-3 alkylene group or an optionally substituted ring; and R ^4a and R ^5a is the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group or an optionally substituted hydroxyl group, or R ^4a And R ^5a may be bonded as needed to form a pendant oxy group, a C _1-3 alkylene group or a ring which is optionally substituted.

Patent Document 3 discloses a compound having a calcium-sensitive receptor (CaSR) antagonistic action, which is used as an agent for treating a bone disease (for example, osteoporosis, a fracture, etc.).

Wherein ring A ^{a is a} ring which is optionally substituted; R ^1a is a group of formula (1): -X ^1a -R ^6a wherein X ^1a is C _1-6 alkyl, C _2-6 alkylene Or a C _3-6 cycloalkyl group, and R ^6a is optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkyloxy, optionally substituted C _{6- a 14} aryl group, optionally substituted C _6-14 aryloxy group, optionally substituted C _7-14 aralkyloxy group, optionally substituted heterocyclic group, optionally substituted heterocyclic oxygen a substituted or substituted amino group, (2) a substituted C _3-6 cycloalkyl group as desired, (3) a substituted C _3-6 cycloalkyloxy group as desired, and (4) optionally Substituted C _6-14 aryl, (5) optionally substituted C _6-14 aryloxy, (6) optionally substituted C _7-14 aralkyloxy, (7) optionally substituted a heterocyclic group, (8) a substituted heterocyclic oxy group, or (9) an optionally substituted amino group; a R ^2a hydrogen atom, optionally substituted C _1-6 alkyl group, the required substituted C _3-6 cycloalkyl or the optionally substituted hydroxyl group, R ^3a Department of optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl of The optionally substituted hydroxy group, or R ^2a and R ^3a optionally bonded to form a C _1-3 alkylene group or the optionally substituted cycloalkyl; and the same or different and each a hydrogen atom donor line R ^4a and R ^5a lines, a halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group or an optionally substituted hydroxyl group, or R ^4a and R ^5a may be bonded as needed to form a pendant oxy group, C _1-3 alkylene or optionally substituted ring.

Prior technical literature

Patent literature

Patent Document 1: WO 2007/127635

Patent Document 2: WO 2010/110400

Patent Document 3: JP 2010-248183

Non-patent literature

Non-Patent Document 1: Science, vol. 261, pages 921-923, 1993

Non-Patent Document 2: Neurobiology of Aging (Neurobiol. Aging), vol. 24, pages 421-426, 2003

Non-Patent Document 3: Molecular Psychiatry (Mol. Psychiatry), vol. 8, pages 635-638, 2003

Non-Patent Document 4: Neuroscience Letters (Neurosci. Lett.), vol. 328, pages 9-12, 2002

Non-Patent Document 5: Journal of the Biological Chemistry (J. Biol. Chem.), vol. 279, pages 34674-34681, 2004

Non-Patent Document 6: Neuroscience Letters (Neurosci. Lett.), vol. 324, pages 83-85, 2002

Non-Patent Document 7: Neuroscience Letters (Neurosci. Lett.), vol. 397, pages 83-87, 2006

Non-Patent Document 8: Brain Research (Brain Res.), vol. 818, pages 171-175, 1999

Non-Patent Document 9: Neuroscience, vol. 164, pages 398-403, 2009

Non-Patent Document 10: British Journal of Pharmacology, vol. 149, pages 998-1012, 2006

Non-Patent Document 11: Journal of Neuroscience Research (J. Neurosci. Res.), vol. 85, pages 1499-1505, 2007

Non-Patent Document 12: Neuroscience Letters (Neurosci. Lett.), vol. 331,, pages 163-166, 2002

Non-Patent Document 13: Proceedings of the National Academy of Sciences USA (Proc. Natl. Acad. Sci. USA), vol. 102, pages 8333-8338, 2005

Non-Patent Document 14: Journal of Neurotrauma (J. Neurotrauma), vol. 25, pages 1087-1098, 2008

Non-Patent Document 15: NeuroReport, vol. 16, pages 909-913, 2005

Non-Patent Document 16: Glia, vol. 50, pages 427-434, 2005

Non-Patent Document 17: Molecular Neurodegeneration (Mol. Neurodegeneration), vol. 4, pages 47-59, 2009

Non-Patent Document 18: Investigative Ophthalmology & Visual Science (Invest. Opthalmol. Vis. Sci.), vol. 50, pages 5712-5717, 2009

Non-Patent Document 19: Epilepsia, vol. 47, pages 867-872, 2006

Non-Patent Document 20: Epilepsia, vol. 52, Supplement 1, pages 39-46, 2011

Non-Patent Document 21: Journal of Neuroscience (J. Neurosci.), vol. 29, pages 3453-3462, 2012

Non-Patent Document 22: Journal of Neurology (J. Neurol.), vol. 65, pages 652-663, 2006

Non-Patent Document 23: Journal of Neurology Neurosurgery Psychiatry (J. Neurol. Neurosurg. Psychiatry), vol. 48, pages 459-468, 1985

Non-Patent Document 24: Journal of Psychiatry Neuroscience (J. Psychiatry Neurosci.), vol. 36, pages 47-55, 2011

Non-Patent Document 25: Psychoneuroendocrinology, vol. 28, pages 83-96, 2003

The object of the present invention is to provide a compound which has excellent CH24H inhibition and is useful for the prevention or treatment of epilepsy, neurodegenerative diseases (for example, Alzheimer's disease, mild cognitive disorders, Huntington's disease). , Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, etc.), schizophrenia and other agents.

In an attempt to solve the above problems, the inventors have conducted intensive studies and found that the compound represented by the following formula (I) has superior CH24H inhibition, which leads to completion of the present invention.

Thus, the present invention provides the following.

[1] A compound represented by the formula (I) or a salt thereof: Wherein X ¹ is a carbon atom or a nitrogen atom; Each is further substituted as needed and bridged as needed; R ¹ is optionally substituted with a C _1-6 alkyl group, optionally substituted hydroxy group, optionally substituted amine group, optionally substituted a carbocyclic group, or an optionally substituted heterocyclic group, or an atom to which R ¹ is bonded to the ring A, and a ring or a fused ring together with the ring A, each of which is substituted with a pendant oxy group and Further substituted as necessary; R ² is optionally substituted C _6-14 aryl or, if desired, substituted aromatic heterocyclic group; and when X ¹ -based carbon atom is R ³ -based hydrogen atom or substituent, Or when the X ¹ nitrogen atom R ³ is absent (subsequently referred to as compound (I)) (excluding 4-(4-phenylpyrimidin-5-yl)per 1-carboxylic acid tert-butyl ester) or a salt thereof.

[2] The compound according to [1] or a salt thereof, wherein R ¹ is a C _1-6 alkyl group which is optionally substituted, a C _1-6 alkoxy group which is optionally substituted, and an optionally substituted amino group. , optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-14 aryl, or optionally substituted non-aromatic heterocyclic group (excluding 4-(4-phenylpyrimidine-5) -base) 1-carboxylic acid tert-butyl ester).

[A] The compound of [1] or a salt thereof, wherein R ¹ is (1) a C _1-6 alkyl (a) cyano group optionally substituted with 1 to 3 substituents selected from the group consisting of b) a C _6-14 aryl group substituted with 1 to 3 C _1-6 alkoxy groups, (c) a C _6-14 aryloxy group, (d) a C _3-8 cycloalkyl group, (e) a 5- or 6-membered monocyclic aromatic heterocyclic group, (f) an 8- to 12-membered fused aromatic heterocyclic group, and (g) a 3 to 8 membered monocyclic non-substituted by 1 to 3 pendant oxy groups An aromatic heterocyclic group, (2) a C _1-6 alkoxy group optionally substituted with 1 to 3 C _6-14 aryl groups, (3) optionally a substituent selected from the group consisting of one or two - Substituted amine group (a) optionally substituted by 1 to 3 substituents of C _1-6 alkyl (i) halogen atom, (ii) cyano group, (iii) C _3-8 naphthenic ring a group, (iv) a C _6-14 aryl group substituted with 1 to 3 substituents selected from a halogen atom and a C _1-6 alkoxy group, (v) a 5 or 6 membered monocyclic aromatic heterocyclic group And (vi) 3 to 8 membered monocyclic non-aromatic heterocyclic groups substituted by 1 to 3 C ₁ - ₆ alkyl groups, (b) C _{3 -} 1 - 3 halogen atoms, optionally substituted ₈ -cycloalkyl, (c) C _6-14 aryl, and (d) 3 to 8 membered monocyclic non-aromatic hybrids substituted with 1 to 3 C _1-6 alkyl groups as needed a cyclic group, (4) a C _3-8 cycloalkyl group substituted with 1 to 3 C _6-14 aryl groups, (5) a C _6-14 aryl group, or (6) optionally selected from the group consisting of 1 to 5 substituents substituted by 3 to 12 members of the non-aromatic heterocyclic group (a) halogen atom, (b) cyano group, (c) hydroxyl group, (d) pendant oxy group, (e) optionally C _{a 1-6} alkyl mono- or di-substituted amine carbenyl group, (f) a C _1-6 alkyl (i) hydroxy group substituted with 1 to 3 substituents selected from the group consisting of, and (ii) ) C _1-6 alkoxy, (g) optionally substituted with 1 to 3 of halogen atoms, C _1-6 alkoxy, (H) C _1-6 alkoxy - carbonyl group, and (i) optionally a C _6-14 aryl group substituted with 1 to 3 halogen atoms, or an atom bonded to the ring A by the R ¹ group, together with the ring A form a spiro ring which is substituted by a pendant oxy group and further optionally subjected to 1 to 3 C _1-6 alkyl substituted; R ² is (1) optionally substituted with 1 to 3 substituents of C _6-14 aryl (a) halogen atom, and (b) a C _1-6 alkyl group substituted with 1 to 3 halogen atoms as needed, or (2) a 5 to 12 membered aromatic heterocyclic group (a) optionally substituted with 1 to 3 substituents selected from the group consisting of Halogen atom, (b) cyano group, (c) 1 to 3 halogen atoms as needed Substituted C _1-6 alkyl, and (d) C _3-8 cycloalkyl; X ¹ -based carbon or nitrogen atom; R ³ -based (1) hydrogen atom, or (2) halogen atom; system Each of them is optionally bridged and, if necessary, further substituted with one to five substituents selected from the group consisting of (a) a halogen atom, (b) a C _1-6 alkyl group, and (c) a pendant oxy group, Exclude 4-(4-phenylpyrimidin-5-yl)peri 1-carboxylic acid tert-butyl ester).

[B] The compound of [1] or [A] or a salt thereof, wherein R ¹ is (1) optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl (a) Cyano, (b) C _6-14 aryl substituted by 1 to 3 C _1-6 alkoxy groups, (c) C _6-14 aryloxy, (d) C _3-8 cycloalkyl , (e) 5 or 6 membered monocyclic aromatic heterocyclic group, (f) 8 to 12 membered fused aromatic heterocyclic group, and (g) 3 to 8 optionally substituted with 1 to 3 pendant oxy groups a monocyclic non-aromatic heterocyclic group, (2) a C _1-3 alkoxy group optionally substituted with 1 to 3 C _6-14 aryl groups, and (3) a substituent selected from the group consisting of Or a di-substituted amine group (a), if desired, a C _1-6 alkyl group (i) halogen atom substituted with one to three substituents selected from the group consisting of (ii) a cyano group, (iii) C _{3 -8} cycloalkyl, (iv) C _6-14 aryl group optionally substituted with 1 to 3 substituents selected from a halogen atom and a C _1-6 alkoxy group, (v) 5 or 6 membered monocyclic aromatic groups a heterocyclic group, and (vi) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted by 1 to 3 C _1-6 alkyl groups, (b) optionally substituted with 1 to 3 halogen atoms a C _3-8 cycloalkyl group, (c) a C _6-14 aryl group, and (d) a 3 to 8 membered monocyclic non-aromatic group substituted with 1 to 3 C _1-6 alkyl groups as needed a heterocyclic group, (4) a C _3-8 cycloalkyl group optionally substituted with 1 to 3 C _6-14 aryl groups, (5) a C _6-14 aryl group, or (6) optionally selected from the following 1 to 5 substituents substituted with 3 to 12 members of non-aromatic heterocyclic group (a) halogen atom, (b) cyano group, (c) hydroxyl group, (d) pendant oxy group, (e) as needed a C _1-6 alkyl mono- or di-substituted amine carbenyl group, (f) a C _1-6 alkyl (i) hydroxy group optionally substituted with 1 to 3 substituents selected from the group consisting of II) C _1-6 alkoxy, (g) optionally substituted with 1 to 3 substituents of halogen atoms, C _1-6 alkoxy, (H) C _1-6 alkoxy - carbonyl group, and (i) depending on A C _6-14 aryl group substituted with 1 to 3 halogen atoms, or an atom bonded to the ring A by the R ¹ group, together with the ring A form a spiro ring which is substituted by a pendant oxy group and optionally further Substituted by 1 to 3 C _1-6 alkyl groups.

[3] The compound of [1] or [A] or a salt thereof, wherein R ¹ is (1) optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl (a) Cyano, (b) C _6-14 aryl substituted by 1 to 3 C _1-6 alkoxy groups, (c) C _6-14 aryloxy, (d) C _3-8 cycloalkyl , (e) pyrazolyl, (f) carbazolyl, and (g) dihydropyridinyl optionally substituted with 1 to 3 pendant oxy groups, (2) 1 to 3 C _6-14 as needed An aryl-substituted C _1-6 alkoxy group, (3) an optionally substituted mono- or di-substituted amine group (a), optionally substituted with one to three substituents selected from the group consisting of Substituted C _1-6 alkyl (i) halogen atom, (ii) cyano group, (iii) C _3-8 cycloalkyl group, (iv) optionally selected from a halogen atom and a C _1-6 alkoxy group a C _6-14 aryl group substituted with 1 to 3 substituents, (v) pyridyl group, and (vi) an oxetanyl group substituted with 1 to 3 C _1-6 alkyl groups as required, (b) a C _3-8 cycloalkyl group substituted with 1 to 3 halogen atoms, (c) a C _6-14 aryl group, and (d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofuranyl group, and pyrrolidinyl, each optionally substituted with donor line 1-3 C _1-6 alkyl, (4) an optionally from 1 to 3 C _6-14 aryl The substituted C _3-8 cycloalkyl group, (5) C _6-14 aryl group, or (6) 3-8 monocyclic non-aromatic heterocyclic group or 3,7-dioxa-9-azabicyclo [3.3.1] fluorenyl, each of which is substituted with 1 to 5 substituents selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) a hydroxyl group, and (d) a pendant oxy group, (e) an optionally substituted by a C _1-6 alkyl mono- or di-substituted amine, and (f) optionally substituted by 1 to 3 substituents selected from the group consisting of C _1-6 alkyl ( i) hydroxy, and (II) C _1-6 alkoxy, (g) optionally substituted with 1 to 3 of halogen atoms, C _1-6 alkoxy, (H) C _1-6 alkoxy - carbonyl group And (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms, or an atom bonded to the ring A by the R ¹ group, together with the ring A to form a 2,8-diaza snail [4.5] a decane ring which is substituted with a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups; the R ² system (1) is optionally substituted with 1 to 3 of the following a C _6-14 aryl (a) halogen atom, and (b) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or (2) 5 or 6 membered monocyclic aromatic a cyclic group or a 8 to 12 member fused aromatic heterocyclic group, each of which is optionally selected from the group consisting of 1 to 3 substituents (a) a halogen atom, (b) cyano, (c) optionally substituted with 1 to 3 substituents of halogen atoms, C _1-6 alkyl, and (d) C _3-8 cycloalkyl group; ^X-1 based carbon atom or a nitrogen atom; R ³ line (1) a hydrogen atom, or (2) a halogen atom; and the ring A system (1) Each of them is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom, (b) a C _1-6 alkyl group, and (c) a pendant oxy group, or (2) an 8-nitrogen group, as needed. Heterobicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0]hexane ring, (excluding 4-(4-benzene) Pyrimidine-5-yl)peri 1-carboxylic acid tert-butyl ester).

[4] The compound or a salt thereof according to any one of [1], [3], [A], or [B], wherein the R ¹ system (1) is optionally substituted with one to three selected from the group consisting of the substituted C _1-6 alkyl group (a) cyano, (b) optionally substituted with 1 to 3 C _1-6 alkoxy groups a C _6-14 aryl group, (c) C _6-14 aryloxy a group, (d) a C _3-8 cycloalkyl group, (e) pyrazolyl, (f) a carbazolyl group, and (g) a dihydropyridyl group optionally substituted with 1 to 3 pendant oxy groups, (2) a C _1-3 alkoxy group substituted with 1 to 3 C _6-14 aryl groups as needed, (3) an optionally substituted mono- or di-substituted amine group (a) depending on the substituent selected from the group consisting of A C _1-6 alkyl (i) halogen atom substituted with 1 to 3 substituents selected from the group consisting of (ii) a cyano group, (iii) a C _3-8 cycloalkyl group, (iv) optionally a C _6-14 aryl group substituted with 1 to 3 substituents of a halogen atom and a C _1-6 alkoxy group, (v) pyridyl group, and (vi) 1 to 3 C _1-6 alkane as needed a substituted oxetane group, (b) a C _3-8 cycloalkyl group substituted with 1 to 3 halogen atoms, (c) a C _6-14 aryl group, and (d) a tetrahydropyran Base, oxetane, tetrahydrofuranyl and pyrrolidinyl, each being substituted by 1 to 3 C _1-6 alkyl groups, (4) as needed a C _3-8 cycloalkyl group substituted with 1 to 3 C _6-14 aryl groups, (5) a C _6-14 aryl group, or a (6) 3 to 8 membered monocyclic non-aromatic heterocyclic group or 3 , 7-dioxa-9-azabicyclo[3.3.1]fluorenyl, each of which is optionally substituted with one to five substituents selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) hydroxy, (d) oxo, (e) C _1-6 alkyl group is optionally substituted by mono - or di - substituted carbamoyl of acyl, (f) an optionally selected from those of 1 to 3, a C _1-6 alkyl (i) hydroxy group substituted by a substituent, and (ii) a C _1-6 alkoxy group, (g) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, (h) a C _1-6 alkoxy-carbonyl group, and (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms, or an atom bonded to the ring A by the R ¹ group, and Ring A together form a 2,8-diazaspiro[4.5]decane ring which is substituted with a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups.

[C] The compound according to [1] or [2] or a salt thereof, wherein R ¹ is a 3 to 8 membered monocyclic non-aromatic heterocyclic group which is optionally substituted with 1 to 5 substituents selected from the group consisting of (a) a halogen atom, (b) cyano, (c) carbamoyl acyl, (d) optionally substituted with 1 to 3 C _1-6 alkoxy groups the C _1-6 alkyl group, and (e) C _1-6 alkoxy; R ² is (1) optionally substituted with 1 to 3 substituents of C _6-14 aryl (a) halogen atom, and (b) optionally 1 a C _1-6 alkyl group substituted with 3 halogen atoms, or (2) a 5 or 6 membered monocyclic aromatic heterocyclic group (a) halogen atom optionally substituted with 1 to 3 substituents selected from the group consisting of And (b) C _1-6 alkyl; X ¹ -based carbon atom; R ³ -based hydrogen atom; and ring A system

[D] The compound of any one of [1], [3] and [A] or a salt thereof, wherein R ¹ is (1) optionally substituted with 1 to 3 substituents selected from the group consisting of _{a 1-6} alkyl (a) cyano group, (b) a phenyl group optionally substituted with 1 to 3 C _1-6 alkoxy groups, (c) a phenoxy group, (d) a cyclopropyl group, (e) Pyrazolyl, (f) carbazolyl, and (g) dihydropyridinyl optionally substituted with 1 to 3 pendant oxy groups, (2) C _1-6 substituted with 1 to 3 phenyl groups as needed Alkoxy, (3) optionally substituted by a substituent selected from the group consisting of a mono- or di-substituted amino group (a), optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkane a base (i) a halogen atom, (ii) a cyano group, (iii) a cyclopropyl group, (iv) a cyclobutyl group, and (v) optionally 1 to 3 selected from a halogen atom and a C _1-6 alkoxy group. Substituted phenyl, (vi) pyridyl, and (vii) oxetanyl substituted by 1 to 3 C _1-6 alkyl, (b) cyclopropyl, cyclobutyl and a cyclopentyl group, each of which is optionally substituted with 1 to 3 halogen atoms, (c) a phenyl group, and (d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofuranyl group, and a pyrrolidinyl group, each system optionally substituted by 1 to 3 C _1-6 alkyl groups, (4) depending on Be 1 to 3 substituents of a phenyl cyclopropyl, (5) phenyl, or (6) azetidinyl, pyrrolidinyl, piperidinyl, piperazine, , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl or 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl, each of which is optionally one to five substituents selected from the group consisting of Substituting (a) a halogen atom, (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) an optionally substituted mono- or di-substituted amine carbenyl group by a C _1-6 alkyl group, f) a C _1-6 alkyl (i) hydroxy group substituted with 1 to 3 substituents selected from the group consisting of, and (ii) a C _1-6 alkoxy group, (g) optionally 1 to 3 a C _1-6 alkoxy group substituted by a halogen atom, (h) a C _1-6 alkoxy-carbonyl group, and (i) a phenyl group substituted with 1 to 3 halogen atoms as required, or an R ¹ -bonding bond The atom to the ring A, together with ring A, forms a 2,8-diazaspiro[4.5]decane ring which is substituted by a pendant oxy group and further optionally 1 to 3 C _1-6 alkyl groups. substituted; R ² lines (1) optionally substituted with 1 to 3 substituents selected from those of the phenyl group substituted with (a) a halogen atom, and (b) Requires 1 to 3 substituents of halogen atoms, C _1-6 alkyl, or (2) pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a carbazolyl group or a benzothiazolyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom and (b) a cyano group. (c) a C _1-6 alkyl group substituted with 1 to 3 halogen atoms, and (d) a cyclopropyl group; an X ¹ -based carbon atom or a nitrogen atom; and an R ³ -based (1) hydrogen atom, or 2) a halogen atom; and a ring A system (1) Each of them is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom, (b) a C _1-6 alkyl group, and (c) a pendant oxy group, or (2) an 8-nitrogen group, as needed. Heterobicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0]hexane ring, (excluding 4-(4-benzene) Pyrimidine-5-yl)peri 1-carboxylic acid tert-butyl ester).

[E] The compound or a salt thereof according to any one of [1], [3], [4], [A], [B], and [D], wherein the R ¹ system (1) is optionally selected from the group consisting of a C _1-6 alkyl (a) cyano group substituted by 1 to 3 substituents of the following, (b) a phenyl group substituted by 1 to 3 C _1-6 alkoxy groups, (c) phenoxy a group, (d) cyclopropyl, (e) pyrazolyl, (f) carbazolyl, and (g) dihydropyridyl group optionally substituted with 1 to 3 pendant oxy groups, (2) as needed 1 to 3 phenyl-substituted C _1-3 alkoxy groups, (3) optionally a mono- or di-substituted amine group (a), optionally substituted with one selected from the group consisting of a C _1-6 alkyl (i) halogen atom substituted with 3 substituents, (ii) a cyano group, (iii) a cyclopropyl group, (iv) a cyclobutyl group, (v) optionally selected from a halogen atom and a phenyl group substituted with 1 to 3 substituents of a C _1-6 alkoxy group, (vi) a pyridyl group, and (vii) an oxetanyl group substituted with 1 to 3 C _1-6 alkyl groups as needed , (b) cyclopropyl, cyclobutyl and cyclopentyl, each of which is optionally substituted with 1 to 3 halogen atoms, (c) phenyl, and (d) tetrahydropyranyl, oxyheterocycle azetidinyl, tetrahydrofuranyl, and pyrrolidinyl, each of those lines is optionally substituted by from 1 to 3 C _1-6 alkoxy Substituted, (4) optionally substituted with 1 to 3 substituents of a phenyl cyclopropyl, (5) phenyl, or (6) azetidinyl, pyrrolidinyl, piperidinyl, piperazine, , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl or 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl, each of which is optionally one to five substituents selected from the group consisting of Substituting (a) a halogen atom, (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) an optionally substituted mono- or di-substituted amine carbenyl group by a C _1-6 alkyl group, f) a C _1-6 alkyl (i) hydroxy group substituted with 1 to 3 substituents selected from the group consisting of, and (ii) a C _1-6 alkoxy group, (g) optionally 1 to 3 a C _1-6 alkoxy group substituted by a halogen atom, (h) a C _1-6 alkoxy-carbonyl group, and (i) a phenyl group substituted with 1 to 3 halogen atoms as required, or an R ¹ -bonding bond The atom to the ring A, together with ring A, forms a 2,8-diazaspiro[4.5]decane ring which is substituted by a pendant oxy group and further optionally 1 to 3 C _1-6 alkyl groups. Replace.

[5] The compound or a salt thereof according to any one of [1] to [4], [A], [B], [D], and [E], wherein the R ¹ system (1) is optionally selected from the group consisting of Substituent mono- or di-substituted amine groups (a) optionally substituted by 1 to 3 substituents of the following C _1-6 alkyl (i) halogen atom, and (ii) a phenyl group substituted with 1 to 3 halogen atoms, (b) tetrahydropyranyl group, and (c) tetrahydrofuranyl group, or (2) azetidinyl group or pyrrolidinyl group, each of which is optionally required One to five substituents selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) an amine formazan group, (d) a C _1-6 alkyl group, and (e) a C _{1-6 group} Alkoxy; R ² is (1) a phenyl group substituted with 1 to 3 halogen atoms, or (2) pyrazolyl, thiazolyl or thiadiazolyl, each of which is selected from the group consisting of Up to 3 substituents substituted for (a) a halogen atom, (b) a C _1-6 alkyl group, and (c) a cyclopropyl group; an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based hydrogen atom; and a ring A system

[F] The compound or a salt thereof according to any one of [1] to [5], [A], [B], [D], and [E], wherein the R ¹ system (1) is optionally selected from the group consisting of Substituent mono- or di-substituted amine groups (a) optionally substituted by 1 to 3 substituents of the following C _1-6 alkyl (i) halogen atom, and (ii) a phenyl group substituted with 1 to 3 halogen atoms, (b) tetrahydropyranyl group, and (c) tetrahydrofuranyl group, or (2) azetidinyl group or pyrrolidinyl group, each of which is optionally required One to five substituents selected from the group consisting of (a) a halogen atom, and (b) a cyano group; an R ² system (1) a phenyl group substituted with 1 to 3 halogen atoms as desired, or (2) pyridyl An oxazolyl or thiazolyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom, (b) a C _1-6 alkyl group, and (c) a cyclopropyl group; an X ¹ -based carbon Atom or nitrogen atom; R ³ hydrogen atom; and ring A system

[G] The compound or a salt thereof according to any one of [1] to [5], [A], [B], and [D] to [F], wherein the R ¹ system (1) is optionally selected from the group consisting of Substituent mono- or di-substituted amine groups (a) optionally substituted by 1 to 3 substituents of the following C _1-6 alkyl (i) halogen atom, and (ii) a phenyl group substituted with 1 to 3 halogen atoms, (b) tetrahydropyranyl group, and (c) tetrahydrofuranyl group, or (2) azetidinyl group or pyrrolidinyl group, each of which is optionally required 1 to 3 halogen atoms are substituted; R ² is (1) a phenyl group substituted with 1 to 3 halogen atoms, or (2) pyrazolyl or thiazolyl group, each of which is selected from the group consisting of 1 Up to 3 substituents substituted with (a) a halogen atom, (b) a C _1-6 alkyl group, and (c) a cyclopropyl group; an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based hydrogen atom; and a ring A system

[H] The compound or a salt thereof according to any one of [1], [2], or [C], wherein R ¹ is a pyrrolidinyl group which is optionally substituted with 1 to 5 substituents selected from the group consisting of a) a halogen atom, (b) cyano, (c) carbamoyl acyl, (d) optionally substituted by 1 to 3 of C _1-6 alkoxy C _1-6 alkyl group, and (e) C _1-6 alkoxy; R ² is (1) a phenyl (a) halogen atom optionally substituted with 1 to 3 substituents selected from the group consisting of, and (b) 1 to 3 halogen atoms, if necessary Substituted C _1-6 alkyl, or (2) pyrazolyl, thiadiazolyl or pyridyl, each substituted by one to three substituents selected from the group consisting of (a) a halogen atom, and (b) C _1-6 alkyl; X ¹ -based carbon atom; R ³ -based hydrogen atom; and ring A system

[I] The compound of any one of [1] to [5], [A], [B], [D], and [E] or a salt thereof, wherein R ¹ is optionally selected from the group consisting of 1 to 5 substituent-substituted pyrrolidinyl (a) halogen atom, (b) cyano group, (c) amine carbaryl group, (d) C _1-6 alkyl group, and (e) C _1-6 alkane An oxy group; R ² is pyrazolyl or thiadiazolyl, each of which is substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, and (b) a C _1-6 alkyl group; X ¹ a carbon atom; a R ³ hydrogen atom; and a ring A system

[6] The compound or a salt thereof according to any one of [1] to [5], [A], [B], [D] to [F] and [I], wherein R ¹ is selected as needed a pyrrolidinyl group (a) halogen atom substituted with 1 to 5 substituents, and (b) a cyano group; R ² is preferably a pyrazolyl group substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, and (b) a C _1-6 alkyl group; an X ¹ -type carbon atom; an R ³ -based hydrogen atom; and a ring A system

[J] The compound or a salt thereof according to any one of [1], [3], [A], or [D], wherein the R ¹ system (1) is optionally substituted with one to three selected from the group consisting of a C _1-6 alkyl (a) cyclopropyl group, and (b) a carbazolyl group, (2) a C _1-6 alkoxy group substituted with 1 to 3 phenyl groups as desired, (3) A mono- or di-substituted amine group (a) which is optionally substituted with one or three substituents selected from the group consisting of a C _1-6 alkyl (i) halogen atom, Ii) a phenyl group substituted with 1 to 3 halogen atoms, (iii) a pyridyl group, and (iv) an oxetanyl group substituted with 1 to 3 C _1-6 alkyl groups as required, (b) Cyclopropyl, (c) cyclopentyl, (d) tetrahydropyranyl, (e) tetrahydrofuranyl, and (f) phenyl, (4) cyclopropyl, or (5) azetidine a pyrrolidinyl group, a 1,1-dioxythiomorpholinyl group or a 3-oxa-6-azabicyclo[3.1.1]heptyl group, each of which is optionally substituted with one to five selected from the group consisting of substituents (a) a halogen atom, (b) cyano, (c) carbamoyl acyl, (d) optionally substituted with 1 to 3 C _1-6 alkoxy groups the C _1-6 alkyl group, (e a C _1-6 alkoxy group, and (f) a phenyl group or a R ¹ group substituted with 1 to 3 halogen atoms as needed An atom bonded to the ring A, together with ring A, forms a 2,8-diazaspiro[4.5]decane ring which is substituted by a pendant oxy group and further optionally 1 to 3 C _1-6 Alkyl substitution; R ² is (1) a phenyl (a) halogen atom substituted with 1 to 3 substituents selected from the group consisting of, and (b) C _1-6 alkyl or (2) pyridyl Azolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group or a benzothiazolyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) a C _1-6 alkyl group substituted with 1 to 3 halogen atoms, and (d) a cyclopropyl group; an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based (1) hydrogen atom; or (2) a halogen atom ; and ring A system (1) Each of them is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom, and (b) a C _1-6 alkyl group, or a (2) 8-azabicyclo ring [3.2.1]. Octane ring or 2,5-diazabicyclo[2.2.1]heptane ring.

[K] The compound or a salt thereof according to any one of [1] to [4], [A], [B], [D], and [E], wherein R ¹ is optionally selected from the following 1 to 3 substituent-substituted pyrrolidinyl (a) halogen atom, (b) cyano group, (c) aminemethanyl group, and (d) optionally substituted with 1 to 3 C _1-6 alkoxy groups a C _1-6 alkyl group; R ² is pyrazolyl, thiazolyl, thiadiazolyl or pyridyl, each of which is substituted by one to three substituents selected from the group consisting of (a) a halogen atom, and b) C _1-6 alkyl; X ¹ -based carbon atom; R ³ -based hydrogen atom; and ring A system

[7](2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2 -carbonitrile or its salt, (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrole Pyridine-2-carbonitrile or its salt, (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl) Piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile or a salt thereof, (3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidine- 5-yl)piperidin-4-yl)methanone or a salt thereof, (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl) (3-fluoroazetidin-1-yl)methanone or a salt thereof, (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4 -())((3S)-3-fluoropyrrolidin-1-yl)methanone or a salt thereof, (1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl) ((3S)-3-fluoropyrrolidin-1-yl)methanone or a salt thereof, N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl) Piper -1-carboxamide or a salt thereof, N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl) Pyridin-3-yl)peri -1-carboxamide or a salt thereof, ((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridine-3 -yl)piperidin-4-yl)methanone or a salt thereof, (3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazole-2-) Pyridin-3-yl)piperidin-4-yl)methanone or a salt thereof, (1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine- 4-yl)(3-fluoroazetidin-1-yl)methanone or a salt thereof, or (1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridine-3) -yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone or a salt thereof.

[8](2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2 -carbonitrile or a salt thereof.

[9](2R)-1-((1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2- Formonitrile or a salt thereof.

[10](2R)-4,4-Difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl )carbonyl)pyrrolidine-2-carbonitrile or a salt thereof.

[11] A pharmaceutical preparation comprising the compound of any one of [1] to [10] or a salt thereof.

[12] The drug according to [11], which is a cholesterol 24-hydroxylase inhibitor.

[13] The medicament according to [11], which is an agent for preventing or treating epilepsy or neurodegenerative diseases.

[14] The drug according to [13], wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive disorder, Huntington's disease, Parkinson's disease or multiple sclerosis.

[15] The compound of any one of [1] to [10] or a salt thereof for use in the prevention or treatment of epilepsy or neurodegenerative diseases.

[16] The compound according to [15] or a salt thereof, wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive disorder, Huntington's disease, Parkinson's disease or multiple sclerosis.

[17] A method for inhibiting cholesterol 24-hydroxylase in a mammal, which comprises administering to the mammal an effective amount of the compound of any one of [1] to [10] or a salt thereof to the mammal.

[18] A method for pre-digesting or treating an epilepsy or a neurodegenerative disease, which comprises administering to the mammal an effective amount of the compound or a salt thereof according to any one of [1] to [10].

[19] The method according to [18], wherein the neurodegenerative disease is Alzheimer's disease, Mild cognitive impairment, Huntington's disease, Parkinson's disease or multiple sclerosis.

[20] Use of a compound according to [1] to [10] or a salt thereof for the preparation of a medicament for preventing or treating epilepsy or a neurodegenerative disease.

[21] The use of [20], wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease or multiple sclerosis.

Compound (I) has excellent CH24H inhibition and is useful for the prevention or treatment of epilepsy, neurodegenerative diseases (eg, Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, multiple Sclerosing disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, etc.), schizophrenia and the like.

In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, "C _1-10 alkyl" means, for example, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, 1-methylpropyl, Tertiary butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, decyl, decyl and the like. Among them, a C _1-6 alkyl group is preferred.

In the present specification, "C _1-6 alkyl (group)" means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, Tributyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3 - dimethyl butyl, 2-ethyl butyl, and the like.

In the present specification, "C _2-10 alkenyl" means, for example, vinyl, 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, 1-heptenyl, 1-octenyl and the like. Among them, a C _2-6 alkenyl group is preferred.

In the present specification, "C _2-6 alkenyl (group)" means, for example, vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butyl Alkenyl, 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 and the like.

In the present specification, "C _2-10 alkynyl" means, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butyl Alkynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Among them, a C _2-6 alkynyl group is preferred.

In the present specification, "C _2-6 alkynyl (group)" means, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl , 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,1-dimethylprop-2-yn-1-yl, 1- An alkynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group, a 5-hexynyl group or the like.

In the present specification, "C _1-6 alkoxy (group)" means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy And a second butoxy group, a third butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group and the like.

In the present specification, "C _1-3 alkoxy" means a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.

In the present specification, "C _2-6 alkenyloxy (group)" means, for example, vinyloxy group, 1-propenyloxy group, 2-propenyloxy group, 2-methyl group- 1-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy , 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3-hexyl Alkenyloxy, 5-hexenyloxy, and the like.

In the present specification, "C _2-6 alkynyloxy (group)" means, for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butyl Alkynyloxy, 2-butynyloxy, 3-butynyloxy, 1-pentynyloxy, 2-pentynyloxy, 3-pentynyloxy, 4-pentynyl Oxyl, 1,1-dimethylprop-2-yn-1-yloxy, 1-hexynyloxy, 2-hexynyloxy, 3-hexynyloxy, 4-hexyne Alkoxy group, 5-hexynyloxy group, and the like.

In the present specification, "C _1-6 alkylenedioxy (group)" means, for example, a methyldioxy group, an ethylenedioxy group, and the like.

In the present specification, "C _1-6 alkoxy-carbonyl (group)" means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy A carbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group or the like.

In the present specification, the "C _1-6 alkyl-carbonyl (group)" means, for example, an ethyl hydrazino group, a propyl fluorenyl group, a butyl fluorenyl group, a 2-methyl propyl fluorenyl group or the like.

In the present specification, "mono-C _1-6 alkylamino group (group)" means, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butyl group Amino group, isobutylamino group, tert-butylamino group and the like.

In the present specification, "di-C _1-6 alkylamino group (group)" means, for example, dimethylamino group, diethylamino group, dipropylamino group, diisopropyl group Amino group, dibutylamino group, diisobutylamino group, di-t-butylamino group and the like.

In the present specification, "C _3-10 cycloalkyl" means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclopethane. Base. Among them, a C _3-6 cycloalkyl group is preferred.

In the present specification, "C _3-8 cycloalkyl (group)" means, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group or the like.

In the present specification, "C _3-6 cycloalkyl (group)" means, for example, a group having 3 to 6 carbon atoms from the above C _3-8 cycloalkyl group (group).

In the present specification, "C _3-8 cycloalkyloxy (group)" means, for example, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, Cycloheptyloxy, cyclooctyloxy and the like.

In the present specification, "C _3-6 cycloalkyloxy (group)" means, for example, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, or the like. .

In the present specification, "C _3-10 cycloalkenyl (group)" means, for example, a cyclopropenyl group (for example, 2-cyclopropen-1-yl), cyclobutenyl group (for example, 2- Cyclobuten-1-yl), cyclopentenyl (for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl), cyclohexenyl (for example, 1-cyclohexene- 1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl), cycloheptenyl (for example, 1-cyclohepten-1-yl, 2-cyclohepten-1- Base, 2-cyclohepten-1-yl), cyclooctenyl (for example, 1-cyclooctene-1-yl, 2-cyclooctene-1-yl, 3-cyclooctene-1-yl) And cyclodecene (for example, 1-cyclodecen-1-yl, 2-cyclodecen-1-yl, 3-cyclodecen-1-yl) and the like. Among them, a C _3-8 cycloalkenyl group is preferred.

In the present specification, "C _3-8 cycloalkenyl (group)" means, for example, a cyclopropenyl group (for example, 2-cyclopropen-1-yl), cyclobutenyl group (for example, 2- Cyclobuten-1-yl), cyclopentenyl (for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl), cyclohexenyl (for example, 2-cyclohexene- 1-yl, 3-cyclohexen-1-yl) and the like.

In the present specification, "C _3-8 cycloalkenyloxy (group)" means, for example, a cyclopropenyloxy group (for example, 2-cyclopropen-1-yloxy), cyclobutene Alkoxy (for example, 2-cyclobuten-1-yloxy), cyclopentenyloxy (for example, 2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy) A cyclohexenyloxy group (for example, 2-cyclohexen-1-yloxy, 3-cyclohexen-1-yloxy) or the like.

In the present specification, "C _4-10 cyclodienyl" means, for example, 1,3-cyclobutadien-1-yl, 1,3-cyclopentadien-1-yl, 1, 4-cyclopentadien-1-yl, 2,4-cyclopentadien-1-yl, 1,3-cyclohexadien-1-yl, 1,4-cyclohexadien-1-yl, 1,5-cyclohexadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, 1,3-cyclooctadiene-1- , 1,4-cyclooctadien-1-yl, 1,5-cyclooctadien-1-yl, 1,6-cyclooctadien-1-yl, 1,7-cyclooctadiene- 1-yl, 2,4-cyclooctadien-1-yl, 2,5-cyclooctadien-1-yl, 2,6-cyclooctadien-1-yl, 2,7-cyclooctane Alken-1-yl, 3,5-cyclooctadien-1-yl, 3,6-cyclooctadien-1-yl and the like. Among them, a C _4-6 cyclodienyl group is preferred.

In the present specification, "C _4-6 cyclodienyl" means, for example, 1,3-cyclobutadien-1-yl, 1,3-cyclopentadien-1-yl, 1, 4-cyclopentadien-1-yl, 2,4-cyclopentadien-1-yl, 1,3-cyclohexadien-1-yl, 1,4-cyclohexadien-1-yl, 1,5-cyclohexadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.

The above C _3-10 cycloalkyl, C _3-10 cycloalkenyl and C _4-10 cyclodienyl groups are optionally fused to a benzene ring to form a fused ring group, and examples of the fused ring group include dihydrogen Indanyl, dihydronaphthyl, tetrahydronaphthyl, anthracenyl and the like.

The above C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group and C _4-10 cyclodienyl group may be a C _7-10 bridged hydrocarbon group. Examples of such C _7-10 bridged hydrocarbyl groups include bicyclo [2.2.1] heptyl (norbornyl), bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] Mercapto, bicyclo [3.3.1] fluorenyl, bicyclo [4.2.1] fluorenyl, bicyclo [4.3.1] fluorenyl, adamantyl and the like.

The above C _3-10 cycloalkyl, C _3-10 cycloalkenyl and C _4-10 cyclodienyl groups are optionally required with C _3-10 naphthenes, C _3-10 cycloolefins or C _4-10 rings The alkene forms a spiro group. Examples of the C _3-10 cycloalkane, C _3-10 cycloalkenene, and C _4-10 cyclic diene include the above-mentioned C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, and C _4-10 cyclodiene. The ring of the base. Examples of the spiro ring group include spiro[4.5]癸-8-yl and the like.

In the present specification, the "C _6-14 aryl (group)" means, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group or the like.

In the present specification, "C _6-14 aryloxy (group)" means, for example, a phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group or the like.

In the present specification, "C _7-14 aralkyl (group)" means, for example, benzyl, phenethyl or the like.

In the present specification, "C _7-14 aralkyloxy (group)" means, for example, a benzyloxy group, a phenethyloxy group or the like.

In the present specification, "C _8-13 arylalkenyl (group)" means, for example, a styryl group or the like.

In the present specification, "hydrocarbyl" means, for example, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkenyl A C _4-10 cyclodienyl group, a C _6-14 aryl group, a C _7-14 aralkyl group, a C _8-13 arylalkenyl group or the like.

In the present specification, "heterocyclic group" means an aromatic heterocyclic group or a non-aromatic heterocyclic group.

In the present specification, the "aromatic heterocyclic group" means a monocyclic aromatic heterocyclic group or a condensed aromatic heterocyclic group, for example, a 5- to 12-membered aromatic heterocyclic group, specifically 5 to A 7-membered monocyclic aromatic heterocyclic group or a 8 to 12-membered fused aromatic heterocyclic group.

In the present specification, examples of the "monocyclic aromatic heterocyclic group" include an atom containing an atom other than a carbon atom selected from an oxygen atom, a sulfur atom (optionally oxidized), and a nitrogen atom (optionally oxidized) 5 to 7 members (preferably 5 or 6 members) of 1 to 4 heteroatoms. Examples thereof include a furyl group (for example, 2-furyl group, 3-furyl group), a thienyl group (for example, 2-thienyl group, 3-thienyl group), a pyridyl group (for example, 2-pyridyl group, 3-pyridyl group). , 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), anthracene Base (for example, 3-嗒 Base, 4-嗒 Base Base (for example, 2-pyridyl a pyrrolyl group (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (for example, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), Pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl ( For example, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), Azolyl (for example, 2- Azolyl, 4- Azolyl, 5- Zozolyl) Azolyl (eg, 3-iso) Azolyl, 4-iso Azolyl, 5-iso Azolyl), Diazolyl (for example, 1,2,4- Diazol-5-yl, 1,3,4- Diazol-2-yl), thiadiazole (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-triazol-1-yl, 1, 2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl) , tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), three Base (for example, 1, 2, 4-three -1-base, 1,2,4-three -3-yl) and so on.

In the present specification, examples of the "fused aromatic heterocyclic group" include a 8 to 12-membered fused aromatic heterocyclic group, in particular, a group derived from a condensed ring (wherein, corresponding to the above 5- to 7-membered single ring) a ring system of an aromatic heterocyclic group fused to a C _6-14 aromatic hydrocarbon; and a group derived from a fused ring (wherein a ring system corresponding to the above 5- to 7-membered monocyclic aromatic heterocyclic group is thickened) Combined). Examples thereof include a quinolyl group (for example, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolinyl (for example, 3-isoquinolinyl), quinolin. Oxazolinyl (eg, 2-quinazolinyl, 4-quinazolinyl), quin Lolinyl (for example, 2-quine Lolinyl, 6-quinoline Phenyl), benzofuranyl (for example, 2-benzofuranyl, 3-benzofuranyl), benzothienyl (for example, 2-benzothienyl, 3-benzothienyl), benzo Azolyl (eg, 2-benzo) Zozolyl) Azolyl (eg, 7-benzazole) Azolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl) Benzotriazolyl (eg, 1H-1,2,3-benzotriazol-5-yl), fluorenyl (eg, indol-1-yl, indol-2-yl, anthracene) 3-yl, indol-5-yl), carbazolyl (eg, 1H-carbazol-3-yl), pyrrolopypene Base (for example, 1H-pyrrolo[2,3-b]pyridyl -2-yl, 1H-pyrrolo[2,3-b]pyridyl -6-yl), imidazopyridyl (for example, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazole And [1,2-a]pyridin-3-yl), thienopyridyl (for example, thieno[2,3-b]pyridin-3-yl), imidazopyridine Base (for example, 1H-imidazo[4,5-b]pyridinyl -2-yl), pyrazolopyridyl (for example, 1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothiophenyl (for example, 2H-pyrazolo[3,4 -b]thiophen-2-yl), pyrazolo Base (for example, pyrazolo[5,1-c][1,2,4] -3-yl) and so on.

In the present specification, the "non-aromatic heterocyclic group" means a monocyclic non-aromatic heterocyclic group or a fused non-aromatic heterocyclic group, for example, a 3 to 12 membered non-aromatic heterocyclic group, specifically It is a 3- to 8-membered monocyclic non-aromatic heterocyclic group or an 8- to 12-membered fused non-aromatic heterocyclic group.

In the present specification, examples of the "monocyclic non-aromatic heterocyclic group" include an oxygen atom, a sulfur atom (optionally oxidized), and a nitrogen atom (which are optionally oxidized) containing an atom constituting a ring other than a carbon atom. 3 to 8 members (preferably 5 or 6 members) of the monocyclic non-aromatic heterocyclic group of 1 to 4 hetero atoms. Examples thereof include azetidinyl (for example, 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (for example, 1-pyrrolidinyl, 2-pyrrolidinyl), Piperidinyl (eg, N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (eg, N-morpholinyl), thiomorpholinyl ( For example, N-thiomorpholinyl), piperazine Base (for example, 1-piperider Base, 2-pipeper Base, 3-piperider base), Azolidinyl (for example, Zoxadin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), dihydrothiopyranyl (eg, dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imidazole Pyridyl (eg, imidazolidin-2-yl, imidazolidin-3-yl), Oxazolinyl (for example, Oxazolin-2-yl), thiazolinyl (eg thiazolin-2-yl), imidazolinyl (eg imidazolin-2-yl, imidazolin-3-yl), dioxanyl (eg, 1,3-dioxan-4-yl), dioxolane (eg, 1,3-dioxolan-4-yl), dihydrogen Diazolyl (eg, 4,5-dihydro-1,2,4- Diazol-3-yl), piperidyl (eg, 2-piperidyl, 4-piperidyl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl) , 4-tetrahydropyranyl), thiopyranyl (eg 4-thiopyranyl), tetrahydrothiopyranyl (eg, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetra Hydrothiopyranyl), 1-oxidized tetrahydrothiopyranyl (eg, 1-oxytetrahydrothiopyran-4-yl), 1,1-dihydrothiopyranyl (eg, 1,1-dioxide) Tetrahydrothiopyran-4-yl), tetrahydrofuranyl (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), oxetanyl (eg, oxetan-2-yl, oxocyclo) Butan-3-yl), pyrazolyl (eg, pyrazin-1-yl, pyrazin-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), tetrahydrogen Pyrimidinyl (eg, tetrahydropyrimidin-1-yl), dihydrotriazolyl (eg, 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl), azepanyl (eg, 1-azepanyl, 2-aza) Cycloheptyl, 3-azepanyl, 4-azepanyl), dihydropyridyl (eg, dihydropyridin-1-yl, dihydropyridin-2-yl, di Hydropyridin-3-yl, dihydropyridin-4-yl), tetrahydropyridyl (for example, 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridine -2-yl, 1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl) and the like.

In the present specification, examples of the "fused non-aromatic heterocyclic group" include a 8 to 12-membered fused non-aromatic heterocyclic group, in particular, a group derived from a fused ring (wherein corresponding to the above 3 to 8 members) a ring system of a monocyclic non-aromatic heterocyclic group fused to a C _6-14 aromatic hydrocarbon; a group derived from a fused ring (wherein a ring corresponding to the above 3- to 8-membered monocyclic non-aromatic heterocyclic group) a fused ring; a ring derived from a fused ring (wherein a ring system corresponding to the above 3- to 8-membered monocyclic non-aromatic heterocyclic group) and a monocyclic aromatic heterocyclic group corresponding to the above 5 to 7 members Fused); and a group in which the above groups are partially saturated. Examples thereof include a dihydroindenyl group (for example, 2,3-dihydro-1H-inden-1-yl) or a dihydroisoindenyl group (for example, 1,3-dihydro-2H-isoindole- 2-yl), dihydrobenzofuranyl (for example, 2,3-dihydro-1-benzofuran-5-yl), tetrahydrobenzofuranyl (for example, 4,5,6,7-tetra Hydro-1-benzofuran-3-yl), dihydrobenzodioxanyl (for example, 2,3-dihydro-1,4-benzodioxan-2-yl), Hydrobenzodioxanyl (for example, 3,4-dihydro-2H-1,5-benzodioxan-2-yl), benzopyranyl (for example, 4H-benzo) Piperan-2-yl, 2H-benzopiperan-3-yl), dihydrobenzopyranyl (for example, 3,4-dihydro-2H-benzopiperan-2-yl), dihydrogen Quinolinyl (for example, 1,2-dihydroquinolin-4-yl), tetrahydroquinolyl (for example, 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinoline A phenyl group (for example, 1,2-dihydroisoquinolin-4-yl), a tetrahydroisoquinolinyl group (for example, 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrogen酞 Base (for example, 1,4-dihydroanthracene -4-base) and so on.

The above "monocyclic non-aromatic heterocyclic group" and "fused non-aromatic heterocyclic group" may be bridged, and examples thereof include 3-oxa-6-azabicyclo[3.1.1]heptyl, 8 -oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1] Octyl, 6-oxa-3-azabicyclo[3.1.1]heptyl and the like.

In the present specification, "carbocyclyl" means a C _6-14 aryl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group or a C _4-10 cyclodienyl group. The "carbocyclyl" is optionally fused to a C _6-14 aromatic hydrocarbon group, a C _3-10 naphthenic, a C _3-10 cycloalene or a C _4-10 cyclodiene, or optionally C _3-10 The cycloalkane, C _3-10 cycloalkenene or C _4-10 cyclic diene forms a spiro ring or, if desired, bridged.

In the present specification, the "C _6-14 aromatic hydrocarbon group" means, for example, benzene or naphthalene.

In the present specification, "C _3-10 naphthenic" means, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclodecane, cyclodecane. Wait.

In the present specification, "C _3-10 cycloalkenyl" means, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclooctene, cyclodecene, cyclodecene, and the like.

In the present specification, "C _4-10 cyclodiene" means, for example, 1,3-cyclobutadiene, 1,3-cyclopentadiene, 1,4-cyclopentadiene, 2, 4-cyclopentadiene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclohexadiene, 2,4-cyclohexadiene, 2,5-cyclohexane Alkene, 1,3-cyclooctadiene, 1,4-cyclooctadiene, 1,5-cyclooctadiene, 1,6-cyclooctadiene, 1,7-cyclooctadiene, 2,4 -cyclooctadiene, 2,5-cyclooctadiene, 2,6-cyclooctadiene, 2,7-cyclooctadiene, 3,5-cyclooctadiene, 3,6-cyclooctadiene Wait.

The symbols in the formula (I) are explained below.

In the formula (I), R ¹ is optionally substituted with a C _1-6 alkyl group, optionally substituted hydroxy group, optionally substituted amino group, optionally substituted carbocyclic group, or optionally substituted. The heterocyclic group or R ¹ is optionally bonded to the atom on the ring A, together with the ring A to form a spiro ring or a fused ring, each of which is substituted by a pendant oxy group and further substituted as necessary.

The "C _1-6 alkyl group" of "C _1-6 alkyl group optionally substituted" in R ¹ may have 1 to 5 (preferably 1 to 3) substituents at a substitutable position as needed. Examples of the substituent include a substituent selected from the following substituent group A. When the number of substituents is plural, the substituents may be the same or different.

Substituent group A: (1) a halogen atom; (2) a cyano group; (3) a nitro group; (4) a hydroxyl group; (5) optionally substituted with 1 to 3 substituents selected from the group consisting of C _{3 - 8} -cycloalkyl (a) halogen atom, (b) cyano group, (c) C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (d) 1 to 3 halogen atoms as needed Substituted C _1-6 alkoxy; (6) C _6-14 aryl (a) halogen atom, (b) cyano group, (c), optionally substituted with 1 to 3 substituents selected from the group consisting of a C _1-6 alkyl group substituted with 1 to 3 halogen atoms, and (d) a C _1-6 alkoxy group substituted with 1 to 3 halogen atoms as needed; (7) optionally selected from the following 1 to 3 substituents substituted with a C _1-6 alkoxy group (a) a halogen atom, (b) a cyano group, (c) a C _3-8 cycloalkyl group having 1 to 3 halogen atoms, if necessary, (d) a C _3-8 cycloalkenyl group having 1 to 3 halogen atoms as needed, (e) a C _6-14 aryl group having 1 to 3 halogen atoms as necessary, and (f) 5 or 6 member a cycloaromatic heterocyclic group; (8) a C _2-6 alkenyloxy group having 1 to 3 halogen atoms as needed (for example, a vinyloxy group, a propenyloxy group, a butenyloxy group, a pentenyl group) Oxyl, hexenyloxy); (9) as needed a C _2-6 alkynyloxy group having 1 to 3 halogen atoms (for example, an ethynyloxy group, a propynyloxy group, a butynyloxy group, a pentynyloxy group, a hexynyloxy group); (10) a C _3-8 cycloalkyloxy group having 1 to 3 halogen atoms as needed (for example, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group); 11) A C _3-8 cycloalkenyloxy group having 1 to 3 halogen atoms as needed (for example, a cyclopropenyloxy group, a cyclobutenyloxy group, a cyclopentenyloxy group, a cyclohexenyloxy group) (12) a C _6-14 aryloxy group having 1 to 3 halogen atoms as needed; (13) a C _7-14 aralkyloxy group having 1 to 3 halogen atoms as needed; (14) A mono- or di-substituted aminemethanyl (a) C _1-6 alkyl group, (b) C _3-6 cycloalkyl group, (c) C _6-14 aryl group, which is substituted with a substituent selected from the group consisting of , (d) C _1-6 alkoxy, (e) 5 or 6 membered monocyclic aromatic heterocyclic group, (f) 8 to 12 membered fused aromatic heterocyclic group, (g) 3 to 8 member a ring non-aromatic heterocyclic group, and (h) an 8- to 12-membered fused non-aromatic heterocyclic group; (15) optionally a mono- or di-substituted amine sulfonyl group selected from the group consisting of: Sulfamoyl group) (a) C _1-6 alkyl, (b) C _3-6 ring Alkyl, (c) C _6-14 aryl, (d) C _1-6 alkoxy, (e) 5 or 6 membered monocyclic aromatic heterocyclic group, (f) 8 to 12 member fused aromatic a heterocyclic group, (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic group, and (h) an 8- to 12-membered fused non-aromatic heterocyclic group; (16) a formazan group; (17) C _{1- 6} alkyl-carbonyl; (18) C _2-6 alkenyl-carbonyl (for example, propylene fluorenyl, butenyl, pentenyl, hexenyl, heptene); (19) C _{2 -6} alkynyl-carbonyl (for example, propynyl fluorenyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl); (20) C _3-8 cycloalkyl-carbonyl (for example, Cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl); (21) C _3-8 cycloalkenyl-carbonyl (for example, cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenyl) Carbonyl, cyclohexenylcarbonyl); (22) C _6-14 aryl-carbonyl (eg, benzindenyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl); (23) C _3-8 cycloalkyl -C _1-6 alkyl-carbonyl (for example, cyclopropylethylhydrazine, 3-cyclopropylpropenyl, cyclobutylethylhydrazine, cyclopentylethenyl, cyclohexylethenyl, cyclohexyl propan-acyl); (24) C _3-8 cycloalkenyl, -C _1-6 alkyl - carbonyl group (e.g., Pentenyl acetyl group, acetyl group cyclohexenyl, 3-cyclohexenyl propionate acyl group, a 3-cyclohexenyl group propan acyl); (25) C _7-14 aralkyl - carbonyl groups (e.g. , phenylethenyl, 3-phenylpropanyl); (26) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl (eg, furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, Azoylcarbonyl, different An azolylcarbonyl group, a thiazolylcarbonyl group, an isothiazolylcarbonyl group, an imidazolylcarbonyl group, a pyridylcarbonyl group, a pyrazolylcarbonyl group; (27) an 8- to 12-membered fused aromatic heterocyclic carbonyl group (for example, a benzofuranylcarbonyl group) , isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothiophenylcarbonyl, fluorenylcarbonyl, isodecylcarbonyl, oxazolylcarbonyl, benzimidazolylcarbonyl, benzo (Z) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl (eg, oxacyclopropylcarbonyl, azetidinylcarbonyl, oxetanylcarbonyl, thioheterocycle) Butylalkylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, thiolanylcarbonyl, piperidinylcarbonyl); (29) 8- to 12-membered fused non-aromatic heterocyclic carbonyl (eg, dihydrobenzene) and furanyl); (30) of an optionally substituted group selected from those mono - or di - substituted amino group of (a) optionally having a C 1 to 3 halogen atoms _C1-6 alkyl, (b) C _1-6 alkyl-carbonyl having 1 to 3 halogen atoms, (c) C _3-8 cycloalkyl-carbonyl, (d) C _6-14 aryl having 1 to 3 halogen atoms as needed Alkyl-carbonyl, (e) 5 or 6 membered monocyclic aromatic heterocyclic carbonyl, (f) 8 to 12 membered fused aromatic heterocyclic carbonyl, (g) 3 to 8 membered monocyclic non-aromatic heterocyclic ring a carbonyl group, and (h) an 8- to 12-membered fused non-aromatic heterocyclic carbonyl group; (31) a sulfanyl group; (32) a C _1-6 alkylsulfanyl group (for example, a methyl group) ethylthio); (33) C _2-6 alkenyl group (e.g., vinyl group, propenyl group); (34) C _2-6 alkynyl group (e.g., Alkynyl group, a propynyl group); (35) C _3-8 cycloalkyl group (e.g., cyclopropyl group, cyclobutyl group); (36) C _3-8 cycloalkenyl group Sulfur (for example, cyclopropenylthio, cyclobutenylthio); (37) C _6-14 arylthio (for example, phenylthio); (38) C _3-8 cycloalkyl- C _1-6 alkylthio (for example, cyclopropylmethylthio); (39) C _3-8 cycloalkenyl-C _1-6 alkylthio (for example, cyclopentenylmethylthio) (40) C _1-6 alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl); (41) C _2-6 alkenylenesulfinyl (for example, ethylene) (42) C _2-6 alkynyl sulfinyl (for example, ethynyl sulfinyl, propynyl sulfinyl); (43) C _3-8 cycloalkylsulfinyl (for example, cyclopropylsulfinyl, cyclobutylsulfinyl); (44) C _3-8 cycloalkenylsulfinyl (for example, cyclopropenyl) Sulfosyl, cyclobutenylsulfinyl); (45) C _6-14 arylsulfinylene (eg, phenylsulfinyl); (46) C _3-8 cycloalkyl- C _1-6 alkylsulfinyl acyl (e.g., cyclopropyl methylsulfinyl acyl); (47) C _3-8 cycloalkenyl, -C _1-6 alkylsulfinyl acyl ( E.g., cyclopentenyl methylsulfinyl acyl); (48) C _1-6 alkylsulfonyl group (e.g., methyl acyl sulfo, sulfo-ethyl-acyl); (49) C _2-6 alkenyl Sulfosyl (for example, vinylsulfonyl, propenylsulfonyl); (50) C _2-6 alkynylsulfonyl (for example, ethynylsulfonyl, propynylsulfonyl); 51) C _3-8 cycloalkylsulfonyl (for example, cyclopropylsulfonyl, cyclobutylsulfonyl); (52) C _3-8 cycloalkenylsulfonyl (for example, cyclopropenylsulfonate) Mercapto, cyclobutenylsulfonyl); (53) C _6-14 arylsulfonyl (eg, phenylsulfonyl); (54) C _3-8 cycloalkyl-C _1-6 alkane Sulfosyl (for example, cyclopropylmethylsulfonyl); (55) C _3-8 cycloalkenyl-C _1-6 alkylsulfonyl (for example, cyclopentenylmethylsulfonyl) (56) C _6-14 aryl-C _1-6 alkylsulfonyl (for example, benzylsulfonyl); (57) 5 or 6 membered monocyclic aromatic heterocyclylsulfonyl (for example) , furanylsulfonyl, thienylsulfonyl, pyridylsulfonyl); (58) 8- to 12-membered fused aromatic heterocyclylsulfonyl (eg, benzofuransulfonyl, isophenyl) And furanylsulfonyl); (59) 3 to 8 membered monocyclic non-aromatic heterocyclic sulfonyl (for example, oxygen) Cyclopropylsulfonylsulfonyl, azetidinylsulfonyl); (60) 8 to 12 membered fused non-aromatic heterocyclylsulfonyl (for example, dihydrobenzofuranylsulfonyl); (61) a 5- or 6-membered monocyclic aromatic heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of (for example, furyl, thienyl, pyrrolyl, Azolyl, different Azolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl, morpholinyl), (a) halogen atom, (b) C _1-6 alkane substituted by 1 to 3 halogen atoms as needed And (c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms; (62) 8 to 12 member fused, optionally substituted with 1 to 3 substituents selected from the group consisting of An aromatic heterocyclic group (for example, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, fluorenyl, isodecyl, oxazolyl, benzimidazolyl, benzo Azolyl) (a) a halogen atom, (b) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (c) a C _1-6 alkane substituted with 1 to 3 halogen atoms as needed An oxygen group; (63) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, an oxiranyl group, an azetidinyl group, optionally substituted with 1 to 3 substituents selected from the group consisting of: Oxetane, thietane, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperidin Base, dihydrogen (oxadiazolyl, thiazolinyl) (a) a halogen atom, (b) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (c) optionally substituted with 1 to 3 halogen atoms _{a 1-6} alkoxy group, and (d) a pendant oxy group; (64) an 8- to 12-membered fused non-aromatic heterocyclic group optionally substituted with one to three substituents selected from the group consisting of (for example, two hydrogen-benzofuranyl) (a) a halogen atom, (b) optionally substituted with 1 to 3 substituents of halogen atoms, C _1-6 alkyl, (c) optionally substituted with 1 to 3 substituents of halogen atoms, C _{1- 6} alkoxy, and (d) pendant oxy; (65) 5 or 6 membered monocyclic aromatic heterocyclyloxy (eg, furyloxy, thienyloxy, pyrrolyloxy, Zoledyloxy, different Azolyloxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy, pyridyloxy, pyrazolyloxy); (66) 8- to 12-membered fused aromatic heterocyclyloxy ( For example, benzofuranyloxy, isobenzofuranyloxy, benzothienyloxy, isobenzothiophenyloxy, decyloxy, isodecyloxy, oxazolyloxy Benzimidazolyloxy, benzo (3) 3- to 8-membered monocyclic non-aromatic heterocyclic oxy (eg, oxiranyloxy, azetidinyloxy, oxetaneoxy) Base, thietaneoxy, pyrrolidinyloxy, tetrahydrofuranyloxy, thiolanyloxy, piperidinyloxy); (68) 8 to 12 member fused non-aromatic Heterocyclyloxy (for example, dihydrobenzofuranyloxy); (69) carboxy; (70) C _1-6 alkoxy-carbonyl; (71) C _2-6 alkenyloxy-carbonyl ( For example, vinyloxycarbonyl, propyleneoxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl); (72) C _2-6 alkynyloxy-carbonyl ( For example, ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl); (73)C _3-8 cycloalkyloxy- a carbonyl group (for example, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl); (74) C _3-8 cycloalkenyloxy-carbonyl (for example, a ring) Propenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl); 75) C _6-14 aryloxy-carbonyl (for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (76) C _3-8 cycloalkyl-C _1-6 Alkoxy-carbonyl (for example, cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, Cyclohexylethyloxycarbonyl); (77) C _3-8 cycloalkenyl-C _1-6 alkoxy-carbonyl (for example, cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxy) Carbonyl, cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl); (78) C _7-14 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyl) (oxylcarbonyl); (79) mono C _1-6 alkyl thiamine methyl sulfhydryl (eg, methyl thiamine methyl thiol, ethyl thiamine methyl sulfhydryl, propyl thiamine methyl sulfhydryl); a di-C _1-6 alkyl thiamine methyl sulfhydryl group (for example, dimethyl thiocarbamyl, diethyl thiamine methyl sulfonyl, dipropyl thiamine methyl sulfhydryl); (81) C _{1 -6} alkyl - carbonyl group (e.g., acetyl group, acyl group, propoxy, butoxy acyl group, acyl group, 2-methyl-propoxy); (82) an optionally substituted hydroxyl group of the imine ; And (83) C _1-6 alkylene dioxy group (e.g., extending methylenedioxy, ethylenedioxy-stretch).

Examples of the "optionally substituted hydroxy group" of R ¹ include a hydroxyl group optionally substituted with a substituent selected from C _1-10 alkyl group, C _2-10 alkenyl group, C _3-10 cycloalkyl group, C _{3 . -10} cycloalkenyl, C _6-14 aryl, C _7-14 aralkyl, C _8-13 arylalkenyl, C _1-6 alkyl-carbonyl, heterocyclic (eg, aromatic heterocyclic) , non-aromatic heterocyclic groups, etc., each of which is optionally substituted.

The C _1-10 alkyl group, the C _2-10 alkenyl group and the C _1-6 alkyl-carbonyl group optionally have 1 to 5 (preferably 1 to 3) substituents at a substitutable position. Examples of the substituent include a substituent selected from the above substituent group A. When the number of substituents is plural, the substituents may each be the same or different.

The C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group and the non-aromatic heterocyclic group have 1 to 5 (preferably 1 to 3) substituents in the substitutable position as needed. Examples of the substituent include a substituent selected from the following substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

Substituent group B: (1) the above-mentioned substituent group A; (2) a C _1-6 alkyl group (a) halogen atom substituted with 1 to 3 substituents selected from the following, (b) a cyano group , (c) a hydroxyl group, (d) a C _3-8 cycloalkyl group (i) a halogen atom, (ii) a cyano group, and (iii) optionally substituted with 1 to 3 substituents selected from the group consisting of a C _1-6 alkyl group substituted with 1 to 3 halogen atoms; (e) a C _6-14 aryl group (i) halogen atom substituted with 1 to 3 substituents selected from the group consisting of (ii) a cyano group, and (iii) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (f) a C _1-6 alkoxy group substituted with 1 to 3 halogen atoms as required, (g) If necessary, a C _1-6 alkyl mono- or di-substituted amine group, (h) a 5 or 6 membered monocyclic aromatic heterocyclic group, (i) an 8- to 12-membered fused aromatic heterocyclic group, j) 3 to 8 membered monocyclic non-aromatic heterocyclic groups, (k) 8 to 12 membered fused non-aromatic heterocyclic group, (1) carboxyl group, and (m) optionally substituted with 1 to 3 halogen atoms a C _1-6 alkoxy-carbonyl group; (3) a C _2-6 alkenyl group (a) halogen atom substituted with one to three substituents selected from the group consisting of, (b) a hydroxyl group, (c) C _1-6 alkoxy, (d) C _1-6 alkyl group is optionally substituted by mono - substituted - A or di- Group, (e) a carboxyl group, and (f) C _1-6 alkoxy - carbonyl group; (4) optionally substituted with 1 to 3 substituents selected from those substituents of the substituted C _7-14 aralkyl group (a) a halogen atom, (b) a hydroxyl group, (c) a C _1-6 alkoxy group, and (d) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; and (5) a pendant oxy group.

The C _6-14 aryl group, the C _7-14 aralkyl group, the C _8-13 arylalkenyl group, and the aromatic heterocyclic group have 1 to 5 (preferably 1 to 3) substituents at a substitutable position. . Examples of the substituent include a substituent selected from the above substituent group B in addition to the pendant oxy group. When the number of substituents is plural, the substituents may each be the same or different.

Examples of the "optionally substituted amino group" of R ¹ include an optionally substituted mono- or di-substituted amino group selected from a substituent selected from the group consisting of C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _6-14 aryl, C _7-14 aralkyl, C _8-13 arylalkenyl, heterocyclic (eg, aromatic heterocyclic) , non-aromatic heterocyclic groups, etc., each of which is optionally substituted; and a mercapto group. When the amine group is di-substituted, the two substituents are bonded as needed to form an optionally substituted heterocyclic group.

The C _1-10 alkyl group and the C _2-10 alkenyl group optionally have 1 to 5 (preferably 1 to 3) substituents at a substitutable position. Examples of the substituent include a substituent selected from the above substituent group A. When the number of substituents is plural, the substituents may each be the same or different.

The C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group and the non-aromatic heterocyclic group have 1 to 5 (preferably 1 to 3) substituents in the substitutable position as needed. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

The C _6-14 aryl group, the C _7-14 aralkyl group, the C _8-13 arylalkenyl group and the aromatic heterocyclic group have 1 to 5 (preferably 1 to 3) as needed in the substitutable position. Substituent. Examples of the substituent include a substituent selected from the above substituent group B excluding the pendant oxy group. When the number of substituents is plural, the substituents may each be the same or different.

Examples of the substituent "mercapto group" exemplified as "amino group" include a group represented by the following formula: -COR ^A , -CO-OR ^A , -SO ₃ R ^A , -S(O) ₂ R ^A , -SOR ^A -CO-NR ^A 'R ^B ', -CS-NR ^A 'R ^B ' or -S(O) ₂ NR ^A 'R ^B ', wherein R ^A is a hydrogen atom, optionally substituted hydrocarbyl group, or a heterocyclic group which is optionally substituted, and R ^A 'and R ^B ' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R ^A 'and R ^B ' is bonded together with an adjacent nitrogen atom to form a nitrogen-containing heterocyclic ring or the like which is optionally substituted.

Examples of the "hydrocarbyl group" of "optionally substituted hydrocarbyl group" of R ^A , R ^A ' or R ^B ' include C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _{3- 10} cycloalkyl, C _3-10 cycloalkenyl, C _4-10 cyclodienyl, C _6-14 aryl, C _7-14 aralkyl, C _8-13 arylalkenyl and the like.

The C _1-10 alkyl group, the C _2-10 alkenyl group and the C _2-10 alkynyl group as the above "hydrocarbon group" are exemplified by having 1 to 5 (preferably 1 to 3) substitutions at a substitutable position. base. Examples of the substituent include a substituent selected from the above substituent group A. When the number of substituents is plural, the substituents may each be the same or different.

The C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group and the C _4-10 cyclodienyl group as the above "hydrocarbon group" are exemplified as having 1 to 5 (preferably 1 to 1) in the substitutable position. 3) substituents. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

The C _6-14 aryl group, the C _7-14 aralkyl group and the C _8-13 arylalkenyl group as the above "hydrocarbon group" are exemplified as having 1 to 5 (preferably 1 to 3) in the substitutable position. (substitute). Examples of the substituent include a substituent selected from the above substituent group B excluding the pendant oxy group. When the number of substituents is plural, the substituents may each be the same or different.

The "heterocyclic group" of the "optionally substituted heterocyclic group" of R ^A , R ^A ' or R ^B ' needs to have 1 to 5 (preferably 1 to 3) substituents in the substitutable position. Examples of the substituent of the aromatic heterocyclic group include the above-mentioned substituent group B excluding the pendant oxy group, and examples of the substituent of the non-aromatic heterocyclic group include the above-mentioned substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

Examples of the "nitrogen-containing heterocyclic ring" of "optionally substituted nitrogen-containing heterocyclic ring" formed by R ^A 'and R ^B ' together with an adjacent nitrogen atom include at least one of atoms constituting a ring other than a carbon atom. The nitrogen atom and, if necessary, a 5- to 7-membered monocyclic aromatic heterocyclic group further comprising one or two hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom. Examples of preferred nitrogen-containing heterocycles include pyrrolidine, imidazolium, pyrazole, piperidine, and piperidine. , morpholine, thiomorpholine and the like.

The nitrogen-containing heterocyclic ring optionally has 1 to 5 (preferably 1 to 3) substituents at a substitutable position. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

Examples of preferred "mercapto" include (1) a fluorenyl group; (2) a carboxyl group; (3) a C _1-6 alkyl-carbonyl group (e.g., an ethyl fluorenyl group) substituted with 1 to 3 halogen atoms as needed. (4) a C _1-6 alkoxy-carbonyl group substituted with 1 to 3 halogen atoms as needed (for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, tert-butoxycarbonyl group); (5) C _3-10 cycloalkyl-carbonyl (for example, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl); (6) C _6-14 aryl-carbonyl (for example, benzhydryl, 1- Naphthoquinone, 2-naphthyl) is optionally substituted with 1 to 3 halogen atoms; (7) optionally substituted with a substituent selected from the group consisting of mono- or di-substituted amines (a) required by a halogen atom selected from, C _1-6 alkoxy, C _1-6 alkoxy - carbonyl group and carboxyl substituent with 1 to 3 substituents of C _1-6 alkyl group, and (b) an optionally C _1-6 alkoxy-carbonyl mono- or di-substituted amine; (8) C _1-6 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) Substituent substituted with 1 to 3 halogen atoms; (9) C _6-14 arylsulfonyl (for example, phenylsulfonyl); (10) aminesulfonyl; (11) thiamine Base; (12 An aromatic heterocyclic carbonyl group (for example, a furylcarbonyl group, a thienylcarbonyl group) substituted with 1 to 3 substituents selected from a C _1-6 alkyl group, if necessary, the C _1-6 alkyl group is optionally subjected to 1 Substituted to 3 halogen atoms; (13) a non-aromatic heterocyclic carbonyl group (for example, tetrahydrofuranylcarbonyl, pyrrolidinylcarbonyl) substituted with 1 to 3 substituents selected from a C _1-6 alkyl group, if necessary, The C _1-6 alkyl group is optionally substituted with 1 to 3 halogen atoms;

The "carbocyclic group" of the "optionally substituted carbocyclic group" of R ¹ may have 1 to 5 (preferably 1 to 3) substituents at the substitutable position as needed. Examples of the substituent of the C _6-14 aryl group include the above substituent group B excluding a pendant oxy group, and the C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, and C _4-10 cyclodienyl group. Examples of the substituent include the above-mentioned substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

The "heterocyclic group" of the "optionally substituted heterocyclic group" of R ¹ may have 1 to 5 (preferably 1 to 3) substituents at the substitutable position as needed. Examples of the aromatic heterocyclic group The substituent includes the above-mentioned substituent group B excluding the pendant oxy group, and examples of the substituent of the non-aromatic heterocyclic group include the above-mentioned substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

An example in which R ^{1 is} bonded to an atom on the ring A, and a "spiro or fused ring, each of which is substituted with a pendant oxy group and, if necessary, further substituted," which is formed with a ring A, includes a spiro ring such as 2, 8-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]decane, etc., and a fused ring such as hexahydroimidazo[1,5-a]pyridin Hexahydropyrrolo[1,2-a]pyridyl Wait.

The "spiro or fused ring" which is bonded to the ring A by R ¹ and which is formed together with the ring A, "each of which is substituted by a pendant oxy group and, if necessary, a further substituted spiro or fused ring", There are 1 to 5 (preferably 1 to 3) substituents as needed in the substitutable position. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

R ¹ is preferably a C _1-6 alkyl group optionally substituted, a C _1-6 alkoxy group optionally substituted, an optionally substituted amino group, and optionally a substituted C _3-8 cycloalkane. group, the optionally substituted C _6-14 aryl group, or an optionally substituted non-aromatic heterocyclic group of or R ¹ based on the atom bonded to the ring A, form a cycloalkyl group together with the A-side Replace the spiro ring with further substitution as needed.

More preferably, the R ¹ system is (1) a C _1-6 alkyl group (e.g., methyl, ethyl) (a) cyano group substituted by one to three substituents selected from the group consisting of (b) a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 C _1-6 alkoxy groups (for example, a methoxy group), (c) a C _6-14 aryloxy group (for example, benzene) Oxygen), (d) C _3-8 cycloalkyl (for example, cyclopropyl), (e) 5 or 6 membered monocyclic aromatic heterocyclic group (for example, pyrazolyl), (f) 8 to 12 members a fused aromatic heterocyclic group (for example, carbazolyl), and (g) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 3 pendant oxy groups (for example, dihydropyridyl group) And (2) a C _1-6 alkoxy group substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group) as desired (for example, a methoxy group, a third butoxy group, preferably C) _1-3 alkoxy (for example, methoxy)), (3) optionally, mono- or di-substituted amino group (a), which is optionally substituted with one selected from the following a C _1-6 alkyl group substituted with 3 substituents (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), (ii) a cyano group, (iii) a C _3-8 cycloalkyl group ( For example, cyclopropyl, cyclobutyl), (iv) optionally 1 to 3 halogen atoms (eg, fluorine) A) the substituted C _6-14 aryl group (e.g., phenyl), (v) 5 or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (vi) optionally substituted with 1 to 3 C _{a 1-6} alkyl (eg, methyl) substituted 3 to 8 membered monocyclic non-aromatic heterocyclic group (eg, oxetane), (b) optionally 1 to 3 halogen atoms (eg, a fluorine atom) substituted C _3-8 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl), (c) C _6-14 aryl (for example, phenyl), and (d) A 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group) (for example, tetrahydropyranyl group, oxetanyl group, tetrahydrofuranyl group) , pyrrolidinyl), (4) C _3-8 cycloalkyl (for example, cyclopropyl) substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group), (5) C _{6 a -14} aryl group (e.g., phenyl), or (6) a 3 to 12 member non-aromatic heterocyclic group (preferably a 3 to 8 member) which is optionally substituted with 1 to 5 substituents selected from the group consisting of a ring non-aromatic heterocyclic group (for example, azetidinyl, pyrrolidinyl, piperidinyl, piperidine) , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl)) (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) an amine carbhydryl group And (f) a C _1-6 alkyl group (for example, methyl, ethyl, isopropyl) (i) hydroxy group substituted with 1 to 3 substituents selected from the group consisting of, and (ii) C _{1 -6} alkoxy (for example, methoxy), (g) C _1-6 alkoxy (for example, methoxy, ethoxy, isopropoxy), (h) C _1-6 alkoxy a carbonyl group (for example, methoxycarbonyl group), and (i) a C _6-14 aryl group (for example, a phenyl group) or an R ¹ -type bond which is optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom). An atom bonded to the ring A, together with the ring A, forms a spiro ring (for example, 2,8-diazaspiro[4.5]decane) which is substituted by a pendant oxy group and further 1 to 3 as needed C _1-6 alkyl (eg, methyl) substituted.

In another embodiment, the R ¹ system is more preferably (1) a C _1-6 alkyl group (e.g., methyl, ethyl) substituted with 1 to 3 substituents selected from the group consisting of a cyano group, (b) a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 C _1-6 alkoxy groups (for example, a methoxy group), (c) C _6-14 An aryloxy group (for example, phenoxy), (d) a C _3-8 cycloalkyl group (for example, a cyclopropyl group), (e) a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, pyrazolyl) (f) an 8- to 12-membered fused aromatic heterocyclic group (for example, carbazolyl), and (g) a 3 to 8 membered monocyclic non-aromatic heterocyclic ring optionally substituted with 1 to 3 pendant oxy groups. a group (for example, dihydropyridyl), (2) a C _1-6 alkoxy group substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group) as desired (for example, methoxy group, third a butoxy group, preferably a C _1-3 alkoxy group (for example, a methoxy group), (3) an optionally substituted mono- or di-substituted amine group (a), optionally selected from the group consisting of a C _1-6 alkyl group (for example, methyl group, ethyl group) substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom (for example, a fluorine atom), (ii) a cyano group, (iii) C _3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl), (IV) is selected from an optionally A halogen atom (e.g., fluorine atom) and C _1-6 alkoxy (e.g., methoxy) 1 to 3 substituents of the substituted C _6-14 aryl group (e.g., phenyl), (v) 5 or a 6-membered monocyclic aromatic heterocyclic group (for example, pyridyl), and (vi) 3 to 8 membered monocyclic non-aromatic substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group) as needed a heterocyclic group (for example, an oxetanyl group), (b) a C _3-8 cycloalkyl group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) (for example, a cyclopropyl group, a cyclobutyl group) a group, a cyclopentyl group, a (c) C _6-14 aryl group (for example, a phenyl group), and (d) optionally substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl groups) to 3 8-membered monocyclic non-aromatic heterocyclic group (for example, tetrahydropyranyl, oxetane, tetrahydrofuranyl, pyrrolidinyl), (4) 1 to 3 C _6-14 aryl groups as needed (eg, phenyl) substituted C _3-8 cycloalkyl (eg, cyclopropyl), (5) C _6-14 aryl (eg, phenyl), or (6) optionally selected from 3 to 12 membered non-aromatic heterocyclic groups substituted by 1 to 5 substituents (preferably 3 to 8 membered monocyclic non-aromatic heterocyclic groups (for example, azetidinyl, pyrrolidinyl, piperidinyl) Pyridyl, piperidine , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl), 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl)) (a) a halogen atom (for example, a fluorine atom), (b) Cyano, (c) hydroxy, (d) pendant oxy, (e) optionally substituted with a C _1-6 alkyl (eg methyl) mono- or di-substituted amine, (f) as needed a C _1-6 alkyl group (for example, methyl, ethyl, isopropyl) (i) hydroxy group substituted with 1 to 3 substituents selected from the group consisting of (ii) C _1-6 alkoxy group ( For example, methoxy), (g) a C _1-6 alkoxy group (for example, methoxy, ethoxy, isopropoxy) substituted with 1 to 3 halogen atoms (for example, a fluorine atom). , (h) C _1-6 alkoxy-carbonyl (for example, methoxycarbonyl), and (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) For example, phenyl), or an atom bonded to the ring A by the R ¹ group, together with the ring A form a spiro ring (eg, 2,8-diazaspiro[4. 5] decane) which is substituted by a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl groups).

Further preferably, the R ¹ system is (1) a C _1-6 alkyl group (e.g., methyl, ethyl) (a) C _3-8 ring optionally substituted with one to three substituents selected from the group consisting of An alkyl group (for example, a cyclopropyl group), and (b) an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group), (2) optionally having 1 to 3 C _6-14 aryl groups ( For example, a phenyl)-substituted C _1-6 alkoxy group (preferably a C _1-3 alkoxy group (for example, methoxy group)), (3) optionally a substituent selected from the group consisting of - or The di-substituted amine group (a) is optionally substituted by a C _1-6 alkyl group (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), which is substituted with 1 to 3 substituents selected from the following ones. And (ii) a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (iii) a 5 or 6 membered monocyclic aromatic heterocyclic group ( For example, pyridyl), and (iv) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) as desired (eg, oxetane) Alkyl), (b) C _3-8 cycloalkyl (eg, cyclopropyl, cyclopentyl), (c) 3 to 8 membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl, Tetrahydrofuranyl), and (d) C _6-14 aryl (eg, phenyl), (4) C _{a 3-8} cycloalkyl group (for example, a cyclopropyl group), or (5) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, nitrogen) which is optionally substituted with 1 to 5 substituents selected from the group consisting of a heterocyclic butane group, a pyrrolidinyl group, a 1,1-dioxythiomorpholinyl group, a 3-oxa-6-azabicyclo[3.1.1]heptyl group (a) a halogen atom (for example, a fluorine atom), (b) cyano, (c) carbamoyl acyl, (d) optionally substituted by 1-3 of C _1-6 alkoxy (e.g., methoxy) C _1-6 alkyl (e.g., methyl Base, isopropyl), (e) C _1-6 alkoxy (eg, methoxy), and (f) C _6-14 substituted with 1 to 3 halogen atoms (eg, fluorine atom) as needed An aryl group (eg, phenyl), or an atom bonded to the ring A by the R ¹ group, together with the ring A forms a spiro ring (eg, 2,8-diazaspiro[4.5]decane), which is a Substituted by a pendant oxy group and optionally further substituted with 1 to 3 C _1-6 alkyl groups (e.g., methyl).

In another embodiment, R ¹ is preferably a C _1-6 alkyl group optionally substituted, a C _1-6 alkoxy group optionally substituted, an optionally substituted amino group, optionally substituted A C _3-8 cycloalkyl group, optionally substituted C _6-14 aryl group, or optionally substituted non-aromatic heterocyclic group.

More preferably, the R ¹ system is (1) a C _1-6 alkyl group (e.g., methyl, ethyl) (a) cyano group substituted by one to three substituents selected from the group consisting of (b) a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 C _1-6 alkoxy groups (for example, a methoxy group), (c) a C _6-14 aryloxy group (for example, benzene) Oxy), (d) C _3-8 cycloalkyl (eg, cyclopropyl), (e) 5 or 6 membered monocyclic aromatic heterocyclic group (eg, pyrazolyl), (f) 8 to 12 a fused aromatic heterocyclic group (for example, carbazolyl), and (g) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 3 pendant oxy groups (for example, dihydropyridine) And (2) a C _1-6 alkoxy group optionally substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group) (for example, a methoxy group, a third butoxy group, preferably a C _1-3 alkoxy group (for example, a methoxy group), (3) an optionally substituted mono- or di-substituted amine group (a), optionally selected from the group consisting of: a C _1-6 alkyl group substituted with 3 substituents (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), (ii) a cyano group, (iii) a C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl), (iv) optionally selected from a halogen atom (eg, fluorine) a C _6-14 aryl group (for example, phenyl) substituted with 1 to 3 substituents of an atom and a C _1-6 alkoxy group (for example, a methoxy group), (v) 5 or 6 membered monocyclic aromatic groups a heterocyclic group (for example, pyridyl group), and (vi) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted by 1 to 3 C _1-6 alkyl groups (for example, methyl group) (for example, An oxetanyl group, (b) a C _3-8 cycloalkyl group substituted with 1 to 3 halogen atoms (for example, a fluorine atom) as needed (for example, cyclopropyl, cyclobutyl, cyclopentyl) , (c) C _6-14 aryl (eg, phenyl), and (d) 3 to 8 membered monocyclic non-aryl substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) as desired a heterocyclic group (for example, tetrahydropyranyl, oxetane, tetrahydrofuranyl, pyrrolidinyl), (4) optionally 1 to 3 C _6-14 aryl groups (for example, phenyl) Substituted C _3-8 cycloalkyl (eg, cyclopropyl), (5) C _6-14 aryl (eg, phenyl), or (6) optionally substituted with from 1 to 5 selected from a 3- to 12-membered non-aromatic heterocyclic group (preferably a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl) , morpholinyl, 1,1-dithiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl), 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl)) (a) a halogen atom (for example, a fluorine atom), (b) Cyano, (c) hydroxy, (d) pendant oxy, (e) optionally substituted with a C _1-6 alkyl (eg methyl) mono- or di-substituted amine, (f) as needed a C _1-6 alkyl group (for example, methyl, ethyl, isopropyl) (i) hydroxy group substituted with 1 to 3 substituents selected from the group consisting of (ii) C _1-6 alkoxy group ( For example, methoxy), (g) a C _1-6 alkoxy group (for example, methoxy, ethoxy, isopropoxy) substituted with 1 to 3 halogen atoms (for example, a fluorine atom). , (h) C _1-6 alkoxy-carbonyl (for example, methoxycarbonyl), and (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) For example, phenyl).

Further, the R ¹ system is further more preferably a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, pyrrolidinyl group) (a) a halogen atom which is optionally substituted with 1 to 5 substituents selected from the group consisting of , a fluorine atom), (B) cyano, (c) carbamoyl acyl, (d) optionally substituted with 1 to 3 C _1-6 alkoxy (e.g., methoxy) substituent of a C _1-6 alkoxy a group (for example, a methyl group), and (e) a C _1-6 alkoxy group (for example, a methoxy group).

Further, the R ¹ system is more preferably a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, pyrrolidine) which is optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) an aminomethyl group, and (d) optionally 1 to 3 C _1-6 alkoxy groups (for example, A Oxy) substituted C _1-6 alkyl (eg, methyl).

In another embodiment, the R ¹ system is further more preferably (1) optionally a mono- or di-substituted amine group (a) optionally substituted with one selected from the group consisting of a C _1-6 alkyl group substituted with 3 substituents (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), and (ii) 1 to 3 halogen atoms (for example, fluorine) a C _6-14 aryl group (eg, phenyl) substituted with an atom, and (b) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl, tetrahydrofuranyl), or (2) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, azetidinyl group, pyrrolidinyl group) substituted with 1 to 5 substituents selected from the group consisting of halogen atoms (for example, a fluorine atom), (b) a cyano group, (c) an amine carbenyl group, (d) a C _1-6 alkyl group (for example, a methyl group), and (e) a C _1-6 alkoxy group (for example, a methoxy group) base).

Further preferably, the R ¹ system is (1) optionally substituted by a mono- or di-substituted amine group selected from the group consisting of: (a) optionally substituted with one to three substituents selected from the group consisting of _{a 1-6} alkyl group (for example, a methyl group, an ethyl group) (i) a halogen atom (for example, a fluorine atom), and (ii) a C _6- substituted with 1 to 3 halogen atoms (for example, a fluorine atom) as needed. _{a 14} aryl group (e.g., phenyl), and (b) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl, tetrahydrofuranyl), or (2) optionally selected from the group consisting of a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 5 substituents (for example, azetidinyl group, pyrrolidinyl group) (a) a halogen atom (for example, a fluorine atom), and (b) ) Cyano group.

Particularly preferred is ^an R & lt system (1) of an optionally substituted group selected from a single person - or di - substituted requires 1 to 3 substituents selected from the following group of persons (a) depending on the C _{1- a 6} alkyl group (for example, a methyl group, an ethyl group) (i) a halogen atom (for example, a fluorine atom), and (ii) a C _6-14 aryl group substituted with 1 to 3 halogen atoms (for example, a fluorine atom) as needed. a group (for example, phenyl), and (b) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, tetrahydropyranyl, tetrahydrofuranyl), or (2) 1 to 3 halogen atoms as needed. A 3- to 8-membered monocyclic non-aromatic heterocyclic group (for example, azetidinyl group, pyrrolidinyl group) substituted with (for example, a fluorine atom).

In another embodiment, the R ¹ system is further more preferably a 3 to 8 membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) substituted with 1 to 5 substituents selected from the group consisting of: (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) an amine formazan group, (d) a C _1-6 alkyl group (for example, a methyl group), and (e) a C _{1-6 group.} Alkoxy (eg, methoxy).

Further, the R ¹ system is more preferably a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, pyrrolidinyl group) (a) a halogen atom which is optionally substituted with 1 to 5 substituents selected from the group consisting of , fluorine atom), and (b) cyano group.

In the formula (I), R ² is optionally a substituted C _6-14 aryl group or an optionally substituted aromatic heterocyclic group.

R "of the optionally substituted C _6-14 aryl group" ² of the "C _6-14 aryl" may be substituted at a desired position depending having 1 to 5 (preferably 1 to 3) substituents. Examples of the substituent include a substituent selected from the above substituent group B excluding the pendant oxy group. When the number of substituents is plural, the substituents may each be the same or different.

The "aromatic heterocyclic group" of the "optionally substituted aromatic heterocyclic group" of R ² may have 1 to 5 (preferably 1 to 3) substituents at the substitutable position. Examples of the substituent include a substituent selected from the above substituent group B excluding the pendant oxy group. When the number of substituents is plural, the substituents may each be the same or different.

The R ² is preferably (1) a C _6-14 aryl (for example, phenyl) (a) halogen atom (for example, a fluorine atom or a chlorine atom) which is optionally substituted with 1 to 3 substituents selected from the following ones. And (b) a C _1-6 alkyl group (for example, a methyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (2) optionally selected from the following ones a 5- to 12-membered aromatic heterocyclic group substituted with 3 substituents (preferably a 5 or 6 membered monocyclic aromatic heterocyclic group (for example, pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group, a benzothiazolyl group) (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group, an ethyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) C _3-8 cycloalkyl (for example, cyclopropyl).

More preferably, the R ² system is (1) a C _6-14 aryl group (for example, a phenyl group) (a) a halogen atom (for example, a fluorine atom or a chlorine atom) which is optionally substituted with 1 to 3 substituents selected from the following ones. Atom), and (b) a C _1-6 alkyl group (for example, a methyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (2) optionally selected from the following ones a 5- or 6-membered monocyclic aromatic heterocyclic group substituted with 3 substituents (for example, pyrazolyl, thiadiazolyl, pyridyl) (a) a halogen atom (for example, a chlorine atom), and (b) C _1-6 alkyl (for example, methyl).

In another embodiment, the R ² system is more preferably (1) a C _6-14 aryl group (eg, phenyl) (a) halogen atom optionally substituted with 1 to 3 substituents selected from the group consisting of (e.g., a fluorine atom), and (b) a C _1-6 alkyl group (e.g., a methyl group), or (2) a 5 to 12 member aromatic group optionally substituted with one to three substituents selected from the group consisting of Heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an 8- to 12-membered fused aromatic heterocyclic group (for example, a benzothiazolyl group)) (a) a halogen atom (for example, a chlorine atom or a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) a C _3-8 cycloalkyl group. (for example, cyclopropyl).

Further, the R ² system is more preferably a 5- or 6-membered monocyclic aromatic heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of pyridyl, thiazolyl, thiadiazolyl, Pyridyl (preferably pyrazolyl, thiadiazole, more preferably pyrazolyl)) (a) a halogen atom (for example, a chlorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group) ).

In another embodiment, the R ² system is more preferably (1) a C _6-14 aryl group (eg, phenyl), or (2), optionally substituted with 1 to 3 halogen atoms (eg, a fluorine atom). a 5- or 6-membered monocyclic aromatic heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of pyridyl, thiazolyl, thiadiazole (preferably pyrazolyl, thiazole) Base)) (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c) a C _3-8 cycloalkyl group (for example, a cyclopropyl group) base).

In the formula (I), X ¹ is a carbon atom or a nitrogen atom.

X ¹ is preferably a carbon atom.

In the formula (I), when X ¹ is a carbon atom, R ³ is a hydrogen atom or a substituent, or when X ¹ is a nitrogen atom, R ^{3 is} not present.

The "substituent" of R ³ means an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, an optionally substituted sulfur group, an optionally substituted amino group, a mercapto group, and the like. , nitro, cyano or halogen atom.

The C _1-10 alkyl group, the C _2-10 alkenyl group and the C _2-10 alkynyl group as the above "hydrocarbon group" are exemplified as having 1 to 5 (preferably 1 to 3) substitutions at a substitutable position. base. Examples of the substituent include a substituent selected from the above substituent group A. When the number of substituents is plural, the substituents may each be the same or different.

The C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group and the C _4-10 cyclodienyl group as the above "hydrocarbon group" are exemplified as having 1 to 5 (preferably 1 to 3) as needed. a substituent at a substitutable position. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

The C _6-14 aryl group, the C _7-14 aralkyl group and the C _8-13 arylalkenyl group as the above "hydrocarbon group" are exemplified as having 1 to 5 (preferably 1 to 3) in the substitutable position. (substitute). Examples of the substituent include a substituent selected from the above substituent group B excluding the pendant oxy group. When the number of substituents is plural, the substituents may each be the same or different.

Examples of R ³ as an "optionally substituted heterocyclic group" as the "substituent" include the "optionally substituted heterocyclic group" similar to R ¹ .

Examples of R ³ as an "optionally substituted hydroxy group" as the "substituent" include the "optionally substituted hydroxy group" similar to R ¹ .

Examples of R ³ exemplified as the "substituted oxythio group" as the "substituent" include, if necessary, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group. , C _3-10 cycloalkenyl, C _6-14 aryl, C _7-14 arylalkyl, C _8-13 arylalkenyl, C _1-6 alkyl-carbonyl, heterocyclic (eg, aromatic) A hydrogenthio group substituted with a substituent such as a heterocyclic group or a non-aromatic heterocyclic group, each of which is optionally substituted.

The C _1-10 alkyl group, the C _2-10 alkenyl group and the C _1-6 alkyl-carbonyl group optionally have 1 to 5 (preferably 1 to 3) substituents at a substitutable position. Examples of the substituent include a substituent selected from the above substituent group A. When the number of substituents is plural, the substituents may each be the same or different.

The C _3-10 cycloalkyl group, the C _3-10 cycloalkenyl group and the non-aromatic heterocyclic group have 1 to 5 (preferably 1 to 3) substituents in the substitutable position as needed. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

The C _6-14 aryl group, the C _7-14 aralkyl group, the C _8-13 arylalkenyl group and the aromatic heterocyclic group have 1 to 5 (preferably 1 to 3) as needed in the substitutable position. Substituent. Examples of the substituent include a substituent selected from the above substituent group B excluding the pendant oxy group. When the number of substituents is plural, the substituents may each be the same or different.

Examples of R ³ exemplified as the "substituent substituted amino group" as the "substituent" include the "substituted amino group as desired" similar to R ¹ .

Examples of R ³ as an "indenyl group" as the "substituent" include the "mercapto group" as a substituent exemplified as "an optionally substituted amino group" similar to R ¹ .

R ³ is preferably (1) a hydrogen atom or (2) a halogen atom (for example, a fluorine atom).

The R ³ system is more preferably a hydrogen atom.

In the formula (I), the ring A system Each is further replaced as needed and bridged as needed.

In ring A, each is connected as needed Examples include 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane, and the like. Preferred are 8-azabicyclo[3.2.1]octane and 2,5-diazabicyclo[2.2.1]heptane.

In ring A, each is connected as needed Preferably, it is bridged as needed Especially good

In ring A Each of them is bridged as needed, and has 1 to 5 (preferably 1 to 3) substituents as needed in the substitutable position. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

Ring A is preferably Each is bridged as needed (for example, a ring represented by the above formula, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3-aza Bicyclo[3.1.0]hexane), each of which is optionally substituted with one to five (preferably one to three) substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (e.g., methyl), and (c) a pendant oxy group.

Ring A is more excellent (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c). a pendant oxy group, or (2) 8-azabicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0] Hexane ring.

Ring A is further more excellent (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group), or 2) 8-Azabicyclo[3.2.1]octane ring or 2,5-diazabicyclo[2.2.1]heptane ring.

Ring A is even more excellent

Ring A is especially good for

Preferred examples of the compound (I) include the following compounds.

[Compound A-1]

Compound (I) wherein R ¹ is optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted amino group, optionally substituted C _{3 - An 8-} cycloalkyl group, optionally substituted C _6-14 aryl group, or optionally substituted non-aromatic heterocyclic group, or an atom to which R ¹ is bonded to the ring A, together with ring A a pendant oxy group and, if desired, a further substituted spiro ring; R ² is optionally a substituted C _6-14 aryl group, or an optionally substituted aromatic heterocyclic group; an X ¹ -based carbon atom or a nitrogen atom; When X ¹ is a carbon atom, R ³ is a hydrogen atom or a substituent, or when X ¹ is a nitrogen atom, R ³ is absent; and ring A is Each is further replaced as needed and bridged as needed.

[Compound A-2]

Compound (I) wherein R ¹ is optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted amino group, optionally substituted C _{3 - 8} cycloalkyl, optionally substituted C _6-14 aryl, or optionally substituted non-aromatic heterocyclic; R ² optionally substituted C _6-14 aryl, or optionally substituted the aromatic heterocyclic group; X ¹ based carbon atom or a nitrogen atom; X ¹ when R ³ based carbon atom-based hydrogen atom or a substituent, or when X ¹ containing nitrogen atom R ³ is absent; A and ring system Each is further replaced as needed and bridged as needed.

[Compound B-1]

Compound (I) wherein R ¹ is (1) a C _1-6 alkyl group (e.g., methyl, ethyl) (a) cyano group substituted with 1 to 3 substituents selected from the group consisting of b) a C _6-14 aryl group (for example, phenyl) substituted with 1 to 3 C _1-6 alkoxy groups (for example, methoxy group), (c) a C _6-14 aryloxy group (for example) , phenoxy), (d) C _3-8 cycloalkyl (eg, cyclopropyl), (e) 5 or 6 membered monocyclic aromatic heterocyclic group (eg, pyrazolyl), (f) 8 a 12-membered fused aromatic heterocyclic group (for example, carbazolyl), and (g) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted by 1 to 3 pendant oxy groups (for example, two Hydropyridyl), (2) a C _1-6 alkoxy group substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group) as desired (for example, methoxy group, third butoxy group, Preferably, a C _1-3 alkoxy group (e.g., methoxy)), (3) an optionally substituted mono- or di-substituted amine group (a), optionally selected from the group consisting of: a C _1-6 alkyl group substituted with 1 to 3 substituents (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), (ii) a cyano group, and (iii) a C _3-8 ring. An alkyl group (for example, a cyclopropyl group, a cyclobutyl group), (iv) optionally having 1 to 3 halogen atoms ( E.g., fluorine atom) of the substituted C _6-14 aryl group (e.g., phenyl), (v) 5 or 6-membered monocyclic aromatic heterocyclic group (e.g., pyridyl), and (vi) optionally substituted with 1 to 3 C _1-6 alkyl (eg, methyl) substituted 3 to 8 membered monocyclic non-aromatic heterocyclic groups (eg, oxetane), (b) 1 to 3 halogens as desired a C _3-8 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group) substituted with an atom (for example, a fluorine atom), (c) a C _6-14 aryl group (for example, a phenyl group), and d) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group) (for example, tetrahydropyranyl group, oxetanyl group) , tetrahydrofuranyl, pyrrolidinyl), (4) C _3-8 cycloalkyl (eg, cyclopropyl) substituted with 1 to 3 C _6-14 aryl (eg, phenyl) as desired, (5) a C _6-14 aryl group (for example, a phenyl group), or (6) a 3 to 12 membered non-aromatic heterocyclic group (preferably 3 to 3), optionally substituted with 1 to 5 substituents selected from the group consisting of 8-membered monocyclic non-aromatic heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperidine) , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl)) (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) an amine formazan group And (f) a C _1-6 alkyl group (for example, methyl, ethyl, isopropyl) (i) hydroxy group substituted with 1 to 3 substituents selected from the group consisting of, and (ii) C _{1 -6} alkoxy (for example, methoxy), (g) C _1-6 alkoxy (for example, methoxy, ethoxy, isopropoxy), (h) C _1-6 alkoxy a carbonyl group (for example, methoxycarbonyl group), and (i) a C _6-14 aryl group (for example, a phenyl group) or an R ¹ -type bond which is optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom). An atom bonded to the ring A, together with the ring A, forms a spiro ring (for example, 2,8-diazaspiro[4.5]decane) which is substituted by a pendant oxy group and further 1 to 3 as needed C _1-6 alkyl (e.g., methyl) substituted; R ² line (1) takes optionally substituted by 1 to 3 substituents selected from those of The C _6-14 aryl group (e.g., phenyl) (a) a halogen atom (e.g., fluorine atom, chlorine atom), and (b) the optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom) C _{a 1-6} alkyl group (for example, a methyl group), or (2) a 5- to 12-membered aromatic heterocyclic group (preferably a 5 or 6 member member) which is optionally substituted with 1 to 3 substituents selected from the group consisting of a cyclic aromatic heterocyclic group (for example, pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group, a benzothiazolyl group) (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group, an ethyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) a C _3-8 cycloalkyl group (for example, a cyclopropyl group); an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based (1) hydrogen atom; or (2) a halogen atom (for example, a fluorine atom); Each is bridged as needed (for example, a ring represented by the above formula, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3-aza Bicyclo[3.1.0]hexane), each of which is optionally substituted with one to five (preferably one to three) substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (e.g., methyl), and (c) a pendant oxy group.

[Compound B-2]

Compound (I) wherein R ¹ is (1) a C _1-6 alkyl group (e.g., methyl, ethyl) (a) cyano group substituted with 1 to 3 substituents selected from the group consisting of b) a C _6-14 aryl group (for example, phenyl) substituted with 1 to 3 C _1-6 alkoxy groups (for example, methoxy group), (c) a C _6-14 aryloxy group (for example) , phenoxy), (d) C _3-8 cycloalkyl (eg, cyclopropyl), (e) 5 or 6 membered monocyclic aromatic heterocyclic group (eg, pyrazolyl), (f) 8 a 12-membered fused aromatic heterocyclic group (for example, carbazolyl), and (g) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted by 1 to 3 pendant oxy groups (for example, two Hydropyridyl), (2) a C _1-6 alkoxy group substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group) as desired (for example, methoxy group, third butoxy group, Preferably, a C _1-3 alkoxy group (e.g., methoxy)), (3) an optionally substituted mono- or di-substituted amine group (a), optionally selected from the group consisting of: a C _1-6 alkyl group substituted with 1 to 3 substituents (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), (ii) a cyano group, and (iii) a C _3-8 ring. An alkyl group (eg, cyclopropyl, cyclobutyl), (iv) optionally selected from a halogen atom (eg, For example, a fluorine atom) and a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 substituents of a C _1-6 alkoxy group (for example, a methoxy group), (v) 5 or 6 member a cycloaromatic heterocyclic group (for example, pyridyl), and (vi) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted by 1 to 3 C _1-6 alkyl groups (for example, methyl group) as needed (e.g., oxetane), (b) a C _3-8 cycloalkyl group substituted with 1 to 3 halogen atoms (e.g., a fluorine atom) as desired (e.g., cyclopropyl, cyclobutyl, ring) Pentyl), (c) C _6-14 aryl (eg, phenyl), and (d) 3 to 8 member units substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl groups) as desired a ring non-aromatic heterocyclic group (for example, tetrahydropyranyl, oxetane, tetrahydrofuranyl, pyrrolidinyl), (4) optionally 1 to 3 C _6-14 aryl groups (for example, Phenyl) substituted C _3-8 cycloalkyl (eg, cyclopropyl), (5) C _6-14 aryl (eg, phenyl), or (6) optionally selected from 1 5 to 12 membered non-aromatic heterocyclic groups substituted by 5 substituents (preferably 3 to 8 membered monocyclic non-aromatic heterocyclic groups (for example, azetidinyl, pyrrolidinyl, piperidinyl, Piper , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl), 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl)) (a) a halogen atom (for example, a fluorine atom), (b) Cyano, (c) hydroxy, (d) pendant oxy, (e) optionally substituted with a C _1-6 alkyl group (eg methyl), (f) optionally selected a C _1-6 alkyl group (for example, methyl, ethyl, isopropyl) (i) hydroxy group substituted with 1 to 3 substituents, and (ii) a C _1-6 alkoxy group (for example, Methoxy), (g) a C _1-6 alkoxy group (for example, methoxy, ethoxy, isopropoxy) substituted by 1 to 3 halogen atoms (for example, a fluorine atom), h) a C _1-6 alkoxy-carbonyl group (for example, a methoxycarbonyl group), and (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) (for example, A phenyl) or R ¹ atom bonded to the ring A, together with ring A, forms a spiro ring (eg, 2,8-diazaspiro[4.5] a decane) which is substituted with a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl groups); the R ² group (1) is optionally selected from the following ones to a C _6-14 aryl group substituted with three substituents (for example, a phenyl group) (a) a halogen atom (for example, a fluorine atom, a chlorine atom), and (b) optionally 1 to 3 halogen atoms (for example, fluorine) a C _1-6 alkyl group (for example, a methyl group) substituted with an atom, or (2) a 5- to 12-membered aromatic heterocyclic group which is optionally substituted with 1 to 3 substituents selected from the following (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group, a benzothiazolyl group) (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group, an ethyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) a C _3-8 cycloalkyl group (for example, a cyclopropyl group); an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based (1) hydrogen atom; or (2) a halogen atom (for example, a fluorine atom); Each is bridged as needed (for example, a ring represented by the above formula, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3-aza Bicyclo[3.1.0]hexane), each of which is optionally substituted with one to five (preferably one to three) substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (e.g., methyl), and (c) a pendant oxy group.

[Compound B-3]

Compound (I) wherein R ¹ is (1) a C _1-6 alkyl group (e.g., methyl, ethyl) (a) cyano group substituted with 1 to 3 substituents selected from the group consisting of b) a C _6-14 aryl group (for example, phenyl) substituted with 1 to 3 C _1-6 alkoxy groups (for example, methoxy group), (c) a C _6-14 aryloxy group (for example) , phenoxy), (d) C _3-8 cycloalkyl (eg, cyclopropyl), (e) 5 or 6 membered monocyclic aromatic heterocyclic group (eg, pyrazolyl), (f) 8 a 12-membered fused aromatic heterocyclic group (for example, carbazolyl), and (g) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted by 1 to 3 pendant oxy groups (for example, two Hydropyridyl), (2) a C _1-3 alkoxy group (eg, methoxy) substituted with 1 to 3 C _6-14 aryl groups (eg, phenyl), (3) as needed A mono- or di-substituted amine group (a) selected from the group consisting of C _1-6 alkyl (e.g., methyl, ethyl) substituted with 1 to 3 substituents selected from the group consisting of a halogen atom (for example, a fluorine atom), (ii) a cyano group, (iii) a C _3-8 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group), and (iv) optionally selected from a halogen atom (for example) 1 to 3 of the fluorine atom) and the C _1-6 alkoxy group (for example, methoxy group) Substituted C _6-14 aryl (eg, phenyl), (v) 5 or 6 membered monocyclic aromatic heterocyclic (eg, pyridyl), and (vi) 1 to 3 C, as desired _{a 1-6} alkyl (eg, methyl) substituted 3 to 8 membered monocyclic non-aromatic heterocyclic group (eg, oxetane), (b) optionally 1 to 3 halogen atoms (eg, a fluorine atom) substituted C _3-8 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl), (c) C _6-14 aryl (for example, phenyl), and (d) A 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group) (for example, tetrahydropyranyl group, oxetanyl group, tetrahydrofuranyl group) , pyrrolidinyl), (4) C _3-8 cycloalkyl (for example, cyclopropyl) substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl), (5) C _{6 a -14} aryl group (e.g., phenyl), or (6) a 3 to 12 member non-aromatic heterocyclic group (preferably a 3 to 8 member) which is optionally substituted with 1 to 5 substituents selected from the group consisting of a ring non-aromatic heterocyclic group (for example, azetidinyl, pyrrolidinyl, piperidinyl, piperidine) , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl), 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl)) (a) a halogen atom (for example, a fluorine atom), (b) Cyano, (c) hydroxy, (d) pendant oxy, (e) optionally substituted with a C _1-6 alkyl group (eg methyl), (f) optionally selected a C _1-6 alkyl group (for example, methyl, ethyl, isopropyl) (i) hydroxy group substituted with 1 to 3 substituents, and (ii) a C _1-6 alkoxy group (for example, Methoxy), (g) a C _1-6 alkoxy group (for example, methoxy, ethoxy, isopropoxy) substituted by 1 to 3 halogen atoms (for example, a fluorine atom), h) a C _1-6 alkoxy-carbonyl group (for example, a methoxycarbonyl group), and (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) (for example, A phenyl) or R ¹ atom bonded to the ring A, together with ring A, forms a spiro ring (eg, 2,8-diazaspiro[4.5] a decane) which is substituted with a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl groups); the R ² group (1) is optionally selected from the following ones to a C _6-14 aryl group substituted with three substituents (for example, a phenyl group) (a) a halogen atom (for example, a fluorine atom, a chlorine atom), and (b) optionally 1 to 3 halogen atoms (for example, fluorine) a C _1-6 alkyl group (for example, a methyl group) substituted with an atom, or (2) a 5- to 12-membered aromatic heterocyclic group which is optionally substituted with 1 to 3 substituents selected from the following (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group, a benzothiazolyl group) (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group, an ethyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) a C _3-8 cycloalkyl group (for example, a cyclopropyl group); an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based (1) hydrogen atom; or (2) a halogen atom (for example, a fluorine atom); Each is bridged as needed (for example, a ring represented by the above formula, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3-aza Bicyclo[3.1.0]hexane), each of which is optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (e.g., methyl), and (c) a pendant oxy group.

[Compound B-4]

Compound (I) wherein R ¹ is (1) a C _1-6 alkyl group (e.g., methyl, ethyl) (a) cyano group substituted with 1 to 3 substituents selected from the group consisting of b) a C _6-14 aryl group (for example, phenyl) substituted with 1 to 3 C _1-6 alkoxy groups (for example, methoxy group), (c) a C _6-14 aryloxy group (for example) , phenoxy), (d) C _3-8 cycloalkyl (eg, cyclopropyl), (e) pyrazolyl, (f) carbazolyl, and (g) 1 to 3 sides as needed An oxy-substituted dihydropyridyl group, (2) a C _1-6 alkoxy group substituted with 1 to 3 C _6-14 aryl groups (for example, phenyl group) as desired (for example, methoxy group, third butyl group) An oxy group, preferably a C _1-3 alkoxy group (for example, a methoxy group), (3) an amine group (a) which is optionally mono- or disubstituted with a substituent selected from the group consisting of One or three substituents of the following substituted C _1-6 alkyl (for example, methyl, ethyl) (i) halogen atom (for example, fluorine atom), (ii) cyano group, (iii) C _{3- 8} -cycloalkyl (for example, cyclopropyl, cyclobutyl), (iv) optionally selected from a halogen atom (for example, a fluorine atom) and a C _1-6 alkoxy group (for example, a methoxy group) to C _6-14 aryl (for example, phenyl) substituted with 3 substituents, (v) pyridyl And (vi) an oxetanyl group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group), (b) optionally 1 to 3 halogen atoms (for example, a fluorine atom) Substituted C _3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl), (c) C _6-14 aryl (eg, phenyl), and (d) tetrahydropyran a group, an oxetanyl group, a tetrahydrofuranyl group and a pyrrolidinyl group, each of which is optionally substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl groups), (4) 1 to 3 as needed. C _6-14 aryl (eg, phenyl) substituted C _3-8 cycloalkyl (eg, cyclopropyl), (5) C _6-14 aryl (eg, phenyl), or (6) 3 Up to 8 membered monocyclic non-aromatic heterocyclic groups (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperidine) , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl) or 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl, each of which is optionally substituted with from 1 to 5 of the following Substituting (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) optionally a C _1-6 alkyl group (for example, a methyl group) a mono- or di-substituted aminemethanyl group, (f) a C _1-6 alkyl group (for example, methyl, ethyl, isopropyl) substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, and (ii) a C _1-6 alkoxy group (for example, a methoxy group), (g) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) For example, methoxy, ethoxy, isopropoxy), (h)C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl), and (i) 1 to 3 halogen atoms, as desired (for example, a fluorine atom) substituted with a C _6-14 aryl group (for example, a phenyl group), or an R ^{1 group} bonded to the ring A And, together with Ring A, form a 2,8-diazaspiro[4.5]decane ring which is substituted by a pendant oxy group and, if necessary, further 1 to 3 C _1-6 alkyl groups (for example, methyl) Substituted; R ² is (1) a C _6-14 aryl (for example, phenyl) (a) halogen atom (for example, a fluorine atom or a chlorine atom) which is optionally substituted with 1 to 3 substituents selected from the following ones. And (b) a C _1-6 alkyl group (for example, a methyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (2) a 5 or 6 membered monocyclic aromatic heterocyclic group. (eg, pyrazolyl, An azole group, a thiazolyl group, a thiadiazolyl group, a pyridyl group or an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group, a benzothiazolyl group), each of which is selected from the group consisting of 1 to The three substituents are substituted by (a) a halogen atom (for example, a chlorine atom or a bromine atom), (b) a cyano group, and (c) a C _{1-6 which is} optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom). An alkyl group (for example, methyl, ethyl), and (d) a C _3-8 cycloalkyl group (for example, a cyclopropyl group); an X ¹ -based carbon atom or a nitrogen atom; and an R ³ -based (1) hydrogen atom, or (2) a halogen atom (for example, a fluorine atom); and a ring A system (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c). a pendant oxy group, or (2) 8-azabicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0] Hexane ring.

[Compound B-5]

In the compound (I), the R ¹ group (1) is optionally substituted with 1 to 3 substituents of a C _1-6 alkyl group (for example, methyl group, ethyl group) (a) cyano group, ( b) a C _6-14 aryl group (for example, phenyl) substituted with 1 to 3 C _1-6 alkoxy groups (for example, methoxy group), (c) a C _6-14 aryloxy group (for example) , phenoxy), (d) C _3-8 cycloalkyl (eg, cyclopropyl), (e) pyrazolyl, (f) carbazolyl, and (g) 1 to 3 sides as needed An oxy-substituted dihydropyridyl group, (2) a C _1-3 alkoxy group (for example, a methoxy group) substituted with 1 to 3 C _6-14 aryl groups (for example, a phenyl group), (3) ) of an optionally substituted mono- or di-substituted amino group of (a) are selected from the following optionally substituted with 1 to 3 substituents selected from the group substituted by the C _1-6 alkyl group (e.g., methyl, ethyl (i) a halogen atom (for example, a fluorine atom), (ii) a cyano group, (iii) a C _3-8 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group), and (iv) optionally selected from the group consisting of a C _6-14 aryl group (for example, phenyl) substituted with 1 to 3 substituents of a halogen atom (for example, a fluorine atom) and a C _1-6 alkoxy group (for example, a methoxy group), (v) pyridyl group and (vi) optionally substituted with 1 to 3 C _1-6 alkyl (e.g., methyl) substituted by the Oxetanyl, (b) the optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom) C _3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), ( c) a C _6-14 aryl group (for example, phenyl), and (d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofuranyl group, and a pyrrolidinyl group, each of which may be 1 to 3 C as needed. _1-6 alkyl (eg, methyl) substituted, (4) C _3-8 cycloalkyl substituted with 1 to 3 C _6-14 aryl (eg, phenyl) as desired (eg, cyclopropyl) ), (5) C _6-14 aryl (eg, phenyl), or (6) 3 to 8 membered monocyclic non-aromatic heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidine) Base , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl) or 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl, each of which is optionally substituted with from 1 to 5 of the following Substituting (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) optionally a C _1-6 alkyl group (for example, a methyl group) a mono- or disubstituted aminemethanyl group, (f) a C _1-6 alkyl group (e.g., methyl, ethyl, isopropyl) substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, and (ii) a C _1-6 alkoxy group (for example, a methoxy group), (g) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) For example, methoxy, ethoxy, isopropoxy), (h)C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl), and (i) 1 to 3 halogen atoms, as desired (e.g., fluorine atom) of the substituted C _6-14 aryl group (e.g., phenyl) or R ¹ based on the ring bonded to the A Promoter, ring A together form a 2,8-diaza-spiro [4.5] decane ring system with oxo and optionally further substituted with 1 to 3 C _1-6 alkyl (e.g., methyl) Substituted; R ² is (1) a C _6-14 aryl (for example, phenyl) (a) halogen atom (for example, a fluorine atom or a chlorine atom) which is optionally substituted with 1 to 3 substituents selected from the following ones. And (b) a C _1-6 alkyl group (for example, a methyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (2) a 5 or 6 membered monocyclic aromatic heterocyclic group. (eg, pyrazolyl, An azole group, a thiazolyl group, a thiadiazolyl group, a pyridyl group or an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group, a benzothiazolyl group), each of which is selected from the group consisting of 1 to The three substituents are substituted by (a) a halogen atom (for example, a chlorine atom or a bromine atom), (b) a cyano group, and (c) a C _{1-6 which is} optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom). An alkyl group (for example, methyl, ethyl), and (d) a C _3-8 cycloalkyl group (for example, a cyclopropyl group); an X ¹ -based carbon atom or a nitrogen atom; and an R ³ -based (1) hydrogen atom, or (2) a halogen atom (for example, a fluorine atom); and a ring A system (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c). a pendant oxy group, or (2) 8-azabicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0] Hexane ring.

[Compound B-6]

In the compound (I), the R ¹ group (1) is optionally substituted with 1 to 3 substituents of a C _1-6 alkyl group (for example, methyl group, ethyl group) (a) cyano group, ( b) a phenyl group substituted with 1 to 3 C _1-6 alkoxy groups (for example, methoxy group), (c) phenoxy group, (d) cyclopropyl group, (e) pyrazolyl group, ( f) a carbazolyl group, and (g) a dihydropyridinyl group optionally substituted with 1 to 3 pendant oxy groups, (2) a C _1-6 alkoxy group substituted with 1 to 3 phenyl groups as needed (for example) , methoxy, tert-butoxy, preferably C _1-3 alkoxy (eg, methoxy)), (3) an amine group optionally substituted with a mono or di substituent selected from the group consisting of (a) a C _1-6 alkyl group (for example, a methyl group, an ethyl group) substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom (for example, a fluorine atom), and (ii) a cyanogen. a group, (iii) a cyclopropyl group, (iv) a cyclobutyl group, (v) optionally selected from a halogen atom (for example, a fluorine atom) and a C _1-6 alkoxy group (for example, a methoxy group) to a phenyl group substituted with 3 substituents, (vi) pyridyl group, and (vii) an oxetanyl group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group), (b) Cyclopropyl, cyclobutyl and cyclopentyl, each as needed Substituted with 1 to 3 halogen atoms (for example, fluorine atom), (c) phenyl group, and (d) tetrahydropiperidyl group, oxetanyl group, tetrahydrofuranyl group and pyrrolidinyl group, each of which is required Substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl), (4) cyclopropyl substituted with 1 to 3 phenyl groups as desired, (5) phenyl group, or (6) nitrogen heterocycle Butyryl, pyrrolidinyl, piperidinyl, piperidine , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl or 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl, each of which is optionally one to five substituents selected from the group consisting of Substituting (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) optionally a C _1-6 alkyl group (for example, a methyl group) Or a disubstituted aminemethanyl group, (f) optionally substituted by 1 to 3 substituents selected from the group consisting of C _1-6 alkyl groups (eg, methyl, ethyl, isopropyl) (i) a hydroxy group, and (ii) a C _1-6 alkoxy group (for example, a methoxy group), (g) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) (for example) , methoxy, ethoxy, isopropoxy), (h) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl), and (i) optionally substituted with 1 to 3 halogen atoms the phenyl (e.g., fluorine atom) or R ¹ based on the atom bonded to the ring A, ring A together form 2,8-diaza-spiro [4.5] decane ring system substituted with oxo and optionally further substituted with 1 to 3 C _1-6 alkyl (e.g., methyl); R ² lines (1 a phenyl group (a) a halogen atom (for example, a fluorine atom or a chlorine atom) substituted with one to three substituents selected from the group consisting of, and (b) optionally having 1 to 3 halogen atoms (for example, a fluorine atom) substituted C _1-6 alkyl (for example, methyl), or (2) pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an oxazolyl group or a benzothiazolyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group, an ethyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) a cyclopropyl group; an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based (1) hydrogen atom; or (2) a halogen atom (for example, a fluorine atom); and a ring A-system (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c). a pendant oxy group, or (2) 8-azabicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0] Hexane ring.

[Compound B-7]

In the compound (I), the R ¹ group (1) is optionally substituted with 1 to 3 substituents of a C _1-6 alkyl group (for example, methyl group, ethyl group) (a) cyano group, ( b) a phenyl group substituted with 1 to 3 C _1-6 alkoxy groups (for example, methoxy group), (c) phenoxy group, (d) cyclopropyl group, (e) pyrazolyl group, ( f) a carbazolyl group, and (g) a dihydropyridinyl group optionally substituted with 1 to 3 pendant oxy groups, (2) a C _1-3 alkoxy group substituted with 1 to 3 phenyl groups as needed (for example) , methoxy), (3) an optionally substituted group of the mono- or di-substituted amino group (a) is selected from the following group optionally substituted by 1 to 3 substituents selected from those of the substituted C _1-6 alkyl (e.g., methyl, ethyl) (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, (iii) a cyclopropyl group, (iv) a cyclobutyl group, (v) optionally selected from the group consisting of a halogen atom (for example, a fluorine atom) and a C _1-6 alkoxy group (for example, a methoxy group) substituted with 1 to 3 substituents of a phenyl group, (vi) a pyridyl group, and (vii) optionally 1 through 3 C _1-6 alkyl (eg, methyl) substituted oxetanyl, (b) cyclopropyl, cyclobutyl, and cyclopentyl, each optionally having 1 to 3 halogen atoms (for example, a fluorine atom), (c) benzene , And (d) tetrahydropyran-yl, oxetanyl, tetrahydrofuranyl, and pyrrolidinyl, each of those lines is optionally substituted by 1-3 C _1-6 alkyl (e.g., methyl), ( 4) a cyclopropyl group substituted with 1 to 3 phenyl groups, (5) phenyl group, or (6) azetidinyl group, pyrrolidinyl group, piperidinyl group, or , morpholinyl, 1,1-dioxythiomorpholinyl, tetrahydropyranyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo [3.2.1] Octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 6-oxa-3 - azabicyclo[3.1.1]heptyl or 3,7-dioxa-9-azabicyclo[3.3.1]fluorenyl, each of which is optionally one to five substituents selected from the group consisting of Substituting (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) a hydroxyl group, (d) a pendant oxy group, (e) optionally a C _1-6 alkyl group (for example, a methyl group) Or a disubstituted aminemethanyl group, (f) optionally substituted by 1 to 3 substituents selected from the group consisting of C _1-6 alkyl groups (eg, methyl, ethyl, isopropyl) (i) a hydroxy group, and (ii) a C _1-6 alkoxy group (for example, a methoxy group), (g) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom) (for example) , methoxy, ethoxy, isopropoxy), (h) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl), and (i) optionally substituted with 1 to 3 halogen atoms the phenyl (e.g., fluorine atom) or R ¹ based on the atom bonded to the ring A, ring A together form 2,8-diaza-spiro [4.5] decane ring system substituted with oxo and optionally further substituted with 1 to 3 C _1-6 alkyl (e.g., methyl); R ² lines (1 a phenyl group (a) a halogen atom (for example, a fluorine atom or a chlorine atom) substituted with one to three substituents selected from the group consisting of, and (b) optionally having 1 to 3 halogen atoms (for example, a fluorine atom) substituted C _1-6 alkyl (for example, methyl), or (2) pyrazolyl, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an oxazolyl group or a benzothiazolyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group, an ethyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) a cyclopropyl group; an X ¹ -based carbon atom or a nitrogen atom; an R ³ -based (1) hydrogen atom; or (2) a halogen atom (for example, a fluorine atom); and a ring A-system (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c). a pendant oxy group, or (2) 8-azabicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0] Hexane ring.

[Compound C-1]

In the compound (I), the R ¹ group (1) is optionally substituted with an amine group (a) which is mono- or disubstituted with a substituent selected from the group consisting of 1 to 3 substituents selected from the following _{: -6} alkyl (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), and (ii) a C _6-14 substituted with 1 to 3 halogen atoms (for example, a fluorine atom) as needed. An aryl group (e.g., phenyl), and (b) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl, tetrahydrofuranyl), or (2) optionally selected from the group consisting of a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 5 substituents (for example, azetidinyl group, pyrrolidinyl group) (a) a halogen atom (for example, a fluorine atom), (b) a cyanogen group a group, (c) an amine carbenyl group, (d) a C _1-6 alkyl group (for example, a methyl group), and (e) a C _1-6 alkoxy group (for example, a methoxy group); an R ² system (1) a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (2) optionally substituted with 1 to 3 substituents selected from the group consisting of a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, pyrazolyl, thiazolyl, thiadiazolyl (preferably pyrazolyl, thiazolyl)) (a) a halogen atom (for example, a chlorine atom) A bromine atom), (b) C _1-6 alkyl (e.g., methyl), and (c) C _3-8 cycloalkyl (e.g., cyclopropyl); X ¹ based carbon atom or a nitrogen atom; R ³ Hydrogen atom; and ring A

[Compound C-2]

In the compound (I), the R ¹ group (1) is optionally substituted with an amine group (a) which is mono- or disubstituted with a substituent selected from the group consisting of 1 to 3 substituents selected from the following _{: a -6} alkyl group (for example, a methyl group, an ethyl group) (i) a halogen atom (for example, a fluorine atom), and (ii) a phenyl group (for example, a fluorine atom) which is optionally substituted with 1 to 3 halogen atoms, ( b) tetrahydropyranyl, and (c) tetrahydrofuranyl, or (2) azetidinyl or pyrrolidinyl, each of which is optionally substituted with from 1 to 5 substituents selected from the group consisting of a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) an amine formazan group, (d) a C _1-6 alkyl group (for example, a methyl group), and (e) a C _1-6 alkoxy group. a base (for example, a methoxy group); a R ² group (1) a phenyl group (for example, a fluorine atom) substituted with 1 to 3 halogen atoms, or (2) pyrazolyl, thiazolyl or thiadiazolyl Each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and c) cyclopropyl; X ¹ -based carbon or nitrogen atom; R ³ -based hydrogen atom; and ring A system

[Compound D-1]

In the compound (I), the R ¹ group (1) is optionally substituted with an amine group (a) which is mono- or disubstituted with a substituent selected from the group consisting of 1 to 3 substituents selected from the following _{: -6} alkyl (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), and (ii) a C _6-14 substituted with 1 to 3 halogen atoms (for example, a fluorine atom) as needed. An aryl group (e.g., phenyl), and (b) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl, tetrahydrofuranyl), or (2) optionally selected from the group consisting of a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 5 substituents (for example, azetidinyl group, pyrrolidinyl group) (a) a halogen atom (for example, a fluorine atom), and (b) a cyano group; an R ² system (1), optionally a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (2) optionally selected from the group consisting of a 5- or 6-membered monocyclic aromatic heterocyclic group substituted with 1 to 3 substituents (for example, pyrazolyl, thiazolyl, thiadiazolyl (preferably pyrazolyl, thiazolyl)) (a) halogen An atom (for example, a chlorine atom, a bromine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c) a C _3-8 cycloalkyl group (for example, a cyclopropyl group); X ¹ is a carbon atom or a nitrogen atom; R ³ is a hydrogen atom; and ring A is a ring

[Compound D-2]

In the compound (I), the R ¹ group (1) is optionally substituted with an amine group (a) which is mono- or disubstituted with a substituent selected from the group consisting of 1 to 3 substituents selected from the following _{: a -6} alkyl group (for example, a methyl group, an ethyl group) (i) a halogen atom (for example, a fluorine atom), and (ii) a phenyl group (for example, a fluorine atom) which is optionally substituted with 1 to 3 halogen atoms, ( b) tetrahydropyranyl, and (c) tetrahydrofuranyl, or (2) azetidinyl or pyrrolidinyl, each of which is optionally substituted with from 1 to 5 substituents selected from the group consisting of a halogen atom (for example, a fluorine atom), and (b) a cyano group; and a R ² system (1) a phenyl group (for example, a fluorine atom) or a (2) pyrazolyl group which is optionally substituted with 1 to 3 halogen atoms. Or a thiazolyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a chlorine atom, a bromine atom), and (b) a C _1-6 alkyl group (for example, a methyl group). And (c) cyclopropyl; X ¹ -based carbon or nitrogen atom; R ³ -based hydrogen atom; and ring A system

[Compound E-1]

In the compound (I), the R ¹ group (1) is optionally substituted with an amine group (a) which is mono- or disubstituted with a substituent selected from the group consisting of 1 to 3 substituents selected from the following _{: -6} alkyl (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), and (ii) a C _6-14 substituted with 1 to 3 halogen atoms (for example, a fluorine atom) as needed. An aryl group (for example, phenyl), and (b) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, tetrahydropyranyl, tetrahydrofuranyl), or (2) 1 to 3 halogens as needed a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with an atom (for example, a fluorine atom) (for example, azetidinyl group, pyrrolidinyl group); R ² system (1) optionally 1 to 3 halogens a C _6-14 aryl group (eg, phenyl) substituted with an atom (eg, a fluorine atom), or (2) a 5 or 6 membered monocyclic aromatic group substituted with one to three substituents selected from the group consisting of Heterocyclic group (for example, pyrazolyl, thiazolyl, thiadiazolyl (preferably pyrazolyl, thiazolyl)) (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) C _{1- a 6} alkyl group (for example, a methyl group), and (c) a C _3-8 cycloalkyl group (for example, a cyclopropyl group); an X ¹ -based carbon atom or a nitrogen atom; and an R ³ -based hydrogen atom; ; and ring A

[Compound E-2]

In the compound (I), the R ¹ group (1) is optionally substituted with an amine group (a) which is mono- or disubstituted with a substituent selected from the group consisting of 1 to 3 substituents selected from the following _{: a -6} alkyl group (for example, a methyl group, an ethyl group) (i) a halogen atom (for example, a fluorine atom), and (ii) a phenyl group (for example, a fluorine atom) which is optionally substituted with 1 to 3 halogen atoms, ( b) tetrahydropyranyl, and (c) tetrahydrofuranyl, or (2) azetidinyl or pyrrolidinyl, each of which is optionally substituted with 1 to 3 halogen atoms (for example, a fluorine atom); R ² is (1) a phenyl group (for example, a fluorine atom) or a (2) pyrazolyl group or a thiazolyl group optionally substituted with 1 to 3 halogen atoms, each of which is selected from 1 to 3 of the following The substituent is substituted by (a) a halogen atom (for example, a chlorine atom or a bromine atom), (b) a C _1-6 alkyl group (for example, a methyl group), and (c) a cyclopropyl group; an X ¹ -type carbon atom or a nitrogen atom; ; R ³ is a hydrogen atom; and ring A

[Compound F-1]

In the compound (I), R ¹ is a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, pyrrolidinyl group) (a) a halogen atom which is optionally substituted with 1 to 5 substituents selected from the following ( For example, a fluorine atom), (b) a cyano group, (c) an amine carbenyl group, (d) a C _1-6 alkyl group (for example, a methyl group), and (e) a C _1-6 alkoxy group (for example, Methoxy); R ² is a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of pyrazolyl, thiazolyl, thiadiazolyl, Pyridyl (preferably pyrazolyl, thiadiazole, more preferably pyrazolyl)) (a) a halogen atom (for example, a chlorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group) ); X ¹ is a carbon atom; R ³ is a hydrogen atom; and a ring A is

[Compound F-2]

In the compound (I), R ¹ is optionally a pyrrolidinyl group substituted with 1 to 5 substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, and (c) an amine. Mercapto, (d) C _1-6 alkyl (eg, methyl), and (e) C _1-6 alkoxy (eg, methoxy); R ² pyrazolyl or thiadiazolyl each line by 1 to 3 substituents (a) a halogen atom selected from the group of persons (e.g., chlorine atom), and (b) C _1-6 alkyl (e.g., methyl); X ¹ based carbon Atom; R ³ hydrogen atom; and ring A

[Compound G-1]

In the compound (I), R ¹ is a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, pyrrolidinyl group) (a) a halogen atom which is optionally substituted with 1 to 5 substituents selected from the following ( For example, a fluorine atom), and (b) a cyano group; and R ² is a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, pyrazolyl, optionally substituted with 1 to 3 substituents selected from the group consisting of: Thiazolyl, thiadiazolyl, pyridyl (preferably pyrazolyl, thiadiazolyl, more preferably pyrazolyl)) (a) a halogen atom (for example, a chlorine atom), and (b) C _{1 -6} alkyl (for example, methyl); X ¹ -based carbon atom; R ³ -based hydrogen atom; and ring A system

[Compound G-2]

Compound (I), R ¹ is an optionally Department 1-5 substituents selected from the group of persons pyrrolidinyl (a) a halogen atom (e.g., fluorine atom), and (b) a cyano group; R ² lines a pyrazolyl group (a) a halogen atom (for example, a chlorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group), optionally substituted with 1 to 3 substituents selected from the group consisting of X ^{1 ;} a carbon atom; a R ³ hydrogen atom; and a ring A system

[Compound H-1]

In the compound (I), the R ¹ group (1) is optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl groups (for example, methyl group, ethyl group) (a) C _3-8. a cycloalkyl group (for example, a cyclopropyl group), and (b) an 8- to 12-membered fused aromatic heterocyclic group (for example, a carbazolyl group), (2) optionally having 1 to 3 C _6-14 aryl groups. (e.g., phenyl) substituted C _1-6 alkoxy (preferably C _1-3 alkoxy (e.g., methoxy)), (3) optionally substituted with a substituent selected from the group consisting of The disubstituted amino group (a) is optionally substituted by a C _1-6 alkyl group (for example, methyl, ethyl) (i) a halogen atom (for example, a fluorine atom), which is substituted with 1 to 3 substituents selected from the following. And (ii) a C _6-14 aryl group (for example, a phenyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), (iii) a 5 or 6 membered monocyclic aromatic heterocyclic group (for example) , pyridyl), and (iv) a 3 to 8 membered monocyclic non-aromatic heterocyclic group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group) (for example, oxetane) (b) a C _3-8 cycloalkyl group (eg, cyclopropyl, cyclopentyl), (c) a 3 to 8 membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl, tetrahydrofuran) (), and (d) C _6-14 aryl (eg, phenyl), (4) a C _3-8 cycloalkyl group (for example, a cyclopropyl group), or (5) a 3 to 8 membered monocyclic non-aromatic heterocyclic group which is optionally substituted with 1 to 5 substituents selected from the group consisting of (for example, Azetidinyl, pyrrolidinyl, 1,1-dioxythiomorpholinyl, 3-oxa-6-azabicyclo[3.1.1]heptyl) (a) halogen atom (for example, fluorine atom) , (b) cyano, (c) carbamoyl acyl, (d) optionally substituted with 1 to 3 C _1-6 alkoxy (e.g., methoxy) substituent of the C _1-6 alkyl group (e.g., Methyl, isopropyl), (e) C _1-6 alkoxy (eg, methoxy), and (f) C _6- substituted with 1 to 3 halogen atoms (eg, fluorine atom) as needed _{a 14} aryl group (for example, a phenyl group), or an atom to which the R ^{1 group} is bonded to the ring A, together with the ring A form a spiro ring (for example, 2,8-diazaspiro[4.5]nonane), which Substituted by a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl groups); the R ² group (1) is optionally substituted with 1 to 3 substituents selected from the group consisting of a C _6-14 aryl group (for example, a phenyl group) (a) a halogen atom (for example, a fluorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group), or (2) optionally selected 5 to 12 members replaced by 1 to 3 substituents of An aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, pyrazolyl, An azole group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, an 8- to 12-membered fused aromatic heterocyclic group (for example, a benzothiazolyl group) (a) a halogen atom (for example, a chlorine atom or a bromine atom), (b) a cyano group, (c) a C _1-6 alkyl group (for example, a methyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), and (d) a C _3-8 cycloalkyl group. (for example, cyclopropyl); X ¹ is a carbon atom or a nitrogen atom; R ³ is a (1) hydrogen atom; or (2) a halogen atom (for example, a fluorine atom); and a ring A system (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group), or 2) 8-Azabicyclo[3.2.1]octane ring or 2,5-diazabicyclo[2.2.1]heptane ring.

[Compound H-2]

In the compound (I), the R ¹ group (1) is optionally a C _1-6 alkyl group (for example, methyl group, ethyl group) (a) cyclopropyl group substituted with 1 to 3 substituents selected from the following. And (b) a carbazolyl group, (2) a C _1-6 alkoxy group (preferably a C _1-3 alkoxy group (for example, methoxy group)) substituted with 1 to 3 phenyl groups, if necessary, 3) an amine group which is mono- or di-substituted with a substituent selected from the following (a), if necessary, a C _1-6 alkyl group substituted with 1 to 3 substituents selected from the following (for example, methyl group, Ethyl) (i) a halogen atom (for example, a fluorine atom), (ii) a phenyl group (for example, a fluorine atom) substituted with 1 to 3 halogen atoms, (iii) a pyridyl group, and (iv) as needed An oxetane group substituted by 1 to 3 C _1-6 alkyl groups (for example, methyl group), (b) cyclopropyl group, (c) cyclopentyl group, (d) tetrahydropyranyl group, ( e) tetrahydrofuranyl, and (f) phenyl, (4) cyclopropyl, or (5) azetidinyl, pyrrolidinyl, 1,1-dioxythiomorpholinyl or 3-oxa-6 - azabicyclo[3.1.1]heptyl, each of which is optionally substituted with one to five substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) Aminomethyl thiol, (d) 1 to 3 C ₁ as needed The substituted _-6 alkoxy (e.g., methoxy) C _1-6 alkyl (e.g., methyl, isopropyl), (E) C _1-6 alkoxy (e.g., methoxy), and (f) a phenyl group (for example, a fluorine atom) substituted with 1 to 3 halogen atoms, or an atom bonded to the ring A by an R ^{1 group} , and a 2,8-diaza snail together with the ring A [4.5] a decane ring which is substituted with a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl groups); the R ² system (1) is optionally selected from the group consisting of One to three substituents substituted with a phenyl group (a) a halogen atom (for example, a fluorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group), or (2) a pyrazolyl group, An azolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group or a benzothiazolyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a chlorine atom, a bromine atom), (b) cyano, (c) the optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom) C _1-6 alkyl (e.g., methyl), and (d) cyclopropyl; X ¹ Department a carbon atom or a nitrogen atom; R ³ is a (1) hydrogen atom; or (2) a halogen atom (for example, a fluorine atom); and a ring A system (1) Each of the substituents is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group), or 2) 8-azabicyclo[3.2.1]octane ring or 2,5-diazabicyclo[2.2.1]heptane ring

[Compound I-1]

In the compound (I), R ¹ is a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, pyrrole) which is optionally substituted with 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of 1 to 5 (preferably 1 to 3). a pyridyl group (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, (c) an amine carbenyl group, and (d) optionally 1 to 3 C _1-6 alkoxy groups (for example, Methoxy) substituted C _1-6 alkyl (eg, methyl); R ² is optionally a 5 or 6 membered monocyclic aromatic heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of For example, pyrazolyl, thiazolyl, thiadiazolyl, pyridyl (preferably pyrazolyl, thiadiazolyl, more preferably pyrazolyl)) (a) a halogen atom (for example, a chlorine atom), And (b) C _1-6 alkyl (for example, methyl); X ¹ -based carbon atom; R ³ -based hydrogen atom; and ring A system

[Compound I-2]

In the compound (I), R ¹ is optionally a pyrrolidinyl group substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, and (c) an amine. methyl acyl, and (d) optionally substituted with 1 to 3 C _1-6 alkoxy (e.g., methoxy) substituent of a C _1-6 alkyl (e.g., methyl); R ^{2-yl-pyrazol-based} a thiazolyl group, a thiadiazolyl group or a pyridyl group, each of which is substituted with one to three substituents selected from the group consisting of (a) a halogen atom (for example, a chlorine atom), and (b) a C _1-6 alkyl group. (eg, methyl); X ¹ is a carbon atom; R ³ is a hydrogen atom; and ring A is

[Compound J-1]

In the compound (I), R ¹ is a 3 to 8 membered monocyclic non-aromatic heterocyclic group (for example, pyrrolidinyl group) (a) a halogen atom which is optionally substituted with 1 to 5 substituents selected from the following ( For example, a fluorine atom), (B) cyano, (c) carbamoyl acyl, (d) optionally substituted with 1 to 3 C _1-6 alkoxy (e.g., methoxy) substituted C _1-6 of An alkyl group (for example, a methyl group), and (e) a C _1-6 alkoxy group (for example, a methoxy group); and the R ² group (1) is optionally substituted with one to three substituents selected from the group consisting of C _6-14 aryl (for example, phenyl) (a) a halogen atom (for example, a fluorine atom, a chlorine atom), and (b) a C ₁ substituted with 1 to 3 halogen atoms (for example, a fluorine atom) as needed _{a -6} alkyl group (for example, a methyl group), or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, pyrazolyl or thiophene) which is optionally substituted with 1 to 3 substituents selected from the group consisting of 1 to 3 substituents selected from the group consisting of (oxadiazolyl, pyridyl) (a) a halogen atom (for example, a chlorine atom), and (b) a C _1-6 alkyl group (for example, a methyl group); a X ¹ -type carbon atom; an R ³ -based hydrogen atom; A system

[Compound J-2]

In the compound (I), R ¹ is optionally a pyrrolidinyl group substituted with 1 to 5 substituents selected from the group consisting of (a) a halogen atom (for example, a fluorine atom), (b) a cyano group, and (c) an amine. methyl acyl, (d) optionally substituted with 1 to 3 C _1-6 alkoxy (e.g., methoxy) substituent of a C _1-6 alkyl (e.g., methyl), and (e) C _{1- 6} alkoxy (for example, methoxy); R ² is (1) a phenyl group (a) halogen atom (for example, a fluorine atom or a chlorine atom) which is optionally substituted with 1 to 3 substituents selected from the following: And (b) a C _1-6 alkyl group (for example, a methyl group) substituted with 1 to 3 halogen atoms (for example, a fluorine atom), or (2) pyrazolyl, thiadiazolyl or pyridyl group each line by 1 to 3 substituents (a) a halogen atom selected from the group of persons (e.g., chlorine atom), and (b) C _1-6 alkyl (e.g., methyl); X ¹ based carbon Atom; R ³ hydrogen atom; and ring A

[Compound K-1]

Compound (I) is selected from (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) Pyrrolidine-2-carbonitrile, (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) Pyrrolidine-2-carbonitrile, (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin Pyridin-4-yl)carbonyl)pyrrolidine-2-carbonitrile, (3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin Pyridin-4-yl)methanone, (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidine Alkyl-1-yl)methanone, (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoro Pyrrolidin-1-yl)methanone, (1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl Ketone, N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl)per 1-Protonamine, N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridine- 3-base) piperidine 1-carbamamine, ((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl) Piperidin-4-yl)methanone, (3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridine-3- (piperidin-4-yl)methanone, (1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoronitrogen) Heterocyclobutane-1-yl)methanone, and (1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl) (3 -Fluoroazetidin-1-yl)methanone.

[Compound K-2]

(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile

[Compound K-3]

(2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile

[Compound K-4]

(2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) Pyrrolidine-2-carbonitrile

When the compound (I) is a salt type, examples thereof include a metal salt, an ammonium salt, an organic base salt, a mineral acid salt, an organic acid salt, a basic or acidic amino acid salt, and the like. Examples of preferred metal salts include alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; aluminum salts and the like. Examples of preferred organic base salts include trimethylamine salt, triethylamine salt, pyridinium salt, pyridinium salt, 2,6-dimethylpyridine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine. Salt, dicyclohexylamine salt, N,N'-diphenylmethylethylidene diamine salt, and the like. Examples of preferred inorganic acid salts include hydrochlorides, hydrobromides, nitrates, sulfates, phosphates and the like. Examples of preferred organic acid salts include formates, acetates, trifluoroacetates, phthalates, fumarates, oxalates, tartrates, maleates, citric acid Salt, succinate, malate, methanesulfonate, besylate, para Benzene sulfonate and the like. Examples of preferred basic amino acid salts include arginine salts, persalts, urinates and the like. Examples of preferred acidic amino acid salts include aspartate, glutamine, and the like.

Among them, a pharmaceutically acceptable salt is preferred. For example, when the compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (for example, sodium salts, potassium salts, etc.), alkaline earth metal salts (for example, calcium salts, magnesium salts, etc.), ammonium salts, and the like. And when the compound has a basic functional group, examples thereof include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and organic acid salts 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 and the like.

[Production method]

The compound of the present invention and the starting compound can be produced by a method known per se, for example, by the method shown in the following scheme or the like. Hereinafter, "room temperature" generally means 0 to 40 ° C and unless otherwise stated, the symbols contained in the chemical formulas of the flowcharts are as defined above. In the equation, each compound contains a salt, and examples of the salt include such salts similar to the compound of the present invention and the like. The compound obtained in each step can be used directly as a reaction mixture or as a crude product of the next reaction. It can also be isolated from the reaction mixture by conventional methods, and can be easily purified by a separation method (meaning, such as recrystallization, distillation, chromatography, etc.). When the compound in the formula is commercially available, a commercially available product can be used as it is. When each ring (I) has a substituent, the corresponding precursor also has a similar substituent.

When the starting compound has an amine group, a carboxyl group, a hydroxyl group or a heterocyclic group, the groups can be protected by a protecting group which is usually used for peptide chemistry or the like. It is necessary to remove the protecting group after the reaction, and the target compound can be obtained. Protection and deprotection according to methods known per se, for example, as described in "Protective Groups in Organic Synthesis, 3rd Ed", John Wiley and Sons, Inc. (1999) (Theodora W. Greene, Peter GMWuts) method. Examples of preferred protecting groups include a third butylamine methyl sulfonyl group, a benzylamine methyl sulfonyl group, a benzyl group, a methyl group, an ethyl group, a third butyl group, and the like.

Examples of the "debonding group" for LG ¹ to LG ³ include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), and a C _1-6 alkylsulfonyloxy group (for example, methanesulfonate) a mercaptooxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or the like, a C _1-6 alkylsulfonyl group (for example, a methanesulfonyl group, an ethanesulfonyl group, etc.). Further, a substituent which can be converted into a leaving group is contained in LG ¹ to LG ³ , and it can be converted into a leaving group in a desired step according to a reaction known per se. For example, when LG ¹ to LG ³ are methylthio groups, they are converted to methanesulfonyl groups by an oxidation reaction.

The following steps can be carried out in the absence of a solvent or by dissolving or suspending the starting compound in a suitable solvent before the reaction. In this case, a solvent may be used alone or two or more of these solvents may be used in an appropriate ratio. Specific examples of the solvent used in the production method of the compound of the present invention include the following.

Alcohols: methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, third amyl alcohol, 2-methoxyethanol, etc.

Ethers: diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, etc.

Aromatic hydrocarbon groups: benzene, chlorobenzene, toluene, xylene, etc.

Saturated hydrocarbon groups: cyclohexane, hexane, etc.

Indoleamines: N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid triamide, N-methylpyrrolidone, etc.

Halogenated hydrocarbons: dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.

Nitrile: acetonitrile, propionitrile, etc.

Amidino group: dimethyl sulfinyl group, etc.

Organic bases: triethylamine, pyridine, dimethylpyridine, etc.

Anhydrides: acetic anhydride, etc.

Organic acids: formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.

Inorganic acids: hydrochloric acid, sulfuric acid, etc.

Ester: methyl acetate, ethyl acetate, butyl acetate, etc.

Ketones: acetone, methyl ethyl ketone, etc.

water

Examples of specific bases or acid scavengers used in the method of producing the compounds of the present invention include the following.

Inorganic bases: sodium hydride, potassium hydride, magnesium hydride, etc.

Basic salt: sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogencarbonate, etc.

Organic bases: triethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, dimethylpyridine, 4-dimethylaminopyridine, N,N-dimethyl Aniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diaza Bicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, etc.

Metal alkoxides: sodium methoxide, sodium ethoxide, potassium butoxide, etc.

Alkali metal hydride: sodium hydride, potassium hydride, etc.

Metal amines: sodium amination, lithium diisopropylamide, hexamethyldidecyl lithium, etc.

Organolithium reagents: methyl lithium, n-butyl lithium, second butyl lithium, tert-butyl lithium, etc.

Specific examples of the acid or acid catalyst used in the production method of the compound of the present invention include the following.

Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.

Organic acids: acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid Wait

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

Compound (I) can be produced according to Production Method A.

Unless otherwise stated, the symbols of the formula in the schemes are as defined above. Each of R ^a is a hydrogen atom or a C _1-6 alkyl group optionally substituted. When each R ^a is optionally substituted with a C _1-6 alkyl group, the two R ^a are bonded as needed to form, for example, 4,4,5,5-tetramethyl-1,3,2-dioxaboron. a ring such as cyclopentane. R ⁴ is optionally a substituted hydrocarbon group, optionally substituted heterocyclic group or hydrogen atom. X ² is a carbon atom or a nitrogen atom which is required to be substituted.

X ³ is an oxygen atom or a sulfur atom.

The R ^a "of the optionally substituted C _1-6 alkyl group" to include examples similar to those "of the optionally substituted C _1-6 alkyl" of R ¹ person.

Examples of the "optionally substituted hydrocarbyl group" of R ⁴ and the "optionally substituted heterocyclic group" include the "optionally substituted hydrocarbon group" similar to R ^A , R ^A ' or R ^B ' and "Substituted heterocyclic groups as needed.

Examples of the substituent of the "optionally substituted carbon atom" of X ² include the substituents of the "optionally substituted aromatic heterocyclic group" similar to R ² .

[Manufacturing Method A]

(Step A-1)

The compound (6) can be produced by reacting the compound (2) with the compound (3), or the compound (2) with the compound (4), or the compound (2) with the compound (5). This reaction is carried out using the compound (2) and the compound (3), or the compound (2) and the compound (4), or the compound (2) and the compound (5) in the presence of an acid catalyst, a base or a metal catalyst. Examples of the acid catalyst include an organic acid or the like. The acid catalyst is used in an amount of about 0.05 to 2 moles per 1 mole of the compound (2). Examples of the base include a basic salt, an organic base, an alkali metal hydride, an organolithium reagent, and the like. The base is used in an amount of about 1 to 20 moles per 1 mole of the compound (2). Examples of the metal catalyst include a palladium compound [for example, palladium (II) acetate, ruthenium (triphenylphosphine) palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine) Palladium (II), ginseng (diphenyleneacetone) dipalladium (0), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), palladium acetate (II) And a complex compound of 1,1'-bis(diphenylphosphino)ferrocene, etc., a copper compound [for example, copper (I) iodide, copper (I) bromide, etc.]. The metal catalyst is used in an amount of from about 0.000001 to 10 moles per 1 mole of the compound (2). The metal catalyst can be coordinated with a phosphine [eg, triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxime, tri-tert-butylphosphine, three - a third butyl phosphine tetrafluoroborate or the like] or an amine ligand [for example, 8-methylquinolin-1-ol, 1,10-morpholine, 1,2-diaminocyclohexane, N , N'-dimethyl-1,2-ethanediamine, etc.] are used together. The phosphine ligand or amine ligand is used in an amount of from about 0.01 to 5 moles per 1 mole of compound (2). The compound (3), the compound (4) or the compound (5) is used in an amount of about 0.8 to 10 mol per 1 mol of the compound (2). When the reaction is carried out using a metal catalyst, The reaction system is preferably carried out in the presence of a base. Examples of the base include an inorganic base, a basic salt and the like. The base is used in an amount of about 1 to 20 moles per 1 mole of the compound (2). When the reaction is carried out using a metal catalyst which is unstable to oxygen, for example, the reaction is preferably carried out in an inert gas (for example, argon gas, nitrogen gas or the like). This reaction is advantageously carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, and preferred examples thereof include alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, decylamines, halogenated hydrocarbons, nitriles, esters, hydrazine, water, mixed solvents thereof and the like. While the reaction time varies depending on the reagent or solvent to be used, it is usually from 1 minute to 200 hours, and the reaction temperature is preferably from 0 to 200 °C. In addition, microwaves can be irradiated to promote the reaction. The compound (2), the compound (3), the compound (4), and the compound (5) may be commercially available products, or may be produced according to a method known per se or according to the method thereof.

(Step A-2)

Compound (I) can be produced by reacting compound (6) with compound (7). This reaction was carried out in the same manner as in the step A-1. The compound (7) may be a commercially available product, or may be produced according to a method known per se or according to the method thereof.

In the compound (6), the R ² system

Compound (8) can also be produced according to steps A-3 to A-4 of a series of reaction steps.

(Step A-3)

The compound (10) can be produced by condensing the compound (8) with the compound (9). This condensation reaction is carried out by reacting the compound (8) or a reactive derivative thereof with the compound (9). Examples of the reactive derivative include an acid halide such as an acid chloride, an acid bromide, etc.; a pyridoxamine such as pyrazole, imidazole or benzotriazole; a mixed acid anhydride of acetic acid, propionic acid, butyric acid or the like; Nitride; activated esters (eg, diethoxy phosphate, diphenoxy phosphate, p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, five Chlorophenyl ester, N-hydroxy amber ylide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 6-chloro-1-hydroxybenzotriazole, 1- Hydroxy-1H-2-pyridinone ester or the like); activated thioester (for example, 2-pyridine thioester, 2-benzothiazole thioester, etc.) and the like. Alternatively, it is also possible to produce by directly reacting the carboxylic acid (8) with the compound (9) in the presence of a suitable condensing agent, instead of using the reactive derivative. Examples of the condensing agent include N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) a carbodiimide (WSC) hydrochloride or the like; an azolides (for example, N,N'-carbonyldiimidazole, etc.); a dehydrating agent (for example, N-ethoxycarbonyl-2-ethoxyl) 2-1,3-dihydroquinoline, phosphonium chloride, alkoxyacetylene, etc.; 2-halopyridinium (for example, 2-chloromethylpyridinium iodide, 2-fluoro-1-methylpyridinium) Iodine, etc.; cyanophosphate (for example, diethyl cyanophosphate, etc.); 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium Fluorophosphate (HATU), O-(7-azabenzotriene) Zin-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU) and the like. When a condensing agent is used, the reaction is considered to proceed via a reactive derivative of the carboxylic acid (8). The amount of the compound (9) to be used is usually about 0.8 to 5 moles per 1 mole of the compound (8) or a reactive derivative thereof. This reaction is advantageously carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction is continued, and preferred examples thereof include ethers, aromatic hydrocarbons, saturated hydrocarbons, decylamines, halogenated hydrocarbons, nitriles, hydrazines, aromatic organic bases, and mixed solvents thereof. Further, when an acidic substance is generated by the reaction, the reaction may be carried out in the presence of an acid scavenger to remove the acidic substance from the reaction system. Examples of the acid scavenger include a basic salt, an organic base, and the like. Further, for example, an alkali salt, an organic base or the like can be used to promote the reaction. The reaction time varies depending on the reagent or solvent to be used, and it is usually from 1 minute to 72 hours. The reaction temperature is preferably from 0 to 100 °C. The compound (8) and the compound (9) may be commercially available products, or may be produced according to a method known per se or according to the method thereof.

(Step A-4)

Compound (6) can be produced by treating compound (10) with an acid or a dehydrating agent. Examples of the acid include organic acids, inorganic acids, and the like. The acid is used in an amount of about 1 to 50 moles per 1 mole of the compound (10). Examples of the dehydrating agent include phosphonium chloride, methyloxycarbonyl-N-(triethylammoniumsulfonyl) (Burgess reagent) and the like. The dehydrating agent is used in an amount of about 1 to 10 moles per 1 mole of the compound (10). The reaction may also preferably be carried out in the presence of a vulcanizing agent. Examples of vulcanizing agents include 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (2,4- Bis(4-methoxyphenyl)-1,3,2,4- Dithiadiphosphetane-2, 4-disulfide, Lawesson's agent, and the like. The vulcanizing agent is used in an amount of about 1 to 10 moles per 1 mole of the compound (10). This reaction is advantageously carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Preferable examples thereof include ethers, aromatic hydrocarbons, saturated hydrocarbons, decylamines, halogenated hydrocarbons, nitriles, hydrazines, aromatic organic bases, mixed solvents thereof and the like. Further, when an acidic substance is generated by the reaction, the reaction may be carried out in the presence of an acid scavenger to remove the acidic substance from the reaction system. Examples of the acid scavenger include a basic salt, an organic base, and the like. Further, for example, an alkali salt, an organic base or the like can be used to promote the reaction. The reaction time varies depending on the reagent or solvent to be used, and it is usually from 1 minute to 72 hours. The reaction temperature is preferably from 0 to 150 °C.

In the compound (I), for example, the compound (Ic) can be produced from the compound (Ia) according to the production method B described below. Further, in the compound (I), for example, the compound (Ie) can be produced from the compound (Id) according to the production method B described below.

Each of R ⁵ and R ^{8 is} optionally substituted with a hydrocarbon group.

R ⁶ and R ^{7 are} each a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a C _7- group. _{a 14} aralkyl group, a C _8-13 arylalkenyl group or a heterocyclic group (for example, an aromatic heterocyclic group, a non-aromatic heterocyclic group), each of which is optionally substituted, or a fluorenyl group, or R ⁶ and R ⁷ may be bonded as needed to form a heterocyclic group which is optionally substituted.

A ¹ is a piperidine ring which is further substituted and optionally bridged as required, and the A ² system is further substituted as needed and bridged as needed ring.

Ring A ¹ and ring A ² optionally have from 1 to 5 (preferably from 1 to 3) substituents in the substitutable position. Examples of the substituent include a substituent selected from the above substituent group B. When the number of substituents is plural, the substituents may each be the same or different.

"bridged piperidine ring and bridged piperazine Examples of the ring include 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane, and the like.

Examples of the "optionally substituted hydrocarbyl group" of R ⁵ or R ⁸ include those "optionally substituted hydrocarbyl groups" similar to R ^A , R ^A ' or R ^B '.

Examples of the "optionally substituted hydrocarbyl group" and "optionally substituted heterocyclic group" of R ⁶ or R ^{7 include} the "replaced hydrocarbyl group" similar to R ^A , R ^A ' or R ^B ' And "substituted heterocyclic groups as needed".

Examples of the "optionally substituted heterocyclic group" formed by the combination of R ⁶ and R ⁷ include those "optionally substituted heterocyclic group" similar to R ^A , R ^A ' or R ^B '.

[Manufacturing Method B]

(Step B-1)

The compound (Ib) can be produced by hydrolyzing the compound (Ia). The hydrolysis reaction can be carried out using an inorganic base or an inorganic acid under the reaction conditions usually used for the hydrolysis reaction. It can be carried out according to a method known per se, for example, a method disclosed in "Protective Groups in Organic Synthesis, 3rd Ed", Wiley-Interscience (1999) (Theodora W. Greene, Peter G. Wuts).

(Step B-2)

The compound (Ic) can be produced by condensing the compound (Ib) with the compound (11). This reaction was carried out in the same manner as in the step A-3. The compound (11) may be a commercially available product, or may be produced according to a method known per se or according to the method thereof.

(Step B-3)

Compound (12) can be produced by removing the amine mercapto group of compound (Id) Made. The removal of the amine carbenyl group can be carried out according to a method known per se, for example, in "Protective Groups in Organic Synthesis, 3rd Ed", Wiley-Interscience (1999) (Theodora W. Greene, Peter G. M. Wuts). The method is performed.

(Step B-4)

The compound (Ie) can be produced by condensing the compound (12) with the compound (11) (R ¹ = N (R ⁶ ) (R ⁷ )) or the compound (13).

When the compound (12) is condensed with the compound (13), the reaction is carried out in the same manner as in the step A-3.

When the compound (12) is condensed with the compound (11), the reaction is carried out by appropriately condensing the compound (12) with the compound (11) by directly reacting the reactive derivative of the compound (12) with the compound (11). The reaction is carried out in the presence of a solvent. Examples of the reactive derivative include methotrexate of imidazole and the like. Examples of the condensing agent include phosgene such as phosgene, triphosgene, etc., mercapto azoles such as N,N'-carbonyldiimidazole and the like. It is believed that the reaction is carried out by using a condensing agent to permeate the reactive derivative of the compound (12). The compound (11) is used in an amount of usually about 0.8 to 5 moles per 1 mole of the compound (12) or a reactive derivative thereof. This reaction is advantageously carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Preferable examples thereof include ethers, aromatic hydrocarbons, saturated hydrocarbons, decylamines, halogenated hydrocarbons, nitriles, hydrazines, aromatic organic bases, mixed solvents thereof and the like. Further, when an acidic substance is generated by the reaction, the reaction may be carried out in the presence of an acid scavenger to remove the acidic substance from the reaction system. Examples of the acid scavenger include a basic salt, an organic base, and the like. In addition, For example, an alkali salt, an organic base or the like can be used to promote the reaction. The reaction time varies depending on the reagent or solvent to be used, and it is usually from 1 minute to 72 hours. The reaction temperature is preferably from 0 to 100 °C. The compound (13) may be a commercially available product, or may be produced according to a method known per se or according to the method thereof.

The starting compound used in the above compound (I) and/or the intermediate to be produced may form a salt as long as the reaction can be carried out, which is not particularly limited, and, for example, the use of the above-mentioned compound is similar to I) Salts formed by the like, etc.

As for the geometric isomer (E, Z form) of the compound (I), when the isomerization occurs by a general separation method (for example, extraction, recrystallization, distillation, chromatography, etc.), the ones can be separated and Purified and pure compounds can be made. Further, it is also possible to use the method described in Jikken Kagaku Kouza (Courses in Experimental Chemistry) 14 (The Chemical Society of Japan ed.), pages 251 to 253, 4th Edition Jikken Kagaku Kouza 19 (The Chemical Society of Japan) Ed.), methods described in pages 273 to 274 or according to methods thereof, using isomerized double bonds such as heating, acidic catalysts, transition metal complexes, metal catalysts, free radical catalysts, optical radiation or strong base catalysts And obtain a relatively pure isomer.

The compound (I) contains a mirror image isomer depending on the kind of the substituent, and each of the mirror image isomers and a mixture thereof are included in the present invention.

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

If necessary, the compound (I) can be subjected to deprotection, deuteration reaction, The alkylation reaction, the hydrogenation reaction, the oxidation reaction, the reduction reaction, the carbon chain extension reaction, and the substituent exchange reaction are synthesized singly or in combination of two or more of these reactions.

When the target product obtained from the above reaction is in a free form, it can be converted into a salt according to a conventional method, or when the desired target product is a salt, it can be converted into a free form or other salt according to a conventional method. Thus, the obtained compound (I) can also be isolated and purified from the reaction mixture according to a conventional method such as phase conversion, concentration, solvent extraction, distillation, crystallization, recrystallization, chromatography and the like.

When the compound (I) contains a geometric isomer, a non-image isomer, a configurational isomer or the like, if necessary, each can be isolated according to the above separation and purification methods. Further, when the compound (I) is a racemate, the d-form and the formula can be separated according to a conventional optical resolution method.

In the above respective reactions, when the compound has a functional group (for example, an amine group, a carboxyl group or a hydroxyl group), the reaction can be carried out after introducing a group such as a protecting group generally used for peptide chemistry. The target compound can be obtained by removing the protecting group after the reaction as needed.

Examples of the protecting group include a mercapto group, a C _1-6 alkyl-carbonyl group (e.g., an ethyl fluorenyl group, a propyl fluorenyl group, etc.), a phenylcarbonyl group, a C _1-6 alkoxy-carbonyl group (e.g., a methoxycarbonyl group). , ethoxycarbonyl, etc.), phenyloxycarbonyl, C _7-10 aralkyloxy-carbonyl (for example, benzyloxycarbonyl, etc.), trityl, phthalic acid, etc. Each is replaced as needed. Examples of the substituent include a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl-carbonyl group (e.g., an ethyl fluorenyl group, a propyl fluorenyl group, a pentyl group, etc.), a nitro group, and the like. The number of substituents is, for example, 1 to 3.

The protecting group removal method can be carried out according to a method known per se, for example, using an acid, a base, an ultraviolet ray, a hydrazine, a phenyl hydrazine, a sodium N-methyldithiocarbamate, a tetrabutyl fluorination. A method such as ammonium or palladium acetate, a reduction method, or the like.

Thus, the obtained compound (I), other reaction intermediates and starting compounds thereof can be isolated and purified from the reaction mixture according to a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, tube Column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), medium pressure preparative liquid chromatography (moderate pressure preparative LC), and the like.

The salt of the compound (I) can be produced by a method known per se. For example, when the compound (I) is a basic compound, it can be produced by adding an inorganic acid or an organic acid, or when the compound (I) is an acidic compound, by adding an organic base or an inorganic base.

When the compound (I) contains an optical isomer, each optical isomer and a mixture thereof are included in the scope of the present invention, and if necessary, the isomers may be optically resolved according to a method known per se or Manufacturing.

When the compound (I) contains a configurational isomer, a non-image isomer, a configurational isomer, etc., if necessary, each can be isolated according to the above separation and purification methods. Further, when the compound (I) is a racemate, the S-form and the R-form can be analyzed according to a conventional optical resolution method.

When the compound (I) contains a mirror image isomer, each isomer and a mixture thereof are included in the present invention.

The compound (I) may be a prodrug, and the prodrug of the compound (I) means that the compound is converted into the compound (I) by an enzyme, a gastric acid or the like in a physiological environment in vivo, and therefore, the enzyme is oxidized, reduced, hydrolyzed, etc. The compound is converted into the compound (I) and converted into the compound (I) by a compound such as hydrolysis by gastric acid or the like.

Examples of the drug for pre-excitation of the compound (I) include (1) a compound obtained by subjecting an amine group to acetylation, alkylation or phosphorylation in the compound (I) (for example, by using the compound (I) Amino group is eicosylated, propylamined, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl , tetrahydrofuranylation, pyrrolylmethylation, neopentyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, cyclopropylcarbonyl The obtained compound (etc.); (2) a compound obtained by subjecting a hydroxyl group of the compound (I) to acetylation, alkylation, phosphorylation or boration (for example, by giving the hydroxyl group of the compound (I) to B) a compound obtained by deuteration, palmitoylation, propylation, neopentylation, amber thiolation, methacrylylation, propylamine thiolation or dimethylaminocarbonylation; (3) a compound obtained by esterifying or amide-forming a carboxyl group of the compound (I), for example, by subjecting a carboxyl group of the compound (I) to ethyl esterification, benzene Esterification, carboxymethyl esterification, dimethylaminomethyl esterification, neopentyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, mercaptoesterification, (5-A) a compound obtained by a thiol-l-oxy-1,3-dioxol-4-yl)methyl esterification, a cyclohexyloxycarbonylethyl esterification or a methyl amidation or the like, etc.) . Any of these compounds can be produced from the compound (I) according to a method known per se.

The prodrug of the compound (I) can also be converted into the compound (I) under physiological conditions, as in "IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)", vol. 7, Design of Molecules, p. -198, Published by HIROKAWA SHOTEN (1990).

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

When the compound (I) has an isomer (for example, an optical isomer, a mirror image isomer, a positional isomer, a rotamer, etc.), the isomer and a mixture thereof are also contained in the compound (I). . For example, when the compound (I) has an optical isomer, an optical isomer resolved from the compound is also contained in the compound (I). The isomers can be obtained as a single product according to a synthetic method or a separation method known per se (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.).

Compound (I) may be crystalline, and has a single crystalline form and a crystalline form. The mixture is contained in the compound (I). This crystallization can be produced by a crystallization method known per se.

The compound (I) may be a hydrate, a non-hydrate, a solvate or an unsolvate.

The compound (I) can be isotopically labeled (for example, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, etc.) and the like.

Compound (I) may also comprise a hydrazine conversion form in which ¹ H is converted to ² H (D).

The compound (I) may be a pharmaceutically acceptable cocrystal or a salt thereof. The eutectic or salt thereof means a crystalline material composed of two or more special solids at room temperature, each having different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Wait). The eutectic and its salt can be produced according to a eutectic method known per se.

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

The compound of the present invention has low toxicity and can be used as a pharmaceutical composition in a mammal (e.g., human, mouse, rat, rabbit, dog) as it is or by mixing with a pharmaceutically acceptable carrier or the like. , cats, cows, horses, pigs, monkeys) are used as medicaments for the prevention or treatment of various diseases as described below. .

As the pharmaceutically acceptable carrier, various organic or inorganic carrier materials conventionally used as a formulation material can be used. These are incorporated into excipients, lubricants, binders and disintegrating agents for solid preparations, solvents, solubilizers, suspending agents, isotonic agents, buffers and soothing agents for liquid preparations, etc. And formulation additives (eg, preservatives, antioxidants, colorants, sweeteners, etc.) that can be added as needed.

Preferred examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, low substituted hydroxypropylcellulose, carboxymethyl Cellulose sodium, gum arabic, pullulan, light anhydrous citric acid, synthetic aluminum silicate and aluminum magnesium silicate.

Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal cerium oxide.

Preferred examples of the binder include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose. , dextrin, branched starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose, sodium carboxymethyl starch, light anhydrous citric acid, and low substitution. Hydroxypropyl cellulose.

Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

Preferred examples of the dissolving agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzyl ester, ethanol, ginsyl methane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and salicyl Sodium and sodium acetate.

Preferred examples of suspending agents include surfactants (for example, stearic triethanolamine, sodium lauryl sulfate, lauryl aminide, lecithin, benzalkonium chloride, benzethonium chloride ), glyceryl monostearate, etc.; hydrophilic polymer (for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose) , hydroxypropyl cellulose, etc.; polysorbate; and polyoxyethylene hydrogenated castor oil.

Preferred examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. .

Preferred examples of the buffer include a buffer such as a phosphate buffer, an acetate buffer, a carbonate buffer, a citrate buffer, and the like.

A preferred example of the soothing agent comprises benzyl alcohol.

Preferred examples of preservatives include parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

Preferred examples of the antioxidant include sulfite and ascorbate.

Preferred examples of the coloring agent include aqueous water-soluble edible tar pigments (for example, food coloring such as food coloring red 2 and 3, food coloring yellow 4 and 5, food coloring blue 1 and 2, etc.), insoluble in water Pigment (for example, the aluminum salt of the above-mentioned water-soluble edible tar pigment) and natural dyes (for example, beta carotene, chlorophyll, iron oxide red).

Preferred examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

Examples of the dosage form of the pharmaceutical composition include oral preparations (for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules, microcapsules), granules, powders, tablets , syrup, emulsion, suspension, film (eg, orally disintegrable film), and the like; and parenteral agents (eg, injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip injections) Liquid), external preparations (for example, skin preparations, ointments), suppositories (for example, rectal suppositories, vaginal suppositories), pills, nasal preparations, pulmonary preparations (inhalation), eye drops, and the like.

These may be administered safely orally or gastrointestinally (e.g., topically, rectally, intravenously).

Such preparations may be release control agents (e.g., sustained release microcapsules), for example, immediate release formulations, sustained release formulations, and the like.

The doctor can be manufactured according to a method conventionally used in the field of pharmaceutical formulations The drug composition is, for example, a method described in the Japanese Pharmacopoeia.

The content of the compound of the present invention varies depending on the dosage form, the dose of the compound of the present invention, and the like, and is, for example, about 0.1 to 100% by weight.

In the manufacture of oral preparations, coatings can be applied as needed to mask taste, intestinal properties or durability.

Examples of film coat substrates for use in film coats include a sugar-coated base, a water-soluble film coat base, a enteric film base, and a sustained release film base.

As a sugar coating base, sucrose is used. Further, one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, branched starch, carnauba wax, and the like may be used in combination.

Examples of the water-soluble film-coating matrix include a cellulose polymer (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, etc.); a synthetic polymer (for example) , polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer [Eudragit E (trade name)], polyvinylpyrrolidone, etc.; and polysaccharides (eg, branched starch, etc.) .

Examples of enteric film film-coating bases include cellulosic polymers (for example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate) Acetate, carboxymethylethylcellulose, cellulose acetate phthalate, etc.; acrylic acid polymer (for example, methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid Copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name), etc.), and naturally occurring substances (for example, shellac, etc.).

Examples of the sustained release film coat medium include a cellulose polymer (for example, ethyl cellulose or the like); and an acrylic polymer (for example, an aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], acrylic acid Ethyl-methyl methacrylate copolymer suspension [Eudragit NE (trade name)], etc.).

The above film base may be used after mixing two or more kinds in an appropriate ratio. For the film coat, for example, an opacifier such as titanium oxide, iron oxide red or the like can be used.

The compounds of the invention exhibit low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects. Therefore, it can be used as a prophylactic or therapeutic or diagnostic agent for various diseases in mammals (for example, human, cow, horse, dog, cat, monkey, mouse, rat).

The compound of the present invention has an excellent CH24H inhibitory action and can inhibit nerve cell death, increase in Aβ, inflammation of the brain, and the like.

Accordingly, the compounds of the present invention are useful for prevention, symptom improvement, inhibition The development of a disease course or a disease involving the promotion of CH24H, for example, the treatment of a neurodegenerative disease.

In the present specification, "neurodegenerative disease" means a disease associated with degeneration of nerve tissue.

Specific examples of neurodegenerative diseases include Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction , glaucoma, etc.

Further, the compound of the present invention is a disease for preventing, improving symptoms, inhibiting the progression of the disease, or promoting the function of CH24H, for example, treatment of epilepsy, schizophrenia, sputum, and the like.

The dose of the compound of the present invention varies depending on the subject to be administered, the route of administration, the target disease, the symptoms, and the like. For example, when an adult patient (body weight 60 kg) is orally administered, the dose is about 0.01 to 100 mg per kg body weight per dose, preferably about 0.05 to 30 mg per kg body weight per dose, more preferably per dose. It is about 0.1 to 10 mg per kilogram of body weight, and is desirably administered in an amount of 1 to 3 parts per day.

When the compound of the present invention is administered to each of the above diseases, it can be used in an appropriate combination with a drug or a therapeutic method generally used for the disease.

Examples of pharmaceuticals used in combination with the compounds of the present invention (hereinafter simply referred to as "concomitant drugs") include acetylcholinesterase inhibitors (for example, donepezil, rivastigmine, galantamine) (galanthamine), zanapezil (zanapezil, etc.), anti-dementia agents (for example, Memantine, an inhibitor of beta-protein production, secretion, accumulation, coagulation and/or deposition, beta-secretase inhibitor (eg, 6-(4-biphenyl)methoxy-2-[ 2-(N,N-Dimethylamino)ethyl]tetrahydronaphthalene, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetrahydro Naphthalene, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetrahydronaphthalene, 2-(N,N-dimethylamino)methyl- 6-(4'-Methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethyl Amino)ethyl]tetrahydronaphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetra Hydrogen naphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-( 2',4'-Dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-[4- (1,3-benzodioxan-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6- (3',4'-Dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, its optically active form Salt and its hydrate OM99-2 (WO01/00663)), γ-secretase inhibitor, β-amyloid protein coagulation inhibitor (for example, PTI-00703, ALZHEMED (NC-531), PPI-368 (JP-A-11-514333), PPI-558 (JP-A-2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), β-amyloid protein vaccine, β-amyloid protein degrading enzyme, etc. Brain function activators (eg, aniracetam, nicergoline), other therapeutic agents for Parkinson's disease [eg, dopamine receptor promoters (eg, L-DOPA) , bromocriptine, pergolide, talilexole, pramipexole, cabergoline, amantadine, monoamine oxygen Chemical enzyme (MAO) inhibitors (eg, deprenyl, selegiline, remacacetide, riluzole), anticholinergic agents (eg, trihexyphenidyl) (trihexyphenidyl), biperiden, COMT inhibitor (eg, entacapone), a therapeutic drug for amyotrophic lateral sclerosis (eg, riluzole) , neurotrophic factors), therapeutic agents for behavioral abnormalities due to progression of dementia, sputum, etc. (eg, sedatives, anxiolytics), apoptosis inhibitors (eg, CPI-1189, IDN-6556, CEP) -1347), a neuronal differentiation or regeneration promoter (for example, leteprinim, xaliproden (SR-57746-A), SB-216763, Y-128, VX-853, sheath Prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro -1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7- Pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7 -pentamethyl-2,3-dihydro-1-benzofuran-5-yl ]-6,7-Dihydro-5H-[1,3]dioxol [4,5-f]isoindoline optically active form, salt and hydrate thereof), antidepressant (eg, desipramine, amitriptyline, imipramine, tramadol), antiepileptic drugs (eg, lamotrigine), anxiolytic Drugs (eg, benzodiazepine), non-steroidal anti-inflammatory drugs (eg, meloxicam, tenoxicam, indomethacin, ibuprofen) (ibuprofen), celecoxib, rofecoxib, aspirin, indomethacin, disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (eg, TNF inhibitors, MAP kinase inhibitors), sterols (eg, dexamethasone, hexestrol, cortisone acetate) a) a therapeutic agent for urinary incontinence or frequent urination (eg, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), Phosphodiesterase inhibitors (eg, sildenafil (citrate)), dopamine receptor promoters (eg, apomorphine, etc.), antiarrhythmic drugs (eg, mexiletine) (mexiletine)), a sex hormone or a derivative thereof (for example, progesterone, estradiol, estradiol benzoate), a therapeutic agent for osteoporosis (for example, Alfa Alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate Disodium pamidronate, sodium alendronate hydrate (sodium alend) Ronate hydrate), disodium incadronate, parathyroid hormone (PTH), calcium receptor antagonist, therapeutic drug for insomnia (eg, benzodiazepine, non-benzodiazepine) (benzodiazepine) agent, melatonin agonist), a therapeutic drug for schizophrenia (for example, a typical antipsychotic agent such as haloperidol, etc.; atypical antipsychotics such as clozapine (clozapine) ), olanzapine, risperidone, aripiprazole, etc.; an agent or phosphodiester acting on a metabotropic glutamate receptor or an ion channel-bound glutamate receptor; Enzyme inhibitors) and the like.

Further, it is used in combination with a conventional transplantation method of neural stem cells or neural precursor cells prepared from embryonic stem cells or nerve tissues, or fetal nerve tissue, and in combination with an agent such as an immunosuppressive agent after transplantation.

Further, the compound of the present invention can be used in combination with the following concomitant drugs.

(1) Diabetes therapeutic agent

For example, insulin preparations (for example, animal insulin preparations extracted from the pancreas of cattle and pigs; human insulin preparations genetically synthesized using Escherichia coli, yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives ( For example, INS-1), an oral insulin preparation), an insulin sensitizer (for example, pioglitazone or a salt thereof (preferably a hydrochloride), rosiglitazone or a salt thereof (preferably) For maleate), Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Nag Naveglitazar, AMG-131, THR-0921), alpha glucosidase inhibitors (eg, voglibose, acarbose, miglitol, B) Emiglitate, biguanide (eg, metformin, buformin or a salt thereof (eg, hydrochloride, fumarate, succinate)), insulin secretagogue [sulfonylurea) (eg, tolbutamide, glibenclamide, glibenclamide) Japanese (gliclazide), chlorpropamide (chlorpropamide), tolazamide (tolazamide), acetohexamide, glyclopyramide, glimepipiride, glipizide, glybuzole, repaglinide ), nateglinide, mitiglinide or its calcium salt hydrate, glucose-dependent insulin secretagogue (for example, [(3S)-6-({2',6'-two Methyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl)acetic acid Or a salt thereof], a dipeptidyl peptidase IV inhibitor (for example, Alogliptin, Vildagliptin, Sitagliptin, Saxagliptin, T -6666, TS-021), β 3 agonist (eg, AJ-9677), GPR40 agonist, GLP-1 receptor agonist [eg, GLP-1, GLP-1MR reagent, NN-2211, AC-2993 (Exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH 2, CJC-1131], amyloid (amylin) stimulating effect Agent (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase) Agent, glucose-6-phosphatase inhibitor, glycosidic antagonist), SGLUT (sodium-glucose cotransporter) inhibitor (eg, T-1095), 11 beta-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498), adiponectin or its agonist, IKK inhibitor (eg, AS-2868), leptin resistance improving drug, somatostatin receptor agonist, glucokinase activation Agent (for example, RO-28-1675), glucose-dependent insulinotropic polypeptide (GIP), and the like.

(2) therapeutic agents for diabetic complications

For example, aldose reductase inhibitors may be mentioned (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minna) Minalrestat, fidarestat, CT-112), neurotrophic factor and its enhancer (eg, NGF, NT-3, BDNF, neurotrophic factors and pro-drugs described in WO 01/14372) (for example, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl] Oxazole)), a nerve regeneration enhancer (eg, Y-128), a PKC inhibitor (eg, ruboxistaurin mesylate), an AGE inhibitor (eg, ALT946, pimadine) ), pyridoxanthine, N-benzhydrylthiazole bromide (ALT766), ALT-711, EXO-226, pyridoramine (pyridoxamine), pyridoxamine (pyridoxamine), active oxygen scavenging Agents (eg, thioctic acid), cerebral vasodilators (eg, tiapuride, mexiletine), somatostatin receptor promoters (eg, BIM23190), apoptosis Signal regulated kinase-1 (ASK-1) inhibitors and the like.

(3) Hyperlipidemia agent

For example, statin compounds (eg, pravastatin, simvastatin, lovastatin, atorvastin, fluvastatin, ru Susuvastatin, pitavastatin, or a salt thereof (eg, sodium salt, calcium salt), a squalene synthetase inhibitor (eg, lapastat acetate or a salt thereof), Bate Fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, celebrate) (clinofibrate)), ACAT inhibitors (eg, Avasimbe, Eflucimibe), anion exchange resins (eg, cystestramine), probucol, Nicotinic acid drugs (for example, nicomol, niceritrol), ethyl eicosapentaenoate, phytosterols (eg, soy sterol, γ-oryzanol) .

(4) Antihypertensive agents

For example, angiotensin-converting enzyme inhibitors (eg, captopril, enalpril, deLapril), angiotensin II antagonists (eg, Candi) Saturninan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tazoza Tassartan, 1-[[2'-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazepine-3-yl)biphenyl-4- Methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid, Azilsartan, Azilsartan medoxomil, calcium antagonists (for example, Manidipine, nifedipine, amlodipine, efenidipine, nicardipine, potassium channel opener (eg, lecromakalim) ), L-27152, AL0671, NIP-121), clonidine, and the like.

(5) Anti-obesity agents

For example, centrally acting anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine) (phentermine), sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex MCH receptor antagonists (such as SB-568849; compounds described in SNAP-7941, WO01/82925 and WO01/87834), neuropeptide Y antagonists (eg, CP-422935), cannabinoid receptors Antagonists (eg, SR-141716, SR-147778); ghrelin receptor antagonists; 11 beta-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), pancreatic lipase inhibitors (eg, For example, orkistat, cisteristat, beta 3 agonists (eg, AJ-9677, AZ40140), anorectic peptides (eg, leptin, CNTF (ciliform) Neurotrophic factor)), cholecystokinin agonist (eg, lintitript, FPL-15849), anorectic agent (eg, P-57), and the like.

(6) diuretics

For example, xanthine derivatives (eg, sodium salicyl theobromine, calcium salicyl theobromine), thiazide preparations (eg, ethiazide, cyclopentazine, trichloromethylthiazide, Hydrochlorothiazide, hydrofluorothiazide, benzyl hydrochlorothiazide, penflutizide, polythiazide, methyl chlorothiazide, anti-aldosterone preparations (eg, spironolactone, ampicillin) Triamterene)), carbonic anhydrase inhibitors (eg, acetazolamide), chlorpheniramine (eg, chlortalidone, mefruside, indapama) Indapamide)), azosemide, isosorbide, ethacrynic acid, pyrrhotani (piretanide), bumetanide, furosemide, and the like.

(7) chemotherapeutic agents

For example, alkylating agents (eg, cyclophosphamide, ifosfamide), metabolic antagonists (eg, methotrexate, 5-fluorouracil or derivatives thereof), antitumor antibiotics (eg, mitomycin) , adriamycin, plant-derived anti-tumor agents (eg, vincristine, vindesine, paclitaxel), cisplatin, carboplatin, itop Etoposide and so on. Among them, preferred are 5-fluorouracil derivatives of Furtulon, NeoFurtulon, and the like.

(8) Immunopharmaceutical

For example, components of microorganisms or bacteria (for example, muramyl dipeptide derivative, Picibanil), polysaccharides having immunopotentiating activity (for example, lentinan, schizophyllum) Polysaccharides (schizophyllan), cytokines (krestin), cytokines obtained by genetic engineering techniques (eg, interferon, interleukin (IL)), colony stimulating factors (eg, granule colony-stimulating factor, erythropoietin) And the like, preferred interleukins such as IL-1, IL-2, IL-12 and the like.

(9) Antithrombotic agent

For example, heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drugs (eg, argatroban), thrombosis Solvent (eg, urokinase, thiolatine Enzyme (tisokinase), alteplase, nateplase, monteplase, pampiteplase, platelet aggregation inhibitor (eg, ticlopidine salt) Titlopidine hydrochloride, cilostazol, ethyl eicosapentaenoate, beraprost sodium, sarpogrelate hydrochloride, and the like.

(10) cachexia improvement drugs

For example, cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, Vol. 49, pp. 5935-5939, page 1989], progesterone derivatives (eg, mestoacetin acetate) (megestrol acetate)) [Journal of Clinical Oncology, Vol. 12, pp. 213-225, 1994), glycocalyx (eg, dexamethasone, etc.), metoclopramide, tetrahydrocannabinol Agents (all publications as described above), fat metabolism improvers (eg, eicosapentaenoic acid, etc.) [British Cancer Journal, vol. 68, pp. 314-318, 1993], growth hormone, IGF-1, or For cachexia-inducing factors, such as TNF-α, LIF, IL-6, oncostatin M antibody, and the like.

Two or more of the above-mentioned concomitant drugs may be used in combination at an appropriate ratio.

The compound of the present invention can also be applied to each of the above diseases in combination with a biological (e.g., antibody, vaccine preparation, etc.), or as a combination therapy, in combination with a gene therapy method, and the like.

Examples of antibodies and vaccine preparations include angiotensin II vaccine preparations, CETP vaccine preparations, CEPT antibodies, TNFα antibodies and other cytokine antibodies, amyloid beta vaccine preparations, type 1 diabetes vaccines (eg, manufactured by Peptor Co., Ltd.) DIAPEP-277), anti-HIV antibody, HIV vaccine preparation, antibody or vaccine preparation of cytokines, renin-angiotensinase and its products, antibodies or vaccine preparations involving enzymes or proteins of lipid metabolism, involving blood An antibody or vaccine for an enzyme or protein of a coagulation or fibrinolytic system, an antibody or vaccine preparation for an enzyme or protein involved in glucose metabolism or insulin resistance, and the like.

In addition, it may be used in combination with biological agents involving growth factors such as growth hormone, IGF, and the like.

Examples of gene therapy methods include treatments using cytokines, renin-angiotensinase and its products, G proteins, G-protein-binding receptors and phosphorylating enzymes thereof, and treatments using DNA decoys (such as NFkB decoys) , treatment with antisense, treatment with genes involved in lipid metabolism enzymes or proteins (eg, genes related to cholesterol, triglyceride or HDL-cholesterol or blood phospholipid metabolism, excretion or absorption) The method, the method for treating a gene related to an angiogenesis involving a peripheral blood vessel or the like, and a gene for targeting an enzyme or protein (for example, a growth factor such as HGF, VEGF, etc.), and a gene for a protein involved in glucose metabolism or insulin resistance Therapeutic methods, such as the inverse of cytokines of tumor necrosis factor (TNF) Righteousness and so on.

In addition, a combination of the following may be used: various organ regeneration methods such as cardiac regeneration, kidney regeneration, pancreas regeneration, angiogenesis, etc., or cell transplantation using bone marrow cells (bone marrow mononuclear cells, myeloid stem cells), or tissue use Artificial organs of engineering (for example, artificial blood vessels and heart muscle cell sheets).

The administration time of the compound of the present invention and the administration time of the concomitant drug are not limited, and the same can be administered to the individual simultaneously or in a staggered manner. Further, the compound of the present invention and the concomitant drug may be administered in two formulations containing the respective active ingredients or in a single preparation containing the two active ingredients.

The dose of the combined drug can be appropriately determined based on the application of the clinical condition. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined depending on the administration target, the administration route, the target disease, the symptom, the combination, and the like. When the administration target is a human, for example, 0.01 to 100 parts by weight of a concomitant drug can be used with respect to 1 part by weight of the compound of the present invention.

Example

The invention is explained in detail below with reference to the examples, the experimental examples and the examples of the examples, which are not limited thereto, and the invention may be varied within the scope of the invention.

In the following examples, "room temperature" generally means from about 10 ° C to about 35 ° C. Unless otherwise stated, the ratio of the indicated mixed solvent is The product mix ratio. Unless otherwise stated, % means % by weight.

In the gum column chromatography, NH means the use of an aminopropyl decane-bonded silicone. In HPLC (High Performance Liquid Chromatography), C18 means the use of an 18-carbon bonded silicone. Unless otherwise stated, the ratio of the solvent to be extracted is the volume mixing ratio.

The abbreviations used in this specification mean the following.

THF: tetrahydrofuran

DME: 1,2-dimethoxyethane

DMF: N,N-dimethylformamide

DMA: N,N-dimethylacetamide

DMSO: dimethyl hydrazine

ESI: electrospray method

APCI: gas phase chemical dissociation

[M+H] ⁺ : molecular ion peak

M: molar concentration

IPE: diisopropyl ether

WSC: 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide

HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate

HOBt: 1-hydroxybenzotriazole

HPLC: high performance liquid chromatography

DIPEA: N,N-diisopropylethylamine

NMP: N-methyl-2-pyrrolidone

DPPF: 1,1'-bis(diphenylphosphino)ferrocene

Pd ₂ (dba) ₃ : ginseng (dibenzylideneacetone) dipalladium (0)

Xantpho class: 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxime

¹ H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier-transform type NMR. The analysis is performed using ACD/SpecManager (trade name) or the like. A very slight proton peak (eg, hydroxyl, amine, etc.) is not recorded.

MS (mass spectrometry) was measured by LC/MS (liquid phase mass spectrometry). For example, a dissociation method, an ESI (electrospray dissociation) method, or an APCI (atmospheric pressure chemical dissociation) method is used. The data indicates the measured value. In general, a molecular ion peak is observed, and in the example having a third butoxycarbonyl (-Boc) compound, a peak as a fragment ion after the third butoxycarbonyl group or the third butyl group is eliminated can be observed. In the example having a hydroxyl group (-OH) compound, a peak as a fragment ion after H ₂ O elimination can be observed. In the case of salts, a free-form molecular ion peak or a fragment ion peak is usually observed.

The elemental analysis value (Anal.) shows the calculated value (Calcd) and the measured value (Found).

Example 1 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide A) 4-(4-Chloro-1H-pyrazol-1-yl)-3-fluoropyridine

a mixture of p-toluenesulfonic acid monohydrate (0.58 g), 4-chloro-3-fluoropyridine (2.0 g), 4-chloro-1H-pyrazole (1.7 g) and 2-propanol (10 mL) in a microwave Under radiation Stir at 130 ° C for 2 hours. The mixture was cooled to room temperature, poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+), measured value: 198.2, 200.0.

B) 4-(dimethylaminocarbamimido)piperidine-1-carboxylic acid benzyl ester

Add HATU (2.1 g), triethylamine (0.83 mL) to a mixture of 1-((benzyloxy)carbonyl)piperidine-4-carboxylic acid (1.2 g) and DMF (12 mL). And dimethylamine THF solution (2M, 2.73 mL). The mixture was stirred at room temperature for 4 hours, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue (NH, EtOAc / hexane) MS (API+): [M+H] ⁺ 291.2.

C) N,N-dimethylpiperidin-4-carboxamide

Benzyl 4-(dimethylaminocarbamimido)piperidine-1-carboxylate (960 mg) was dissolved in ethanol (15 mL) and ethyl acetate (15 mL), and then 10% palladium bromide (96 mg) The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (530 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.31-1.57 (4H, m), 2.45 (1H, d, J = 3.0 Hz), 2.63 (1H, tt, J = 11.1, 4.0 Hz), 2.79 (3H) , s), 2.91 (2H, dt, J = 12.1, 3.0 Hz), 2.99 (3H, s), 3.29 (2H, brs).

D) 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

4-(4-Chloro-1H-pyrazol-1-yl)-3-fluoropyridine (98 mg), N,N-dimethylpiperidine-4-carboxamide (160 mg), potassium carbonate (140 mg) A mixture of DMA (0.50 mL) was stirred with microwave irradiation at 200 ° C for 10 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.57-1.74 (4H, m), 2.67-2.79 (3H, m), 2.82 (3H, s), 2.86-2.96 (2H, m), 3.02 (3H, s), 7.52 (1H, d, J = 5.3 Hz), 7.96 (1H, s), 8.36 (1H, d, J = 5.3 Hz), 8.48 (1H, s), 8.77 (1H, s).

Example 13 (3-exo)-N,N-dimethyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-8-azabicyclo[3.2.1 Octane-3-carboxamide A) 3-(dimethylaminocarbamimido)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

8-(Tertibutoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (400 mg), dimethylamine hydrochloride (260 mg), HATU (770 mg), DIPEA A mixture of (0.96 mL) and DMF (5.0 mL) was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate / water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAcjjjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.45-1.56 (11H, m), 1.60-1.70 (2H, m), 1.95-2.07 (4H, m), 2.93 (3H, s), 3.00-3.13 (4H, m), 4.20-4.35 (2H, m).

B) N,N-Dimethyl-8-azabicyclo[3.2.1]octane-3-carboxamide hydrochloride

Add 4M to a mixture of 3-(dimethylaminocarbazyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (440 mg) and ethyl acetate (4.0 mL) Hydrochloric acid / ethyl acetate (10 mL).

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.59-1.71 (2H, m), 1.86-2.06 (6H, m), 2.81 (3H, s), 2.99-3.15 (4H, m), 3.86-4.00 ( 2H, m), 8.68 (1H, brs), 9.39 (1H, brs).

C) 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine

a mixture of p-toluenesulfonic acid monohydrate (0.83 g), 4-chloro-3-fluoropyridine (2.9 g), 4-methyl-1H-pyrazole (1.9 mL) and 2-propanol (14 mL) The microwave irradiation was stirred at 130 ° C for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.12 (3H, s), 7.76 (1H, s), 7.93 (1H, dd, J = 7.0,5.5Hz), 8.18 (1H, dd, J = 1.9, 0.8Hz), 8.49 (1H, d, J = 5.3Hz), 8.74 (1H, d, J = 4.2Hz).

D) (3-exo)-N,N-dimethyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-8-azabicyclo[3.2 .1] Octane-3-carboxamide

N,N-Dimethyl-8-azabicyclo[3.2.1]octane-3-carboxamide hydrochloride (170 mg), 3-fluoro-4-(4-methyl-1H-pyrazole A mixture of -1-yl)pyridine (260 mg), potassium carbonate (320 mg) and NMP (2.0 mL) was stirred with microwaves at 200 ° C for 16 hours. The mixture was diluted with ethyl acetate / water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHHH

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.45-1.55 (2H, m), 1.63-1.72 (2H, m), 1.98-2.13 (4H, m), 2.18 (3H, s), 2.90-3.03 (4H, m ), 3.05 (3H, s), 3.59-3.67 (2H, m), 7.36 (1H, d, J = 5.3 Hz), 7.52 (1H, s), 8.03-8.07 (1H, m), 8.20 (1H, d, J = 4.9 Hz), 8.32 (1H, s).

Example 21 1-(4-(1,3-Benzothiazol-2-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide A) 2-(3-Fluoropyridin-4-yl)benzo[d]thiazole

Add 2,4,6-tripropyl-1,3,5,2,4,6-trioxabenzene to a mixture of 3-fluoroisonicotinic acid (1.0 g) and DIPEA (1.9 mL) at room temperature Triphosphonium-2,4,6-trioxide (1.9 mL, 50% ethyl acetate solution) and 2-aminothiophenol (0.76 mL), and the mixture was stirred at 70 ° C overnight. The mixture was diluted with water and ethyl acetate and heated to 60 °C. The insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+): [M+H] ⁺ 231.1.

B) 1-(4-(1,3-Benzothiazol-2-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

2-(3-Fluoropyridin-4-yl)benzo[d]thiazole (100 mg), N,N-dimethylpiperidine-4-carboxamide (81 mg), potassium carbonate (90 mg) at 150 °C A mixture of NMP (0.50 mL) was stirred overnight. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.86 (2H, d, J = 13.0 Hz), 2.24 - 2.37 (2H, m), 2.72 (1H, tt, J = 11.6, 3.6 Hz), 2.93-3.04 (5H , m), 3.12 (3H, s), 3.29 (2H, d, J = 11.7 Hz), 7.41-7.48 (1H, m), 7.52 (1H, td, J = 7.6, 1.2 Hz), 8.00 (1H, d, J = 7.8 Hz), 8.11 (1H, d, J = 8.1 Hz), 8.25 (1H, d, J = 5.1 Hz), 8.52 (1H, d, J = 5.1 Hz), 8.66 (1H, s) .

Example 33 (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile A) Ethyl 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

4-(4-Chloro-1H-pyrazol-1-yl)-3-fluoropyridine (3.4 g), piperidine-4-carboxylic acid ethyl ester (13 mL), potassium carbonate (7.1 g) at 180 ° C A mixture of NMP (15 mL) was stirred for 4 hours. Water was added to the mixture at 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.16-1.23 (3H, m), 1.56-1.74 (2H, m), 1.80-1.93 (2H, m), 2.37-2.46 (1H, m), 2.66- 2.79 (2H, m), 2.89 (2H, dt, J = 12.1, 3.2 Hz), 4.09 (2H, q, J = 7.2 Hz), 7.52 (1H, d, J = 4.9 Hz), 7.96 (1H, s ), 8.36 (1H, d, J = 4.9 Hz), 8.48 (1H, s), 8.77 (1H, s).

B) 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate (5.3 g) was dissolved in THF (55 mL) To the mixture was added 2M aqueous sodium hydroxide (12 mL), and the mixture was stirred at room temperature overnight. The mixture was neutralized with 1 M hydrochloric acid (24 mL), and the precipitated solid was collected by filtration. The title compound (4.0 g) was obtained.

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.55-1.71 (2H, m), 1.84 (2H, dd, J = 13.3,3.0Hz), 2.25-2.39 (1H, m), 2.64-2.76 (2H, m), 2.89 (2H, dt, J = 12.0, 3.3 Hz), 7.52 (1H, d, J = 5.3 Hz), 7.96 (1H, s), 8.36 (1H, d, J = 5.3 Hz), 8.48 ( 1H, s), 8.77 (1H, s), 12.27 (1H, brs).

C) (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-yl Nitrile

Add HATU to a mixture of 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (300 mg) and DMF (6.0 mL). (480 mg), triethylamine (0.30 mL) and (R)-pyrrolidine-2-carbonitrile hydrochloride (160 mg), and the mixture was stirred for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.60-1.84 (4H, m), 1.95-2.31 (4H, m), 2.66-3.04 (5H, m), 3.36-3.59 (1H, m), 3.60- 3.75 (1H, m), 4.72 (1H, dd, J = 7.6, 3.8 Hz), 7.52 (1H, d, J = 4.9 Hz), 7.97 (1H, s), 8.36 (1H, d, J = 4.9 Hz) ), 8.49 (1H, s), 8.78 (1H, s).

Example 43 1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-methyl Guanamine A) 4-(4-Bromo-1H-pyrazol-1-yl)-3-fluoropyridine

a mixture of p-toluenesulfonic acid monohydrate (0.30 g), 4-chloro-3-fluoropyridine (1.0 g), 4-bromo-1H-pyrazole (1.3 g) and 2-propanol (5.0 mL) The microwave irradiation was stirred at 130 ° C for 2 hours. The mixture was allowed to cool to room temperature, poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAcjjjjj elut elut

MS (API+), measured value: 242.0, 244.0.

B) 1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

4-(4-Bromo-1H-pyrazol-1-yl)-3-fluoropyridine (700 mg), N,N-dimethylpiperidine-4-carboxamide (680 mg), potassium carbonate (800 mg) A mixture of NMP (2.5 mL) was heated at 180 °C for 5 hours. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.49-1.78 (4H, m), 2.64-2.84 (6H, m), 2.86-2.96 (2H, m), 3.02 (3H, s), 7.52 (1H, d, J = 4.9 Hz), 7.96 (1H, s), 8.36 (1H, d, J = 5.3 Hz), 8.48 (1H, s), 8.77 (1H, d, J = 0.8 Hz).

Example 54 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-(tetrahydro-2H-piperidin-4-yl)piperidine-4 -Procarbamide

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.50 g), N-methyltetrahydro-2H-pyran- A mixture of 4-amine (0.16 g), HATU (0.81 g), triethylamine (0.91 mL) and DMF (8.2 mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

¹ H NMR (300MHz, CDCl ₃ ) δ 1.45-1.65 (2H, m), 1.65-2.11 (6H, m), 2.61 (1H, brs), 2.71-2.97 (5H, m), 3.13 (2H, d, J=11.7Hz), 3.37-3.59(2H,m),3.94-4.16(2H,m),4.66-4.84(1H,m),7.59(1H,s),7.66(1H,s),8.40(1H , s), 8.46 (1H, s), 8.59 (1H, s).

Example 58 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-cyclopropyl-N-methylpiperidine-4-carboxamide

Add HATU (0.81) to a mixture of 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.5 g) and DMF (8.2 mL) g), triethylamine (0.91 mL) and N-methylcyclopropylamine (0.14 g), and the mixture was stirred at room temperature 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAcjHHHHHH

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 0.71-0.99 (4H, m), 1.71-1.85 (2H, m), 1.96 (2H, dd, J = 12.3,2.8Hz), 2.64-2.85 (3H, m) , 2.94 (3H, s), 3.06-3.22 (3H, m), 7.60 (1H, d, J = 4.9 Hz), 7.66 (1H, s), 8.37 (1H, s), 8.46 (1H, s), 8.62 (1H, s).

Example 59 1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide (80 mg), cyanoboronic acid ( 36 mg), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (17 mg), cesium carbonate (210 mg), DME (1.5 mg) and water (0.30) The mixture of mg) was stirred by microwave irradiation at 100 ° C for 30 minutes. Dichloro 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (17 mg) and cyclopropaneboronic acid (36 mg) were added thereto, and the mixture was irradiated with microwaves. Stir at 100 ° C for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was poured and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc In the income section A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate,

¹ H NMR (300MHz, CDCl ₃ ) δ 0.56-0.63 (2H, m), 0.88-0.96 (2H, m), 1.73-1.83 (3H, m), 1.86-2.02 (2H, m), 2.56-2.67 ( 1H, m), 2.73 (2H, td, J = 11.9, 2.3 Hz), 2.98 (3H, s), 3.08 (3H, s), 3.09-3.17 (2H, m), 7.49 (1H, s), 7.60 (1H, d, J = 5.3 Hz), 8.34 (1H, d, J = 5.3 Hz), 8.36 (1H, s), 8.40 (1H, s).

Example 68 1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (1.0 g), tetrahydro-2H-pyran- at room temperature A mixture of 4-amine (0.36 mL), HATU (1.7 g), triethylamine (1.9 mL) and DMF (12 mL) was stirred for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.35-1.54 (2H, m), 1.78-1.98 (6H, m), 2.06-2.21 (4H, m), 2.70 (2H, dt, J = 11.7,7.2Hz) , 3.12 (2H, d, J = 12.1 Hz), 3.48 (2H, td, J = 11.7, 2.3 Hz), 3.88-4.09 (3H, m), 5.37 (1H, d, J = 7.6 Hz), 7.54 ( 1H, s), 7.60 (1H, d, J = 5.3 Hz), 8.30-8.36 (2H, m), 8.39 (1H, s).

Example 70 (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile A) Ethyl 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

3-Fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (2.5 g), piperidine-4-carboxylic acid ethyl ester (4.3 mL), potassium carbonate (5.8 g) and NMP A mixture of (12 mL) was stirred at 180 ° C for 7 hours. Ethyl piperidine-4-carboxylate (2.0 mL) was added to the mixture at room temperature, and the mixture was stirred at 180 ° C for 2 hr and then at room temperature overnight. Water was added to the mixture at 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+): [M+H] ⁺ 315.2.

B) 1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate (1.2 g), THF (15 mL) A 2 M aqueous sodium hydroxide solution (3.0 mL) was added and the mixture was stirred at room temperature overnight. The mixture was cooled to 0 ° C and neutralized with 1M hydrochloric acid (6.0 mL). The precipitated solid was collected by suction and washed with water to yield the title compound (0.84 g).

MS (API+): [M+H] ⁺ 287.2.

C) (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2- Nitrile

In a solution of 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.25 g) in DMF (6.0 mL) HATU (0.43 g), triethylamine (0.27 mL) and (R)-pyrrolidine-2-carbonitrile hydrochloride (0.14 g) were added, and the mixture was stirred for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.64-1.83 (4H, m), 1.97-2.07 (2H, m), 2.10-2.21 (5H, m), 2.54-2.61 (1H, m), 2.69- 2.81 (2H, m), 2.89-3.04 (2H, m), 3.49-3.59 (1H, m), 3.63-3.73 (1H, m), 4.72 (1H, dd, J = 7.6, 3.8 Hz), 7.54 ( 1H, d, J = 5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J = 5.3 Hz), 8.42 (1H, s), 8.44 (1H, s).

Example 70 (other manufacturing methods) (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile A) Ethyl 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

3-Fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (0.80 g), piperidine-4-carboxylic acid ethyl ester (1.5 mL) and NMP (4.5 mL) The mixture was stirred for 8.5 hours. The mixture was purified by EtOAc EtOAc EtOAc (EtOAc)

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.19 (3H, t, J = 7.2Hz), 1.60-1.76 (2H, m), 1.81-1.93 (2H, m), 2.12 (3H, s), 2.37 -2.48(1H,m), 2.65-2.77(2H,m),2.88-2.99(2H,m),4.09(2H,q,J=7.2Hz),7.53(1H,d,J=4.9Hz), 7.63 (1H, s), 8.31 (1H, d, J = 5.3 Hz), 8.41 (1H, s), 8.42 (1H, s).

B) 1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate (2.8 g), THF (30 mL) A 2 M aqueous sodium hydroxide solution (7.0 mL) was added and the mixture was stirred at room temperature overnight. The mixture was neutralized with 1 M hydrochloric acid (14 mL) at 0 °C. The obtained solid was collected by filtration and washed with water toiel

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.54-1.75 (2H, m), 1.78-1.92 (2H, m), 2.12 (3H, s), 2.25-2.41 (1H, m), 2.63-2.75 ( 2H,m),2.86-2.98(2H,m),7.53(1H,d,J=4.9Hz), 7.63(1H,s),8.30(1H,d,J=5.3Hz),8.39-8.45(2H , m), 12.33 (1H, brs).

C) (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2- Nitrile (crude crystal)

Add DIPEA to a suspension of 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (80 g) and acetonitrile (0.32 L) 0.21L), (R)-Amidoxime ((R)-prolinamide) (40g) and 2,4,6-Tripropyl-1,3,5,2,4,6-trioxaphosphonium Heterocyclohexane-2,4,6-trioxide (1.7 M in ethyl acetate, 0.28 L) was at 0 °C. The mixture was stirred at room temperature for 1 hour, and the mixture was added. Add 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphonane-2,4,6-trioxide (1.7 M ethyl acetate solution, 0.35 L), and the mixture was stirred at 70 ° C overnight. A saturated aqueous solution of sodium hydrogencarbonate (1600 mL) was added to the mixture, and the mixture was extracted with a solvent mixture of ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the mixture was stirred at room temperature overnight. The solid was collected by filtration and washed with diisopropyl ether to afford the title compound (93 g).

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.57-1.82 (4H, m), 1.89-2.30 (7H, m), 2.53-2.83 (3H, m), 2.86-3.06 (2H, m), 3.41- 3.58 (1H, m), 3.62-3.75 (1H, m), 4.72 (1H, dd, J = 7.4, 4.0 Hz), 7.53 (1H, d, J = 5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J = 5.3 Hz), 8.41 (1H, s), 8.43 (1H, s).

D) (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2- Nitrile

(2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine- at 70 °C The crystal of 2-carbonitrile (103 g) was dissolved in ethanol (620 mL), and heptane (620 mL) was added dropwise at the same temperature, and the mixture was stirred for 1 hour. Heptane (820 mL) was again added thereto over 1 hour, and the mixture was stirred at room temperature overnight. The crystals were collected by EtOAc (EtOAc) eluting

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.59-1.83 (4H, m), 1.89-2.29 (7H, m), 2.53-2.82 (3H, m), 2.88-3.07 (2H, m), 3.43- 3.58 (1H, m), 3.66-3.72 (1H, m), 4.72 (1H, dd, J = 7.6, 3.8 Hz), 7.53 (1H, d, J = 4.9 Hz), 7.63 (1H, s), 8.31 (1H, d, J = 5.3 Hz), 8.41 (1H, s), 8.43 (1H, s).

Mp: 178 ° C

Example 79 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl)piperidine -4-carboxamide A) 3-(4-((Benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-chloropyridine

4-((Benzyloxy)methyl)-3,3-difluoropiperidine (560 mg), 3-bromo-4-chloropyridine (490 mg), palladium acetate (26 mg), 4,5-double A mixture of diphenylphosphine-9,9-dimethyloxaxane (140 mg), sodium butoxide (340 mg) and toluene (12 mL) was stirred under microwave irradiation at 120 ° C for 3 hours. The mixture was filtered through a pad of EtOAc (EtOAc) and concentrated. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

¹ H NMR (300MHz, CDCl ₃ ) δ 1.74-1.92 (1H, m), 2.13 - 2.37 (2H, m), 2.83 - 2.94 (1H, m), 2.98-3.15 (1H, m), 3.44 - 3.56 ( 2H,m),3.59-3.71(1H,m),3.94(1H,dd,J=9.3,4.0Hz),4.53(1H,d,J=12.0Hz),4.59(1H,d,J=12.0Hz ), 7.27-7.40 (6H, m), 8.21 (1H, d, J = 4.9 Hz), 8.29 (1H, s).

B) 3-(4-((Benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-(4-chloro- 1H-pyrazol-1-yl)pyridine

3-(4-((Benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-chloropyridine (1.9 g), 4-chloro-1H-pyrazole ( A mixture of 0.72 g), p-toluenesulfonic acid monohydrate (0.21 g) and 2-propanol (12 mL) was stirred under microwave irradiation at 150 ° C for 6 hours. The mixture was diluted with ethyl acetate / aq. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The residue (NH, EtOAc / hexane)

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.59-1.74 (1H, m), 2.05-2.33 (2H, m), 2.65-2.79 (1H, m), 2.94-3.16 (2H, m), 3.27-3.40 ( 1H, m), 3.52 (1H, t, J = 8.9 Hz), 3.92 (1H, dd, J = 9.3, 4.0 Hz), 4.53 (1H, d, J = 12.0 Hz), 4.57 (1H, d, J =12.0Hz), 7.27-7.40(5H,m), 7.63(1H,d,J=5.3Hz), 7.67(1H,s),8.42(1H,s),8.44(1H,d,J=4.9Hz ), 8.52 (1H, s).

C) (1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)methanol

3-(4-((Benzyloxy)methyl)-3,3-difluoropiperidin-1-yl)-4-(4-chloro-1H-pyrazole-1-) under ice cooling To a mixture of pyridine (1.5 g) and acetonitrile (30 mL) was added trimethylsulfonium iodide (5.0 mL), and the mixture was stirred at room temperature for 20 hr. Water was added to the mixture under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Pyridine (15 mL), an aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and Dry over sodium sulfate and distill off the solvent under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.57-1.78 (2H, m), 1.90-2.21 (2H, m), 2.70-2.83 (1H, m), 2.95-3.17 (2H, m), 3.29-3.42 ( 1H, m), 3.70-3.81 (1H, m), 4.03-4.12 (1H, m), 7.64 (1H, d, J = 5.3 Hz), 7.68 (1H, s), 8.43 (1H, s), 8.46 (1H, d, J = 5.3 Hz), 8.51 (1H, s).

D) (1r, 3s, 5R, 7S)-1-methyl-2-oxa-2-aza-adamantane-2-indole tetrafluoroborate

A 42% aqueous solution of tetrafluoroboric acid (1.9 mL) was added dropwise to a mixture of 1-methyl-2-aza-adamantane N-oxyl (1.5 g) and water (5.0 mL) over 30 min. After confirming that the reaction solution became golden brown, an aqueous sodium hypochlorite solution (6.1 mL) was added over 1 hour under ice cooling, and the mixture was additionally stirred at the same temperature for 1 hour. The precipitate was collected by filtration, washed with EtOAc EtOAc EtOAc (EtOAc) 850mg).

Calculated value of the elemental analysis value (Calcd) of C ₁₀ H ₁₆ BF ₄ NO: C, 47.46; H, 6.37; N, 5.49. Found: C, 47.47; H, 6.40; N, 5.50.

E) 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidin-4-carboxylate acid

(1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidin-4-yl)methanol (0.91 g) and acetonitrile (20 mL) Sodium chlorite (1.3 g) and (1r, 3s, 5R, 7S)-1-methyl-2-oxa-2-aza are added sequentially to a mixture of pH 6.8 phosphate buffer solution (10 mL). Adamantane-2-indole tetrafluoroborate (42 mg). The mixture was stirred at room temperature for 1.5 hours, 2-methylbut-2-ene (6.0 mL) was added, and the mixture was stirred for additional 15 min. Most of the solvent was evaporated, water was added, and the mixture was stirred for 30 minutes under ice cooling. The obtained precipitate was collected by filtration, washed with water and diethyl ether, and dried to give the title compound (0.85 g).

^{1 H NMR (400MHz, DMSO-} d 6) δ 1.82-2.00 (2H, m), 2.79-2.94 (2H, m), 3.00-3.13 (1H, m), 3.19-3.34 (2H, m), 7.58 ( 1H, d, J = 5.1 Hz), 7.99 (1H, d, J = 0.5 Hz), 8.43 (1H, d, J = 5.4 Hz), 8.57 (1H, s), 8.63 (1H, d, J = 0.5) Hz), 12.90 (1H, brs).

F) 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoro-N-(tetrahydro-2H-pyran-4-yl) Piperidine-4-carboxamide

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-3,3-difluoropiperidin-4-carboxylic acid (30 mg), tetrahydropyran-4 A mixture of the base amine (12 mg), HATU (43 mg), DIPEA (20 μL) and DMF (1.0 mL) was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate / water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.43-1.59 (2H, m), 1.87-2.01 (2H, m), 2.05-2.15 (2H, m), 2.64-2.83 (2H, m), 3.02-3.25 ( 2H, m), 3.41-3.56 (3H, m), 3.90-4.11 (3H, m), 5.80 (1H, d, J = 5.7 Hz), 7.63 (1H, d, J = 5.3 Hz), 7.68 (1H , s), 8.43-8.50 (3H, m).

Example 82 2-methyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]indol-1-one A) 4-(cyanomethyl)piperidine-1,4-dicarboxylic acid 4-ethyl ester 1-t-butyl ester

An n-butyllithium hexane solution (1.6 M, 29 mL) was added to a mixture of diisopropylamine (4.7 g) and THF (75 mL), and the mixture was stirred for 30 minutes. A mixture of 4-ethylpiperidine-1,4-dicarboxylic acid 1-t-butyl ester (6.0 g) and THF (10 mL) was added to the mixture under ice-cooling, and the mixture was stirred for 3 hours under ice cooling, and 2-Bromoacetonitrile (5.6 g) was added under ice cooling. The mixture was stirred for 12 hours, and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.21. (3H, t, J = 7.0 Hz), 1.39 (9H, s), 1.43-1.54 (2H, m), 1.90-2.00 (2H, m), 2.87 (2H, s), 2.96-3.12 (2H, m), 3.57-3.67 (2H, m), 4.11-4.22 (2H, m).

B) 1-tert-oxy-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

4-ethyl 4-(cyanomethyl)piperidine-1,4-dicarboxylic acid 1- under ice cooling Sodium borohydride (1.6 g) was added to a mixture of the third butyl ester (2.5 g), cobalt (II) chloride hexahydrate (1.0 g) and methanol (50 mL), and the mixture was stirred for 2 hours under ice cooling. It was then stirred at room temperature for 2 days and then at 60 ° C for 1 hour. 28% aqueous ammonia was added, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.25-1.35 (2H, m), 1.40 (9H, s), 1.45-1.58 (2H, m), 1.90-1.98 (2H, m), 2.90 (2H, Brs), 3.16 (2H, t, J = 7.2 Hz), 3.76-3.86 (2H, m), 7.56 (1H, brs).

C) 2,8-diazaspiro[4.5]nonan-1-one hydrochloride

a mixture of 1-butoxy-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (400 mg), ethyl acetate (10 mL) and ethanol (2.0 mL) at room temperature 4M Hydrochloric acid/ethyl acetate solution (5.0 mL) was added, and the mixture was stirred at 60 ° C for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.47-1.64 (2H, m), 1.77-1.92 (2H, m), 1.93-2.03 (2H, m), 2.81-3.03 (2H, m), 3.11-3.34 ( 4H, m), 7.72 (1H, brs), 8.62-9.33 (2H, m).

D) 8-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]indol-1-one

3-Fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (50 mg), 2,8-diaza A mixture of heterospiro[4.5]nonan-1-one hydrochloride (54 mg), potassium carbonate (120 mg) and NMP (0.20 mL) was stirred at 160 ° C for 1 day and then at 180 ° C for 7 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+): [M+H] ⁺ 312.2.

E) 2-methyl-8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]indol-1-one

8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]indol-1-one (35 mg) under ice cooling Sodium hydride (60%, 6.7 mg) was added to a mixture of DMF (0.50 mL). The mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, and a mixture of methylene chloride (7.0 μL) and DMF (0.50 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.46 (2H, d, J = 13.6 Hz), 1.95-2.12 (4H, m), 2.17 (3H, s), 2.76 (2H, td, J = 12.0, 2.5 Hz) ), 2.87 (3H, s), 3.08 (2H, dt, J = 12.1, 3.4 Hz), 3.27-3.37 (2H, m), 7.53 (1H, s), 7.60 (1H, d, J = 5.3 Hz) , 8.34 (1H, d, J = 5.3 Hz), 8.40 (2H, d, J = 4.9 Hz).

Example 83 1-(4-(4-Cyano-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide

1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperidine-4-carboxamide (60 mg), Pd ₂ (dba) A mixture of ₃ (15 mg), zinc cyanide (56 mg), DPPF (18 mg) and anhydrous DMF (1.5 mL) was heated at 100 ° C for 7 hours under argon. The mixture was allowed to cool to room temperature, and Pd ₂ (dba) ₃ (7.0 mg) was again added to the mixture, and the mixture was heated at 100 ° C for 5 hours under an argon atmosphere. The mixture was allowed to cool to room temperature and the insoluble material was removed by filtration. Ethyl acetate and water were added to the filtrate, and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained portion, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate,

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.58-1.69 (4H, m), 2.65-2.91 (8H, m), 3.01 (3H, s), 7.54 (1H, d, J = 5.3Hz), 8.39 (1H, d, J = 4.9 Hz), 8.44 (1H, s), 8.53 (1H, s), 9.32 (1H, s).

Example 86 N-cyclopropyl-N-methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)peri Pyridyl-4-carboxamide

Add HATU to a mixture of 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.5 g) and DMF (8.2 mL) 0.86 g), triethylamine (0.97 mL) and N-methylcyclopropylamine (0.15 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 0.68-1.00 (4H, m), 1.77 (2H, s), 1.96 (2H, dd, J = 12.3,2.8Hz), 2.17 (3H, s), 2.65-2.83 (3H, m), 2.94 (3H, s), 3.14 (3H, d, J = 11.7 Hz), 7.54 (1H, s), 7.62 (1H, d, J = 5.3 Hz), 8.25-8.50 (3H, m).

Example 87 (2R)-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine -2-carbonitrile A) N'-Ethyl-3-fluoroisoindolin

A mixture of 3-fluoroisonicotinic acid (4.5 g) and sulfinium chloride (20 mL) was heated under reflux for 4 hours under nitrogen. The solvent was evaporated under reduced pressure. The residue was suspended in toluene, and the solvent was evaporated under reduced pressure. The residue was suspended in THF (20 mL). EtOAc (EtOAc m. The mixture was stirred at room temperature for 30 minutes. Removing the insoluble matter by filtration The solvent was evaporated under pressure. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+): [M+H] ⁺ 198.1.

B) 2-(3-Fluoropyridin-4-yl)-5-methyl-1,3,4-thiadiazole

Add 2,4-bis(4-methoxyphenyl)-1,3-disulfide to a mixture of N'-acetamido-3-fluoroisonicotinium ruthenium (3.8g) and toluene (100mL) Hetero-2,4-diphosphetane 2,4-disulfide (7.8 g), and the mixture was stirred at 110 ° C for 5 hours. The solvent was evaporated under reduced pressure. The residue (NH, EtOAc / hexane)

MS (API+): [M+H] ⁺ 196.1.

C) Ethyl 1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate

2-(3-Fluoropyridin-4-yl)-5-methyl-1,3,4-thiadiazole (1.5 g), ethyl piperidine-4-carboxylate (1.8 g), potassium carbonate ( A mixture of 1.6 g) and NMP (8.0 mL) was stirred at 150 ° C for 2 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (API+): [M+H] ⁺ 333.2.

D) 1-(4-(5-Methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate (1.5 g), THF (10 mL) A 2 M aqueous sodium hydroxide solution (2.2 mL) was added to a mixture of methanol (3.0 mL) and the mixture was stirred overnight. A 2 M aqueous sodium hydroxide solution (2.2 mL) was again added to the mixture, and the mixture was stirred at room temperature for 15 minutes. The mixture was neutralized with 1M EtOAc.

MS (API+): [M+H] ⁺ 305.2.

E) (2R)-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) Pyrrolidine-2-carbonitrile

1-(4-(5-Methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid (80 mg), DIPEA (0.23 mL) and DMF HATU (150 mg) was added to a mixture (0.50 mL), and a mixture of (R)-pyrrolidine-2-carbonitrile hydrochloride (52 mg) and DMF (0.50 mL) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.77-2.01 (2H, m), 2.07-2.41 (6H, m), 2.45-2.63 (1H, m), 2.80-2.88 (3H, m), 2.89-3.08 ( 2H, m), 3.18 (2H, d, J = 3.4 Hz), 3.44 - 3.65 (1H, m), 3.68 - 3.81 (1H, m), 4.66 - 4.85 (1H, m), 8.20 (1H, d, J = 5.7 Hz), 8.53 (1H, d, J = 4.9 Hz), 8.60-8.68 (1H, m).

Example 114 1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-L-nonylamine decylamine

To 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (100 mg), DIPEA (0.31 mL) and DMF (2.0 mL) HATU (200 mg) and (S)-pyrrolidine-2-carbamide (48 mg) were added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and brine, and extracted with ethyl acetate / THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.74-2.23 (10H, m), 2.36-2.58 (2H, m), 2.65-2.82 (2H, m), 3.05-3.23 (2H, m), 3.49-3.72 ( 2H,m), 4.61 (1H, dd, J=8.1, 2.1 Hz), 5.28 (1H, brs), 6.88 (1H, brs), 7.54 (1H, s), 7.58-7.63 (1H, m), 8.30 -8.37(2H,m), 8.37-8.42(1H,m).

Example 118 4,4-Difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-L-indole Amine

Add HATU (520 mg) to a mixture of 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (300 mg) and DMF (6.0 mL) Triethylamine (0.32 mL) and (S)-4,4-difluoropyrrolidine-2-carboxamide (240 mg) were stirred at room temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. Wash the organic with water and saturated brine The layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.56-1.85 (4H, m), 2.12 (3H, s), 2.25-2.37 (1H, m), 2.62-2.80 (3H, m), 2.88-3.04 ( 3H,m),3.86-4.24(2H,m),4.44(1H,dd,J=9.5,4.9Hz),7.07(1H,s),7.38(1H,brs),7.53(1H,d,J= 5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J = 4.9 Hz), 8.40 (1H, s), 8.43 (1H, s).

Example 120 (2S)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile

To 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (100 mg), DIPEA (0.31 mL) and DMF (2.0 mL) HATU (200 mg) and (S)-pyrrolidine-2-carbonitrile hydrochloride (56 mg) were added to the mixture, and the mixture was stirred at room temperature for 30 min. The mixture was diluted with water and brine, and extracted with ethyl acetate / THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-2.05 (4H, m), 2.10-2.60 (8H, m), 2.62-2.88 (2H, m), 3.02-3.27 (2H, m), 3.44 - 3.60 ( 1H, m), 3.64-3.77 (1H, m), 4.59-4.88 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.30-8.38 (2H, m) , 8.40 (1H, s).

Example 121 (2S)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) Pyrrolidine-2-carbonitrile

4,4-Difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl at -40 °C To a mixture of -L-decylamine (380 mg), imidazole (62 mg) and pyridine (4.5 mL) was added chlorobenzene (0.17 mL), and the mixture was stirred at -20 ° C for 1 hour. 1M Hydrochloric acid (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue (NH, EtOAc / EtOAc)

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.52-1.85 (4H, m), 2.12 (3H, s), 2.61-3.06 (6H, m), 3.92-4.32 (3H, m), 5.04 (1H, Dd, J = 9.1, 3.0 Hz), 7.53 (1H, d, J = 5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J = 4.9 Hz), 8.42 (2H, d, J = 6.8) Hz).

Example 124 1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-nonylamine decylamine

Add at room temperature to a mixture of 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (52 mg) and DMF (1.0 mL) HATU (90 mg), triethylamine (0.056 mL) and (R)- amidoxime (25 mg), and the mixture was stirred for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. Things. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.58-1.98 (8H, m), 2.12 (3H, s), 2.62-2.81 (2H, m), 2.87-3.04 (2H, m), 3.40-3.67 ( 2H, m), 4.15-4.39 (1H, m), 5.74 (1H, s), 6.84 (1H, s), 7.12-7.23 (1H, m), 7.50-7.56 (1H, m), 7.63 (1H, s), 8.30 (1H, d, J = 5.3 Hz), 8.39-8.46 (2H, m).

Example 125 2-Methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-amidoxime amine A) (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride

Thionyl chloride (0.68 mL) was added dropwise to a mixture of (R)-2-methylpyrrolidine-2-carboxylic acid (400 mg) and methanol (10 mL), and the mixture was stirred at room temperature. overnight. The solvent was evaporated under reduced pressure. The residue was suspended in ethyl acetate.

¹ H NMR (300MHz, CDCl ₃ ) δ 1.86 (3H, s), 1.93-2.25 (3H, m), 2.33-2.53 (1H, m), 3.48-3.69 (2H, m), 3.86 (3H, s) , 9.47 (1H, brs), 10.48 (1H, brs).

B) (R)-2-methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-carbonyl)pyrrolidine- 2-carboxylic acid methyl ester

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (200 mg), (R)-2-methylpyrrolidine-2 HATU (400 mg) and DIPEA (0.61 mL) were added to a mixture of carboxylic acid methyl ester hydrochloride (150 mg) and DMF (3.0 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue (NH, EtOAc / hexane)

MS (API+): [M+H] ⁺ 412.3.

C) (R)-2-methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-carbonyl)pyrrolidine- 2-carboxylic acid

(R)-2-Methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-carbonyl)pyrrolidine-2 A 2M aqueous sodium hydroxide solution (0.39 mL) was added to a mixture of carboxylic acid methyl ester (160 mg), THF (1.0 mL) and methanol (0.30 mL), and the mixture was stirred at room temperature for 3 hours, then at 50 ° C overnight. . The mixture was acidified with 1M hydrochloric acid (pH = 4), diluted with brine, and ethyl acetate/THF. The organic layer was washed with EtOAc.

MS (API+): [M+H] ⁺ 398.2.

D) 2-methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)-D-oxime Amine

(R)-2-Methyl-1-(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl) HATU (230 mg) was added to a mixture of piperidine-4-carbonyl)pyrrolidin-2-carboxylic acid (160 mg), DIPEA (0.11 mL) and DMF (2.0 mL), and the mixture was stirred at room temperature for 30 min. A 0.4 M ammonia/THF solution (1.5 mL) was added to the mixture, and the mixture was stirred at room temperature overnight. The mixture was diluted with water, a saturated aqueous sodium hydrogen sulfate solution and brine, and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.68 (3H, s), 1.70-2.03 (7H, m), 2.17 (3H, s), 2.43-2.79 (4H, m), 3.09-3.21 (2H, m) , 3.55-3.77 (2H, m), 5.25 (1H, brs), 6.91 (1H, s), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.31-8.38 (2H, m ), 8.40 (1H, s).

Example 126 2-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)- D-Amidoxime A) (R)-2-Methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- Carbonyl pyrrolidine-2-carboxylic acid methyl ester

1-(4-(5-Methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid (200 mg), (R)-2-A HATU (380 mg) and DIPEA (0.57 mL) were added to a mixture of <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Warp hose column The residue (NH, EtOAc / EtOAc)

MS (API+): [M+H]+430.1.

B) (R)-2-Methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- Carbonyl pyrrolidine-2-carboxylic acid

(R)-2-Methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-carbonyl To a mixture of pyrrolidine-2-carboxylic acid methyl ester (250 mg), THF (1.5 mL) and methanol (0.50 mL), 2M aqueous sodium hydroxide (1.1 mL) was added, and the mixture was heated to reflux for 2 hr. The mixture was acidified with 1 M hydrochloric acid (pH = 4 to 5), diluted with brine, and ethyl acetate/THF. The organic layer was washed with EtOAc.

MS (API+): [M+H] ⁺ 416.2.

C) 2-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) )-D-Amidoxime

(R)-2-Methyl-1-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-carbonyl HATU (300 mg) was added to a mixture of pyrrolidine-2-carboxylic acid (220 mg), DIPEA (0.14 mL) and DMF (2.0 mL), and the mixture was stirred at room temperature under nitrogen for 1 hour. A 0.4 M ammonia/THF solution (2.0 mL) was added to the mixture, and the mixture was stirred at room temperature overnight. The mixture was diluted with brine and extracted with ethyl acetate / THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAcjjjjj elut elut elut

¹ H NMR (300MHz, CDCl ₃ ) δ 1.71 (3H, s), 1.73-2.23 (7H, m), 2.49-2.68 (2H, m), 2.84 (3H, s), 2.89-3.01 (2H, m) , 3.1-3.22 (2H, m), 3.60-3.81 (2H, m), 5.29 (1H, brs), 6.83 (1H, brs), 8.20 (1H, d, J = 5.3 Hz), 8.52 (1H, d , J = 5.3 Hz), 8.65 (1H, s).

Example 127 (2R)-2-methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine -2-carbonitrile

2-methyl-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)- Trifluoroacetic anhydride (0.039 mL) was added to a mixture of D-decylamine (100 mg) and pyridine (2.0 mL), and the mixture was stirred at room temperature for 30 min. Trifluoroacetic anhydride (0.039 mL) was again added to the mixture under ice cooling, and the mixture was stirred at room temperature for 30 min. Trifluoroacetic anhydride (0.078 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.76 (3H, s), 1.80-2.14 (7H, m), 2.18 (3H, s), 2.36-2.60 (2H, m), 2.71 (2H, t, J = 11.7 Hz), 3.07-3.24 (2H, m), 3.53-3.76 (2H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.31-8.36 (2H, m), 8.40 (1H, s).

Example 128 (2R)-2-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl) )carbonyl)pyrrolidine-2-carbonitrile

2-methyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-) under ice cooling Trifluoroacetic anhydride (0.12 mL) was added to a mixture of dimethyl)-D-decylamine (160 mg) and pyridine (2.0 mL), and the mixture was stirred under a nitrogen atmosphere and stirred for 15 minutes under ice cooling. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was diluted with brine, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.78 (3H, s), 1.82-1.97 (2H, m), 2.03-2.28 (5H, m), 2.44-2.61 (2H, m), 2.86 (3H, s) , 2.93 (2H, tt, J = 11.9, 2.5 Hz), 3.11-3.22 (2H, m, J = 5.9, 3.6 Hz), 3.59-3.79 (2H, m), 8.20 (1H, d, J = 4.5 Hz) ), 8.53 (1H, d, J = 4.9 Hz), 8.64 (1H, s).

Example 129 (2R)-1-((1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-yl Nitrile A) 3-Fluoro-N-(2-hydroxypropyl) isonicotinium amide

a mixture of 3-fluoroisonicotinic acid (4.5 g) and sulfinium chloride (20 mL) The mixture was heated under reflux for 4 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and anhydrous THF (20 mL). A mixture of 1-aminopropan-2-ol (2.9 g), DIPEA (12 mL) and THF (20 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and THF was added to the residue. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+): [M+H] ⁺ 199.1.

B) 3-Fluoro-N-(2-oxopropyl)isonicotinamide

Add sulfur trioxide complex to a mixture of 3-fluoro-N-(2-hydroxypropyl)isonicotinamide (4.4g), triethylamine (6.2mL) and DMSO (70mL) at room temperature (7.0 g), and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The mixture was basified with 1M aqueous sodium hydroxide and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+): [M+H] ⁺ 197.2.

C) 2-(3-Fluoropyridin-4-yl)-5-methylthiazole

Add 2,4-bis(4-methoxyphenyl)-1 to a mixture of 3-fluoro-N-(2-oxopropyl)isonicotinamine (1.9 g) and toluene (30 mL) , 3-dithia-2,4-diphosphetane 2,4-disulfide (4.7 g), and stirred at 110 ° C The mixture was 1 hour. The mixture was concentrated under reduced pressure and purified mjjjjjjd

MS (API+): [M+H] ⁺ 195.1.

D) Ethyl 1-(4-(5-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate

a mixture of 2-(3-fluoropyridin-4-yl)-5-methylthiazole (500 mg), ethyl piperidine-4-carboxylate (610 mg), potassium carbonate (530 mg) and NMP (2.0 mL) Stir at 150 ° C overnight. The mixture was allowed to cool to room temperature and ethyl piperidine-4-carboxylate (2.0 mL) was added. The mixture was stirred at 180 ° C for 2 hours, then overnight at room temperature. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAcjjjjj elut elut elut

MS (API+): [M+H] ⁺ 332.2.

E) 1-(4-(5-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(5-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate (770 mg) was dissolved in THF (q. A 2 M aqueous sodium hydroxide solution (2.3 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The mixture was neutralized with 1M EtOAc (EtOAc)EtOAc.

MS (API+): [M+H] ⁺ 304.1.

F) (2R)-1-((1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2 -carbonitrile

Add HATU (86 mg), triethyl ether to a mixture of 1-(4-(5-methylthiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid and DMF (1.0 mL) at room temperature Base amine (0.053 mL) and (R)-pyrrolidine-2-carbonitrile hydrochloride (28 mg), and the mixture was stirred for 2 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.75-2.30 (8H, m), 2.53 (3H, d, J = 0.8 Hz), 2.61-2.75 (1H, m), 2.91-3.11 (4H, m) , 3.52-3.63 (1H, m), 3.68-3.78 (1H, m), 4.75 (1H, dd, J = 7.2, 3.8 Hz), 7.72 (1H, d, J = 1.1 Hz), 8.03 (1H, d , J = 5.3 Hz), 8.44 (1H, d, J = 5.3 Hz), 8.68 (1H, s).

Example 130 (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) Pyrrolidine-2-carbonitrile A) (2R,4R)-1-(Tertibutoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

A mixture of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (5.3 g), di-tert-butyl dicarbonate (19 mL), triethylamine (10 mL) and methanol (90 mL) was refluxed. 2 hours. The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was adjusted with sodium dihydrogen phosphate (400 mg) and dilute hydrochloric acid under ice cooling. To pH 2. The mixture was stirred under ice cooling for 30 minutes and extracted with ethyl acetate / 2-propanol (5:1). The organic layer was separated, washed with EtOAcjjjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.31-1.41 (9H, m), 1.75-1.86 (1H, m), 2.23-2.39 (1H, m), 3.03-3.15 (1H, m), 3.43- 3.54 (1H, m), 4.03-4.13 (1H, m), 4.15-4.25 (1H, m).

B) (2R,4R)-2-Aminomethylmercapto-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

WSC hydrochloride was added to a mixture of (2R,4R)-1-(t-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (500 mg) and acetonitrile (6.0 mL) 500 mg) and HOBt monohydrate (400 mg). The mixture was stirred at room temperature for 1.5 hours, cooled to 0 ° C, and then added with 28% aqueous ammonia (0.60 mL). The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 30 minutes. Sodium sulfate was added to the mixture, and the insoluble material was removed by silica gel (NH, ethyl acetate), and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.30-1.43 (9H, m), 1.65-1.75 (1H, m), 2.21-2.35 (1H, m), 3.13 - 3.22 (1H, m), 3.41 3.50 (1H, m), 3.97-4.17 (2H, m), 5.25 (1H, d, J = 6.8 Hz), 7.04-7.16 (1H, m), 7.39-7.49 (1H, m).

C) (R)-2-Aminomethylmercapto-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester

(2R,4R)-2-Aminocarboxy-4-hydroxypyrrolidin-1-carboxylate under ice cooling To a mixture of acid tert-butyl ester (4.0 g) and ethyl acetate (40 mL) / water (40 mL), cerium (IV) oxide monohydrate (0.13 g) and sodium periodate (11 g) were added. The mixture was stirred at room temperature for 4 hours and extracted with ethyl acetate / 2-propanol (5:1). The organic layer was washed with water and brine and dried over magnesium sulfate. The residue was purified by EtOAcjjjjj elut elut

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.36-1.44 (9H, m), 2.24-2.37 (1H, m), 2.93-3.12 (1H, m), 3.63-3.85 (2H, m), 4.44 4.58 (1H, m), 7.04-7.21 (1H, m), 7.58 (1H, brs).

D) (R)-2-Aminomethylmercapto-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

Adding double (2) to a mixture of (R)-2-aminocarbamido-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (2.4 g) and dichloromethane (50 mL) at -5 °C -Methoxyethyl)aminothiotrifluoride (5.8 mL). The mixture was stirred at the same temperature for 15 minutes, then at room temperature for 3.5 hours. The mixture was poured into sodium hydrogencarbonate and ice, stirred for 40 min and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAcjjjjj elut elut elut

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.30-1.46 (9H, m), 2.20-2.42 (1H, m), 2.65-2.88 (1H, m), 3.61-3.83 (2H, m), 4.19- 4.32(1H,m), 7.05-7.19(1H,m), 7.40-7.53(1H,m).

E) (R)-2-cyano-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

Adding trifluoroethane to a mixture of 2-aminocarbamimido-4,4-difluoropyrrolidine-1-carboxylic acid (R)-tert-butyl ester (1.1 g) and pyridine (10 mL) at -5 °C Anhydride (0.79 mL). The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 1 hour. The mixture was diluted with ethyl acetate / water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The residue was purified by EtOAcjjjjj elut elut elut

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.45 (9H, s), 2.67-3.01 (2H, m), 3.63-3.87 (2H, m), 4.96 (1H, dd, J = 9.1,2.7Hz) .

F) (R)-4,4-difluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonate

(R)-2-cyano-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (0.82 g), p-toluenesulfonic acid monohydrate (1.3 g) and acetonitrile (15 mL) The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. Diethyl ether and ethyl acetate were added sequentially to the obtained solid, and the crystals were collected by filtration, and washed with ethyl acetate, to afford the title compound (0.67 g).

¹ H NMR (300 MHz, CD ₃ OD) δ 2.37 (3H, s), 2.81-3.13 (2H, m), 3.71-3.95 (2H, m), 5.02-5.11 (1H, m), 7.23 (2H, d , J = 8.0 Hz), 7.68-7.74 (2H, m).

G) (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl) Carbonyl)pyrrolidine-2-carbonitrile

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (60 mg), (R)-4,4-difluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (96 mg), HATU (110 mg), DIPEA (0.11 mL) and DMF (2.0 mL) The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate / water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.60-1.84 (4H, m), 2.12 (3H, s), 2.54-3.04 (7H, m), 4.04-4.30 (2H, m), 5.04 (1H, Dd, J = 9.3, 3.2 Hz), 7.53 (1H, d, J = 5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J = 4.9 Hz), 8.39-8.44 (2H, m).

Example 131 (2R)-1-((4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl) Carbonyl)pyrrolidine-2-carbonitrile A) Ethyl 4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate

2-(3-Fluoropyridin-4-yl)-5-methyl-1,3,4-thiadiazole (300 mg), 4-fluoropiperidine-4-carboxylic acid ethyl ester (650 mg), potassium carbonate A mixture of (320 mg) and NMP (1.0 mL) was stirred under microwave irradiation at 180 ° C for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue (NH, EtOAc / hexane)

MS (API+): [M+H] ⁺ 351.1.

B) (2R)-1-((4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4- (carbonyl)pyrrolidine-2-carbonitrile

Ethyl 4-fluoro-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylate (120 mg) A 2M aqueous sodium hydroxide solution (0.35 mL) was added to a mixture of THF (1.0 mL) and methanol (0.30 mL), and the mixture was stirred at room temperature for 4 hr. The mixture was acidified (pH = 4) with EtOAc (EtOAc)EtOAc. The residue was suspended in toluene, and the solvent was evaporated under reduced pressure. The resulting solid was washed with ethyl acetate. HATU (160 mg) and DIPEA (0.19 mL) were added to a mixture of the obtained solid, (R)-pyrrolidine-2-carbonitrile hydrochloride (56 mg) and DMF (1.0 mL), and the mixture was stirred at room temperature. overnight. The mixture was diluted with brine and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAcjHHHHHH

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.96-2.76 (8H, m), 2.80-2.91 (3H, m), 2.96-3.11 (2H, m), 3.17-3.39 (2H, m), 3.47-4.03 ( 2H, m), 4.70-5.21 (1H, m), 8.21 (1H, d, J = 5.3 Hz), 8.55 (1H, d, J = 5.3 Hz), 8.70 (1H, s).

Example 132 (2R)-4,4-difluoro-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4 -yl)carbonyl)pyrrolidine-2-carbonitrile

1-(4-(5-Methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid (60 mg), (R)-4,4 To a mixture of difluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (54 mg) and DMF (1 mL) was added HATU (100 mg) and DIPEA (0.12mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with brine and extracted with ethyl acetate / THF. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.80-1.99 (2H, m), 2.08-2.28 (2H, m), 2.37-2.56 (1H, m), 2.72-2.84 (2H, m), 2.86 (3H, s), 2.95 (2H, td, J = 11.9, 2.7 Hz), 3.12-3.25 (2H, m), 3.92-4.11 (2H, m), 5.00 (1H, t, J = 6.6 Hz), 8.21 (1H) , d, J = 4.9 Hz), 8.54 (1H, d, J = 5.3 Hz), 8.64 (1H, s).

Example 133 ((2R)-2-(methoxymethyl)pyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridine-3 -yl)piperidin-4-yl)methanone

In 1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid (80 mg), (R)-2-( HATU (150 mg) and DIPEA (0.14 mL) were added to a mixture of methoxymethyl)pyrrolidine (36 mg) and DMF (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) The title compound (76 mg) was obtained.

¹ H NMR (300MHz, CDCl ₃ ) δ 1.73-2.38 (8H, m), 2.46-2.81 (1H, m), 2.84 (3H, s), 2.94 (2H, t, J = 12.1 Hz), 3.08-3.22 (2H, m), 3.27-3.67 (7H, m), 4.08-4.36 (1H, m), 8.20 (1H, d, J = 5.3 Hz), 8.52 (1H, d, J = 5.3 Hz), 8.64 ( 1H, s).

Example 142 (2R)-1-((1-(2,4'-bipyridyl-3'-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile A) 1,3-Dimethyl-2,3-dihydro-2-oxooxypyridinium sulphate

Concentrated sulfuric acid (27 mL) was slowly added dropwise to a mixture of 1,3-dimethylurea (40 g), 1,1,3,3-tetramethoxypropane (55 mL) and methanol (400 mL) at room temperature. The mixture was stirred at 50 ° C for 30 minutes. The mixture was cooled to 5 ° C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.71 (6H, s), 7.05 (1H, t, J = 6.1 Hz), 9.09 (2H, d, J = 6.1 Hz).

B) 3'-bromo-2,4'-bipyridine

1-(3-Bromopyridin-4-yl)ethanone (1.0 g), 1,3-dimethyl-2,3-dihydro-2-oxooxypyridinium sulfate (0.91) under ice cooling To a mixture of g) and acetonitrile (4.0 mL) was added triethylamine (1.1 mL), and the mixture was warmed to 45. The mixture was stirred at the same temperature for 1.5 hours and concentrated under reduced pressure. Acetic acid (4,0 mL) and ammonium acetate (2.1 g) were added to the residue, and at 120 ° C The mixture was stirred for 4 hours. The mixture was allowed to cool to room temperature, poured into aqueous 8M sodium hydroxide (35 mL, cooled to 0 ° C) and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.38 (1H, ddd, J = 7.6, 4.9, 1.1 Hz), 7.52 (1H, dd, J = 4.9, 0.8 Hz), 7.66-7.73 (1H, m), 7.78 -7.87 (1H, m), 8.61 (1H, d, J = 4.9 Hz), 8.73-8.79 (1H, m), 8.85 (1H, s).

C) ethyl 1-([2,4'-bipyridyl]-3'-yl)piperidine-4-carboxylate

3'-Bromo-2,4'-bipyridyl (1.1 g), 1,4-diazabicyclo[2.2.2]octane (0.25 g), isohexahydronicotinic acid ethyl ester (7.0 mL) A mixture of DIPEA (5.0 mL) was stirred with microwave irradiation at 200 ° C for 18 hours. The mixture was diluted with ethyl acetate / water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAcjjjjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.25 (3H, t, J = 7.2 Hz), 1.58-1.75 (1H, m), 1.82-1.93 (2H, m), 2.28-2.40 (1H, m), 2.67 -2.78(2H,m),3.12-3.22(2H,m), 4.14(2H,q,J=7.2Hz), 7.25-7.31(2H,m), 7.50 (1H,d,J=4.5Hz), 7.72-7.80(1H,m), 8.08 (1H,d,J=8.3Hz), 8.36-8.40(2H,m), 8.71-8.76(1H,m).

D) 1-([2,4'-bipyridyl]-3'-yl)piperidine-4-carboxylic acid

Add 2M hydrogen to a mixture of ethyl 1-([2,4'-bipyridyl]-3'-yl)piperidine-4-carboxylate (0.44g) and THF (4.0mL) / ethanol (1.0mL) An aqueous solution of sodium oxide (1.8 mL) was added and the mixture was stirred at 60 ° C for 1.5 hours. The mixture was neutralized with 2M hydrochloric acid (1.8 mL) under ice cooling. The precipitate was collected by filtration and washed with water to afford the title compound (0.40 g).

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.43-1.60 (2H, m), 1.71-1.82 (2H, m), 2.21-2.35 (1H, m), 2.64-2.76 (2H, m), 2.99- 3.10(2H,m), 7.38-7.44(1H,m), 7.47(1H,d,J=4.9Hz), 7.87-7.95(1H,m),8.08-8.14(1H,m),8.31(1H, d, J = 4.9 Hz), 8.38 (1H, s), 8.70-8.74 (1H, m), 12.21 (1H, s).

E) (2R)-1-((1-(2,4'-bipyridyl-3'-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile

1-([2,4'-Bipyridyl]-3'-yl)piperidine-4-carboxylic acid (57 mg), (R)-pyrrolidine-2-carbonitrile hydrochloride (32 mg), HATU ( A mixture of 92 mg), DIPEA (0.11 mL) and DMF (2.0 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate / water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.67-1.92 (4H, m), 2.09-2.45 (5H, m), 2.66-2.79 (2H, m), 3.18-3.31 (2H, m), 3.45-3.56 ( 1H, m), 3.63-3.73 (1H, m), 4.61-4.78 (1H, m), 7.27-7.31 (1H, m), 7.52 (1H, d, J = 4.9 Hz), 7.75-7.83 (1H, m), 8.10 (1H, d, J = 8.0 Hz), 8.37-8.41 (2H, m), 8.71-8.75 (1H, m).

Example 144 (2R,4S)-4-methoxy-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl Pyrrolidine-2-carbonitrile A) (2R,4S)-1-(Tertibutoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

Heating a mixture of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid (7.1 g), di-tert-butyl dicarbonate (25 mL), triethylamine (14 mL) and methanol (130 mL) Reflux for 2 hours. The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Sodium dihydrogen phosphate (590 mg) was added to the residue at 0 ° C, and the mixture was acidified (pH = 2) with dilute hydrochloric acid. The mixture was stirred at 0 ° C for 30 minutes and extracted with ethyl acetate / 2-propanol (5:1). The organic layer was washed with EtOAc.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.40-1.52 (9H, m), 2.07-2.43 (2H, m), 3.43-3.68 (2H, m), 4.34-4.57 (2H, m), 5.00 (2H, Brs).

B) (2R,4S)-2-Aminomethylmercapto-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

Add WSC hydrochloride (11 g) to a mixture of (2R,4S)-1-(t-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (11 g) and acetonitrile (130 mL). And HOBt monohydrate (8.7 g), and the mixture was stirred at room temperature for 2.5 hours. The mixture was cooled to 0 ° C, 28% aqueous ammonia (25 mL) was added, and the mixture was stirred at 0 ° C for 15 min and then at room temperature overnight. Remove the insoluble by filtration The material was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-methanol (4:1), and the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.31-1.41 (9H, m), 1.73-1.87 (1H, m), 1.93-2.09 (1H, m), 3.20-3.28 (1H, m), 3.33- 3.44 (1H, m), 4.02-4.13 (1H, m), 4.21 (1H, d, J = 1.9 Hz), 4.96 (1H, d, J = 3.4 Hz), 6.79-6.93 (1H, m), 7.26 -7.39 (1H, m).

C) (2R, 4S)-2-cyano-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

Trifluoroacetic anhydride was added to a mixture of (2R,4S)-2-aminocarbamido-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g) and pyridine (30 mL) at 0 ° C ( 4.6 mL), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300 MHz, CD ₃ OD) δ 1.46-1.54 (9H, m), 2.29-2.40 (2H, m), 3.37-3.56 (2H, m), 4.37-4.45 (1H, m), 4.61 (1H) , t, J = 8.0Hz).

D) (2R, 4S)-2-cyano-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester

(2R,4S)-2-cyano-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (550 mg), methyl iodide (3.2 mL), silver oxide (1.0 g) and acetonitrile (6.0 mL) Mixed The mixture was heated to reflux for 5 hours under a nitrogen atmosphere and stirred at room temperature for 9 hours. The mixture was filtered through NH-gelatin and Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.43 (9H, s), 2.20-2.35 (1H, m), 2.37-2.47 (1H, m), 3.31 (3H, s), 3.39-3.45 (2H, m), 3.98 (1H, brs), 4.55 (1H, t, J = 7.8 Hz).

E) (2R, 4S)-4-methoxypyrrolidine-2-carbonitrile

Add p-toluenesulfonic acid monol to a mixture of (2R,4S)-2-cyano-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (85 mg) and acetonitrile (1.0 mL) at room temperature Hydrate (140 mg), and the mixture was stirred for 2 hours and heated at 50 °C for 2 hours. The mixture was concentrated under reduced pressure.

¹ H NMR (300MHz, CDCl ₃ ) δ 2.09-2.36 (2H, m), 2.99-3.09 (1H, m), 3.12-3.21 (1H, m), 3.29 (3H, s), 3.97-4.04 (1H, m), 4.10-4.21 (1H, m), 5.25 (1H, brs).

F) (2R,4S)-4-methoxy-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl) )carbonyl)pyrrolidine-2-carbonitrile

Add at room temperature to a mixture of 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (52 mg) and DMF (1.0 mL) HATU (90 mg), triethylamine (0.051 mL) and (2R,4S)-4-methoxypyrrolidine-2-carbonitrile (45 mg), The mixture was stirred for 1.5 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.62-1.84 (4H, m), 2.13 (3H, s), 2.22-2.32 (1H, m), 2.37-2.47 (1H, m), 2.67-2.83 ( 2H, m), 2.90-3.05 (2H, m), 3.25 (3H, s), 3.34-3.40 (1H, m), 3.66-3.76 (2H, m), 4.05-4.11 (1H, m), 4.63 ( 1H, t, J = 8.0 Hz), 7.53 (1H, d, J = 5.3 Hz), 7.63 (1H, s), 8.31 (1H, d, J = 5.3 Hz), 8.41 (1H, s), 8.43 ( 1H, s).

Example 160 (1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester A) (1S,4S)-5-(4-chloropyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

3-Bromo-4-chloropyridine (580 mg), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl at 110 ° C under argon atmosphere Ester (500 mg), Pd ₂ (dba) ₃ (69 mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (130 mg), sodium butoxide (364 mg) A mixture of toluene (10 mL) was stirred for 3 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.34-1.55 (9H, m), 1.86-2.03 (2H, m), 3.24-3.51 (2H, m), 3.55-3.75 (1H, m), 3.92 (1H, Dd, J = 9.4, 2.3 Hz), 4.44 - 4.66 (2H, m), 7.20 (1H, d, J = 4.5 Hz), 7.95 (1H, d, J = 5.3 Hz), 8.08 (1H, s).

B) (1S,4S)-5-(4-Phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

(1S,4S)-5-(4-chloropyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (590 mg), benzene A mixture of boronic acid (260 mg), hydrazine (triphenylphosphine) palladium (0) (110 mg) and potassium carbonate (790 mg) in DME / water (10 / 2.0 mL) was stirred under microwave irradiation at 140 ° C for 1 hour. The mixture was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The solid obtained was recrystallized from ethyl acetate /hexane toield

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.39 (9H, s), 1.72-1.89 (2H, m), 2.55 (1H, d, J = 9.4Hz), 2.87-3.04 (1H, m), 3.25-3.35 (1H, m), 3.51-3.61 (1H, m), 4.17-4.40 (2H, m), 6.98-7.10 (1H, m), 7.29-7.46 (5H, m), 8.03-8.20 (2H, m) .

Example 161 2-cyclopropyl-1-((1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethanone A) (1S,4S)-2-(4-Phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane dihydrochloride

(1S,4S)-5-(4-Phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (440 mg) and methanol 4M Hydrochloric acid/ethyl acetate solution (10 mL) was added to a mixture (5.0 mL), and the mixture was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure.

^{1 H NMR (300MHz, DMSO-} d 6) δ 1.85-2.10 (2H, m), 2.81-3.00 (2H, m), 3.08-3.42 (2H, m), 4.22 (1H, brs), 4.63 (1H, s), 7.41-7.61 (5H, m), 7.72 (1H, d, J = 5.7 Hz), 8.34 (1H, d, J = 5.7 Hz), 8.54 (1H, s), 9.14 (1H, brs), 9.82 (1H, brs).

B) 2-cyclopropyl-1-((1S,4S)-5-(4-phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl) Ethyl ketone

(1S,4S)-2-(4-Phenylpyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (140 mg), cyclopropylacetic acid (0.047) A mixture of mL), HATU (190 mg), triethylamine (0.29 mL) and DMF (3.0 mL) was stirred at room temperature for 3 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 0.02-0.15 (2H, m), 0.41-0.56 (2H, m), 0.89-1.05 (1H, m), 1.74-2.26 (4H, m), 2.47-2.59 ( 1H, m), 2.97 (0.6H, dd, J = 9.8, 2.3 Hz), 3.05 (0.4H, dd, J = 9.4, 1.9 Hz), 3.37-3.47 (1H, m), 3.66 (0.6H, d , J=9.4Hz), 3.74 (0.4H, dd, J=11.5, 1.3Hz), 4.22 (0.4H, s), 4.36 (1H, brs), 4.75 (0.6H, s), 7.00-7.09 (1H , m), 7.30-7.46 (5H, m), 8.06-8.21 (2H, m).

Example 165 Cyclopropyl (4-(5-fluoro-4-phenylpyridin-3-yl)peri -1-yl)methanone A) 3-bromo-5-fluoro-4-phenylpyridine

Phenyl chloroformate (2.0) was added dropwise to a mixture of 3-bromo-5-fluoropyridine (2.5 g), copper iodide (0.28 g), lithium chloride (0.12 g) and THF (23 mL) at -20 °C. (mL), and the mixture was stirred at the same temperature for 30 minutes. 2M phenylmagnesium bromide THF solution (7.9 mL) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 1.5 hr. The mixture was stirred again at room temperature for 30 minutes, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. A mixture of the obtained residue, 2,3,5,6-tetrachlorocyclohexane-2,5-diene-1,4-dione (3.6 g) and toluene (15 mL) was heated under reflux for 6 hr. The mixture was cooled to room temperature, diluted with EtOAc EtOAc (EtOAc) The organic layer was separated, washed with EtOAc EtOAc EtOAc. The residue (NH, EtOAc / hexane) _{^{1 H NMR (300MHz, CDCl 3}} ) δ 7.33-7.41 (2H, m), 7.46-7.56 (3H, m), 8.48 (1H, s), 8.67 (1H, s).

B) 4-(5-fluoro-4-phenylpyridin-3-yl)peri 1-carboxylic acid tert-butyl ester

3-bromo-5-fluoro-4-phenylpyridine (600 mg), 1-piperid D-butyl carboxylic acid (490 mg), Pd ₂ (dba) ₃ (65 mg), 4,5-bisdiphenylphosphine-9,9-dimethyloxaxan (83 mg), third butyl A mixture of sodium alkoxide (270 mg) and toluene (10 mL) was stirred under microwave irradiation at 110 ° C for 2 hours. The mixture was filtered through EtOAc (EtOAc, ethyl acetate) and concentrated. The residue (NH, EtOAc / hexane)

¹ H NMR (300MHz, CDCl ₃ ) δ 1.43 (9H, s), 2.77-2.89 (4H, m), 3.22-3.33 (4H, m), 7.37-7.57 (5H, m), 8.14 (1H, s) , 8.27 (1H, s).

C) 1-(5-fluoro-4-phenylpyridin-3-yl)peri Dihydrochloride

4-(5-fluoro-4-phenylpyridin-3-yl)per A mixture of 1-carboxylic acid tert-butyl ester (480 mg) and 2M hydrochloric acid/methanol (16 mL) was stirred at room temperature for 5 hr.

^{1 H NMR (300MHz, DMSO-} d 6) δ 2.84-2.97 (4H, m), 3.02-3.13 (4H, m), 7.45-7.64 (5H, m), 8.33 (1H, s), 8.47 (1H, d, J = 0.8 Hz), 9.33 (2H, brs).

D) cyclopropyl (4-(5-fluoro-4-phenylpyridin-3-yl)peri -1-yl)methanone

1-(5-fluoro-4-phenylpyridin-3-yl)peridine under ice cooling DIPEA (0.21 mL) and cyclopropanecarbonyl chloride (0.036 mL) were sequentially added to a mixture of dihydrochloride (100 mg) and THF (2.0 mL), and the mixture was stirred at room temperature for 2 hr. The mixture was diluted with ethyl acetate / aq. The organic layer was separated, washed with water and brine, dried over sodium sulfate. The residue was purified by EtOAcjjjjjjjd

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 0.69-0.79 (2H, m), 0.90-1.01 (2H, m), 1.58-1.71 (1H, m), 2.80-2.97 (4H, m), 3.44-3.59 ( 4H, m), 7.37-7.58 (5H, m), 8.15 (1H, s), 8.28 (1H, s).

Example 169 4-(4-phenylpyrimidin-5-yl)perazine -1-carboxylic acid benzyl ester A) 4-(2-Sideoxy-2-phenylethyl)peri -1-carboxylic acid benzyl ester

At room temperature in piperazine 2-Chloro-1-phenylethanone (2.0 g) and acetonitrile (20 mL) were added dropwise to a mixture of -1-carboxylic acid benzyl ester (3.1 g), potassium carbonate (2.7 g) and acetonitrile (30 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue (NH, EtOAc / hexane)

MS (API+): [M+H] ⁺ 339.1.

B) 4-(4-phenylpyrimidin-5-yl)piperidin -1-carboxylic acid benzyl ester

4-(2-Sideoxy-2-phenylethyl)per A mixture of -1-carboxylic acid benzyl ester (4.2 g) and N,N-dimethylformamide dimethyl acetal (40 mL) was stirred at 100 ° C overnight. The solvent was evaporated under reduced pressure. For the residue, a mixture of n-butanol (50 mL) and DIPEA (50 mL) was added with acetonitrile (7.7 g), and the mixture was stirred overnight at 110 °C. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute

¹ H NMR (300MHz, CDCl ₃ ) δ 2.92 (4H, brs), 3.46-3.59 (4H, m), 5.12 (2H, s), 7.29-7.39 (5H, m), 7.42-7.52 (3H, m) , 7.99-8.07 (2H, m), 8.39 (1H, s), 8.95 (1H, s).

Example 175 N-benzyl-4-(4-phenylpyrimidin-5-yl)perazine -1-carboxamide A) 4-phenyl-5-(piperider -1-yl)pyrimidine

4-(4-phenylpyrimidin-5-yl)per A mixture of -1-carboxylic acid benzyl ester (3.1 g), 10% palladium carbide (about 50% aqueous wet product, 0.30 g) and ethanol (30 mL) was stirred at 50 ° C under a hydrogen atmosphere. The catalyst was removed by filtration.

MS (API+): [M+H] ⁺ 241.1.

B) N-Benzyl-4-(4-phenylpyrimidin-5-yl)perazine -1-carboxamide

4-phenyl-5-(piperidin at room temperature To a mixture of -1-yl)pyrimidine (100 mg) and THF (2.0 mL) was added benzyl isocyanate (0.054mL), and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 2.85-3.00 (4H, m), 3.28-3.47 (4H, m), 4.42 (2H, d, J = 5.3 Hz), 4.69 (1H, t, J = 5.1 Hz) ), 7.27-7.37 (5H, m), 7.41-7.51 (3H, m), 7.99-8.07 (2H, m), 8.40 (1H, s), 8.95 (1H, s).

Example 186 Methyl 4-methyl-1-(4-phenylpyrimidin-5-yl)piperidine-4-carboxylate

5-Bromo-4-phenyl-pyrimidine (600mg), 4- methyl-piperidine-4-carboxylate hydrochloride _{(520mg), Pd 2 (dba} ) 3 (120mg), 4,5- bis Phenylphosphine-9,9-dimethyloxaxan (150 mg), sodium butoxide (620 mg) and 1,4-two The degassed mixture of alkane (20 mL) was stirred with microwave irradiation at 110 ° C for 9 hours. The mixture was filtered through EtOAc (EtOAc, ethyl acetate) and concentrated. The residue (NH, EtOAc / hexane)

¹ H NMR (300MHz, CDCl ₃ ) δ 1.22 (3H, s), 1.41-1.54 (2H, m), 2.06-2.15 (2H, m), 2.68-2.79 (2H, m), 2.98-3.08 (2H, m), 3.69 (3H, s), 7.39-7.51 (3H, m), 8.01-8.07 (2H, m), 8.39 (1H, s), 8.89 (1H, s).

Example 198 (2R)-1-((4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin -1-yl)carbonyl)pyrrolidine-2-carbonitrile A) 4-(2-(4-Fluorophenyl)-2-oxoethyl)piper 1-carboxylic acid tert-butyl ester

At room temperature in piperazine 2-Chloro-1-(4-fluorophenyl)ethanone (5.0 g) was added dropwise to a mixture of 1-butyl carboxylic acid (5.9 g), potassium carbonate (6.0 g) and acetonitrile (60 mL). A mixture of acetonitrile (40 mL) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc.

MS (API+): [M+H] ⁺ 323.2.

B) 4-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidin 1-carboxylic acid tert-butyl ester

4-(2-(4-fluorophenyl)-2-oxoethyl)piperidin A mixture of 1-carboxylic acid tert-butyl ester (8.2 g) and N,N-dimethylformamide dimethyl acetal (50 mL) was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure. To the residue, a mixture of n-butanol (40 mL) and DIPEA (40 mL) was added to the mixture, and the mixture was stirred at 100 ° C overnight. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

MS (API+): [M+H] ⁺ 359.2.

C) 4-(4-fluorophenyl)-5-(piperidin -1-yl)pyrimidine dihydrochloride

4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin at room temperature A mixture of 1-carboxylic acid tert-butyl ester (5.8 g) and ethyl acetate (50 mL) was added 4M hydrochloric acid / ethyl acetate (50 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate.

MS (API+): [M+H] ⁺ 259.1.

D) (2R)-1-((4-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin -1-yl)carbonyl)pyrrolidine-2-carbonitrile

4-(4-fluorophenyl)-5-(piperidin at room temperature To a mixture of -1-ylpyrimidine dihydrochloride (200 mg), DIPEA (0.74 mL) and acetonitrile (2.0 mL) was added bis(trichloromethyl) carbonate (72 mg). The mixture was stirred at room temperature for 10 minutes, and (R)-pyrrolidine-2-carbonitrile hydrochloride (160 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.83-2.01 (1H, m), 2.01-2.39 (3H, m), 2.87-3.05 (4H, m), 3.27-3.52 (6H, m), 4.73-4.85 ( 1H, m), 7.12-7.22 (2H, m), 8.07-8.16 (2H, m), 8.42 (1H, s), 8.95 (1H, s).

Example 219 N-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)perazine -1-carboxamide A) 4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)peri 1-carboxylic acid tert-butyl ester

At -78 ° C in the pipe A mixture of n-butyl carboxylic acid (0.41 g) and THF (5.0 mL) was added hexane solution of n-butyllithium (1.6 M, 1.4 mL), and the mixture was stirred for 30 min under nitrogen atmosphere. . A solution of 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (0.30 g) in THF (1.0 mL) was added to the mixture, and the mixture was stirred at -78 ° C under nitrogen atmosphere. The mixture was allowed to stand for 15 minutes. The mixture was allowed to warm to room temperature and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.46-1.49 (9H, m), 2.17 (3H, s), 2.81-2.88 (4H, m), 3.45-3.56 (4H, m), 7.55 (1H, s) , 7.58 (1H, d, J = 5.3 Hz), 8.29 (1H, s), 8.38 (2H, t, J = 2.7 Hz).

B) 1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)peri

4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)peri To a mixture of 1-carboxylic acid tert-butyl ester (1.2 g), ethyl acetate (10 mL) and methanol (5OmL) was added 4M hydrochloric acid / ethyl acetate (10 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The aqueous solution was basified with 1 M aqueous sodium hydroxide solution, saturated brine was added, and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with EtOAc.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.17 (3H, s), 2.81-2.90 (4H, m), 2.91-3.00 (4H, m), 7.54 (1H, s), 7.59 (1H, d, J = 4.9Hz), 8.32-8.43 (3H, m).

C) N-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)peri -1-carboxamide

Add (4-fluorophenyl)methylamine (0.035 mL) to THF (0.5) in a mixture of bis(trichloromethyl) carbonate (31 mg), DIPEA (0.11 mL) and THF (2.0 mL). A solution of mL) and the mixture was stirred for 10 minutes. Add 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)peridine to the mixture (50 mL) a solution in THF (0.5 mL). Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.16 (3H, s), 2.84 - 2.92 (4H, m), 3.41-3.51 (4H, m), 4.40 (2H, d, J = 5.7 Hz), 4.74 (1H) ,t,J=5.3Hz), 6.97-7.06(2H,m), 7.27-7.33(2H,m),7.53-7.59(2H,m),8.24(1H,d,J=0.8Hz),8.34- 8.42 (2H, m).

Example 265 (5-(Methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl) Pyridin-3-yl)piperidin-4-yl)methanone (optical isomer)

Racemic (5-(methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazole)- 2-Benzylpyridin-3-yl)piperidin-4-yl)methanone (120 mg) was dissolved and applied by HPLC (column: CHIRALPAKAD, 50 mm ID x 500 mmL, mobile phase: hexane/ethanol/diethylamine = 860/140/1) gave the title compound (56 mg) with a shorter retention time.

Example 266 (5-(Methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl) Pyridin-3-yl)piperidin-4-yl)methanone (optical isomer)

Racemic (5-(methoxymethyl)-2,2-dimethylpyrrolidin-1-yl)(1-(4-(5-methyl-1,3,4-thiadiazole)- 2-Benzylpyridin-3-yl)piperidin-4-yl)methanone (120 mg) was dissolved and applied by HPLC (column: CHIRALPAKAD, 50 mm ID x 500 mmL, mobile phase: hexane/ethanol/diethylamine = 860/140/1) gave the title compound (56 mg) with a longer retention time.

Example 267 5,5-Dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl) Carbonyl) amidoxime (optical isomer)

Racemic 5,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4 -yl)carbonyl) amidoxime (63 mg) was dissolved and passed through HPLC (column: CHIRALPAKAS, 50 mm ID x 500 mmL, mobile phase: Hexane/ethanol/diethylamine = 700/300/1) gave the title compound (30 mg) with a shorter retention time.

Example 268 5,5-Dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidin-4-yl) Carbonyl) amidoxime (optical isomer)

Racemic 5,5-dimethyl-1-((1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-3-yl)piperidine-4 -yl)carbonyl) amidoxime (63 mg) was dissolved and obtained by HPLC (column: CHIRALPAKAS, 50 mm ID x 500 mmL, mobile phase: hexane/ethanol/diethylamine = 700/300/1) The title compound (22 mg) was obtained for a long retention time.

Example 277 N-cyclopropyl-1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-methylpiperidine-4-carboxamide A) Ethyl 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylate

2-Chloro-1-(4-fluorophenyl)ethanone was added dropwise to a mixture of piperidine-4-carboxylic acid ethyl ester (5.0 g), potassium carbonate (6.0 g) and acetonitrile (60 mL) at room temperature A mixture of (5.0 g) and acetonitrile (40 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.19-1.30 (3H, m), 1.75-1.98 (4H, m), 2.15-2.37 (3H, m), 2.92 (2H, dt, J = 11.6,3.5Hz) , 3.72 (2H, s), 4.13 (2H, q, J = 7.2 Hz), 7.05-7.17 (2H, m), 8.01-8.13 (2H, m).

B) Ethyl 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylate

Ethyl 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylate (8.0 g) and N,N-dimethylformamide dimethyl condensate A mixture of aldehyde (50 mL) was heated under reflux for 5 hr. To a mixture of the obtained residue, n-butanol (40 mL) and DIPEA (40 mL), toluene acetate (9.9 g) was added, and the mixture was stirred at 100 ° C overnight. 1M hydrochloric acid was added to the mixture, and the solvent was evaporated under reduced pressure. The residue was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.27 (3H, t, J = 7.2 Hz), 1.67-1.84 (2H, m), 1.87-2.00 (2H, m), 2.38 (1H, tt, J = 11.2, 4.0 Hz), 2.68 (2H, td, J = 11.5, 2.7 Hz), 3.21 (2H, dt, J = 12.2, 3.2 Hz), 4.16 (2H, q, J = 7.2 Hz), 7.12-7.21 (2H, m), 8.07-8.18 (2H, m), 8.41 (1H, s), 8.90 (1H, s).

C) 1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylate (2.2 g) was dissolved in THF (20 mL) and methanol (5.0 mL). Aqueous sodium hydroxide (6.6 mL) was added and the mixture was stirred at room temperature for 3.5 hr. The mixture was concentrated, and the residue was neutralized with 2M hydrochloric acid and collected by filtration. The solid was precipitated to give the title compound (2.0 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.51-1.68 (2H, m), 1.76-1.88 (2H, m), 2.24-2.38 (1H, m), 2.62-2.75 (2H, m), 3.06- 3.18 (2H, m), 7.30-7.41 (2H, m), 8.09-8.20 (2H, m), 8.54 (1H, s), 8.85 (1H, s), 12.25 (1H, brs).

D) N-cyclopropyl-1-(4-(4-fluorophenyl)pyrimidin-5-yl)-N-methylpiperidine-4-carboxamide

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.10 g), N-methylcyclopropylamine (28 mg), HATU (0.15 g), DIPEA (0.15) A mixture of mL) and DMF (2.0 mL) was stirred at room temperature for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHHH

¹ H NMR (300MHz, CDCl ₃ ) δ 0.70-0.81 (2H, m), 0.85-0.96 (2H, m), 1.65-1.77 (2H, m), 1.82-1.99 (2H, m), 2.62-2.75 ( 3H,m), 2.93(3H,s), 3.02-3.17(1H,m),3.24-3.37(2H,m),7.13-7.22(2H,m),8.11-8.20(2H,m),8.42( 1H, s), 8.90 (1H, s).

Example 278 (3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)methanone

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.10 g), 3-fluoroazetidine hydrochloride (0.056 g), HATU (0.16) g), DIPEA (0.23mL) A mixture of DMF (2.0 mL) was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.62-1.94 (4H, m), 2.18-2.31 (1H, m), 2.59-2.73 (2H, m), 3.21-3.34 (2H, m), 4.03-4.49 ( 4H, m), 5.18-5.46 (1H, m), 7.12-7.21 (2H, m), 8.09-8.17 (2H, m), 8.41 (1H, s), 8.90 (1H, s).

Example 280 (3-fluoroazetidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (60 mg), 3-fluoroazetidine hydrochloride ( A mixture of 28 mg), HATU (96 mg), DIPEA (0.091 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.67-1.99 (4H, m), 2.17 (3H, s), 2.20-2.33 (1H, m), 2.64-2.78 (2H, m), 3.07-3.19 (2H, m), 4.04-4.52 (4H, m), 5.19-5.48 (1H, m), 7.54 (1H, s), 7.60 (1H, d, J = 5.3 Hz), 8.32 - 8.36 (2H, m), 8.39 (1H, s).

Example 281 (1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.060 g), 3-fluoroazetidine hydrochloride ( A mixture of 0.026 g), HATU (0.089 g), DIPEA (0.085 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.69-2.01 (4H, m), 2.21-2.36 (1H, m), 2.68-2.81 (2H, m), 3.05-3.18 (2H, m), 4.03-4.53 ( 4H, m), 5.19-5.48 (1H, m), 7.59 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.44 (1H, s ), 8.56 (1H, s).

Example 282 ((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)- ketone

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (60 mg), (S)-3-fluoropyrrolidine hydrochloride Mixture of (32 mg), HATU (96 mg), DIPEA (0.091 mL) and DMF (2.0 mL) Time. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.68-2.10 (5H, m), 2.17 (3H, s), 2.20-2.56 (2H, m), 2.66-2.79 (2H, m), 3.09-3.20 (2H, m), 3.45-3.99 (4H, m), 5.14 - 5.44 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.32 - 8.37 (2H, m), 8.40 (1H, s).

Example 283 ((3R)-3-fluoropyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)- ketone

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (60 mg), (R)-3-fluoropyrrolidine hydrochloride A mixture of (32 mg), HATU (96 mg), DIPEA (0.091 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHHH

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-2.15 (5H, m), 2.17 (3H, s), 2.21-2.56 (2H, m), 2.65-2.80 (2H, m), 3.08-3.20 (2H, m), 3.45-4.00 (4H, m), 5.15-5.43 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.33 - 8.37 (2H, m), 8.40 (1H, s).

Example 284 (1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.060 g), (S)-3-fluoropyrrolidine hydrochloride A mixture of (0.030 g), HATU (0.089 g), DIPEA (0.085 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.72-2.58 (7H, m), 2.69-2.84 (2H, m), 3.08-3.20 (2H, m), 3.46-4.01 (4H, m), 5.13-5.44 ( 1H, m), 7.60 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.45 (1H, s), 8.59 (1H, s).

Example 285 (1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-fluoropyrrolidin-1-yl)methanone

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (60 mg), (R)-3-fluoropyrrolidine hydrochloride ( A mixture of 30 mg), HATU (89 mg), DIPEA (0.085 mL) and DMF (2.0 mL) was stirred at room temperature for 2 min. Time. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.74-2.59 (7H, m), 2.69-2.84 (2H, m), 3.07-3.20 (2H, m), 3.45-3.99 (4H, m), 5.15-5.44 ( 1H, m), 7.60 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.46 (1H, s), 8.59 (1H, s).

Example 286 (1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.060 g), (S)-3-fluoropyrrolidine hydrochloride (0.030 g), HATU ( A mixture of 0.091 g), DIPEA (0.087 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hr. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

¹ H NMR (300MHz, CDCl ₃ ) δ 1.66-2.54 (7H, m), 2.61-2.74 (2H, m), 3.25-3.36 (2H, m), 3.45-3.98 (4H, m), 5.14-5.41 ( 1H, m), 7.12-7.22 (2H, m), 8.11-8.18 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 287 (1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3R)-3-fluoropyrrolidin-1-yl)methanone

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (60 mg), (R)-3-fluoropyrrolidine hydrochloride (30 mg), HATU (91 mg) A mixture of DIPEA (0.087 mL) and DMF (2.0 mL) was stirred at room temperature for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.64-2.53 (7H, m), 2.61-2.75 (2H, m), 3.24-3.37 (2H, m), 3.46-3.98 (4H, m), 5.13-5.43 ( 1H, m), 7.12-7.21 (2H, m), 8.10-8.18 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 288 1-(4-(4-Fluorophenyl)pyrimidin-5-yl)-N-methyl-N-(tetrahydro-2H-piperidin-4-yl)piperidine-4-carboxamide

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (60 mg), N-methyl-N-(tetrahydro-2H-pyran-4-yl) A mixture of the amine (28 mg), HATU (91 mg), DIPEA (0.087mL) and DMF (2.0mL) was stirred at room temperature for 4 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. Make The organic layer was washed with water and brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAcjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.46-2.06 (8H, m), 2.48-2.77 (3H, m), 2.81-2.95 (3H, m), 3.21-3.57 (4H, m), 3.96-4. 2H, m), 4.62-4.84 (1H, m), 7.12-7.21 (2H, m), 8.10-8.19 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 290 1-(4-(4-Fluorophenyl)pyrimidin-5-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.30 g), (S)-tetrahydrofuran-3-amine hydrochloride (0.15 g), HATU ( A mixture of 0.45 g), DIPEA (0.43 mL) and DMF (5.0 mL) was stirred at room temperature for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. By silica gel column chromatography (NH, ethyl acetate / hexane) of the residue was purified, and from ethyl acetate / heptane, the resultant solid was recrystallized to give the title compound ^{(0.32g). 1 H NMR (} 300MHz, CDCl ₃ ) δ 1.70-1.87 (5H, m), 2.06-2.19 (1H, m), 2.22-2.36 (1H, m), 2.59-2.71 (2H, m), 3.21-3.34 (2H, m), 3.66 ( 1H, dd, J=9.4, 2.3 Hz), 3.74-3.85 (2H, m), 3.89-3.99 (1H, m), 4.47-4.60 (1H, m), 5.63 (1H, d, J = 6.4 Hz) , 7.12-7.21 (2H, m), 8.08-8.16 (2H, m), 8.41 (1H, s), 8.90 (1H, s).

Example 291 1-(4-(4-Fluorophenyl)pyrimidin-5-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.30 g), (R)-tetrahydrofuran-3-amine hydrochloride (0.15 g), HATU ( A mixture of 0.45 g), DIPEA (0.43 mL) and DMF (5.0 mL) was stirred at room temperature for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHHH

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71-1.86 (5H, m), 2.04-2.18 (1H, m), 2.22-2.36 (1H, m), 2.59-2.71 (2H, m), 3.22-3.32 ( 2H, m), 3.62-3.69 (1H, m), 3.74-3.85 (2H, m), 3.89-3.99 (1H, m), 4.47-4.60 (1H, m), 5.63 (1H, d, J = 7.5 Hz), 7.12-7.22 (2H, m), 8.06-8.17 (2H, m), 8.41 (1H, s), 8.90 (1H, s).

Example 292 1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (1.0 g), (S)-tetrahydrofuran-3-amine hydrochloride A mixture of salt (0.43 g), HATU (1.7 g), triethylamine (1.9 mL) and DMF (12 mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. Using water The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.72-1.92 (5H, m), 2.07-2.21 (4H, m), 2.22-2.38 (1H, m), 2.69 (2H, dt, J = 11.7,7.2Hz) , 3.12 (2H, d, J = 12.1 Hz), 3.66 (1H, dd, J = 9.5, 2.7 Hz), 3.74 - 3.87 (2H, m), 3.88 - 4.01 (1H, m), 4.47 - 4.61 (1H , m), 5.73 (1H, d, J = 7.2 Hz), 7.54 (1H, s), 7.60 (1H, d, J = 5.3 Hz), 8.31 (1H, d, J = 0.8 Hz), 8.35 (1H , d, J = 5.3 Hz), 8.39 (1H, s).

Example 293 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.50 g), (S)-tetrahydrofuran-3-amine hydrochloride A mixture of (0.20 g), HATU (0.81 g), triethylamine (0.91 mL) and DMF (5.4 mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.72-1.96 (5H, m), 2.10-2.37 (2H, m), 2.73 (2H, td, J = 10.8, 4.2 Hz), 3.04-3.18 (2H, m) , 3.67 (1H, dd, J = 9.5, 2.3 Hz), 3.74 - 3.87 (2H, m), 3.89 - 4.00 (1H, m), 4.49 - 4.62 (1H, m), 5.71 (1H, d, J = 7.2 Hz), 7.59 (1H, d, J = 5.3 Hz), 7.66 (1H, d, J = 0.8 Hz), 8.39 (1H, d, J = 5.3 Hz), 8.44 (1H, s), 8.54 (1H) , d, J = 0.8Hz).

Example 294 1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (1.0 g), (R)-tetrahydrofuran-3-amine hydrochloride A mixture of salt (0.43 g), HATU (1.7 g), triethylamine (1.9 mL) and DMF (12 mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.67-1.93 (5H, m), 2.05-2.37 (5H, m), 2.69 (2H, dt, J = 12.0,7.2Hz), 3.12 (2H, d, J = 11.7 Hz), 3.67 (1H, dd, J=9.5, 2.3 Hz), 3.73-3.87 (2H, m), 3.88-4.00 (1H, m), 4.55 (1H, dtd, J=7.6, 4.8, 2.8 Hz ), 5.75 (1H, d, J = 7.2 Hz), 7.54 (1H, s), 7.60 (1H, d, J = 4.9 Hz), 8.31 (1H, s), 8.34 (1H, d, J = 5.3 Hz) ), 8.39 (1H, s).

Example 295 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.50 g), (R)-tetrahydrofuran-3-amine hydrochloride A mixture of (0.20 g), HATU (0.81 g), triethylamine (0.91 mL) and DMF (5.4 mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.69-1.97 (5H, m), 2.10-2.37 (2H, m), 2.73 (2H, td, J = 10.8, 4.2 Hz), 3.05-3.17 (2H, m) , 3.67 (1H, dd, J = 9.5, 2.3 Hz), 3.73-3.87 (2H, m), 3.89-4.01 (1H, m), 4.55 (1H, ddt, J = 7.6, 5.1, 2.4 Hz), 5.69 (1H, d, J = 7.2 Hz), 7.59 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.44 (1H, s), 8.54 (1H, d, J = 0.8Hz).

Example 296 N-methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-piperidin-4-yl)piperidine- 4-carboxamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (80 mg), N-methyl-N-(tetrahydro-2H A mixture of -piperazin-4-yl)amine (39 mg), HATU (0.13 g), DIPEA (0.12mL) and DMF (2.0mL) was stirred at room temperature for 4 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. Things. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.49-2.07 (8H, m), 2.17 (3H, s), 2.52-2.81 (3H, m), 2.84-2.96 (3H, m), 3.08-3.21 (2H, m), 3.38-3.57 (2H, m), 3.97-4.13 (2H, m), 4.67-4.83 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.33 -8.39(2H,m), 8.40(1H,s).

Example 297 N-(4-fluorobenzyl)-N-methyl-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)per -1-carboxamide

N-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)peridine under ice cooling Sodium hydride (60%, 30 mg) was added to a mixture of 1-carbamide (0.20 g) and DMF (3.0 mL), and the mixture was stirred at the same temperature for 30 min. Methyl iodide (0.047 mL) was added to the mixture under ice cooling, and the mixture was stirred at the same temperature for 30 min. A saturated aqueous ammonium chloride solution, ethyl acetate and pyridine were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 2.17 (3H, s), 2.78 (3H, s), 2.88-2.95 (4H, m), 3.30-3.38 (4H, m), 4.38 (2H, s), 6.97 -7.07(2H,m), 7.19-7.26(2H,m),7.55(1H,s),7.58(1H,d,J=5.3Hz), 8.30(1H,s),8.35-8.41(2H,m ).

Example 298 N-benzyl-N-methyl-4-(4-phenylpyrimidin-5-yl)peri -1-carboxamide

N-Benzyl-4-(4-phenylpyrimidin-5-yl)peridine under ice cooling Sodium hydride (60%, 24 mg) was added to a mixture of 1-carbamide (0.15 g) and DMF (3.0 mL), and the mixture was stirred at the same temperature for 30 min. Methyl iodide (0.038 mL) was added to the mixture, and the mixture was stirred under ice cooling for 1.5 hr. A saturated aqueous ammonium chloride solution, ethyl acetate and pyridine were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

¹ H NMR (300MHz, CDCl ₃ ) δ 2.75 (3H, s), 2.93-3.02 (4H, m), 3.25-3.33 (4H, m), 4.40 (2H, s), 7.19-7.37 (5H, m) , 7.42 - 7.52 (3H, m), 8.03 - 8.11 (2H, m), 8.41 (1H, s), 8.94 (1H, s).

Example 299 (1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-methoxypyrrolidin-1-yl) Ketone

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.10 g), (S)-3-methoxypyrrolidinium salt A mixture of the acid salt (49 mg), HATU (0.16 g), triethylamine (0.18mL) and DMF (1.1mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. Make The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.73-2.22 (6H, m), 2.37-2.55 (1H, m), 2.69-2.82 (2H, m), 3.06-3.20 (2H, m), 3.34 (3H, d, J = 5.3 Hz), 3.41-3.76 (4H, m), 3.92-4.07 (1H, m), 7.60 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.38 (1H, d , J = 5.3 Hz), 8.45 (1H, s), 8.60 (1H, s).

Example 300 (1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl) Ketone

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.10 g), (R)-3-methoxypyrrolidinium salt A mixture of the acid salt (49 mg), HATU (0.16 g), triethylamine (0.18mL) and DMF (1.1mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.73-2.20 (6H, m), 2.36-2.55 (1H, m), 2.68-2.83 (2H, m), 3.13 (2H, dd, J = 11.4,3.0Hz) , 3.34 (3H, d, J = 5.3 Hz), 3.41-3.76 (4H, m), 3.92-4.07 (1H, m), 7.60 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.45 (1H, s), 8.60 (1H, s).

Example 301 ((3S)-3-methoxypyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl Ketone

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.10 g), (S)-3-methoxypyrrolidine A mixture of the hydrochloride (53 mg), HATU (0.17 g), triethylamine (0.20mL) and DMF (1.2mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue (NH, EtOAc / EtOAc)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.71-2.20 (9H, m), 2.44 (1H, d, J = 17.0Hz), 2.72 (2H, td, J = 11.9,2.7Hz), 3.14 (2H, d , J = 12.1 Hz), 3.34 (3H, d, J = 5.3 Hz), 3.42-3.77 (4H, m), 3.92-4.06 (1H, m), 7.53 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.31 - 8.42 (3H, m).

Example 302 ((3R)-3-methoxypyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl Ketone

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (100 mg), (R)-3-methoxypyrrolidinium salt Acid salt (53mg), HATU (0.17g), A mixture of triethylamine (0.20 mL) and DMF (1.2 mL) was stirred at room temperature for 3 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.72-2.21 (9H, m), 2.33 - 2.55 (1H, m), 2.72 (2H, td, J = 12.0, 2.5 Hz), 3.14 (2H, d, J = 12.1 Hz), 3.34 (3H, d, J = 5.3 Hz), 3.43 - 3.76 (4H, m), 3.90-4.11 (1H, m), 7.53 (1H, s), 7.61 (1H, d, J = 4.9 Hz), 8.29-8.43 (3H, m).

Example 303 (1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3S)-3-methoxypyrrolidin-1-yl)methanone

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.10 g), (S)-3-methoxypyrrolidinium hydrochloride (50 mg), HATU (0.16 g), a mixture of triethylamine (0.19 mL) and DMF (1.1 mL) was stirred at room temperature for 3 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue (NH, EtOAc / EtOAc)

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-2.20 (6H, m), 2.34 - 2.51 (1H, m), 2.67 (2H, td, J = 11.8, 2.5 Hz), 3.21-3.37 (5H, m) , 3.41-3.74 (4H, m), 3.89-4.05 (1H, m), 7.09-7.23 (2H, m), 8.07-8.19 (2H, m), 8.41 (1H, s), 8.90 (1H, s) .

Example 304 (1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.10 g), (R)-3-methoxypyrrolidinium hydrochloride (50 mg), HATU (0.16 g), a mixture of triethylamine (0.19 mL) and DMF (1.1 mL) was stirred at room temperature for 3 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.66-2.22 (6H, m), 2.31-2.51 (1H, m), 2.58-2.76 (2H, m), 3.21-3.38 (5H, m), 3.39-3.77 ( 4H, m), 3.90-4.07 (1H, m), 7.16 (2H, t, J = 8.7 Hz), 8.15 (2H, dd, J = 8.7, 5.7 Hz), 8.41 (1H, s), 8.90 (1H) , s).

Example 305 N-Methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidin-4- Formamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidin-4- Sodium hydride (60%, 20 mg) was added to a mixture of carbamide (0.12 g) and DMF (2.0 mL), and the mixture was stirred for 30 min. Methyl iodide (0.032 mL) was added to the mixture, and the mixture was stirred for 1 hour under ice cooling. Adding saturated ammonium chloride to the mixture Aqueous solution, ethyl acetate and pyridine were added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.69-2.05 (5H, m), 2.17 (3H, s), 2.20-2.35 (1H, m), 2.51-3.03 (6H, m), 3.08-3.20 (2H, m), 3.60-3.85 (3H, m), 4.00-4.13 (1H, m), 5.30-5.43 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.33 -8.37(2H,m), 8.40(1H,s).

Example 306 N-Methyl-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidin-4- Formamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidin-4- Sodium hydride (60%, 20 mg) was added to a mixture of carbamide (0.12 g) and DMF (2.0 mL), and the mixture was stirred for 30 min. Methyl iodide (0.032 mL) was added to the mixture, and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution, ethyl acetate and pyridine were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.70-2.03 (5H, m), 2.17 (3H, s), 2.20-2.35 (1H, m), 2.51-3.03 (6H, m), 3.09-3.19 (2H, m), 3.61-3.85 (3H, m), 4.01-4.14 (1H, m), 5.30-5.43 (1H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.33 -8.37(2H,m), 8.40(1H,s).

Example 307 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-((3S)-tetrahydrofuran-3-yl)piperidin-4-yl Guanamine

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidin-4-yl under ice cooling Sodium hydride (60%, 19 mg) was added to a mixture of decylamine (0.12 g) and DMF (2.0 mL), and the mixture was stirred for 30 min. Methyl iodide (0.030 mL) was added to the mixture, and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution, ethyl acetate and pyridine were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.71-2.03 (5H, m), 2.19-2.35 (1H, m), 2.53-3.02 (6H, m), 3.07-3.19 (2H, m), 3.60-3.85 ( 3H, m), 4.01-4.12 (1H, m), 5.30-5.44 (1H, m), 7.60 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 4.9 Hz), 8.45 (1H, s), 8.58 (1H, s).

Example 308 1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-((3R)-tetrahydro Furan-3-yl)piperidine-4-carboxamide

1-(4-(4-Chloro-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidin-4-yl under ice cooling Sodium hydride (60%, 19 mg) was added to a mixture of decylamine (0.12 g) and DMF (2.0 mL), and the mixture was stirred for 30 min. Methyl iodide (0.030 mL) was added to the mixture, and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution, ethyl acetate and pyridine were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue (NH, EtOAc / EtOAc)

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70-2.03 (5H, m), 2.18-2.35 (1H, m), 2.53-3.04 (6H, m), 3.08-3.20 (2H, m), 3.60-3.85 ( 3H, m), 4.01-4.12 (1H, m), 5.31-5.43 (1H, m), 7.60 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.45 (1H, s), 8.58 (1H, s).

Example 309 1-(4-(4-Fluorophenyl)pyrimidin-5-yl)-N-methyl-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.12 g) Sodium hydride (60%, 19 mg) was added to a mixture of DMF (2.0 mL) and the mixture was stirred for 30 min. Methyl iodide (0.034 mL) was added to the mixture, and the mixture was stirred under ice cooling for 2.5 hr. Adding saturated ammonium chloride aqueous solution, acetic acid B to the mixture The ester and pyridine were extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 1.66-2.03 (5H, m), 2.17-2.35 (1H, m), 2.46-2.75 (3H, m), 2.83-3.01 (3H, m), 3.23-3.35 ( 2H, m), 3.60-3.82 (3H, m), 4.00-4.12 (1H, m), 5.27-5.42 (1H, m), 7.12-7.22 (2H, m), 8.09-8.19 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 310 1-(4-(4-Fluorophenyl)pyrimidin-5-yl)-N-methyl-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide

1-(4-(4-Fluorophenyl)pyrimidin-5-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.12 g) Sodium hydride (60%, 19 mg) was added to a mixture of DMF (2.0 mL) and the mixture was stirred for 30 min. Methyl iodide (0.034 mL) was added to the mixture, and the mixture was stirred under ice cooling for 2.5 hr. A saturated aqueous ammonium chloride solution, ethyl acetate and pyridine were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65-2.02 (5H, m), 2.16-2.36 (1H, m), 2.48-2.77 (3H, m), 2.84-3.02 (3H, m), 3.24-3.35 (2H , m), 3.60-3.81 (3H, m), 4.00-4.11 (1H, m), 5.29-5.41 (1H, m), 7.12- 7.21 (2H, m), 8.10-8.19 (2H, m), 8.42 (1H, s), 8.90 (1H, s).

Example 311 N-(2-Fluoroethyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4- Piperidine-4-carboxamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-(tetrahydro-2H-piperidin-4-yl)piperidine-4-carboxamidine Sodium hydride (60%, 19 mg) was added to a mixture of amine (0.12 g) and DMF (2.0 mL), and the mixture was stirred for 30 min. A solution of 2-fluoroethyl 4-methylbenzenesulfonate (0.11 g) in DMF (1.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 16 hr. A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAcjjjjj elut elut elut

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.61-2.04 (8H, m), 2.17 (3H, s), 2.56-2.85 (3H, m), 3.06-3.22 (2H, m), 3.38-3.89 (5H, m), 3.97-4.15 (2H, m), 4.35-4.74 (2H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.31 - 8.45 (3H, m).

Example 312 N-(2-Fluoroethyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl) Piperidine-4-carboxamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3S)-tetrahydrofuran-3-yl)piperidine-4-carboxamide a mixture of 0.12 g) and DMF (2.0 mL) Sodium hydride (60%, 20 mg) was added and the mixture was stirred for 30 min. A solution of 2-fluoroethyl 4-methylbenzenesulfonate (0.11 g) in DMF (1.0 mL) was added and the mixture was stirred at room temperature for 16 hr. A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.70-2.06 (5H, m), 2.18 (3H, s), 2.23-2.41 (1H, m), 2.62-2.84 (3H, m), 3.06-3.22 (2H, m), 3.51-3.90 (5H, m), 4.03-4.14 (1H, m), 4.42-5.00 (3H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.31 -8.43(3H,m).

Example 313 N-(2-Fluoroethyl)-1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl) Piperidine-4-carboxamide

1-(4-(4-Methyl-1H-pyrazol-1-yl)pyridin-3-yl)-N-((3R)-tetrahydrofuran-3-yl)piperidine-4-carboxamide Sodium hydride (60%, 20 mg) was added to a mixture of 0.12 g) and DMF (2.0 mL), and the mixture was stirred for 30 min. A solution of 2-fluoroethyl 4-methylbenzenesulfonate (0.11 g) in DMF (1.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 16 hr. A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.70-2.04 (5H, m), 2.17 (3H, s), 2.22-2.39 (1H, m), 2.62-2.84 (3H, m), 3.07-3.22 (2H, m), 3.50-3.92 (5H, m), 4.03-4.14 (1H, m), 4.43-5.01 (3H, m), 7.54 (1H, s), 7.61 (1H, d, J = 5.3 Hz), 8.31 -8.44(3H,m).

Example 314 N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl)peri -1-carboxamide

N-Benzyl-4-(4-phenylpyrimidin-5-yl)peridine under ice cooling Sodium hydride (16 mg) was added to a mixture of -1-carbamide (0.11 g), EtOAc (EtOAc) (EtOAc) A solution of 2-fluoroethyl 4-methylbenzenesulfonate (0.12 g) in THF (1.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 4 days. The reaction was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.91-3.01 (4H, m), 3.28-3.50 (6H, m), 4.42-4.65 (4H, m), 7.17-7.38 (5H, m), 7.43-7.52 ( 3H, m), 8.03-8.10 (2H, m), 8.40 (1H, s), 8.94 (1H, s).

Example 315 N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)per -1-carboxamide

N-(4-fluorobenzyl)-4-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin at 0 ° C Sodium hydride (0.016 g) was added to a mixture of -1-carbamide (0.12 g), 15-cr. 5-ether (0.079mL) and THF (2.0mL), and the mixture was stirred at room temperature for 30 minutes. A solution of 2-fluoroethyl 4-methylbenzenesulfonate (0.12 g) in THF (1.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 4 days. An aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H NMR (300MHz, CDCl ₃ ) δ 2.17 (3H, s), 2.87-2.96 (4H, m), 3.32-3.50 (6H, m), 4.44 - 4.67 (4H, m), 6.99-7.09 (2H, m), 7.17-7.25 (2H, m), 7.55 (1H, s), 7.58 (1H, d, J = 4.9 Hz), 8.28 (1H, s), 8.36-8.40 (2H, m).

Example 316 ((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl) Ketone

1-(4-(5-Methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.080 g), (S)-3-fluoropyrrolidinium salt A mixture of the acid salt (0.040 g), HATU (0.12 g), DIPEA (0.12mL) and DMF (2.0mL) was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc (EtOAc/EtOAc) elute Compound (0.075 g).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.78-2.65 (10H, m), 2.87-3.02 (2H, m), 3.17-3.28 (2H, m), 3.49-4.03 (4H, m), 5.16-5.47 ( 1H, m), 7.60 (1H, d, J = 0.9 Hz), 8.09 (1H, d, J = 5.1 Hz), 8.45 (1H, d, J = 5.1 Hz), 8.59 (1H, s).

Example 317 (3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidin-4-yl)- ketone

1-(4-(5-Methyl-1,3-thiazol-2-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.080 g), 3-fluoroazetidine hydrochloride A mixture of salt (0.035 g), HATU (0.12 g), DIPEA (0.12mL) and DMF (2.0mL) was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 1.74-1.92 (2H, m), 2.12-2.28 (2H, m), 2.29-2.41 (1H, m), 2.53 (3H, d, J = 0.9Hz), 2.86 -2.99 (2H, m), 3.15-3.27 (2H, m), 4.07-4.57 (4H, m), 5.22-5.50 (1H, m), 7.60 (1H, d, J = 0.9 Hz), 8.09 (1H , d, J = 5.1 Hz), 8.45 (1H, d, J = 5.1 Hz), 8.58 (1H, s).

Example 318 (1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl)methanone A) Ethyl 1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate

a mixture of 4-(4-bromo-1H-pyrazol-1-yl)-3-fluoropyridine (3.0 g), ethyl piperidine-4-carboxylate (4.2 mL) and NMP (12 mL) Stir for 4 hours. The mixture was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H NMR (300MHz, CDCl ₃ ) δ 1.28 (3H, t, J = 7.1 Hz), 1.73-1.91 (2H, m), 1.95-2.07 (2H, m), 2.35-2.50 (1H, m), 2.68 -2.82 (2H, m), 2.99-3.13 (2H, m), 4.18 (2H, q, J = 7.2 Hz), 7.58 (1H, d, J = 5.1 Hz), 7.70 (1H, s), 8.39 ( 1H, d, J = 5.1 Hz), 8.44 (1H, s), 8.58 (1H, s).

B) 1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid

Ethyl 1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylate (1.2 g), 2M aqueous sodium hydroxide (2.4 mL), A mixture of THF (4.0 mL) and ethanol (4.0 mL) was stirred at room temperature for 3 hr. The mixture was concentrated, and the residue was neutralized with 2M hydrochloric acid (2.4 mL). The precipitate was collected by filtration, washed with water and dried

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.54-1.72 (2H, m), 1.77-1.90 (2H, m), 2.26-2.41 (1H, m), 2.64-2.77 (2H, m), 2.83 2.95 (2H, m), 7.52 (1H, d, J = 5.1 Hz), 7.96 (1H, s), 8.36 (1H, d, J = 5.1 Hz), 8.48 (1H, s), 8.77 (1H, s ), 12.26 (1H, s).

C) (1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl) Ketone

1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.30 g), (S)-3-fluoropyrrolidine hydrochloride A mixture of (0.13 g), HATU (0.39 g), DIPEA (0.37 mL) and DMF (3.0 mL) was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHH

¹ H NMR (300MHz, CDCl ₃ ) δ 1.73-2.59 (7H, m), 2.68-2.85 (2H, m), 3.06-3.21 (2H, m), 3.47-4.01 (4H, m), 5.14-5.44 ( 1H, m), 7.59 (1H, d, J = 5.3 Hz), 7.69 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.46 (1H, s), 8.61 (1H, s).

Example 319 (1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone

1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.078 g), 3-fluoroazetidine hydrochloride ( A mixture of 0.025 g), HATU (0.11 g), triethylamine (0.12 mL) and DMF (1.0 mL) was stirred at room temperature for 3 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. Chromatography by column chromatography (NH, ethyl acetate / hexane) The residue was purified by EtOAcqqqqqqq

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68-2.03 (4H, m), 2.17-2.37 (1H, m), 2.64-2.84 (2H, m), 3.03-3.19 (2H, m), 4.02-4.53 ( 4H, m), 5.15-5.49 (1H, m), 7.59 (1H, d, J = 5.3 Hz), 7.69 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.44 (1H, s ), 8.59 (1H, s).

Example 322 (1-(4-(4-Cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3S)-3-fluoropyrrolidin-1-yl) Ketone

(S)-(1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoropyrrolidin-1-yl)- Ketone (0.10g), potassium carbonate (0.13g), bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.017g), cyclopropyltrifluoro A mixture of potassium borate (0.11 g), toluene (2.0 mL) and water (0.40 mL) was stirred at 110 ° C for 12 hours under microwave irradiation. The mixture was purified by hydrazine column chromatography (NH, ethyl acetate / hexane) and HPLC (C18, mobile phase: water/acetonitrile (including 0.1% TFA)). The obtained fraction was concentrated, the residue was neutralized with aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, evaporated

¹ H NMR (300MHz, CDCl ₃ ) δ 0.55-0.66 (2H, m), 0.87-0.99 (2H, m), 1.70-2.57 (8H, m), 2.65-2.83 (2H, m), 3.07-3.21 ( 2H, m), 3.46-4.01 (4H, m), 5.13-5.45 (1H, m), 7.48-7.71 (2H, m), 8.32-8.64 (3H, m).

Example 323 (1-(4-(4-Cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)- ketone

(1-(4-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone (0.10 g), potassium carbonate (0.14 g), bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.017 g), cyclopropyltrifluoroboric acid A mixture of salt potassium salt (0.11 g), toluene (2.0 mL) and water (0.40 mL) was stirred at 110 ° C for 12 hours under microwave irradiation. The mixture was purified by hydrazine column chromatography (NH, ethyl acetate / hexane) and HPLC (C18, mobile phase: water/acetonitrile (including 0.1% TFA)). The obtained fraction was concentrated, the residue was neutralized with aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, evaporated

¹ H NMR (300MHz, CDCl ₃ ) δ 0.56-0.63 (2H, m), 0.88-0.97 (2H, m), 1.67-2.00 (5H, m), 2.21-2.33 (1H, m), 2.63-2.80 ( 2H, m), 3.05-3.18 (2H, m), 4.04-4.52 (4H, m), 5.18-5.50 (1H, m), 7.46-7.73 (2H, m), 8.30-8.61 (3H, m).

The example compounds produced according to the above methods or similar methods therein are shown in the following table. MS in the table means the measured value of the analog.

Formulation Example 1 (manufacturing of capsules)

Mix 1), 2), 3) and 4) and fill in gelatin capsules.

Formulation Example 2 (manufacture of tablets)

The total amount (30 g) of 1), 2) and 3) and 4) was combined with water, dried in a vacuum and sieved. The sieved powder was mixed with 4) (14 g) and 5) (1 g), and the mixture was pressed by a tablet press, whereby 1000 tablets containing 30 mg of the compound of Example 1 per tablet were obtained.

Experimental Example 1: Construction of human CH24H (CYP46) expression vector

Expression of human CH24H plastids in FreeStyle 293 cell line The DNA was produced as follows. Full length mammalian gene collection (Invitrogen) No. 4819975 was used as a template, and the following two synthetic DNAs: 5'-GCCCCGGAGCCATGAGCCCCGGGCTG-3' (SEQ ID NO: 1) and 5'-GTCCTGCCTGGAGGCCCCCTCAGCAG-3' (SEQ ID NO: 2), PCR was performed to amplify the 91 to 1625 bp segment of human CH24H (BC022539). Fragments obtained by colonization using the TOPO TACloning kit (Invitrogen). The obtained fragment was subcultured to pcDNA3.1 (+) digested with BamHI and XhoI to obtain plastid DNA (pcDNA3.1(+)/hCH24H) for expressing human CH24H.

Experimental Example 2: Characterization of human CH24H and preparation of human CH24H lysate

Human CH24H was performed using the FreeStyle 293 Expression System (Invitrogen). The transient expression using the FreeStyle 293-F cell line was performed according to the manual attached to the FreeStyle 293 Expression System and the plastid DNA (pcDNA3.1(+)/hCH24H) expressing human CH24H constructed in Experimental Example 1. After transfection, the cell strain was cultured for 2 days with shaking at 37 ° C, 8% CO ₂ and 125 rpm. The cell strain was collected by centrifugation and suspended in a suspension buffer (100 mM potassium phosphate (pH 7.4), 0.1 mM EDTA, 1 mM DTT, 20% glycerol). The suspended product was disrupted by a polytron homogenizer (manufactured by Kinematica) and centrifuged at 9000 x g for 10 minutes and the supernatant was collected. The collected supernatant was cryopreserved (-80 ° C) as a standard product of human CH24H lysate.

Experimental Example 3: Measurement of inhibition activity of CH24H

For the measurement of CH24H inhibitory activity, the human CH24H lysate prepared in Experimental Example 2 was used, and the 24-HC content produced by cholesterol catalyzed by CH24H was measured in the presence of the test compound, and the content was not present in the test compound. The content of the time is compared. That is, different concentrations of test compound solution were mixed with reaction buffer (50 mM potassium phosphate including 0.1% BSA and a protease inhibitor completely free of EDTA, pH 7.4) and human CH24H lysate. Then, [ ¹⁴ C]cholesterol (53 mCi/mmol specific activity, 15 μM) was added, and CH24H reaction was carried out at 37 ° C for 5 hours. After completion of the reaction, a quenching solution consisting of chloroform/methanol/distilled water (2:2:1 (v/v)) was added, and the obtained 24-HC was extracted by shaking. The extract was applied to silica gel thin layer chromatography (ethyl acetate: toluene = 4:6), and the obtained ¹⁴ C-24HC fraction was measured by BAS 2500 (Fujifilm Corporation). .

The inhibition rate (%) was calculated from the ratio of the radioactivity in the presence of the test compound to the radioactivity in the absence of the test compound. The results are shown in Table 2 below.

Experimental Example 4: Quantitative test of 24-HC

The animals used were 6 week old female C57BL/6N mice (3 mice per group). The test compound was suspended in an aqueous solution of 0.5% methylcellulose [133-14255 WAKO] (1 mg/ml). The body weight of the mice was measured and the solution was orally administered orally, and repeated once a day for 3 days. Half of the brain was recovered 16 hours after the third administration and the 24-HC content was measured.

The wet weight of the brain was measured and the brain was homogenized in approximately 4 times (0.5 ml) of physiological saline, which was used as a brain extract. The 24-HC in the brain extract was extracted with an acetonitrile solution (98% acetonitrile, 1.98% methanol, 0.02% formic acid) and quantified by HPLC. The average of the 24-HC content was calculated and the results are shown as relative values of 100% in the control group. The result is shown in the table below 3 in.

Experimental Example 5: Novel object recognition using APP gene-transferred mouse (Tg2576)

The animals used were 6 week old Tg2576 mice and their wild type mice (10 mice per group). The test compound was suspended in a 0.5% methylcellulose [133-14255 WAKO] aqueous solution (3 mg/ml). The body weight of the mice was measured, and the solution was orally administered orally, once a day (10 mL/kg), and repeated for 6 weeks. Thereafter, a novel object recognition test was performed in the following manner. Prior to the date of the acquisition trial, mice in the same cage were placed in an observation box with a brightness set at 300 lx and allowed to get used for 30 minutes. Oral after oral use This compound is administered. On the next day, if the test was taken, the mice were placed in an observation box in which two identical objects were placed, and the number of times of contact with the object and time was measured at 300 lx for 5 minutes. The compound is administered orally after the measurement. After the date of the test, an object is replaced with a new object, and the number of contacts and time is measured for each new object for 5 minutes. This test uses metal cylinders and ceramic triangular cones. Comparisons were made using a control group (test compound-untreated group) and a control group of wild type mice. The result is expressed as the ratio (%) of the number of contacts to the novel object versus time and the total number of contacts and time for the object. The results are shown in Table 4 below.

Industrial utilization

The compound of the present invention has excellent CH24H inhibitory action and is useful for preventing or treating epilepsy and neurodegenerative diseases (for example, Alzheimer's disease, mild cognitive disorder, Huntington's disease, Parkinson's disease, multiple hairs) Sclerosing disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, glaucoma, etc.), schizophrenia and the like.

This application is based on Japanese Patent Application No. 2013-210439 (filed on October 7, 2013) and PCT/JP2013/083140 (applied on December 10, 2013), which is entirely filed in Japan. Into this article.

<110> Takeda Pharmaceutical Industry Co., Ltd.

<120> Heterocyclic compound

<130> 092118

<150> JP2013-210439

<151> 2013-10-07

<150> PCT/JP2013/083140

<151> 2013-12-10

<160> 2

<170> PatentIn version 3.4

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<211> 26

<212> DNA

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<220>

<223> PCR primer

<400> 1

<210> 2

<211> 26

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<213> Labor

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<223> PCR primer

<400> 2

Claims (21)

A compound represented by the formula (I) or a salt thereof: Wherein X ¹ is a carbon atom or a nitrogen atom; Each of them is further substituted as needed and bridged as needed; R ¹ is optionally substituted with a C _1-6 alkyl group, optionally substituted hydroxy group, optionally substituted amine group; a carbocyclic group, or an optionally substituted heterocyclic group, or an R ¹ group, optionally bonded to an atom on the ring A, together with the ring A, form a spiro ring or a fused ring, each of which is a pendant oxy group. Substituted and further substituted as necessary; R ² is optionally substituted C _6-14 aryl, or optionally substituted aromatic heterocyclic group; and when X ¹ -based carbon atom, R ³ -based hydrogen atom or substituted Base, or when X ¹ is a nitrogen atom, R ³ is absent, except 4-(4-phenylpyrimidin-5-yl)per 1-carboxylic acid tert-butyl ester. The compound of claim 1, or a salt thereof, wherein R ¹ is optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted Amino, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-14 aryl, or optionally substituted non-aromatic heterocyclic, except 4-(4-phenyl Pyrimidine-5-yl)peri 1-carboxylic acid tert-butyl ester. The compound of claim 1, or a salt thereof, wherein the R ¹ group (1) is optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl (a) cyano group. , (b) a C _6-14 aryl group substituted with 1 to 3 C _1-6 alkoxy groups, (c) a C _6-14 aryloxy group, (d) a C _3-8 cycloalkyl group, ( e) pyrazolyl, (f) carbazolyl, and (g) dihydropyridinyl optionally substituted with 1 to 3 pendant oxy groups, (2) 1 to 3 C _6-14 aryl groups as needed Substituted C _1-6 alkoxy, (3) optionally substituted with a substituent selected from the group consisting of a substituent or a di-substituted amino group (a), optionally substituted with one to three substituents selected from the group consisting of _1-6 alkyl (i) halogen atom, (ii) cyano group, (iii) C _3-8 cycloalkyl group, (iv) optionally 1 to 3 selected from a halogen atom and a C _1-6 alkoxy group a substituent substituted with a C _6-14 aryl group, (v) pyridyl group, and (vi) an oxetanyl group substituted with 1 to 3 C _1-6 alkyl groups as desired, (b) optionally a C _3-8 cycloalkyl group substituted with 1 to 3 halogen atoms, (c) a C _6-14 aryl group, and (d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofuranyl group and a pyrrolidinyl group, each of which are optionally substituted with lines with 1 to 3 C _1-6 alkyl, (4) optionally The substituted by 1 to 3 C _6-14 aryl C _3-8 cycloalkyl group, (5) C _6-14 aryl group; or (6) 3-8 monocyclic non-aromatic heterocyclic group or 3,7 a -dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is optionally substituted with one to five substituents selected from the group consisting of (a) a halogen atom, (b) a cyano group, c) a hydroxy group, (d) a pendant oxy group, (e) an amine carbenyl group which is mono- or disubstituted by a C _1-6 alkyl group, and (f) optionally one to three substituents selected from the group consisting of Substituted C _1-6 alkyl (i) hydroxy, and (ii) C _1-6 alkoxy, (g) optionally substituted with 1 to 3 halogen atoms, C _1-6 alkoxy, (h) a C _1-6 alkoxy-carbonyl group, and (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms, or an atom bonded to the ring A by the R ¹ group, and ring A Forming a 2,8-diazaspiro[4.5]decane ring together, which is substituted by a pendant oxy group and further substituted with 1 to 3 C _1-6 alkyl groups as needed; R ² is (1) as needed a C _6-14 aryl (a) halogen atom substituted with one to three substituents selected from the group consisting of: (b) a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or (2) a 5- or 6-membered monocyclic aromatic heterocyclic group or an 8- to 12-membered fused aromatic heterocyclic group, each of which is a Are selected from 1-3 of substituents (a) a halogen atom, (b) cyano, (c) optionally substituted with 1 to 3 substituents of halogen atoms, C _1-6 alkyl, and (d) C _3-8 cycloalkyl; X ¹ is a carbon atom or a nitrogen atom; R ³ is a (1) hydrogen atom, or (2) a halogen atom; and a ring A system (1) Each of them is further substituted with one to three substituents selected from the group consisting of (a) a halogen atom, (b) a C _1-6 alkyl group, and (c) a pendant oxy group, or (2) 8- Azabicyclo[3.2.1]octane ring, 2,5-diazabicyclo[2.2.1]heptane ring or 3-azabicyclo[3.1.0]hexane ring, except 4-(4- Phenylpyrimidin-5-yl)peri 1-carboxylic acid tert-butyl ester. The compound or a salt thereof according to claim 3, wherein the R ¹ group (1) is optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl (a) cyano group. , (b) a C _6-14 aryl group substituted with 1 to 3 C _1-6 alkoxy groups, (c) a C _6-14 aryloxy group, (d) a C _3-8 cycloalkyl group, ( e) pyrazolyl, (f) carbazolyl, and (g) dihydropyridinyl optionally substituted with 1 to 3 pendant oxy groups, (2) 1 to 3 C _6-14 aryl groups as needed Substituted C _1-3 alkoxy group, (3) an amine group which is mono- or disubstituted by a substituent selected from the group consisting of (a) optionally substituted with 1 to 3 substituents selected from the following _1-6 alkyl (i) halogen atom, (ii) cyano group, (iii) C _3-8 cycloalkyl group, (iv) optionally 1 to 3 selected from a halogen atom and a C _1-6 alkoxy group a substituent substituted with a C _6-14 aryl group, (v) pyridyl group, and (vi) an oxetanyl group substituted with 1 to 3 C _1-6 alkyl groups as desired, (b) optionally a C _3-8 cycloalkyl group substituted with 1 to 3 halogen atoms, (c) a C _6-14 aryl group, and (d) a tetrahydropyranyl group, an oxetanyl group, a tetrahydrofuranyl group and a pyrrolidinyl group, each of which are optionally substituted with lines with 1 to 3 C _1-6 alkyl, (4) optionally The substituted by 1 to 3 C _6-14 aryl C _3-8 cycloalkyl group, (. 5) a C _6-14 aryl group, or (6) 3-8 monocyclic non-aromatic heterocyclic group or 3,7 a -dioxa-9-azabicyclo[3.3.1]nonyl group, each of which is optionally substituted with one to five substituents selected from the group consisting of (a) a halogen atom, (b) a cyano group, c) a hydroxy group, (d) a pendant oxy group, (e) an amine carbenyl group which is mono- or disubstituted by a C _1-6 alkyl group, and (f) optionally one to three substituents selected from the group consisting of Substituted C _1-6 alkyl (i) hydroxy, and (ii) C _1-6 alkoxy, (g) optionally substituted with 1 to 3 halogen atoms, C _1-6 alkoxy, (h) a C _1-6 alkoxy-carbonyl group, and (i) a C _6-14 aryl group optionally substituted with 1 to 3 halogen atoms, or an atom bonded to the ring A by the R ¹ group, and ring A Together, a 2,8-diazaspiro[4.5]decane ring is formed which is substituted with a pendant oxy group and, if necessary, further substituted with 1 to 3 C _1-6 alkyl groups. The compound of claim 1, or a salt thereof, wherein the R ¹ group (1) is optionally mono- or disubstituted with a substituent selected from the group consisting of: (a) optionally selected from the group consisting of a C _1-6 alkyl (i) halogen atom substituted with 1 to 3 substituents, and (ii) a phenyl group optionally substituted with 1 to 3 halogen atoms, (b) tetrahydropyranyl group, and c) tetrahydrofuranyl, or (2) azetidinyl or pyrrolidinyl, each of which is optionally substituted with one to five substituents selected from the group consisting of (a) a halogen atom and (b) a cyano group. , (c) an amine carbenyl group, (d) a C _1-6 alkyl group, and (e) a C _1-6 alkoxy group; and a R ² group (1) a phenyl group substituted with 1 to 3 halogen atoms as needed Or (2) pyrazolyl, thiazolyl or thiadiazolyl, each of which is substituted by one to three substituents selected from the group consisting of (a) a halogen atom, (b) a C _1-6 alkyl group, And (c) cyclopropyl; X ¹ -based carbon or nitrogen atom; R ³ -based hydrogen atom; and ring A system The compound of claim 1, or a salt thereof, wherein R ¹ is a pyrrolidine group (a) halogen atom substituted with 1 to 5 substituents selected from the group consisting of, and (b) cyanide R ² is a pyrazolyl (a) halogen atom substituted with 1 to 3 substituents selected from the group consisting of, and (b) C _1-6 alkyl; X ¹ -based carbon atom; R ³ system Hydrogen atom; and ring A system (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile Or a salt thereof, (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2 -carbonitrile or its salt, (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine 4-yl)carbonyl)pyrrolidine-2-carbonitrile or a salt thereof, (3-fluoroazetidin-1-yl)(1-(4-(4-fluorophenyl)pyrimidin-5-yl) Piperidin-4-yl)methanone or its salt, (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)(3- Fluoroazetidin-1-yl)methanone or its salt, (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl) ((3S)-3-fluoropyrrolidin-1-yl)methanone or its salt, (1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl) ((3S) )-3-fluoropyrrolidin-1-yl)methanone or its salt, N-benzyl-N-(2-fluoroethyl)-4-(4-phenylpyrimidin-5-yl)per 1-Protonamine or its salt, N-(4-fluorobenzyl)-N-(2-fluoroethyl)-4-(4-(4-methyl-1H-pyrazol-1-yl) Pyridin-3-yl)peri 1-Procarbamide or a salt thereof, ((3S)-3-fluoropyrrolidin-1-yl)(1-(4-(5-methyl-1,3-thiazol-2-yl)pyridine-3 -yl)piperidin-4-yl)methanone or its salt, (3-fluoroazetidin-1-yl)(1-(4-(5-methyl-1,3-thiazole-2-) Pyridin-3-yl)piperidin-4-yl)methanone or a salt thereof, (1-(4-(4-bromo-1H-pyrazol-1-yl)pyridin-3-yl)piperidine- 4-yl)(3-fluoroazetidin-1-yl)methanone or a salt thereof, or (1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)pyridine-3) -yl)piperidin-4-yl)(3-fluoroazetidin-1-yl)methanone or a salt thereof. (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile Or its salt. (2R)-1-((1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidin-2-carbonitrile or Its salt. (2R)-4,4-difluoro-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl) Pyrrolidine-2-carbonitrile or a salt thereof. A pharmaceutical product comprising the compound as described in claim 1 or a salt thereof. The pharmaceutical product according to claim 11, which is a cholesterol 24 hydroxylase inhibitor. The pharmaceutical product according to claim 11 is an agent for preventing or treating epilepsy or neurodegenerative diseases. The pharmaceutical product according to claim 13, wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive disorder, Huntington's disease, Parkinson's disease or multiple sclerosis. The compound of claim 1 or a salt thereof for use in the prevention or treatment of epilepsy or neurodegenerative diseases. The compound according to claim 15 or a salt thereof, wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive disorder, Huntington's disease, Parkinson's disease or multiple sclerosis. A method for inhibiting cholesterol 24-hydroxylase in a mammal, which comprises administering to the mammal an effective amount of a compound as described in claim 1 or a salt thereof. A method for pre-fat or treating epilepsy or a neurodegenerative disease comprising administering to the mammal an effective amount of a compound of the formula 1 or a salt thereof. The method of claim 18, wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease or multiple sclerosis. A use of a compound according to claim 1 or a salt thereof for the preparation of a medicament for preventing or treating epilepsy or neurodegenerative diseases. The use according to claim 20, wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease or multiple sclerosis.