Patent Publication Number: US-11655241-B2

Title: Heterocyclic compound and use thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is the U.S. National Stage of PCT/JP2019/025555, filed Jun. 27, 2019, which claims priority to JP 2018-125334, filed Jun. 29, 2018. 
     TECHNICAL FIELD 
     The present invention relates to a heterocyclic compound, particularly, a heterocyclic compound having an orexin type 2 receptor agonist activity. 
     BACKGROUND OF THE INVENTION 
     Orexin is a neuropeptide specifically produced in particular neurons located sparsely in the lateral hypothalamus and its surrounding area, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptors, which are G protein-coupled receptors mainly present in the brain, and two types of subtypes, type 1 and type 2, are known for the orexin receptors (non-patent document 1). 
     Since orexin-producing neurons (orexin neurons) are localized in the vicinity of the feeding center, and intraventricular administration of orexin peptide results in an increase in food intake, orexin initially attracted attention as a neuropeptide having a feeding behavioral regulation. Thereafter, however, it was reported that the cause of dog narcolepsy is genetic variation of orexin type 2 receptor (non-patent document 2), and the role of orexin in controlling sleep and wakefulness has been also attracted. 
     From the studies using a transgenic mouse having denatured orexin neurons and a double transgenic mouse obtained by crossing this mouse with orexin overexpressing transgenic mouse, it was clarified that narcolepsy-like symptoms that appear by degeneration of orexin neurons disappear due to sustained expression of orexin. Similarly, when orexin peptide was intraventricularly administered to a transgenic mouse having denatured orexin neuron, improvement of narcolepsy-like symptoms was also observed (non-patent document 3). Studies of orexin type 2 receptor knockout mice have suggested that orexin type 2 receptor is important for maintaining arousal (non-patent document 4, non-patent document 5). Such background suggests that orexin type 2 receptor agonists become therapeutic drugs for narcolepsy or therapeutic drugs for other sleep disorders exhibiting excessive sleepiness (non-patent document 6). 
     In addition, it is suggested that a peptidic agonist that selectively acts on the orexin type 2 receptor improves obesity due to high fat diet load in mice (non-patent document 7). 
     In addition, it is suggested that intraventricular administration of orexin peptide shortens the systemic anesthetic time of rat (non-patent document 8). 
     In addition, it is suggested that patients with sleep apnea syndrome show low orexin A concentration levels in plasma (non-patent document 9). 
     In addition, it is suggested that intraventricular administration of orexin peptide improves memory retention of senescence-accelerated model mouse (SAMP8) with cognitive dysfunction (non-patent document 10). 
     In addition, it is suggested that Orexin type 2 receptor agonist will be a therapeutic drug for cardiac failure (patent document 1, non-patent document 11). 
     In addition, it is suggested that the daytime sleepiness of Parkinson&#39;s disease patients is caused by orexin nerve fallout (non-patent document 12). 
     In addition, it is suggested that orexin regulates bone formation and bone loss, and orexin type 2 receptor agonist will be a therapeutic drug for diseases related to bone loss such as osteoporosis, rheumatoid arthritis and the like (patent document 2). 
     In addition, it is suggested that orexin receptor agonist is useful for the prophylaxis or treatment of sepsis, severe sepsis and septic shock, since the mortality was significantly improved by mere continuous administration of orexin from the periphery in septic shock model mouse (patent document 3). 
     Therefore, a compound having an orexin type 2 receptor agonist activity is expected to be useful as a novel therapeutic drug for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbance of consciousness such as coma and the like, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson&#39;s disease, Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis and the like, further, anesthetic antagonist, a prophylactic or therapeutic drug for side effects and complications due to anesthesia. 
     As sulfonamide derivatives, a compound represented by the formula 
                         
wherein each symbol is as described in the document (Patent Document 4) has been reported.
 
     In addition, as compounds having an orexin type 2 receptor agonist activity, the following compounds have been reported. 
     A compound represented by the formula 
                         
wherein each symbol is as described in the document (Patent Document 5).
 
     A compound represented by the formula 
                         
wherein each symbol is as described in the document (Patent Document 6).
 
     A compound represented by the formula 
                         
wherein each symbol is as described in the document (Patent Document 7).
 
     Development of a compound having an orexin type 2 receptor agonist activity is desired. 
     DOCUMENT LIST 
     Patent Document 
     
         
         Patent Document 1: WO 2015/073707 A1 
         Patent Document 2: WO 2015/048091 A1 
         Patent Document 3: WO 2015/147240 A1 
         Patent Document 4: WO 2012/137982 A9 
         Patent Document 5: WO 2015/088000 A1 
         Patent Document 6: WO 2016/133160 A1 
         Patent Document 7: WO 2016/199906 A1 
       
    
     Non-Patent Document 
     
         
         Non-Patent Document 1: Cell, Vol. 92, 573-585, 1998 
         Non-Patent Document 2: Cell, Vol. 98, 365-376, 1999 
         Non-Patent Document 3: Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004 
         Non-Patent Document 4: Cell, Vol. 98, 437-451, 1999 
         Non-Patent Document 5: Neuron, Vol. 38, 715-730, 2003 
         Non-Patent Document 6: CNS Drugs, Vol. 27, 83-90, 2013 
         Non-Patent Document 7: Cell Metabolism, Vol. 9, 64-76, 2009 
         Non-Patent Document 8: Neuroscience, Vol. 121, 855-863, 2003 
         Non-Patent Document 9: Respiration, Vol. 71, 575-579, 2004 
         Non-Patent Document 10: Peptides, Vol. 23, 1683-1688, 2002 
         Non-Patent Document 11: Journal of the American College of Cardiology. Vol. 66, 2015, Pages 2522-2533 
         Non-Patent Document 12: Brain. Vol. 130, 2007, Pages 1586-1595 
       
    
     SUMMARY OF THE INVENTION 
     Problems to be Solved by the Invention 
     The present invention aims to provide a heterocyclic compound having an orexin type 2 receptor agonist activity. 
     Means of Solving the Problems 
     The present inventors have found that a compound represented by the following formula (I) or a salt thereof (sometimes to be referred to as compound (I) in the present specification) has an orexin type 2 receptor agonist activity. As a result of further studies, they have completed the present invention. 
     Accordingly, the present invention relates to 
     [1] A compound represented by the formula (I): 
                         
wherein
 
R 1  is an optionally substituted C 1-6  alkyl group, an optionally substituted C 1-6  alkoxy group, an optionally substituted mono- or di-C 1-6  alkylamino group, an acyl group, or an optionally substituted 3- to 6-membered cyclic group;
 
R 2  is a hydrogen atom, an acyl group, or an optionally substituted 3- to 6-membered cyclic group;
 
R 3  and R 4  are each independently a hydrogen atom, a halogen atom, an optionally substituted C 1-6  alkyl group, an optionally substituted C 1-6  alkoxy group, or a hydroxy group;
 
Ring A is an optionally further substituted 5- to 6-membered nitrogen-containing monocyclic saturated heterocycle; and
 
Ring B and Ring C are each independently an optionally further substituted 4- to 7-membered ring, or a salt thereof;
 
[2] The compound or salt according to the above-mentioned [1], wherein
 
R 1  is
 
(1) a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from
         (i) a halogen atom,   (ii) a hydroxy group, and   (iii) a C 1-6  alkoxy group,
 
(2) a C 1-6  alkoxy group,
 
(3) a mono- or di-C 1-6  alkyl-carbamoyl group,
 
(4) a C 3-6  cycloalkyl group optionally substituted by 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) a cyano group,   (iii) a hydroxy group, and   (iv) a C 1-6  alkoxy group, or
 
(5) a 3- to 6-membered monocyclic non-aromatic heterocyclic group;
 
R 2  is
 
(1) a C 1-6  alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
   (i) a hydroxy group, and   (ii) a C 1-6  alkoxy group,
 
(2) a C 3-10  cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) a cyano group,   (iii) a hydroxy group,   (iv) an optionally halogenated C 1-6  alkyl group, and   (v) a C 1-6  alkoxy group, or
 
(3) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group;
 
R 3  and R 4  are both hydrogen atoms;
 
Ring A is
 
(1) a pyrrolidine ring having no additional substituent, or
 
(2) a piperidine ring having no additional substituent;
 
Ring B is
 
[1] a benzene ring having no additional substituent, or
 
[2] a 5- to 6-membered monocyclic aromatic heterocycle having no additional substituent; and
 
Ring C is a benzene ring optionally further substituted by 1 to 3 halogen atoms;
 
[3] The compound or salt according to the above-mentioned [1], wherein
 
R 1  is
 
(1) a mono- or di-C 1-6  alkyl-carbamoyl group, or
 
(2) a 3- to 6-membered monocyclic non-aromatic heterocyclic group;
 
R 2  is
 
(1) a C 3-10  cycloalkyl-carbonyl group, or
 
(2) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group;
 
R 3  and R 4  are both hydrogen atoms;
 
Ring A is a pyrrolidine ring having no additional substituent;
 
Ring B is a benzene ring having no additional substituent; and
 
Ring C is a benzene ring further substituted by 1 to 3 halogen atoms;
 
[4] The compound or salt according to the above-mentioned [1], wherein
 
R 1  is
 
(1) a mono- or di-C 1-6  alkyl-carbamoyl group, or
 
(2) a tetrahydrofuryl group;
 
R 2  is
 
(1) a cyclobutylcarbonyl group, or
 
(2) an azetidinylcarbonyl group;
 
R 3  and R 4  are both hydrogen atoms;
 
Ring A is a pyrrolidine ring having no additional substituent;
 
Ring B is a benzene ring having no additional substituent; and
 
Ring C is a benzene ring further substituted by 1 to 3 halogen atoms;
 
[5] N ˜ 2 ˜ -{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl) methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide, or a salt thereof;
 
[6] (2S)—N-{(2S,3S)-1-(Azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide, or a salt thereof;
 
[7] (2S)—N-{(2S,3S)-1-(Cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide, or a salt thereof;
 
[8] A medicament comprising the compound or salt according to claim  1 ;
 
[9] The medicament according to the above-mentioned [8], which is an orexin type 2 receptor agonist;
 
[10] The medicament according to the above-mentioned [8], which is an agent for the prophylaxis or treatment of narcolepsy;
 
[11] The compound or salt according to the above-mentioned [1] for use in the prophylaxis or treatment of narcolepsy;
 
[12] A method of activating an orexin type 2 receptor in a mammal, which comprises administering an effective amount of the compound or salt according to the above-mentioned [1] to the mammal;
 
[13] A method for the prophylaxis or treatment of narcolepsy in a mammal, which comprises administering an effective amount of the compound or salt according to the above-mentioned [1] to the mammal; and
 
[14] Use of the compound or salt according to the above-mentioned [1] for the manufacture of an agent for the prophylaxis or treatment of narcolepsy.
       

     Effect of the Invention 
     The compound of the present invention has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition. 
     In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine. 
     In the present specification, examples of the “C 1-6  alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. In the present specification, examples of the “optionally halogenated C 1-6  alkyl group” include a C 1-6  alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl. 
     In the present specification, examples of the “C 2-6  alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl. 
     In the present specification, examples of the “C 2-6  alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl. 
     In the present specification, examples of the “C 3-10  cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl. In the present specification, examples of the “optionally halogenated C 3-10  cycloalkyl group” include a C 3-10  cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. 
     In the present specification, examples of the “C 3-10  cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. 
     In the present specification, examples of the “C 6-14  aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl. 
     In the present specification, examples of the “C 7-16  aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl. 
     In the present specification, examples of the “C 1-6  alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkoxy group” include a C 1-6  alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy. 
     In the present specification, examples of the “C 3-10  cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. 
     In the present specification, examples of the “C 1-6  alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkylthio group” include a C 1-6  alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio. 
     In the present specification, examples of the “C 1-6  alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkyl-carbonyl group” include a C 1-6  alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl. 
     In the present specification, examples of the “C 1-6  alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. 
     In the present specification, examples of the “C 6-14  aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl. In the present specification, examples of the “C 7-16  aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl. 
     In the present specification, examples of the “5- to 14-membered aromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl. 
     In the present specification, examples of the “3- to 14-membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl. 
     In the present specification, examples of the “mono- or di-C 1-6  alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl. 
     In the present specification, examples of the “mono- or di-C 7-16  aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl. 
     In the present specification, examples of the “C 1-6  alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. 
     In the present specification, examples of the “optionally halogenated C 1-6  alkylsulfonyl group” include a C 1-6  alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl. 
     In the present specification, examples of the “C 6-14  arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl. 
     In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group. 
     In the present specification, examples of the “hydrocarbon group” (including “hydrocarbon group” of “optionally substituted hydrocarbon group”) include a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-10  cycloalkyl group, a C 3-10  cycloalkenyl group, a C 6-14  aryl group and a C 7-16  aralkyl group. 
     In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent (s) selected from the following Substituent Group A. 
     [Substituent Group A] 
     (1) a halogen atom, 
     (2) a nitro group, 
     (3) a cyano group, 
     (4) an oxo group, 
     (5) a hydroxy group, 
     (6) an optionally halogenated C 1-6  alkoxy group, 
     (7) a C 6-14  aryloxy group (e.g., phenoxy, naphthoxy), 
     (8) a C 7-16  aralkyloxy group (e.g., benzyloxy), 
     (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), 
     (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy), 
     (11) a C 1-6  alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), 
     (12) a C 6-14  aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), 
     (13) a C 1-6  alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), 
     (14) a mono- or di-C 1-6  alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), 
     (15) a C 6-14  aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), 
     (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 
     (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), 
     (18) an optionally halogenated C 1-6  alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), 
     (19) a C 6-14  arylsulfonyloxy group optionally substituted by a C 1-6  alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), 
     (20) an optionally halogenated C 1-6  alkylthio group, 
     (21) a 5- to 14-membered aromatic heterocyclic group, 
     (22) a 3- to 14-membered non-aromatic heterocyclic group, 
     (23) a formyl group, 
     (24) a carboxy group, 
     (25) an optionally halogenated C 1-6  alkyl-carbonyl group, 
     (26) a C 6-14  aryl-carbonyl group, 
     (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group, 
     (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, 
     (29) a C 1-6  alkoxy-carbonyl group, 
     (30) a C 6-14  aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), 
     (31) a C 7-16  aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), 
     (32) a carbamoyl group, 
     (33) a thiocarbamoyl group, 
     (34) a mono- or di-C 1-6  alkyl-carbamoyl group, 
     (35) a C 6-4  aryl-carbamoyl group (e.g., phenyl carbamoyl), 
     (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), 
     (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), 
     (38) an optionally halogenated C 1-6  alkylsulfonyl group, 
     (39) a C 6-14  arylsulfonyl group, 
     (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), 
     (41) an optionally halogenated C 1-6  alkylsulfinyl group, 
     (42) a C 6-14  arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), 
     (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), 
     (44) an amino group, 
     (45) a mono- or di-C 1-6  alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), 
     (46) a mono- or di-C 6-14  arylamino group (e.g., phenylamino), 
     (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), 
     (48) a C 7-16  aralkylamino group (e.g., benzylamino), 
     (49) a formylamino group, 
     (50) a C 1-6  alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), 
     (51) a (C 1-6  alkyl) (C 1-6  alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino), 
     (52) a C 6-14  aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), 
     (53) a C 1-6  alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), 
     (54) a C 7-16  aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), 
     (55) a C 1-6  alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), 
     (56) a C 6-14  arylsulfonylamino group optionally substituted by a C 1-6  alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino), 
     (57) an optionally halogenated C 1-6  alkyl group, 
     (58) a C 2-6  alkenyl group, 
     (59) a C 2-6  alkynyl group, 
     (60) a C 3-10  cycloalkyl group, 
     (61) a C 3-10  cycloalkenyl group, and 
     (62) a C 6-14  aryl group. 
     The number of the above-mentioned substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. 
     In the present specification, examples of the “heterocyclic group” (including “heterocyclic group” of “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 
     In the present specification, examples of the “aromatic is heterocyclic group” (including “5- to 14-membered aromatic heterocyclic group”) include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 
     Preferable examples of the “aromatic heterocyclic group” include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and 8- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. 
     In the present specification, examples of the, “non-aromatic heterocyclic group” (including “3- to 14-membered non-aromatic heterocyclic group”) include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 
     Preferable examples of the “non-aromatic heterocyclic group” include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and 9- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like. 
     In the present specification, preferable examples of the “7- to 10-membered bridged heterocyclic group” include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. 
     In the present specification, examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom. 
     In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent(s) selected from the above-mentioned Substituent Group A. 
     The number of the substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. 
     In the present specification, examples of the “acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 3-10  cycloalkenyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1-6  alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group”. 
     Examples of the “acyl group” also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group. 
     Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group. 
     Preferable examples of the “acyl group” include a formyl group, a carboxy group, a C 1-6  alkyl-carbonyl group, a C 2-6  alkenyl-carbonyl group (e.g., crotonoyl), a C 3-10  cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C 3-10  cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C 6-14  aryl-carbonyl group, a C 7 -16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a C 6-14  aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a C 7-16  aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 2-6  alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C 3-10  cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- or di-C 6-14  aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C 7-16  aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C 1-6  alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C 2-6  alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C 3-10  cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C 6-14  aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C 7-16  aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), a sulfino group, a C 1-6  alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C 1-6  alkylsulfonyl group, a C 6-14  arylsulfonyl group, a phosphono group and a mono- or di-C 1-6  alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono). 
     In the present specification, examples of the “optionally substituted amino group” include an amino group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 7-16  aralkyl-carbamoyl group, a C 1-6  alkylsulfonyl group and a C 6-14  arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”. 
     Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6  alkyl) amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C 2-6  alkenylamino group (e.g., diallylamino), a mono- or di-C 3-10  cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di-C 6-14  arylamino group (e.g., phenylamino), a mono- or di-C 7-16  aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- or di-(optionally halogenated C 1-6  alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), a mono- or di-C 6-14  aryl-carbonylamino group (e.g., benzoylamino), a mono- or di-C 7-16  aralkyl-carbonylamino group (e.g., benzylcarbonylamino), a mono- or di-5- to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), a mono- or di-3- to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), a mono- or di-C 1-6  alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a (mono- or di-C 1-6  alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino), a (mono- or di-C 7-16  aralkyl-carbamoyl) amino group (e.g., is benzylcarbamoylamino), a C 1-6  alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a C 6-14  arylsulfonylamino group (e.g., phenylsulfonylamino), a (C 1-6  alkyl)(C 1-6  alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino) and a (C 1-6  alkyl) (C 6-14  aryl-carbonyl) amino group (e.g., N-benzoyl-N-methylamino). 
     In the present specification, examples of the “optionally substituted carbamoyl group” include a carbamoyl group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6 -14 aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group and a mono- or di-C 7-16  aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”. 
     Preferable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 2-6  alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C 3-10  cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C 6-14  aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C 7-16  aralkyl-carbamoyl group, a mono- or di-C 1-6  alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C 6-14  aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl). 
     In the present specification, examples of the “optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group and a mono- or di-C 7-16  aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”. 
     Preferable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C 1-6  alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C 2-6  alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C 3-10  cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C 6-14  aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C 7-16  aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or di-C 1-6  alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di-C 6-14  aryl-carbonyl-thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl). 
     In the present specification, examples of the “optionally substituted sulfamoyl group” include a sulfamoyl group optionally having “1 or 2 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6 -14 aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group and a mono- or di-C 7-16  aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”. 
     Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C 1-6  alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C 2-6  alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C 3-10  cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C 6-14  aryl-sulfamoyl group (e.g., phenylsulfamoyl), a mono- or di-C 7-16  aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C 1-6  alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), a mono- or di-C 6-14  aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl). 
     In the present specification, examples of the “optionally substituted hydroxy group” include a hydroxy group optionally having “a substituent selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7-16  aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group, a C 7-16  aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6  alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6  alkyl-carbamoyl group, a mono- or di-C 7-16  aralkyl-carbamoyl group, a C 1-6  alkylsulfonyl group and a C 6-14  arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”. 
     Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6  alkoxy group, a C 2-6  alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C 3-10  cycloalkyloxy group (e.g., cyclohexyloxy), a C 6-4  aryloxy group (e.g., phenoxy, naphthyloxy), a C 7-16  aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C 1-6  alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C 6-14  aryl-carbonyloxy group (e.g., benzoyloxy), a C 7-16  aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a C 1-6  alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), a carbamoyloxy group, a C 1-6  alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C 7-16  aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C 1-6  alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a C 6-14  arylsulfonyloxy group (e.g., phenylsulfonyloxy). 
     In the present specification, examples of the “optionally substituted sulfanyl group” include a sulfanyl group optionally having “a substituent selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a C 6-14  aryl group, a C 7 -16 aralkyl group, a C 1-6  alkyl-carbonyl group, a C 6-14  aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from Substituent Group A” and a halogenated sulfanyl group. 
     Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6  alkylthio group, a C 2-6  alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C 3-10  cycloalkylthio group (e.g., cyclohexylthio), a C 6-14  arylthio group (e.g., phenylthio, naphthylthio), a C 7-16  aralkylthio group (e.g., benzylthio, phenethylthio), a C 1-6  alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C 6-14  aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio). 
     In the present specification, examples of the “optionally substituted silyl group” include a silyl group optionally having “1 to 3 substituents selected from a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-10  cycloalkyl group, a Ce-14 aryl group and a C 7-16  aralkyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”. 
     Preferable examples of the optionally substituted silyl group include a tri-C 1-6  alkylsilyl group (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl). 
     In the present specification, examples of the “hydrocarbon ring” include a C 6-14  aromatic hydrocarbon ring, C 3-10  cycloalkane and C 3-10  cycloalkene. 
     In the present specification, examples of the “C 6-14  aromatic hydrocarbon ring” include benzene and naphthalene. 
     In the present specification, examples of the “C 3-10  cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane. 
     In the present specification, examples of the “C 3-10  cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene. 
     In the present specification, examples of the “heterocycle” include an aromatic heterocycle and a non-aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 
     In the present specification, examples of the “aromatic heterocycle” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the “aromatic heterocycle” include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and 
     8- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and the like. 
     In the present specification, examples of the “non-aromatic heterocycle” include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the “non-aromatic heterocycle” include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, oxepane and the like; and 9- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline and the like. 
     In the present specification, examples of the “nitrogen-containing heterocycle” include a heterocycle containing at least one nitrogen atom as a ring-constituting atom, from among the “heterocycle”. 
     In the present specification, examples of the “cyclic group” include a “C 3-10  cycloalkyl group”, a “C 3-10  cycloalkenyl group”, a “C 6-14  aryl group” and a “heterocyclic group”. 
     In the present specification, examples of the “3- to 6-membered cyclic group” include 3- to 6-membered groups from among the “cyclic group”. Specific examples thereof include 3- to 6-membered groups from among the “C 3-10  cycloalkyl group”, 3- to 6-membered groups from among the “C 3-10  cycloalkenyl group”, a phenyl group, a “5- to 6-membered monocyclic aromatic heterocyclic group”, and 3- to 6-membered groups from among the “3- to 8-membered monocyclic non-aromatic heterocyclic group”. 
     In the present specification, examples of the “ring” include a “hydrocarbon ring” and a “heterocycle”. 
     In the present specification, examples of the “4- to 7-membered ring” include 4- to 7-membered rings from among the “ring”. Specific examples thereof include 4- to 7-membered rings from among the “C 3-10  cycloalkane”, a benzene ring, and 4- to 7-membered rings from among the “5- to 6-membered monocyclic aromatic heterocycle” and “3- to 8-membered monocyclic non-aromatic heterocycle”. 
     In the present specification, examples of the “5- to 6-membered nitrogen-containing monocyclic saturated heterocycle” include 5- to 6-membered saturated groups containing at least nitrogen atom as ring constituting atom, from among the “3- to 8-membered monocyclic non-aromatic heterocycle”. 
     The definition of each symbol in the formula (I) is explained in detail in the following. 
     R 1  is an optionally substituted C 1-6  alkyl group, an optionally substituted C 1-6  alkoxy group, an optionally substituted mono- or di-C 1-6  alkylamino group, an acyl group, or an optionally substituted 3- to 6-membered cyclic group. 
     Examples of the substituents of the “optionally substituted C 1-6  alkyl group”, “optionally substituted C 1-6  alkoxy group”, “optionally substituted mono- or di-C 1-6  alkylamino group” and “optionally substituted 3- to 6-membered cyclic group” represented by R 1  include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     R 1  is preferably 
     (1) an optionally substituted C 1-6  alkyl group (e.g., methyl, ethyl, isopropyl), 
     (2) an optionally substituted C 1-6  alkoxy group (e.g., methoxy), 
     (3) an acyl group (preferably an optionally substituted mono- or di-C 1-6  alkyl-carbamoyl group (e.g., dimethylcarbamoyl)), or 
     (4) an optionally substituted 3- to 6-membered cyclic group (preferably a C 3-6  cycloalkyl group (e.g., cyclopropyl, cyclobutyl), a 3- to 6-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl)). 
     Examples of the substituents of the above-mentioned “optionally substituted mono- or di-C 1-6  alkyl-carbamoyl group”, “optionally substituted C 3-6  cycloalkyl group” and “optionally substituted 3- to 6-membered monocyclic non-aromatic heterocyclic group” include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     R 1  is more preferably 
     (1) a C 1-6  alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents selected from 
     
         
         
           
             (i) a halogen atom (e.g., a fluorine atom), 
             (ii) a hydroxy group, and 
             (iii) a C 1-6  alkoxy group (e.g., methoxy),
 
(2) a C 1-6  alkoxy group (e.g., methoxy),
 
(3) a mono- or di-C 1-6  alkyl-carbamoyl group (e.g., dimethylcarbamoyl),
 
(4) a C 3-6  cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 to 3 substituents selected from
 
             (i) a halogen atom (e.g., a fluorine atom), 
             (ii) a cyano group, 
             (iii) a hydroxy group, and 
             (iv) a C 1-6  alkoxy group (e.g., methoxy), or
 
(5) a 3- to 6-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl).
 
           
         
       
    
     R 1  is particularly preferably 
     (1) a mono- or di-C 1-6  alkyl-carbamoyl group (e.g., dimethylcarbamoyl), or 
     (2) a 3- to 6-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydrofuryl). 
     R 2  is a hydrogen atom, an acyl group, or an optionally substituted 3- to 6-membered cyclic group. 
     Examples of the substituent of the “optionally substituted 3- to 6-membered cyclic group” represented by R 2  include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     R 2  is preferably an acyl group (e.g., 
     (1) an optionally substituted C 1-6  alkyl-carbonyl group (e.g., 2-methylpropanoyl, 2,2-dimethylpropanoyl), 
     (2) an optionally substituted C 3-10  cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl), or 
     (3) an optionally substituted 3- to 14-membered non-aromatic heterocyclylcarbonyl group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl, tetrahydrofurylcarbonyl))). 
     Examples of the substituents of the above-mentioned “optionally substituted C 1-6  alkyl-carbonyl group”, “optionally substituted C 3-10  cycloalkyl-carbonyl group” and “optionally substituted 3- to 14-membered non-aromatic heterocyclylcarbonyl group” include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     R 2  is more preferably 
     (1) a C 1-6  alkyl-carbonyl group (e.g., 2-methylpropanoyl, 2,2-dimethylpropanoyl) optionally substituted by 1 to 3 substituents selected from 
     
         
         
           
             (i) a hydroxy group, and 
             (ii) a C 1-6  alkoxy group (e.g., methoxy),
 
(2) a C 3-10  cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl) optionally substituted by 1 to 3 substituents selected from
 
             (i) a halogen atom (e.g., a fluorine atom), 
             (ii) a cyano group, 
             (iii) a hydroxy group, 
             (iv) an optionally halogenated C 1-6  alkyl group (e.g., trifluoromethyl), and 
             (v) a C 1-6  alkoxy group (e.g., methoxy), or
 
(3) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl, tetrahydrofurylcarbonyl)).
 
           
         
       
    
     R 2  is particularly preferably 
     (1) a C 3-10  cycloalkyl-carbonyl group (e.g., cyclobutylcarbonyl), or 
     (2) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl). 
     R 3  and R 4  are each independently a hydrogen atom, a halogen atom, an optionally substituted C 1-6  alkyl group, an optionally substituted C 1-6  alkoxy group, or a hydroxy group. 
     Examples of the substituent of “optionally substituted C 1-6  alkyl group” and “optionally substituted C 1-6  alkoxy group” represented by R 3  or R 4  include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     R 3  and R 4  are preferably both hydrogen atoms. 
     Ring A is an optionally further substituted 5- to 6-membered nitrogen-containing monocyclic saturated heterocycle. 
     The substituent of “optionally further substituted 5- to 6-membered nitrogen-containing monocyclic saturated heterocycle” represented by Ring A is an additional substituent that the heterocycle optionally further has in addition to —NHCOR 1  and R 2 , and examples thereof include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     Ring A is preferably 
     (1) an optionally further substituted pyrrolidine ring, or 
     (2) an optionally further substituted piperidine ring. 
     Ring A is more preferably 
     (1) a pyrrolidine ring having no additional substituent, or 
     (2) a piperidine ring having no additional substituent. 
     Ring A is particularly preferably a pyrrolidine ring having no additional substituent. 
     Ring B is an optionally further substituted 4- to 7-membered ring. 
     The substituent of “optionally further substituted 4- to 7-membered ring” represented by Ring B is an additional substituent that the ring optionally further has in addition to —CR 3 R 4 -Ring A and -Ring C, and examples thereof include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     Ring B is preferably 
     (1) an optionally further substituted benzene ring, or 
     (2) an optionally further substituted 5- to 6-membered monocyclic aromatic heterocycle (e.g., a pyridine ring, a thiazole ring). 
     Ring B is more preferably 
     (1) a benzene ring having no additional substituent, or 
     (2) a 5- to 6-membered monocyclic aromatic heterocycle (e.g., a thiazole ring, a pyridine ring) having no additional substituent. 
     Ring B is particularly preferably a benzene ring having no additional substituent. 
     Ring C is an optionally further substituted 4- to 7-membered ring. 
     The substituent of “optionally further substituted 4- to 7-membered ring” represented by Ring C is an additional substituent that the ring optionally further has in addition to -Ring B, and examples thereof include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. 
     Ring C is preferably an optionally further substituted benzene ring. 
     Ring C is more preferably a benzene ring optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom). 
     Ring C is particularly preferably a benzene ring further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom). 
     Regarding Ring A of compound (I), the configuration based on the carbon atom that —NHCOR 1  is bonded to and the carbon atom that —CR 3 R 4 -Ring B is bonded to (for example, when Ring A is a pyrrolidine ring or a piperidine ring, the configuration based on the 2- and 3-positions) is preferably cis-form. That is, compound (I) is preferably represented by the formula (IA) or (IB): 
                         
each symbol in the formula is as defined above,
 
more preferably represented by the formula (IA):
 
                         
each symbol in the formula is as defined above.
 
     Compound (I) is preferably a compound wherein 
     R 1  is 
     (1) a C 1-6  alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents selected from 
     
         
         
           
             (i) a halogen atom (e.g., a fluorine atom), 
             (ii) a hydroxy group, and 
             (iii) a C 1-6  alkoxy group (e.g., methoxy),
 
(2) a C 1-6  alkoxy group (e.g., methoxy),
 
(3) a mono- or di-C 1-6  alkyl-carbamoyl group (e.g., dimethylcarbamoyl),
 
(4) a C 3-6  cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 to 3 substituents selected from
 
             (i) a halogen atom (e.g., a fluorine atom), 
             (ii) a cyano group, 
             (iii) a hydroxy group, and 
             (iv) a C 1-6  alkoxy group (e.g., methoxy), or
 
(5) a 3- to 6-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl);
 
R 2  is
 
(1) a C 1-6  alkyl-carbonyl group (e.g., 2-methylpropanoyl, 2,2-dimethylpropanoyl) optionally substituted by 1 to 3 substituents selected from
 
             (i) a hydroxy group, and 
             (ii) a C 1-6  alkoxy group (e.g., methoxy),
 
(2) a C 3-10  cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl) optionally substituted by 1 to 3 substituents selected from
 
             (i) a halogen atom (e.g., a fluorine atom), 
             (ii) a cyano group, 
             (iii) a hydroxy group, 
             (iv) an optionally halogenated C 1-6  alkyl group (e.g., trifluoromethyl), and 
             (v) a C 1-6  alkoxy group (e.g., methoxy), or
 
(3) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl, tetrahydrofurylcarbonyl));
 
R 3  and R 4  are both hydrogen atoms;
 
Ring A is
 
(1) a pyrrolidine ring having no additional substituent, or
 
(2) a piperidine ring having no additional substituent;
 
Ring B is
 
(1) a benzene ring having no additional substituent, or
 
(2) a 5- to 6-membered monocyclic aromatic heterocycle (e.g., a thiazole ring, a pyridine ring) having no additional substituent;
 
and
 
Ring C is a benzene ring optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).
 
           
         
       
    
     Compound (I) is more preferably a compound wherein 
     R 1  is 
     (1) a mono- or di-C 1-6  alkyl-carbamoyl group (e.g., dimethylcarbamoyl), or 
     (2) a 3- to 6-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydrofuryl); 
     R 2  is 
     (1) a C 3-10  cycloalkyl-carbonyl group (e.g., cyclobutylcarbonyl), or 
     (2) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl); 
     R 3  and R 4  are both hydrogen atoms; 
     Ring A is a pyrrolidine ring having no additional substituent; 
     Ring B is a benzene ring having no additional substituent; and 
     Ring C is a benzene ring further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom). 
     Compound (I) is particularly preferably a compound wherein 
     R 1  is 
     (1) a mono- or di-C 1-6  alkyl-carbamoyl group (e.g., dimethylcarbamoyl), or 
     (2) a tetrahydrofuryl group; 
     R 2  is 
     (1) a cyclobutylcarbonyl group, or 
     (2) an azetidinylcarbonyl group; 
     R 3  and R 4  are both hydrogen atoms; 
     Ring A is a pyrrolidine ring having no additional substituent; 
     Ring B is a benzene ring having no additional substituent; and 
     Ring C is a benzene ring further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom). 
     Specific examples of compound (I) include the compounds of the below-mentioned Examples 1 to 46. 
     Specifically, compound (I) is preferably N ˜ 2 ˜ -{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide (Example 30), or a salt thereof; (2S)—N-{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide (Example 31), or a salt thereof; or, (2S)—N-{(2S,3S)-1-(cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide (Example 33), or a salt thereof. 
     As a salt of a compound represented by the formula (I), a pharmacologically acceptable salt is preferable, and examples of such salt include a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid and the like. 
     Preferable examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like. 
     Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like. 
     Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. 
     Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. 
     Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. 
     The production method of the compound of the present invention is explained below. 
     The raw material compound and reagent used and the compound obtained in each step in the following production method may be each in a form of a salt, and examples of such salt include those similar to the salts of the compound represented by the formula (I), and the like. 
     When the compound obtained in each step is a free form, it can be converted to the objective salt according to a method known per se. When the compound obtained in each step is a salt, it can be converted to the objective free form or the other salt according to a method known per se. 
     The compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next reaction. Alternatively, the compound obtained in each step can be isolated and purified from a reaction mixture according to a method known per se, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography and the like. 
     When the raw material compound and reagent used in each step are commercially available, the commercially available product can also be used directly. 
     In the reaction in each step, while the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min-48 hr, preferably 10 min-8 hr, unless otherwise specified. 
     In the reaction in each step, while the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally −78° C.-300° C., preferably −78° C.-150° C., unless otherwise specified. 
     In the reaction in each step, while the pressure varies depending on the kind of the reagent and solvent to be used, it is generally 1 atm-20 atm, preferably 1 atm-3 atm, unless otherwise specified. 
     Microwave synthesizer such as Initiator manufactured by Biotage and the like may be used for the reaction in each step. While the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally room temperature −300° C., preferably 50° C.-250° C., unless otherwise specified. While the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min-48 hr, preferably 1 min-8 hr, unless otherwise specified. 
     In the reaction in each step, the reagent is used in an amount of 0.5 equivalents-20 equivalents, preferably 0.8 equivalents-5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent-1 equivalent, preferably 0.01 equivalent-0.2 equivalent, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in a solvent amount. 
     Unless otherwise specified, the reaction in each step is carried out without solvent, or by dissolving or suspending the raw material compound in a suitable solvent. Examples of the solvent include those described in Examples and the following solvents. 
     alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and the like; 
     ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like; 
     aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like; 
     saturated hydrocarbons: cyclohexane, hexane and the like; amides: N,N-dimethylformamide, N-methylpyrrolidone and the like; 
     halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like; 
     nitriles: acetonitrile and the like; 
     sulfoxides: dimethyl sulfoxide and the like; 
     aromatic organic bases: pyridine and the like; 
     anhydrides: acetic anhydride and the like; 
     organic acids: formic acid, acetic acid, trifluoroacetic acid and the like; 
     inorganic acids: hydrochloric acid, sulfuric acid and the like; 
     esters: ethyl acetate and the like; 
     ketones: acetone, methyl ethyl ketone and the like; 
     water. 
     The above-mentioned solvent can be used in a mixture of two or more kinds thereof in an appropriate ratio. 
     When a base is used for the reaction in each step, examples thereof include those described in Examples and the following bases. 
     inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like; 
     organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine and the like; 
     metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like; 
     alkali metal hydrides: sodium hydride and the like; 
     metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like; 
     organic lithiums: n-butyllithium and the like. 
     When an acid or an acid catalyst is used for the reaction in each step, examples thereof include those described in Examples and the following acids and acid catalysts. 
     inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like; 
     organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; 
     Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like. 
     Unless otherwise specified, the reaction in each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol. 13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol. 14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley &amp; Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or the like, or the method described in Examples. 
     In each step, the protection or deprotection reaction of an functional group is carried out according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski), or the like, or the method described in Examples. 
     Examples of the protecting group for a hydroxy group of an alcohol and the like and a phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester-type protecting groups such as acetate ester and the like; sulfonate ester-type protecting groups such as methanesulfonate ester and the like; carbonate ester-type protecting groups such as tert-butylcarbonate and the like, and the like. 
     Examples of the protecting group for a carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal and the like; cyclic acetal-type protecting groups such as 1,3-dioxane and the like, and the like. 
     Examples of the protecting group for a carbonyl group of a ketone include ketal-type protecting groups such as dimethylketal and the like; cyclic ketal-type protecting groups such as 1,3-dioxane and the like; oxime-type protecting groups such as O-methyloxime and the like; hydrazone-type protecting groups such as N,N-dimethylhydrazone and the like, and the like. 
     Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester and the like; amide-type protecting groups such as N,N-dimethylamide and the like, and the like. 
     Examples of the protecting group for a thiol include ether-type protecting groups such as benzyl thioether and the like; ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like. 
     Examples of the protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate-type protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like; alkyl amine-type protecting groups such as N-triphenylmethylamine and the like; sulfonamide-type protecting groups such as methanesulfonamide and the like, and the like. 
     The protecting groups can be removed according to a method known per se, for example, by employing a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method, and the like. 
     When reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes such as borane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. When carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar&#39;s catalyst and the like may be employed. 
     When oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese such as manganese dioxide, potassium permanganate and the like; leads such as lead tetraacetate and the like; reagents containing chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and the like; halogen compounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like. 
     When radical cyclization reaction is carried out in each step, examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reagent to be used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like. 
     When Wittig reaction is carried out in each step, examples of the Wittig reagent to be used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared according to a method known per se, for example, by reacting a phosphonium salt with a strong base. 
     When Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organic lithiums and the like. 
     When Friedel-Crafts reaction is carried out in each step, a combination of a Lewis acid and an acid chloride or a combination of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an alcohol, an olefin etc.) is used as a reagent. Alternatively, an organic acid or an inorganic acid can also be used instead of a Lewis acid, and an anhydride such as acetic anhydride and the like can also be used instead of an acid chloride. 
     When aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (e.g., an amine, imidazole etc.) and a base (e.g., an organic base etc.) are used as a reagent. 
     When nucleophilic addition reaction by a carbo anion, nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbo anion or nucleophilic substitution reaction by a carbo anion is carried out in each step, and examples of the base to be used for generation of the carbo anion include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like. 
     When Grignard reaction is carried out in each step, examples of the Grignard reagent to be used include arylmagnesium halides such as phenylmagnesium bromide and the like; and alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metal magnesium in an ether or tetrahydrofuran as a solvent. 
     When Knoevenagel condensation reaction is carried out in each step, a compound having an activated methylene group with two electron withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., an organic base, a metal alkoxide, an inorganic base) are used as a reagent. 
     When Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (e.g., N,N-dimethylformamide etc.) are used as a reagent. 
     When azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in each step, examples of the azidating agent to be used include diphenylphosphorylazide (DPPA), trimethylsilylazide, sodium azide and the like. For so example, for the azidation reaction of an alcohol, a method using diphenylphosphorylazide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilylazide and a Lewis acid, and the like are employed. 
     When reductive amination reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine and the like, and the like. 
     When Mitsunobu reaction is carried out in each step, an azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) etc.) and triphenylphosphine are used as a reagent. 
     When esterification reaction, amidation reaction or urea formation reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic acids such as acid anhydrides, activated esters, sulfates and the like. Examples of the activating agent of the carboxylic acid include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; combinations thereof and the like. When carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be added to the reaction system. 
     When coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide and the like; platinum compounds and the like. In addition, a base can be added to the reaction system, and examples thereof include inorganic bases and the like. 
     When thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent) etc.) can also be used instead of phosphorus pentasulfide. 
     When Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like. In addition, the reaction can be accelerated by subjecting a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile and the like to the reaction system reaction. 
     When halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent to be used include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. In addition, a method of producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can be employed. Alternatively, a method of producing an alkyl halide via two steps comprising converting an alcohol to the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can also be employed. 
     When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like. 
     When sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like. 
     When hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent. For acid hydrolysis reaction of tert-butyl ester, formic acid, triethylsilane and the like may be added to reductively-trap tert-butyl cation which is by-produced. 
     When dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N,N′dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like. 
     Compound (8) used in the below-mentioned Reaction Scheme 3 can be produced from compound (1) according to the method shown in the following Reaction Scheme 1. In the reaction scheme, M is a magnesium halide, or an alkali metal such as lithium and the like, and the other symbols are as defined above. 
     
       
         
         
             
             
         
       
     
     Compound (1) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     Compound (4) can be produced by subjecting compound (2) to a nucleophilic addition reaction with organic metal reagent (3). Examples of the organic metal reagent to be used include organic magnesium halides, organic lithiums and the like. Organic metal reagent (3) can be produced according to a method known per se. 
     Compound (5) can be produced, for example, by subjecting compound (4) wherein R 3  is a hydrogen atom to an oxidation reaction. 
     Compound (6) wherein R 4  is a hydrogen atom can be produced, for example, by subjecting compound (4) to a reduction reaction. 
     Compound (6) wherein R 4  is a C 1-6  alkoxy group can be produced, for example, by subjecting compound (4) to a nucleophilic substitution reaction with an electrophile in the presence of a base. Examples of the electrophile to be used include alkyl halides and the like. Examples of the base to be used include alkali metal hydrides and the like. 
     Compound (6) wherein R 3  and R 4  are both fluorine atoms can be produced, for example, by subjecting compound (5) to a fluorination reaction. Examples of the reagent to be used include fluorinating agents such as diethylaminosulfur trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride (BAST), 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA) and the like. 
     Compound (8) can be produced by subjecting compound (6) to a coupling reaction with compound (7). Compound (7) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     Compound (8) can also be produced from compound (9) according to the method shown in the following Reaction Scheme so 2. In the reaction scheme, Hal is a halogen atom, LG 1  is a leaving group, and the other symbols are as defined above. 
     
       
         
         
             
             
         
       
     
     Examples of the “leaving group” represented by LG 1  include halogen atoms, optionally halogenated C 1-6  alkylsulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), and C 6-14  arylsulfonyloxy groups optionally substituted by C 1-6  alkyl group(s) (e.g., benzenesulfonyloxy, toluenesulfonyloxy) and the like. 
     Compound (9) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     Compound (12) can be produced by subjecting compound (10) to a nucleophilic substitution reaction with compound (11). Examples of compound (11) to be used include cyclic amines (e.g., pyrrolidine, piperidine), pyrazole and the like. In addition, a base may be added to the reaction system. Examples of such base include inorganic bases, organic bases, alkali metal hydrides and the like. 
     Compound (8) can be produced by subjecting compound (13) to an amidation reaction with compound (14) or compound (15). Compound (14) and compound (15) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     Compound (Ia) and compound (Ib), which are compound (I) wherein Ring A is a piperidine ring, can be produced from compound (8) according to the method shown in the following Reaction Scheme 3. In the reaction scheme, LG 2  is a leaving group, and the other symbols are as defined above. 
     
       
         
         
             
             
         
       
     
     Examples of “leaving group” represented by LG 2  include those exemplified as the “leaving group” represented by LG 1 . 
     Compound (Ia) can be produced by subjecting compound (8) to a reduction reaction. Examples of the reducing agent to be used include catalysts such as palladium carbon, rhodium carbon, platinum carbon and the like. 
     Compound (Ib) can be produced by subjecting compound (la) to a condensation reaction with compound (16) or compound (17). The condensation reaction includes an amidation reaction, an ureation reaction, a coupling reaction and the like. Examples of compound (16) to be used include acyl halides such as acid chlorides, acid bromides, alkyl chloroformates, carbamoyl chlorides and the like, aryl halides and the like. Compound (16) and compound (17) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     Compound (Ic), which is compound (I) wherein R 2  is a hydrogen atom, and compound (I) can be produced from compound (18) according to the method shown in the following Reaction Scheme 4. In the reaction scheme, P 1  is a protecting group, LG 3 , LG 4  and LG 5  are each a leaving group, and the other symbols are as defined above. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Examples of the “protecting group” represented by P 1  include those exemplified as the above-mentioned “protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like”. 
     Examples of the “leaving group” represented by LG 3 , LG 4  or LG 5  include those exemplified as the “leaving group” represented by LG 1 . 
     Compound (18) and compound (19) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     Compound (20) can be produced by subjecting compound (18) to a nucleophilic substitution reaction with compound (19) in the presence of a base. Examples of the base to be used include alkali metal hydrides, organic lithiums and the like. Alternatively, a method via two-step reaction, i.e., a method of converting compound (18) to the corresponding enamine, and then reacting the enamine with compound (19) may be employed. 
     Examples of the amine to be used for the enamine formation include pyrrolidine, morpholine, N,N-dimethylhydrazine and the like. A base may be added to the reaction of the enamine with compound (19). Examples of such base include alkali metal hydrides, organic lithiums and the like. Moreover, in order to promote the reaction, a catalyst may be added, and examples of the catalyst to be used include tetrabutylammonium iodide and the like. 
     Compound (21) can be produced by subjecting compound (20) to a reductive amination reaction. Examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. Examples of the amine to be used include ammonia and the like. In addition, a metal catalyst may be added, and examples of the catalyst to be used include iridium catalysts and the like. Alternatively, a method via two-step reaction, i.e., a method of converting compound (20) to the corresponding oxime, and then subjecting the oxime to a reduction reaction may be employed. Examples of the amine to be used for the oxime formation include hydroxylamine, O-methylhydroxylamine and the like. Examples of the reducing agent to be used include boranes such as borane-tetrahydrofuran complex and the like, sodium borohydride and the like. Moreover, a metal catalyst may be added, and examples of the catalyst to be used include molybdenum trioxide and the like. 
     Compound (24) can be produced by subjecting compound (21) to an amidation reaction with compound (22) or compound (23). Compound (22) and compound (23) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     Compound (I) can be produced by subjecting compound (Ic) to a condensation reaction with compound (25) or compound (26). The condensation reaction includes an amidation reaction, an ureation reaction, a coupling reaction and the like. Examples of compound (25) to be used includes acyl halides such as acid chlorides, acid bromides, alkyl chloroformates, carbamoyl chlorides and the like, aryl halides and the like. Compound (25) and compound (26) may be commercially available, or can be produced according to a method known per se or a method analogous thereto. 
     In the thus-obtained compound (I), an intramolecular is functional group can also be converted to an object functional group by a combination of chemical reactions known per se. Examples of the chemical reaction include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, ureation reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like. 
     In the above-mentioned production method, when a starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in the peptide chemistry may be introduced into these groups, and the object compound can be obtained by removing the protecting group as necessary after the reaction. 
     Compound (I) obtained by the above-mentioned production method can be isolated and purified by a known means, such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. 
     When compound (I) contains optical isomer, stereoisomer, regio isomer and rotamer, these compounds are also included in compound (I), and each can be obtained as a single product by a synthesis method or a separation method known per se. For example, when an optical isomer exists in compound (I), an optical isomer resolved from the compound is also encompassed in compound (I). 
     Here, an optical isomer can be produced by a method known per se. 
     Compound (I) may be a crystal. 
     A crystal of compound (I) (hereinafter sometimes to be abbreviated as the crystal of the present invention) can be produced by crystallizing compound (I), by applying a crystallization method known per se. 
     In the present specification, the melting point means a melting point measured, for example, by micro melting point apparatus (Yanako, MP-500D or Buchi, B-545), DSC (differential scanning calorimetry analysis) apparatus (SEIKO, EXSTAR6000) and the like. 
     Generally, the melting point sometimes varies depending on the measurement device, measurement condition and the like. The crystal in the present specification may be a crystal showing a melting point different from the values described in the present specification as long as the difference is within a general error range. 
     The crystal of the present invention is superior in the physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics so (absorbability, distribution, metabolism, excretion), efficacy expression), and is extremely useful as a medicament. 
     Compound (I) may be used as a prodrug. A prodrug of the compound (I) means a compound which is converted to the compound (I) of the present invention with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to the compound (I) of the present invention with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to the compound (I) of the present invention by hydrolysis etc. due to gastric acid, etc. 
     A prodrug of compound (I) may be 
     a compound obtained by subjecting an amino group in compound (I) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in compound (I) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.);
 
a compound obtained by subjecting a hydroxy group in compound (I) to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in compound (I) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.);
 
a compound obtained by subjecting a carboxyl group in compound (I) to an esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in compound (I) to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification and methylamidation, etc.)
 
and the like. Any of these compounds can be produced from compound (I) by a method known per se.
 
     A prodrug for compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in  IYAKUHIN no KAIHATSU  (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990). 
     In the present specification, a prodrug may form a salt, and as such salt, those exemplified as a salt of the compound represented by the above-mentioned formula (I) can be mentioned. 
     Compound (I) may be labeled with an isotope (e.g.,  3 H,  13 C,  14 C,  18 F,  35 S,  125 I) and the like. 
     Compound (I) labeled with or substituted by an isotope can be used, for example, as a tracer used for Positron Emission Tomography (PET) (PET tracer), and is useful in the field of medical diagnosis and the like. 
     Furthermore, compound (I) may be a hydrate or a non-hydrate, or a non-solvate (e.g., anhydride), or a solvate (e.g., hydrate). 
     Compound (I) also encompasses a deuterium conversion form wherein  1 H is converted to  2 H(D). 
     Furthermore, compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. The cocrystal or cocrystal salt means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability). The cocrystal or cocrystal salt can be produced by a cocrystallization method known per se. 
     Compound (I) or a prodrug thereof (hereinafter sometimes to be simply abbreviated as the compound of the present invention) can be used as it is or in the form of a pharmaceutical composition (also referred to as a medicament) by mixing with a pharmacologically acceptable carrier etc. to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agent for the prophylaxis or treatment of various diseases mentioned below. 
     As pharmacologically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations; and the like; and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary. 
     Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate and magnesium alumino metasilicate. 
     Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica. 
     Preferable examples of the binder include gelatinated starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. 
     Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted hydroxypropylcellulose. 
     Preferable examples of the solvent include water for injection, physiological brine, Ringer&#39;s solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil. 
     Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate. 
     Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like, polysorbates; and polyoxyethylene hydrogenated castor oil. 
     Preferable examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose. 
     Preferable examples of the buffer include buffers of phosphate, acetate, carbonate, citrate etc. 
     Preferable examples of the soothing agent include benzyl alcohol. 
     Preferable examples of the preservative include p-oxybenzoate esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. 
     Preferable examples of the antioxidant include sulfite salts and ascorbate salts. 
     Preferable examples of the colorant include aqueous food tar colors (e.g., food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like food colors), water insoluble lake dyes (e.g., aluminum salt of the above-mentioned aqueous food tar color), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide) and the like. 
     Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia. 
     Examples of the dosage form of the above-mentioned pharmaceutical composition include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet), capsule (including soft capsule, microcapsule), pill, granule, powder, troche, syrup, liquid, emulsion, suspension, aerosol, films (e.g., orally disintegrable films, oral mucosa-adhesive film) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., transdermal absorption type preparation, ointment, lotion, adhesive preparation), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like. The compound and medicament of the present invention can be respectively safely administered orally or parenterally (e.g., intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intravaginal, intraperitoneal, intratumoral, proximal tumor administrations, and administration to the lesion). 
     These preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate-release preparation, a sustained-release preparation and the like. 
     The pharmaceutical composition can be produced according to a method conventionally used in the field of pharmaceutical formulation, for example, the method described in the Japanese Pharmacopoeia, and the like. 
     While the content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, dose of the compound of the present invention and the like, it is, for example, about 0.1 to 100 wt %. 
     When an oral preparation is produced, coating may be applied where necessary for the purpose of taste masking, enteric solubility or sustainability. 
     Examples of the coating base used for coating include sugar coating base, water-soluble film coating base, enteric film coating base, and sustained-release film coating base. 
     As the sugar coating base, sucrose is used, and one or more kinds selected from talc, and the precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be further used in combination. 
     Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone and the like; and polysaccharides such as pullulan and the like. 
     Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)] and the like; and naturally-occurring substances such as shellac and the like. 
     Examples of the sustained-release film coating base include cellulose polymers such as ethylcellulose and the like; and acrylic acid polymers such as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like. 
     Two or more kinds of the above-mentioned coating bases may be used in a mixture at an appropriate ratio. In addition, for example, light shielding agents such as titanium oxide, red ferric oxide and the like may also be used during coating. 
     Since the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and less side effects, it can be used as a prophylactic or therapeutic agent, or diagnostic agent for various diseases in mammals (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat). 
     The compound of the present invention has an excellent an orexin type 2 receptor agonist activity, and may treat, prevent or ameliorate the risk of various neurological and psychiatric diseases associated with an orexin type 2 receptor. The compound of the present invention is useful as an agent for the prophylaxis or treatment of various diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Kleine Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson&#39;s disease, progressive supranuclear paralysis, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen&#39;s encephalitis, Wernicke&#39;s encephalitis, limbic encephalitis, Hashimoto&#39;s encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypop hyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer&#39;s disease, disturbance of consciousness such as coma and the like, side effects and complications due to anesthesia, sleep disturbance, sleep problem, insomnia, Intermittent sleep, nocturnal myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of alternating worker, sleep disorder, night terror, depression, major depression, sleepwalking disease, enuresis, sleep disorder, Alzheimer&#39;s dusk, diseases associated with circadian rhythm, fibromyalgia, condition arising from decline in the quality of sleep, overeating, obsessive compulsive eating disorder, obesity-related disease, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, cardiac disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive cardiac failure, cardiac failure, coronary heart disease, cardiovascular disorder, sudden death, polycysticovarian disease, craniopharingioma, Froelich&#39;s syndrome, growth hormone deficient, normal mutant short stature, Turner&#39;s syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, declining fertility, infertility, male gonadal function decline, sexual and reproductive dysfunction such as female male hirsutism, fetal defects associated with pregnant women obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gall bladder disease, gout, kidney cancer, risk of secondary outcomes of obesity such as lowering the risk of left ventricular hypertrophy, migraine pain, headache, neuropathic pain, Parkinson&#39;s disease, psychosis, schizophrenia, facial flushing, night sweats, diseases of the genital/urinary system, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral deficit, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington&#39;s disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorders associated with muscle spasticity, delirium, amnestic disorder, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced Parkinsonism syndrome, Jill-do La Tourette&#39;s syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavior disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and traumatic brain injury. 
     Particularly, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson&#39;s disease, Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer&#39;s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness such as coma and the like, side effects and complications due to anesthesia, and the like, or anesthetic antagonist. 
     While the dose of the compound of the present invention varies depending on the subject of administration, administration route, target disease, symptom and the like, for example, when the compound of the present invention is administered orally or parenterally to an adult patient, its dose is for example, about 0.01 to 100 mg/kg body weight per dose, preferably 0.1 to 50 mg/kg body weight per dose and more preferably 0.5 to 20 mg/kg body weight per dose. This amount is desirably administered in one to 3 portions daily. 
     The compound of the present invention can be used in combination with other drugs (hereinafter to be abbreviated as concomitant drug). 
     By combining the compound of the present invention and a concomitant drug, a superior effect, for example, 
     (1) the dose can be reduced as compared to single administration of the compound of the present invention or a concomitant drug, 
     (2) the drug to be combined with the compound of the present invention can be selected according to the condition of patients (mild case, severe case and the like), 
     (3) the period of treatment can be set longer by selecting a concomitant drug having different action and mechanism from the compound of the present invention, 
     (4) a sustained treatment effect can be designed by selecting a concomitant drug having different action and mechanism from the compound of the present invention, 
     (5) a synergistic effect can be afforded by a combined use of the compound of the present invention and a concomitant drug, and the like, can be achieved. 
     In the present specification, the compound of the present invention and a concomitant drug used in combination are referred to as the “combination agent of the present invention”. 
     When using the combination agent of the present invention, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition thereof can be administered to an administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like. 
     The administration mode of the combination agent of the present invention and the concomitant drug is not particularly limited, and the compound of the present invention and the concomitant drug only need to be combined on administration. Examples of such administration mode include the following: (1) administration of a single preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like. 
     The dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations. The mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptom, combination and the like. 
     For example, the content of the compound of the present invention in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt %, preferably from about 0.1 to about 50 wt %, further preferably from about 0.5 to about 20 wt %, based on the whole preparation. 
     The content of the concomitant drug in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt %, preferably from about 0.1 to about 50 wt %, further preferably from about 0.5 to about 20 wt %, based on the whole preparation. 
     The content of additives such as a carrier and the like in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 1 to about 99.99 wt %, preferably from about 10 to about 90 wt %, based on the preparation. 
     Similar contents may be employed even when the compound of the present invention and a concomitant drug are separately formulated into preparations. 
     Examples of the concomitant drug include the followings. A therapeutic drug for narcolepsy (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drug (amphetamine, benzfetamine, bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trade mark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, Lorcaserin, metformin), acetylcholine esterase inhibitor (e.g., donepezil, rivastigmine, galanthamine, zanapezil, idebenone, tacrine), antidementia agent (e.g., memantine), inhibitor of β amyloid protein production, secretion, accumulation, aggregation and/or deposition, β secretase inhibitor (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4′-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methoxybiphenyl-4-yl)methoxytetralin, 6-(2′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, an optically active form thereof, a salt thereof and a hydrate thereof, OM99-2 (WO01/00663)), y secretase inhibitor, β amyloid protein aggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of International Patent Application No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), β amyloid vaccine, β amyloid-degrading enzyme and the like, brain function enhancer (e.g., aniracetam, nicergoline), therapeutic drug for Parkinson&#39;s disease [(e.g., dopamine receptor agonist (e.g., L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase enzyme (MAO) inhibitor (e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergic agent (e.g., trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)], therapeutic drug for amyotrophic lateral sclerosis (e.g., riluzole etc., neurotrophic factor), therapeutic drug for abnormal behavior accompanying progress of dementia, wandering and the like (e.g., sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation-regenerate promoter (e.g., leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and an optically active form, salt or hydrate thereof), non-steroidal antiinflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin etc.), steroid drug (dexamethasone, hexestrol, cortisone acetate etc.), disease-modifying anti-rheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor, MAP kinase inhibitor), therapeutic agent for incontinence, frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitor (e.g., sildenafil(citrate)), dopamine agonist (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormone or a derivative thereof (e.g., progesterone, estradiol, estradiol benzoate), therapeutic agent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drug for insomnia (e.g., benzodiazepines medicament, non-benzodiazepines medicament, melatonin agonist, orexin receptor antagonists), therapeutic drug for schizophrenia (e.g., typical antipsychotic agents such as haloperidol and the like; atypical antipsychotic agents such as clozapine, olanzapine, risperidone, aripiprazole and the like; medicament acting on metabotropic glutamate receptor or ion channel conjugated-type glutamate receptor; phosphodiesterase inhibitor), benzodiazepines medicament (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam etc.), L-type calcium channel inhibitor (pregabalin etc.), tricyclic or tetracyclic antidepressant (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate etc.), serotonin-noradrenaline reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride etc.), noradrenaline reuptake inhibitor (reboxetine mesylate etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT 1A  agonist, (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride etc.), 5-HT 2A  antagonist, 5-HT 2A  inverse agonist, 5-HT 3  antagonist (cyamemazine etc.), heart non-selective β inhibitor (propranolol hydrochloride, oxprenolol hydrochloride etc.), histamine Hi antagonist (hydroxyzine hydrochloride etc.), CRF antagonist, other antianxiety drug (meprobamate etc.), tachykinin antagonist (MK-869, saredutant etc.), medicament that acts on metabotropic glutamate receptor, CCK antagonist, β3 adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor (tiagabine hydrochloride etc.), N-type calcium channel inhibitor, carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDA antagonist (memantine etc.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin V1b antagonist, vasopressin Via antagonist, phosphodiesterase inhibitor, opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate etc.), cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHD drug (methylphenidate hydrochloride, methamphetamine hydrochloride etc.), therapeutic drug for alcoholism, therapeutic drug for autism, therapeutic drug for chronic fatigue syndrome, therapeutic drug for spasm, therapeutic drug for fibromyalgia syndrome, therapeutic drug for headache, therapeutic drug for quitting smoking, therapeutic drug for myasthenia gravis, therapeutic drug for cerebral infarction, therapeutic drug for mania, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic ataxia, therapeutic drug for male and female sexual dysfunction, therapeutic drug for migraine, therapeutic drug for pathological gambler, therapeutic drug for restless legs syndrome, therapeutic drug for substance addiction, therapeutic drug for alcohol-related syndrome, therapeutic drug for irritable bowel syndrome, therapeutic drug for lipid abnormality such as cholesterol-lowering drug (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin etc.), fibrate (clofibrate etc.), squalene synthetase inhibitor), therapeutic drug for abnormal behavior or suppressant of dromomania due to dementia (sedatives, antianxiety drug etc.), therapeutic drug for diabetes, therapeutic agent for diabetic complications, therapeutic drug for hypertension, therapeutic drug for hypotension, diuretic, chemotherapeutic agent, immunotherapeutic agent, antithrombotic agent, anti-cancer agent and the like. 
     Two or more kinds of the above-mentioned concomitant drug may be used in a mixture at an appropriate ratio. 
     When the compound of the present invention is applied to each of the above-mentioned diseases, it can also be used in combination with biologies (e.g., antibody drug, nucleic acid or nucleic acid derivative, aptamer drug, vaccine preparation), or can be used in combination with a gene therapy method and the like, or can also be used in combination with a treatment in psychiatric field without using drugs. 
     Examples of the antibody drug and vaccine preparation include vaccine preparation against angiotensin II, vaccine preparation against CETP, CETP antibody, antibody against TNFα antibody and other cytokines, amyloid β vaccine preparation, vaccine for type 1 diabetes (e.g., DIAPEP-277 of Peptor), anti-HIV antibody and HIV vaccine preparation, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin type enzymes and products thereof, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines relating to enzymes and proteins involved in blood coagulation or fibrinolysis system, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, and the like. In addition, it can be used in combination with biologies relating to growth factors such as GH, IGF and the like. 
     Examples of the gene therapy method include a treatment method using gene relating to cytokine, renin-angiotensin type enzyme and product thereof, G protein, G protein conjugated receptor and phosphorylating enzyme thereof, a treatment method using a DNA decoy such as NFκB decoy and the like, a treatment method using antisense, a treatment method using a gene relating to an enzyme or protein involved in blood lipid metabolism (e.g., a gene relating to metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipid), a treatment method using a gene relating to an enzyme or protein involved in angiogenesis therapy for peripheral vascular obstruction and the like (e.g., growth factors such as HGF, VEGF etc.), a treatment method using a gene relating to a protein involved in glucose metabolism and insulin resistance, antisense against cytokines such as TNF etc., and the like. 
     Examples of the treatment method in the psychiatric field without using drug include modified electroconvulsive therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, psychotherapy including cognitive behavioral therapy and the like. 
     The compound of the present invention can also be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, revascularization and the like, cell transplantation therapy utilizing bone marrow cells (bone marrow-derived mononuclear cell, myelogenic stem cell), or artificial organ utilizing tissue engineering (e.g., artificial blood vessel, cardiomyocyte sheet). 
     EXAMPLES 
     The present invention is explained in detail in the following by referring to Examples, Experimental Examples and Formulation Examples. However, the examples do not limit the present invention and the examples can be modified within the scope of the present invention. 
     The “room temperature” in the following Examples is generally about 10° C. to about 35° C. The ratio for mixed solvent is, unless otherwise specified, a volume mixing ratio and % means wt % unless otherwise specified. 
     The elution by column chromatography in the Examples was performed under the observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the observation by TLC, 60 F 254  manufactured by Merck was used as a TLC plate, the solvent used as an elution solvent in column chromatography was used as an eluent, and UV detector was used for the detection. In silica gel column chromatography, the indication of NH means use of aminopropylsilane-bonded silica gel and the indication of Diol means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high performance liquid chromatography), the indication of C18 means use of octadecyl-bonded silica gel. The ratio for elution solvent is, unless otherwise specified, a volume mixing ratio. 
       1 H NMR was measured by Fourier transform NMR. For the analysis of  1 H NMR, ACD/SpecManager (trade name) software and the like were used. Peaks of a hydroxyl group, an amino group and the like, having very mild proton peak, are not sometimes described. 
     MS was measured by LC/MS. As the ionization method, ESI method, or APCI method was used. The data indicates actual measured value (found). While molecular ion peak is generally observed, a fragment ion is sometimes observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed. 
     The unit of sample concentration (c) for optical rotation ([α] D ) is g/100 mL. 
     Elemental analysis value (Anal.) is described as calculated value (Calcd) and actual measured value (Found). 
     In Example, the cis/trans expression contained in compound name basically means a cis or trans mixture of two kinds of optical isomers when the corresponding partial structure contains asymmetric center (s). Exceptionally, the cis/trans expression means a single optical isomer when indicated as “optional active”. 
     Peaks by powder X-ray diffraction in the Examples mean peaks measured at room temperature by using Ultima IV (Rigaku Corporation, Japan) using Cu Kα radiation as a radiation source. The measurement conditions are as follows. 
     Electric pressure/Electric current: 40 kV/50 mA 
     Scan speed: 6 degrees/min 
     Scan range of 2 Theta: 2-35 degrees 
     The crystallinity by powder X-ray diffraction in the Examples was calculated by the Hermans method. 
     In the following Examples, the following abbreviations are used, 
     mp: melting point 
     MS: mass spectrum 
     M: mol concentration 
     N: normality 
     CDCl 3 : deuterochloroform 
     DMSO-d 6 : deuterodimethyl sulfoxide 
       1 H NMR: proton nuclear magnetic resonance 
     LC/MS: liquid chromatograph mass spectrometer 
     ESI: electronspray ionization 
     APCI: atmospheric pressure chemical ionization 
     Pd 2  (dba) 3 : tris(dibenzylideneacetone)dipalladium(O) 
     TFA: trifluoroacetic acid 
     DIPEA: N-ethyl-N-isopropylpropan-2-amine 
     DMF: N,N-dimethylformamide 
     THF: tetrahydrofuran 
     CH 3 CN: acetonitrile 
     DME: 1,2-dimethoxyethane 
     MeOH: methanol 
     EtOH: ethanol 
     t-AmOH: 2-methyl-2-butanol 
     Pd(PPh 3 ) 4 : palladium-triphenylphosphine (1:4) 
     tBuXphos: 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl 
     XPhos Pd G3: (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate 
     PPh 3 : triphenylphosphine 
     AcOH: acetic acid 
     TBAI: tetrabutylammonium iodide 
     TEA: triethylamine 
     (A-taPhos) 2 PdCl 2 : 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) 
     T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide 
     HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 
     CPME: cyclopentyl methyl ether 
     Example 1 
     Methyl {cis-1-(cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}carbamate 
     A) tert-butyl 2-[(3-bromophenyl)methyl]-3-oxopyrrolidine-1-carboxylate 
     To a mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (5.4 g) and toluene (50.0 ml) was added pyrrolidine (2.49 g) at room temperature. After 15 min, the reaction mixture was concentrated. The residue was mixed with CH 3 CN (50 ml), and 1-bromo-3-(bromomethyl)benzene (7.29 g) and TBAI (2.15 g) were added thereto. The mixture was heated with reflux for 1 hr, and the reaction mixture was diluted with water, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.00 g). 
     MS, found: 254.2. 
     B) tert-butyl cis-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate 
     To a mixture of tert-butyl 2-[(3-bromophenyl)methyl]-3-oxopyrrolidine-1-carboxylate (1.54 g), ammonium formate (1.37 g) and MeOH (25 ml) was added chloro[N-[4-(dimethylamino)phenyl]-2-pyridine carboxamidato](pentamethylcyclopentadienyl)iridium(III) (0.026 g) at room temperature. The mixture was stirred under nitrogen atmosphere at 70° C. for 2 hr. The mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution at 0° C., and concentrated under reduced pressure. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate) to give the title compound (565 mg). 
     MS, found: 299.2. 
     C) tert-butyl cis-3-{[(benzyloxy)carbonyl]amino}-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate 
     To a mixture of tert-butyl cis-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate (10.4 g), 2M sodium hydroxide aqueous solution (19 ml) and DME (100 ml) was added benzyl carbonochloridate (5.98 g) at 0° C. The mixture was stirred at room temperature for 30 min. To the mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the obtained residue (14.2 g), (3-fluorophenyl)boronic acid (4.90 g), (A-taPhos) 2 PdCl 2  (0.500 g), cesium carbonate (12.0 g), DME (200 ml) and water (50 ml) was stirred overnight under nitrogen atmosphere at 80° C. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.6 g). 
     MS: [M+H-Boc] +  405.3. 
     D) Benzyl {cis-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}carbamate Hydrochloride 
     To a mixture of tert-butyl cis-3-{[(benzyloxy)carbonyl]amino}-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate (12.6 g) and CPME (40 ml) was added 4M hydrogen chloride/CPME solution (40 ml) at room temperature. The mixture was stirred overnight under nitrogen atmosphere at room temperature, and concentrated under reduced pressure. The residue was washed with diethyl ether, and dried under nitrogen atmosphere to give the title compound (9.18 g). 
     MS: [M+H] +  405.3. 
     E) Benzyl {cis-1-(cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}carbamate 
     To a mixture of benzyl {cis-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}carbamate hydrochloride (4.0 g), cyclobutanecarboxylic acid (1.49 g), DIPEA (3.83 g) and ethyl acetate (40 ml) was added 1.7M T3P ethyl acetate solution (12 ml) at room temperature. The mixture was stirred under nitrogen atmosphere at 60° C. for 2 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.49 g). 
     MS: [M+H] +  487.4. 
     F) {cis-3-amino-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-1-yl}(cyclobutyl)methanone 
     A mixture of benzyl {cis-1-(cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}carbamate (4.49 g), 10% palladium on carbon (0.49 g), EtOH (70 ml) and THF (50 ml) was stirred under normal pressure of hydrogen atmosphere at room temperature for 1 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate) to give the title compound (3.20 g). 
     MS: [M+H] +  353.3. 
     G) Methyl {cis-1-(cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}carbamate 
     To a mixture of {cis-3-amino-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-1-yl}(cyclobutyl) methanone (50.0 mg), TEA (43.6 mg) and THF (2.0 ml) was added methyl carbonochloridate (36.9 mg) at room temperature. The mixture was stirred at room temperature for 1 hr, and purified by silica gel column chromatography (ethyl acetate/hexane, and NH, w ethyl acetate/hexane) to give the title compound (33.3 mg). 
       1 H NMR (300 MHz, CDCl 3 ) δ 1.36-2.46 (7H, m), 2.51-2.69 (1H, m), 2.81-2.97 (1H, m), 3.05-3.80 (7H, m), 4.05-4.45 (1H, m), 4.57-4.88 (2H, m), 6.96-7.49 (8H, m). 
     Example 30 
     N ˜ 2-{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide 
     A) tert-butyl (2S,3S)-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate 
     A racemate of tert-butyl cis-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate (1.5 g) was resolved by HPLC (column: CHIRALPAK AD(AK001), 50 mmID×500 mmL, Manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol/diethylamine=850/150/1) to give the title compound (650 mg) having a shorter retention time. 
     MS, found: 299.0. 
     B) tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[2-(dimethylamino)(oxo)acetamido]pyrrolidine-1-carboxylate 
     To a mixture of tert-butyl (2S,3S)-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate (1.00 g), (dimethylamino) (oxo)acetic acid (0.429 g), DIPEA (0.728 g) and DMF (18 ml) was added HATU (1.61 g) at room temperature. The mixture was stirred at room temperature for 15 hr. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.20 g). 
     MS: [M+H−Boc] +  354.0. 
     C) tert-butyl (2S,3S)-3-[2-(dimethylamino)(oxo)acetamido]-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate 
     A mixture of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[2-(dimethylamino)(oxo)acetamido]pyrrolidine-1-carboxylate (1.20 g), (3-fluorophenyl)boronic acid (0.739 g), XPhos Pd G3 (0.112 g), 1M aqueous tripotassium phosphate solution (7.92 ml) and THF (26 ml) was stirred under argon atmosphere at 70° C. for 1 hr. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.31 g). 
     MS: [M+H−Boc] +  370.1. 
     D) N ˜ 2 ˜ -{(2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl) methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide 
     To a mixture of tert-butyl (2S,3S)-3-[2-(dimethylamino)(oxo)acetamido]-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate (1.30 g) and toluene (14 ml) was added TFA (14 ml) at room temperature. The mixture was stirred at room temperature for 1 hr. The mixture was carefully poured into ice-cooled saturated aqueous sodium hydrogencarbonate solution, and adjusted to pH=8 with potassium carbonate, and extracted with ethyl acetate-THF (3:1). The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/ethyl acetate) to give the title compound (797 mg). 
     MS: [M+H] +  370.1. 
     E) (2S,3S)-3-[2-(dimethylamino)(oxo)acetamido]-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidine-1-carbonyl Chloride 
     To a mixture of N ˜ 2 ˜ -{(2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide (73 mg), DIPEA (51.1 mg) and THF (1.8 ml) was added bis(trichloromethyl) carbonate (46.9 mg) at 0° C. The mixture was stirred at 0° C. for 10 min, and then at room temperature for 10 min. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (83 mg). 
     MS: [M−H] −  430.0. 
     F) N ˜ 2 ˜ -{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide 
     To a mixture of (2S,3S)-3-[2-(dimethylamino)(oxo)acetamido]-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidine-1-carbonyl chloride (78 mg) and THF (1.6 ml) was added azetidine (61.9 mg) at room temperature. The mixture was stirred at 55° C. for 30 min. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate-THF (3:1). The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate), and the obtained solid was washed with diisopropyl ether-hexane to give the title compound (54.1 mg).  1 H NMR (300 MHz, CDCl 3 ) δ 1.69-1.82 (1H, m), 1.98-2.11 (1H, m), 2.23 (2H, quin, J=7.7 Hz), 2.74 (1H, dd, J=14.0, 9.1 Hz), 2.96 (3H, s), 3.23-3.31 (4H, m), 3.37 (2H, t, J=7.4 Hz), 3.91 (2H, q, J=8.0 Hz), 4.09 (2H, q, J=8.0 Hz), 4.27-4.38 (1H, m), 4.43-4.51 (1H, m), 7.01 (1H, dtd, J=8.9, 4.4, 2.5 Hz), 7.28-7.44 (7H, m), 7.69 (1H, d, J=8.3 Hz). 
     Example 31 
     (2S)—N-{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl) methyl]pyrrolidin-3-yl}oxolane-2-carboxamide 
     A) tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-{[(2S)-oxolane-2-carbonyl]amino}pyrrolidine-1-carboxylate 
     To a mixture of tert-butyl (2S,3S)-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate (1.00 g), (2S)-tetrahydrofuran-2-carboxylic acid (0.425 g), DIPEA (0.728 g) and DMF (18 ml) was added HATU (1.61 g) at room temperature. The mixture was stirred at room temperature for 15 hr. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.20 g). 
     MS: [M+H−Boc] +  353.0. 
     B) tert-butyl (2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-3-{[(2S)-oxolane-2-carbonyl]amino}pyrrolidine-1-carboxylate 
     A mixture of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-{[(2S)-oxolane-2-carbonyl]amino}pyrrolidine-1-carboxylate (1.19 g), (3-fluorophenyl)boronic acid (0.735 g), XPhos Pd G3 (0.111 g), 1M aqueous tripotassium phosphate solution (7.87 ml) and THF (26 ml) was stirred under argon atmosphere at 70° C. for 1 hr. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.22 g). 
     MS: [M+H−Boc] + 369.1. 
     C) (2S)—N-{(2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide 
     To a mixture of tert-butyl (2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-3-{[(2S)-oxolane-2-carbonyl]amino}pyrrolidine-1-carboxylate (1.22 g) and toluene (13 ml) was added TFA (13 ml) at room temperature. The mixture was stirred at room temperature for 1 hr. The mixture was carefully poured into saturated aqueous sodium hydrogencarbonate solution under ice-cooling, adjusted to pH=8 with potassium carbonate, and extracted with ethyl acetate-THF (3:1). The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/ethyl acetate) to give the title compound (849 mg). 
     MS: [M+H] +  369.1. 
     D) (2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-3-{[(2S)-oxolane-2-carbonyl]amino}pyrrolidine-1-carbonyl Chloride 
     To a mixture of (2S)—N-{(2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide (82 mg), DIPEA (57.5 mg) and THF (2 ml) was added bis(trichloromethyl) carbonate (52.8 mg) at 0° C. The mixture was stirred at 0° C. for 10 min, and then at room temperature for 10 min. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (88 mg). 
     MS: [M−H] −  429.0. 
     E) (2S)—N-{(2S,3S)-1-(azetidine-1-carbonyl)-2-[(3′-fluoro [1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide 
     To a mixture of (2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]-3-{[(2S)-oxolane-2-carbonyl]amino}pyrrolidine-1-carbonyl chloride (80 mg) and THF (1.6 ml) was added azetidine (63.6 mg) at room temperature. The mixture was stirred at 55° C. for 30 min. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate-THF (3:1). The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate), and the obtained solid was collected by filtration, and washed with diisopropyl ether-hexane to give the title compound (60.9 mg). 
       1 H NMR (300 MHz, CDCl 3 ) δ 1.46-1.60 (1H, m), 1.76-2.07 (4H, m), 2.15-2.31 (3H, m), 2.89 (1H, dd, J=13.8, 8.2 Hz), 3.07 (1H, dd, J=13.8, 3.8 Hz), 3.29-3.36 (2H, m), 3.77-3.88 (2H, m), 3.92 (2H, q, J=7.8 Hz), 4.08 (2H, q, J=7.6 Hz), 4.18 (1H, dd, J=8.1, 6.2 Hz), 4.34-4.54 (2H, m), 6.88 (1H, d, J=8.3 Hz), 6.98-7.06 (1H, m), 7.27-7.44 (6H, m), 7.48 (1H, s). 
     Example 32 
     N ˜ 2 ˜ -{(2S,3S)-1-(cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide 
     To a mixture of N ˜ 2 ˜ -{(2S,3S)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N ˜ 1 ˜ ,N ˜ 1 ˜ -dimethylethanediamide (60 mg), TEA (49.3 mg) and THF (1.4 ml) was added cyclobutanecarbonyl chloride (38.5 mg) at room temperature. The mixture was stirred at room temperature for 1 hr. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate-THF (3:1). The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate) to give the title compound (67.2 mg). 
       1 H NMR (300 MHz, CDCl 3 ) δ 1.49-1.60 (1H, m), 1.72-2.04 (3H, m), 2.06-2.43 (5H, m), 2.57-2.75 (1H, m), 2.81-2.99 (4H, m), 3.06-3.75 (6H, m), 4.27-4.75 (2H, m), 6.97-7.19 (1H, m), 7.28-7.47 (6H, m), 7.64-7.72 (1H, m). 
     Example 33 
     (2S)—N-{(2S,3S)-1-(cyclobutanecarbonyl)-2-[(3′-fluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide 
     To a mixture of (2S)—N-{(2S,3S)-2-[(3′-fluoro [1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}oxolane-2-carboxamide (65 mg), TEA (53.6 mg) and THF (1.6 ml) was added cyclobutanecarbonyl chloride (41.8 mg) at room temperature. The mixture was stirred at room temperature for 1 hr. The mixture was poured into aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate-THF (3:1). The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/ethyl acetate), and the obtained solid was collected by filtration, and washed with diisopropyl ether-hexane to give the title compound (64.2 mg). 
       1 H NMR (300 MHz, CDCl 3 ) δ1.45-1.60 (1H, m), 1.73-2.46 (11H, m), 2.58-3.94 (7H, m), 4.01-4.22 (1H, m), 4.31-4.74 (2H, m), 6.77-6.89 (1H, m), 6.99-7.16 (1H, m), 7.27-7.50 (7H, m). 
     The compounds of Examples are shown in the following tables. MS in the tables means actual measured value. The compounds of Examples 2 to 29 and 34 to 46 in the following tables were produced according to the methods described in the above-mentioned Examples, or methods analogous thereto. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-1 
               
               
                   
               
               
                 EXAMPLE 
                 IUPACNAME 
                 Structure 
                 ADDITIVE 
                 MS 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 methyl{cis-1- (cyclobutanecarbonyl)-2-[(3′- fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}carbamate 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 411.3 
               
               
                   
               
               
                 2 
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fIuoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-2- methoxyacetamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 425.3 
               
               
                   
               
               
                 3 
                 1-cyano-N-{cis-1- (cyclobutanecarbonyl)-2-[(3′- fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3- yl}cyclopropane-1-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 446.2 
               
               
                   
               
               
                 4 
                 N ~ 2 ~ -{cis-1-(cyclobutanecarbonyl)- 2-[(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 452.2 
               
               
                   
               
               
                 5 
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}oxolane-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 451.3 
               
               
                   
               
               
                 6 
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-2- hydroxyacetamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 411.3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-2 
               
               
                   
               
               
                 EXAMPLE  
                 IUPACNAME  
                 Structure  
                 ADDITIVE  
                 MS 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 7  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-2,2- difluoroacetamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 429.2  
               
               
                   
               
               
                 8  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro [1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-2,2- difluoropropanamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 443.2  
               
               
                   
               
               
                 9  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-2- fluoropropanamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 427.3  
               
               
                   
               
               
                 10  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-1- fluorocyclobutane-1-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 453.3  
               
               
                   
               
               
                 11  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-1- methoxycyclopropane-1- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 451.2  
               
               
                   
               
               
                 12  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-2- methoxy-2-methylpropanamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 453.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-3 
               
               
                   
               
               
                 EXAMPLE  
                 IUPACNAME  
                 Structure  
                 ADDITIVE  
                 MS 
               
               
                   
               
             
            
               
                 13  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}oxetane-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 437.1  
               
               
                   
               
               
                 14  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-1- fluorocyclopropane-1-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 439.4  
               
               
                   
               
               
                 15  
                 N-{cis-1-(cyclobutanecarbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-1- hydroxycyclopropane-1-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 437.4  
               
               
                   
               
               
                 16  
                 (2S)-N-{cis-1- (cyclobutanecarbonyl)-2-[(3′- fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}oxolane-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 451.4  
               
               
                   
               
               
                 17  
                 N ~ 2 ~ -[(2S,3S)-1-(azetidine-1- carbonyl)-2-{[6-(3- fluorophenyl)pyridin-2- yl]methyl)pyrrolidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 454.2  
               
               
                   
               
               
                 18  
                 N ~ 2 ~ -[(2S,3S)-1- (cyclobutanecarbonyl)-2-{[6-(3- fluorophenyl)pyridin-2- yl]methyl)pyrrolidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 453.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-4 
               
               
                   
               
               
                 EXAMPLE  
                 IUPACNAME  
                 Structure  
                 ADDITIVE  
                 MS 
               
               
                   
               
             
            
               
                 19  
                 N ~ 2 ~ -[(2S,3S)-1-(azetidine-1- carbonyl)-2-{[2-(3-fluorophenyl)- 1,3-thiazol-4-yl]methyl}pyrrolidin-3- yl]-N ~ 1,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 460.2  
               
               
                   
               
               
                 20  
                 N ~ 2 ~ -[(2S,3S)-1- (cyclobutanecarbonyl)-2-{[2-(3- fluorophenyl)-1,3-thiazol-4- yl]methyl}pyrrolidin-3-yl]-N ~ 1,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 459.1  
               
               
                   
               
               
                 21  
                 (2S)-N-[(2S,3S)-1-(azetidine-1- carbonyl)-2-{[6-(3- fluorophenyl)pyridin-2- yl]methyl]pyrrolidin-3-yl]oxolane-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 453.2  
               
               
                   
               
               
                 22  
                 (2S)-N-[(2S,3S)-1- (cyclobutanecarbonyl)-2-{[6-(3- fluorophenyl)pyridin-2- yl]methyl}pyrrolidin-3-yl]oxolane-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 452.2  
               
               
                   
               
               
                 23  
                 (2S)-N-[(2S,3S)-1-(azetidine-1- carbonyl)-2-{[2-(3-fluorophenyl)- 1,3-thiazol-4-yl]methyl}pyrrolidin-3- yl]oxolane-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 459.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-5 
               
               
                   
               
               
                 EXAMPLE  
                 IUPACNAME  
                 Structure  
                 ADDITIVE  
                 MS 
               
               
                   
               
             
            
               
                 24  
                 (2S)-N-[(2S,3S)-1- (cyclobutanecarbonyl)-2-{[2-(3- fluorophenyl)-1,3-thiazol-4- yl]methyl}pyrrolidin-3-yl]oxolane-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 458.2  
               
               
                   
               
               
                 25  
                 N-[(2S,3S)-1-(azetidine-1- carbonyl)-2-([6-(3- fluorophenyl)pyridin-2- yl]methyl]pyrrolidin-3-yl]-1- methoxycyclopropane-1- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 453.4  
               
               
                   
               
               
                 26  
                 N-[(2S,3S)-1-(azetidine-1- carbonyl)-2-{[2-(3-fluorophenyl)- 1,3-thiazol-4-yl]methyl}pyrrolidin-3- yl]-1-methoxycyclopropane-1- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 459.2  
               
               
                   
               
               
                 27  
                 N-[(2S,3S)-1- (cyclobutanecarbonyl)-2-{[2-(3- fluorophenyl)-1,3-thiazol-4- yl]methyl}pyrrolidin-3-yl]-1- methoxycyclopropane-1- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 458.3  
               
               
                   
               
               
                 28  
                 N ~ 2 ~ -{cis-1-(azetidine-1-carbonyl)- 2-[(3′-fluoro[1,1′-bipheny]-3- yl)methyl]piperidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 467.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-6 
               
               
                   
               
               
                 EXAMPLE  
                 IUPACNAME  
                 Structure  
                 ADDITIVE  
                 MS 
               
               
                   
               
             
            
               
                 29  
                 N ~ 2 ~ -{cis-1-(cyclobutanecarbonyl)- 2-[(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]piperidin-3-yl}-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 466.2  
               
               
                   
               
               
                 30  
                 N ~ 2 ~ -{(2S,3S)-1-(azetidine-1- carbonyl)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]pyrrolidin-3- yl}-N ~ 1 ~ ,N ~ 1 ~ -dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 453.2  
               
               
                   
               
               
                 31  
                 (2S)-N-{(2S,3S)-1-(azetidine-1- carbonyl)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]pyrrolidin-3- yl}oxolane-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 452.2  
               
               
                   
               
               
                 32  
                 N ~ 2 ~ -{(2S,3S)-1- (cyclobutanecarbonyl)-2-[(3′- fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 450.2  
               
               
                   
               
               
                 33  
                 (2S)-N-{(2S,3S)-1- (cyclobutanecarbonyl)-2-[(3′- fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}oxolane-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 449.3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-7 
               
               
                   
               
               
                 EXAMPLE  
                 IUPACNAME  
                 Structure  
                 ADDITIVE  
                 MS 
               
               
                   
               
             
            
               
                 34  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-[1- (trifluoromethyl)cyclobutane-1- carbonyl]pyrrolidin-3-yl}-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 520.3  
               
               
                   
               
               
                 35  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(1- fluorocyclobutane-1- carbonyl)pyrrolidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 470.3  
               
               
                   
               
               
                 36  
                 N ~ 2 ~ -((2S,3S)-1-(1- cyanocyclobutane-1-carbonyl)-2- [(3′-flluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 477.3  
               
               
                   
               
               
                 37  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(1- hydroxycyclobutane-1- carbonyl)pyrrolidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 468.3  
               
               
                   
               
               
                 38  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(1- methoxycyclobutane-1- carbonyl)pyrrolidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 482.3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-8 
               
               
                   
               
               
                 EXAMPLE  
                 IUPACNAME  
                 Structure  
                 ADDITIVE  
                 MS 
               
               
                   
               
             
            
               
                 39  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(1- methoxycyclopropane-1- carbonyl)pyrrolidin-3-yl]-N ~ 1 ~ ,N ~ 1 ~ - dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 468.3  
               
               
                   
               
               
                 40  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(3- hydroxy-2,2- dimethylpropanoyl)pyrrolidin-3-yl]- N ~ 1 ~ ,N ~ 1 ~ -dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 470.3  
               
               
                   
               
               
                 41  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(2- methoxy-2- methylpropanoyl)pyrrolidin-3-yl]- N ~ 1 ~ ,N ~ 1 ~ -dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 470.3  
               
               
                   
               
               
                 42  
                 N ~ 2 ~ -[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-[(2R)- oxolane-2-carbonyl]pyrrolidin-3-yl]- N ~ 1 ~ ,N ~ 1 ~ -dimethylethanediamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 468.3  
               
               
                   
               
               
                 43  
                 (2S)-N-[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(1- fluorocyclobutane-1- carbonyl)pyrrolidin-3-yl]oxolane-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 469.3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1-9 
               
               
                   
               
               
                 EXAMPLE 
                 IUPACNAME 
                 Structure 
                 ADDITIVE 
                 MS 
               
               
                   
               
             
            
               
                 44 
                 (2S)-N-{(2S,3S)-1-(1- cyanocyclobutane-1-carbonyl)-2- [(3′-fluoro[1,1′-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}oxolane-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 476.3 
               
               
                   
               
               
                 45 
                 (2S)-N-[(2S,3S)-2-[(3′-fluoro[1,1′- bipheny]-3-yl)methyl-1-(1- hydroxycyclobutane-1- carbonyl)pyrrolidin-3-yl]oxolane-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 467.3 
               
               
                   
               
               
                 46 
                 (2S)-N-[(2S,3S)-2-[(3′-fluoro[1,1′- biphenyl]-3-yl)methyl]-1-(3- hydroxy-2,2- dimethylpropanoyl)pyrrolidin-3- yl]oxolane-2-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 469.3 
               
               
                   
               
            
           
         
       
     
     Experimental Example 1: Obtainment of Cell Stably Expressing Human Orexin Type 2 Receptor (hOX2R) 
     To obtain a cell clone stably expressing human orexin type 2 receptor, human orexin type 2 receptor cDNA was inserted into pcDNA3.1(+) plasmid vector (Invitrogen), and a plasmid DNA for expression of human orexin type 2 receptor (pcDNA3.1(+)/hOX2R) was cloned. The plasmid DNA was introduced into CHO-dhfr cell by an electroporation method, and human orexin type 2 receptor expressing clone cells were obtained by limiting dilution method by using G418 drug resistance as a selection marker. 
     Experimental Example 2: Measurement of Orexin Type 2 Receptor Agonist Activity 
     CHO cells forcibly expressing human OX2 receptor were seeded in each well of 384 well black transparent bottom plate (BD Falcon) at 7,500 cells/well, and cultured for one day in a 5% CO 2  incubator at 37° C. After removal of the medium in the cell plate, assay buffer A containing a calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Wako Pure Chemical Industries, Ltd. or Sigma-Aldrich), 2.5 μg/mL Fluo-4 AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical), 1.25 mM probenecid (DOJINDO Chemical)) was added at 30 μL/well. The plate was stood for 30 min in a 5% CO 2  incubator at 37° C., and further stood at room temperature for 30 min. A test compound prepared by diluting with assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) was added at 10 μL/well, and the fluorescence value was measured by FDSSμCELL (Hamamatsu Photonics K.K.) every one sec for 1 min, and thereafter every two sec for 1 min 40 sec. The activity (%) of the test compound was calculated assuming that variation in the fluorescence value when DMSO was added instead of the test compound was 0%, and variation in the fluorescence value when orexin A (human) (PEPTIDE INSTITUTE, INC.) was added at the final concentration of 10 nM was 100%. The activity of each compound at the concentration of 3 μM was shown below. As is clear from the results, the compound of the present invention was shown to have an agonist activity on human orexin type 2 receptor. 
     
       
         
           
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                 OX2R agonist activity 
               
               
                   
                 Example No. 
                 (3 μM, %) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 1 
                 33 
               
               
                   
                 4 
                 95 
               
               
                   
                 5 
                 92 
               
               
                   
                 6 
                 60 
               
               
                   
                 8 
                 66 
               
               
                   
                 10 
                 79 
               
               
                   
                 11 
                 93 
               
               
                   
                 16 
                 90 
               
               
                   
                 19 
                 89 
               
               
                   
                 20 
                 82 
               
               
                   
                 21 
                 59 
               
               
                   
                 23 
                 76 
               
               
                   
                 24 
                 65 
               
               
                   
                 25 
                 54 
               
               
                   
                 26 
                 67 
               
               
                   
                 27 
                 60 
               
               
                   
                 29 
                 80 
               
               
                   
                 30 
                 101 
               
               
                   
                 31 
                 104 
               
               
                   
                 32 
                 103 
               
               
                   
                 33 
                 97 
               
               
                   
                 35 
                 75 
               
               
                   
                 36 
                 86 
               
               
                   
                 37 
                 101 
               
               
                   
                 40 
                 79 
               
               
                   
                 43 
                 62 
               
               
                   
                 45 
                 86 
               
               
                   
                 46 
                 67 
               
               
                   
               
            
           
         
       
     
     Formulation Example 1 (Production of Capsule) 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                   
                 1) compound of Example 1 
                 30 mg 
               
               
                   
                 2) crystalline cellulose 
                 10 mg 
               
               
                   
                 3) lactose 
                 19 mg 
               
               
                   
                 4) magnesium stearate 
                  1 mg 
               
               
                   
                 total 
                 60 mg 
               
               
                   
               
            
           
         
       
     
     1), 2), 3) and 4) are mixed and filled in a gelatin capsule. 
     Formulation Example 2 (Production of Tablet) 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                   
                 1) compound of Example 1 
                 30 g 
               
               
                   
                 2) lactose 
                 50 g 
               
               
                   
                 3) cornstarch 
                 15 g 
               
               
                   
                 4) calcium carboxymethylcellulose 
                 44 g 
               
               
                   
                 5) magnesium stearate 
                  1 g 
               
               
                   
                 1000 tablets 
                 140 g in total 
               
               
                   
               
            
           
         
       
     
     The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is punched by a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained. 
     INDUSTRIAL APPLICABILITY 
     The compound of the present invention has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy. 
     This application is based on patent application No. 2018-125334 filed on Jun. 29, 2018 in Japan, the contents of which are encompassed in full herein.