Azacycloalkyl carbonyl cyclic amine compounds

Abstract

Provided is an azacycloalkyl carbonyl cyclic amine compound useful as an active ingredient of a pharmaceutical composition for the treatment of neutrophil-related inflammatory diseases. The azacycloalkyl carbonyl cyclic amine compound according to the present invention is a compound represented by formula (I) or a salt thereof. [chemical formula 1] # imgabs0 # (In the formula, ring A represents an azacycloalkyl group which may have a substituent or may undergo a spiro condensation; y represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or the like; l represents a nitrogen-containing aromatic heterocyclic ring or the like; z represents a cycloalkyl group which may have a substituent, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, or the like; and m and n each independently represent an integer of 1 or 2. ).

Description

Technical Field

[0001] The present invention relates to an azacycloalkylcarbonyl cyclic amine compound that functions as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating neutrophil-related inflammatory diseases. This application claims priority based on provisional application No. US63 / 351,580 filed in the United States Patent and Trademark Office on June 13, 2022, and provisional application No. US63 / 410,421 filed in the United States Patent and Trademark Office on September 27, 2022, and these contents are cited herein. Background Art

[0002] Cathepsin C (CTSC) is a cystine exopeptidase known by another name, dipeptidyl peptidase 1 (DPP1; EC 3.4.14.1), and functions as a tetramer composed of four identical subunits belonging to the papain family.

[0003] CTSC is permanently expressed in many tissues, and is particularly thought to be expressed most prominently in the lung, placenta, spleen, and kidney. CTSC is considered to be a major intracellular processing enzyme that cleaves two residues from the N-terminus of proteins and peptides, and is implicated as an enzyme essential for the activation of granular serine proteases in neutrophil elastase (NE), cathepsin G (CTSG), proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4), mast cells (chemosynthesis and pancreatin), cytotoxic T lymphocytes, and natural killer cells (granzymes A and B). Neutrophils are produced in the bone marrow, released to the periphery after maturation, and show mobility against inflammatory cytokines, bacteria, and fungal components. They play a major role in the pathogenesis defense mechanism of infectious diseases through strong antibacterial functions such as aggregation, phagocytosis, degranulation, and neutrophil extracellular traps (NETs) in the inflamed area. At this time, neutrophil serine proteases (NE, CTSG, PR3, NSP4) play an important role in the antibacterial function of neutrophils due to their proteolytic activity, but on the other hand, it is known that excessive release of proteases to the outside of the cell accompanying the activation of neutrophils can cause destruction of biological tissues in addition to the original bactericidal effect. In particular, it is known that excessive degradation of extracellular matrices such as collagen, fibronectin, and laminin caused by excessive expression of NE will interfere with the pathogenesis of various inflammatory diseases (such as bronchiectasis, cystic fibrosis, acute respiratory distress syndrome, bronchitis, emphysema, etc.).

[0004] Based on the pathophysiological functions of granule serine proteases reported to date, CTSCs, as the major enzymes controlling them, are considered therapeutic targets for neutrophil-associated inflammatory diseases.

[0005] As compounds having a CTSC inhibitory effect, for example, compounds described in Patent Documents 1 to 6 and Non-Patent Document 1 are known. Prior art literature Patent Literature

[0006] Patent Document 1: International Publication No. 2011 / 112685 Patent Document 2: International Publication No. 2011 / 075634 Patent Document 3: International Publication No. 2015 / 110826 Patent Document 4: International Publication No. 2012 / 109415 Patent Document 5: International Publication No. 2015 / 032943 Patent Document 6: International Publication No. 2014 / 140075 Non-patent literature 1: Pharmacology & Therapeutics, 2018, Vol. 190, pp. 202-236 Summary of the invention Technical problem to be solved by the invention

[0007] The present invention provides an azacycloalkylcarbonyl cyclic amine compound having a CTSC inhibitory effect, which acts as an active ingredient of a pharmaceutical composition for treating neutrophil-related inflammatory diseases. Solutions for solving technical problems

[0008] The present invention has the following aspects. [1] A compound of formula (I) or a salt thereof. [Chemistry 1] (wherein, ring A represents, which may have a substituent, or may be 3-6 Cycloalkyl or a spiro-condensed azocycloalkyl group having a saturated heterocyclic ring with 3 to 6 ring members; Y represents hydrogen, an alkyl group which may have a substituent, a C 3-6 a cycloalkyl group, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, an aromatic heterocyclic ring which may have a substituent, or -N(R Y1 )-R Y2 ; R Y1 and R Y2One of them represents a C which may have a substituent 1-4 Alkyl, the other represents a C optionally substituted 1-4 Alkyl, -C(=O)-(C 1-4 alkyl), or -S(=O)2-(C 1-4 alkyl); L represents a nitrogen-containing aromatic heterocyclic ring which may have a substituent, a nitrogen-containing aromatic heterocyclic ring which may have a substituent, 1-2 Alkylene), -C(=O)-N(R L1 )-、-C(=O)-N(R L1 )-(C 1-2 alkylene), -C(=O)-, or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent; R L1 represents hydrogen or optionally substituted C 1-4 alkyl; Z represents a cycloalkyl group which may have a substituent, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, an aromatic heterocycle which may have a substituent, or -O-(alkyl group which may have a substituent), wherein when L is -C(=O)- or a nitrogen-containing aromatic heterocycle -C(=O)- which may have a substituent, Z represents a cyclic amino group which may have a substituent; m and n each independently represent an integer of 1 or 2.) [2] The compound or salt thereof according to [1], wherein ring A may have a substituent or may be conjugated to C 3-6 Cycloalkyl or piperidinyl in which a saturated heterocyclic ring having 3 to 6 ring members is spiro-condensed. [3] The compound or salt thereof according to [2], wherein ring A is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl which may have a substituent, 4-hydroxy-5,5-dimethylpiperidin-2-yl which may have a substituent, or 1-oxa-6-azaspiro[3.5]nonan-7-yl which may have a substituent. [4] The compound or salt thereof according to [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. [5] The compound or salt thereof according to any one of [1] to [4], wherein m is 2 and n is 2. [6] The compound or a salt thereof according to any one of [1] to [5], wherein L is a nitrogen-containing aromatic heterocyclic ring which may have a substituent. [7] The compound or salt thereof according to [6], wherein L is 1,2,4-oxadiazole or tetrazole. [8] The compound or salt thereof according to any one of [1] to [7], wherein Y is an alkyl group which may have a substituent or a C 3-6 Cycloalkyl. [9] The compound or salt thereof according to any one of [1] to [8], wherein Z is an optionally substituted cycloalkyl group or an optionally substituted non-aromatic heterocyclic ring.

[10] The compound or salt thereof according to [9], wherein Z is cyclobutyl, cyclohexyl or tetrahydropyran substituted with 2 to 3 substituents each selected from the group consisting of fluorine and methyl.

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

[12] The compound or salt thereof according to

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

[13] The compound or salt thereof according to [1], wherein the compound or salt thereof is a compound of formula (Ia) or a salt thereof, or a compound of formula (Ib) or a salt thereof. [Chemistry 2] [Chemistry 3] (In formula (Ia) and formula (Ib), R 1 and R 2 Respectively represent methyl, or, R 1 and R 2 Together with their adjacent carbon atoms they form cyclobutane: [Chemistry 4] (The wavy line indicates the point of attachment to the rest of the molecule.) Y represents hydrogen, or C optionally having a substituent 1-4 Alkyl, optionally substituted C 3-6 A cycloalkyl group, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, or an aromatic heterocyclic ring which may have a substituent; L represents a nitrogen-containing aromatic heterocyclic ring which may have a substituent, a nitrogen-containing aromatic heterocyclic ring which may have a substituent, 1-2 Alkylene), -C(=O)-N(R L1 )-、-C(=O)-N(R L1 )-(C 1-2alkylene), -C(=O)-, or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent; R L1 represents hydrogen or optionally substituted C 1-4 alkyl; Z represents C which may have a substituent 3-6 Cycloalkyl, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, an aromatic heterocycle which may have a substituent, or -O-(alkyl which may have a substituent), wherein when L is -C(=O)- or a nitrogen-containing aromatic heterocycle -C(=O)- which may have a substituent, Z represents a cyclic amino group which may have a substituent; m and n each independently represent an integer of 1 or 2.)

[14] The compound or salt thereof according to [1], wherein the compound or salt thereof is a compound of formula (Iaa) or a salt thereof, or a compound of formula (Ibb) or a salt thereof. [Chemistry 5] [Chemistry 6] (In Formula (Iaa) and Formula (Ibb), R 1 and R 2 Respectively represent methyl, or, R 1 and R 2 Together with their adjacent carbon atoms they form cyclobutane: [Chemistry 7] (The wavy line indicates the point of attachment to the rest of the molecule.) Y represents hydrogen, or C optionally having a substituent 1-4 Alkyl, optionally substituted C 3-6 A cycloalkyl group, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, or an aromatic heterocyclic ring which may have a substituent; L represents a nitrogen-containing aromatic heterocyclic ring which may have a substituent, a nitrogen-containing aromatic heterocyclic ring which may have a substituent, 1-2 Alkylene), -C(=O)-N(R L1 )-、-C(=O)-N(R L1 )-(C 1-2 alkylene), -C(=O)-, or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent; R L1 represents hydrogen or optionally substituted C 1-4 alkyl; Z represents C which may have a substituent 3-6 Cycloalkyl, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, an aromatic heterocycle which may have a substituent, or -O-(alkyl which may have a substituent), wherein when L is -C(=O)- or a nitrogen-containing aromatic heterocycle -C(=O)- which may have a substituent, Z represents a cyclic amino group which may have a substituent; m and n each independently represent an integer of 1 or 2.)

[15] The compound or salt thereof according to

[13] or

[14] , wherein Y is hydrogen, C which may be substituted by 1 to 5 halogens; 1-4 Alkyl, or C 3-6 Cycloalkyl; L is a nitrogen-containing aromatic heterocyclic ring which may have a substituent, or a nitrogen-containing aromatic heterocyclic ring which may have a substituent (C 1-2 alkylene); Z is a C 3-6 A cycloalkyl group, a phenyl group which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, or an aromatic heterocyclic ring which may have a substituent.

[16] The compound or salt thereof according to

[13] or

[14] , wherein Y is hydrogen, C which may be substituted by 1 to 5 halogens 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, non-aromatic heterocycle, or aromatic heterocycle, wherein the C 3-6 The cycloalkyl, phenyl, non-aromatic heterocyclic ring, and aromatic heterocyclic ring can be 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, halogen-substituted C 1-4 Alkyl, and -O-(C 1-4 alkyl).

[17] The compound or salt thereof according to

[16] , 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 the compound or a salt thereof according to any one of [1] to

[17] and a pharmaceutically acceptable excipient.

[19] The pharmaceutical composition according to

[18] , wherein the pharmaceutical composition is a pharmaceutical composition for treating neutrophil-related inflammatory diseases.

[20] Use of the compound or salt thereof according to any one of [1] to

[17] for the manufacture of a pharmaceutical composition for treating a neutrophil-associated inflammatory disease.

[21] Use of the compound or salt thereof according to any one of [1] to

[17] for treating neutrophil-related inflammatory diseases.

[22] The compound or salt thereof according to any one of [1] to

[17] , wherein the compound or salt thereof is used to treat a neutrophil-related inflammatory disease.

[23] A method for treating a neutrophil-related inflammatory disease, comprising administering to a subject an effective amount of the compound or salt thereof according to any one of [1] to

[17] .

[0009] The "subject" is a person or other animal that needs the treatment, as a form, it is a person that needs the treatment.

[0010] Unless otherwise specified, when a symbol in a chemical formula in the present specification is also used in another chemical formula, the same symbol has the same meaning. Effects of the Invention

[0011] The azacycloalkylcarbonyl cyclic amine compound or a salt thereof of the present invention (sometimes also referred to as "the azacycloalkylcarbonyl cyclic amine compound of the present invention", or respectively referred to as "the compound of formula (I)", "the compound of formula (Ia)", "the compound of formula (Ib)", "the compound of formula (Iaa)", "the compound of formula (Ibb)". In addition, 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 effect and can be used as an active ingredient of a pharmaceutical composition for the treatment of neutrophil-related inflammatory diseases including gastrointestinal inflammatory diseases, glomerulonephritis, chronic obstructive pulmonary disease (COPD), bronchiectasis, rheumatoid arthritis, multiple sclerosis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, etc. DETAILED DESCRIPTION

[0012] In this specification, "may have a substituent" means no substitution or having one or more substituents. In the case of having a substituent, it may have multiple substituents as long as it is allowed as a chemical structure. In the case of having multiple substituents, each substituent may be the same or different.

[0013] In addition to the alkyl group which may have a substituent, the substituents permitted in the group which is set as “may have a substituent” include the groups shown in the following S1 group. In the following description of the S1 group, “C 1-4 The "alkyl" may be selected from fluorine, -OH, -O-(C 1-4 alkyl) and amino groups.

[0014] The S1 group is composed of (1) halogen, (2)-OH, -O-(C 1-4 Alkyl), -O-(C 3-6 Cycloalkyl), -OC(=O)-(C 1-4 alkyl), -OC(=O)-(C 3-6 Cycloalkyl), oxo (=O), -SH, -S-(C 1-4 alkyl), and -S(=O)2-(C 1-4 alkyl), (3) amino, cyano, and nitro groups, (4)-C(=O)-(C 1-4 alkyl), -C(=O)-OH, -C(=O)-O-(C 1-4 alkyl), -C(=O)-amino, (5) may be selected from halogen, -OH, -O-(C 1-4 Alkyl) and C 1-4 An aromatic hydrocarbon ring substituted with 1 to 3 substituents of an alkyl group, (6) may be selected from halogen, -OH, -O-(C 1-4 Alkyl) and C 1-4 1 to 3 substituents of the alkyl group substituted with C 3-6 Cycloalkyl, (7) may be selected from halogen, -OH, -O-(C 1-4 Alkyl) and C 1-4 An aromatic heterocyclic ring substituted with 1 to 3 substituents on an alkyl group, (8) may be selected from halogen, -OH, -O-(C 1-4 Alkyl) and C 1-4 A non-aromatic heterocyclic ring substituted with 1 to 3 substituents of the alkyl group, and (9) C 1-4 Alkyl and -O-(C 1-4 alkyl).

[0015] Permissible substituents for the alkyl group which may have a substituent include the groups (1) to (8) listed in Group S1.

[0016] In this specification, "alkyl" includes C 1-10 The invention also includes linear alkyl groups and branched alkyl groups. As C 1-4 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. One form is a methyl group or an ethyl group, and the other form is a methyl group.

[0017] "Cycloalkyl" is C 3-10 The cycloalkyl group may have a cross-linked structure. Examples of the cycloalkyl group 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 form is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicyclo[1.1.1]pentyl. Another form is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. As C 3-6 Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. One embodiment is cyclopropyl and cyclobutyl.

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

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

[0020] "Non-aromatic heterocycle" is a monocyclic or bicyclic non-aromatic heterocycle with 3 to 10 ring members and 1 to 4 identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. A portion of the bonds constituting the non-aromatic heterocycle may also be an unsaturated bond. A portion of the bicyclic non-aromatic heterocycle may also have aromaticity. For example, a monocyclic non-aromatic heterocycle with 5 to 6 ring members and a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring or a pyridine ring condensed form, and at least a portion of an unsaturated hydrocarbon ring and a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring or a pyridine ring condensed form. Examples of the monovalent group of the non-aromatic heterocycle include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dihydrothiopyranyl, piperazinyl, dihydropyrazinyl, morpholinyl, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, tetrahydrobenzoxazolyl, dihydrofuranyl, dihydropyrazolylmorpholinyl, pyridyldioxanyl, dihydroazabenzofuranyl, dihydroisobenzofuranyl and dihydroazaindolyl.

[0021] The "aromatic heterocycle" is a monovalent group of a monocyclic or bicyclic aromatic heterocycle having 5 to 10 ring members and having 1 to 4 identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of the monovalent group of the aromatic heterocycle include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl and imidazopyridinyl.

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

[0023] "Cyclic amino group" is a monovalent group of a non-aromatic heterocycle or an aromatic heterocycle having at least one nitrogen atom as an element forming a ring structure of a non-aromatic heterocycle or an aromatic heterocycle and having a bonding point on at least one nitrogen atom forming the ring structure of the non-aromatic heterocycle or the aromatic heterocycle. Examples of the cyclic amino group include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, and piperazin-1-yl. As one form, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, and morpholin-4-yl are listed.

[0024] The "saturated heterocycle" is a non-aromatic heterocycle, and in a certain form, is a non-aromatic heterocycle in which the bonds constituting the non-aromatic heterocycle do not have an unsaturated bond in a monocyclic non-aromatic heterocycle. Examples of the saturated heterocycle include aziridine, azetidine, pyrrolidine, oxirane, oxetane, and tetrahydrofuran, and in one form, oxetane.

[0025] "Alkylene" contains C 1-10 The invention also includes linear alkylene groups and branched alkylene groups. As C 1-2 Examples of the alkylene group include methylene, ethylene, and methylmethylene. As one embodiment, it is methylene or methylmethylene.

[0026] The "halogen" is fluorine, chlorine, bromine and iodine, and in one form, is fluorine and chlorine, and in another form, is fluorine.

[0027] In addition to -NH2, "amino" also includes -NH2, where one or two hydrogen atoms are replaced by C 1-4 In addition, the C 1-4 The alkyl group can be -OH, -O-(C 1-4 Alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)(C 1-4 alkyl) substituted.

[0028] In formula (I), ring A is an azacycloalkyl group, which may have a substituent or may be 3-6 The cycloalkyl group or the saturated heterocyclic ring having 3 to 6 ring members undergoes spiro condensation. One form of azacycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, azetidinyl, azabicyclo[2.2.1]heptyl or azabicyclo[2.2.2]octyl; another form is piperidinyl.

[0029] Ring A as an azacycloalkyl group can be 3-6 Cycloalkyl or 3-6 saturated heterocyclic spiro condensation.3-6 Examples of the cycloalkyl group or the azacycloalkyl group which is a spiro-condensed saturated heterocyclic group 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; 5-azaspiro[2.5]octyl including 5-azaspiro[2.5]octane-6-yl; and as one form, 6-azaspiro[3.5]nonan-7-yl and 1-oxa-6-azaspiro[3.5]nonan-7-yl.

[0030] Permissible substituents in ring A include the groups listed in group S1 above; in one embodiment, C may be substituted with the groups listed in (1) or (2) listed in group S1 above, or with 1 to 5 groups selected from the group consisting of the groups listed in (1) or (2) above. 1-4 Alkyl; as another form, halogen, -OH, C 1-4 alkyl.

[0031] As a substituent that can be substituted, 3-6 One form of a cycloalkyl group or a saturated heterocyclic spiro-condensed azacycloalkyl group having 3 to 6 ring members is a piperidinyl group which may have a substituent and may be spiro-condensed with a cyclobutane or oxetane group; another form is a piperidinyl group which may be selected from halogen, -OH and C 1-4 A piperidinyl group substituted with 1 to 5 groups in the group consisting of an alkyl group and capable of spiro-condensation with cyclobutane or oxetane; as another embodiment, a piperidinyl group which can be selected from halogen, -OH and C 1-4 6-azaspiro[3.5]nonane-7-yl, 5,5-dimethylpiperidin-2-yl, or 1-oxa-6-azaspiro[3.5]nonane-7-yl substituted with 1 to 5 groups in the group consisting of alkyl; as another embodiment, 9-hydroxy-6-azaspiro[3.5]nonane-7-yl, 4-hydroxy-5,5-dimethylpiperidin-2-yl, or 1-oxa-6-azaspiro[3.5]nonane-7-yl. Can have substituents, can be combined with C 3-6 One form of the cycloalkyl group or the azacycloalkyl group of the spiro-condensed saturated heterocyclic group having 3 to 6 ring members is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl, another form is 4-hydroxy-5,5-dimethylpiperidin-2-yl, yet another form is 1-oxa-6-azaspiro[3.5]nonan-7-yl, yet another form is (7S,9R)-9-hydroxy-6-azaspiro[3.5]nonan-7-yl, yet another form is (2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl, or yet another form is (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] [Chemistry 8]

[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] [Chemistry 9]

[0036] 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] [Chemistry 10]

[0038] As C in Y which may have a substituent 3-6 The substituents permitted in the cycloalkyl group, 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 S1 group; as 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 which may be substituted by halogen 1-4 Alkyl, -O-(C 1-4 alkyl); as another form, halogen, C 1-4 Alkyl; in another aspect, fluorine or methyl. Permissible substituents for the optionally substituted alkyl group in Y include the groups (1) to (8) listed in the above group S1; one form is halogen; and another form is fluorine.

[0039] One form of Y is hydrogen, an alkyl group which may have a substituent, or a C 3-6 Cycloalkyl; as another embodiment, hydrogen; as yet another embodiment, an alkyl group which may have a substituent, or a C 3-6 Cycloalkyl. as an alkyl group which may have a substituent or a C3-6 Cycloalkyl, as one form, is a C 1-4 Alkyl or C 3-6 Cycloalkyl; as another form, C may be substituted by 1 to 5 halogens 1-4 Alkyl or cyclopropyl; in another aspect, isopropyl, trifluoromethyl or cyclopropyl.

[0040] One form of Y is hydrogen, another form is isopropyl, another form is trifluoromethyl, and another form is cyclopropyl.

[0041] As R Y1 and R Y2 One form of C 1-4 Alkyl, the other is C 1-4 Alkyl, -C(=O)-(C 1-4 alkyl), or -S(=O)2-(C 1-4 alkyl); as another aspect, 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 heterocyclic ring which may have a substituent, a nitrogen-containing aromatic heterocyclic ring which may have a substituent, 1-2 Alkylene), -C(=O)-N(R L1 )-, or -C(=O)-N(R L1 )-(C 1-2 In this case, Z represents a cycloalkyl group which may have a substituent, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, an aromatic heterocyclic ring which may have a substituent, a cyclic amino group which may have a substituent, or -O-(alkyl group which may have a substituent). Another aspect of L is -C(=O)- or a nitrogen-containing aromatic heterocyclic -C(=O)- which may have a substituent. In this case, Z represents a cyclic amino group which may have a substituent.

[0043] One form of L is a nitrogen-containing aromatic heterocyclic ring which may have a substituent or a nitrogen-containing aromatic heterocyclic ring which may have a substituent 1-2 Alkylene); as another form, -C(=O)-N(R L1 )-or-C(=O)-N(R L1 )-(C 1-2 as another aspect, -C(=O)- or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent.

[0044] The nitrogen-containing aromatic heterocyclic ring which may have a substituent or the nitrogen-containing aromatic heterocyclic ring which may have a substituent (C 1-2 In one form, the alkylene group is a nitrogen-containing aromatic heterocycle which may have a substituent; in another form, it is a nitrogen-containing aromatic heterocycle; in still another form, it is pyrrole, pyrazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine or pyrazine; in still another form, it is 1,2,4-oxadiazole or tetrazole; in still another form, 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 One form of the alkylene group is -C(=O)-NH-, -C(=O)-N(-CH3)-, -C(=O)-NH-CH2-, -C(=O)-N(-CH3)-CH2- or -C(=O)-NH-CH(-CH3)-.

[0046] One form of -C(=O)- or the optionally substituted nitrogen-containing aromatic heterocyclic -C(=O)- is -C(=O)- or (1,2,4-oxadiazole)-C(=O)-, and another form is -C(=O)-.

[0047] Permissible substituents for the cycloalkyl group which may have a substituent, the aromatic hydrocarbon ring which may have a substituent, the non-aromatic heterocyclic ring which may have a substituent, the aromatic heterocyclic ring which may have a substituent, and the cyclic amino group which may have a substituent in Z include the groups shown in the above S1 group; as 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 which may be substituted by halogen 1-4 Alkyl, -O-(C 1-4 alkyl); as another form, halogen, C 1-4 Alkyl; in another aspect, fluorine, methyl, or trifluoromethyl. Permissible substituents for -O-(alkyl which may have a substituent) in Z include the groups listed in (1) to (8) in Group S1; in one embodiment, halogen; and in another embodiment, fluorine. In the cyclic amino group which may have a substituent in Z, the non-aromatic heterocyclic ring having a bonding point on at least one nitrogen atom forming the ring structure of the non-aromatic heterocyclic ring may be condensed with a cyclospiro ring selected from the group consisting of cyclopropane, cyclobutane, oxirane and oxetane.

[0048] As one form of Z, it is a cycloalkyl group which may have a substituent, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, -O-(alkyl group which may have a substituent), or a cyclic amino group which may have a substituent; as another form, it is a cycloalkyl group which may have a substituent or a non-aromatic heterocycle which may have a substituent; as yet another form, it is an aromatic hydrocarbon ring which may have a substituent; as yet another form, it is -O-(alkyl group which may have a substituent); as yet another form, it is a cyclic amino group which may have a substituent.

[0049] As one form of the cycloalkyl group which may have a substituent or the non-aromatic heterocycle which may have a substituent, it is a cycloalkyl group or a non-aromatic heterocycle which may be substituted by 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl. As another form, it is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a bicyclo[1.1.1]pentyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group which may be substituted by 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl. As another form, it is a As one form, it is cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, tetrahydrofuranyl, or tetrahydropyranyl, which may be substituted by 1 to 3 substituents selected from the group consisting of fluorine and methyl, respectively; as another form, it is cyclobutyl, cyclohexyl, or tetrahydropyranyl, which may be substituted by 2 to 3 substituents selected from the group consisting of fluorine and methyl, respectively; as another form, it is 3,3-difluorocyclobutane-1-yl, 4,4-difluorocyclohexane-1-yl, or 5,5-difluorotetrahydro-2H-pyran-2-yl. One form of the cycloalkyl group which may have a substituent is a cyclobutyl group, a cyclopentyl group or a cyclohexyl group which may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl groups, respectively. Another form is a cyclobutyl group, a cyclopentyl group or a cyclohexyl group which may be substituted by 1 to 3 fluorine groups, respectively. Still another form is a cyclobutyl group or a cyclohexyl group which may be substituted by 1 to 3 fluorine groups, respectively. As one form of the non-aromatic heterocycle which may have substituents, it is tetrahydrofuranyl or tetrahydropyranyl which may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl. As another form, it is tetrahydrofuranyl or tetrahydropyranyl which may be substituted by 1 to 3 fluorines. As yet another form, it is tetrahydro-2H-pyranyl which may be substituted by 1 to 3 fluorines.

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

[0051] One form of -O-(alkyl group which may have a substituent) is -O-(C 1-4 Alkyl); another form is -O- (C 1-4 alkyl); another form is -O-(2,2,2-trifluoroethyl) or -O-(trifluoromethyl); yet another form is -O-(2,2,2-trifluoroethyl).

[0052] One form of the cyclic amino group which may have a substituent is a cyclic amino group which may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl. Another form is an azetidin-1-yl group, a pyrrolidin-1-yl group, a piperidin-1-yl group, a morpholin-4-yl group or a 4-oxa-7-azaspiro[2.5]octan-7-yl group which may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl.

[0053] As one form of m and n, m is 2 and n is 2; as another form, m is 1 and n is 1.

[0054] Several forms of the compound of formula (I) are shown below. In addition, the following forms can be replaced by the forms of the compounds of formula (Ia), formula (Ib), formula (Iaa) and formula (Ibb) as long as they do not contradict with formula (Ia), formula (Ib), formula (Iaa) and formula (Ibb).

[0055] (1A) In the compound of formula (I), the azacycloalkyl group is a piperidinyl group. (1A-1) As a compound of formula (I), it can be combined with C 3-6 The cycloalkyl group or the azacycloalkyl group in which a saturated heterocyclic ring having 3 to 6 ring members is spiro-condensed is piperidinyl, 6-azaspiro[3.5]nonyl, 1-oxa-6-azaspiro[3.5]nonyl or 5-azaspiro[2.5]octyl. (1A-2) As the compound of formula (I), it can be 3-6 The azacycloalkyl group or the azacycloalkyl group in which a saturated heterocyclic ring having 3 to 6 ring members is spiro-condensed is piperidinyl, 6-azaspiro[3.5]nonan-7-yl, 1-oxa-6-azaspiro[3.5]nonan-7-yl. (1A-3) The 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) The 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) A compound of the formula (I), wherein ring A is 4-hydroxy-5,5-dimethylpiperidin-2-yl. (1A-7) A compound of the formula (I), wherein ring A is (2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl. (1A-8) The compound of the formula (I), wherein ring A is 1-oxa-6-azaspiro[3.5]nonan-7-yl. (1A-9) The compound of the formula (I), wherein ring A is (4R,7S)-1-oxa-6-azaspiro[3.5]nonan-7-yl.

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

[0057] (2B) A compound of formula (I), wherein Y is an alkyl group which may have a substituent, or a C 3-6 Cycloalkyl. (2B-1) A compound of formula (I), wherein Y is C optionally substituted 1-4 Alkyl or C 3-6 Cycloalkyl. (2B-2) As a compound of formula (I), Y is C which may be substituted by 1 to 5 halogens 1-4 Alkyl or cyclopropyl. (2B-3) The compound of formula (I), wherein Y is isopropyl, trifluoromethyl or cyclopropyl. (2B-4) The compound of formula (I), wherein Y is isopropyl. (2B-5) The compound of formula (I), wherein Y is a trifluoromethyl group. (2B-6) The compound of formula (I), wherein Y is cyclopropyl.

[0058] (3A) A compound of formula (I), wherein L is a nitrogen-containing aromatic heterocyclic ring which may have a substituent or a nitrogen-containing aromatic heterocyclic ring which may have a substituent 1-2 alkylene). (3A-1) A compound of formula (I), wherein L is a nitrogen-containing aromatic heterocyclic ring which may have a substituent. (3A-2) The compound of formula (I), wherein L is a nitrogen-containing aromatic heterocyclic ring. (3A-3) The compound of formula (I), wherein L is 1,2,4-oxadiazole or tetrazole. (3A-4) The compound of formula (I), wherein L is 1,2,4-oxadiazole-3,5-diyl. (3A-5) The compound of formula (I), wherein L is 2H-tetrazolyl-2,5-diyl.

[0059] (3B) As a compound of formula (I), L is -C(=O)-N(R L1 )-or-C(=O)-N(R L1 -(C 1-2 alkylene). (3B-1) As a compound of formula (I), L is -C(=O)-NH-, -C(=O)-N(-CH3)-, -C(=O)-NH-CH2-, -C(=O)-N(-CH3)-CH2-, or -C(=O)-NH-CH(-CH3)-.

[0060] (3C) The compound of formula (I), wherein L is -C(=O)- or an optionally substituted nitrogen-containing aromatic heterocyclic ring -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) The compound of formula (I), wherein Z is a cycloalkyl group which may have a substituent or a non-aromatic heterocyclic ring which may have a substituent. (4A-1) The compound of formula (I), wherein Z is a cycloalkyl group or a non-aromatic heterocyclic ring which may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl. (4A-2) As a compound of formula (I), Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, tetrahydrofuranyl or tetrahydropyranyl, which may be substituted by 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl. (4A-3) The compound of formula (I), wherein Z is cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, tetrahydrofuranyl or tetrahydropyranyl, which may be substituted by 1 to 3 substituents selected from the group consisting of fluorine and methyl. (4A-4) The compound of formula (I), wherein Z is cyclobutyl, cyclohexyl or tetrahydropyranyl substituted with 2 to 3 substituents selected from the group consisting of fluorine and methyl. (4A-5) The compound of formula (I), wherein Z is 3,3-difluorocyclobutane-1-yl, 4,4-difluorocyclohexane-1-yl or 5,5-difluorotetrahydro-2H-pyran-2-yl. (4A-6) The compound of formula (I), wherein Z is 3,3-difluorocyclobutane-1-yl. (4A-7) The compound of formula (I), wherein Z is 4,4-difluorocyclohexane-1-yl. (4A-8) The 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 which may have a substituent. (4B-1) The compound of formula (I), wherein Z is a phenyl group which may have a substituent. (4B-2) The compound of formula (I), wherein Z is a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl.

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

[0064] (4D) The compound of formula (I), wherein Z is a cyclic amino group which may have a substituent. (4D-1) The compound of formula (I), wherein Z is a cyclic amino group which may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl. (4D-2) As a compound of formula (I), Z is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholine-4-yl or 4-oxa-7-azaspiro[2.5]octane-7-yl, which may be substituted by 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl.

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

[0066] (6) The compound of formula (I) is defined by a combination of two or more of the compounds of formula (I) described in (1) to (5B) above. Furthermore, any two or more of the above (1) to (5B) may be combined as long as there is no conflict with the chemical structure of the compound of formula (I).

[0067] Examples of the combination described in (6) include the following. The combination described in (6) is not limited to the following examples. (7A) A compound of formula (I), wherein the azacycloalkyl group is a piperidinyl group, and Y is an alkyl group which may have a substituent, or a C 3-6 Cycloalkyl, m is 2, and n is 2. (7A-1) as a compound of formula (I), and C 3-6 The azacycloalkyl group or the azacycloalkyl group which is spiro-condensed with a saturated heterocyclic ring 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) The compound of formula (I), wherein the azacycloalkyl group is a piperidinyl group, L is a nitrogen-containing aromatic heterocycle, m is 2, and n is 2. (7B-1) as a compound of formula (I), with C 3-6 The azacycloalkyl group or the azacycloalkyl group in which a saturated heterocyclic ring having 3 to 6 ring members is spiro-condensed 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) The compound of formula (I), wherein the azacycloalkyl group is a piperidinyl group, Z is a cycloalkyl group which may have a substituent or a non-aromatic heterocycle which may have a substituent, m is 2, and n is 2. (7C-1) as a compound of formula (I), with C 3-6 The cycloalkyl group or the azacycloalkyl group in which a saturated heterocyclic ring having 3 to 6 ring members is spiro-condensed 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 substituted with 2 to 3 substituents selected from the group consisting of fluorine and methyl, m is 2, and n is 2.

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

[0071] (7E) A compound of formula (I), wherein Y is an alkyl group which may have a substituent or a C 3-6 Cycloalkyl, Z is a cycloalkyl group which may have a substituent or a non-aromatic heterocyclic ring which may have a substituent, m is 2, and n is 2. (7E-1) As a compound of formula (I), Y is isopropyl, trifluoromethyl or cyclopropyl, Z is cyclobutyl, cyclohexyl or tetrahydropyranyl substituted by 2 to 3 substituents selected from the group consisting of fluorine 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 a cycloalkyl group which may have a substituent or a non-aromatic heterocycle which may have a substituent, m is 2 and n is 2. (7F-1) As a compound of formula (I), L is 1,2,4-oxadiazole or tetrazole, Z is cyclobutyl, cyclohexyl or tetrahydropyranyl substituted by 2 to 3 substituents selected from the group consisting of fluorine and methyl, m is 2 and n is 2.

[0073] (7G) A compound of formula (I), wherein the azacycloalkyl group is a piperidinyl group, and Y is an alkyl group which may have a substituent, or a C 3-6 Cycloalkyl, L is a nitrogen-containing aromatic heterocycle, m is 2, and n is 2. (7G-1) as a compound of formula (I), with C 3-6 The azacycloalkyl group or the azacycloalkyl group which undergoes spiro condensation with 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) as a compound of formula (I), the azacycloalkyl group is a piperidinyl group, and Y is an alkyl group which may have a substituent or a C 3-6 Cycloalkyl, Z is a cycloalkyl group which may have a substituent or a non-aromatic heterocyclic ring which may have a substituent, m is 2, and n is 2. (7H-1) as a compound of formula (I), with C 3-6The azacycloalkyl group or the azacycloalkyl group which is spiro-condensed with 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 substituted with 2 to 3 substituents selected from the group consisting of fluorine and methyl, m is 2, and n is 2.

[0075] (7I) As a compound of formula (I), the azacycloalkyl group is a piperidinyl group, L is a nitrogen-containing aromatic heterocycle, Z is a cycloalkyl group which may have a substituent or a non-aromatic heterocycle which may have a substituent, m is 2 and n is 2. (7I-1) as a compound of formula (I), with C 3-6 The azacycloalkyl group or the azacycloalkyl group which is spiro-condensed with 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 substituted with 2 to 3 substituents selected from the group consisting of fluorine and methyl, respectively, m is 2 and n is 2.

[0076] (7J) As a compound of formula (I), Y is an alkyl group which may have a substituent or a C 3-6 cycloalkyl, L is a nitrogen-containing aromatic heterocycle, Z is a cycloalkyl which may have a substituent or a non-aromatic heterocycle which may have a substituent, m is 2, and n is 2. (7J-1) As a compound of formula (I), Y is isopropyl, trifluoromethyl or cyclopropyl, L is 1,2,4-oxadiazole or tetrazole, Z is cyclobutyl, cyclohexyl or tetrahydropyranyl substituted by 2 to 3 substituents selected from the group consisting of fluorine and methyl, m is 2, and n is 2.

[0077] (7K) As a compound of formula (I), the azacycloalkyl group is a piperidinyl group, and Y is an alkyl group which may have a substituent or a C 3-6 cycloalkyl, L is a nitrogen-containing aromatic heterocycle, Z is a cycloalkyl which may have a substituent or a non-aromatic heterocycle which may have a substituent, m is 2, and n is 2. (7K-1) as a compound of formula (I), with C 3-6The azacycloalkyl group or the azacycloalkyl group which is spiro-condensed with a saturated heterocyclic ring 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 substituted with 2 to 3 substituents respectively selected from the group consisting of fluorine and methyl, m is 2, and n is 2.

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

[0079] (9A) A compound of formula (I), wherein L is -C(=O)-, Z is a cyclic amino group which may have a substituent, m is 2, and n is 2. (9A-1) A compound of formula (I), L is -C(=O)-, Z is a cyclic amino group which may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl, m is 2 and n is 2. (9A-2) as a compound of formula (I), the azacycloalkyl group is a piperidinyl group, and Y is an alkyl group which may have a substituent or a C 3-6 Cycloalkyl, L is -C(=O)-, Z is a cyclic amino group which may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl, m is 2, and n is 2.

[0080] As specific examples of the compound included in the present invention, the following compounds or salts thereof can be mentioned. In addition, in this specification, compound names generated by the molecular structural formula editor software ChemDraw (produced by 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]nonane-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]nonane-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]nonane-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]nonane- 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]nonane-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]nonane-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[3.55] nonane-7-yl)methanone (Example 89), (4-(2-(4-fluorophenyl)-2H-tetrazolyl-5-yl)piperidin-1-yl)((2S,4R)-4-hydroxy-5,5-dimethylpiperidin-2-yl)methanone (Example 90). .

[0082] In the compound of formula (I), tautomers and geometric isomers may exist depending on the type of substituents. In this specification, the compound of formula (I) is sometimes recorded as only one form of isomer, but the present invention also includes other isomers, and also includes isomer isolates, or mixtures thereof. In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers may exist based on this. The present invention also includes isolated optical isomers of the compound of formula (I) or mixtures thereof.

[0083] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compounds represented by formula (I). Pharmaceutically acceptable prodrugs refer to compounds having groups that can be decomposed by solvent or converted into amino, hydroxyl, carboxyl, etc. under physiological conditions. As the groups forming the prodrug, for example, Prog.Med., 5, 2157-2161 (1985), "Development of Pharmaceuticals" (Hirokawa Bookstore, 1990) Volume 7 Molecular Design 163-198 can be cited.

[0084] In addition, the salt of the compound of formula (I) refers to a pharmaceutically acceptable salt of the compound of formula (I), and sometimes forms an acid addition salt or a salt formed with a base depending on the type of the substituent. Specifically, examples include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, 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, and glutamic acid; salts formed with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine; salts formed with various amino acids such as acetylleucine and amino acid derivatives, ammonium salts, and the like.

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

[0086] (Manufacturing method) The compound of formula (I) and its salt can utilize the feature based on its basic structure or the kind of substituent, and various known synthetic methods are applied to manufacture.At this moment, according to the kind of functional group, this functional group is replaced with suitable protecting group (group that can be easily converted into this functional group) in advance in the stage from raw material to intermediate, and sometimes it is effective in manufacturing technology.As such protecting group, for example, can list the protecting group recorded in " Greene's Protective Groups in Organic Synthesis (4th edition, 2006) " written by Wu Zi (PGMWuts) and Green (TWGreene), according to these reaction conditions, appropriately select and use.In such method, after importing this protecting group and reacting, remove protecting group as required, so that desired compound can be obtained. In addition, the prodrug of the compound of formula (I) can be prepared by introducing a specific group from the raw material to the intermediate stage, or by further reacting the obtained compound of formula (I) in the same manner as the above-mentioned protecting group. The reaction can be carried out by applying conventional methods known to those skilled in the art such as esterification, amidation, dehydration, etc. Representative methods for producing the compound of formula (I) are described below. Each method can also be carried out with reference to the references attached to the description. In addition, the production method of the present invention is not limited to the examples shown below.

[0087] [Chemistry 11]

[0088] This preparation method is a method for producing the compound of formula (I) of the present invention by removing the protecting group of the compound represented by formula (1) (hereinafter referred to as "compound (1)"; the same applies to compounds represented by other formulae) in which the nitrogen atom of ring A in formula (I) is protected by a protecting group (PGr). Examples of the protecting group PGr in the compound (1) include groups generally used as protecting groups for aliphatic amino groups, including tert-butoxycarbonyl and 9-fluorenylmethoxycarbonyl. The removal of the protecting group is carried out using a catalytic amount, or an equal amount or even an excess amount of a reagent corresponding to the type of the protecting group used, and under temperature, time and solvent conditions suitable for the removal of the protecting group used. For example, when a tert-butoxycarbonyl group or a 9-fluorenylmethoxycarbonyl group is used as a protecting group, the protecting group can be removed by applying the conditions described in the above-mentioned "Greene's Protective Groups in Organic Synthesis (4th edition, 2006)".

[0089] [Chemistry 12]

[0090] Compound (1) can be produced by an amidation reaction of compound (1A) and compound (1B) or a reaction corresponding to the amidation reaction. The reaction is carried out by using an equivalent amount or an excess amount of one of the compounds (1A) and (1B), and stirring their mixture in the presence of a condensing agent in a solvent inert to the reaction, from cooling to heating, preferably at -20°C to 60°C, for usually 0.1 hour to 5 days. Examples of solvents used herein are not particularly limited, and include 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 or water, and mixtures thereof. Examples of the condensing agent include 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-carbonium hexafluorophosphate, diphenylphosphoryl azide, and phosphorus oxychloride, but are not limited thereto. Sometimes, it is preferred to use an additive (e.g., 1-hydroxybenzotriazole) in the reaction. For reacting in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, it is sometimes advantageous in terms of allowing the reaction to proceed smoothly. Alternatively, the carboxylic acid of compound (1A) may be converted into a reactive derivative and then reacted with compound (1B). Examples of the reactive derivative of carboxylic acid include acid halides obtained by reaction with a halogenating agent such as phosphorus oxychloride or thionyl chloride; mixed acid anhydrides obtained by reaction with isobutyl chloroformate or the like; and active esters obtained by condensation with 1-hydroxybenzotriazole or the like. The reaction of these reactive derivatives with compound (1B) is carried out in a solvent inert to the reaction such as a halogenated hydrocarbon, an aromatic hydrocarbon, or an ether, from cooling to heating, preferably at -20°C to 60°C, and usually with stirring for 0.1 hour to 5 days. It is sometimes 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 facilitate the reaction.

[0091] Compound (1A) and Compound (1B) can be produced by the methods described in the Examples or Production Examples described later, or by methods based on the Examples or Production Examples.

[0092] The compound of formula (I) is isolated and purified as a free compound, a salt, a hydrate, a solvate, or a crystalline polymorph thereof. A salt of the compound of formula (I) can also be produced by performing a salt-forming reaction according to a conventional method. Separation and purification are carried out by common chemical operations such as extraction, fractional crystallization, various fractional chromatography methods, etc. Various isomers can be produced by selecting appropriate raw material compounds, or can be separated by utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution methods of racemates (e.g., fractional crystallization of diastereoisomer salts with optically active bases or acids, chromatography using chiral columns, etc.), or can be produced from appropriate optically active raw material compounds.

[0093] In the present specification, compounds of formula (Ia), formula (Ib), formula (Iaa) and formula (Ibb) and their salts are included in compounds of formula (I) and their salts. For examples and forms of compounds of formula (Ia), formula (Ib), formula (Iaa) and formula (Ibb) and their salts, reference may be made to the examples and forms of compounds of formula (I) and their salts as long as they do not conflict 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 test.

[0095] 1. CTSC inhibition assay (in vitro) The test samples were evaluated by CTSC inhibition assay using the fluorescent substrate GF-AFC (Gly-Phe-7-Amino-4-trifluoromethylcoumarin, MP Biomedical, 03AFC03325). GF-AFC is converted into aminotrifluoromethylcoumarin with a specific fluorescence wavelength by CTSC, and the amount generated is proportional to the CTSC activity, so the fluorescence intensity is measured by a microplate reader for quantitative analysis. The CTSC inhibition assay of each compound was carried out using a black 384-well plate made of polystyrene with a non-adhesive surface treatment under the following conditions. The human recombinant protein CTSC (R&D systems, 1071-CY) was dissolved in CTSC activated mixed antibody (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)) to make 100 ng / ml, and incubated at 18°C ​​for 30 minutes. When performing 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). The test sample was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution at 10 mmol / L. The stock solution was diluted 15 times with DMSO and used as the maximum evaluation concentration (0.667 mmol / L), and then repeatedly diluted 5 times with DMSO to prepare a serial dilution solution. 248.8 μL of CTSC assay buffer was added to 1.12 μL of the dilution series sample prepared with DMSO to prepare a CTSC inhibition assay compound solution. The final composition of the CTSC inhibition assay mixture is 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, and the following steps are followed. That is, 4 μL of the compound solution and 4 μL of the 2 ng / mL activated CTSC solution are mixed in a 384-well plate and incubated at 25°C for 30 minutes. Then, 4 μL of the GF-AFC solution dissolved in the CTSC assay buffer is added in such a way that it becomes 90 μmol / L. After mixing evenly and incubating at 25°C for 1 hour, the fluorescence intensity at 505 nm when excited at 390 nm is measured using an enzyme reader. Based on the curve of the fluorescence intensity at 505 nm and the sample concentration, a 4-parameter regression analysis is performed using GraphPad Prism (manufactured by GraphPad Software) software to calculate the IC 50 value. In Table 1, the results of several test compounds of formula (I) are expressed as IC values ​​calculated based on CTSC inhibition (%) for 50% inhibition concentration. 50 In addition, in the table, Ex represents the example number.

[0096]

Table 1

[0097] 2. In vitro CTSC inhibition assay The test sample was evaluated by the degree of cell death when the substrate LLOMe (L-Leucyl-L-Leucine methyl ester, hydrobromidesalt, Sigma, 555045152) was added to U937 cells. LLOMe is taken into the cell by endocytosis and cut by CTSC. Through this product, lysosomal disorders are induced in the cell, causing cell death in leukocytes and the like. Thus, the degree of cell death is related to the amount of LLOMe decomposition products, i.e., CTSC activity, and therefore the CTSC inhibitory activity of the test sample in the cell is obtained by quantitatively analyzing cell death. The inhibition assay is implemented using a white 384-well plate made of polystyrene. The test sample was prepared as a stock solution dissolved in DMSO at 0.2 mmol / L, and the solution obtained by diluting 50 times with RPMI-1640 medium containing 10% FBS was used as the maximum evaluation concentration (4000 nmol / L). From this, stepwise dilution solutions were prepared by 3-fold dilution with the medium to prepare a 4-fold concentrated test sample solution of the target final concentration. U937 cells were cultured in RPMI-1640 medium containing 10% FBS, and diluted on the day of the measurement to prepare a cell suspension of 90,000 cells / mL. 10 μL of the cell suspension was seeded in each well. Next, 10 μL of the test sample solution at a concentration 4 times the target final concentration was added and allowed to stand for 30 minutes. After that, 20 μL of a 300 μmol / L LLOMe solution dissolved in RPMI-1640 medium containing 10% FBS was added and cultured for 3 hours. After the culture was completed, 40 μL of CellTiter-Glo (registered trademark) reagent (Promega, G7570) was added to each well and mixed. After 15 minutes, 20 μL of the reaction solution in each well was transferred to a white 384-well plate, and the chemiluminescence intensity was measured using an enzyme reader. Based on the curve of luminescence intensity and sample concentration, a 4-parameter regression analysis was performed using GraphPad Prism (manufactured by GraphPad Software) software to calculate the IC 50 value. In Table 2, the results of several test compounds of formula (I) are expressed as IC values ​​calculated based on CTSC inhibition (%) for 50% inhibition concentration. 50 In addition, in the table, Ex represents the example number.

[0098]

Table 2

[0099] In the results of the above experiments, CTSC inhibitory effects were confirmed in several compounds of formula (I). Therefore, the compounds of formula (I) can be used to treat neutrophil-related inflammatory diseases. Examples of the neutrophil-associated inflammatory diseases 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), α-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 dermatosis (acute febrile neutrophilic dermatosis, Behcet's disease, etc.).

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

[0101] As solid compositions for oral administration, tablets, powders, granules, etc. can be used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition can contain inert additives such as lubricants, disintegrants, stabilizers, and solubilizers according to conventional methods. Tablets or pills can be coated with sugar coatings or films of gastric or enteric soluble substances as needed. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and include commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain adjuvants such as solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, aromatics, and preservatives.

[0102] Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. As aqueous solvents, for example, distilled water for injection or physiological saline are included. As non-aqueous solvents, for example, alcohols such as ethanol are included. Such compositions may further include isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or solubilizers. They are sterilized, for example, by filtering through a bacterial retention filter, adding a bactericide or irradiating. In addition, they can also be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or a sterile injection solvent before use.

[0103] In the case of conventional oral administration, the daily dosage is approximately 0.001 to 100 mg / kg per kilogram of body weight, 0.01 to 30 mg / kg as one form, and 0.1 to 10 mg / kg as another form is appropriate, and it is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dosage can be approximately 0.0001 to 10 mg / kg per kilogram of body weight, and can be administered once a day or divided into multiple doses. In addition, as a transmucosal agent, approximately 0.001 to 100 mg / kg per kilogram of body weight can be administered once a day or divided into multiple doses. The dosage is appropriately determined according to each situation in consideration of symptoms, age, sex, etc.

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

[0105] The compound of formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of formula (I) is believed to be effective. The combination can be administered simultaneously, or administered continuously alone, or administered at desired time intervals. The preparation for simultaneous administration can be a compounding agent or a separate preparation. [Example]

[0106] Hereinafter, the 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, the method for producing the raw material compound is shown as a production example. The production method of the compound of formula (I) is not limited to the production methods of the examples shown below, and the compound can also be produced by a combination of these production methods or a method that is obvious to those skilled in the art. The concentration mol / L is expressed as M.

[0107] Production Example 1 Under nitrogen environment, cyclobutanecarbonitrile (33.8g, 416mmol) was added to a THF (450mL) solution of 2.0M lithium diisopropylamide in tetrahydrofuran (THF) solution (187mL, 375mmol) cooled to -78°C, and stirred at the same temperature for 30 minutes. A THF (50mL) solution of (R)-2-(2,2-dimethyl-1,3-dioxolane-4-yl)acetaldehyde (30g, 208mmol) was added dropwise to the reaction solution and stirred at -78°C for 45 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution, 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 give 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 environment, benzyl bromide (15.94 g, 93 mmol) and a solution of 1-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-hydroxyethyl)cyclobutane-1-carbonitrile (21 g, 93 mmol) in DMF (50 mL) were added to a suspension of sodium hydride (60%, 3.73 g, 93 mmol) in N,N-dimethylformamide (DMF) (300 mL) cooled to 0°C. The reaction mixture was slowly returned to room temperature and then stirred for 3 hours. After the reaction mixture was cooled to 10°C, a saturated aqueous solution of ammonium chloride was added. The organic layer was extracted with ethyl acetate and washed with a 10% aqueous solution of sodium bicarbonate and saturated brine. The organic layer was 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 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 environment, a THF (350 mL) solution of 1-(1-(benzyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl)cyclobutane-1-carbonitrile (35 g, 111 mmol) was cooled to 0°C, and sodium bis(2-methoxyethoxy)aluminum hydroxide (Red-Al) (60% toluene solution, 131 mL, 388 mmol) was added. After that, the mixture was slowly returned to room temperature and stirred at room temperature for 3 hours. After the reaction solution was cooled to 0°C, sodium sulfate decahydrate (110.0 g) was slowly added. The mixture was returned to room temperature and stirred for 15 minutes. The mixture was filtered through diatomaceous earth and the solid was washed with ethyl acetate. The collected filtrate was concentrated under reduced pressure. THF (700 mL) was added to the obtained residue and cooled to 0°C. Diisopropylethylamine (DIPEA) (23.60 mL, 131 mmol) and 2-nitrobenzenesulfonyl chloride (29.1 g, 131 mmol) were added in sequence under a nitrogen atmosphere. The reaction mixture was returned to room temperature and stirred for 2 hours. A 10% aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Under nitrogen environment, THF (250 mL) and hydrochloric acid (1.5 N, 250 mL, 375 mmol) were added to the obtained residue at room temperature and stirred for 16 hours. Water (250 mL) was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution 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%) in liquid form.

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

[0111] Production Example 5 Under a nitrogen environment, to a THF (400 mL) solution of N-((1-(3R)-(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 was added diethyl azodicarboxylate (16.0 mL, 101 mmol), the mixture was returned to room temperature, and stirred for 3 hours. Ice-cold water (300 mL) 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to obtain (7S)-9-(benzyloxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6-((2-nitrophenyl)sulfonyl)-6-azaspiro[3.5]nonane (36 g, 95%) in liquid form.

[0112] Production Example 6 Under nitrogen environment, 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 then the mixture was returned to room temperature and stirred for 3 hours. Ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with ice-cold water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Under nitrogen environment, DCM (200mL) was added to the residue, followed by di-tert-butyl dicarbonate (16.8mL, 72.7mmol), triethylamine (11.69mL, 84mmol), 4-dimethylaminopyridine (0.683g, 5.59mmol), and stirred at room temperature for 16 hours. Water (250mL) was added to the reaction mixture and 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), thereby obtaining (7S)-9-(benzyloxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (22g, 72%) in liquid form.

[0113] Production Example 7 20% palladium hydroxide / carbon (3.25 g) was added to a solution of (7S)-9-(benzyloxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (22 g, 46.2 mmol) in methanol (250 mL), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 1 atmosphere. The reaction mixture was filtered through celite, the solid was washed with methanol (200 mL), and the filtrate was concentrated under reduced pressure. DCM (200mL) is added to the obtained residue, and after being cooled to 0 DEG C, imidazole (3.45g, 50.8mmol) and tert-butyldimethylsilyl chloride (7.6g, 50.8mmol) are added successively, and then room temperature is restored, and stirred for 12 hours. Ice-cold water (300mL) is added to the reaction solution and extracted with DCM. The organic layer is cleaned with saturated brine, concentrated under reduced pressure after being dried over anhydrous sodium sulfate, and the residue is purified by silica gel column chromatography (30% ethyl acetate / petroleum ether), so as to obtain (7S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (14.5g, 81%) in liquid form.

[0114] Production Example 8 Under 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. Saturated aqueous sodium bicarbonate solution (100 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes. The reaction mixture was extracted with DCM, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain (S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9-oxo-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (15.3 g, 93%) in liquid form.

[0115] Production Example 9 Under nitrogen environment, cerium chloride heptahydrate (19.44 g, 52.2 mmol) was added to a solution of (S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-9-oxo-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (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 slowly added to the reaction mixture, and after stirring at -78°C for 1 hour, the mixture was slowly warmed to 0°C and stirred for 30 minutes. A 10% aqueous solution of citric acid (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. After THF (40 mL) was added to the resulting residue under nitrogen environment, a tetrabutylammonium fluoride THF solution (1.0 M, 78 mL, 78 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Ice-cold water (100 mL) 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain (7S, 9R)-9-hydroxy-7-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (9.2 g, 84%) as a colloidal solid.

[0116] Production Example 10 Under nitrogen atmosphere, 1.0 M phosphate buffer (Na2HPO4:NaH2PO4=1:1, 11 mL) was added to a solution (20 mL) of tert-butyl (7S, 9R)-9-hydroxy-7-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylate (2.0 g, 7.37 mmol) in acetonitrile. 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. A 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 adjust the pH of the aqueous layer to 2, and the mixture was extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (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 nitrogen environment, potassium tert-butoxide (39.27 g, 0.350 mol) was added to an ice-cold solution of trimethylsulfonium iodide (77.18 g, 0.350 mol) in dimethyl sulfoxide (DMSO) (850 mL), and the mixture was slowly returned to room temperature and stirred for 1 hour. The reaction mixture was cooled to 10°C, (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-1-carboxylic acid benzyl ester (85 g, 0.233 mol) was added little by little, returned to room temperature, and stirred for 1 hour. Ice-cold water (400 mL) was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (85% ethyl acetate / petroleum ether) to obtain (S)-(1-((tert-butyldimethylsilyl)oxy)-6-(dimethyl(oxo)-6-sulfonamido)-5-oxohexan-2-yl)benzylcarbamate (57 g, 53%) as a red tea liquid.

[0118] Production Example 12 Under nitrogen environment, a toluene solution (700 mL) of benzyl (S)-((tert-butyldimethylsilyl)oxy)-6-(dimethyl(oxo)-6-sulfonyl)-5-oxohexane-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 obtained residue, and extracted with ethyl acetate. 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 obtain (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopiperidine-1-carboxylic acid benzyl ester (26 g, 55%) as a colorless liquid.

[0119] Production Example 13 Under nitrogen environment, potassium tert-butoxide (19.79 g, 0.1619 mol) was added to a tert-butanol solution (300 mL) of trimethylsulfonium iodide (35.64 g, 0.1619 mol) heated to 50°C, and stirred for 1 hour. The reaction mixture was cooled to room temperature, and a tert-butanol solution (100 mL) of (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopiperidine-carboxylic acid benzyl ester (26 g, 0.0689 mol) was added dropwise. The reaction mixture was heated to 50°C and stirred for 16 hours. The reaction solution was cooled to room temperature, ice-cold water (200 mL) was added, and then extracted with ethyl acetate. 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 obtain (4R, 7S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylic acid benzyl ester (8.0 g, 0.068 mol, 28%, low polar fraction, Preparation Example 13) and (4S, 7S)-7-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylic acid benzyl ester (3.8 g, 13%, high polar fraction) as light brown liquids.

[0120] Production Example 15 10% palladium / 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 stirred at room temperature for 8 hours under a hydrogen atmosphere of 1 atmosphere. The solid was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to obtain ((4R, 7S)-1-oxa-6-azaspiro[3.5]nonane-7-yl)methanol (2.4 g).

[0121] Production Example 16 1,4-dioxane (25 mL) and water (40 mL) were added to ((4R, 7S)-1-oxa-6-azaspiro [3.5] nonane-7-yl) methanol (2.4 g) and then ice-cooled. Sodium bicarbonate (3.07 g, 36.4 mmol) and 9-fluorenylmethyl chloroformate (3.93 g, 15.2 mmol) were added in sequence. The reaction mixture was warmed to room temperature and stirred for 1 hour. Water was added to the reaction solution and extracted with ethyl acetate. 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 (25% ethyl acetate / petroleum ether) to obtain (4R, 7S)-7-(hydroxymethyl)-1-oxa-6-azaspiro [3.5] nonane-6-carboxylic acid (9H-fluoren-9-yl) methyl ester (5.0 g, 86%) as a colorless liquid.

[0122] Production Example 18 Under a nitrogen environment, 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 to separate the liquids. The organic layer was washed with 10% aqueous sodium bisulfate solution, water, and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and stirred at 80°C for 4 hours under a nitrogen environment. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (15%-20% ethyl acetate / petroleum ether) to give (S)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4,6-dioxopiperidine-1-carboxylate (12 g, 33.6 mmol, 74.6%).

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

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

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

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

[0127] Production Example 29 Under 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-carboxyguanidinopyrazole (18.81 g, 125 mmol), and the mixture was cooled to 0°C, and DIPEA (43.8 mL, 251 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide (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 obtain (Z)-4-((((amino(3,3-difluorocyclobutyl)methylene)amino)oxy)carbonyl)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (31 g, 61.3%) as a white solid.

[0128] Production Example 30 Under nitrogen environment, potassium hydroxide (7.93g, 141mmol) was added to a solution of (Z)-4-((((amino(3,3-difluorocyclobutyl)methylene)amino)oxy)carbonyl)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (57g, 141mmol) in DMSO (340mL) at room temperature and stirred for 12 hours. Cooling water was added to the reaction solution, and after extraction with petroleum ether, the organic layer was washed with water. The organic layer was concentrated under reduced pressure to obtain 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (44g, 80%) as a light white solid.

[0129] Production Example 31 Under nitrogen environment, 4M hydrogen chloride 1,4-dioxane solution (114mL, 457mmol) was added to a DCM (225mL) solution of tert-butyl 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)-4-isopropylpiperidine-1-carboxylate (44g, 114mmol) cooled to 0°C, and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, DCM was added to the residue and concentrated again under reduced pressure. After repeating it 3 times, tert-butyl methyl ether was added to the residue and ground. The solid was filtered and dried to obtain 3-(3,3-difluorocyclobutyl)-5-(4-isopropylpiperidin-4-yl)-1,2,4-oxadiazole hydrochloride (32.5g, 88%) as an off-white solid.

[0130] Production Example 32 Under 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 after cooling to 0°C, 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 in sequence, and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and 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 obtain (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-carboxylic acid tert-butyl ester (29 g, 74%) as an off-white solid.

[0131] Production Example 37 Under nitrogen environment, hydroxylamine aqueous solution (50%, 150mL, 180mmol) was added to 4-cyano-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (50g, 180mmol) in ethanol (500mL) at room temperature, and then the mixture was 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 filtered and washed with water to obtain (Z)-4-(N'-hydroxycarbamic acid group)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (50g, 89%) as a gray solid.

[0132] Production Example 39 Under nitrogen environment, a solution of (Z)-tert-butyl 4-(N'-((3,3-difluorocyclobutane-1-carbonyl)oxy)carbamoyl)-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 obtain 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] Production Example 42 Under nitrogen environment, sodium hydrosulfide hydrate (240 mg, 3.23 mmol) was added to a mixture of 4-cyano-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.719 mmol), ammonium chloride (173 mg, 3.23 mmol) and DMF (5 mL), and stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the residue concentrated under reduced pressure was purified by silica gel column chromatography (ethyl acetate) to obtain 4-carbon oil-resistant-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.537 mmol, 74.7%) as a light yellow solid.

[0134] Production Example 43 A mixture of tert-butyl 4-carbamate-4-(trifluoromethyl)piperidine-1-carboxylate (270 mg, 0.864 mmol), 2-bromo-1-(4,4-difluorocyclohexyl)ethane-1-one (208 mg, 0.864 mmol), DIPEA (0.453 mL, 2.59 mmol) and THF (2 mL) was heated at 80° C. for 16 hours in a sealed tube. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (20% ethyl acetate / petroleum ether) to obtain 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] Production Example 44 Under nitrogen environment, 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. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (10% methanol / DCM) to obtain 4-(4,4-difluorocyclohexyl)-2-(4-(trifluoromethyl)piperidin-4-yl)thiazole (140 mg, 0.395 mmol, 74.7%) as a yellow solid.

[0136] Production Example 45 Under nitrogen atmosphere, DIPEA (0.138 mL, 0.790 mmol) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate (COMU) (254 mg, 0.593 mmol) were added to an ice-cold 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), and stirred for 15 minutes. Then, 4-(4,4-difluorocyclohexyl)-2-(4-(trifluoromethyl)piperidin-4-yl)thiazole (140 mg, 0.395 mmol) was added, and 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55% ethyl acetate / petroleum ether) to obtain (4R, 7S)-7-(4-(4-(4,4-difluorocyclohexyl)thiazol-2-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylic acid (9H-fluoren-9-yl)methyl ester (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. After HATU (2.425 g, 6.38 mmol), (Z)-4-(N'-hydroxycarbamic acid)-4-isopropylpiperidine-1-carboxylic acid tert-butyl ester (2.0 g, 4.91 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and washed with water and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate). The obtained product was dissolved in dioxane (15.0 mL) and stirred at 150 ° C for 1 hour under microwave (MW) irradiation. The solvent was distilled off under reduced pressure to obtain 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 a pale white solid.

[0138] Production Example 52 Under 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)methylamine hydrochloride (106 mg, 0.571 mmol), and after cooling to 0° C., 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) were added in sequence. After the reaction mixture was stirred at room temperature for 5 hours, water was added, and the organic layer and the aqueous layer were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60%-70% ethyl acetate / petroleum ether) to obtain 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 nitrogen environment, 3-cyanoazetidine-1-carboxylic acid tert-butyl ester (3g, 16.5mmol) THF (15mL) solution was slowly dripped and bis (trimethylsilyl) lithium amide (LHMDS) (1M, THF solution, 3.313g, 19.8mmol) was added to the solution. After the reaction mixture was stirred at -78 ° C for 30 minutes, a THF (15mL) solution of isopropyl iodide (3.28g, 19.8mmol) was slowly added dropwise, stirred at the same temperature for 2 hours, and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / petroleum ether) to obtain 3-cyano-3-isopropylazetidine-1-carboxylic acid tert-butyl ester (1.8g, 8.02mmol, 48.6%).

[0140] Production Example 55 Under nitrogen environment, hydroxylamine hydrochloride (62mg, 0.89mmol) and triethylamine (0.2mL, 1.34mmol) are added to ethanol (2mL) solution of 3-cyano-3-isopropylazetidine-carboxylic acid tert-butyl ester (100mg, 0.44mmol), heated to 80 DEG C and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and DCM is extracted. After the organic layer is dried over anhydrous sodium sulfate, it is concentrated under reduced pressure to obtain (Z)-3-(N'-hydroxycarbamic acid group)-3-isopropylazetidine-1-carboxylic acid tert-butyl ester (100mg, 0.39mmol).

[0141] Production Example 59 Under nitrogen environment, sodium hydride (60%, 105mg, 2.6mmol) was added to a DMF (10mL) solution of 4-(((4,4-difluorohexyl)methyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (700mg, 1.7mmol) cooled to 0°C, and stirred for 10 minutes. Methyl iodide (0.23mL, 3.4mmol) was added to the reaction mixture and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to obtain 4-(((4,4-difluorohexyl)methyl)(methyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (600mg, 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 phosphorus oxychloride (3 mL, 1.275 mmol) was heated at 100° C. for 48 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with 10% aqueous sodium bicarbonate solution, water, and saturated brine in sequence, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2-3% methanol / DCM) to obtain 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] Production Example 101 Under 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 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 for liquid separation. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60%-70% ethyl acetate / petroleum ether) to obtain (2S,4S)-2-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-isopropylpiperidine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (140 mg, 0.239 mmol, 27.8%) as a white solid.

[0144] Production Example 109 Under nitrogen atmosphere, Oxone (1.656 g, 5.39 mmol) was added to a DCM (10 mL) solution of (2S,4S)-2-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-isopropylpiperidine-1-carbonyl)-4-(methylthio)pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.539 mmol) cooled to 0°C, and 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 obtain (2S,4S)-2-(4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-isopropylpiperidine-1-carbonyl)-4-(methylsulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.130 g, 0.217 mmol, 40.3%) as a white solid.

[0145] Production Example 114 Under nitrogen environment, 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 obtain (4-oxa-7-azaspiro[2.5]octane-7-yl)(4-(trifluoromethyl)piperidin-4-yl)methanone trifluoroacetate (0.15 g, 0.438 mmol, 86%).

[0146] Production Example 146 Under nitrogen environment, n-butyl lithium-hexane solution (1.6M, 6.21mL, 9.93mmol) was added to a mixture of methyltriphenylphosphonium bromide (3.55g, 9.93mmol) in THF (30mL) cooled to -20°C, and stirred at 0°C for 1 hour. A solution of (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopiperidine-1-carboxylic acid benzyl ester (2.5g, 6.62mmol) in THF (10mL) was added dropwise to the reaction solution at 0°C, and stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture, and 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 (5-10% ethyl acetate / petroleum ether) to give (S)-benzyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylenepiperidine-1-carboxylate (1.2 g, 3.19 mmol, 48.1%) as a colorless liquid.

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

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

[0149] Production Example 173 Under nitrogen environment, a mixture of 3-(1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidin-4-yl)-1,2,4-oxadiazole-carboxylic acid ethyl ester (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 extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 4-(5-(3,3-dimethylazetidine-1-carbonyl)-1,2,4-oxadiazole-3-yl)-4-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.208 mmol, 82%) as a white solid.

[0150] Production Example 209 Under nitrogen environment, 1-bromo-2-(2-bromoethoxy)ethane (0.539 g, 2.323 mmol) was added to a mixture of 4-aminopiperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-methyl ester (0.600 g, 2.323 mmol), potassium iodide (0.771 g, 4.65 mmol), potassium carbonate (0.642 g, 4.65 mmol) in DMF (10 mL) at room temperature, and then stirred at 100 ° C for 24 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water, 1.5 M hydrochloric acid, water, and saturated brine in sequence. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 4-morpholinopiperidin-1,4-dicarboxylic acid 1-(tert-butyl) 4-methyl (250 mg, 2.32 mmol).

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

[0152] Production Example 213 Under nitrogen environment, 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, heated to 100 ° C and stirred for 24 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain tert-butyl 4-(2H-tetrazolyl-5-yl)-4-(trifluoromethyl)piperidine-1-carboxylate (430 mg, 1.338 mmol, 74.5%) as a colorless liquid.

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

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

[0155] Production Example 256 Under nitrogen environment, DCM (3mL) solution of 4-amino-4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylic acid tert-butyl ester (160mg, 0.446mmol) and triethylamine (113mg, 1.116mmol) was cooled to 0°C, acetyl chloride (35.0mg, 0.446mmol) was added and stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 4-acetamide-4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylic acid tert-butyl ester (180mg, 0.356mmol, 80%) as an off-white solid.

[0156] Production Example 257 Under nitrogen environment, sodium hydride (60%, 32.4 mg, 1.349 mmol) was added to a solution of 4-acetamide-4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.450 mmol) in THF (5 mL), and methyl iodide (77 mg, 0.539 mmol) was added and stirred at room temperature for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)-4-(N-methylacetamide)piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.384 mmol, 85%) as a yellow liquid.

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

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

[0159] Production Example 264 Under nitrogen environment, 2-(thiophene-3-yl)acetonitrile (0.5g, 4.06mmol) was added dropwise to a mixture of sodium hydride (60%, 0.357g, 8.93mmol) in DMF (5mL) cooled to 0°C, and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C again, and a solution of tert-butyl bis(2-chloroethyl)carbamate (1.081g, 4.47mmol) in DMF (5.00mL) was added dropwise, and stirred at room temperature for 16 hours. Ice-cold water was slowly added to the reaction mixture and extracted with ethyl acetate. 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 (10-15% ethyl acetate / petroleum ether) to obtain tert-butyl 4-cyano-4-(thiophene-3-yl)piperidine-1-carboxylate (0.610g, 2.083mmol, 51.3%) as a yellow liquid.

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

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

[0162] Production Example 282 To a suspension of tert-butyl 4-(2H-tetrazolyl-5-yl)piperidine-1-carboxylate (2 g, 7.90 mmol), 4-fluorophenylboric acid (1.768 g, 12.63 mmol) and potassium carbonate (1.200 g, 8.69 mmol) in DCM (50 mL) was added di-μ-hydroxy-bis[(N, N, N', N'-tetramethylethylenediamine)copper (II)] dichloride (0.442 g, 0.947 mmol), the reaction vessel was replaced with an oxygen environment, and stirred at room temperature for 16 hours under an oxygen environment of 1 atmosphere. After filtering through diatomaceous earth to remove the solid, 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] Production Example 286 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), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.074 g, 0.090 mmol) were added to 1,4-dioxane (6 mL) bubbled with nitrogen, 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. After the filtrate was concentrated under reduced pressure, 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] Production Example 287 A methanol solution (10 mL) of 2'-(4,4-difluoropiperidin-yl)-3,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylic acid tert-butyl ester (0.3g, 0.791mmol) was bubbled with nitrogen for 5 minutes. Then, 10% palladium / carbon (0.084g, 0.079mmol) was added to the mixture under a nitrogen environment. The reaction mixture was stirred for 3 hours at room temperature under a hydrogen environment of 1 atmosphere. After bubbling the reaction mixture with nitrogen for 5 minutes, diatomaceous earth was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 4-(2-(4,4-difluoropiperidin-1-yl)pyridine-4-yl)piperidine-1-carboxylic acid tert-butyl ester (0.3g, 0.724mmol, 92%) as a colorless liquid.

[0165] Production 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 after stirring for 10 minutes, 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 obtain 5-bromo-2-(4,4-difluoropiperidin-1-yl)thiazole (0.340 g, 0.781 mmol, 37.9%) as a white solid.

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

[0167] Production Example 311 Under nitrogen environment, 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 L, 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 obtain 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] Production Example 314 Potassium carbonate (0.436 g, 3.15 mmol) was added 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), and the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with ice-cold water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (15% ethyl acetate / petroleum ether) to obtain 2-bromo-4-(4-fluoro-1H-pyrazol-1-yl)pyrimidine (0.3 g, 1.199 mmol, 57.0%) as a white solid.

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

[0170] Example 1 Under nitrogen environment, 4M hydrogen chloride 1,4-dioxane solution (157mL, 630mmol) was added dropwise to a solution of (7S, 9R)-7-(4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazole-5-yl)-4-isopropylpiperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (29g, 52.5mmol) in DCM (290mL) cooled to 0°C, and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with DCM and washed with 10% aqueous sodium bicarbonate solution. After the organic layer was concentrated under reduced pressure, 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 obtain (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 nitrogen atmosphere, to a solution of (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-carboxylic acid tert-butyl ester (220 mg, 0.38 mmol) in DCM (2 mL) cooled to 0°C was added 4M hydrogen chloride 1,4-dioxane solution (1 mL), and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, 10% sodium bicarbonate aqueous solution was added to make it alkaline, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (4-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonane-7-yl)methanone (120 mg, 0.25 mmol, 66%) as a white solid.

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

[0173] Example 7 Under nitrogen environment, a DMF (2 mL) solution of (4R, 7S)-7-(4-(((4,4-difluorohexyl)methyl)(methyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carbonyl)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylic acid (9H-fluorene-9-yl)methyl ester (300 mg, 0.418 mmol) was cooled to 0 ° C, piperidine (0.2 mL) was added, and stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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 nitrogen environment, trifluoroacetic acid (0.063mL, 0.814mmol) was added to a DCM (5mL) solution of (7S, 9R)-7-(3-(5-(4,4-difluorocyclohexyl)-1,3,4-oxadiazole-2-yl)-3-isopropylazetidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (45mg, 0.081mmol) cooled to 0°C, and stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, 10% aqueous sodium bicarbonate solution was added to the residue and extracted with DCM. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (0.1% trifluoroacetic acid aqueous 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]nonane-7-yl)methanone trifluoroacetate (8 mg, 0.017 mmol, 21.25%).

[0175] Embodiment 31 Under nitrogen environment, to a solution of (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-carboxylic acid tert-butyl ester (0.15 g, 0.247 mmol) in DCM (2 mL) cooled to 0°C, 4M hydrogen chloride 1,4-dioxane solution (1 mL) was added, and stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, a 10% aqueous sodium bicarbonate solution was added to the obtained white solid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidin-1-yl)((7S,9R)-9-hydroxy-6-azaspiro[3.5]nonane-7-yl)methanone (0.09 g, 0.177 mmol, 71.4%) as a white solid.

[0176] Embodiment 51 Under nitrogen environment, to a solution of (2S,4R)-2-(4-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)piperidine-1-carbonyl)-4-hydroxy-5,5-dimethylpiperidine-carboxylic acid tert-butyl ester (53 mg, 0.094 mmol) in DCM (2 mL) cooled to 0° C., 4M hydrogen chloride 1,4-dioxane solution (1 mL) was added, and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, a 10% aqueous sodium bicarbonate solution was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (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] Embodiment 56 Under nitrogen environment, to a solution of (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-carboxylic acid tert-butyl ester (150 mg, 0.252 mmol) in DCM (2 mL) cooled to 0° C., 4M hydrogen chloride 1,4-dioxane solution (1 mL) was added, and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, a 10% aqueous sodium bicarbonate solution was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (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] Embodiment 63 A methanol / acetonitrile solution (7:3, 40 mL) 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) was separated into optically active substances by supercritical fluid chiral chromatography (SFC) (15% [0.5% isopropylamine-methanol solution] / CO2). The obtained eluents were concentrated under reduced pressure to obtain Example 64 (1.7 g, from the previous effluent) and Example 63 (1.7 g, from the subsequent effluent) as off-white solids. In the table described below, Example 63 and Example 64 are represented by the same chemical structural formula and are respectively one and the other of a compound in which the stereochemistry at the 2-position of the tetrahydropyran ring is α and β.

[0179] Embodiment 67 Under nitrogen environment, to a solution of (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-carboxylic acid tert-butyl ester (0.22 g, 0.380 mmol) in DCM (2 mL) cooled to 0°C, 4M hydrogen chloride 1,4-dioxane solution (1 mL) was added, and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, 10% sodium bicarbonate aqueous solution was added to make it alkaline, and the organic layer was extracted with 2% methanol / DCM solution. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether and filtered to obtain (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] Embodiment 80 Under nitrogen environment, 4M hydrogen chloride 1,4-dioxane solution (1 mL) was added to a solution of (2S, 4R)-2-(4-cyclopropyl-4-(5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazole-3-yl)piperidine-1-carbonyl)-4-hydroxy-5,5-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.070 g, 0.124 mmol) in DCM (2 mL) cooled to 0°C, and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, 10% sodium bicarbonate aqueous solution was added to make it alkaline, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by fractionation HPLC (10 mM aqueous ammonium bicarbonate solution / acetonitrile) to obtain (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] Embodiment 89 Under nitrogen environment, 4M hydrogen chloride 1,4-dioxane solution (2.67ml, 10.69mmol) was added to a DCM (20mL) solution of (7S, 9R)-7-(4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidine-1-carbonyl)-9-hydroxy-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester (1.1g, 2.138mmol) cooled to 0°C, and stirred at room temperature for 2 hours. After adding 10% aqueous sodium bicarbonate solution to the reaction solution to make it alkaline, it was extracted with DCM. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol / DCM) to give (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] Embodiment 90 Under nitrogen environment, 4M hydrogen chloride 1,4-dioxane solution (1 mL) was added to a solution of (2S, 4R)-2-(4-(2-(4-fluorophenyl)-2H-tetrazol-5-yl)piperidine-1-carbonyl)-4-hydroxy-5,5-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.239 mmol) in DCM (2 mL) cooled to 0°C, and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the obtained solid was dissolved in water, 10% sodium bicarbonate aqueous solution was added to make it alkaline, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was suspended in methyl tert-butyl ether and filtered to obtain (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 above-described production examples or examples. The physicochemical data of each compound are shown in Tables 3 to 52 and Tables 68 to 85.

[0184] In the tables, the following abbreviations are used. PEx: Manufacturing example number Ex: Example number PSyn: Manufacturing example number manufactured by the same method Syn: Example number manufactured by the same method Chemical Structure

[0185] Data: Physical and chemical data NMR: DMSO-d6 1 δ value (ppm) of signal in H-NMR (400 MHz) NMR (300): in DMSO-d6 1 δ value (ppm) of signal in H-NMR (300 MHz) NMR (CDCl3): CDCl3 1 δ value (ppm) of signal in H-NMR (400 MHz) NMR(CD3OD): in CD3OD 1 δ value (ppm) of signal in H-NMR (400 MHz) ES+APCI: m / z value in mass analysis measured by ionization using the ESI method (electrospray ionization) and APCI method (atmospheric pressure chemical ionization) ES: m / z value in mass analysis measured by ionization using the ESI method In addition, the m / z value represented by only numerical values ​​represents the value of [M+H] +. In addition, the m / z value after the tert-butoxycarbonyl group is separated is marked as "-100", the value after the tert-butyl group is separated is marked as "-56", and the value after the water molecule is separated is marked as "-18".

[0186] In the chemical structural formula, the following abbreviations are used. Boc: tert-Butyloxycarbonyl CN:Cyano NO2: Nitro TBS: tert-butyldimethylsilyl A compound in which the structure of hydrogen chloride, trifluoroacetic acid or formic acid is described near the chemical structural formula means that the compound is isolated as a chlorate, trifluoroacetate or formate, respectively.

[0187] Except for the following cases, stereochemistry in chemical structural formulae indicates that the compound is an isomer having the stereo configuration of the indicated structure.

[0188] Production Example 1: A mixture of isomers related to the stereochemistry of the secondary hydroxyl group. The mixing ratio is not determined, but is approximately 1:1. Production Example 2, Production Example 3, Production Example 4, Production Example 5, Production Example 6: The stereochemistry of the benzyloxy group is a mixture of isomers. The ratio is not determined, but is approximately 1:1. Preparation Example 7, Preparation Example 20: A mixture of isomers involving the stereochemistry of the secondary hydroxyl group. The mixing ratio is not determined. Production Example 24, Production Example 25: The stereochemistry of the hydroxyl and methyl groups involves an approximately 9:1 mixture of isomers. The stereochemistry is not determined. Preparation Example 26, Preparation Example 27, Preparation Example 28, Preparation Example 254: However, the stereochemistry of the tertiary hydroxyl group was not determined. Production Example 43: A racemic mixture of tertiary hydroxyl groups. Production Example 116, Production Example 117: A racemic mixture in methyl. Production Example 118: Diastereomeric mixture in methyl. Production Example 120, Production Example 121: A racemic mixture of trifluoromethyl substituted on the pyrrolidine ring. Production Example 122: A diastereomeric mixture of trifluoromethyl groups substituted on the pyrrolidine ring. Production Example 132, Production Example 133: A racemic mixture in the 2-position of dimethylpiperidine. Production Example 134, Production Example 135, Production Example 136, Production Example 137, Production Example 138: A roughly 1:1 diastereomeric mixture in methyl. Production Example 163, Production Example 164, Production Example 165, Production Example 186, Production Example 187, Production Example 188, Production Example 190, Production Example 191, Production Example 192, Production Example 198, Production Example 199, Production Example 200: A racemic mixture in the 2- or 3-position of tetrahydrofuran or tetrahydropyran. Production Example 166, Production Example 189, Production Example 193, Production Example 201: A diastereomeric mixture in the 2- or 3-position of tetrahydrofuran or tetrahydropyran.

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

[0190]

Table 3

[0191]

Table 4

[0192]

Table 5

[0193]

Table 6

[0194]

Table 7

[0195]

Table 8

[0196]

Table 9

[0197]

Table 10

[0198]

Table 11

[0199]

Table 12

[0200]

Table 13

[0201]

Table 14

[0202]

Table 15

[0203]

Table 16

[0204]

Table 17

[0205]

Table 18

[0206]

Table 19

[0207]

Table 20

[0208]

Table 21

[0209]

Table 22

[0210]

Table 23

[0211]

Table 24

[0212]

Table 25

[0213]

Table 26

[0214]

Table 27

[0215]

Table 28

[0216]

Table 29

[0217]

Table 30

[0218]

Table 31

[0219]

Table 32

[0220]

Table 33

[0221]

Table 34

[0222]

Table 35

[0223]

Table 36

[0224]

Table 37

[0225]

Table 38

[0226]

Table 39

[0227]

Table 40

[0228]

Table 41

[0229]

Table 42

[0230]

Table 43

[0231]

Table 44

[0232]

Table 45

[0233]

Table 46

[0234]

Table 47

[0235]

Table 48

[0236]

Table 49

[0237]

Table 50

[0238]

Table 51

[0239]

Table 52

[0240]

Table 53

[0241]

Table 54

[0242]

Table 55

[0243]

Table 56

[0244]

Table 57

[0245]

Table 58

[0246]

Table 59

[0247]

Table 60

[0248]

Table 61

[0249]

Table 62

[0250]

Table 63

[0251]

Table 64

[0252]

Table 65

[0253]

Table 66

[0254]

Table 67

[0255]

Table 68

[0256]

Table 69

[0257]

Table 70

[0258]

Table 71

[0259]

Table 72

[0260]

Table 73

[0261]

Table 74

[0262]

Table 75

[0263]

Table 76

[0264]

Table 77

[0265]

Table 78

[0266]

Table 79

[0267]

Table 80

[0268]

Table 81

[0269]

Table 82

[0270]

Table 83

[0271]

Table 84

[0272]

Table 85

[0273]

Table 86

[0274]

Table 87

[0275]

Table 88

[0276]

Table 89

[0277]

Table 90

[0278]

Table 91

[0279]

Table 92

[0280]

Table 93

[0281]

Table 94

[0282]

Table 95

[0283]

Table 96

[0284]

Table 97

[0285]

Table 98

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

Claims

1. A compound of formula (I) or a salt thereof. [Chemistry 1] (wherein, ring A represents, which may have a substituent or may be 3-6 Cycloalkyl or a spiro-condensed azocycloalkyl group having a saturated heterocyclic ring with 3 to 6 ring members; Y represents hydrogen, an alkyl group which may have a substituent, a C 3-6 a cycloalkyl group, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, an aromatic heterocyclic ring which may have a substituent, or -N(R Y1 )-R Y2 ; R Y1 and R Y2 One of them represents a C which may have a substituent 1-4 Alkyl, the other represents a C optionally substituted 1-4 Alkyl, -C(=O)-(C 1-4 alkyl), or -S(=O)2-(C 1-4 alkyl); L represents a nitrogen-containing aromatic heterocyclic ring which may have a substituent, a nitrogen-containing aromatic heterocyclic ring which may have a substituent, 1-2 Alkylene), -C(=O)-N(R L1 )-、-C(=O)-N(R L1 )-(C 1-2 alkylene), -C(=O)-, or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent; R L1 represents hydrogen or optionally substituted C 1-4 alkyl; Z represents a cycloalkyl group which may have a substituent, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, an aromatic heterocyclic ring which may have a substituent, or -O-(alkyl group which may have a substituent), wherein, When L is -C(=O)- or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent, Z represents a cyclic amino group which may have a substituent; m and n each independently represent an integer of 1 or 2.) 2. The compound or salt thereof according to claim 1, wherein Ring A may have a substituent or may be 3-6 Cycloalkyl or piperidinyl in which a saturated heterocyclic ring having 3 to 6 ring members is spiro-condensed.

3. The compound or salt thereof according to claim 2, wherein Ring A is 9-hydroxy-6-azaspiro[3.5]nonan-7-yl which may have a substituent, 4-hydroxy-5,5-dimethylpiperidin-2-yl which may have a substituent, or 1-oxa-6-azaspiro[3.5]nonan-7-yl which may have a substituent.

4. The compound or salt thereof according to claim 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.

5. The compound or salt thereof according to any one of claims 1 to 4, wherein m is 2, and n is 2.

6. The compound or salt thereof according to any one of claims 1 to 5, wherein L is a nitrogen-containing aromatic heterocyclic ring which may have a substituent.

7. The compound or salt thereof according to claim 6, wherein L is 1,2,4-oxadiazole or tetrazole.

8. The compound or salt thereof according to any one of claims 1 to 7, wherein Y is an alkyl group which may have a substituent or a C 3-6 Cycloalkyl.

9. The compound or salt thereof according to any one of claims 1 to 8, wherein Z is a cycloalkyl group which may have a substituent or a non-aromatic heterocyclic ring which may have a substituent.

10. The compound or salt thereof according to claim 9, wherein Z is cyclobutyl, cyclohexyl or tetrahydropyran, each of which is substituted with 2 to 3 substituents selected from the group consisting of fluorine and methyl.

11. The compound or salt thereof according to any one of claims 1 to 7, wherein Y is hydrogen.

12. The compound or salt thereof according to claim 11, wherein Z is a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of fluorine, methyl and trifluoromethyl.

13. The compound or salt thereof according to claim 1, wherein The compound or a salt thereof is a compound of formula (Ia) or a salt thereof, or a compound of formula (Ib) or a salt thereof. [Chemistry 2] [Chemistry 3] (In formula (Ia) and formula (Ib), R 1 and R 2 Respectively represent methyl, or, R 1 and R 2 Together with their adjacent carbon atoms they form cyclobutane: [Chemistry 4] (The wavy line indicates the point of attachment to the rest of the molecule.) Y represents hydrogen, or C optionally having a substituent 1-4 Alkyl, optionally substituted C 3-6 A cycloalkyl group, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, or an aromatic heterocyclic ring which may have a substituent; L represents a nitrogen-containing aromatic heterocyclic ring which may have a substituent, a nitrogen-containing aromatic heterocyclic ring which may have a substituent, 1-2 Alkylene), -C(=O)-N(R L1 )-、-C(=O)-N(R L1 )-(C 1-2 alkylene), -C(=O)-, or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent; R L1 represents hydrogen or optionally substituted C 1-4 alkyl; Z represents C which may have a substituent 3-6 Cycloalkyl, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, an aromatic heterocycle which may have a substituent, or -O-(alkyl which may have a substituent), wherein when L is -C(=O)- or a nitrogen-containing aromatic heterocycle -C(=O)- which may have a substituent, Z represents a cyclic amino group which may have a substituent; m and n each independently represent an integer of 1 or 2.) 14. The compound or salt thereof according to claim 1, wherein The compound or a salt thereof is a compound of formula (Iaa) or a salt thereof, or a compound of formula (Ibb) or a salt thereof. [Chemistry 5] [Chemistry 6] (In Formula (Iaa) and Formula (Ibb), R 1 and R 2 Respectively represent methyl, or, R 1 and R 2 Together with their adjacent carbon atoms they form cyclobutane: [Chemistry 7] (The wavy line indicates the point of attachment to the rest of the molecule.) Y represents hydrogen, or C optionally having a substituent 1-4 Alkyl, optionally substituted C 3-6 A cycloalkyl group, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, or an aromatic heterocyclic ring which may have a substituent; L represents a nitrogen-containing aromatic heterocyclic ring which may have a substituent, a nitrogen-containing aromatic heterocyclic ring which may have a substituent, 1-2 Alkylene), -C(=O)-N(R L1 )-、-C(=O)-N(R L1 )-(C 1-2 alkylene), -C(=O)-, or a nitrogen-containing aromatic heterocyclic ring -C(=O)- which may have a substituent; R L1 represents hydrogen or optionally substituted C 1-4 alkyl; Z represents C which may have a substituent 3-6 Cycloalkyl, an aromatic hydrocarbon ring which may have a substituent, a non-aromatic heterocycle which may have a substituent, an aromatic heterocycle which may have a substituent, or -O-(alkyl which may have a substituent), wherein when L is -C(=O)- or a nitrogen-containing aromatic heterocycle -C(=O)- which may have a substituent, Z represents a cyclic amino group which may have a substituent; m and n each independently represent an integer of 1 or 2.) 15. The compound or salt thereof according to claim 13 or 14, wherein Y is hydrogen, C which may be substituted by 1 to 5 halogens 1-4 Alkyl, or C 3-6 Cycloalkyl; L is a nitrogen-containing aromatic heterocyclic ring which may have a substituent, or a nitrogen-containing aromatic heterocyclic ring which may have a substituent (C 1-2 alkylene); Z is a C which may have a substituent 3-6 A cycloalkyl group, a phenyl group which may have a substituent, a non-aromatic heterocyclic ring which may have a substituent, or an aromatic heterocyclic ring which may have a substituent.

16. The compound or salt thereof according to claim 13 or 14, wherein Y is hydrogen, C which may be substituted by 1 to 5 halogens 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, non-aromatic heterocycle, or aromatic heterocycle, wherein the C 3-6 The cycloalkyl, phenyl, non-aromatic heterocyclic ring, and aromatic heterocyclic ring can be 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 which may be substituted by halogen 1-4 Alkyl, and -O-(C 1-4 alkyl).

17. The compound or salt thereof according to claim 16, 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, wherein The pharmaceutical composition contains the compound or a salt thereof according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 18, wherein The pharmaceutical composition is a pharmaceutical composition for treating neutrophil-related inflammatory diseases.

20. Use of the compound or salt thereof according to any one of claims 1 to 17 in the manufacture of a pharmaceutical composition for treating neutrophil-related inflammatory diseases.

21. Use of the compound or salt thereof according to any one of claims 1 to 17 in treating neutrophil-related inflammatory diseases.

22. The compound or salt thereof according to any one of claims 1 to 17, wherein The compound or the salt thereof is used for treating neutrophil-related inflammatory diseases.

23. A method for treating a neutrophil-related inflammatory disease, wherein: The method of treatment comprises administering to a subject an effective amount of the compound or a salt thereof according to any one of claims 1 to 17.

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