Substituted piperidine compounds and uses thereof

Abstract

The invention relates to substituted piperidine compounds and uses thereof. The present invention provides a compound represented by formulae (I), (II), (III) and (IV) or a pharmaceutically acceptable salt thereof, said compound having an orexin type 2 receptor agonist activity. [chemical] # imgabs0 #

Description

[0001] This application is a divisional application of Chinese invention patent application No. 202180044081.3 (PCT application number is PCT / JP2021 / 026649), with an application date of July 15, 2021 and an invention name of “Substituted piperidine compounds and their uses”. Technical Field

[0002] The present invention relates to a substituted piperidine compound having orexin type 2 receptor agonist activity or a pharmaceutically acceptable salt thereof and its medical use. In addition, the present invention relates to a medicine containing the compound as an active ingredient. Background Art

[0003] Two brain neuropeptides, orexin-A (OX-A) and orexin-B (OX-B), which are specifically produced by specific neurons located in the lateral hypothalamus, are found as endogenous ligands of orexin receptors (Patent Documents 1-4) (Patent Document 5, Non-Patent Document 1), which are G protein-coupled receptors mainly present in the brain. It is known that there are two subtypes of orexin receptors, namely, OX1 receptor (hereinafter also referred to as OX1R), which is a type 1 subtype, and OX2 receptor (hereinafter also referred to as OX2R), which is a type 2 subtype. It has been found that orexin can increase the feeding behavior of rats (Non-Patent Document 1).

[0004] On the other hand, it is reported that the cause of canine narcolepsy is a genetic mutation of OX2R (non-patent document 2), and in addition, orexin-deficient mice show narcolepsy-like symptoms that are very similar to narcolepsy in humans or dogs (non-patent document 3). In addition, according to studies using transgenic mice and double transgenic mice, narcolepsy-like symptoms that appear due to the modification of orexin neurons disappear due to the continued expression of orexin (non-patent document 4), and the transgenic mice are mice after orexin nerve degeneration, and the double transgenic mice are obtained by mating the transgenic mice and orexin overexpressing transgenic mice. Similarly, even when OX-A is applied to the intracerebroventricular ventricle of transgenic mice obtained by degeneration of orexin neurons, improvements in narcolepsy-like symptoms are observed, such as inhibition of cataplexy-like behavioral stagnation and increased wakefulness (non-patent document 4). In addition, according to studies on OX2R knockout mice, OX2R is important for maintaining wakefulness (non-patent document 5). In addition, it is suggested that the daytime sleepiness of patients with Parkinson's disease is caused by the loss of orexin nerves (Non-Patent Document 6). In addition, it is suggested that the OX-A concentration level in the plasma of patients with sleep apnea syndrome is low (Non-Patent Document 7). In this context, it is suggested that OX2R agonists can be used as therapeutic drugs for narcolepsy and other sleep disorders that present with excessive sleep (Non-Patent Document 8).

[0005] Therefore, it is believed that compounds having OX2R agonist activity can be used as therapeutic drugs for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, consciousness disorders such as lethargy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, and hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, Kleine-Levin syndrome).

[0006] Regarding TAK-925, a compound having OX2R agonist activity, a Phase I trial (intravenous administration) is being conducted on healthy subjects and narcolepsy patients.

[0007] Prior art literature

[0008] Patent Literature

[0009] [Patent Document 1] International Publication No. 1996 / 34877

[0010] [Patent Document 2] Japanese Patent Application Laid-Open No. 10-327888

[0011] [Patent Document 3] Japanese Patent Application Laid-Open No. 10-327889

[0012] [Patent Document 4] Japanese Patent Application Laid-Open No. 11-178588

[0013] [Patent Document 5] Japanese Patent Application Laid-Open No. 10-229887

[0014] Non-patent literature

[0015] [Non-patent document 1] Sakurai T. et al, Cell, 1998, 92, 573-585

[0016] [Non-patent document 2] Lin L. et al, Cell, 1999, 98, 365-376

[0017] [Non-patent document 3] Chemelli RM et al, Cell, 1999, 98, 437-451

[0018] [Non-patent document 4] Mieda M. et al, Proc. Natl. Acad. Sci. USA, 2004, 101, 4649-4654

[0019] [Non-patent document 5] Willie JT et al, Neuron, 2003, 38, 715-730

[0020] [Non-patent document 6] Thannickal TC et al, Brain. 2007, 130, 1586-1595

[0021] [Non-patent document 7] Busquets X. et al, Respiration, 2004, 71, 575-579

[0022] [Non-patent document 8] Mieda M. et al, CNSDrugs, 2013, 27, 83-90 Summary of the invention

[0023] Problems to be solved by the invention

[0024] An object of the present invention is to provide a substituted piperidine compound having orexin type 2 receptor agonist activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.

[0025] Technical means of solving problems

[0026] That is, the present invention relates to the following [1] to

[21] .

[0027] [1] A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following formula (I):

[0028] [Chemistry 1]

[0029]

[0030] (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide,

[0031] The following formula (II)

[0032] [Chemistry 2]

[0033]

[0034] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide,

[0035] The following formula (III)

[0036] [Chemistry 3]

[0037]

[0038] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide,

[0039] and

[0040] The following formula (IV)

[0041] [Chemistry 4]

[0042]

[0043] (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide

[0044] One of the groups formed.

[0045] [2] (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (I):

[0046] [Chemistry 5]

[0047]

[0048] [3] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide or a pharmaceutically acceptable salt thereof, the compound being represented by the following formula (II):

[0049] [Chemistry 6]

[0050]

[0051] [4] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide or a pharmaceutically acceptable salt thereof, the compound being represented by the following formula (III):

[0052] [Chemistry 7]

[0053]

[0054] [5] (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (IV):

[0055] [Chemistry 8]

[0056]

[0057] [6] A pharmaceutical composition comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.

[0058] [7] An orexin type 2 receptor agonist comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.

[0059] [8] A therapeutic agent for narcolepsy, comprising the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof.

[0060] [9] A method for treating narcolepsy in a subject, comprising administering a pharmacologically effective amount of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof to the subject.

[0061]

[10] A method for activating orexin type 2 receptor in a subject, comprising administering a pharmacologically effective amount of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof to the subject.

[0062]

[11] A method for treating narcolepsy, comprising administering the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof to a subject.

[0063]

[12] Use of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating narcolepsy.

[0064]

[13] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, which is used for treating narcolepsy.

[0065]

[14] A therapeutic agent for cataplexy, comprising the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof.

[0066]

[15] A method for treating cataplexy in a subject, comprising administering a pharmacologically effective amount of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof to the subject.

[0067]

[16] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, which is used for treating cataplexy.

[0068]

[17] Use of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating cataplexy.

[0069]

[18] A therapeutic agent for hypersomnia, comprising the compound described in any one of [1] to [5] or a pharmaceutically acceptable salt thereof.

[0070]

[19] A method for treating hypersomnia in a subject, comprising administering a pharmacologically effective amount of the compound described in any one of [1] to [5] or a pharmaceutically acceptable salt thereof to the subject.

[0071]

[20] A compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, for use in treating hypersomnia.

[0072]

[21] Use of the compound described in any one of [1] to [5] or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating hypersomnia.

[0073] This application relates to the following items:

[0074] Item 1. A compound or a pharmaceutically acceptable salt thereof, the compound being selected from the following formula (I):

[0075]

[0076] (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide,

[0077] The following formula (II)

[0078]

[0079] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide,

[0080] The following formula (III)

[0081]

[0082] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide,

[0083] and

[0084] The following formula (IV)

[0085]

[0086] (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide

[0087] One of the groups formed.

[0088] Item 2. (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide represented by the following formula (I), or a pharmaceutically acceptable salt thereof

[0089]

[0090] Item 3. (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide represented by the following formula (II), or a pharmaceutically acceptable salt thereof

[0091]

[0092] Item 4. (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide represented by the following formula (III), or a pharmaceutically acceptable salt thereof

[0093]

[0094] Item 5. (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide represented by the following formula (IV), or a pharmaceutically acceptable salt thereof

[0095]

[0096] Item 6. A pharmaceutical composition comprising the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0097] Item 7. An orexin type 2 receptor agonist comprising the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0098] Item 8. A therapeutic agent for narcolepsy, comprising the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0099] Item 9. A method for treating narcolepsy in a subject, comprising administering a pharmacologically effective amount of the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof to the subject.

[0100] Item 10. The compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, which is used for treating narcolepsy.

[0101] Item 11. Use of the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating narcolepsy.

[0102] Item 12. A therapeutic agent for cataplexy, comprising the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0103] Item 13. A method for treating cataplexy in a subject, comprising administering a pharmacologically effective amount of the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof to the subject.

[0104] Item 14. The compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof, for use in preventing or treating cataplexy.

[0105] Item 15. Use of the compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating cataplexy.

[0106] Effects of the Invention

[0107] The substituted piperidine compounds represented by formula (I), (II), (III) and (IV) of the present invention (hereinafter referred to as compounds (I), (II), (III) and (IV)) or pharmaceutically acceptable salts thereof have orexin type 2 receptor agonist activity as shown by the activity data in the following pharmacological test examples. The compounds (I), (II), (III) and (IV) of the present invention have orexin type 2 receptor agonist activity and are useful as therapeutic agents for narcolepsy. BRIEF DESCRIPTION OF THE DRAWINGS

[0108] Figure 1 It is an ORTEP diagram (Oak Ridge Thermal Ellipsoid Plot) showing the result of X-ray crystal structure analysis of the compound obtained in Example 1.

[0109] Figure 2 This is an ORTEP diagram showing the results of X-ray crystal structure analysis of the compound obtained in Example 3 (a dimer obtained by adding two molecules of acetonitrile).

[0110] Figure 3 This is an ORTEP diagram showing the results of X-ray crystal structure analysis of the compound obtained in Example 4. DETAILED DESCRIPTION

[0111] Hereinafter, the contents of the present invention will be described in detail.

[0112] The compounds of the present invention may exist in polymorphic forms, but are not limited to any one of them. They may be a single substance of any crystalline form or a mixture. In addition, the compounds of the present invention also include amorphous bodies, and the compounds of the present invention include anhydrates and solvates (especially hydrates).

[0113] The present invention also includes isotope-labeled compounds of compounds (I), (II), (III) and (IV). In an isotope-labeled compound, one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature, and otherwise are the same as compounds (I), (II), (III) and (IV). Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, iodine, and chlorine, including 2 H. 3 H. 11 C. 14 C. 15 N. 18 O. 18 F. 32 P. 35 S. 123 I, and 125 I etc.

[0114] The isotope-labeled compound, for example, 3 H and / or 14 Compounds containing radioactive isotopes such as C can be used to examine the tissue distribution of drugs and / or substrates. 3 H and 14 C is considered useful because it is easy to prepare and detect. 11 C and 18 F is considered to be useful for PET (positron emission tomography), an isotope 125 I is considered useful in SPECT (single photon emission computed tomography), and all of the isotopes are useful for brain imaging. 2 Heavier isotope substitutions such as H may produce certain therapeutic benefits, such as increased metabolic stability leading to increased half-life in vivo or reduced dosage, and are therefore considered useful in certain circumstances. The isotope-labeled compounds may also be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents and performing the steps disclosed in the following examples.

[0115] The "pharmaceutically acceptable salt" in the present specification is not particularly limited as long as it forms a salt with the compound of the present invention, and specific examples thereof include acid addition salts such as inorganic acid salts, organic acid salts, and acidic amino acid salts.

[0116] Unless otherwise specified, the "pharmaceutically acceptable salt" in this specification means that when a salt is formed in an appropriate ratio, the number of acid molecules in the formed salt is not particularly limited relative to 1 molecule of the compound. Preferably, the number of acid molecules is about 0.5 to about 2 molecules relative to 1 molecule of the compound, and more preferably, the number of acid molecules is about 0.5, about 1, or about 2 molecules relative to 1 molecule of the compound.

[0117] Preferred examples of inorganic acid salts include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates and the like, and preferred examples of organic acid salts include acetates, succinates, fumarates, maleates, tartrates, citrates, lactates, stearates, benzoates, methanesulfonates, p-toluenesulfonates, benzenesulfonates and the like.

[0118] Preferred examples of the acidic amino acid salt include aspartate and glutamate.

[0119] When the compounds (I), (II), (III) and (IV) of the present invention are obtained in the form of free bodies, they can be converted into salts or hydrates thereof that the compounds (I), (II), (III) and (IV) can form according to conventional methods.

[0120] When the compounds (I), (II), (III) and (IV) of the present invention are obtained in the form of salts of the compounds (I), (II), (III) and (IV) or hydrates of the compounds (I), (II), (III) and (IV), they can be converted into free forms of the compounds (I), (II), (III) and (IV) according to conventional methods.

[0121] In addition, various isomers (e.g., optical isomers, rotational isomers, stereoisomers, etc.) obtained from compounds (I), (II), (III) and (IV) of the present invention can be purified and separated by using conventional separation means, such as recrystallization, diastereoisomer salt method, enzyme cleavage method, various chromatography methods (e.g., thin layer chromatography, column chromatography, gas chromatography, etc.).

[0122] [preparation]

[0123] The pharmaceutical composition of the present invention can be prepared by mixing a pharmaceutically acceptable additive with a compound selected from compound group (I), (II), (III) and (IV) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention can be prepared by a known method such as the method described in the general rules for preparations of the seventeenth revised edition of the Japanese Pharmacopoeia.

[0124] The pharmaceutical composition of the present invention can be appropriately administered to patients according to its dosage form.

[0125] The dosage of the compounds (I), (II), (III) and (IV) of the present invention, or their pharmaceutically acceptable salts, varies depending on the severity of symptoms, age, sex, body weight, administration form / type of salt, specific type of disease, etc. Generally, for adults, about 30 μg to 10 g, preferably 100 μg to 5 g, more preferably 100 μg to 1 g, are administered once a day or in divided doses; and about 30 μg to 1 g, preferably 100 μg to 500 mg, more preferably 100 μg to 300 mg, are administered once a day or in divided doses.

[0126] In the present specification, the term "orexin type 2 receptor agonist" refers to a drug that binds to orexin type 2 receptor and activates orexin type 2 receptor in the same manner as a ligand in vivo.

[0127] The compounds of the present invention can be made into chemical probes for capturing target proteins of low molecular weight compounds with physiological activity. That is, the compounds of the present invention can be converted into affinity chromatography probes, photoaffinity probes, etc. by introducing a labeling group, a linking group, etc. into a part different from the structural part required for the activity expression of the compound using the method described in J.Mass Spectrum.Soc.Jpn. [Japan Mass Spectrometry Society] Vol. 51, No. 5, 2003, pp. 492-498 or WO 2007 / 139149, etc.

[0128] Examples of labeling groups, linking groups, and the like used in chemical probes include groups shown in the group consisting of the following (1) to (5).

[0129] (1) Protein labeling groups such as photoaffinity labeling groups (e.g., benzoyl, benzophenone, azido, carbonylazido, diaziridinyl, enone, diazo, and nitro) and chemical affinity groups (e.g., keto groups with α-carbon atoms substituted by halogen atoms, carbamoyl, ester groups, alkylthio groups, α,β-unsaturated ketones, esters, and Michael acceptors, and oxirane groups);

[0130] (2) cleavable linkers such as -SS-, -O-Si-O-, monosaccharides (glucose, galactosyl, etc.) or disaccharides (lactose, etc.), and oligopeptide linkers cleavable by enzymatic reactions;

[0131] (3) Fishing tag groups such as biotin and 3-(4,4-difluoro-5,7-dimethyl-4H-3a,4a-diaza-4-boron-s-indane-3-yl) propionyl;

[0132] (4) 125 I. 32 P. 3 H. 14C and other radioactive labeling groups; fluorescent labeling groups such as fluorescein, rhodamine, dansyl, umbelliferone, 7-nitrofurazolyl, 3-(4,4-difluoro-5,7-dimethyl-4H-3a,4a-diaza-4-boron-s-benzodiinden-3-yl) propionyl; chemiluminescent groups such as firefly fluorescein and luminol; detectable markers such as lanthanide metal ions, heavy metal ions such as radium ions, etc.; or

[0133] (5) Groups that bind to solid phase carriers such as glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, nylon beds, etc.

[0134] According to the methods described in the literature, etc., the labeling group selected from the group consisting of (1) to (5) is introduced into the compound of the present invention to prepare a probe. The prepared probe can be used as a chemical probe to identify the labeled protein, and the labeled protein can be used to explore new drug development targets, etc.

[0135] Implementation

[0136] Compounds (I), (II), (III) and (IV) of the present invention can be manufactured by the method described in the following examples, for example. In addition, the effect of the compound can be confirmed by the method described in the following test examples. However, these are illustrative, and the present invention is not limited by the following specific examples under any circumstances. In addition, it can also be changed within the scope of the present invention.

[0137] The compounds described with reference names etc. indicate that they were produced based on the references etc.

[0138] In addition, the abbreviations used in this specification are commonly used abbreviations well known to those skilled in the art. The following abbreviations are used in this specification.

[0139] n-: positive

[0140] tert-: uncle

[0141] 1 H-NMR: Proton Nuclear Magnetic Resonance Spectrometer

[0142] MS: mass spectrometer

[0143] HPLC: High Speed ​​Liquid Chromatography

[0144] In the following examples and preparation examples, "room temperature" generally means about 10° C. to about 35° C. Unless otherwise specified, % means weight percentage.

[0145] Chemical shifts in proton nuclear magnetic resonance spectra are reported in δ units (ppm) for tetramethylsilane, and coupling constants are reported in Hertz (Hz). Graphics are represented, for example, by s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, brs: broad singlet, etc.

[0146] Mass spectrometry was performed using Acquity UPLC (registered trademark) or Acquity UPC 2 (Registered Trademark) is carried out.

[0147] For chromatography, silica gel was used: Silica Gel 60 (70-230 mesh, or 230-400 mesh ASTM) manufactured by Merck, or PSQ60B manufactured by Fuji Silicon Chemical Co., Ltd., or a pre-packed column {column: Hi-Flash manufactured by Yamazen Co., Ltd. TM Column (silicone), size: S (16 × 60 mm), M (20 × 75 mm), L (26 × 100 mm), 2L (26 × 150 mm), 3L (46 × 130 mm), or Biotage manufactured by Biotage TM SNAP Ultra Silica Cartridge, size: any one of 10 g, 25 g, and 50 g}. In addition, fractionation by supercritical fluid chromatography (SFC) was performed using Prep100q manufactured by Waters Corporation.

[0148] NH silica gel uses CHROMATOREX NH-DM2035 manufactured by Fuji Silicon Chemical Co., Ltd., or a pre-packed column {column: Hi-Flash manufactured by Yamazen Co., Ltd. TM (Registered trademark) Column (amino), size: any one of S (16 × 60 mm), M (20 × 75 mm), L (26 × 100 mm), 2L (26 × 150 mm), 3L (46 × 130 mm), or Presep manufactured by Wako Pure Chemical Industries, Ltd. TM (Registered trademark) (Luer lock) NH2 (HC), size: any one of M type (14 g / 25 mL), L type (34 g / 70 mL), 2L type (50 g / 100 mL), and 3L type (110 g / 200 mL).

[0149] The nomenclature of the compounds shown below uses the nomenclature described in "E-notebook" 12th or 13th edition (PerkinElmer) except for commonly used reagents.

[0150] Production Example 1

[0151] Synthesis of 2-Bromo-2-cyclopropylacetamide

[0152] [Chemistry 9]

[0153]

[0154] To a solution of cyclopropylacetic acid (CAS No.5239-82-7) (3.30 g, 33.0 mmol) in 1,2-dichloroethane (60 mL) was added oxalyl chloride (CAS No.79-37-8) (3.11 mL, 36.3 mmol) and N,N-dimethylformamide (60.0 μL, 0.775 mmol), and the mixture was stirred at room temperature for 40 minutes. Hydrobromic acid (56.0 mg, 0.330 mmol) and N-bromosuccinimide (CAS No.128-08-5) (7.04 g, 39.6 mmol) were added to the reaction solution, and the mixture was heated under reflux for 18 hours. The reaction solution was added to aqueous ammonia (28% aqueous solution, 60 mL, 2.77 mol) at 0°C, and ethyl acetate and sodium hydroxide (2N aqueous solution) were added for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was triturated with ethyl acetate / n-heptane, and the precipitate was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (1.20 g).

[0155] MS (ESI) m / z: 178 [M+H] +

[0156] Production Example 2

[0157] Synthesis of 3-methoxyisonicotinonitrile

[0158] [Chemistry 10]

[0159]

[0160] To a solution of 3-chloro-4-cyanopyridine (CAS No. 68325-15-5) (5.00 g, 36.1 mmol) in tetrahydrofuran (36.0 mL) was added sodium methoxide (CAS No. 124-41-4) (3.90 g, 72.2 mmol) at room temperature, and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The obtained solid was ground with ethyl acetate / n-heptane, and the precipitate was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (1.91 g).

[0161] 1H-NMR (400MHz, CDCl3) δ (ppm): 4.06 (s, 3H), 7.44 (d, J = 5.0Hz, 1H), 8.37 (d, J = 4.5Hz, 1H), 8.49 (s, 1H).

[0162] MS (ESI) m / z: 135 [M+H] +

[0163] Production Example 3

[0164] Synthesis of (R)-2-Bromo-3-methylbutyramide

[0165] [Chemistry 11]

[0166]

[0167] To a solution of (R)-2-bromo-3-methylbutyric acid (CAS No. 76792-22-8) (9.80 g, 54.1 mmol) in dichloromethane (100 mL) was added oxalyl chloride (9.28 mL, 108 mmol) and N,N-dimethylformamide (30.0 μL, 0.387 mmol) at 0°C, and the mixture was stirred at room temperature for 6 hours. The reaction solution was added to aqueous ammonia (28% aqueous solution, 50.0 mL, 2.31 mol) at 0°C, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The obtained solid was ground with ethyl acetate / n-heptane, and the precipitate was filtered out. The obtained solid was dried under reduced pressure to obtain the title compound (8.20 g).

[0168] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.01 (d, J = 6.3Hz, 3H), 1.07 (d, J = 6.8Hz, 3H), 2.34-2.39 (m, 1H), 4.28 (d, J = 4.5Hz, 1H), 5.58 (brs, 1H), 6.41 (brs, 1H).

[0169] MS (ESI) m / z: 180 [M+H] +

[0170] Production Example 4

[0171] (1R,3s,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo [3.2.1] Synthesis of octane

[0172] [Chemistry 12]

[0173]

[0174] (1) (1R,3r,5S)-3-Hydroxy-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate Synthesis of tert-butyl ester

[0175] To a solution of N-(tert-butoxycarbonyl)-nortropinone (CAS No. 185099-67-6) (1.00 g, 4.44 mmol) in methyl tert-butyl ether (18.0 mL) was added 3-methoxyisonicotinonitrile (1.19 g, 8.88 mmol) and bis(pinacolato)diboron (CAS No. 73183-34-3) (2.25 g, 8.88 mmol), and the mixture was heated to reflux for 16 hours. Sodium carbonate (2 mol / L aqueous solution, 20.0 mL) was added to the reaction mixture at 0°C, and stirred at 0°C for 20 minutes. Ethyl acetate was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% methanol / ethyl acetate) to obtain the title compound (1.12 g).

[0176] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.48 (s, 9H), 1.77 (m, 2H), 1.94-1.99 (m, 2H), 2.21-2.32 (m, 2H), 2.37-2.48 (m, 1H), 2.63 -2.74(m,1H),2.78(s,1H),3.96(s,3H),4.22-4.29(m,1H),4.31-4.42(m,1H),7.28(d,J=5.4Hz,1H),8.22-8.25(m,2H).

[0177] MS (ESI) m / z: 335 [M+H] +

[0178] (2) tert-Butyl (1R,5S)-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate Synthesis of esters

[0179] Concentrated sulfuric acid (1.60 mL, 30.0 mmol) was added to tert-butyl (1R, 3r, 5S)-3-hydroxy-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (610 mg, 1.82 mmol) and stirred at room temperature for 40 minutes. The reaction mixture was added to a solution of potassium hydroxide (5.00 g, 89.1 mmol) in water (10.0 mL) at 0°C. Tetrahydrofuran (10.0 mL) and di-tert-butyl dicarbonate (CAS No. 24424-99-5) (478 mg, 2.19 mmol) were added to the reaction mixture and stirred at room temperature for 10 minutes. Ethyl acetate was added to the reaction mixture and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 5-100% ethyl acetate / n-heptane) to obtain the title compound (420 mg).

[0180] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.46 (s, 9H), 1.72-1.81 (m, 1H), 1.97-2.03 (m, 2H), 2.05-2.36 (m, 2H), 2.94-3.26 ( m,1H),3.87(s,3H),4.21-4.61(m,2H),6.30(brs,1H),6.99(d,J=4.5Hz,1H),8.17(d,J=5.0Hz,1H),8.21(s,1H).

[0181] MS (ESI) m / z: 317 [M+H] +

[0182] (3) Tert-butyl (1R,5S)-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate synthesis

[0183] 10% palladium on carbon (Kawaken Fine Chemicals Co., Ltd., AD, 52.7% water-containing product, 284 mg, 0.126 mmol) was added to a solution of (1R,5S)-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (400 mg, 1.26 mmol) in methanol (3.00 mL), and stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through celite (registered trademark), and the residue was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure to obtain a mixture of endo-form and exo-form (endo-form:exo-form = 1:2, 398 mg).

[0184] 1H-NMR (400MHz, CDCl3) δ (ppm): 1.49 (s, 6H), 1.50 (s, 3H), 1.61-2.13 (m, 22 / 3H), 2.40-2.45 (m, 2 / 3H), 2.96-3.01 (m, 1 / 3H), 3.47-3.59 (m, 2 / 3H),3.88(s,1H),3.90(s,2H),4.16-4.28(m,1H),4.34(brs,1H),7.04(d,J=4.5Hz,2 / 3H),7.06(d,J=5.0Hz,1 / 3H),8.13-8.23(m,2H).

[0185] MS (ESI) m / z: 319 [M+H] +

[0186] (4) tert-Butyl (1R,3s,5S)-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate Synthesis of esters

[0187] To a solution of (1R,5S)-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (398 mg, 1.25 mmol) in tert-butanol (4.00 mL) was added potassium tert-butoxide (281 mg, 2.50 mmol) and heated under reflux for 17 hours. Ethyl acetate and saturated brine were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure to obtain the title compound (385 mg).

[0188] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 1.58-2.06 (m, 8H), 3.49-3.56 (m, 1H), 3 .90(s,3H),4.24(brs,1H),4.34(brs,1H),7.04(d,J=5.0Hz,1H),8.17-8.19(m,2H).

[0189] MS (ESI) m / z: 319 [M+H] +

[0190] (5) (1R,3s,5S)-3-(1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo [3.2.1] Synthesis of tert-butyl octane-8-carboxylate

[0191] To a solution of (1R,3s,5S)-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (11.2 g, 35.2 mmol) in acetic acid (100 mL) was added 10% palladium on carbon (Kawaken Fine Chemicals Co., Ltd., AD, 52.7% water-containing product, 7.91 g, 3.52 mmol), and stirred at 70°C for 18 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth (registered trademark), and the residue was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure. Ethyl acetate and sodium hydroxide (2N) were added to the residue to separate the organic layer. The organic layer was dried and filtered using ISOLUTE (registered trademark) HM-N, and concentrated under reduced pressure. N,N-dimethylformamide (50.0 mL), 2-chloro-5-fluoropyrimidine (CAS No. 62802-42-0) (5.21 mL, 42.2 mmol) and potassium carbonate (7.29 g, 52.8 mmol) were added to the residue and stirred at 80°C for 40 minutes. Ethyl acetate and saturated brine were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10-60% ethyl acetate / n-heptane) to obtain the title compound (9.84 g).

[0192] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.19-1.30 (m, 3H), 1.46 (s, 9H), 1.46-1.65 (m, 6H), 1.81-1.97 (m, 3H), 2.68 (d, J=14.5Hz, 1 H),2.71-2.81(m,1H),3.30(s,3H),3.35(brs,1H),4.08-4.31(m,2H),4.64-4.77(m,1H),5.04-5.18(m,1H),8.13(s,2H).

[0193] MS (ESI) m / z: 421 [M+H] +

[0194] (6) (1R,3s,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-aza Synthesis of tert-butyl bicyclo[3.2.1]octane-8-carboxylate

[0195] For tert-butyl (1R,3s,5S)-3-(1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.00 g, 16.6 mmol), supercritical fluid chromatography (mobile phase CO2:methanol (90:10), 120 bar, 40°C, flow rate: 100 mL / min) using CHIRALPAK (registered trademark) IC / SFC (3 cm×25 cm) manufactured by Daicel Corporation was performed, and 100 mg was taken each time to obtain the title compound (3.02 g) with a retention time of 8.45 minutes.

[0196] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.17-1.29 (m, 3H), 1.46 (s, 9H), 1.46-1.66 (m, 6H), 1.85-1.97 (m, 3H), 2.68 (d, J = 15.0Hz, 1H), 2.75 (t d,J=12.9,3.2Hz,1H),3.30(s,3H),3.35(brs,1H),4.11-4.31(m,2H),4.66-4.76(m,1H),5.10(dt,J=14.4,2.6Hz,1H),8.13(s,2H).

[0197] MS (ESI) m / z: 443 [M+Na] +

[0198] (Analysis conditions) Supercritical fluid chromatography using CHIRALPAK (registered trademark) IC-3 (3.0 mm×50 mm) manufactured by Daicel Corporation (mobile phase CO2:methanol (85:15), 40°C, flow rate: 1.2 mL / min, detection: UV (254 nm))

[0199] (Analysis results) The retention time of the title compound was 1.34 minutes and the optical purity was >99%ee.

[0200] (7) (1R,3s,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-aza Synthesis of Bicyclo[3.2.1]octane

[0201] Trifluoroacetic acid (5.00 mL, 64.9 mmol) was added to tert-butyl (1R, 3s, 5S)-3-((3S, 4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.38 mmol) and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure. A 2N aqueous sodium hydroxide solution was added to the residue and extracted with ethyl acetate (3 times). The combined organic layer was dried over anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure to obtain the title compound (620 mg).

[0202] MS (ESI) m / z: 321 [M+H] +

[0203] Production Example 5

[0204] Synthesis of (S)-2-Bromo-2-cyclopropylacetamide

[0205] [Chemistry 13]

[0206]

[0207] (1) Synthesis of (S)-3-(2-cyclopropylacetyl)-4-phenyloxazolidin-2-one

[0208] Pivaloyl chloride (302 mL, 2470 mmol) was added to tetrahydrofuran (7000 mL) at room temperature. Cyclopropylacetic acid (238 mL, 2450 mmol) was added thereto at room temperature and cooled at 0°C. Triethylamine (350 mL) was added dropwise over 10 minutes, and then triethylamine (400 mL, total amount 5340 mmol) was added and stirred at 0°C for 76 minutes. (S)-4-phenyloxazolidin-2-one (350 g, 2140 mmol) was added to the reaction mixture at one time, and then lithium chloride (109 g, 2570 mmol) was added at one time. After the reaction mixture was stirred at room temperature for 18 hours, ethyl acetate (7000 mL) and water (3500 mL) were added and stirred at room temperature for 40 minutes. The organic layer was separated and washed with 5% aqueous sodium bicarbonate solution (3500 mL) and water (1750 mL) in sequence. The obtained organic layer was concentrated to 1750 mL. Ethyl acetate (2100mL) was added and concentrated to 1750mL. After repeating this azeotropic operation 3 times, ethyl acetate (1050mL) was further added and concentrated to 1750mL. The obtained concentrated solution was stirred and n-heptane (1000mL) was added dropwise. The resulting suspension was stirred for 10 minutes, and n-heptane (2500mL) was further added dropwise. After the mixed solution was stirred at room temperature overnight, it was further stirred at 0°C for 3.5 hours. The generated solid was filtered out using a glass filter and washed with ethyl acetate / n-heptane (550mL of a mixed solution of 1:3). The obtained solid was dried under reduced pressure to obtain the title compound (407g).

[0209] 1 H-NMR (400MHz, CDCl3) δ (ppm): 0.09-0.24 (m, 2H) 0.46-0.58 (m, 2H) 1.00-1.13 (m, 1H), 2.74-2.83 (m, 1H), 2.8 8-2.98(m,1H),4.25-4.32(m,1H),4.70(t,J=8.83Hz,1H),5.45(dd,J=8.83,3.85Hz,1H),7.28-7.43(m,5H).

[0210] (2) Synthesis of (S)-2-Bromo-2-cyclopropylacetamide

[0211] Under ice-bath cooling, a 1M dichloromethane solution (500 mL, 500 mmol) of dibutylboron trifluoromethanesulfonate was added dropwise to a dichloromethane (1000 mL) solution of (S)-3-(2-cyclopropylacetyl)-4-phenyloxazolidin-2-one (100 g, 408 mmol) over 40 minutes, and stirred under ice-bath cooling for 10 minutes. N,N-diisopropylethylamine (92 mL, 530 mmol) was added dropwise over 25 minutes under ice-bath cooling, and stirred under ice-bath cooling for 1 hour. Thereafter, the reaction mixture was cooled to an internal temperature of -72°C using a dry ice-ethanol bath. N-bromosuccinimide (80 g, 448 mmol) was added all at once, and stirred under a dry ice-ethanol bath for 1 hour and 20 minutes. After adding 28-30% aqueous ammonia (800 mL, 6390 mmol) and tetrahydrofuran (1000 mL), the mixture was stirred under a water bath for 2 hours. After separation of the organic layer and the aqueous layer, the aqueous layer was extracted 3 times with ethyl acetate (500 mL). The obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel 4 kg, 30-40% ethyl acetate / n-heptane) to obtain 132 g of crude product. Tert-butyl methyl ether (1440 mL) was added to the obtained crude product, stirred at 50 ° C for one hour to dissolve the crude product, and then stirred at room temperature for 1 day. The generated solid was filtered and washed with tert-butyl methyl ether (200 mL). The filtrate and the washing liquid were combined, ethyl acetate (700 mL) and activated carbon (purified white egret, 26 g) were added thereto, and stirred at room temperature for 30 minutes. The activated carbon was removed by filtration through diatomaceous earth (registered trademark), and the activated carbon was washed with ethyl acetate (700 mL). After combining the filtrate and the washing liquid, they were concentrated under reduced pressure to obtain the title compound (97.1 g, content 65.9%).

[0212] 1 H-NMR (400MHz, CDCl3) δ (ppm): 0.40-0.52 (m, 1H), 0.63-0.73 (m, 1H), 0.77-0.86 (m, 1H), 0.8 6-0.97(m,1H),1.41-1.50(m,1H),3.59-3.83(m,1H),5.34-5.71(m,1H),5.94-6.30(m,1H).

[0213] MS (ESI) m / z: 180 [M+H] +

[0214] (Analysis conditions) Chromatography using CHIRALPAK (registered trademark) IA (0.46 cm × 25 cm × 2 strips) manufactured by Daicel Corporation (mobile phase ethanol:n-hexane (10:90), 40°C, flow rate: 0.8 mL / min, detection: UV (210 nm))

[0215] (Analysis results) The retention time of the title compound was 24.5 minutes.

[0216] Example 1

[0217] (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin- Synthesis of 4-(4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide

[0218] [Chemistry 14]

[0219]

[0220] 2-Bromo-2-cyclopropylacetamide (433 mg, 2.43 mmol), cesium carbonate (793 mg, 2.43 mmol), and silver oxide (564 mg, 2.43 mmol) were added to a solution of (1R, 3s, 5S)-3-((3S, 4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane (260 mg, 0.811 mmol) in acetonitrile (4.00 mL), and the mixture was stirred at room temperature for 40 hours. The reaction solution was directly purified by column chromatography (silica gel, 20% methanol / ethyl acetate). The obtained product was dissolved in methanol (10 mL) and supplied to Waters Porapak Rxn (registered trademark) CX (2 2 g cartridges). After the solid phase was washed with methanol (20 mL), the product was eluted with aqueous ammonia (2 mol / L methanol solution, 20 mL), and the combined eluent was concentrated under reduced pressure. The residue was dissolved in methanol, and supercritical fluid chromatography (mobile phase CO2: methanol (85:15), 120 bar, 40°C, flow rate: 70 mL / min) using CHIRALPAK (registered trademark) OD-H / SFC (2 cm×25 cm) manufactured by Daicel Corporation was used. 10 mg / 500 μL (methanol) was taken each time to obtain a compound (120 mg) with a retention time of 6.41 minutes as an enantiomeric mixture. The obtained compound was dissolved in methanol, and 13 mg / 500 μL (methanol) was fractionated by supercritical fluid chromatography using CHIRALPAK (registered trademark) IG / SFC (2 cm×25 cm) manufactured by Daicel Corporation (mobile phase CO2: methanol (75:25), 120 bar, 40°C, flow rate: 70 mL / min), and a compound (75 mg) with a retention time of 9.11 minutes mainly composed of the component eluted later was obtained. The obtained compound was dissolved in methanol, and 4 mg / 100 μL (methanol) was fractionated by supercritical fluid chromatography using CHIRALPAK (registered trademark) IG / SFC (2 cm×25 cm) manufactured by Daicel Corporation (mobile phase CO2: methanol (75:25), 120 bar, 40°C, flow rate: 70 mL / min), and a compound (52 mg) with a retention time of 7.52 minutes mainly composed of the component eluted later was obtained. The obtained compound was dissolved in methanol, and 7 mg / 500 μL (methanol) was taken each time using supercritical fluid chromatography (mobile phase CO2: methanol (75:25), 120 bar, 40°C, flow rate: 70 mL / min) using CHIRALPAK (registered trademark) IG / SFC (2 cm×25 cm) manufactured by Daicel Corporation to obtain the title compound (31.3 mg) with a retention time of 7.18 minutes.

[0221] 1H-NMR (400MHz, CDCl3) δ (ppm): 0.28-0.37 (m, 1H), 0.45-0.52 (m, 1H), 0.53-0.58 (m, 1H), 0.60-0.68 (m, 1H), 0.78 (dd, J = 8.8, 4.3Hz,1H),1.20-1.27(m,2H),1.32-1.45(m,2H),1.46-1.52(m,2H),1.59-1.65(m,3H),1.70-1.80(m,2H),1.81-1.88(m,1H) ,2.08(d,J=9.1Hz,1H),2.68(dd,J=14.3,1.1Hz,1H),2.75(td,J=12.8,2.9Hz,1H),3.21-3.24(m,1H),3.30(s,3H),3.36(brs ,1H),3.86-3.91(m,1H),4.65-4.76(m,1H),5.10(dt,J=14.2,2.4Hz,1H),5.14-5.24(m,1H),6.92-7.02(m,1H),8.14(s,2H).

[0222] MS (ESI) m / z: 418 [M+H] +

[0223] (Analysis conditions) Chromatography using CHIRALPAK (registered trademark) IA (0.46 cm × 15 cm) manufactured by Daicel Corporation (mobile phase ethanol:hexane (20:80), 40°C, flow rate: 1 mL / min, detection: UV (254 nm))

[0224] (Analysis results) The retention time of the title compound was 4.91 minutes and the optical purity was >99%ee.

[0225] (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin- Preparation and X-ray Crystal Structure Analysis of Single Crystal of 8-Azabicyclo[3.2.1]octan-8-yl)acetamide

[0226] The title compound (2.97 mg) obtained in Example 1 was dissolved in methanol (1 mL). 500 μL of the solution was added to a small glass bottle and the lid was gently closed (solvent evaporation method). After 1 day, a single crystal of the title compound was obtained in the small glass bottle. X-ray crystal structure analysis was performed on the obtained single crystal under the following conditions. The X-ray crystal structure of the title compound is shown in Figure 1 .

[0227] Analysis machine: XtaLAB PRO P200 MM007HF (Rigaku, Japan)

[0228] Software: CrysAlisPro (Science Oxford Diffraction)

[0229] X-ray: Multi-layer mirror monochromatic Cu-Kα (40kV / 30mA)

[0230] Measurement method: ω axis oscillation method

[0231] Camera length: 35mm

[0232] Measuring temperature: -170℃

[0233] In addition, the IUPAC name of (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide synthesized in Example 1 is (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide.

[0234] Example 2

[0235] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8- Synthesis of Azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide

[0236] [Chemistry 15]

[0237]

[0238] To a solution of (1R,3s,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane (290 mg, 0.905 mmol) in acetonitrile (8.00 mL) were added (R)-2-bromo-3-methylbutanamide (326 mg, 1.81 mmol), cesium carbonate (590 mg, 1.81 mmol), and silver oxide (419 mg, 1.81 mmol), and stirred at room temperature for 40 hours. The reaction solution was filtered through silica gel, and the residue was washed with 20% methanol / ethyl acetate. The obtained filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and supplied to Waters Porapak Rxn (registered trademark) CX (block, 4 g). After washing the solid phase with methanol (40 mL), the product was eluted with aqueous ammonia (2N methanol solution, 40 mL), and the eluate was concentrated under reduced pressure. 5 mg of the residue was fractionated each time using CHIRALPAK (registered trademark) IG / SFC (2 cm×25 cm) manufactured by Daicel Corporation (mobile phase CO2: methanol (80:20), 120 bar, 40°C, flow rate: 70 mL / min) to obtain the title compound (154 mg) with a retention time of 4.41 minutes.

[0239] 1 H-NMR (400MHz, CDCl3) δ (ppm): 0.95 (d, J = 6.8Hz, 3H), 1.02 (d, J = 6.8Hz, 3H), 1.15-1.56 (m, 8H) ,1.75(td,J=10.8,6.1Hz,3H),1.86-2.10(m,2H),2.67(d,J=13.1Hz,1H),2.75(td,J=12.9,3. 2Hz,1H),2.95(d,J=4.1Hz,1H),3.19-3.27(m,1H),3.30(s,3H),3.33-3.46(m,2H),4.70(dt,J =13.3, 2.2Hz, 1H), 5.06-5.16 (m, 1H), 5.30-5.36 (m, 1H), 6.79 (brd, J = 5.0Hz, 1H), 8.14 (s, 2H).

[0240] MS (ESI) m / z: 421 [M+H] +

[0241] Example 3

[0242] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8- Synthesis of Azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide

[0243] [Chemistry 16]

[0244]

[0245] (1) (1R, 3s, 5S)-3-((3S, 4R)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8- Synthesis of tert-butyl formate hemi(2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate

[0246] A mixture of tert-butyl (1R, 3s, 5S)-3-(3-methoxypyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (20 g, 62.8 mmol) and 10% palladium on carbon (AD type manufactured by Kawaken Fine Chemicals, about 50% water content, 6 g) in acetic acid (160 mL) was stirred overnight at 70°C under a hydrogen atmosphere. The palladium on carbon was removed by filtration, washed with methanol (10 times the amount), and the filtrate was concentrated to about 2 times the amount. Isopropyl acetate (15 times the amount) and n-heptane (3 times the amount) were added to the obtained concentrated solution, and then washed with 48% sodium hydroxide aqueous solution (54.7 mL). n-heptane (100 mL) was added, washed with water (5 times the amount), and then concentrated to about 5 times the amount. Isopropyl acetate (5-fold amount) was added to the obtained concentrated liquid, and the solution was concentrated to about 5-fold amount. This azeotropic operation was repeated twice to obtain tert-butyl (1R,3s,5S)-3-(3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (15.1 g) as an isopropyl acetate solution.

[0247] To a solution of the obtained (1R,3s,5S)-3-(3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7.55 g, 23.3 mmol) and (+)-dipivaloyl-D-tartaric acid (1.85 g, 5.82 mmol) in isopropyl acetate (151 mL), acetonitrile (30.2 mL) and methanol (38 mL) was added (-)-di-p-toluoyl-L-tartaric acid (2.70 g, 6.98 mmol), and the mixture was stirred at room temperature for 3 days to obtain a solid.

[0248] After filtering out the obtained solid, the solid was washed with a mixed solution of isopropyl acetate and acetonitrile (9 / 1). The obtained mother liquor was concentrated to 10 times, and isopropyl acetate (10 times), 5N sodium hydroxide aqueous solution (4.65ml, 23.269mmol) and water (4 times) were added. After removing the water layer, it was washed with water (4 times). After concentrating to 5 times, isopropyl acetate (10 times) was added, and azeotropy was reduced to 5 times. (+)-di-pivaloyl-D-tartaric acid (3.15g, 8.144mmol) was added to a solution of (+)-dipivaloyl-D-tartaric acid (1.852g, 5.817mmol) in methanol (38mL), acetonitrile (30.2mL) and isopropyl acetate (151mL), and stirred overnight at room temperature. (+)-di-p-toluoyl-D-tartaric acid (0.05 equivalent) and isopropyl acetate (10 times the amount) were added. All were recovered by concentration, neutralization with sodium hydroxide, and washing with pure water. (+)-di-p-toluoyl-D-tartaric acid (0.2 equivalent) in isopropyl acetate (151 mL), acetonitrile (30.2 mL) and methanol (38 mL) were added to (+)-di-p-toluoyl-D-tartaric acid (3.15 g, 8.144 mmol) and stirred at room temperature overnight. (+)-di-p-toluoyl-D-tartaric acid (0.05 equivalent) was added to the reaction mixture and stirred at room temperature for 4 hours. (+)-di-p-toluoyl-D-tartaric acid (0.025 equivalent) and isopropyl acetate (10 times the amount) were added to the reaction mixture and stirred at room temperature overnight. The whole was recovered by concentration, neutralization with sodium hydroxide, and washing with pure water. (+)-di-p-toluoyl-D-tartaric acid (3.15 g, 8.14 mmol) was added to a solution of (+)-dipivaloyl-D-tartaric acid (0.2 equivalent) in isopropyl acetate (151 mL), acetonitrile (30.2 mL) and methanol (38 mL), and stirred overnight at room temperature. Isopropyl acetate (10 times the amount) was added. After 7 hours, the generated solid was filtered out and washed with isopropyl acetate to obtain the title compound (3.45 g).

[0249] (Analysis conditions) Chromatography using CHIRALPAK (registered trademark) IA (0.46 cm × 25 cm) manufactured by Daicel Corporation (mobile phase ethanol:n-hexane (20:80), 40°C, flow rate: 1.0 mL / min, detection: UV (254 nm))

[0250] (Analysis results) The retention time of the title compound was 8.52 minutes and the optical purity was 99.2%ee.

[0251] (2) (1R,3s,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-aza Synthesis of tert-butyl bicyclo[3.2.1]octane-8-carboxylate

[0252] 2,5-Dichloropyrimidine (288 mg, 1.93 mmol), (1R, 3s, 5S)-3-((3S, 4R)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester hemi(2S, 3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (500 mg, 0.966 mmol) and potassium carbonate (267 mg, 1.93 mmol) in N,N-dimethylformamide (10 mL) were stirred at 80°C for 24 hours. After cooling to room temperature, water was added and extracted with ethyl acetate three times. The organic layer was collected and concentrated. The obtained residue was purified by column chromatography (silica gel, 10-100% ethyl acetate / n-heptane) to obtain the title compound (368 mg).

[0253] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.24-1.27 (m, 2H), 1.41-1.49 (m, 2H), 1.46 (s, 9H), 1.61 (brs, 4H), 1.82-1.98 (m, 4H), 2.68 (d, J = 14.04Hz, 1H), 2 .75(td,J=12.91,3.17Hz,1H),3.30(s,3H),3.36(brs,1H),4.11-4.32( m, 2H), 4.68-4.80 (m, 1H), 5.12 (dt, J = 14.27, 2.61Hz, 1H), 8.16 (s, 2H).

[0254] (3) (1R,3s,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-8-azabi Synthesis of tert-butyl cyclo[3.2.1]octane-8-carboxylate

[0255] A mixture of (1R,3s,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.687 mmol) and 48% hydrobromic acid (5 mL) was stirred at room temperature for 20 minutes, and then heated at 100°C for 2.5 hours. The mixture was then stirred overnight at room temperature, and the obtained reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (10 mL) and a saturated aqueous sodium bicarbonate solution were added to the obtained residue, and di-tert-butyl dicarbonate (165 mg, 0.755 mmol) was added thereto at room temperature. After confirming the completion of the reaction by UPLC, ethyl acetate and water were added to separate the organic layer. The aqueous layer was extracted again with ethyl acetate, combined with the organic layer obtained first, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of 10% ethyl acetate / n-heptane to obtain the title compound (226 mg).

[0256] 1 H-NMR (400MHz, CDCl3) δ (ppm): 1.28-1.34 (m, 2H), 1.46 (s, 9H), 1.59-1.72 (m, 6H), 1.75-1.97 (m, 4H), 2.70-2.83 (m, 1H), 2.91(dd,J=14.04,0.91Hz,1H),3.97-4.03(m,1H),4.09-4.34(m,2H),4.68-4.79(m,1H),4.81-4.91(m,1H),8.18(s,2H). MS(ESI)m / z:423[M+H] +

[0257] (4) (1R,3s,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-aza Synthesis of tert-butyl bicyclo[3.2.1]octane-8-carboxylate

[0258] To a solution of (1R,3s,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.118 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, dispersed in liquid paraffin, 7.09 mg, 0.177 mmol) under ice bath cooling. After stirring for 30 minutes, iodoethane (0.019 mL, 0.236 mmol) was added and stirred at room temperature for 16 hours. After adding water and ethyl acetate to the reaction solution, the organic layer was separated and concentrated. The obtained residue was purified by column chromatography (silica gel, 1-20% ethyl acetate / n-heptane) to obtain the title compound (42.5 mg).

[0259] MS (ESI) m / z: 451 [M+H] +

[0260] (5) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)- Synthesis of 8-Azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide

[0261] Tert-butyl (1R,3s,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (42.5 mg, 0.094 mmol) was treated with trifluoroacetic acid (1 mL) for 30 minutes and then concentrated. The obtained residue was dissolved in methanol and applied to Waters Porapak Rxn (registered trademark) CX (0.4 g). The solid phase was washed with methanol (6 mL), and the product was eluted with aqueous ammonia (2 mol / L methanol solution, 6 mL), and the eluate was concentrated under reduced pressure. A mixture of the obtained residue, (S)-2-bromo-2-cyclopropylacetamide (51.6 mg, 0.188 mmol) obtained by the same operation as in Preparation Example 5, potassium carbonate (26.0 mg, 0.188 mmol) and acetonitrile (2 mL) was stirred at room temperature for 17 days. The reaction mixture was filtered using acetonitrile (3 mL), and 500 μL of the obtained filtrate was collected each time by supercritical fluid chromatography using CHIRALPAK (registered trademark) IA / SFC (3 cm×25 cm) manufactured by Daicel Corporation (mobile phase CO2:methanol (75:25), 120 bar, 40°C, flow rate: 100 mL / min) to obtain the title compound (22.2 mg) with a retention time of 7.55 minutes.

[0262] 1 H-NMR(400MHz, CDCl3)δ(ppm):0.26-0.38(m,1H),0.40-0.58(m,2H),0.59-0.68(m,1H),0 .71-0.83(m,1H),0.98-1.92(m,12H),1.04(t,J=7.02Hz,3H),2.07(brd,J=9.06Hz,1H),2 .61-2.81(m,2H),3.13-3.30(m,2H),3.45(brs,1H),3.61-3.75(m,1H),3.84-3.92(m,1H) ,4.66-4.76(m,1H),4.93-5.11(m,1H),5.17-5.32(m,1H),6.90-7.03(m,1H),8.16(s,2H).

[0263] MS (ESI) m / z: 448 [M+H] +

[0264] (Analysis conditions) Supercritical fluid chromatography using CHIRALPAK (registered trademark) IA-3 (0.46 cm × 25 cm) manufactured by Daicel Corporation (mobile phase: CO2:methanol (80:20), 40°C, flow rate: 1.2 mL / min, detection: UV (257 nm))

[0265] (Analysis results) The retention time of the title compound was 2.19 minutes and the optical purity was >99.9%ee.

[0266] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8- Preparation and X-ray Crystal Structure Analysis of Single Crystal of Azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide

[0267] The title compound (1.37 mg) obtained in Example 3 was dissolved in acetonitrile (600 μL). 200 μL of the solution was added to a small glass bottle and the lid was gently closed (solvent evaporation method). After 1 day, a single crystal of the title compound was obtained in the small glass bottle (crystal of a dimer obtained by adding 2 molecules of acetonitrile). X-ray crystal structure analysis was performed on the obtained single crystal under the following conditions. The X-ray crystal structure of the title compound is shown in Figure 2 .

[0268] Analysis machine: XtaLAB PRO P200 MM007HF (Japan Rigaku)

[0269] Software: CrysAlisPro (Science Oxford Diffraction)

[0270] X-ray: Multi-layer mirror monochromatic Cu-Kα (40kV / 30mA)

[0271] Measurement method: ω axis oscillation method

[0272] Camera length: 35mm

[0273] Measuring temperature: -170℃

[0274] Example 4

[0275] (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl) Synthesis of 8-azabicyclo[3.2.1]octan-8-yl)acetamide

[0276] [Chemistry 17]

[0277]

[0278] (1) (1R,3s,5S)-3-((S)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8-azabicyclo[3.2.1] Synthesis of ethyl octane-8-carboxylate

[0279] In a 13 mm screw cap test tube was added ethyl (1R,3s,5S)-3-(tosyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (CAS No. 2236076-85-8) (200 mg, 0.566 mmol), nickel (II) bromide ethylene glycol dimethyl ether complex (17.5 mg, 0.057 mmol), 4,4-di-tert-butyl-2,2-bipyridine (15.2 mg, 0.057 mmol), potassium iodide (94.0 mg, 0.566 mmol) and manganese (62.2 mg, 1.13 mmol). Then, under a nitrogen stream, a solution of (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (CAS No.876922-74-6) (195 mg, 0.566 mmol) in N,N-dimethylacetamide (4.0 mL) and 4-ethylpyridine (0.064 mL, 0.566 mmol) were added. The obtained mixture was stirred at 80° C. for 12.5 hours under a nitrogen atmosphere. After cooling to room temperature, it was diluted with ethyl acetate. Insoluble matter was removed by filtration with a cotton plug, and the elution was distributed with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with water 3 times, and concentrated under reduced pressure to obtain the coupling reaction product as a crude product.

[0280] Trifluoroacetic acid (1.0 mL) was added to a solution of the obtained crude product in dichloromethane (4.0 mL) and stirred at room temperature for 1 hour. The solvent was distilled off by blowing nitrogen into the reaction mixture, and the residue was diluted with methanol. The obtained methanol solution was supplied to Waters PοraPak Rxn (registered trademark) CX (20cc (2g) cartridge). After washing the solid phase with methanol (20.0 mL), ammonia (2N methanol solution, 20 mL) was used to dissolve it. The crude product (120 mg) of the title compound was obtained by concentrating the eluate under reduced pressure.

[0281] MS (ESI) m / z: 279 [M+H] +

[0282] (2) (1R,3s,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabi Synthesis of ethyl cyclo[3.2.1]octane-8-carboxylate

[0283] A mixture of ethyl (1R, 3s, 5S)-3-((S)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.431 mmol), 10% palladium on carbon (NE Chemcat Co., Ltd., 48.47% water-containing product, 183 mg, 0.083 mmol) and methanol (4.0 mL) was stirred for 6.5 hours under a hydrogen atmosphere. Insoluble matter was filtered off using celite (registered trademark) and concentrated under reduced pressure to obtain a reduced product (113 mg) as a cis-trans mixture.

[0284] MS (ESI) m / z: 281 [M+H] +

[0285] A mixture of the obtained reduced product (113 mg), 2-chloro-5-fluoropyrimidine (0.048 mL, 0.517 mmol), cesium carbonate (281 mg, 0.862 mmol) and N,N-dimethylacetamide (2.0 mL) was stirred at 100° C. for 8 hours. The mixture was purified by column chromatography (silica gel, 0-30% ethyl acetate / n-heptane) to obtain the title compound (82.0 mg) as a cis-trans mixture.

[0286] MS (ESI) m / z: 377 [M+H] +

[0287] (Analysis conditions) Supercritical fluid chromatography using CHIRALPAK (registered trademark) IF-3 (3.0 mm×50 mm) manufactured by Daicel Corporation (mobile phase: CO2:methanol (70:30), 40°C, flow rate: 1.2 mL / min, detection: UV (210-400 nm))

[0288] (Analysis results) The retention time of the title compound was 1.02 minutes, and the retention time of the trans isomer was 1.23 minutes. The cis:trans ratio was 4:5 (peak area ratio), and the optical purity was >99%ee.

[0289] By using supercritical fluid chromatography (mobile phase CO2:methanol (70:30), 120 bar, 40°C, flow rate: 100 mL / min) using CHIRALPAK (registered trademark) IF / SFC (3 cm×25 cm) manufactured by Daicel Corporation, 10 mg of the obtained cis-trans mixture was taken each time to obtain the title compound (34.0 mg) which was first eluted with a retention time of 5.55 minutes.

[0290] 1H-NMR (400MHz, CDCl3) δ (ppm): 1.17 (d, J = 6.34Hz, 3H), 1.23 (t, J = 7.25Hz, 3H), 1.19-2.02 (m, 14H), 3.09 (ddd, J = 1 3.70,10.99,5.66Hz,1H),4.10(q,J=7.10Hz,2H),4.17-4.30(m,3H),4.34(dd,J=13.59,7.25Hz,1H),8.13(s,2H).

[0291] MS (ESI) m / z: 377 [M+H] +

[0292] (Analysis conditions) Supercritical fluid chromatography using CHIRALPAK (registered trademark) IF-3 (3.0 mm×50 mm) manufactured by Daicel Corporation (mobile phase CO2:methanol (70:30), 40°C, flow rate: 1.2 mL / min, detection: UV (245 nm))

[0293] (Analysis results) The retention time of the title compound was 1.02 minutes, the cis:trans ratio was >99:1, and the optical purity was >99%ee.

[0294] (3) (1R,3s,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabi Synthesis of Cyclo[3.2.1]octane

[0295] A mixture of ethyl (1R, 3s, 5S)-3-((2S, 4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (34 mg, 0.09 mmol) and 48% hydrobromic acid (2.0 mL) was stirred at 100° C. for 1 hour. A 5N aqueous sodium hydroxide solution was added to the reaction mixture at 0° C. for neutralization. The mixture was extracted 3 times with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (21.7 mg).

[0296] MS (ESI) m / z: 305 [M+H] +

[0297] (4) (R)-2-Cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin Synthesis of 4-pyridin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide

[0298] A mixture of (1R, 3s, 5S)-3-((2S, 4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octane (5.00 mg, 0.016 mmol), potassium carbonate (4.54 mg, 0.033 mmol), (S)-2-bromo-2-cyclopropylacetamide (8.24 mg, 0.033 mmol) and acetonitrile (1.0 mL) was stirred at room temperature for 7 days. Potassium carbonate (4.54 mg, 0.033 mmol) and (S)-2-bromo-2-cyclopropylacetamide (8.24 mg, 0.033 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for 3 days. An aqueous ammonium chloride solution was added to the reaction mixture to terminate the reaction. The mixture was extracted with ethyl acetate, the organic layer was washed with water, and concentrated under reduced pressure to obtain a crude product.

[0299] The obtained crude product was diluted with methanol and supplied to Waters PortaPak Rxn (registered trademark) CX (6cc (400mg) cartridge). The solid phase was washed with methanol (6.0mL), and then dissolved with aqueous ammonia (2N methanol solution, 6mL). The eluate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (NH, dichloromethane) to obtain the title compound (3.74mg).

[0300] 1 H-NMR (400MHz, CDCl3) δ (ppm): 0.25-0.36 (m, 1H), 0.39-0.51 (m, 1H), 0.51-0.59 (m, 1H), 0.59-0. 70(m,1H),0.70-0.84(m,1H),1.18(d,J=6.34Hz,3H),1.21-1.55(m,9H),1.61-1.95(m,5H),2.04 (d,J=9.06Hz,1H),3.10(ddd,J=13.70,10.99,5.21Hz,1H),3.15-3.28(m,1H),3.80-3.94(m,1H) ,4.17-4.29(m,1H),4.35(dd,J=13.59,7.25Hz,1H),5.18(brs,1H),6.94(brs,1H),8.14(s,2H).

[0301] MS (ESI) m / z: 402 [M+H] +

[0302] (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl) Preparation and X-ray Crystal Structure Analysis of Single Crystal of 8-Azabicyclo[3.2.1]octan-8-yl)acetamide

[0303] The title compound (0.81 mg) obtained in Example 4 was dissolved in methanol (600 μL). The small glass bottle containing 200 μL of the solution was slowly placed into a small glass bottle one size larger than the small glass bottle and containing 2 mL of tert-butyl methyl ether, and the lid was closed (vapor diffusion method). After 12 days, a single crystal of the title compound was obtained in the small glass bottle. X-ray crystal structure analysis was performed on the obtained single crystal under the following conditions. The X-ray crystal structure of the title compound is shown in Figure 3 .

[0304] Analysis machine: XtaLAB PRO P200 MM007HF (Rigaku, Japan)

[0305] Software: CrysAlisPro (Science Oxford Diffraction)

[0306] X-ray: Multi-layer mirror monochromatic Cu-Kα (40kV / 30mA)

[0307] Measurement method: ω axis oscillation method

[0308] Camera length: 35mm

[0309] Measuring temperature: -170℃

[0310] Pharmacological test examples

[0311] The following pharmacological tests were carried out using the compounds of Examples 1 to 4.

[0312] Test Example 1-1 Evaluation of agonist activity on OX1R and OX2R

[0313] Human embryonic kidney cells 293 (HEK293) forced to express hOX1R and hOX2R were seeded at 10,000 cells per well in each well of a 384-well microtiter plate (Greiner) and cultured for 24 hours in high-glucose DMEM (Fujifilm Wako Pure Chemical Industries, Ltd.) supplemented with 10% FBS (Thermo Fisher Scientific) and 1% penicillin-streptomycin (Fujifilm Wako Pure Chemical Industries, Ltd.). After removing the culture medium, 40 μL of an analysis buffer (20 mM HEPES (Sigma-Aldrich), Hank's balanced salt solution (Gibco), 0.1% BSA (Sigma-Aldrich), 0.1% Pluronic F-127 (Biotium)) containing calcium 4 dye (Molecular Devices) and 2.5 mM probenecid (Sigma-Aldrich) was added and cultured for 60 minutes. After further adding 20 μL of the analysis buffer, 20 μL of the analysis buffer containing the test compound was added to start the reaction. The reaction will cause a change in the intracellular calcium ion concentration, which is measured by using FDSS7000 (Hamamatsu Photonics) to measure the fluorescence intensity ratio obtained by two wavelengths of excitation at 480 nm and 540 nm as the fluorescence value. In addition, the test compound was dissolved in DMSO at 10 mM and diluted with the analysis buffer so that the final concentration was from 3×10 -10 M becomes 1×10 -7 M (the final concentration of DMSO is 0.1%). The fluorescence value of the wells added with the buffer containing no compound was set to 0%, and the fluorescence value of the wells added with 10 nM of OX-A (Peptide Research Institute) was set to 100%, and the 50% agonist concentration (EC50 value) was calculated based on the fluorescence values ​​when the test compound of various concentrations was added. Table 1 shows the agonist activity values ​​of each compound.

[0314] [Table 1]

[0315] Example No. hOX1R EC50(nM) hOX2R EC50(nM) 1 >100 0.99 2 >100 3.08

[0316] Test Example 1-2 Evaluation of agonist activity on OX1R and OX2R

[0317] Human embryonic kidney 293 (HEK293) cells forcibly expressing hOX1R and hOX2R were seeded in each well of a 384-well microplate (Greiner) at 10,000 cells per well and cultured for 1 day in high-glucose DMEM (Fujifilm Wako Pure Chemical Industries, Ltd.) supplemented with 10% FBS (Thermo Fisher Scientific) and 1% penicillin-streptomycin (Fujifilm Wako Pure Chemical Industries, Ltd.). After the medium was removed, 30 μL of an assay buffer (20 mM HEPES (Sigma-Aldrich), Hank's balanced salt solution (Gibco), 0.1% BSA (Sigma-Aldrich), 0.1% Pluronic F-127 (Biotium)) containing calcium 4 dye (Molecular Devices) and 2.5 mM probenecid (Sigma-Aldrich) was added and cultured for 60 minutes. The reaction was started by adding 30 μL of the assay buffer containing the test compound. The reaction caused a change in the intracellular calcium ion concentration, which was measured by measuring the fluorescence intensity ratio obtained by two wavelengths of excitation at 480 nm and 540 nm using FDSS7000 (Hamamatsu Photonics Co., Ltd.). In addition, the test compound was dissolved in DMSO at 10 mM and diluted with the assay buffer to a final concentration of 3 × 10 -11 M becomes 1×10 -5 M (the final concentration of DMSO is 0.1%). The fluorescence value of the wells added with the buffer containing no compound was set to 0%, and the fluorescence value of the wells added with 10 nM of OX-A (Peptide Research Institute) was set to 100%, and the 50% agonist concentration (EC50 value) was calculated based on the fluorescence values ​​when the test compound of various concentrations was added. Table 2 shows the agonist activity values ​​of each compound.

[0318] [Table 2]

[0319] Example No. hOX1R EC50(nM) hOX2R EC50(nM) 1 4700 2.3 3 1400 4.3 4 3900 4.4

[0320] Test Example 2: Increase in spontaneous exercise volume

[0321] The increase in the amount of exercise of mice is an indicator of awakening effect, as is the increase in wakefulness time, the rise in body temperature, and the enhancement of cardiovascular system parameters. In this test example, the awakening effect was evaluated by measuring the spontaneous exercise amount of mice. Male C57BL / 6NCrl mice (18-19 weeks old, Charles River Laboratories Japan, 4 cases in each group) were used in the experiment. The spontaneous exercise amount was measured as follows: infrared rays were irradiated from the side of the measurement cage using an exercise measurement device (VersaMax open field, AccuScan Instrument), and the number of times the mouse passed through the irradiation line was measured. The mice were placed in the measurement cage, and after the mice were adapted for 3 hours, the compound (10 mg / kg) was orally administered. The spontaneous exercise amount was measured 2 hours after administration. In the test compound administration group, the test compound was dissolved in 0.1 mol / L hydrochloric acid containing 5% (v / v) DMSO and 5% (v / v) Kolliphor (registered trademark) EL to obtain a solution, and the obtained solution was applied to mice. In the control group, only the solvent without the test compound was administered to the mice.

[0322] The results are shown in Table 3. The spontaneous exercise amount in the test compound-administered group is expressed as %, with the spontaneous exercise amount in the control group being 100%.

[0323] [Table 3]

[0324]

[0325] Table 3 shows that the compound of the present invention increases the spontaneous movement of mice, which indicates that the compound of the present invention has a wakefulness effect.

[0326] Experimental Example 3 Awakening Effect of Oral Administration of the Compound of the Present Invention to Wild-Type Mice During the Dark Phase

[0327] The experimental animals were wild-type (WT) male mice of the C57BL / 6 system. Under isoflurane anesthesia, 13-week-old mice underwent electrode implantation surgery for EEG and EMG measurements. After the surgery, the mice were adapted to the lighting cycle and experimental operations, and then the EEG and EMG were measured. Mice that could record EEG and EMG normally were provided for the experiment. A solution (1, 3 or 10 mg / kg) obtained by dissolving the solvent (0 mg / kg) or the compound of Example 1 in the solvent was orally administered 30 to 15 minutes before the lights went out. In addition, the solvent used was a 0.1 mol / L hydrochloric acid solution containing 5% (v / v) DMSO and 5% (v / v) Kolliphor (registered trademark) EL. EEG and EMG were recorded for about 24 hours starting from 1 hour before the lights went out. For mice, a wash-out period of more than 2 days was set and used repeatedly. The EEG and EMG data of each mouse were obtained using sleep analysis software (SleepSign; KISSEI COMTEC Co., Ltd.), and each epoch (10 seconds) was determined as a sleep stage. The time (sleep latency) from the time the lights went out until the first sleep (from the start of non-rapid eye movement sleep (non-REM) to sleep for more than 8 epochs) was measured for each case. The number of cases in each administration group was set to 16. In the comparison of sleep latency between the solvent administration group (control group) and the compound administration group of Example 1, the survival time was analyzed by considering the corresponding relationship between the same individual and the number of experiments, and a Dunnet-type multiple comparison test was performed, and the significance level was set to 5% on both sides.

[0328] The sleep latency of mice administered with solvent and 1, 3 and 10 mg / kg of the compound of Example 1 was 0.23 hours, 0.28 hours, 0.44 hours and 2.07 hours, respectively. In addition, in the group administered with 3 or 10 mg / kg of the compound of Example 1, the sleep latency was significantly increased compared with the solvent-administered group. That is, when the compound of Example 1 was orally administered at the light stage (ZT12) when the mouse's activity period begins, it was confirmed that the extension of the sleep latency was dose-dependent.

[0329] Test Example 4 Awakening effect and cataplexy-like action inhibition effect induced by oral administration of the compound of the present invention to orexin-deficient mice (orexin / ataxin 3 mice) during the dark period

[0330] The experimental animals used orexin / ataxin-3 mice (orexin / ataxin-3Tg / + (hereinafter referred to as "Tg mice") with C57BL / 6 system as the genetic background, Hara et al., Neuron, 30, 345-54, 2001), and wild-type mice of the same litter (hereinafter referred to as "WT mice") were used as the control group. Electrode implantation surgery for EEG and EMG measurement was performed on 12-week-old mice (±2 weeks) under isoflurane anesthesia. After the surgery, the mice were adapted to the lighting cycle and experimental operation, and then the EEG and EMG were measured. The mice that could record EEG and EMG normally were provided for the experiment. The solvent (0 mg / kg) or the sample (the solution obtained by dissolving the compound of Example 1 in the solvent; 0.3, 1, or 3 mg / kg) was orally administered 30 to 15 minutes before the lights were turned off. In addition, the solvent used was a 0.1 mol / L hydrochloric acid solution containing 5% (v / v) DMSO and 5% (v / v) Kolliphor (registered trademark) EL. EEG and EMG were recorded for about 24 hours starting from 1 hour before the lights went out. For mice, a wash-out period of more than 2 days was set for repeated use. The EEG and EMG data obtained for each mouse were analyzed using sleep analysis software (SleepSign; KISSEI COMTEC Co., Ltd.), and each epoch (10 seconds) was determined as a sleep stage, up to 4 hours. The cataplexy-like symptoms in this experiment refer to the phenomenon of rapid eye movement sleep occurring immediately after a continuous wakefulness state of more than 4 epochs (direct transition from wakefulness to rapid eye movement sleep (DREM)). DREM in mice is similar to cataplexy in humans (ExpNeurol. 2009; 217: 46-54). The time from lights out to the first sleep (sleep of more than 8 consecutive epochs other than DREM) (sleep latency) and the time until the first DREM (DREM latency) appeared were measured for each case. The number of cases was 8 in the solvent administration group and 14 in the compound administration group of Example 1. In the comparison of sleep latency between the condition control group and the compound administration group, the survival time was analyzed by considering the correspondence between the same individual and the number of experiments, and then the Dunnet-type multiple comparison test was performed, and the significance level was set to 5% on both sides. In addition, in the comparison of DREM latency between the normal control group and the condition control group, the survival time was analyzed by considering the correspondence between the same individual and the number of experiments. In the comparison between the condition control group and the compound administration group of Example 1 where the test was meaningful, the survival time was analyzed by considering the correspondence between the same individual and the number of experiments, and then the Dunnet-type multiple comparison test was performed, and the significance level was set to 5% on both sides.

[0331] The sleep latency of Tg mice administered with the solvent and 0.3, 1, and 3 mg / kg of the compound of Example 1 was 0.21 hours, 0.31 hours, 0.64 hours, and 2.42 hours, respectively, and the sleep latency was significantly increased in the groups administered with 1 and 3 mg / kg of the compound of Example 1. That is, when the compound of Example 1 was orally administered at the light period (ZT12) when the mouse activity period begins, it was confirmed that the sleep latency was prolonged in orexin-deficient mice starting from 1 mg / kg, and the prolonged sleep latency was dose-dependent.

[0332] The DREM latency of WT mice was 4.00 hours when the vehicle was administered. On the other hand, the DREM latency of Tg mice was 1.16 hours, 1.50 hours, 2.26 hours and 4.00 hours when the solvent and 0.3, 1 and 3 mg / kg of the compound of Example 1 were administered, respectively. In the 0.3, 1 and 3 mg / kg groups administered with the compound of Example 1, the increase in DREM latency was confirmed to be significant and dose-dependent compared with the solvent-administered group. That is, by administering the compound of the present invention, the cataplexy-like symptoms (DREM) exhibited by orexin-deficient mice were suppressed in a dose-dependent manner.

Claims

1. A pharmaceutical composition comprising a compound selected from the group consisting of: (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide The compound or its pharmaceutically acceptable salt in the composed group, and pharmaceutically acceptable additives.

2. A therapeutic agent for sleep apnea syndrome, comprising a compound selected from the following formula (I): (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide The compound or the pharmaceutically acceptable salt thereof in the composed group.

3. Selected from the following formula (I) (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide Use of the compounds in the group consisting of the above or their pharmaceutically acceptable salts for the manufacture of a pharmaceutical composition for treating sleep apnea syndrome.

4. A therapeutic agent for Parkinson's disease accompanied by excessive daytime sleepiness, comprising a compound selected from the group consisting of the following formula (I): (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide The compound or the pharmaceutically acceptable salt thereof in the composed group.

5. Selected from the following formula (I) (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide Use of the compounds in the above group or their pharmaceutically acceptable salts for the manufacture of a pharmaceutical composition for treating Parkinson's disease accompanied by excessive daytime sleepiness.

6. A therapeutic agent for impaired consciousness, comprising a compound selected from the group consisting of the following formula (I): (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide The compound or the pharmaceutically acceptable salt thereof in the composed group.

7. Selected from the following formula (I) (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide Use of the compounds in the above group or pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition for treating disorders of consciousness.

8. A therapeutic agent for idiopathic hypersomnia, comprising a compound selected from the group consisting of: (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide The compound or the pharmaceutically acceptable salt thereof in the composed group.

9. Selected from the following formula (I) (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, The following formula (II) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutanamide, The following formula (III) (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide, and The following formula (IV) (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide Use of the compounds in the group consisting of the above-mentioned compounds or their pharmaceutically acceptable salts for the manufacture of a pharmaceutical composition for treating idiopathic hypersomnia.

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