Azacycloalkyl carbonyl cyclic amine compound

Abstract

Provided is an azacycloalkyl carbonyl cyclic amine compound that is useful as an active ingredient in a pharmaceutical composition for treating neutrophilic inflammatory diseases. An azacycloalkyl carbonyl cyclic amine compound according to the present invention is a compound represented by formula (I) or a salt thereof. [Chem. 1] (In the formula: ring A represents an azacycloalkyl that optionally has a substituent group and that is optionally spiro-fused; Y represents an alkyl optionally having a substituent group, a cycloalkyl optionally having a substituent group, or the like; L represents a nitrogen-containing aromatic hetero ring or the like; Z represents a cycloalkyl optionally having a substituent group, an aromatic hydrocarbon ring optionally having a substituent group, a non-aromatic hetero ring optionally having a substituent group, or the like; and m and n each independently represent an integer of 1 or 2.)

Description

Azacycloalkylcarbonyl cyclic amine compounds

[0001] The present invention relates to azacycloalkylcarbonyl cyclic amine compounds useful as active ingredients in pharmaceutical compositions, for example, pharmaceutical compositions for treating neutrophil-associated inflammatory diseases. This application claims priority to provisional application US63 / 351,580, filed with the U.S. Patent and Trademark Office on June 13, 2022, and provisional application US63 / 410,421, filed with the U.S. Patent and Trademark Office on September 27, 2022, the contents of which are incorporated herein by reference.

[0002] Cathepsin C (CTSC), also known as dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1), is a lysosomal cysteine ​​exopeptidase that functions as a tetramer of four identical subunits belonging to the papain family.

[0003] CTSC is constitutively expressed in many tissues, with the most prominent expression observed in the lungs, placenta, spleen, and kidneys. It is believed to be a major intracellular processing enzyme that cleaves two residues from the N-terminus of proteins and peptides. It has been suggested that CTSC is an essential enzyme for the activation of neutrophil elastase (NE), cathepsin G (CTSG), proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4), as well as granule serine proteases in mast cells (chymase and tryptase), cytotoxic T lymphocytes, and natural killer cells (granzymes A and B). Neutrophils are produced and mature in the bone marrow and then released into the periphery. They exhibit chemotactic activity toward inflammatory cytokines, bacterial, and fungal components, and play a key role in the defense against infectious diseases through their potent antibacterial functions, including accumulation at sites of inflammation, phagocytosis, degranulation, and neutrophil extracellular trap (NET). Neutrophil serine proteases (NE, CTSG, PR3, and NSP4) play an important role in the antibacterial function of neutrophils due to their proteolytic activity. However, excessive release of proteases into the extracellular space following neutrophil activation is known to cause tissue destruction in addition to their original bactericidal role. In particular, excessive degradation of extracellular matrices such as collagen, fibronectin, and laminin due to overexpression of NE is known to be involved in the pathogenesis of various inflammatory diseases (e.g., bronchiectasis, cystic fibrosis, acute respiratory distress syndrome, bronchitis, emphysema, etc.).

[0004] Based on the pathophysiological functions of granule serine proteases reported so far, CTSC, the main enzyme that regulates them, is considered to be a therapeutic target for neutrophil-related inflammatory diseases.

[0005] Compounds having a CTSC inhibitory effect are known, for example, as described in Patent Documents 1 to 6 and Non-Patent Document 1.

[0006] International Publication No. WO 2011 / 112685 International Publication No. WO 2011 / 075634 International Publication No. WO 2015 / 110826 International Publication No. WO 2012 / 109415 International Publication No. WO 2015 / 032943 International Publication No. WO 2014 / 140075 Pharmacology & Therapeutics, 2018, Vol. 190, pp. 202-236

[0007] The present invention provides an azacycloalkylcarbonyl cyclic amine compound having a CTSC inhibitory activity, which is useful as an active ingredient in a pharmaceutical composition for treating neutrophil-associated inflammatory diseases.

[0008] The present invention has the following aspects: [1] A compound of formula (I) or a salt thereof. (Wherein, ring A may have a substituent, C ３－６ represents a cycloalkyl or an azacycloalkyl which may be spiro-fused with a saturated heterocycle having 3 to 6 ring members; Y represents hydrogen, an alkyl which may have a substituent, or a C ３－６ Cycloalkyl, an optionally substituted aromatic hydrocarbon ring, an optionally substituted non-aromatic heterocycle, an optionally substituted aromatic heterocycle, or —N(R Ｙ１ )-R Ｙ２ indicates; R Ｙ１ and R Ｙ２ C, one of which may have a substituent １－４ C represents an alkyl group, and the other C may have a substituent. １－４ Alkyl, —C(═O)—(C １－４ alkyl), or —S(═O) ２ -(C １－４ L represents an optionally substituted nitrogen-containing aromatic heterocycle, an optionally substituted nitrogen-containing aromatic heterocycle-(C １－２ alkylene), —C(═O)—N(R Ｌ１ )-, -C(=O)-N(R Ｌ１ )-(C １－２ alkylene), —C(═O)—, or an optionally substituted nitrogen-containing aromatic heterocycle —C(═O)—; R Ｌ１ is hydrogen or optionally substituted C １－４

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[0120] [ ３－６ The compound of [1], wherein ring A is piperidinyl optionally spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members, or a salt thereof. [3] The compound of [2], wherein ring A is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl which may have substituents, 4-hydroxy-5,5-dimethylpiperidin-2-yl which may have substituents, or 1-oxa-6-azaspiro[3.5]nonan-7-yl which may have substituents, or a salt thereof. [4] The compound of [3], wherein ring A is (7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl, (2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl, or (4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl, or a salt thereof. [5] The compound of any of [1] to [4], wherein m is 2 and n is 2, or a salt thereof. [6] The compound of any one of [1] to [5], wherein L is an optionally substituted nitrogen-containing aromatic heterocycle, or a salt thereof. [7] The compound of [6], wherein L is 1,2,4-oxadiazole or tetrazole, or a salt thereof. [8] The compound of [6], wherein Y is an optionally substituted alkyl or an optionally substituted C ３－６[9] A compound according to any one of [1] to [7], wherein Z is cycloalkyl, or a salt thereof. [9] A compound according to any one of [1] to [8], wherein Z is cycloalkyl which may have a substituent or a non-aromatic heterocycle which may have a substituent, or a salt thereof.

[10] A compound according to [9], wherein Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each of which is substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl, or a salt thereof.

[11] A compound according to any one of [1] to [7], wherein Y is hydrogen, or a salt thereof.

[12] A compound according to

[11] , wherein Z is phenyl which may be substituted with 1 to 3 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl, or a salt thereof.

[13] A compound according to [1], wherein the compound is a compound of formula (Ia) or a salt thereof, or a compound of formula (Ib) or a salt thereof. (In formula (Ia) and formula (Ib), R １ and R ２ represents methyl, or R １ and R ２ are cyclobutanes, along with their adjacent carbon atoms: wherein the wavy line indicates the point of attachment to the remainder of the molecule; Y is hydrogen, optionally substituted C １－４ alkyl, optionally substituted C ３－６ L represents a cycloalkyl, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, or an aromatic heterocycle which may have a substituent; L represents a nitrogen-containing aromatic heterocycle which may have a substituent, a nitrogen-containing aromatic heterocycle-(C １－２ alkylene), —C(═O)—N(R Ｌ１ )-, -C(=O)-N(R Ｌ１ )-(C １－２ alkylene), —C(═O)—, or an optionally substituted nitrogen-containing aromatic heterocycle —C(═O)—; R Ｌ１ is hydrogen or optionally substituted C １－４ Z represents an optionally substituted C ３－６and m and n each independently represent an integer of 1 or 2.)

[14] The compound of [1] or a salt thereof, which is a compound of formula (Iaa) or a salt thereof, or a compound of formula (Ibb) or a salt thereof. (In formula (Iaa) and formula (Ibb), R １ and R ２ represents methyl, or R １ and R ２ are cyclobutanes, along with their adjacent carbon atoms: wherein the wavy line indicates the point of attachment to the remainder of the molecule; Y is hydrogen, optionally substituted C １－４ alkyl, optionally substituted C ３－６ L represents a cycloalkyl, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, or an aromatic heterocycle which may have a substituent; L represents a nitrogen-containing aromatic heterocycle which may have a substituent, a nitrogen-containing aromatic heterocycle-(C １－２ alkylene), —C(═O)—N(R Ｌ１ )-, -C(=O)-N(R Ｌ１ )-(C １－２ alkylene), —C(═O)—, or an optionally substituted nitrogen-containing aromatic heterocycle —C(═O)—; R Ｌ１ is hydrogen or optionally substituted C １－４ Z represents an optionally substituted C ３－６

[15] Y is a cycloalkyl, an optionally substituted aromatic hydrocarbon ring, an optionally substituted non-aromatic heterocycle, an optionally substituted aromatic heterocycle, or -O- (optionally substituted alkyl), provided that when L is -C(=O)- or an optionally substituted nitrogen-containing aromatic heterocycle-C(=O)-, Z is an optionally substituted cyclic amino; m and n each independently represent an integer of 1 or 2.)

[16] Y is a C optionally substituted with 1 to 5 halogen atoms, １－４ Alkyl, or C ３－６ L is an optionally substituted nitrogen-containing aromatic heterocycle or an optionally substituted nitrogen-containing aromatic heterocycle-(C １－２ alkylene); Z is optionally substituted C ３－６

[16] The compound of

[13] or

[14] , wherein Y is cycloalkyl, optionally substituted phenyl, optionally substituted non-aromatic heterocycle, or optionally substituted aromatic heterocycle, or a salt thereof. １－４ Alkyl, or C ３－６ cycloalkyl; L is a nitrogen-containing aromatic heterocycle or a nitrogen-containing aromatic heterocycle-(C １－２ alkylene); Z is C ３－６ cycloalkyl, phenyl, a non-aromatic heterocycle, or an aromatic heterocycle, ３－６ Cycloalkyl, phenyl, non-aromatic heterocycle, and aromatic heterocycle are each selected from halogen, —OH, amino, cyano, nitro, —C(═O)—(C １－４ alkyl), -C(=O)-OH, -C(=O)-O-(C １－４ alkyl), —C(═O)-amino, C optionally substituted with halogen １－４ alkyl, and —O—(C optionally substituted with halogen) １－４The compound of

[13] or

[14] , or a salt thereof, optionally substituted with one or more substituents selected from the group consisting of alkyl).

[17] The compound of

[16] , or a salt thereof, wherein L is pyrrole, pyrazole, imidazole, 1,3-oxazole, 1,3-thiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, or pyrazine.

[18] A pharmaceutical composition comprising any of the compounds of [1] to

[17] , or a salt thereof, and a pharmaceutically acceptable excipient.

[19] The pharmaceutical composition of

[18] , which is a pharmaceutical composition for treating neutrophil-associated inflammatory diseases.

[20] Use of any of the compounds of [1] to

[17] , or a salt thereof, for the manufacture of a pharmaceutical composition for treating neutrophil-associated inflammatory diseases.

[21] Use of any of the compounds [1] to

[17] or a salt thereof for treating a neutrophil-associated inflammatory disease.

[22] Any of the compounds [1] to

[17] or a salt thereof for treating a neutrophil-associated inflammatory disease.

[23] A method for treating a neutrophil-associated inflammatory disease, comprising administering an effective amount of any of the compounds [1] to

[17] or a salt thereof to a subject.

[0009] A "subject" is a human or other animal in need of such treatment, and in one embodiment, a human in need of such treatment.

[0010] Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0011] The azacycloalkylcarbonyl cyclic amine compound of the present invention or a salt thereof (sometimes simply referred to as the "azacycloalkylcarbonyl cyclic amine compound of the present invention," or the "compound of formula (I)," the "compound of formula (Ia)," the "compound of formula (Ib)," the "compound of formula (Iaa)," or the "compound of formula (Ibb)," respectively; the azacycloalkylcarbonyl cyclic amine compound of the present invention includes the compound of formula (I), the compound of formula (Ia), the compound of formula (Ib), the compound of formula (Iaa), and the compound of formula (Ibb)), has a CTSC inhibitory activity and can be used as an active ingredient in a pharmaceutical composition for the treatment of neutrophil-associated inflammatory diseases, including gastrointestinal inflammatory diseases, glomerulonephritis, chronic obstructive pulmonary disease (COPD), bronchiectasis, rheumatoid arthritis, multiple sclerosis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and the like.

[0012] In this specification, the phrase "optionally having a substituent" means that the group is unsubstituted or has one or more substituents. When the group has a substituent, the group may have multiple substituents as long as the chemical structure allows. When the group has multiple substituents, the respective substituents may be the same or different from each other.

[0013] Other than alkyl which may have a substituent, examples of the substituents permitted in the group which is described as "optionally having a substituent" include the groups shown in the following S1 group. １－４ "Alkyl" includes fluoro, -OH, -O-(C １－４ It may be substituted with 1 to 5 groups selected from the group consisting of alkyl, and amino.

[0014] The S1 group includes: (1) halogens, (2) —OH, —O—(C １－４ alkyl), —O—(C ３－６ cycloalkyl), —O—C(═O)—(C １－４ alkyl), —O—C(═O)—(C ３－６ cycloalkyl), oxo (=O), -SH, -S-(C １－４ alkyl), and —S(═O) ２ -(C １－４alkyl), (3) amino, cyano, and nitro, (4) —C(═O)—(C １－４ alkyl), -C(=O)-OH, -C(=O)-O-(C １－４ (5) halogen, —OH, —O—(C １－４ alkyl), and C １－４ (6) an aromatic hydrocarbon ring optionally substituted with 1 to 3 substituents selected from halogen, —OH, —O—(C １－４ alkyl), and C １－４ C optionally substituted with 1 to 3 substituents selected from alkyl ３－６ (7) halogen, —OH, —O—(C １－４ alkyl), and C １－４ (8) an aromatic heterocycle optionally substituted with 1 to 3 substituents selected from halogen, —OH, —O—(C １－４ alkyl), and C １－４ (9) a non-aromatic heterocycle optionally substituted with 1 to 3 substituents selected from alkyl, and (10) a C １－４ Alkyl and —O—(C １－４ alkyl).

[0015] As the substituents permitted for the alkyl group which may have a substituent, there can be mentioned the groups described in (1) to (8) in the S1 group.

[0016] As used herein, "alkyl" refers to a C 1－１０ C includes straight chain alkyl and branched alkyl. １－４ Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. One embodiment is methyl or ethyl, and another embodiment is methyl.

[0017] "Cycloalkyl" is C ３－１０and may have a bridged structure. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and bicyclo[4.3.1]nonyl. One embodiment is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or bicyclo[1.1.1]pentyl, and another embodiment is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. C ３－６ Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and one embodiment is cyclopropyl or cyclobutyl.

[0018] "Azacycloalkyl" refers to a cycloalkyl in which at least one carbon atom forming the ring structure of the cycloalkyl is replaced with a nitrogen atom. Examples of azacycloalkyl include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azabicyclo[2.2.1]heptyl, and azabicyclo[2.2.2]octyl, and one embodiment is piperidinyl.

[0019] The "aromatic hydrocarbon ring" is C ６－１４ One embodiment of the monovalent group of the aromatic hydrocarbon ring is phenyl or naphthyl, and another embodiment is phenyl.

[0020] A "non-aromatic heterocycle" is a monocyclic or bicyclic non-aromatic heterocycle having 3 to 10 ring members and containing 1 to 4 identical or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Some bonds constituting the non-aromatic heterocycle may be unsaturated. Bicyclic non-aromatic heterocycles may be partially aromatic. Examples include a 5- or 6-membered monocyclic non-aromatic heterocycle fused with a benzene ring, pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, or pyridine ring, and an at least partially unsaturated hydrocarbon ring fused with a pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, or pyridine ring. Examples of monovalent groups of non-aromatic heterocycles include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridyl, oxetanyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, dihydrothiopyranyl, piperazinyl, dihydropyrazyl, morpholinyl, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuryl, dihydroisobenzofuryl, tetrahydrobenzoxazolyl, dihydrofuropyridyl, dihydropyrazolomorpholinyl, pyridinodioxanyl, dihydroazabenzofuryl, dihydroazaisobenzofuryl, and dihydroazaindolyl.

[0021] An "aromatic heterocycle" is a monovalent radical of a monocyclic or bicyclic aromatic heterocycle having 5 to 10 ring members and 1 to 4 of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of monovalent aromatic heterocycle radicals include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalyl, pyrrolopyridyl, and imidazolopyridyl.

[0022] The "nitrogen-containing aromatic heterocycle" is an aromatic heterocycle having at least one nitrogen atom as an element forming the ring structure of the aromatic heterocycle. Examples of the nitrogen-containing aromatic heterocycle include pyrrole, pyrazole, imidazole, oxazoles including 1,3-oxazole, thiazoles including 1,3-thiazole, oxadiazoles including 1,2,4-oxadiazole and 1,3,4-oxadiazole, thiadiazoles including 1,2,4-thiadiazole and 1,3,4-thiadiazole, triazoles including 1,2,3-triazole and 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, and pyrazine, and in one embodiment, 1,2,4-oxadiazole and tetrazole.

[0023] The term "cyclic amino" refers to a monovalent group of a non-aromatic heterocycle or aromatic heterocycle having at least one nitrogen atom as an element forming the ring structure of the non-aromatic heterocycle or aromatic heterocycle, and having a bond on at least one nitrogen atom forming the ring structure of the non-aromatic heterocycle or aromatic heterocycle. Examples of cyclic amino include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, and piperazin-1-yl, and in one embodiment, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, and morpholin-4-yl.

[0024] The term "saturated heterocycle" refers to a non-aromatic heterocycle, and in one embodiment, a monocyclic non-aromatic heterocycle that does not have an unsaturated bond among the bonds that constitute the non-aromatic heterocycle. Examples of saturated heterocycles include aziridine, azetidine, pyrrolidine, oxirane, oxetane, and tetrahydrofuran, and one embodiment is oxetane.

[0025] "Alkylene" is C 1－１０ C includes straight chain alkylene and branched alkylene. １－２ Examples of the alkylene include methylene, ethylene, and methylmethylene, and one embodiment is methylene or methylmethylene.

[0026] "Halogen" means fluoro, chloro, bromo, and iodo, and in one embodiment, it is fluoro and chloro, and in another embodiment, it is fluoro.

[0027] "Amino" is -NH ２ In addition, -NH ２ One or two hydrogen atoms of １－４ It also includes groups substituted with alkyl. ２ C substituted with hydrogen １－４ Alkyl is —OH, —O—(C １－４ alkyl), -NH ２ , —NH(C １－４ alkyl), -N(C １－４ alkyl) (C １－４ It may be substituted with alkyl.

[0028] In formula (I), ring A is an azacycloalkyl, which may have a substituent; ３－６ It may be spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members. One embodiment of an azacycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azabicyclo[2.2.1]heptyl, or azabicyclo[2.2.2]octyl; another embodiment is piperidinyl.

[0029] The azacycloalkyl ring A is C ３－６It may be spiro-condensed with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members. ３－６ Examples of an azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members include 6-azaspiro[3.5]nonyl including 6-azaspiro[3.5]nonan-7-yl; 1-oxa-6-azaspiro[3.5]nonyl including 1-oxa-6-azaspiro[3.5]nonan-7-yl; and 5-azaspiro[2.5]octyl including 5-azaspiro[2.5]octan-6-yl; one embodiment is 6-azaspiro[3.5]nonan-7-yl or 1-oxa-6-azaspiro[3.5]nonan-7-yl.

[0030] Examples of the substituents permitted for ring A include the groups shown in the above S1 group; in one embodiment, C may be substituted with 1 to 5 groups selected from the group consisting of the groups shown in (1) or (2) in the above S1 group, or the groups shown in (1) or (2). １－４ alkyl; in another embodiment, halogen, —OH, C １－４ It is alkyl.

[0031] may have a substituent, C ３－６ One embodiment of the azacycloalkyl which may be spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is piperidinyl which may have a substituent and which may be spiro-fused with a cyclobutane or oxetane; another embodiment is a cycloalkyl which may be spiro-fused with a halogen atom, —OH, or C １－４ piperidinyl, optionally substituted with 1 to 5 groups selected from the group consisting of alkyl, and optionally spiro-fused with cyclobutane or oxetane; in yet another embodiment, piperidinyl, optionally substituted with 1 to 5 groups selected from the group consisting of halogen, —OH, and C １－４In yet another embodiment, it is 6-azaspiro[3.5]nonan-7-yl, 5,5-dimethylpiperidin-2-yl, or 1-oxa-6-azaspiro[3.5]nonan-7-yl, each of which is optionally substituted with 1 to 5 groups selected from the group consisting of alkyl; in yet another embodiment, it is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl, 4-hydroxy-5,5-dimethylpiperidin-2-yl, or 1-oxa-6-azaspiro[3.5]nonan-7-yl. ３－６ One embodiment of an azacycloalkyl optionally spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl, another embodiment is 4-hydroxy-5,5-dimethylpiperidin-2-yl, yet another embodiment is 1-oxa-6-azaspiro[3.5]nonan-7-yl, yet another embodiment is (7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl, yet another embodiment is (2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl, and yet another embodiment is or (4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl.

[0032] Here, when ring A is (7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl, the compound of formula (I) is represented by the following general formula:

[0033]

[0034] When ring A is (2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl, the compound of formula (I) is represented by the following general formula:

[0035]

[0036] Furthermore, when ring A is (4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl, the compound of formula (I) is represented by the following general formula:

[0037]

[0038] C optionally having a substituent in Y ３－６ Examples of the substituents permitted for the cycloalkyl, the aromatic hydrocarbon ring which may have a substituent, the non-aromatic heterocycle which may have a substituent, and the aromatic heterocycle which may have a substituent include the groups shown in the above Group S1; in one embodiment, halogen, —OH, amino, cyano, nitro, —C(═O)—(C １－４ alkyl), -C(=O)-OH, -C(=O)-O-(C １－４ alkyl), —C(═O)-amino, C optionally substituted with halogen １－４ alkyl, —O—(C optionally substituted with halogen) １－４ alkyl); in another embodiment, halogen, C optionally substituted with halogen １－４ In another embodiment, it is fluoro or methyl. Acceptable substituents for the optionally substituted alkyl of Y include the groups described in (1) to (8) in the above Group S1; in one embodiment, it is halogen; in another embodiment, it is fluoro.

[0039] One embodiment of Y is hydrogen, alkyl which may have a substituent, or C which may have a substituent. ３－６ In another embodiment, it is hydrogen; in yet another embodiment, it is optionally substituted alkyl or optionally substituted C ３－６ Optionally substituted alkyl or optionally substituted C ３－６ In one embodiment, the cycloalkyl is optionally substituted C １－４ Alkyl or C ３－６ In another embodiment, C cycloalkyl is optionally substituted with 1 to 5 halogen atoms. １－４ In a further embodiment, it is isopropyl, trifluoromethyl, or cyclopropyl.

[0040] In one embodiment, Y is hydrogen, in another embodiment, it is isopropyl, in yet another embodiment, it is trifluoromethyl, and in yet another embodiment, it is cyclopropyl.

[0041] R Ｙ１ and R Ｙ２ In one embodiment, one of the １－４ alkyl and the other is C １－４ Alkyl, —C(═O)—(C １－４ alkyl), or —S(═O) ２ -(C １－４ In another embodiment, one is methyl and the other is methyl, —C(═O)-methyl, or —S(═O) ２ -methyl.

[0042] One embodiment of L is a nitrogen-containing aromatic heterocycle which may have a substituent, a nitrogen-containing aromatic heterocycle-(C １－２ alkylene), —C(═O)—N(R Ｌ１ )-, or -C(=O)-N(R Ｌ１ )-(C １－２ In this case, Z represents an optionally substituted cycloalkyl, an optionally substituted aromatic hydrocarbon ring, an optionally substituted non-aromatic heterocycle, an optionally substituted aromatic heterocycle, an optionally substituted cyclic amino, or -O-(optionally substituted alkyl). Another embodiment of L is -C(=O)- or an optionally substituted nitrogen-containing aromatic heterocycle-C(=O)-, in which case Z represents an optionally substituted cyclic amino.

[0043] One embodiment of L is a nitrogen-containing aromatic heterocycle which may have a substituent or a nitrogen-containing aromatic heterocycle-(C １－２ alkylene); in another embodiment, —C(═O)—N(R Ｌ１ )- or -C(=O)-N(R Ｌ１ )-(C １－２ alkylene); in yet another embodiment, it is —C(═O)— or an optionally substituted nitrogen-containing aromatic heterocycle-C(═O)—.

[0044] Optionally substituted nitrogen-containing aromatic heterocycle or Optionally substituted nitrogen-containing aromatic heterocycle-(C １－２ In one embodiment, the alkylene is a nitrogen-containing aromatic heterocycle which may have a substituent; in another embodiment, it is a nitrogen-containing aromatic heterocycle; in yet another embodiment, it is pyrrole, pyrazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, or pyrazine; in yet another embodiment, it is 1,2,4-oxadiazole or tetrazole; and in yet another embodiment, it is 1,2,4-oxadiazole-3,5-diyl or 2H-tetrazole-2,5-diyl.

[0045] -C(=O)-N(R Ｌ１ )- or -C(=O)-N(R Ｌ１ )-(C １－２ Examples of alkylene include -C(=O)-NH-, -C(=O)-N(-CH ３ )-, -C(=O)-NH-CH ２ -, -C(=O)-N(-CH ３ )-CH ２ -, or -C(=O)-NH-CH(-CH ３ )-.

[0046] One embodiment of —C(═O)— or optionally substituted nitrogen-containing aromatic heterocycle-C(═O)— is —C(═O)— or (1,2,4-oxadiazole)-C(═O)—; another embodiment is —C(═O)—.

[0047] Examples of the substituents permissible for the cycloalkyl which may have a substituent, the aromatic hydrocarbon ring which may have a substituent, the non-aromatic heterocycle which may have a substituent, the aromatic heterocycle which may have a substituent, and the cyclic amino which may have a substituent in Z include the groups shown in the above group S1; in one embodiment, halogen, —OH, amino, cyano, nitro, —C(═O)—(C １－４ alkyl), -C(=O)-OH, -C(=O)-O-(C １－４alkyl), —C(═O)-amino, C optionally substituted with halogen １－４ alkyl, —O—(C optionally substituted with halogen) １－４ alkyl); in another embodiment, halogen, C optionally substituted with halogen １－４ In another embodiment, it is alkyl; and in another embodiment, it is fluoro, methyl, or trifluoromethyl. Permissible substituents for -O- (optionally substituted alkyl) in Z include the groups described in (1) to (8) in the above Group S1; in one embodiment, it is halogen; and in another embodiment, it is fluoro. In the optionally substituted cyclic amino in Z, the non-aromatic heterocycle having a bond on at least one nitrogen atom that forms the ring structure of the non-aromatic heterocycle may be spiro-condensed with a ring selected from the group consisting of cyclopropane, cyclobutane, oxirane, and oxetane.

[0048] In one embodiment, Z is an optionally substituted cycloalkyl, an optionally substituted aromatic hydrocarbon ring, an optionally substituted non-aromatic heterocycle, -O- (optionally substituted alkyl), or an optionally substituted cyclic amino; in another embodiment, Z is an optionally substituted cycloalkyl or an optionally substituted non-aromatic heterocycle; in yet another embodiment, Z is an optionally substituted aromatic hydrocarbon ring; in yet another embodiment, Z is -O- (optionally substituted alkyl); and in yet another embodiment, Z is an optionally substituted cyclic amino.

[0049] One embodiment of the cycloalkyl which may have a substituent or the non-aromatic heterocycle which may have a substituent is a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl; another embodiment is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, tetrahydrofuryl, or tetrahydropyranyl, each of which may be substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl; and Another embodiment is cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, tetrahydrofuryl, or tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro and methyl; yet another embodiment is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each of which is substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl; and still another embodiment is 3,3-difluorocyclobutan-1-yl, 4,4-difluorocyclohexan-1-yl, or 5,5-difluorotetrahydro-2H-pyran-2-yl. One embodiment of optionally substituted cycloalkyl is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl; another embodiment is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1 to 3 fluoro groups; and still another embodiment is cyclobutyl or cyclohexyl, each of which is optionally substituted with 1 to 3 fluoro groups.One embodiment of the optionally substituted non-aromatic heterocycle is tetrahydrofuran or tetrahydropyran, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl; another embodiment is tetrahydrofuran or tetrahydropyran, each of which is optionally substituted with 1 to 3 fluoro groups; and yet another embodiment is tetrahydro-2H-pyran, which is optionally substituted with 1 to 3 fluoro groups.

[0050] One embodiment of the aromatic hydrocarbon ring which may have a substituent is phenyl which may have a substituent; another embodiment is phenyl which may be substituted with 1 to 3 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl; a further embodiment is fluorophenyl; and a further embodiment is 4-fluorophenyl.

[0051] One embodiment of -O-(optionally substituted alkyl) is -O-(optionally substituted C １－４ In another embodiment, —O—(C optionally substituted with 1 to 5 fluoro alkyl) １－４ In yet another embodiment, it is —O-(2,2,2-trifluoroethyl) or —O-(trifluoromethyl); in yet another embodiment, it is —O-(2,2,2-trifluoroethyl).

[0052] One embodiment of the optionally substituted cyclic amino is a cyclic amino optionally substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl; another embodiment is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, or 4-oxa-7-azaspiro[2.5]octan-7-yl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl.

[0053] In one embodiment of m and n, m is 2 and n is 2; in another embodiment, m is 1 and n is 1.

[0054] Some embodiments of the compound of formula (I) are shown below. Note that, unless the following embodiments are inconsistent with formulas (Ia), (Ib), (Iaa), and (Ibb), they may be interpreted as embodiments of the compounds of formulas (Ia), (Ib), (Iaa), and (Ibb).

[0055] (1A) A compound of formula (I) wherein azacycloalkyl is piperidinyl. (1A-1)C ３－６ A compound of formula (I), wherein the azacycloalkyl optionally spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is piperidinyl, 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl. ３－６ (1A-1) A compound of formula (I) wherein the azacycloalkyl optionally spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is piperidinyl, 6-azaspiro[3.5]nonan-7-yl, or 1-oxa-6-azaspiro[3.5]nonan-7-yl. (1A-2) A compound of formula (I) wherein ring A is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl, 4-hydroxy-5,5-dimethylpiperidin-2-yl, or 1-oxa-6-azaspiro[3.5]nonan-7-yl. (1A-3) A compound of formula (I) wherein ring A is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl, 4-hydroxy-5,5-dimethylpiperidin-2-yl, or 1-oxa-6-azaspiro[3.5]nonan-7-yl. (1A-4) A compound of formula (I) wherein ring A is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl. (1A-5) The compound of formula (I) wherein ring A is (7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl. (1A-6) The compound of formula (I) wherein ring A is 4-hydroxy-5,5-dimethylpiperidin-2-yl. (1A-7) The compound of formula (I) wherein ring A is (2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl. (1A-8) The compound of formula (I) wherein ring A is 1-oxa-6-azaspiro[3.5]nonan-7-yl. (1A-9) The compound of formula (I) wherein ring A is (4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl.

[0056] (2A) A compound of formula (I) wherein Y is hydrogen.

[0057] (2B) Y is an alkyl group which may have a substituent, or a C group which may have a substituent. ３－６ (2B-1) A compound of formula (I) wherein Y is cycloalkyl. １－４ Alkyl or C ３－６ (2B-2) A compound of formula (I) wherein Y is cycloalkyl. １－４ (2B-1) A compound of formula (I) wherein Y is alkyl, cyclopropyl, or methyl. (2B-2) A compound of formula (I) wherein Y is isopropyl, trifluoromethyl, or cyclopropyl. (2B-3) A compound of formula (I) wherein Y is isopropyl, trifluoromethyl, or cyclopropyl. (2B-4) A compound of formula (I) wherein Y is isopropyl. (2B-5) A compound of formula (I) wherein Y is trifluoromethyl. (2B-6) A compound of formula (I) wherein Y is cyclopropyl.

[0058] (3A) L is a nitrogen-containing aromatic heterocycle optionally having a substituent or a nitrogen-containing aromatic heterocycle-(C １－２ (3A-1) A compound of formula (I) wherein L is a nitrogen-containing aromatic heterocycle which may have a substituent. (3A-2) A compound of formula (I) wherein L is a nitrogen-containing aromatic heterocycle. (3A-3) A compound of formula (I) wherein L is 1,2,4-oxadiazole or tetrazole. (3A-4) A compound of formula (I) wherein L is 1,2,4-oxadiazole-3,5-diyl. (3A-5) A compound of formula (I) wherein L is 2H-tetrazole-2,5-diyl.

[0059] (3B) L is -C(=O)-N(R Ｌ１ )- or -C(=O)-N(R Ｌ１ )-(C １－２ (3B-1) A compound of formula (I) wherein L is —C(═O)—NH—, —C(═O)—N(—CH ３ )-, -C(=O)-NH-CH ２ -, -C(=O)-N(-CH ３ )-CH ２ -, or -C(=O)-NH-CH(-CH ３ )-.

[0060] (3C) The compound of formula (I) wherein L is -C(=O)- or an optionally substituted nitrogen-containing aromatic heterocycle-C(=O)-. (3C-1) The compound of formula (I) wherein L is -C(=O)- or (1,2,4-oxadiazole)-C(=O)-. (3C-2) The compound of formula (I) wherein L is -C(=O)-.

[0061] (4A) A compound of formula (I) wherein Z is an optionally substituted cycloalkyl or an optionally substituted non-aromatic heterocycle. (4A-1) A compound of formula (I) wherein Z is a cycloalkyl or a non-aromatic heterocycle, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl. (4A-2) A compound of formula (I) wherein Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, tetrahydrofuryl, or tetrahydropyranyl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl. (4A-3) A compound of formula (I) wherein Z is cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, tetrahydrofuryl, or tetrahydropyranyl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro and methyl. (4A-4) A compound of formula (I) wherein Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl. (4A-5) A compound of formula (I) wherein Z is 3,3-difluorocyclobutan-1-yl, 4,4-difluorocyclohexan-1-yl, or 5,5-difluorotetrahydro-2H-pyran-2-yl. (4A-6) A compound of formula (I) wherein Z is 3,3-difluorocyclobutan-1-yl. (4A-7) A compound of formula (I) wherein Z is 4,4-difluorocyclohexan-1-yl. (4A-8) A compound of formula (I) wherein Z is 5,5-difluorotetrahydro-2H-pyran-2-yl.

[0062] (4B) The compound of formula (I), wherein Z is an aromatic hydrocarbon ring optionally having a substituent. (4B-1) The compound of formula (I), wherein Z is phenyl optionally having a substituent. (4B-2) The compound of formula (I), wherein Z is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro, methyl and trifluoromethyl.

[0063] (4C) Compounds of formula (I) in which Z is -O-(alkyl which may have a substituent). (4C-1) Compounds in which Z is -O-(C which may have a substituent) １－４ The compound of formula (I), wherein

[0064] (4D) A compound of formula (I) wherein Z is a cyclic amino optionally having substituents. (4D-1) A compound of formula (I) wherein Z is a cyclic amino optionally substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl and trifluoromethyl. (4D-2) A compound of formula (I) wherein Z is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, or 4-oxa-7-azaspiro[2.5]octan-7-yl, each of which is optionally substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl and trifluoromethyl.

[0065] (5A) A compound of formula (I) wherein m is 2 and n is 2. (5B) A compound of formula (I) wherein m is 1 and n is 1.

[0066] (6) A compound of formula (I) defined by a combination of two or more of the compounds of formula (I) described in (1) to (5B) above. Any two or more of the compounds (1) to (5B) above can be combined as long as no contradiction occurs in the chemical structure of the compound of formula (I).

[0067] Examples of the combination described in (6) above include the following: The combination described in (6) above is not limited to the following examples: (7A) Azacycloalkyl is piperidinyl, and Y is an alkyl group which may have a substituent, or an alkyl group which may have a substituent. ３－６ A compound of formula (I) wherein m is 2 and n is 2.３－６ A compound of formula (I), wherein the azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl; Y is isopropyl, trifluoromethyl, or cyclopropyl; m is 2; and n is 2.

[0068] (7B) A compound of formula (I) in which azacycloalkyl is piperidinyl, L is a nitrogen-containing aromatic heterocycle, m is 2, and n is 2. (7B-1) C ３－６ A compound of formula (I) in which the azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl; L is 1,2,4-oxadiazole or tetrazole; m is 2; and n is 2.

[0069] (7C) A compound of formula (I) wherein azacycloalkyl is piperidinyl, Z is an optionally substituted cycloalkyl or an optionally substituted non-aromatic heterocycle, m is 2, and n is 2. (7C-1)C ３－６ A compound of formula (I) wherein the azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl; Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each of which is substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl; m is 2; and n is 2.

[0070] (7D) Y is an alkyl group which may have a substituent, or a C group which may have a substituent. ３－６ (7D-1) A compound of formula (I) wherein Y is isopropyl, trifluoromethyl or cyclopropyl, L is 1,2,4-oxadiazole or tetrazole, m is 2 and n is 2. (7D-2) A compound of formula (I) wherein Y is cycloalkyl, L is a nitrogen-containing aromatic heterocycle, m is 2 and n is 2. (7D-3) A compound of formula (I) wherein Y is isopropyl, trifluoromethyl or cyclopropyl, L is 1,2,4-oxadiazole or tetrazole, m is 2 and n is 2.

[0071] (7E) Y is an alkyl group which may have a substituent, or a C group which may have a substituent. ３－６ (7E-1) A compound of formula (I) wherein Y is isopropyl, trifluoromethyl or cyclopropyl, Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each of which is substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl, m is 2, and n is 2.

[0072] (7F) A compound of formula (I) wherein L is a nitrogen-containing aromatic heterocycle, Z is an optionally substituted cycloalkyl or an optionally substituted non-aromatic heterocycle, m is 2, and n is 2. (7F-1) A compound of formula (I) wherein L is 1,2,4-oxadiazole or tetrazole, Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each of which is substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl, m is 2, and n is 2.

[0073] (7G) Azacycloalkyl is piperidinyl, and Y is optionally substituted alkyl or optionally substituted C ３－６ A compound of formula (I) in which C is cycloalkyl, L is a nitrogen-containing aromatic heterocycle, m is 2, and n is 2. ３－６ A compound of formula (I), wherein the azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl; Y is isopropyl, trifluoromethyl, or cyclopropyl; L is 1,2,4-oxadiazole or tetrazole; m is 2; and n is 2.

[0074] (7H) azacycloalkyl is piperidinyl, and Y is optionally substituted alkyl or optionally substituted C ３－６A compound of formula (I) wherein (7H-1)C is cycloalkyl, Z is an optionally substituted cycloalkyl or an optionally substituted non-aromatic heterocycle, m is 2, and n is 2. ３－６ A compound of formula (I), wherein the azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl; Y is isopropyl, trifluoromethyl, or cyclopropyl; Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl; m is 2; and n is 2.

[0075] (7I) A compound of formula (I) in which azacycloalkyl is piperidinyl, L is a nitrogen-containing aromatic heterocycle, Z is an optionally substituted cycloalkyl or an optionally substituted non-aromatic heterocycle, m is 2, and n is 2. (7I-1) C ３－６ A compound of formula (I) wherein the azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl; L is 1,2,4-oxadiazole or tetrazole; Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl; m is 2; and n is 2.

[0076] (7J) Y is an alkyl group which may have a substituent, or a C group which may have a substituent. ３－６(7J-1) A compound of formula (I) wherein Y is isopropyl, trifluoromethyl or cyclopropyl, L is 1,2,4-oxadiazole or tetrazole, Z is cyclobutyl, cyclohexyl or tetrahydropyranyl, each of which is substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl, m is 2 and n is 2.

[0077] (7K) Azacycloalkyl is piperidinyl, and Y is optionally substituted alkyl or optionally substituted C ３－６ A compound of formula (I), wherein L is a cycloalkyl, L is a nitrogen-containing aromatic heterocycle, Z is an optionally substituted cycloalkyl or an optionally substituted non-aromatic heterocycle, m is 2, and n is 2. (7K-1)C ３－６ A compound of formula (I) wherein the azacycloalkyl spiro-fused with a cycloalkyl or a saturated heterocycle having 3 to 6 ring members is 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl, or 5-azaspiro[2.5]octyl; Y is isopropyl, trifluoromethyl, or cyclopropyl; L is 1,2,4-oxadiazole or tetrazole; Z is cyclobutyl, cyclohexyl, or tetrahydropyranyl, each substituted with 2 to 3 substituents selected from the group consisting of fluoro and methyl; m is 2; and n is 2.

[0078] (8A) A compound of formula (I) wherein the azacycloalkyl is piperidinyl, Y is hydrogen, L is a nitrogen-containing aromatic heterocycle, Z is an aromatic hydrocarbon ring which may have a substituent, m is 2, and n is 2. (8A-1) A compound of formula (I) wherein the azacycloalkyl is piperidinyl, Y is hydrogen, L is a nitrogen-containing aromatic heterocycle, Z is phenyl which may be substituted with 1 to 3 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl, m is 2, and n is 2.

[0079] (9A) A compound of formula (I) wherein L is -C(=O)-, Z is an optionally substituted cyclic amino, m is 2, and n is 2. (9A-1) A compound of formula (I) wherein L is -C(=O)-, Z is an optionally substituted cyclic amino with 1 to 5 substituents selected from the group consisting of fluoro, methyl, and trifluoromethyl, m is 2, and n is 2. (9A-2) Azacycloalkyl is piperidinyl, and Y is an optionally substituted alkyl or an optionally substituted C ３－６ A compound of formula (I) wherein L is cycloalkyl, L is -C(=O)-, Z is cyclic amino optionally substituted with 1 to 5 substituents selected from the group consisting of fluoro, methyl and trifluoromethyl, m is 2, and n is 2.

[0080] Specific examples of compounds encompassed by the present invention include the following compounds or salts thereof. In this specification, compound names named using molecular structure editor software ChemDraw (CambridgeSoft) may be used.

[0081] (4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-isopropylpiperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 1), (4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 2), (4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 3), (4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 31), (4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (Example 51), (4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (Example 56), (4-(5-(5,5-difluorotetrahydro-2H-pyran-2-yl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 63), (4-(5-(5,5-difluorotetrahydro-2H-pyran-2-yl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 64), (4-(2-(3,3-Difluorocyclobutyl)-2H-tetrazol-5-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 67), (4-cyclopropyl-4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (Example 80), (4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (Example 89), (4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (Example 90).

[0082] Compounds of formula (I) may exist as tautomers or geometric isomers depending on the type of substituents. Although compounds of formula (I) may be described herein in only one isomeric form, the present invention also encompasses other isomers, including isolated isomers and mixtures thereof. Furthermore, compounds of formula (I) may have asymmetric carbon atoms or axial asymmetry, which may result in the existence of optical isomers. The present invention also encompasses isolated optical isomers of compounds of formula (I) and mixtures thereof.

[0083] Furthermore, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198.

[0084] Furthermore, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent.Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc., inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, etc., salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine, and ammonium salts.

[0085] Furthermore, the present invention also includes various hydrates, solvates, and crystalline polymorphs of the compound of formula (I) and its salts, as well as compounds labeled with various radioactive or non-radioactive isotopes.

[0086] (Production Method) The compound of formula (I) and its salts can be produced by various known synthesis methods, taking advantage of characteristics based on their basic structure or the type of substituent. In this case, depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006) by P.G.M. Wuts and T.W. Greene, and these protecting groups may be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary. Furthermore, prodrugs of the compound of formula (I) can be produced by introducing a specific group at the stage leading from the raw material to the intermediate, as in the case of the above-mentioned protecting groups, or by further reacting the obtained compound of formula (I). The reaction can be carried out by applying methods known to those skilled in the art, such as conventional esterification, amidation, dehydration, etc. Representative production methods for the compound of formula (I) are described below. Each production method can also be carried out with reference to the references attached to the description. It should be noted that the production methods of the present invention are not limited to the examples shown below.

[0087]

[0088] This production method is a method for producing a compound of formula (I) of the present invention by removing the protecting group from a compound of formula (1) (hereinafter referred to as "compound (1)"; the same applies to compounds of other formulas) in which the nitrogen atom of ring A in formula (I) is protected with a protecting group (PGr). Examples of the protecting group PGr in compound (1) include groups that are commonly used as protecting groups for aliphatic amino groups, including tert-butyloxycarbonyl and 9-fluorenylmethyloxycarbonyl. The protecting group is removed using a catalytic amount, or an equivalent or excess amount, of a reagent depending on the type of protecting group used, under temperature, time, and solvent conditions appropriate for the removal of the protecting group used. For example, when tert-butyloxycarbonyl or 9-fluorenylmethyloxycarbonyl is used as the protecting group, the protecting group can be removed by applying the conditions described in the aforementioned "Greene's Protective Groups in Organic Synthesis (4th edition, 2006)."

[0089]

[0090] Compound (1) can be produced by an amidation reaction between compound (1A) and compound (1B) or a reaction equivalent thereto. The reaction is carried out by using equivalent amounts of compound (1A) and compound (1B) or an excess amount of either compound (1A) or compound (1B), and stirring a mixture of these in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at −20° C. to 60° C., usually for 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, water, and mixtures thereof. Condensing agents include, but are not limited to, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, diphenylphosphoryl azide, and phosphorus oxychloride. The use of an additive (e.g., 1-hydroxybenzotriazole) may be preferable for the reaction. Carrying out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine; or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide; may be advantageous in order to ensure smooth reaction. Alternatively, the carboxylic acid compound (1A) can be converted into a reactive derivative and then reacted with compound (1B). Examples of reactive derivatives of carboxylic acid include acid halides obtained by reacting with a halogenating agent such as phosphorus oxychloride or thionyl chloride; mixed acid anhydrides obtained by reacting with isobutyl chloroformate or the like; and activated esters obtained by condensing with 1-hydroxybenzotriazole or the like.The reaction of these reactive derivatives with compound (1B) is carried out in a reaction-inert solvent such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, with stirring under cooling or heating, preferably at −20° C. to 60° C., usually for 0.1 hour to 5 days. In some cases, it is advantageous to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine, in order to ensure smooth progress of the reaction.

[0091] Compound (1A) and compound (1B) can be produced by the methods shown in the Examples or Production Examples described below, or by methods analogous thereto.

[0092] The compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorph. A salt of the compound of formula (I) can also be produced by a conventional salt formation reaction. Isolation and purification are carried out using conventional chemical procedures such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between isomers. For example, optical isomers can be obtained by conventional optical resolution methods of racemates (e.g., fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.), or can also be produced from appropriate optically active starting compounds.

[0093] In this specification, the compounds of formula (Ia), formula (Ib), formula (Iaa), and formula (Ibb) and salts thereof are included in the compounds of formula (I) and salts thereof, and examples and embodiments of the compounds of formula (Ia), formula (Ib), formula (Iaa), and formula (Ibb) and salts thereof can refer to those of the compounds of formula (I) and salts thereof, as long as they are not inconsistent with formula (Ia), formula (Ib), formula (Iaa), and formula (Ibb).

[0094] The pharmacological activity of the compound of formula (I) was confirmed by the following tests.

[0095] 1. CTSC Inhibition Assay (In Vitro) Test samples were evaluated in a CTSC inhibition assay using the fluorescent substrate GF-AFC (Gly-Phe-7-Amino-4-trifluoromethylcoumarin, MP Biomedical, 03AFC03325). GF-AFC is converted by CTSC to aminotrifluoromethylcoumarin, which has a specific fluorescence wavelength. The amount produced is proportional to CTSC activity, and quantitative analysis was performed by measuring the fluorescence intensity using a plate reader. The CTSC inhibition assay for each compound was performed using a black 384-well polystyrene plate with a non-adhesive surface under the following conditions: Human recombinant CTSC (R&D systems, 1071-CY) was dissolved in CTSC activation cocktail (20 ng / mL human recombinant cathepsin L (R&D systems, 952-CY, 25 mmol / L MES / NaOH (pH 6.0), 5 mmol / L dithiothreitol (DTT)) at 100 ng / mL and incubated at 18°C ​​for 30 minutes. For the CTSC inhibition assay, the solution was diluted to 2 ng / mL with CTSC assay buffer (50 mmol / L MES / NaOH (pH 5.0), 50 mmol / L NaCl, 0.001% Triton X-100, 5 mmol / L DTT). Test samples were dissolved in dimethyl sulfoxide (DMSO) at 10 mmol / L to prepare stock solutions. The stock solutions were diluted 15-fold with DMSO to the maximum concentration (0.667%) evaluated. Serial dilutions were prepared by repeatedly diluting five-fold with DMSO. 248.8 μL of CTSC assay buffer was added to 1.12 μL of the DMSO-prepared dilution series to prepare the CTSC inhibition assay compound solution. The final composition of the CTSC inhibition assay mixture was 0.66 ng / mL activated CTSC, 50 mmol / L MES / NaOH (pH 5.0), 50 mmol / L NaCl, 0.001% Triton X-100, 5 mmol / L DTT, 30 μmol / L GF-AFC, and 0.15% DMSO. The assay was performed as follows:Specifically, 4 μL of compound solution and 4 μL of 2 ng / mL activated CTSC solution were mixed in a 384-well plate and incubated at 25°C for 30 minutes. Then, 4 μL of GF-AFC solution dissolved in CTSC assay buffer at 90 μmol / L was added. The mixture was mixed uniformly and incubated at 25°C for 1 hour. The fluorescence intensity at 505 nm upon excitation at 390 nm was measured using a plate reader. A four-parameter regression analysis was performed using GraphPad Prism (GraphPad Software) software to plot the fluorescence intensity at 505 nm versus the sample concentration, and the IC was calculated. ５０ The results of some test compounds of formula (I) were analyzed using IC values ​​calculated as the 50% inhibitory concentration based on CTSC inhibition (%). ５０ The values ​​(nM) are shown in Table 1. In the table, Ex indicates the example number.

[0096]

[0097] 2. Intracellular CTSC Inhibition Assay (In Vitro) Test samples were evaluated by the degree of cell death upon addition of the substrate LLOMe (L-Leucyl-L-Leucine methyl ester, hydrobromide salt, Sigma, 555045152) to U937 cells. LLOMe is taken up into cells by endocytosis and cleaved by CTSC. The resulting product induces lysosomal damage in cells, leading to cell death in leukocytes and other cells. Therefore, the degree of cell death correlates with the amount of LLOMe degradation product, i.e., CTSC activity. Therefore, the CTSC inhibitory activity of the test sample in cells was determined by quantitatively analyzing cell death. The inhibition assay was performed using a white 384-well polystyrene plate. Test samples were dissolved in DMSO to prepare a stock solution at 0.2 mmol / L. This was diluted 50-fold with RPMI-1640 medium containing 10% FBS to obtain the maximum concentration (4000 nmol / L). From there, serial dilutions were made in 3-fold increments with medium to prepare 4x concentrated test sample solutions at the target final concentration. U937 cells were cultured in RPMI-1640 medium containing 10% FBS and diluted on the day of the assay to prepare a 90,000 cells / mL cell suspension. 10 μL of this cell suspension was seeded per well. Next, 10 μL of test sample solution at 4x the target final concentration was added and allowed to stand for 30 minutes. Then, 20 μL of a 300 μmol / L LLOMe solution dissolved in RPMI-1640 medium containing 10% FBS was added, and the cells were incubated for 3 hours. After incubation, 40 μL of CellTiter-Glo® reagent (Promega, G7570) was added to each well and mixed. After 15 minutes, 20 μL of the reaction solution from each well was transferred to a white 384-well plate, and the chemiluminescence intensity was measured using a plate reader. A four-parameter regression analysis was performed using GraphPad Prism (GraphPad Software) software from the plot of luminescence intensity versus sample concentration to determine the IC. ５０ The results of some test compounds of formula (I) were analyzed using IC values ​​calculated as the 50% inhibitory concentration based on CTSC inhibition (%). ５０ The values ​​(nM) are shown in Table 2. In the table, Ex indicates the example number.

[0098]

[0099] As a result of the above test, it was confirmed that some compounds of formula (I) have a CTSC inhibitory effect, and therefore the compounds of formula (I) can be used for the treatment of neutrophil-associated inflammatory diseases. Examples of the neutrophil-associated inflammatory disease include rheumatoid arthritis, multiple sclerosis, cystic fibrosis (CF), non-cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, chronic bronchitis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), alpha-1-antitrypsin deficiency (AATD), gastrointestinal inflammatory diseases (inflammatory bowel disease, ulcerative colitis, etc.), glomerulonephritis, lupus nephritis, ANCA-associated vasculitis (granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), etc.), hidradenitis suppurativa, palmoplantar pustulosis, chronic sinusitis, and neutrophilic dermatoses (Sweet's syndrome, Behcet's disease, etc.).

[0100] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as an active ingredient can be prepared by a commonly used method using pharmaceutically acceptable excipients, i.e., excipients commonly used in the art, such as pharmaceutical excipients and pharmaceutical carriers. Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using intra-articular, intravenous, intramuscular, etc. injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc.

[0101] Solid compositions for oral administration include tablets, powders, granules, and the like. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, as per common practices. Tablets or pills may be coated with sugar or a film of a gastric or enteric coating, as needed. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluent, the liquid compositions may contain auxiliary agents such as solubilizers, wetting agents, and suspending agents, as well as sweeteners, flavors, fragrances, and preservatives.

[0102] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain an isotonic agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. These are sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizer, or irradiation. Alternatively, sterile solid compositions can be prepared and dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0103] In general, for oral administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, in one embodiment 0.01 to 30 mg / kg, and in another embodiment 0.1 to 10 mg / kg, and is administered once or in two to four divided doses. For intravenous administration, the daily dosage can be approximately 0.0001 to 10 mg / kg of body weight, and can be administered once or multiple times a day. Furthermore, for transmucosal administration, approximately 0.001 to 100 mg / kg of body weight can be administered once or multiple times a day. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, etc.

[0104] Although it varies depending on the route of administration, dosage form, administration site, and types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0105] The compound of formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the compound of formula (I) is considered to be effective. The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparation may be a combined preparation or may be formulated separately.

[0106] Hereinafter, a method for producing the compound of formula (I) will be described based on examples. The present invention is not limited to the compounds described in the following examples. In addition, methods for producing raw material compounds are shown as production examples. The method for producing the compound of formula (I) is not limited to the production methods in the examples shown below, and the compound can also be produced by a combination of these production methods or by methods obvious to those skilled in the art. The concentration in mol / L is represented as M.

[0107] Production Example 1 Under a nitrogen atmosphere, cyclobutanecarbonitrile (33.8 g, 416 mmol) was added to a tetrahydrofuran (THF) solution (450 mL) of 2.0 M lithium diisopropylamide (187 mL, 375 mmol) cooled to −78°C, and the mixture was stirred at the same temperature for 30 minutes. A solution of (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)acetaldehyde (30 g, 208 mmol) in THF (50 mL) was added dropwise to the reaction solution, and the mixture was stirred at −78°C for 45 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was slowly returned to room temperature and stirred for 15 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / petroleum ether) to obtain 1-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-hydroxyethyl)cyclobutane-1-carbonitrile (15.5 g, 43%) as a liquid.

[0108] Production Example 2 Under a nitrogen atmosphere, to a suspension of sodium hydride (60%, 3.73 g, 93 mmol) in N,N-dimethylformamide (DMF) (300 mL) cooled to 0°C was added a solution of benzyl bromide (15.94 g, 93 mmol) and 1-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-hydroxyethyl)cyclobutane-1-carbonitrile (21 g, 93 mmol) in DMF (50 mL) in that order. The reaction mixture was slowly returned to room temperature and then stirred for 3 hours. The reaction mixture was cooled to 10°C, and then saturated aqueous ammonium chloride solution was added. The organic layer was extracted with ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to obtain 1-(1-(benzyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)cyclobutane-1-carbonitrile (25.0 g, 84%) as a liquid.

[0109] Production Example 3 Under a nitrogen atmosphere, a solution of 1-(1-(benzyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)cyclobutane-1-carbonitrile (35 g, 111 mmol) in THF (350 mL) was cooled to 0°C, and sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) (60% toluene solution, 131 mL, 388 mmol) was added. The mixture was then slowly returned to room temperature and stirred at room temperature for 3 hours. After cooling the reaction solution to 0°C, sodium sulfate decahydrate (110.0 g) was gradually added. The mixture was returned to room temperature and stirred for 15 minutes. The mixture was filtered through Celite, and the solid was washed with ethyl acetate. The collected filtrate was concentrated under reduced pressure. THF (700 mL) was added to the resulting residue, and the mixture was cooled to 0°C. Diisopropylethylamine (DIPEA) (23.60 mL, 131 mmol) and 2-nitrobenzenesulfonyl chloride (29.1 g, 131 mmol) were then added sequentially under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. A 10% aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. THF (250 mL) and hydrochloric acid (1.5 N, 250 mL, 375 mmol) were added to the resulting residue at room temperature under a nitrogen atmosphere, and the mixture was stirred for 16 hours. Water (250 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60% ethyl acetate / petroleum ether) to obtain N-((1-((3R)-1-(benzyloxy)-3,4-dihydroxybutyl)cyclobutyl)methyl)-2-nitrobenzenesulfonamide (34.1 g, 66%) as a liquid.

[0110] Production Example 4 Under a nitrogen atmosphere, imidazole (5.00 g, 73.4 mmol) and tert-butyldimethylchlorosilane (11.06 g, 73.4 mmol) were added sequentially to a dichloromethane (DCM) solution (400 mL) of N-((1-((3R)-1-(benzyloxy)-3,4-dihydroxybutyl)cyclobutyl)methyl)-2-nitrobenzenesulfonamide (34.1 g, 73.4 mmol) cooled to 0°C, and the mixture was then returned to room temperature and stirred for 12 hours. Ice-cold water (300 mL) was added to the reaction solution, which was then extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / petroleum ether) to give N-((1-((3R)-1-(benzyloxy)-4-((tert-butyldimethylsilyl)oxy)-3-hydroxybutyl)cyclobutyl)methyl)-2-nitrobenzenesulfonamide (39.0 g, 91%) as a liquid.

[0111] Production Example 5 Under a nitrogen atmosphere, diethyl azodicarboxylate (16.0 mL, 101 mmol) was added to a THF (400 mL) solution of N-((1-((3R)-1-(benzyloxy)-4-((tert-butyldimethylsilyl)oxy)-3-hydroxybutyl)cyclobutyl)methyl)-2-nitrobenzenesulfonamide (39.0 g, 67.4 mmol) and triphenylphosphine (26.5 g, 101 mmol) cooled to 0°C, and the mixture was allowed to warm to room temperature and stirred for 3 hours. Ice-cold water (300 mL) was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to give (7S)-9-(benzyloxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6-((2-nitrophenyl)sulfonyl)-6-azaspiro[3.5]nonane (36 g, 95%) as a liquid.

[0112] Production Example 6 Under a nitrogen atmosphere, thioglycolic acid (8.96 mL, 128 mmol) and lithium hydroxide monohydrate (10.78 g, 257 mmol) were added to a DMF (300 mL) solution of (7S)-9-(benzyloxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6-((2-nitrophenyl)sulfonyl)-6-azaspiro[3.5]nonane (36 g, 64.2 mmol) cooled to 0°C, and the mixture was then allowed to warm to room temperature and stirred for 3 hours. Ice-cold water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with ice-cold water and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Under a nitrogen atmosphere, DCM (200 mL) was added to the residue, followed by the addition of di-tert-butyl dicarbonate (16.8 mL, 72.7 mmol), triethylamine (11.69 mL, 84 mmol), and 4-dimethylaminopyridine (0.683 g, 5.59 mmol), and the mixture was stirred at room temperature for 16 hours. Water (250 mL) was added to the reaction mixture, which was then extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to give tert-butyl (7S)-9-(benzyloxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6-azaspiro[3.5]nonane-6-carboxylate (22 g, 72%) as a liquid.

[0113] Production Example 7 To a solution of tert-butyl (7S)-9-(benzyloxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6-azaspiro[3.5]nonane-6-carboxylate (22 g, 46.2 mmol) in methanol (250 mL) was added 20% palladium hydroxide on carbon (3.25 g), and the mixture was stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 16 hours. The reaction mixture was filtered through Celite, the solid was washed with methanol (200 mL), and the filtrate was concentrated under reduced pressure. DCM (200 mL) was added to the resulting residue, and the mixture was cooled to 0°C. Then, imidazole (3.45 g, 50.8 mmol) and tert-butyldimethylchlorosilane (7.6 g, 50.8 mmol) were added sequentially, and the mixture was then returned to room temperature and stirred for 12 hours. Ice-cold water (300 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to give tert-butyl (7S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (14.5 g, 81%) as a liquid.

[0114] Preparation Example 8 Under a nitrogen atmosphere, Dess-Martin periodinane (19.96 g, 47.1 mmol) was added to a solution of tert-butyl (7S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (16.5 g, 42.8 mmol) in DCM (250 mL), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate (100 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes. The reaction mixture was extracted with DCM, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to give tert-butyl (S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9-oxo-6-azaspiro[3.5]nonane-6-carboxylate (15.3 g, 93%) as a liquid.

[0115] Production Example 9 Under a nitrogen atmosphere, cerium chloride heptahydrate (19.44 g, 52.2 mmol) was added to a solution of tert-butyl (S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9-oxo-6-azaspiro[3.5]nonane-6-carboxylate (15.3 g, 40.0 mmol) in methanol (40 mL), and the mixture was cooled to −78° C. Sodium borohydride (1.823 g, 48.2 mmol) was gradually added to the reaction mixture, and the mixture was stirred at −78° C. for 1 hour, then gradually warmed to 0° C. and stirred for 30 minutes. A 10% aqueous citric acid solution (50 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue was added THF (40 mL) under a nitrogen atmosphere, followed by the addition of a tetrabutylammonium fluoride THF solution (1.0 M, 78 mL, 78 mmol), and the mixture was stirred at room temperature for 12 hours. Ice-cold water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to give tert-butyl (7S,9R)-9-hydroxy-7-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylate (9.2 g, 84%) as a gummy solid.

[0116] Preparation Example 10 Under a nitrogen atmosphere, a solution of tert-butyl (7S,9R)-9-hydroxy-7-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylate (2.0 g, 7.37 mmol) in acetonitrile (20 mL) was added to 1.0 M phosphate buffer (Na ２ HPO ４ : NaH ２ P.O. ４A 1:1, 11 mL mixture was added. Sodium chlorite (2.466 g, 27.3 mmol) and 2-hydroxy-2-azaadamantane (0.113 g, 0.737 mmol) were added to the mixture, and the mixture was stirred at room temperature for 16 hours. 2-Methyl-2-butene (4.0 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. 10% aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with DCM. 1.5 M hydrochloric acid was added to the aqueous layer to adjust the pH to 2, and the mixture was extracted with DCM. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (1.91 g, 84%) as a white solid.

[0117] Production Example 11: Under a nitrogen atmosphere, potassium tert-butoxide (39.27 g, 0.350 mol) was added to an ice-cooled solution of trimethylsulfoxonium iodide (77.18 g, 0.350 mol) in dimethyl sulfoxide (DMSO) (850 mL), and the mixture was gradually returned to room temperature and stirred for 1 hour. The reaction mixture was cooled to 10°C, and benzyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-1-carboxylate (85 g, 0.233 mol) was added portionwise, the mixture was returned to room temperature, and stirred for 1 hour. Ice-cold water (400 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (85% ethyl acetate / petroleum ether) to give benzyl (S)-(1-((tert-butyldimethylsilyl)oxy)-6-(dimethyl(oxo)-6-sulfaneilidene)-5-oxohexan-2-yl)carbamate (57 g, 53%) as a reddish-brown liquid.

[0118] Production Example 12 Under a nitrogen atmosphere, a toluene solution (700 mL) of benzyl (S)-(1-((tert-butyldimethylsilyl)oxy)-6-(dimethyl(oxo)-6-sulfaneilidene)-5-oxohexan-2-yl)carbamate (57 g, 0.127 mol) was degassed for 15 minutes, and then iridium(I) chloride 1,5-cyclooctadiene complex dimer (0.840 g, 0.00125 mol) was added. The reaction mixture was stirred at 80°C for 2 hours, cooled to room temperature, and concentrated under reduced pressure. Ice-cold water (200 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to give benzyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopiperidine-1-carboxylate (26 g, 55%) as a colorless liquid.

[0119] Production Example 13: Under a nitrogen atmosphere, potassium tert-butoxide (19.79 g, 0.1619 mol) was added to a tert-butyl alcohol solution (300 mL) of trimethylsulfoxonium iodide (35.64 g, 0.1619 mol) heated to 50°C, and the mixture was stirred for 1 hour. The reaction mixture was cooled to room temperature, and a tert-butyl alcohol solution (100 mL) of benzyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopiperidine-1-carboxylate (26 g, 0.0689 mol) was added dropwise. The reaction mixture was heated to 50°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and ice-cold water (200 mL) was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to give benzyl (4R,7S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (8.0 g, 0.068 mol, 28%, low-polarity fraction, Production Example 13) as a pale brown liquid, and benzyl (4S,7S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (3.8 g, 13%, high-polarity fraction) as a pale brown liquid.

[0120] Preparation Example 15: 10% palladium on carbon (2.0 g) was added to an ethanol solution (80 mL) of (4R,7S)-7-(hydroxymethyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylic acid benzyl ester (4.5 g, 15.4 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 8 hours. The solids were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give ((4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl)methanol (2.4 g).

[0121] Preparation Example 16: 1,4-Dioxane (25 mL) and water (40 mL) were added to ((4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl)methanol (2.4 g) and the mixture was cooled on ice. Sodium bicarbonate (3.07 g, 36.4 mmol) and 9-fluorenylmethyl chloroformate (3.93 g, 15.2 mmol) were added sequentially. The reaction mixture was warmed to room temperature and stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / petroleum ether) to give (9H-fluoren-9-yl)methyl (4R,7S)-7-(hydroxymethyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (5.0 g, 86%) as a colorless liquid.

[0122] Production Example 18 Under a nitrogen atmosphere, a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.93 g, 67.5 mmol) in DCM (100 mL) was added to a solution of (S)-3-((tert-butoxycarbonyl)amino)-4-((tert-butyldimethylsilyl)oxy)butanoic acid (15 g, 45.0 mmol), 4-dimethylaminopyridine (8.24 g, 67.5 mmol), and 2,2-dimethyl-1,3-dioxane-4,6-dione (6.48 g, 45.0 mmol) in DCM (225 mL) cooled to 0°C, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the layers were separated. The organic layer was washed successively with 10% aqueous sodium hydrogen sulfate, water, and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and stirred at 80°C for 4 hours under a nitrogen atmosphere. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (15-20% ethyl acetate / petroleum ether) to give tert-butyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4,6-dioxopiperidine-1-carboxylate (12 g, 33.6 mmol, 74.6%).

[0123] Preparation Example 19: Under a nitrogen atmosphere, to a mixture of tert-butyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4,6-dioxopiperidine-1-carboxylate (10 g, 28 mmol) and potassium carbonate (11.6 g, 84 mmol) in DMF (100 mL) cooled to 0°C, was added methyl iodide (9.93 g, 69.9 mmol), and the mixture was stirred for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% ethyl acetate / petroleum ether) to give tert-butyl (S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-dimethyl-2,4-dioxopiperidine-1-carboxylate (6.8 g, 17.64 mmol, 63.1%) as a colorless liquid.

[0124] Production Example 20 Under a nitrogen atmosphere, borane dimethyl sulfide complex (12.97 mL, 130 mmol) was added to a tetrahydrofuran (100 mL) solution of tert-butyl (S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-dimethyl-2,4-dioxopiperidine-1-carboxylate (10 g, 25.9 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 24 hours. The reaction solution was cooled to 0°C, and methanol (150 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate (9.5 g, 15.41 mmol, 59.4%).

[0125] Production Example 24 Under a nitrogen atmosphere, a solution of benzyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopiperidine-1-carboxylate (3 g, 7.95 mmol) in THF (30 mL) was cooled to −78° C., and a methylmagnesium bromide-diethyl ether solution (3.0 M, 7.95 mL, 23.84 mmol) was added dropwise, followed by stirring at room temperature for 12 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / petroleum ether) to give benzyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-hydroxy-5-methylpiperidine-1-carboxylate (600 mg, 1.524 mmol, 19.18%).

[0126] Production Example 27 Under a nitrogen atmosphere, a solution of tert-butyl (2S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-hydroxy-5-methylpiperidine-1-carboxylate (200 mg, 0.556 mmol) in THF (2 mL) was cooled to 0°C, and acetic acid (167 mg, 2.78 mmol) and a THF solution of tetrabutylammonium fluoride (1 M, 1.112 mL, 1.112 mmol) were added dropwise. The reaction solution was stirred at room temperature for 12 hours, then diluted with water and extracted with methyl tert-butyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-70% ethyl acetate / petroleum ether) to give tert-butyl (2S)-5-hydroxy-2-(hydroxymethyl)-5-methylpiperidine-1-carboxylate (83.5 mg, 0.339 mmol, 60.9%) as a colorless gum.

[0127] Preparation Example 29: Under a nitrogen atmosphere, DMF (200 mL) was added to 1-(tert-butoxycarbonyl)-4-isopropylpiperidine-4-carboxylic acid (34 g, 125 mmol) and (Z)-3,3-difluoro-N'-hydroxycyclobutane-1-carboximidamide (18.81 g, 125 mmol), and the mixture was cooled to 0°C. DIPEA (43.8 mL, 251 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (52.4 g, 138 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (35-45% ethyl acetate / petroleum ether) to give tert-butyl (Z)-4-((((amino(3,3-difluorocyclobutyl)methylene)amino)oxy)carbonyl)-4-isopropylpiperidine-1-carboxylate (31 g, 61.3%) as a white solid.

[0128] Production Example 30 Under a nitrogen atmosphere, potassium hydroxide (7.93 g, 141 mmol) was added to a solution of tert-butyl (Z)-4-((((amino(3,3-difluorocyclobutyl)methylene)amino)oxy)carbonyl)-4-isopropylpiperidine-1-carboxylate (57 g, 141 mmol) in DMSO (340 mL) at room temperature, and the mixture was stirred for 12 hours. Cooling water was added to the reaction solution, which was then extracted with petroleum ether, and the organic layer was washed with water. The organic layer was concentrated under reduced pressure to give tert-butyl 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-isopropylpiperidine-1-carboxylate (44 g, 80%) as an off-white solid.

[0129] Production Example 31 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (114 mL, 457 mmol) was added to a DCM (225 mL) solution of tert-butyl 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-isopropylpiperidine-1-carboxylate (44 g, 114 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then DCM was added to the residue, followed by further concentration under reduced pressure. This procedure was repeated three times, after which the residue was triturated with tert-butyl methyl ether. The solid was collected by filtration and dried to give 3-(3,3-difluorocyclobutyl)-5-(4-isopropylpiperidin-4-yl)-1,2,4-oxadiazole hydrochloride (32.5 g, 88%) as an off-white solid.

[0130] Preparation Example 32: Under a nitrogen atmosphere, DCM (120 mL) was added to 3-(3,3-difluorocyclobutyl)-5-(4-isopropylpiperidin-4-yl)-1,2,4-oxadiazole hydrochloride (22.56 g, 70.1 mmol), and the mixture was cooled to 0°C. Then, DIPEA (24.5 mL, 140.3 mmol), (7S,9R)-6-(tert-butoxycarbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-7-carboxylic acid (20 g, 70.1 mmol), and HATU (31.98 g, 84.12 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with 10% aqueous sodium bicarbonate solution and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (30-35% ethyl acetate / petroleum ether) to give tert-butyl (7S,9R)-7-(4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-isopropylpiperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (29 g, 74%) as an off-white solid.

[0131] Production Example 37: Under a nitrogen atmosphere, an aqueous hydroxylamine solution (50%, 150 mL, 180 mmol) was added to a solution of tert-butyl 4-cyano-4-(trifluoromethyl)piperidine-1-carboxylate (50 g, 180 mmol) in ethanol (500 mL) at room temperature, and the mixture was then heated to 80°C and stirred for 16 hours. The reaction solution was cooled to 10°C and stirred for 1 hour. The precipitated solid was collected by filtration and washed with water to obtain tert-butyl (Z)-4-(N'-hydroxycarbamimidoyl)-4-(trifluoromethyl)piperidine-1-carboxylate (50 g, 89%) as an off-white solid.

[0132] Preparation Example 39 Under a nitrogen atmosphere, a solution of tert-butyl (Z)-4-(N'-((3,3-difluorocyclobutane-1-carbonyl)oxy)carbamimidoyl)-4-(trifluoromethyl)piperidine-1-carboxylate (66 g, 154 mmol) in dioxane (500 mL) was stirred at 110°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate / petroleum ether) to give tert-butyl 4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (60 g, 95%) as an off-white solid.

[0133] Preparation Example 42: Under a nitrogen atmosphere, sodium hydrosulfide hydrate (240 mg, 3.23 mmol) was added to a mixture of tert-butyl 4-cyano-4-(trifluoromethyl)piperidine-1-carboxylate (200 mg, 0.719 mmol), ammonium chloride (173 mg, 3.23 mmol), and DMF (5 mL), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl 4-carbamothioyl-4-(trifluoromethyl)piperidine-1-carboxylate (170 mg, 0.537 mmol, 74.7%) as a pale yellow solid.

[0134] Preparation Example 43: A mixture of tert-butyl 4-carbamothioyl-4-(trifluoromethyl)piperidine-1-carboxylate (270 mg, 0.864 mmol), 2-bromo-1-(4,4-difluorocyclohexyl)ethan-1-one (208 mg, 0.864 mmol), DIPEA (0.453 mL, 2.59 mmol), and THF (2 mL) was heated in a sealed tube at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate / petroleum ether) to give tert-butyl 4-(4-(4,4-difluorocyclohexyl)-4-hydroxy-4,5-dihydrothiazol-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (260 mg, 0.550 mmol, 63.7%) as a brown gummy solid.

[0135] Preparation Example 44 Under a nitrogen atmosphere, a mixture of tert-butyl 4-(4-(4,4-difluorocyclohexyl)-4-hydroxy-4,5-dihydrothiazol-2-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (250 mg, 0.529 mmol), p-toluenesulfonic acid monohydrate (101 mg, 0.529 mmol), and toluene (5.0 mL) was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% methanol / DCM) to give 4-(4,4-difluorocyclohexyl)-2-(4-(trifluoromethyl)piperidin-4-yl)thiazole (140 mg, 0.395 mmol, 74.7%) as a yellow solid.

[0136] Preparation Example 45 Under a nitrogen atmosphere, to an ice-cooled solution of (4R,7S)-6-(((9H-fluoren-9-yl)methoxy)carbonyl)-1-oxa-6-azaspiro[3.5]nonane-7-carboxylic acid (155 mg, 0.395 mmol) in DCM (15 mL) were successively added DIPEA (0.138 mL, 0.790 mmol) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) (254 mg, 0.593 mmol), and the mixture was stirred for 15 minutes. Then, 4-(4,4-difluorocyclohexyl)-2-(4-(trifluoromethyl)piperidin-4-yl)thiazole (140 mg, 0.395 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55% ethyl acetate / petroleum ether) to give (9H-fluoren-9-yl)methyl (4R,7S)-7-(4-(4-(4,4-difluorocyclohexyl)thiazol-2-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (200 mg, 0.274 mmol, 69.4%) as a light brown solid.

[0137] Production Example 46: A solution of 3,3-difluorocyclobutane-1-carboxylic acid (0.801 g, 5.89 mmol) and DIPEA (2.57 mL, 14.72 mmol) in DCM (20 mL) was cooled to 0°C, and HATU (2.425 g, 6.38 mmol) and tert-butyl (Z)-4-(N'-hydroxycarbamimidoyl)-4-isopropylpiperidine-1-carboxylate (2.0 g, 4.91 mmol) were added, followed by stirring at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue, which was then washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The resulting product was dissolved in dioxane (15.0 mL) and stirred at 150°C for 1 hour under microwave (MW) irradiation. The solvent was evaporated under reduced pressure to give tert-butyl 4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-isopropylpiperidine-1-carboxylate (1.1 g, 2.85 mmol, 96%) as an off-white solid.

[0138] Preparation Example 52: Under a nitrogen atmosphere, DCM (10 mL) was added to 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-4-carboxylic acid (170 mg, 0.571 mmol) and (4,4-difluorohexyl)methanamine hydrochloride (106 mg, 0.571 mmol), and the mixture was cooled to 0° C., followed by the sequential addition of DIPEA (1.20 mL, 1.143 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142.5 mg, 0.743 mmol), and 1-hydroxybenzotriazole (100.5 mg, 0.743 mmol). The reaction mixture was stirred at room temperature for 5 hours, and then water was added, and the organic layer and aqueous layer were separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-70% ethyl acetate / petroleum ether) to give tert-butyl 4-(((4,4-difluorohexyl)methyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylate (170 mg, 0.396 mmol, 70.8%) as a white solid.

[0139] Production Example 54: Under a nitrogen atmosphere, lithium bis(trimethylsilyl)amide (LHMDS) (1 M THF solution, 3.313 g, 19.8 mmol) was slowly added dropwise to a THF (15 mL) solution of tert-butyl 3-cyanoazetidine-1-carboxylate (3 g, 16.5 mmol) cooled to -78°C. The reaction mixture was stirred at -78°C for 30 minutes, and then a THF (15 mL) solution of isopropyl iodide (3.28 g, 19.8 mmol) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours and then at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / petroleum ether) to obtain tert-butyl 3-cyano-3-isopropylazetidine-1-carboxylate (1.8 g, 8.02 mmol, 48.6%).

[0140] Production Example 55: Under a nitrogen atmosphere, hydroxylamine hydrochloride (62 mg, 0.89 mmol) and triethylamine (0.2 mL, 1.34 mmol) were added to a solution of tert-butyl 3-cyano-3-isopropylazetidine-1-carboxylate (100 mg, 0.44 mmol) in ethanol (2 mL), and the mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with DCM. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give tert-butyl (Z)-3-(N'-hydroxycarbamimidoyl)-3-isopropylazetidine-1-carboxylate (100 mg, 0.39 mmol).

[0141] Preparation Example 59 Under a nitrogen atmosphere, sodium hydride (60%, 105 mg, 2.6 mmol) was added to a DMF (10 mL) solution of tert-butyl 4-(((4,4-difluorohexyl)methyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylate (700 mg, 1.7 mmol) cooled to 0°C, and the mixture was stirred for 10 minutes. Methyl iodide (0.23 mL, 3.4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to give tert-butyl 4-(((4,4-difluorohexyl)methyl)(methyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylate (600 mg, 80%) as an off-white solid.

[0142] Production Example 75 A mixture of tert-butyl 4-(2-(4,4-difluorocyclohexane-1-carbonyl)hydrazine-1-carbonyl)-4-isopropylpiperidine-1-carboxylate (0.55 g, 1.275 mmol) and phosphoryl chloride (3 mL, 1.275 mmol) was heated in a sealed tube at 100° C. for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed successively with 10% aqueous sodium bicarbonate solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2-3% methanol / DCM) to give 2-(4,4-difluorocyclohexane)-5-(4-isopropylpiperidin-4-yl)-1,3,4-oxadiazole (0.14 g, 0.362 mmol, 28.4%) as a light brown solid.

[0143] Preparation Example 101: Under a nitrogen atmosphere, triethylamine (262 mg, 2.58 mmol) was added to a DCM (5 mL) solution of 5-(4,4-difluorocyclohexyl)-3-(4-isopropylpiperidin-4-yl)-1,2,4-oxadiazole hydrochloride (270 mg, 0.862 mmol) cooled to 0° C., followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (165 mg, 0.862 mmol), 1-hydroxybenzotriazole (158 mg, 1.034 mmol), and (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (200 mg, 0.865 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then water was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-70% ethyl acetate / petroleum ether) to give tert-butyl (2S,4S)-2-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-isopropylpiperidine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate (140 mg, 0.239 mmol, 27.8%) as a white solid.

[0144] Preparation Example 109 Under a nitrogen atmosphere, Oxone (1.656 g, 5.39 mmol) was added to a solution of tert-butyl (2S,4S)-2-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-isopropylpiperidine-1-carbonyl)-4-(methylthio)pyrrolidine-1-carboxylate (0.3 g, 0.539 mmol) in DCM (10 mL) cooled to 0° C., and the mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (10 mM aqueous ammonium acetate solution / acetonitrile) to give tert-butyl (2S,4S)-2-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-isopropylpiperidine-1-carbonyl)-4-(methylsulfonyl)pyrrolidine-1-carboxylate (0.130 g, 0.217 mmol, 40.3%) as a white solid.

[0145] Preparation Example 114: Under a nitrogen atmosphere, a solution of tert-butyl 4-(4-oxa-7-azaspiro[2.5]octane-7-carbonyl)-4-(trifluoromethyl)piperidine-1-carboxylate (0.2 g, 0.510 mmol) in DCM (3.2 mL) was cooled to 0°C, trifluoroacetic acid (0.8 mL, 10.38 mmol) was added, and the mixture was slowly returned to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to give (4-oxa-7-azaspiro[2.5]octan-7-yl)(4-(trifluoromethyl)piperidin-4-yl)methanone trifluoroacetate (0.15 g, 0.438 mmol, 86%).

[0146] Production Example 146 Under a nitrogen atmosphere, a n-butyllithium-hexane solution (1.6 M, 6.21 mL, 9.93 mmol) was added to a mixture of methyltriphenylphosphonium bromide (3.55 g, 9.93 mmol) in THF (30 mL) cooled to -20°C, and the mixture was stirred at 0°C for 1 hour. To the reaction solution, a THF (10 mL) solution of benzyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopiperidine-1-carboxylate (2.5 g, 6.62 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% ethyl acetate / petroleum ether) to obtain benzyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylenepiperidine-1-carboxylate (1.2 g, 3.19 mmol, 48.1%) as a colorless liquid.

[0147] Preparation Example 147 Under a nitrogen atmosphere, to a solution of benzyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylenepiperidine-1-carboxylate (1.0 g, 2.66 mmol) in DCM (30 mL) cooled to −10° C. was added a diethylzinc-toluene solution (1.5 M, 9.32 mL, 9.32 mmol), and then diiodomethane (1.718 mL, 21.30 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with DCM. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give benzyl (S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-azaspiro[2.5]octane-5-carboxylate (1 g, 1.785 mmol, 67.1%) as a yellow liquid.

[0148] Preparation Example 148 To a solution of benzyl (S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-azaspiro[2.5]octane-5-carboxylate (0.5 g, 1.283 mmol) in ethanol (10 mL) was added 10% palladium hydroxide on activated carbon (0.3 g, 0.214 mmol). The reaction mixture was degassed with nitrogen gas and then stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 16 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give (S)-(5-azaspiro[2.5]octan-6-yl)methanol (0.17 g, 1.082 mmol, 84%) as a colorless liquid.

[0149] Preparation Example 173: Under a nitrogen atmosphere, a mixture of ethyl 3-(1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidin-4-yl)-1,2,4-oxadiazole-5-carboxylate (100 mg, 0.254 mmol), 3,3-dimethylazetidine hydrochloride (30.9 mg, 0.254 mmol), DIPEA (0.131 mL, 0.763 mmol), and ethanol (3 mL) was stirred at 80° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give tert-butyl 4-(5-(3,3-dimethylazetidine-1-carbonyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (90 mg, 0.208 mmol, 82%) as a white solid.

[0150] Preparation Example 209: Under a nitrogen atmosphere, 1-bromo-2-(2-bromoethoxy)ethane (0.539 g, 2.323 mmol) was added to a mixture of 1-(tert-butyl)4-methyl 4-aminopiperidine-1,4-dicarboxylate (0.600 g, 2.323 mmol), potassium iodide (0.771 g, 4.65 mmol), and potassium carbonate (0.642 g, 4.65 mmol) in DMF (10 mL) at room temperature, followed by stirring at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed successively with water, 1.5 M hydrochloric acid, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 1-(tert-butyl)4-methyl 4-morpholinopiperidine-1,4-dicarboxylate (250 mg, 2.32 mmol).

[0151] Preparation Example 210: Under a nitrogen atmosphere, sodium hydroxide (0.049 g, 1.218 mmol) was added to a solution of 1-(tert-butyl)4-methyl 4-morpholinopiperidine-1,4-dicarboxylate (0.200 g, 0.609 mmol) and 3,3-difluoro-N'-hydroxycyclobutane-1-carboximidamide (0.101 g, 0.670 mmol) in DMSO (5 mL) at room temperature, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give tert-butyl 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-morpholinopiperidine-1-carboxylate (40 mg, 0.44 mmol, 20.8%).

[0152] Preparation Example 213: Under a nitrogen atmosphere, sodium azide (409 mg, 6.29 mmol) was added to a mixture of tert-butyl 4-cyano-4-(trifluoromethyl)piperidine-1-carboxylate (500 mg, 1.797 mmol), ammonium chloride (336 mg, 6.29 mmol), and DMF (5 mL) at room temperature, and the mixture was heated to 100°C and stirred for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain tert-butyl 4-(2H-tetrazol-5-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (430 mg, 1.338 mmol, 74.5%) as a colorless liquid.

[0153] Preparation Example 217: Under a nitrogen atmosphere, potassium carbonate (0.387 g, 2.80 mmol) was added to a solution of tert-butyl 4-(2H-tetrazol-5-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (0.3 g, 0.934 mmol) and 3,3-difluorocyclobutyl trifluoromethanesulfonate in DMF (5.00 mL), and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with cold water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give tert-butyl 4-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (0.25 g, 0.602 mmol, 64.4%).

[0154] Preparation Example 236: Under a nitrogen atmosphere, trifluoroacetic anhydride (0.524 mL, 3.70 mmol) was added dropwise to a solution of tert-butyl 4-carbamoyl-4-(4-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (570 mg, 1.848 mmol) and pyridine (0.747 mL, 9.24 mmol) in DCM (12 mL) cooled to 0°C, and the mixture was stirred at room temperature for 3 hours. DCM and water were added to the reaction solution, and the layers were separated. The organic layer was washed with 10% aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give tert-butyl 4-cyano-4-(4-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.640 mmol, 89%).

[0155] Preparation Example 256: Under a nitrogen atmosphere, a solution of tert-butyl 4-amino-4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (160 mg, 0.446 mmol) and triethylamine (113 mg, 1.116 mmol) in DCM (3 mL) was cooled to 0°C, and acetyl chloride (35.0 mg, 0.446 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and then the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give tert-butyl 4-acetamido-4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (180 mg, 0.356 mmol, 80%) as an off-white solid.

[0156] Preparation Example 257 Under a nitrogen atmosphere, sodium hydride (60%, 32.4 mg, 1.349 mmol) was added to a solution of tert-butyl 4-acetamido-4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (180 mg, 0.450 mmol) in THF (5 mL), and then methyl iodide (77 mg, 0.539 mmol) was added, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give tert-butyl 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-(N-methylacetamido)piperidine-1-carboxylate (170 mg, 0.384 mmol, 85%) as a yellow liquid.

[0157] Preparation Example 260 Under a nitrogen atmosphere, a DCM (5 mL) solution of tert-butyl 4-amino-4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (210 mg, 0.586 mmol) and triethylamine (178 mg, 1.758 mmol) was cooled to 0°C, methanesulfonyl chloride (67.1 mg, 0.586 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give tert-butyl 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-(methanesulfonamido)piperidine-1-carboxylate (220 mg, 0.395 mmol, 67.4%) as a yellow liquid.

[0158] Preparation Example 261: Under a nitrogen atmosphere, a solution of tert-butyl 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-(methanesulfonamido)piperidine-1-carboxylate (180 mg, 0.412 mmol) in DMF (6 mL) was cooled to 0° C., and cesium carbonate (161 mg, 0.495 mmol) and methyl iodide (146 mg, 1.031 mmol) were added. The mixture was stirred for 15 minutes and then at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl 4-[3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl]-4-[methyl(methylsulfonyl)amino]piperidine-1-carboxylate (192 mg, 0.286 mmol, 69.4%).

[0159] Production Example 264: Under a nitrogen atmosphere, 2-(thiophen-3-yl)acetonitrile (0.5 g, 4.06 mmol) was added dropwise to a mixture of sodium hydride (60%, 0.357 g, 8.93 mmol) in DMF (5 mL) cooled to 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was again cooled to 0°C, and a solution of tert-butyl bis(2-chloroethyl)carbamate (1.081 g, 4.47 mmol) in DMF (5.00 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. Ice-cold water was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-15% ethyl acetate / petroleum ether) to give tert-butyl 4-cyano-4-(thiophen-3-yl)piperidine-1-carboxylate (0.610 g, 2.083 mmol, 51.3%) as a yellow liquid.

[0160] Preparation Example 271: Under a nitrogen atmosphere, a suspension of dimethyl (1-diazo-2-oxopropyl)phosphonate (85 mg, 0.444 mmol) and molecular sieves (4 Å, 100 mg) in methanol (5 mL) was cooled to 0°C, and potassium carbonate (81 mg, 0.587 mmol) and tert-butyl 4-formyl-4-(trifluoromethyl)piperidine-1-carboxylate (100 mg, 0.356 mmol) were added. The mixture was stirred in an ice bath for 30 minutes and then at room temperature for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the solid was removed by filtration through Celite, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / petroleum ether) to obtain tert-butyl 4-ethynyl-4-(trifluoromethyl)piperidine-1-carboxylate (60 mg, 0.216 mmol, 60.9%).

[0161] Preparation Example 272: Under a nitrogen atmosphere, 4-azido-1,1-difluorocyclohexane (349 mg, 2.164 mmol), copper(II) sulfate (11.51 mg, 0.072 mmol), and sodium L-ascorbate (42.8 mg, 0.216 mmol) were added sequentially to a mixture of tert-butyl 4-ethynyl-4-(trifluoromethyl)piperidine-1-carboxylate (200 mg, 0.721 mmol) in tert-butyl alcohol (5 mL) and water (5.00 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain tert-butyl 4-(1-(4,4-difluorocyclohexyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (311 mg, 0.591 mmol, 82%) as an off-white solid.

[0162] Preparation Example 282: To a suspension of tert-butyl 4-(2H-tetrazol-5-yl)piperidine-1-carboxylate (2 g, 7.90 mmol), 4-fluorophenylboronic acid (1.768 g, 12.63 mmol), and potassium carbonate (1.200 g, 8.69 mmol) in DCM (50 mL) was added di-μ-hydroxobis[(N,N,N',N'-tetramethylethylenediamine)copper(II)] dichloride (0.442 g, 0.947 mmol), and the reaction vessel was purged with an oxygen atmosphere, followed by stirring at room temperature under an oxygen atmosphere at 1 atmosphere pressure for 16 hours. The solid was removed by filtration through Celite, and the filtrate was washed with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12% ethyl acetate / petroleum ether) to give tert-butyl 4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidine-1-carboxylate (1.86 g, 5.35 mmol, 67.8%) as an off-white solid.

[0163] Preparation Example 286: To 1,4-dioxane (6 mL) with nitrogen gas bubbling was added 4-bromo-2-(4,4-difluoropiperidin-1-yl)pyridine (0.250 g, 0.902 mmol), 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.307 g, 0.992 mmol), potassium carbonate (0.249 g, 1.804 mmol), water (1.5 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.074 g, 0.090 mmol), and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was filtered through Celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to obtain tert-butyl 2'-(4,4-difluoropiperidin-1-yl)-3,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylate (0.370 g, 0.885 mmol, 98%) as a yellow liquid.

[0164] Preparation Example 287: A methanol solution (10 mL) of tert-butyl 2'-(4,4-difluoropiperidin-1-yl)-3,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylate (0.3 g, 0.791 mmol) was bubbled with nitrogen gas for 5 minutes. Then, 10% palladium on carbon (0.084 g, 0.079 mmol) was added to the mixture under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 3 hours. After bubbling with nitrogen gas for 5 minutes, the reaction mixture was filtered through Celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give tert-butyl 4-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)piperidine-1-carboxylate (0.3 g, 0.724 mmol, 92%) as a colorless liquid.

[0165] Preparation Example 290: 4,4-Difluoropiperidine hydrochloride (0.324 g, 2.058 mmol) and DIPEA (3.00 mL, 17.23 mmol) were added to a sealed tube and stirred for 10 minutes, then 2,5-dibromothiazole (0.5 g, 2.058 mmol) was added and stirred for 16 hours at 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (6% ethyl acetate / petroleum ether) to give 5-bromo-2-(4,4-difluoropiperidin-1-yl)thiazole (0.340 g, 0.781 mmol, 37.9%) as a white solid.

[0166] Preparation Example 296: Under a nitrogen atmosphere, 4,4-difluoropiperidine hydrochloride (198 mg, 1.261 mmol), DIPEA (0.881 mL, 5.04 mmol), and 4-dimethylaminopyridine (15.41 mg, 0.126 mmol) were added to an ice-cooled ethanol solution (5 mL) of 2,4-dibromopyrimidine (300 mg, 1.261 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to give 2-bromo-4-(4,4-difluoropiperidin-1-yl)pyrimidine (220 mg, 0.783 mmol, 62.1%) as an off-white solid.

[0167] Preparation Example 311: Under a nitrogen atmosphere, a suspension of tert-butyl 4-ethynylpiperidine-1-carboxylate (50 mg, 0.239 mmol), 1-azido-4-fluorobenzene (32.8 mg, 0.239 mmol), copper(I) iodide (45.5 mg, 0.239 mmol), and DIPEA (1043 μL, 5.97 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and filtered through Celite. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl 4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (50 mg, 0.144 mmol, 60.4%) as a light brown solid.

[0168] Preparation Example 314: To a DMF solution (10.51 mL) of 2,4-dibromopyrimidine (0.5 g, 2.102 mmol) and 4-fluoro-1H-pyrazole (0.163 g, 1.892 mmol), potassium carbonate (0.436 g, 3.15 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with ice-cold water. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to give 2-bromo-4-(4-fluoro-1H-pyrazol-1-yl)pyrimidine (0.3 g, 1.199 mmol, 57.0%) as a white solid.

[0169] Preparation Example 323: Under a nitrogen atmosphere, potassium carbonate (486 mg, 3.51 mmol) was added to a DMF solution (10 mL) of 5-(2,4-difluorophenyl)-2H-tetrazole (320 mg, 1.757 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (464 mg, 1.757 mmol), and the mixture was stirred at 90°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / petroleum ether) to give tert-butyl 4-(5-(2,4-difluorophenyl)-2H-tetrazol-2-yl)piperidine-1-carboxylate (290 mg, 0.794 mmol, 45.2%) as a pale yellow liquid.

[0170] Example 1 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (157 mL, 630 mmol) was added dropwise to a solution of tert-butyl (7S,9R)-7-(4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-isopropylpiperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (29 g, 52.5 mmol) in DCM (290 mL) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM and washed with 10% aqueous sodium bicarbonate solution. The organic layer was concentrated under reduced pressure, and the residue was diluted with diethyl ether and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and dried to give (4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-isopropylpiperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (21 g, 88%) as an off-white solid.

[0171] Example 2 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (7S,9R)-7-(4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (220 mg, 0.38 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and made basic by adding 10% aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give (4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (120 mg, 0.25 mmol, 66%) as a white solid.

[0172] Example 3 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (7S,9R)-7-(4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.15 g, 0.259 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then 10% aqueous sodium hydrogen carbonate solution was added to the resulting white solid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give (4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (0.096 g, 0.200 mmol, 77%) as a white solid.

[0173] Example 7 Under a nitrogen atmosphere, a solution of (9H-fluoren-9-yl)methyl (4R,7S)-7-(4-(((4,4-difluorohexyl)methyl)(methyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carbonyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (300 mg, 0.418 mmol) in DMF (2 mL) was cooled to 0°C, piperidine (0.2 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6-8% methanol / DCM) to give N-((4,4-difluorohexyl)methyl)-N-methyl-1-((4R,7S)-1-oxa-6-azaspiro[3.5]nonane-7-carbonyl)-4-(trifluoromethyl)piperidine-4-carboxamide (112 mg, 0.226 mmol, 56.0%).

[0174] Example 16 Under a nitrogen atmosphere, trifluoroacetic acid (0.063 mL, 0.814 mmol) was added to a DCM (5 mL) solution of tert-butyl (7S,9R)-7-(3-(5-(4,4-difluorocyclohexyl)-1,3,4-oxadiazol-2-yl)-3-isopropylazetidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (45 mg, 0.081 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then a 10% aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with DCM. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (0.1% aqueous trifluoroacetic acid solution / acetonitrile) to give (3-(5-(4,4-difluorocyclohexyl)-1,3,4-oxadiazol-2-yl)-3-isopropylazetidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone trifluoroacetate (8 mg, 0.017 mmol, 21.25%).

[0175] Example 31 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (7S,9R)-7-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.15 g, 0.247 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then 10% aqueous sodium hydrogen carbonate solution was added to the resulting white solid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give (4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (0.09 g, 0.177 mmol, 71.4%) as a white solid.

[0176] Example 51 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (2S,4R)-2-(4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate (53 mg, 0.094 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then 10% aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give (4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (32 mg, 0.069 mmol) as a white solid.

[0177] Example 56 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (2S,4R)-2-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate (150 mg, 0.252 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then 10% aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give (4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (80 mg, 0.161 mmol, 63.9%) as a white solid.

[0178] Example 63 A solution of (4-(5-(5,5-difluorotetrahydro-2H-pyran-2-yl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (4 g, 7.87 mol) in methanol / acetonitrile (7:3, 40 mL) was subjected to supercritical fluid chiral chromatography (SFC) using a 15% [0.5% isopropylamine-methanol solution] / CO ２ ) to separate the optically active compounds. The eluates obtained were concentrated under reduced pressure to give Example 64 (1.7 g, from the first effluent) and Example 63 (1.7 g, from the second effluent), respectively, as off-white solids. In the table below, Example 63 and Example 64 are shown with the same chemical structure, but they are one of the compounds in which the stereochemistry at the 2-position of the tetrahydropyran ring is α and the other is the β compound, respectively.

[0179] Example 67 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (7S,9R)-7-(4-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.22 g, 0.380 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. 10% aqueous sodium bicarbonate solution was added to make the mixture basic, and the organic layer was extracted with a 2% methanol / DCM solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether and collected by filtration to give (4-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (0.12 g, 0.250 mmol, 65.8%) as a white solid.

[0180] Example 80 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (2S,4R)-2-(4-cyclopropyl-4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate (0.070 g, 0.124 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in water and made basic by adding 10% aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (10 mM aqueous ammonium bicarbonate solution / acetonitrile) to give (4-cyclopropyl-4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (0.015 g, 0.032 mmol, 25.8%) as an off-white solid.

[0181] Example 89 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (2.67 ml, 10.69 mmol) was added to a DCM (20 mL) solution of tert-butyl (7S,9R)-7-(4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (1.1 g, 2.138 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was made basic with the addition of 10% aqueous sodium bicarbonate solution, and then extracted with DCM. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol / DCM) to obtain (4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl)methanone (710 mg, 1.713 mmol, 80%) as a white solid.

[0182] Example 90 Under a nitrogen atmosphere, a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to a DCM (2 mL) solution of tert-butyl (2S,4R)-2-(4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidine-1-carbonyl)-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate (0.12 g, 0.239 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was dissolved in water and made basic by adding 10% aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether and collected by filtration to give (4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (0.07 g, 0.173 mmol, 72.4%) as an off-white solid.

[0183] The compounds shown in Tables 3 to 67 were produced in the same manner as in the production examples or examples shown above. The physicochemical data of each compound are shown in Tables 3 to 52 and Tables 68 to 85.

[0184] The following abbreviations are used in the table: PEx: Production Example Number Ex: Example Number PSyn: Production Example Number produced by a similar method Syn: Example Number produced by a similar method Chemical Structure: Chemical structure

[0185] Data: Physicochemical data NMR: DMSO-d ６ During １ δ value (ppm) of signal in H-NMR (400 MHz) NMR (300): DMSO-d ６ During １ δ value (ppm) of signal in H-NMR (300 MHz) NMR (CDCl ３ ): CDCl ３ During １ δ value (ppm) of signal in H-NMR (400 MHz) NMR (CD ３ OD): CD ３ During OD １δ value (ppm) of the signal in H-NMR (400 MHz) ES+APCI: m / z value in mass spectrometry measured after ionization by ESI (electrospray ionization) and APCI (atmospheric pressure chemical ionization) ES: m / z value in mass spectrometry measured after ionization by ESI Note that m / z values ​​expressed only as a number are [M+H] ＋ In addition, the m / z value is expressed as "-100" when the tert-butyloxycarbonyl group is eliminated, "-56" when the tert-butyl group is eliminated, and "-18" when the water molecule is eliminated.

[0186] The following abbreviations are used in the chemical structural formulas: Boc: tert-butyloxycarbonyl CN: cyano NO ２ : nitro TBS: tert-butyldimethylsilyl Compounds with hydrogen chloride, trifluoroacetic acid, or formic acid structures written near their chemical structures indicate that the compounds were isolated as hydrochloride, trifluoroacetate, or formate, respectively.

[0187] Except as noted below, the stereochemistry in a chemical structure indicates that the compound is an isomer having the configuration of the depicted structure.

[0188] Production Example 1: A mixture of isomers depending on the stereochemistry of the secondary hydroxyl group. The mixing ratio is undetermined but is approximately 1:1. Production Examples 2, 3, 4, 5, and 6: A mixture of isomers depending on the stereochemistry of the benzyloxy group. The mixing ratio is undetermined but is approximately 1:1. Production Examples 7 and 20: A mixture of isomers depending on the stereochemistry of the secondary hydroxyl group. The mixing ratio is undetermined. Production Examples 24 and 25: A mixture of isomers in an approximately 9:1 ratio depending on the stereochemistry of the hydroxyl group and the methyl group. The stereochemistry is undetermined. Production Examples 26, 27, 28, and 254: Single isomers. However, the stereochemistry of the tertiary hydroxyl group is undetermined. Production Example 43: A racemic mixture at the tertiary hydroxyl group. Production Examples 116 and 117: A racemic mixture at the methyl group. Preparation 118: Diastereomeric mixture at the methyl group. Preparation 120, Preparation 121: Racemic mixture at the trifluoromethyl group substituted on the pyrrolidine ring. Preparation 122: Diastereomeric mixture at the trifluoromethyl group substituted on the pyrrolidine ring. Preparation 132, Preparation 133: Racemic mixture at the 2-position of dimethylpiperidine. Preparation 134, Preparation 135, Preparation 136, Preparation 137, Preparation 138: Approximately 1:1 diastereomeric mixture at the methyl group. Preparation 163, Preparation 164, Preparation 165, Preparation 186, Preparation 187, Preparation 188, Preparation 190, Preparation 191, Preparation 192, Preparation 198, Preparation 199, Preparation 200: Racemic mixture at the 2- or 3-position of tetrahydrofuran or tetrahydropyran. Preparation Example 166, Preparation Example 189, Preparation Example 193, Preparation Example 201: Diastereomeric mixtures at the 2- or 3-position of tetrahydrofuran or tetrahydropyran.

[0189] Example 33: A diastereomeric mixture at the methyl group. Example 35: A diastereomeric mixture at the trifluoromethyl group substituted on the pyrrolidine ring. Example 41, Example 42: A racemic mixture at the 2-position of the piperidine ring corresponding to ring A. Example 43: A diastereomeric mixture at the methyl on the piperidine ring corresponding to ring A. Example 50, Example 59, Example 60, Example 62: A diastereomeric mixture at the 2- or 3-position of tetrahydrofuran or tetrahydropyran. Example 63, Example 64: Compounds obtained by optically resolving the diastereomeric mixture of Example 50 using a chiral column. The stereochemistry of the carbon atom where the tetrahydropyranyl substituted on the oxadiazole ring is bonded to the oxadiazole is (R) in one example and (S) in the other, but it has not been determined which is which. Example 76: A single isomer. However, the stereochemistry of the tertiary hydroxyl group has not been determined.

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[0286] The azacycloalkylcarbonyl cyclic amine compound or a salt thereof of the present invention has a CTSC inhibitory activity and can be used as an active ingredient in a pharmaceutical composition for treating neutrophil-associated inflammatory diseases including chronic obstructive pulmonary disease (COPD), bronchiectasis, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Claims

1. A compound of formula (I) or a salt thereof. 【Chemistry 1】 (In the formula, Ring A is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl, 4-hydroxy-5,5-dimethylpiperidine-2-yl, or 1-oxa-6-azaspiro[3.5]nonan-7-yl; Y is hydrogen, optionally substituted alkyl, optionally substituted C ３－６ Cycloalkyl, optionally substituted aromatic hydrocarbon ring, optionally substituted non-aromatic heterocycle, optionally substituted aromatic heterocycle, or -N(R Ｙ１ )-R Ｙ２ And; R Ｙ１ and R Ｙ２ is one of optionally substituted C １－４ alkyl, the other being optionally substituted C １－４ alkyl, -C(=O)-(C １－４ alkyl), or -S(=O) ２ -(C １－４ alkyl); L is a nitrogen-containing aromatic heterocycle which may have substituents, a nitrogen-containing aromatic heterocycle which may have substituents - (C １－２ Alkylene), -C(=O)-N(R Ｌ１ )-, -C(=O)-N(R Ｌ１ ) - (C １－２ It is an alkylene, -C(=O)-, or a nitrogen-containing aromatic heterocyclic -C(=O)- which may have substituents; R Ｌ１ C is hydrogen, or a C which may have substituents. １－４ It is alkyl; Z is a cyclic alkyl group which may have substituents, an aromatic hydrocarbon ring which may have substituents, a non-aromatic heterocycle which may have substituents, an aromatic heterocycle which may have substituents, or an -O-alkyl group which may have substituents. However, if L is a -C(=O)- or a nitrogen-containing aromatic heterocyclic -C(=O)- which may have substituents, then Z is a cyclic amino which may have substituents; (m and n are independently either 1 or 2.)

2. The compound or a salt thereof according to claim 1, wherein ring A is (7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl.

3. The compound or a salt thereof according to claim 1, wherein ring A is (2S,4R)-4-hydroxy-5,5-dimethylpiperidine-2-yl.

4. The compound or a salt thereof according to claim 1, wherein ring A is (4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl.

5. The compound or a salt thereof according to claim 1, wherein m is 2 and n is 2.

6. The compound or salt thereof according to claim 1, wherein m is 1 and n is 1.

7. A compound or salt thereof according to any one of claims 1 to 6, wherein L is a nitrogen-containing aromatic heterocycle which may have substituents.

8. The compound or salt thereof according to claim 7, wherein L is 1,2,4-oxadiazole or tetrazole.

9. The compound or salt thereof according to any one of claims 1 to 6, wherein L is -C(=O)-N(R L1)-(C 1-2 alkylene).

10. The compound or salt thereof according to claim 9, wherein R L1 is hydrogen or methyl.

11. Y is an optionally substituted alkyl group or optionally substituted C ３－６ A compound or salt thereof according to any one of claims 1 to 6, which is a cycloalkyl compound.

12. The compound or salt thereof according to any one of claims 1 to 6, wherein Y is an aromatic hydrocarbon ring which may have substituents or an aromatic heterocycle which may have substituents.

13. The compound or salt thereof according to any one of claims 1 to 6, wherein Z is a cyclic alkyl group which may have substituents or a non-aromatic heterocycle which may have substituents.

14. The compound or salt thereof according to claim 13, wherein Z is cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, azetidine-1-yl, piperidine-1-yl, tetrahydrofuryl, or tetrahydropyranyl, each of which may be substituted with two or three substituents independently selected from fluoro and methyl.

15. A compound or salt thereof according to any one of claims 1 to 6, wherein Y is hydrogen.

16. The compound or salt thereof according to claim 15, wherein Z is a phenyl compound which may be substituted with 1 to 3 substituents independently selected from fluoro, methyl, and trifluoromethyl.

17. The compound or salt thereof according to claim 1, which is a compound of formula (Ia) or a salt thereof. 【Chemistry 2】 (In the formula, R1 and R ２ These, together with their adjacent carbon atoms, form cyclobutane: 【Transformation 3】 (In the formula, the wavy lines represent the bonding points with the rest of the compound.) Forming; Y is hydrogen, and C may have substituents. １－４ C, which may have alkyl or substituents ３－６ A cycloalkyl, optionally substituted aromatic hydrocarbon ring, optionally substituted non-aromatic heterocycle, or optionally substituted aromatic heterocycle; and Z may have substituents on C. ３－６ (This includes cycloalkyl groups, optionally substituted aromatic hydrocarbon rings, optionally substituted non-aromatic heterocycles, optionally substituted aromatic heterocycles, or optionally substituted -O-alkyl groups.)

18. The compound or salt thereof according to claim 1, which is a compound of formula (Ia) or a salt thereof. 【Chemistry 4】 (In the formula, R1 and R2 are methyl atoms, respectively; Y represents hydrogen, optionally substituted C1-4 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aromatic hydrocarbon ring, optionally substituted non-aromatic heterocycle, or optionally substituted aromatic heterocycle; and Z is a optionally substituted C3-6 cycloalkyl group, an optionally substituted aromatic hydrocarbon ring, an optionally substituted non-aromatic heterocycle, an optionally substituted aromatic heterocycle, or an optionally substituted -O-alkyl group.

19. The compound or salt thereof according to claim 1, which is a compound of formula (Ib) or a salt thereof. 【Transformation 5】 (In the formula, Y is hydrogen, optionally substituted C1-4 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aromatic hydrocarbon ring, optionally substituted non-aromatic heterocycle, or optionally substituted aromatic heterocycle; and Z is a optionally substituted C3-6 cycloalkyl group, an optionally substituted aromatic hydrocarbon ring, an optionally substituted non-aromatic heterocycle, an optionally substituted aromatic heterocycle, or an optionally substituted -O-alkyl group.

20. The compound or salt thereof according to claim 17, which is a compound of formula (Iaa) or a salt thereof. 【Transformation 6】

21. The compound or salt thereof according to claim 18, which is a compound of formula (Iaa) or a salt thereof. 【Transformation 7】

22. The compound or salt thereof according to claim 19, which is a compound of formula (Ibb) or a salt thereof. 【Transformation 8】

23. Y may be substituted with hydrogen or a halogen independently selected from 1 to 5. １－４ An aromatic hydrocarbon ring which may be substituted with 1 to 3 substituents independently selected from alkyl, C3-6 cycloalkyl, fluoro and methyl, or an aromatic heterocycle which may be substituted with 1 to 3 substituents independently selected from fluoro and methyl; L is a nitrogen-containing aromatic heterocycle which may have substituents, a nitrogen-containing aromatic heterocycle which may have substituents - (C １－２ It is an alkylene, or -C(=O)-N(R L1)-(C 1-2 alkylene); Z may have substituents. ３－６ A compound or salt thereof according to any one of claims 17 to 22, wherein the compound is a cycloalkyl group, a substituted phenyl group, a substituted non-aromatic heterocycle, or a substituted aromatic heterocycle.

24. The compound or salt thereof according to claim 23, wherein Y is a C1-4 alkyl group which may be substituted with a halogen independently selected from 1 to 5.

25. The compound or a salt thereof according to claim 24, wherein Z is a C3-6 cycloalkyl group which may have substituents, or a non-aromatic heterocycle which may have substituents.

26. The compound or salt thereof according to claim 23, wherein Y is hydrogen.

27. ​​The compound or salt thereof according to claim 26, wherein Z is a phenyl group which may have substituents, or an aromatic heterocycle which may have substituents.

28. Y may be substituted with hydrogen or a halogen independently selected from 1 to 5. １－４ Alkyl, or C ３－６ It is a cycloalkyl; L is a nitrogen-containing aromatic heterocycle, or a nitrogen-containing aromatic heterocycle - (C １－２ It is alkylene; Z is C ３－６ A cycloalkyl, phenyl, non-aromatic heterocycle, or aromatic heterocycle, where Z is C ３－６ Cycloalkyl, phenyl, non-aromatic heterocycle, and aromatic heterocycle are halogen, -OH, amino, cyano, nitro, and -C(=O)-(C), respectively. １－４ Alkyl), -C(=O)-OH, -C(=O)-O-(C １－４ C may be substituted with alkyl, -C(=O)-amino, or halogen. １－４ -O-(C) which may be substituted with alkyl and halogen compounds. １－４ The compound or a salt thereof according to any one of claims 17 to 22, which may be substituted with one or more substituents independently selected from alkyl.

29. The compound or salt thereof according to claim 28, wherein L is selected from pyrrole, pyrazole, imidazole, 1,3-oxazole, 1,3-thiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, and pyrazine. 【Request Item 30】 【Table 1-1】 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 The compound or a salt thereof according to claim 2, which is a compound selected from or a salt thereof. 【Request Item 31】 【Table 2】 The compound or salt thereof according to claim 3, which is a compound selected from or a salt thereof. 【Request Item 32】 【Table 3-1】 Table 3-2 Table 3-3 The compound or salt thereof according to claim 4, which is a compound selected from or a salt thereof.

33. A pharmaceutical composition comprising a compound or salt thereof according to any one of claims 1 to 32, and a pharmaceutically acceptable excipient.

34. The pharmaceutical composition according to claim 33, for the treatment of neutrophil-related inflammatory diseases.

35. Use of a compound or salt thereof according to any one of claims 1 to 32 in the manufacture of a pharmaceutical product for the treatment of neutrophil-related inflammatory diseases.

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