Cyclic amine derivatives having serotonin receptor binding activity

Abstract

The present invention provides compounds that have a serotonin 5-HT2A receptor antagonist and / or inverse agonist activity, and pharmaceutically acceptable salts thereof, and also provides a serotonin 5-HT2A receptor antagonist and / or inverse agonist composition that contains such a compound or salt. Provided are compounds represented by formula (I): (in the formula, R1 is a substituted or unsubstituted aromatic heterocyclic group, etc.; each R2 is independently a hydrogen atom, etc.; each R3 is independently a hydrogen atom, etc.; n is 1, etc.; the combination of (L1, L2) is (NH,N), etc.; R4 is a group represented by the formula (AAA): (in the formula, p and q are each independently 2, etc., Ra is substituted or unsubstituted alkyl, etc., each Xb is independently CRbRb', each Rb is independently a hydrogen atom, etc., each Rb' is independently a hydrogen atom, etc., each Xc is independently CRcRc', each Rc is independently a hydrogen atom, etc., each Rc' is independently a hydrogen atom, etc., Xd is CRd, etc., and Rd is a hydrogen atom, etc.); R5 and R6 are each independently a hydrogen atom, etc.; and R7 is a group represented by formula (BBB): (in the formula, A is CR11, etc., R9 is substituted or unsubstituted alkyloxy, etc., R10 is a hydrogen atom, etc., and each R11 is independently a hydrogen atom, etc.)), and pharmaceutically acceptable salts thereof.

Description

Cyclic amine derivatives with serotonin receptor binding activity

[0001] The present invention relates to a compound or a pharmaceutically acceptable salt thereof which has serotonin 5-HT2A receptor antagonistic and / or inverse agonist activity and is useful in the treatment and / or prevention of diseases caused by the serotonin 5-HT2A receptor, and to a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0002] Neurodegenerative disorders (NDs) are a group of related human diseases that share a common pathophysiological feature: the progressive degeneration of selective neuronal populations over time. These neurodegenerative disorders include, but are not limited to, Alzheimer's disease and related dementias, Parkinson's disease, Huntington's disease, Lewy body disease and related movement disorders. Each of these disorders has unique clinical aspects, including age of onset, time course of progression, neurological signs and symptoms, neuropsychiatric symptoms, and sensitivity to known therapeutic agents. Furthermore, the pathophysiological basis of each of these disorders is caused by genetic mechanisms unique to each disorder (Non-Patent Document 1).

[0003] Despite considerable progress in understanding the genetic causes underlying these disparate disorders, relatively little is known about the biochemical mechanisms underlying the selective neuronal degeneration common to all of them. Furthermore, while genetic factors that cause rare familial forms of the most common of these disorders, including Parkinson's disease and Alzheimer's disease, have been identified, the pathophysiological basis of the majority of sporadic cases remains unknown. Consequently, there are currently no specific therapeutic agents that can directly alter disease progression. Instead, clinicians rely on a variety of existing medications to achieve symptomatic relief of the motor, cognitive, and neuropsychiatric manifestations that characterize these disorders (Non-Patent Documents 2, 3).

[0004] Among the various neurological symptoms that characterize ND, the occurrence of motor abnormalities, including bradykinesia, dyskinesia, and chorea, as well as neuropsychiatric symptoms, including psychosis and emotional symptoms such as anxiety and depression, are common symptoms and seriously affect the functional status and quality of life of patients (Non-Patent Documents 4, 5). Most existing treatments, including antipsychotics and antidepressants, are often effective in these patients, but are significantly poorly tolerated (Non-Patent Document 6). Furthermore, available Parkinson's disease treatments, including L-dopa and dopamine agonists, are generally effective, but cause severe treatment-limiting side effects that cannot currently be addressed by pharmacological therapy.

[0005] For a long time, there were no approved drugs specifically for ND, but in 2016, the 5-HT2A receptor inverse agonist pimavanserin was approved in the United States for the first time for the treatment of hallucinations and delusions associated with Parkinson's disease (Non-Patent Document 7). Unlike existing antipsychotics, this drug has not been reported to cause side effects such as worsening of motor symptoms or impaired cognitive function. Pimavanserin's primary pharmacological action is serotonin 5-HT2A receptor inverse agonism / antagonism, but it also possesses serotonin 5-HT2C receptor inverse agonism (Non-Patent Document 8). The results of 5-HT2A occupancy measured in a PET study of pimavanserin in humans and the results of clinical trials of pimavanserin suggest that pimavanserin exerts its therapeutic effects via 5-HT2A and 2C receptors (Non-Patent Document 9). Furthermore, pimavanserin has significant adverse effects on the cardiovascular system, limiting its use.

[0006] These findings highlight the need to develop novel therapeutic agents specifically designed to be not only effective against these specific disabling conditions, but also well-tolerated in these specific patient populations. This can be achieved by improving the selectivity of drug-target interactions of new therapeutic agents, specifically by having potent activity and selectivity for the target 5-HT2A, preferably 5-HT2A and 2C, and reducing adverse cardiovascular effects.

[0007] Compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity are described in Patent Documents 3 to 14 and 16 to 22, but none of these documents describe or suggest compounds related to the present invention. ３ Although Patent Document 15 discloses quinuclidine derivatives having receptor inhibitory activity, it does not describe serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and therapeutic effect against hallucinations and delusions, nor does it describe or suggest compounds related to the present invention.

[0008] International Publication No. WO 2018 / 131672, U.S. Patent No. 8,377,959, International Publication No. WO 2001 / 066521, International Publication No. WO 2004 / 064738, International Publication No. WO 2019 / 040104, International Publication No. WO 2019 / 040105, International Publication No. WO 2019 / 040106, International Publication No. WO 2019 / 040107, International Publication No. WO 2010 / 111353, International Publication No. WO 2004 / 000808, International Publication No. WO 2003 / 057698, Chinese Patent Application Publication No. 1091 International Publication No. 11385 International Publication No. 2009 / 039461 International Publication No. 2007 / 124136 International Publication No. 2004 / 000840 International Publication No. 2021 / 147818 International Publication No. 2021 / 147909 Chinese Patent Application Publication No. 109111385 Chinese Patent Application Publication No. 113214141 Chinese Patent Application Publication No. 113214231 Chinese Patent Application Publication No. 113214289 International Publication No. 2021 / 218863

[0009] Nature Reviews Neurology volume 10, pages 620-633 (2014) Progress in Neurology and Psychiatry I Vol. 22 Iss. 1 2018 Movement Disorders Vol. 24, No. 11, 2009, pp. 1641-1649Parkisonism and related disorder 155.200 9. S 105-110 Neurology. 2004; 63 (2): 293-300. JAMA Neurol. 2016; 73 (5): 535-541. Lancet; 383: 533-40 (2014) Journal of Pharmacology and Experimental Therapeutics May 2006, 317 (2) 910-918CNS Spectrams (2016), 21, 271-275

[0010] An object of the present invention is to provide novel compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity. Preferably, the present invention provides novel compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity, and thereby having an effect on diseases involving serotonin, including hallucinations and delusions associated with Parkinson's disease and / or dementia, and pharmaceuticals containing the same.

[0011] The present invention relates to the following items (1) to (31), (1') to (20'), and (26') to (31'): (1) Formula (I): (In the formula, R １ is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ３ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; n is 0, 1, or 2; (L 1 , L２ ) combination is (NR Ｌ１ , N), (CR Ｌ１ R Ｌ１’ , N), (O, N), (O, CR Ｌ２ ) or (NR Ｌ１ , C.R. Ｌ２ ) and R Ｌ１ , R Ｌ１’ and R Ｌ２ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ４ is the formula: wherein p and q are each independently 1, 2, or 3; p″ and q″ are each independently 1 or 2; R ａ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; R ａ’’ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; X ｂ are each independently, CR ｂ R ｂ’ and X ｃ are each independently, CR ｃ R ｃ’ and R ｂ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｂ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｂ’’ is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ｃ’’is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; X ｄ is CR ｄ or N; X ｄ’’ is CR ｄ or N; R ｄ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl; R ｂ and R ｂ’ and R ｃ and R ｃ’ may be taken together with the same carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R ａ , and R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｂ , and R ａ , and R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｃ is R ａ and a nitrogen atom to which R ｂ or R ｃ may be taken together with the carbon atom to which R is attached to form a substituted or unsubstituted non-aromatic heterocycle; ｂ and R ｃ together form a (C1-C3) bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom; R ａ and R ｄ are taken together to form a (C1-C3) bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom; R ５ and R ６ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ５ and R ６ may be taken together with the same carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocyclic ring; R ７ is the formula: (Wherein, A is CR１１ or N; R ９ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted amino, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group or cyano; R １０ is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R １１ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; 1 , L ２ ) combination is (CR Ｌ１ R Ｌ１’ , N), (O, N), (O, CR Ｌ２ ) or (NR Ｌ１ , C.R. Ｌ２ (ii) when (L 1 , L ２ ) combination is (NR Ｌ１ , N), and R ４ is the formula: When R is a group represented by ａ is not an alkyl substituted with an aromatic carbocyclic group and an alkyl substituted with a non-aromatic heterocyclic group) (provided that the compound shown below: (2) A is CR or a pharmaceutically acceptable salt thereof. １１ (3) The compound according to the above item (1) or (2), wherein A is CH, or a pharmaceutically acceptable salt thereof. (4) The compound according to any one of the above items (1) to (3), wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof. (5) (L 1 , L ２ ) combination is (NR Ｌ１ , N) or (CRＬ１ R Ｌ１’ (6) The compound according to any one of the above items (1) to (4), or a pharmaceutically acceptable salt thereof, wherein (L 1 , L ２ ) combination is (NH, N) or (CH ２ (7) The compound according to any one of the above items (1) to (5), or a pharmaceutically acceptable salt thereof, wherein X ｄ is CR ｄ and R ｄ (8) The compound according to any one of the above items (1) to (6), wherein X is a hydrogen atom or a substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. ｄ (9) The compound according to any one of the above items (1) to (8), wherein p is 2 and q is 2, or a pharmaceutically acceptable salt thereof. (10) R ２ are each independently a hydrogen atom or a substituted or unsubstituted alkyl, and R ３ (11) The compound according to any one of the above items (1) to (9), or a pharmaceutically acceptable salt thereof, wherein R ５ and R ６ (12) The compound according to any one of the above items (1) to (10), or a pharmaceutically acceptable salt thereof, wherein R １ (13) The compound according to any one of the above items (1) to (11), wherein R is a substituted or unsubstituted 5-membered aromatic heterocyclic group, a substituted or unsubstituted pyridin-2-yl, a substituted or unsubstituted pyridin-3-yl, a substituted or unsubstituted pyridazin-3-yl, a substituted or unsubstituted pyrimidin-2-yl, a substituted or unsubstituted pyrimidin-5-yl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted 9-membered aromatic heterocyclic group, a substituted or unsubstituted 10-membered aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. １is a substituted or unsubstituted 5-membered aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (14) A pharmaceutical composition containing a compound according to any of items (1) to (13) above, or a pharmaceutically acceptable salt thereof. (15) The pharmaceutical composition according to item (14) above, which is a serotonin 5-HT2A receptor inverse agonist. (16) The pharmaceutical composition according to item (14) above, which is a serotonin 5-HT2A and 5-HT2C receptor inverse agonist. (17) A compound of formula (I): (In the formula, R １ is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ３ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; n is 0, 1, or 2; (L 1 , L ２ ) combination is (NR Ｌ１ , N), (CR Ｌ１ R Ｌ１’ , N), (O, N), (O, CR Ｌ２ ) or (NR Ｌ１ , C.R. Ｌ２ ) and R Ｌ１ , R Ｌ１’ and R Ｌ２ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ４ is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group; R ５ and R ６ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ５ and R ６ may be taken together with the same carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocyclic ring; R ７ is the formula: (Wherein, A is CR１１ or N; R ９ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted amino, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group or cyano; R １０ is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R １１ (18) A serotonin 5-HT2A receptor inverse agonist comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, wherein R is independently a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group. ４ is the formula: (19) The serotonin 5-HT2A receptor inverse agonist according to item (17) above, which is a group represented by the formula: (wherein each symbol has the same meaning as in item (1) above). (19) The serotonin 5-HT2A receptor inverse agonist according to item (17) or (18) above, which is a serotonin 5-HT2A and 5-HT2C receptor inverse agonist. (1') A compound represented by formula (I): (In the formula, R １ is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ３ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; n is 0, 1, or 2; (L 1 , L ２ ) combination is (NR Ｌ１ , N), (CR Ｌ１ R Ｌ１’ , N), (O, N), (O, CR Ｌ２ ) or (NR Ｌ１, C.R. Ｌ２ ) and R Ｌ１ , R Ｌ１’ and R Ｌ２ are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R ４ is the formula: wherein p and q are each independently 1, 2, or 3; p″ and q″ are each independently 1 or 2; R ａ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ａ’’ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; X ｂ are each independently, CR ｂ R ｂ’ and X ｃ are each independently, CR ｃ R ｃ’ and R ｂ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｂ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｂ’’ is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ｃ’’ is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; X ｄ is CRｄ or N; X ｄ’’ is CR ｄ or N; R ｄ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl; R ｂ and R ｂ’ and R ｃ and R ｃ’ may be taken together with the same carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｂ is R ａ and a nitrogen atom to which R ｂ together with the carbon atom to which R is attached may form a substituted or unsubstituted non-aromatic heterocycle; or ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｃ is R ａ and a nitrogen atom to which R ｃ may be taken together with the carbon atom to which R is attached to form a substituted or unsubstituted non-aromatic heterocycle; ｂ and R ｃ together form a (C1-C3) bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom; R ａ and R ｄ are taken together to form a (C1-C3) bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom; R ５ and R ６ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ５ and R ６ may be taken together with the same carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocyclic ring; R ７ is the formula: (Wherein, A is CR １１or N; R ９ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted amino, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group or cyano; R １０ is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R １１ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy); 1 , L ２ ) combination is (CR Ｌ１ R Ｌ１’ , N), (O, N), (O, CR Ｌ２ ) or (NR Ｌ１ , C.R. Ｌ２ (ii) when (L 1 , L ２ ) combination is (NR Ｌ１ , N), and R ４ is the formula: When R is a group represented by ａ is not an alkyl substituted with an aromatic carbocyclic group and an alkyl substituted with a non-aromatic heterocyclic group) (provided that the compound shown below: (2') A is CR or a pharmaceutically acceptable salt thereof. １１ (3') The compound according to the above item (1') or (2'), wherein A is CH, or a pharmaceutically acceptable salt thereof. (4') The compound according to any one of the above items (1') to (3'), wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof. (5') (L 1 , L ２ ) combination is (NR Ｌ１ , N), (CRＬ１ R Ｌ１’ (6') (L , N) or (O, N), or a pharmaceutically acceptable salt thereof. 1 , L ２ ) combination is (NH, N) or (CH ２ (7') The compound according to any one of the above items (1') to (5') or a pharmaceutically acceptable salt thereof, wherein X is ｄ is CR ｄ and R ｄ (8') The compound according to any one of the above items (1') to (6'), wherein X is a hydrogen atom or a substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. ｄ (9') The compound according to any one of the above items (1') to (8') or a pharmaceutically acceptable salt thereof, wherein p is 2 and q is 2. (10') R ２ are each independently a hydrogen atom or a substituted or unsubstituted alkyl, and R ３ (11') The compound according to any one of the above items (1') to (9'), or a pharmaceutically acceptable salt thereof, wherein R ５ and R ６ (12') The compound according to any one of the above items (1') to (10') or a pharmaceutically acceptable salt thereof, wherein R １ (13') The compound according to any one of the above items (1') to (11'), wherein R is a substituted or unsubstituted 5-membered aromatic heterocyclic group, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-3-yl, substituted or unsubstituted pyridazin-3-yl, substituted or unsubstituted pyrimidin-2-yl, substituted or unsubstituted pyrimidin-5-yl, substituted or unsubstituted pyrazinyl, a substituted or unsubstituted 9-membered aromatic heterocyclic group, a substituted or unsubstituted 10-membered aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. １is a substituted or unsubstituted 5-membered aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (14') The compound according to the above item (1') or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of I-016, I-028, I-043, I-077, I-080, I-084, I-086, I-087, I-096, I-099, I-101, I-102, I-104, I-105, I-113, I-115, I-116, I-117, I-118, I-121 and I-122. (15') A pharmaceutical composition comprising the compound according to any of the above items (1') to (14') or a pharmaceutically acceptable salt thereof. (16') The pharmaceutical composition according to the above item (14) or (15'), which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist. (17') The pharmaceutical composition according to the above item (14) or (15'), which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist and a 5-HT2C receptor antagonist and / or inverse agonist. (18') A compound of formula (I): (In the formula, R １ is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ３ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; n is 0, 1, or 2; (L 1 , L ２ ) combination is (NR Ｌ１ , N), (CR Ｌ１ R Ｌ１’ , N), (O, N), (O, CR Ｌ２ ) or (NR Ｌ１ , C.R. Ｌ２ ) and R Ｌ１ , R Ｌ１’ and R Ｌ２ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ４is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group or a group of the formula: wherein p and q are each independently 1, 2, or 3; R ａ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; X ｂ are each independently, CR ｂ R ｂ’ and X ｃ are each independently, CR ｃ R ｃ’ and R ｂ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｂ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; ｄ is CR ｄ or N; R ｄ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl; R ｂ and R ｂ’ and R ｃ and R ｃ’ may be taken together with the same carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｂ is R ａ and a nitrogen atom to which R ｂtogether with the carbon atom to which R is attached may form a substituted or unsubstituted non-aromatic heterocycle; or ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｃ is R ａ and a nitrogen atom to which R ｃ may be taken together with the carbon atom to which R is attached to form a substituted or unsubstituted non-aromatic heterocycle; ｂ and R ｃ together form a (C1-C3) bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom; R ａ and R ｄ are taken together to form a (C1-C3) bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom; R ５ and R ６ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ５ and R ６ may be taken together with the same carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocyclic ring; R ７ is the formula: (Wherein, A is CR １１ or N; R ９ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted amino, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group or cyano; R １０ is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R １１(19') R is a group represented by the formula (19) (wherein R is independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy), or a pharmaceutically acceptable salt thereof. ４ is the formula: (Wherein, p″ and q″ are each independently 1 or 2; R ａ’’ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; R ｂ’’ is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ｃ’’ is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; X ｄ’’ is CR ｄor N; other symbols are as defined in item (18') above). (20') The serotonin 5-HT2A receptor antagonistic and / or inverse agonist composition according to item (18') above, which is a serotonin 5-HT2A receptor antagonistic and / or inverse agonist composition and a 5-HT2C receptor antagonistic and / or inverse agonist composition according to item (18') or (19') above. (20) A method for treating and / or preventing a disease involving the serotonin 5-HT2A receptor, comprising administering a compound according to any one of items (1) to (13) and (1') to (14') above, or a pharmaceutically acceptable salt thereof. (21) A method for treating and / or preventing a disease involving serotonin 5-HT2A and 5-HT2C receptors, comprising administering a compound according to any one of the above items (1) to (13) and (1') to (14') or a pharmaceutically acceptable salt thereof. (22) A compound according to any one of the above items (1) to (13) and (1') to (14') or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing a disease involving serotonin 5-HT2A receptors. (23) A compound according to any one of the above items (1) to (13) and (1') to (14') or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing a disease involving serotonin 5-HT2A and 5-HT2C receptors. (24) Use of the compound according to any one of the above items (1) to (13) and (1') to (14') or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor. (25) Use of the compound according to any one of the above items (1) to (13) and (1') to (14') or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment and / or prevention of diseases involving the serotonin 5-HT2A and 5-HT2C receptors. (26) A method for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor, comprising administering a serotonin 5-HT2A receptor inverse agonist according to the above item (17) or (18).(26') A method for treating and / or preventing a disease involving the serotonin 5-HT2A receptor, which comprises administering the composition according to item (18') or (19') above. (27) A method for treating and / or preventing a disease involving the serotonin 5-HT2A receptor, which comprises administering the serotonin 5-HT2A and 5-HT2C receptor inverse agonist according to item (19) above. (27') A method for treating and / or preventing a disease involving the serotonin 5-HT2A receptor, which comprises administering the composition according to item (20') above. (28) A serotonin 5-HT2A receptor inverse agonist according to item (17) or (18) above for use in treating and / or preventing a disease involving the serotonin 5-HT2A receptor. (28') The composition according to the above item (18') or (19') for use in the treatment and / or prevention of a disease involving the serotonin 5-HT2A receptor. (29) The serotonin 5-HT2A and 5-HT2C receptor inverse agonist according to the above item (19) for use in the treatment and / or prevention of a disease involving the serotonin 5-HT2A and 5-HT2C receptor. (29') The composition according to the above item (20') for use in the treatment and / or prevention of a disease involving the serotonin 5-HT2A and 5-HT2C receptor. (30) Use of the serotonin 5-HT2A receptor inverse agonist according to the above item (17) or (18) for the manufacture of an agent for the treatment and / or prevention of a disease involving the serotonin 5-HT2A receptor. (30') Use of the composition according to the above item (18') or (19') for producing an agent for treating and / or preventing diseases associated with serotonin 5-HT2A receptors. (31) Use of the serotonin 5-HT2A and 5-HT2C receptor inverse agonist according to the above item (19) for producing an agent for treating and / or preventing diseases associated with serotonin 5-HT2A and 5-HT2C receptors. (31') Use of the composition according to the above item (20') for producing an agent for treating and / or preventing diseases associated with serotonin 5-HT2A and 5-HT2C receptors.

[0012] The compound according to the present invention (as used herein, "the compound according to the present invention" means the compound of the present invention, a compound related to the 5-HT2A receptor antagonist and / or inverse agonist of the present invention, or a compound related to the pharmaceutical composition of the present invention) has a serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity, and is useful as a therapeutic agent and / or preventive agent for diseases involving serotonin.

[0013] Figure 1 shows the results of a test on the inhibitory effect of administration of a vehicle and example compound I-016 on MK801-induced hyperlocomotion in rats. Figure 2 shows the results of a test on the inhibitory effect of administration of a vehicle and example compound I-043 on MK801-induced hyperlocomotion in rats.

[0014] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprises" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0015] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms, with fluorine and chlorine atoms being particularly preferred.

[0016] The term "alkyl" includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl. R ９ The alkyl moiety of the alkyloxy in R is preferably C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. ９ When the amino in the formula (I) is substituted with alkyl, the alkyl is preferably C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0017] "Haloalkyl" means the above alkyl substituted with one or more halogens. When substituted with two or more halogens, the halogens may be the same or different. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, etc.

[0018] The term "alkenyl" encompasses straight-chain or branched hydrocarbon groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl and n-propenyl.

[0019] "Alkynyl" includes a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more triple bonds at any position. It may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

[0020] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0021] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0022] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated or non-aromatic unsaturated hydrocarbon group. A bicyclic or multicyclic "non-aromatic carbocyclic group" also includes a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group to which the ring of the above-mentioned "aromatic carbocyclic group" is fused. Furthermore, the term "non-aromatic carbocyclic group" also includes bridged groups or groups that form spiro rings as shown below. The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The bicyclic or higher non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0023] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0024] "R ｂ and R ｂ’ together with the same carbon atom to which they are attached," and "R ｃ and R ｃ’ Examples of "a non-aromatic carbocyclic ring formed by combining a carbon atom with the carbon atom to which it is bonded" include the following rings.

[0025] "R ５ and R ６ and the same carbon atom to which they are attached to form a non-aromatic carbocycle" includes, for example, the following non-aromatic carbocycles.

[0026] "R ９ and R １０ and the same carbon atom to which they are attached to form a non-aromatic carbocycle" includes, for example, the following non-aromatic carbocycles.

[0027] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or multicyclic aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or multicyclic aromatic heterocyclic groups also include those in which the rings in the "aromatic carbocyclic group" are fused to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group, and the bond may be on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5- to 8-membered, and more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. Examples of the 9-membered aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuranyl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, thiazolopyridyl, etc. Examples of the 10-membered aromatic heterocyclic group include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, etc.The aromatic heterocyclic group having three or more rings is preferably 13 to 15-membered, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0028] The term "aromatic nitrogen-containing heterocyclic group" refers to a monocyclic or bicyclic or more aromatic heterocyclic group containing one or more N atoms in the ring and optionally containing one or more identical or different heteroatoms selected from O and S in the ring. Bicyclic or more aromatic nitrogen-containing heterocyclic groups also include those in which a ring in the above-mentioned "aromatic carbocyclic group" is fused to a monocyclic or bicyclic or more aromatic nitrogen-containing heterocyclic group, and the bond may be on either ring.

[0029] The monocyclic aromatic nitrogen-containing heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of 5-membered aromatic nitrogen-containing heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic nitrogen-containing heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The bicyclic aromatic nitrogen-containing heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. The aromatic nitrogen-containing heterocyclic group having three or more rings is preferably 13 to 15-membered. Examples thereof include carbazolyl, acridinyl, and phenothiazinyl.

[0030] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include monocyclic or bicyclic or more non-aromatic heterocyclic groups fused with the respective rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as monocyclic or bicyclic or more non-aromatic carbocyclic groups fused with the rings of the above-mentioned "aromatic heterocyclic group," and the bond may be on any of the rings. Furthermore, the term "non-aromatic heterocyclic group" also includes bridged groups or groups forming spiro rings as described below. The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Examples of 8-membered non-aromatic heterocyclic groups include azocane, thiocane, and oxocane. Non-aromatic heterocyclic groups having two or more rings preferably have 8 to 20 members, and more preferably have 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0031] The term "non-aromatic nitrogen-containing heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic heterocyclic group having one or more nitrogen atoms in the ring. A bicyclic or more non-aromatic heterocyclic group includes a monocyclic or bicyclic or more non-aromatic nitrogen-containing heterocyclic group fused with any of the rings in the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," and the bond may be on any of the rings. For example, the following rings are shown: Furthermore, the term "non-aromatic nitrogen-containing heterocyclic group" also includes bridged groups or groups that form spiro rings, as shown below.

[0032] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0033] "R ｂ and R ｂ’ together with the same carbon atom to which they are attached," and "R ｃ and R ｃ’ Examples of "a non-aromatic heterocycle formed by combining with the same carbon atom to which it is bonded" include the following rings.

[0034] "R ａ , and R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｂ But, R ａ and the nitrogen atom to which R ｂ "a non-aromatic heterocyclic ring formed together with the carbon atom to which R is attached," and "R ａ , and R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｃ But, R ａ and the nitrogen atom to which R ｃ Examples of the "non-aromatic heterocycle formed together with the carbon atom to which it is bonded" include the following rings. (wherein each symbol has the same meaning as in item (1') above)

[0035] "R ９ and R １０ Examples of the "non-aromatic heterocycle formed by combining these rings" include the following rings.

[0036] R ｂ and R ｂ’ and R ｃ and R ｃ’ together with the same carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic ring, R ４ Examples of the groups include the following: (wherein each symbol has the same meaning as in item (1') above)

[0037] "Trialkylsilyl" refers to a group in which three of the above-mentioned "alkyl" groups are bonded to a silicon atom. The three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0038] In this specification, "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α." The same applies to substituent groups β, γ, and γ'.

[0039] Examples of substituents such as "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted alkyloxy," "substituted alkenyloxy," "substituted alkynyloxy," "substituted alkylcarbonyloxy," "substituted alkenylcarbonyloxy," "substituted alkynylcarbonyloxy," "substituted alkylcarbonyl," "substituted alkenylcarbonyl," "substituted alkynylcarbonyl," "substituted alkyloxycarbonyl," "substituted alkenyloxycarbonyl," "substituted alkynyloxycarbonyl," "substituted alkylsulfanyl," "substituted alkenylsulfanyl," "substituted alkynylsulfanyl," "substituted alkylsulfinyl," "substituted alkenylsulfinyl," "substituted alkynylsulfinyl," "substituted alkylsulfonyl," "substituted alkenylsulfonyl," and "substituted alkynylsulfonyl" include the following Substituent Group A. A carbon atom at any position may be bonded to one or more groups selected from the following Substituent Group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α,alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic carbocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted by substituent group γ', aromatic heterocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted by substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted by substituent group γ,Non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0040] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0041] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0042] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0043] Substituent group γ': Substituent group γ and oxo.

[0044] Substituents on the ring of an "aromatic carbocycle" and an "aromatic heterocycle", such as a "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic nitrogen-containing heterocyclic group", "substituted aromatic carbocycleoxy", "substituted aromatic heterocycleoxy", "substituted aromatic carbocyclecarbonyloxy", "substituted aromatic heterocyclecarbonyloxy", "substituted aromatic carbocyclecarbonyl", "substituted aromatic heterocyclecarbonyl", "substituted aromatic carbocycleoxycarbonyl", "substituted aromatic heterocycleoxycarbonyl", "substituted aromatic carbocyclesulfanyl", "substituted aromatic heterocyclesulfanyl", "substituted aromatic carbocyclesulfinyl", "substituted aromatic heterocyclesulfinyl", "substituted aromatic carbocyclesulfonyl", and "substituted aromatic heterocyclesulfonyl", include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α,alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, An aromatic carbocyclic group optionally substituted with a substituent group γ, a non-aromatic carbocyclic group optionally substituted with a substituent group γ', an aromatic heterocyclic group optionally substituted with a substituent group γ, a non-aromatic heterocyclic group optionally substituted with a substituent group γ', an aromatic carbocyclic oxy optionally substituted with a substituent group γ, a non-aromatic carbocyclic oxy optionally substituted with a substituent group γ', an aromatic heterocyclic oxy optionally substituted with a substituent group γ, a non-aromatic heterocyclic oxy optionally substituted with a substituent group γ', "aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ", "non-aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ'", "aromatic heterocyclic carbonyloxy optionally substituted with a substituent group γ", and "non-aromatic heterocyclic carbonyloxy optionally substituted with a substituent group γ'", an aromatic heterocyclic oxy optionally substituted with a substituent group γ, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ,Non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', non-aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ' alkyloxyalkyl, aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0045] "Substituted non-aromatic carbocyclic group", "Substituted non-aromatic heterocyclic group", "Substituted non-aromatic nitrogen-containing heterocyclic group", "R ９ and R １０ "a substituted non-aromatic heterocycle formed by combining "R ２２ and R ２３"substituted non-aromatic carbocycle formed together with the carbon atom to which it is bonded," "substituted non-aromatic carbocycleoxy," "substituted non-aromatic heterocycleoxy," "substituted non-aromatic carbocyclecarbonyloxy," "substituted non-aromatic heterocyclecarbonyloxy," "substituted non-aromatic carbocyclecarbonyl," "substituted non-aromatic heterocyclecarbonyl," "substituted non-aromatic carbocycleoxycarbonyl," "substituted non-aromatic heterocycleoxycarbonyl," "substituted non-aromatic carbocyclesulfanyl," "substituted non-aromatic heterocyclesulfanyl," "substituted non-aromatic carbocyclesulfinyl," "substituted non-aromatic heterocyclesulfinyl," "substituted non-aromatic carbocyclesulfonyl," "substituted non-aromatic heterocyclesulfonyl," "R ｂ and R ｂ’ together with the same carbon atom to which they are attached to form a substituted non-aromatic carbocyclic ring," "R ｃ and R ｃ’ together with the same carbon atom to which they are attached to form a substituted non-aromatic carbocyclic ring," "R ｂ and R ｂ’ together with the same carbon atom to which they are attached," "R ｃ and R ｃ’ together with the same carbon atom to which they are attached," "R ａ , and R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｂ But, R ａ and a nitrogen atom to which R ｂ "a substituted non-aromatic heterocyclic ring formed together with the carbon atom to which R is attached," "R ａ , and R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｃ But, R ａ and a nitrogen atom to which R ｃ "a substituted non-aromatic heterocyclic ring formed together with the carbon atom to which R is attached," "R ５ and R ６ together with the same carbon atom to which they are attached to form a substituted non-aromatic carbocyclic ring," "R ９ and R １０ "a substituted non-aromatic carbocyclic ring formed by combining R ９ and R １０Substituents on the ring of the "non-aromatic carbocycle" and "non-aromatic heterocycle" of the "substituted non-aromatic heterocycle formed by combining these" include the following Substituent Group C. An atom at any position on the ring may be bonded to one or more groups selected from the following Substituent Group C. Substituent Group C: Substituent Group B and oxo.

[0046] When a "non-aromatic carbocycle," a "non-aromatic heterocycle," or a "non-aromatic nitrogen-containing heterocycle" is substituted with "oxo," it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows:

[0047] Substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following Substituent Group D. Each group may be substituted with 1 or 2 groups selected from Substituent Group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0048] In the compound of formula (I), R １ , R ２ , R ３ , n, (L 1 , L ２ ) combination, R Ｌ１ , R Ｌ１’ , R Ｌ２ , R４ , p, q, p'', q'', R ａ , R ａ’’ , R ｂ , R ｂ’ , R ｃ , R ｃ’ , R ｂ’’ , R ｃ’’ , X ｄ , X ｄ’’ , R ｄ , R ５ , R ６ , R ７ , A, R ９ , R １０ and R １１ Preferred embodiments of the compound represented by formula (I) are shown below. Examples of the compound represented by formula (I) include all combinations of the specific examples shown below. １ R may be a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-1). １ R is a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-2). １ R includes a substituted or unsubstituted 5-membered aromatic heterocyclic group, a substituted or unsubstituted pyridin-2-yl, a substituted or unsubstituted pyridin-3-yl, a substituted or unsubstituted pyridazin-3-yl, a substituted or unsubstituted pyrimidin-2-yl, a substituted or unsubstituted pyrimidin-5-yl, a substituted or unsubstituted pyrazinyl, a substituted or unsubstituted 9-membered aromatic heterocyclic group, a substituted or unsubstituted 10-membered aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-3). １ R is a substituted or unsubstituted 5-membered aromatic heterocyclic group or a substituted or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as A-4). １ R includes a substituted or unsubstituted 5-membered aromatic heterocyclic group, a substituted or unsubstituted pyridin-2-yl, a substituted or unsubstituted pyridin-3-yl, a substituted or unsubstituted pyridazin-3-yl, a substituted or unsubstituted pyrimidin-2-yl, a substituted or unsubstituted pyrimidin-5-yl, and a substituted or unsubstituted pyrazinyl (hereinafter referred to as A-5). １R is a substituted or unsubstituted 5-membered aromatic heterocyclic group (hereinafter referred to as A-6). １ R includes substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-3-yl, substituted or unsubstituted pyridazin-3-yl, substituted or unsubstituted pyrimidin-2-yl, substituted or unsubstituted pyrimidin-5-yl, and substituted or unsubstituted pyrazinyl (hereinafter referred to as A-7). １ R includes substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, and substituted or unsubstituted benzofuranyl (hereinafter referred to as A-8). １ R includes substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-3-yl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidin-2-yl, substituted or unsubstituted pyrimidin-5-yl, and substituted or unsubstituted benzofuranyl (hereinafter referred to as A-9). １Examples of R include pyrazolyl which may be substituted by substituent group B, pyridin-2-yl which may be substituted by substituent group B, pyridin-3-yl which may be substituted by substituent group B, pyrrolyl which may be substituted by substituent group B, furyl which may be substituted by substituent group B, thiophenyl which may be substituted by substituent group B, oxazolyl which may be substituted by substituent group B, triazolyl which may be substituted by substituent group B, isoxazolyl which may be substituted by substituent group B, pyrazinyl which may be substituted by substituent group B, pyrimidin-2-yl which may be substituted by substituent group B, pyrimidin-5-yl which may be substituted by substituent group B, and benzofuranyl which may be substituted by substituent group B (hereinafter referred to as A-10). １ Examples of R include pyrazolyl which may be substituted with a substituent group ω, pyridin-2-yl which may be substituted with a substituent group ω, pyridin-3-yl which may be substituted with a substituent group ω, pyrrolyl which may be substituted with a substituent group ω, furyl which may be substituted with a substituent group ω, thiophenyl which may be substituted with a substituent group ω, oxazolyl which may be substituted with a substituent group ω, triazolyl which may be substituted with a substituent group ω, isoxazolyl which may be substituted with a substituent group ω, pyrazinyl which may be substituted with a substituent group ω, pyrimidin-2-yl which may be substituted with a substituent group ω, pyrimidin-5-yl which may be substituted with a substituent group ω, and benzofuranyl which may be substituted with a substituent group ω (substituent group ω: halogen, cyano, haloalkyl, and unsubstituted alkyl) (hereinafter referred to as A-11). １ R includes substituted or unsubstituted pyrazolyl (hereinafter referred to as A-12). １ Examples of R include pyrazolyl substituted with a substituent group ω′ (substituent group ω′: halogen, haloalkyl, non-aromatic carbocyclic group, and unsubstituted alkyl) (hereinafter referred to as A-13). １ R includes pyrazolyl substituted with a substituent group ω″ (substituent group ω″: haloalkyl, unsubstituted alkyl, and non-aromatic carbocyclic group) (hereinafter referred to as A-14). １R includes pyrazolyl substituted with alkyl (hereinafter referred to as A-15). １ R includes pyrazolyl substituted with haloalkyl (hereinafter referred to as A-16). １ R includes pyrazolyl substituted with a non-aromatic carbocyclic group (hereinafter referred to as A-17). １ R includes substituted or unsubstituted furyl (hereinafter referred to as A-18). １ Examples of R include furyl substituted with a substituent group ω' (substituent group ω': halogen, haloalkyl, non-aromatic carbocyclic group, and unsubstituted alkyl) (hereinafter referred to as A-19). １ R includes unsubstituted furyl (hereinafter referred to as A-20). １ R includes substituted or unsubstituted pyridin-2-yl (hereinafter referred to as A-21). １ Examples of R include pyridin-2-yl substituted with a substituent group ω′ (substituent group ω′: halogen, haloalkyl, non-aromatic carbocyclic group, and unsubstituted alkyl) (hereinafter referred to as A-22). １ Examples of R include pyridin-2-yl substituted with halogen (hereinafter referred to as A-23). １ R includes substituted or unsubstituted oxazolyl (hereinafter referred to as A-24). １ Examples of R include oxazolyl substituted with a substituent group ω′ (substituent group ω′: halogen, haloalkyl, non-aromatic carbocyclic group, and unsubstituted alkyl) (hereinafter referred to as A-25). １ Examples of R include oxazolyl substituted with a substituent group ω″ (substituent group ω″: haloalkyl, unsubstituted alkyl, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as A-26). １ R includes oxazolyl substituted with alkyl (hereinafter referred to as A-27). １ Examples of R include oxazolyl substituted with haloalkyl (hereinafter referred to as A-28). １ R includes oxazolyl substituted with a non-aromatic carbocyclic group (hereinafter referred to as A-29). １R includes substituted or unsubstituted triazolyl (hereinafter referred to as A-30). １ Examples of R include triazolyl substituted with a substituent group ω′ (substituent group ω′: halogen, haloalkyl, non-aromatic carbocyclic group, and unsubstituted alkyl) (hereinafter referred to as A-31). １ Examples of R include triazolyl substituted with a substituent group ω″ (substituent group ω″: haloalkyl, unsubstituted alkyl, and unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as A-32). １ R includes triazolyl substituted with alkyl (hereinafter referred to as A-33). １ Examples of R include triazolyl substituted with haloalkyl (hereinafter referred to as A-34). １ R includes triazolyl substituted with a non-aromatic carbocyclic group (hereinafter referred to as A-35). ２ R each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (hereinafter referred to as B-1). ２ are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as B-2). ２ are each independently a hydrogen atom (hereinafter referred to as B-3). ３ R each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (hereinafter referred to as C-1). ３ are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as C-2). ３ are each independently a hydrogen atom (hereinafter referred to as C-3). n can be 0, 1, or 2 (hereinafter referred to as D-1). n can be 0 or 1 (hereinafter referred to as D-2). n can be 1 or 2 (hereinafter referred to as D-3). n can be 0 (hereinafter referred to as D-4). n can be 1 (hereinafter referred to as D-5). n can be 2 (hereinafter referred to as D-6). (L 1 , L ２) combination is (NR Ｌ１ , N), (CR Ｌ１ R Ｌ１’ , N), (O, N), (O, CR Ｌ２ ) or (NR Ｌ１ , C.R. Ｌ２ ) (hereinafter referred to as E-1). 1 , L ２ ) combination is (NR Ｌ１ , N), (CR Ｌ１ R Ｌ１’ , N) or (O, N) (hereinafter referred to as E-2). 1 , L ２ ) combination is (NR Ｌ１ , N) or (CR Ｌ１ R Ｌ１’ , N) (hereinafter referred to as E-3). 1 , L ２ ) combination is (NR Ｌ１ , N) or (O, N) (hereinafter referred to as E-4). 1 , L ２ ) combination is (NR Ｌ１ , N) (hereinafter referred to as E-5). 1 , L ２ ) combination is (CR Ｌ１ R Ｌ１’ , N) (hereinafter referred to as E-6). 1 , L ２ ) combinations include (O, N) (hereinafter referred to as E-7). 1 , L ２ ) combination is (O, CR Ｌ２ ) (hereinafter referred to as E-8). 1 , L ２ ) combination is (NR Ｌ１ , C.R. Ｌ２ ) (hereinafter referred to as E-9). 1 , L ２ ) combinations are (NH, N), (CH ２ , N), (O, N), (O, CH) or (NH, CH) (hereinafter referred to as E-10). 1 , L２ ) combinations are (NH, N), (CH ２ , N) or (O, N) (hereinafter referred to as E-11). 1 , L ２ ) combination is (NH, N) or (CH ２ , N) (hereinafter referred to as E-12). 1 , L ２ The combination of (L) includes (NH, N) or (O, N) (hereinafter referred to as E-13). 1 , L ２ ) combinations include (NH, N) (hereinafter referred to as E-14). 1 , L ２ ) combination is (CH ２ , N) (hereinafter referred to as E-15). 1 , L ２ ) combinations include (O, N) (hereinafter referred to as E-16). Ｌ１ , R Ｌ１’ and R Ｌ２ R each independently represents a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as F-1). Ｌ１ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as F-2). Ｌ１ is a hydrogen atom or a halogen (hereinafter referred to as F-3). Ｌ１ R is a hydrogen atom or a fluorine atom (hereinafter referred to as F-4). Ｌ１ is a hydrogen atom (hereinafter referred to as F-5). Ｌ１’ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as F-6). Ｌ１’ is a hydrogen atom or a halogen atom (hereinafter referred to as F-7). Ｌ１’ R is a hydrogen atom or a fluorine atom (hereinafter referred to as F-8). Ｌ１’ is a hydrogen atom (hereinafter referred to as F-9). Ｌ２R is a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as F-10). Ｌ２ R is a hydrogen atom or a halogen atom (hereinafter referred to as F-11). Ｌ２ R is a hydrogen atom or a fluorine atom (hereinafter referred to as F-12). Ｌ２ is a hydrogen atom (hereinafter referred to as F-13). ４ R is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group (hereinafter referred to as G-1). ４ R is a substituted or unsubstituted 4- to 7-membered non-aromatic nitrogen-containing heterocyclic group (hereinafter referred to as G-2). ４ R is a substituted or unsubstituted 6-membered non-aromatic nitrogen-containing heterocyclic group (hereinafter referred to as G-3). ４ is the formula: (wherein each symbol has the same meaning as in the above item (1')) (hereinafter referred to as G-4). ４ is the formula: (wherein each symbol has the same meaning as in the above item (1')) (hereinafter referred to as G-5). ４ is the formula: (wherein each symbol has the same meaning as in the above item (1')) (hereinafter referred to as G-6). ４ is the formula: (wherein each symbol has the same meaning as in the above item (1')) (hereinafter referred to as G-7). ４ is the formula: (In the formula, X ｃ are each independently CH ２ and R ｃ’’ are hydrogen atoms, and p, q, p'', q'', R ａ , R ａ’’ , X ｂ , R ｂ’’ and R ｄ is the same as the above item (1') (hereinafter referred to as G-8). ４ is the formula: (In the formula, X ｃ are each independently CH ２ and p, q, R ａ, X ｂ and R ｄ is the same as the above item (1') (hereinafter referred to as G-9). ４ is the formula: (wherein each symbol has the same meaning as in the above item (1')) (hereinafter referred to as G-10). ４ is the formula: (wherein each symbol has the same meaning as in the above item (1')) (hereinafter referred to as G-11). ４ is the formula: (wherein each symbol has the same meaning as in the above item (1')) (hereinafter referred to as G-12). ４ is the formula: (In the formula, R ａ is a hydrogen atom or unsubstituted alkyl; X ｂ is CR ｂ R ｂ’ and R ｂ is a hydrogen atom or a halogen; R ｂ’ is a hydrogen atom or a halogen; R ｂ and R ｂ’ may form a substituted or unsubstituted non-aromatic carbocyclic ring together with the carbon atom to which it is attached; R ｄ is a hydrogen atom) (hereinafter referred to as G-13). ４ is the formula: (In the formula, R ａ is a hydrogen atom) (hereinafter referred to as G-14). ４ is the formula: (In the formula, R ａ is an unsubstituted alkyl) (hereinafter referred to as G-15). ４ is the formula: (In the formula, R ａ is a hydrogen atom or unsubstituted alkyl; R ｂ and R ｂ’ is a hydrogen atom or a halogen) (hereinafter referred to as G-16). ４ is the formula: (In the formula, R ａis a hydrogen atom or an unsubstituted alkyl) (hereinafter referred to as G-17). p and q each independently represent 1, 2, or 3 (hereinafter referred to as H-1). p and q each independently represent 2 or 3 (hereinafter referred to as H-2). p can be 2 and q can be 1 (hereinafter referred to as H-3). p can be 2 and q can be 2 (hereinafter referred to as H-4). p can be 2 and q can be 3 (hereinafter referred to as H-5). p can be 1, 2, or 3 (hereinafter referred to as H-6). p can be 2 or 3 (hereinafter referred to as H-7). q can be 1, 2, or 3 (hereinafter referred to as H-8). q can be 2 or 3 (hereinafter referred to as H-9). p can be 1 (hereinafter referred to as H-10). p can be 2 (hereinafter referred to as H-11). p can be 3 (hereinafter referred to as H-12). Examples of q include 1 (hereinafter referred to as H-13). Examples of q include 2 (hereinafter referred to as H-14). Examples of q include 3 (hereinafter referred to as H-15). Examples of p'' and q'' are each independently 1 or 2 (hereinafter referred to as J-1). Examples of p'' and q'' are each independently 1 (hereinafter referred to as J-2). R ａ R is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as K-1). ａ R is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl (hereinafter referred to as K-2). ａ is a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as K-3). ａ R is a hydrogen atom, an alkyl substituted with a halogen, or an unsubstituted alkyl (hereinafter referred to as K-4). ａ is a hydrogen atom or an unsubstituted alkyl (hereinafter referred to as K-5). ａ is a hydrogen atom (hereinafter referred to as K-6).ａ R is substituted or unsubstituted alkyl (hereinafter referred to as K-7). ａ R is an unsubstituted alkyl (hereinafter referred to as K-8). ａ’’ R is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as L-1). ａ’’ R is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl (hereinafter referred to as L-2). ａ’’ is a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as L-3). ａ’’ is a hydrogen atom (hereinafter referred to as L-4). ａ’’ X may be a substituted or unsubstituted alkyl (hereinafter referred to as L-5). ｂ are each independently, CR ｂ R ｂ’ (hereinafter referred to as M-1). ｃ are each independently, CR ｃ R ｃ’ (hereinafter referred to as M-2). ｂ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as N-1). ｂ are each independently a hydrogen atom or a halogen (hereinafter referred to as N-2). ｂ are each independently a hydrogen atom (hereinafter referred to as N-3). ｂ are each independently a halogen (hereinafter referred to as N-4). ｂ’ R each independently represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as N-5). ｂ’ are each independently a hydrogen atom or a halogen (hereinafter referred to as N-6). ｂ’are each independently a hydrogen atom (hereinafter referred to as N-7). ｃ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as O-1). ｃ are each independently a hydrogen atom or a halogen (hereinafter referred to as O-2). ｃ are each independently a hydrogen atom (hereinafter referred to as O-3). ｃ are each independently a halogen (hereinafter referred to as O-4). ｃ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as O-5). ｃ’ are each independently a hydrogen atom or a halogen (hereinafter referred to as O-6). ｃ’ are each independently a hydrogen atom (hereinafter referred to as O-7). ｂ’’ R is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as P-1). ｂ’’ is a hydrogen atom or a halogen (hereinafter referred to as P-2). ｃ’’ R is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (hereinafter referred to as Q-1). ｃ’’ is a hydrogen atom or a halogen (hereinafter referred to as Q-2). ｄ is CR ｄ or N (hereinafter referred to as R-1). ｄ is CR ｄ (hereinafter referred to as R-2). ｄ’’ is CR ｄ Or N (hereinafter referred to as S-1). ｄ’’ is CR ｄ (hereinafter referred to as S-2). ｄR is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl (hereinafter referred to as T-1). ｄ R is a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as T-2). ｄ is a hydrogen atom (hereinafter referred to as T-3). ｂ and R ｂ’ and R ｃ and R ｃ’ together with the same carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as U-1). ｂ and R ｂ’ and R ｃ and R ｃ’ R forms a substituted or unsubstituted non-aromatic carbocyclic ring together with the same carbon atom to which it is attached (hereinafter referred to as U-2). ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｂ is R ａ and a nitrogen atom to which R ｂ together with the carbon atom to which R is attached, form a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as U-3). ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｃ is R ａ and a nitrogen atom to which R ｃ together with the carbon atom to which R is attached, form a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as U-4). ｂ and R ｃ together form a (C1-C3) bridge, and one of the carbon atoms constituting the bridge may be replaced by an oxygen atom (hereinafter referred to as U-5). ｂ and R ｃ together form a (C1-C3) bridge (hereinafter referred to as U-6). ｂ and R ｃ together form a (C2-C3) bridge (hereinafter referred to as U-7).ａ and R ｄ together form a (C1-C3) bridge, and one of the carbon atoms constituting the bridge may be replaced by an oxygen atom (hereinafter referred to as U-8). ａ and R ｄ together form a (C1-C3) bridge (hereinafter referred to as U-9). ａ and R ｄ together form a (C2-C3) bridge (hereinafter referred to as U-10). ５ and R ６ R each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (hereinafter referred to as V-1). ５ and R ６ are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as V-2). ５ and R ６ are each independently a hydrogen atom (hereinafter referred to as V-3). ７ is the formula: (In the formula, R ９ is substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocycleoxy, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocycle or cyano; R １０ is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or R ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; A and R １１ has the same meaning as in the above item (1') (hereinafter referred to as W-1). ７ is the formula: (In the formula, R ９ is substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocycleoxy, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocycle or cyano; R１０ is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; A and R １１ has the same meaning as in the above item (1') (hereinafter referred to as W-2). ７ is the formula: (In the formula, R ９ is substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocycleoxy, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocycle or cyano; R １１ is a hydrogen atom or a halogen) (hereinafter referred to as W-3). ７ is the formula: (In the formula, R ９ is substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocycleoxy, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocycle or cyano; R １１ is a hydrogen atom or a halogen) (hereinafter referred to as W-4). ７ is the formula: (In the formula, R ９ has the same meaning as in the above item (1′) (hereinafter referred to as W-5). １１ or N (hereinafter referred to as X-1). A is CR １１ (hereinafter referred to as X-2). A is CH (hereinafter referred to as X-3). R ９ R may be substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic ring, or cyano (hereinafter referred to as Y-1). ９ R may be substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted alkyl, or substituted or unsubstituted non-aromatic carbocyclic ring (hereinafter referred to as Y-2). ９R may be a substituted or unsubstituted alkyloxy, a substituted or unsubstituted amino, a substituted or unsubstituted aromatic carbocyclic oxy, or a substituted or unsubstituted alkyl (hereinafter referred to as Y-3). ９ R is substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl (hereinafter referred to as Y-4). ９ R includes substituted alkyloxy (substituent: halogen), unsubstituted alkyloxy, substituted amino (substituent: alkyl), substituted alkyl (substituent: halogen), and unsubstituted alkyl (hereinafter referred to as Y-5). ９ R is substituted or unsubstituted alkyloxy (hereinafter referred to as Y-6). ９ R is an alkyloxy group substituted or unsubstituted with halogen (hereinafter referred to as Y-7). ９ R is an unsubstituted alkyloxy (hereinafter referred to as Y-8). ９ R includes alkyloxy substituted with halogen (hereinafter referred to as Y-9). ９ R may be a substituted or unsubstituted amino (hereinafter referred to as Y-10). ９ R is an amino substituted with alkyl (hereinafter referred to as Y-11). ９ R is substituted or unsubstituted alkyl (hereinafter referred to as Y-12). ９ R is an alkyl group substituted or unsubstituted with halogen (hereinafter referred to as Y-13). ９ is an unsubstituted alkyl (hereinafter referred to as Y-14). ９ R is an alkyl substituted with halogen (hereinafter referred to as Y-15). １０ R is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter referred to as Y-16). １０ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as Y-17). １０ is a hydrogen atom or a halogen (hereinafter referred to as Y-18).１０ is a hydrogen atom (hereinafter referred to as Y-19). ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as Y-20). ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring (hereinafter referred to as Y-21). ９ and R １０ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as Y-22). １１ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (hereinafter referred to as Y-23). １１ R each independently represents a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as Y-24). １１ are each independently a hydrogen atom or a halogen (hereinafter referred to as Y-25). １１ each independently represents a hydrogen atom (hereinafter referred to as Y-26).

[0049] In the compound represented by formula (I), for example, the following embodiments are more preferred. All combinations of the following specific examples are exemplified. (I) Formula (I'): or a pharmaceutically acceptable salt thereof. １ (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (A-10), (A-11), (A-12), (A-13), (A-14), (A-15), (A-16), (A-17), (A-18), (A-19), (A-20) ), (A-21), (A-22), (A-23), (A-24), (A-25), (A-26), (A-27), (A-28), (A-29), (A-30), (A-31), (A-32), (A-33), (A-34) or (A-35). R ４Examples of R include (G-12), (G-13), (G-14), (G-15), (G-16), and (G-17). ７ is the formula: In the formula, R ９ Examples of R include (Y-4), (Y-5), (Y-6), (Y-7), (Y-8), (Y-9), (Y-10), (Y-11), (Y-12), (Y-13), (Y-14) and (Y-15). １０ Examples of R include (Y-17), (Y-18) and (Y-19). １１ are each independently exemplified by (Y-24), (Y-25) or (Y-26). (ii) Formula (II'): or a pharmaceutically acceptable salt thereof. 1 , L ２ ) combinations such as (E-12), (E-14) and (E-15) above. １ Examples of R include (A-6), (A-12), (A-13), (A-14), (A-15), (A-16), (A-23), (A-24), (A-25), (A-26), (A-27), (A-28), (A-29), (A-30), (A-31), (A-32), (A-33), (A-34) and (A-35). ４ Examples of R include (G-13), (G-14), (G-15), (G-16), and (G-17). ７ is the formula: In the formula, R ９ Examples of R include (Y-6), (Y-7), (Y-8), (Y-9), (Y-12), (Y-13), (Y-14) and (Y-15). １０ Examples of R include (Y-18) and (Y-19). １１ are each independently exemplified by (Y-25) or (Y-26).

[0050] The following embodiments are particularly preferred: (i) Formula (II'): (In the formula, R １is a substituted or unsubstituted 5-membered aromatic heterocyclic group; 1 , L ２ ) combination is (NH, N) or (CH ２ , N); R ４ is the formula: (In the formula, R ａ is a hydrogen atom or unsubstituted alkyl; X ｂ is CR ｂ R ｂ’ and R ｂ is a hydrogen atom or a halogen; R ｂ’ is a hydrogen atom or a halogen; R ｂ and R ｂ’ may form a substituted or unsubstituted non-aromatic carbocyclic ring together with the carbon atom to which it is attached; R ｄ is a hydrogen atom); ７ is the formula: (In the formula, R ９ is substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl; R １０ is a hydrogen atom or a halogen; R １１ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy), or a pharmaceutically acceptable salt thereof. (In the formula, R １ is a substituted or unsubstituted oxazolyl, a substituted or unsubstituted triazolyl, or a substituted or unsubstituted pyrazolyl; 1 , L ２ ) combination is (NH, N) or (CH ２ , N); R ４ is the formula: (In the formula, R ａ is a hydrogen atom or unsubstituted alkyl; X ｂ is CR ｂ R ｂ’ and R ｂ is a hydrogen atom or a halogen; R ｂ’is a hydrogen atom or a halogen; R ｂ and R ｂ’ may form a substituted or unsubstituted non-aromatic carbocyclic ring together with the carbon atom to which it is attached; R ｄ is a hydrogen atom); ７ is the formula: (In the formula, R ９ is substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl; R １０ is a hydrogen atom or a halogen; R １１ (iii) a compound represented by formula (II'): or a pharmaceutically acceptable salt thereof. (In the formula, R １ is an oxazolyl substituted with a substituent group ω'', a triazolyl substituted with a substituent group ω'', or a pyrazolyl substituted with a substituent group ω'' (substituent group ω'': haloalkyl, unsubstituted alkyl, and non-aromatic carbocyclic group); (L 1 , L ２ ) combination is (NH, N) or (CH ２ , N); R ４ is the formula: (In the formula, R ａ is a hydrogen atom or unsubstituted alkyl; X ｂ is CR ｂ R ｂ’ and R ｂ is a hydrogen atom or a fluorine atom; R ｂ’ is a hydrogen atom or a fluorine atom; R ｂ and R ｂ’ may be taken together with the carbon atom to which it is attached to form an unsubstituted cyclopropane ring; R ｄ is a hydrogen atom); ７ is the formula: (In the formula, R ９ is alkyloxy substituted with halogen, unsubstituted alkyloxy, haloalkyl or unsubstituted alkyl; R １０ is a hydrogen atom or a halogen; R１１ are each independently a hydrogen atom or a halogen), or a pharmaceutically acceptable salt thereof.

[0051] The compounds represented by formula (I), formula (I') or formula (II') are not limited to specific isomers, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates or mixtures thereof.

[0052] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), formula (I') or formula (II') may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. 123 I and ３６ The isotopes of the compounds represented by formula (I), (I') or (II') include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as Cl. The compounds represented by formula (I), (I') or (II') also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals, and include all radiolabeled compounds of the compounds represented by formula (I), (I') or (II'). Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compound," and the "radiolabeled compound" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0053] Radiolabeled compounds of Formula (I), (I'), or (II') can be prepared by methods well known in the art. For example, tritium-labeled compounds of Formula (I), (I'), or (II') can be prepared by introducing tritium into a specific compound of Formula (I), (I'), or (II') via catalytic dehalogenation using tritium. This method involves reacting an appropriately halogen-substituted precursor of Formula (I), (I'), or (II') with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. For other suitable methods for preparing tritium-labeled compounds, see "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0054] Pharmaceutically acceptable salts of the compound represented by formula (I), formula (I') or formula (II') include, for example, salts of the compound represented by formula (I), formula (I') or formula (II') with an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metal (e.g., zinc, iron, etc.), ammonia, organic base (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethyl Examples of suitable salts include salts with carboxylic acids (e.g., diamine, pyridine, picoline, quinoline, etc.) and amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[0055] The compound of the present invention represented by formula (I), formula (I'), or formula (II') or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.), a co-crystal, and / or a crystalline polymorph, and the present invention also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with a compound of formula (I), formula (I'), or formula (II') with any number of solvent molecules (e.g., water molecules, etc.). When a compound of formula (I), formula (I'), or formula (II') or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, and adsorbed water may adhere, or a hydrate may be formed. Furthermore, a crystalline polymorph may be formed by recrystallizing a compound of formula (I), formula (I'), or formula (II') or a pharmaceutically acceptable salt thereof. A "co-crystal" means that a compound of formula (I), formula (I'), or formula (II') or a salt thereof and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.

[0056] The compounds of the present invention represented by Formula (I), Formula (I'), or Formula (II') or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds of the present invention having a chemically or metabolically decomposable group, and are compounds that become pharmaceutically active compounds of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to compounds of Formula (I), Formula (I'), or Formula (II') by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to compounds of Formula (I), Formula (I'), or Formula (II') by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0057] When the compound represented by formula (I), formula (I') or formula (II') or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH ３ COO-, C ２ H ５ COO-, tert-BuCOO-, C １５ H ３１ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ２ CH ２ COO-, CH ３ CH(NH ２ ) COO-, CH ２ N (CH ３ ) ２ COO-, CH ３ SO ３ -, CH ３ CH ２ SO３ -, CF ３ SO ３ -, CH ２ FSO ３ -, CF ３ CH ２ SO ３ -, p-CH ３ O-PhSO ３ -, PhSO ３ -, p-CH ３ PhSO ３ - are some examples.

[0058] The compounds according to the present invention have serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and are therefore useful as therapeutic and / or preventive agents for diseases involving the serotonin 5-HT2A receptor. Examples of diseases involving the serotonin 5-HT2A receptor include serotonin-mediated diseases such as hallucinations and delusions associated with Parkinson's disease, hallucinations and delusions associated with dementia, hallucinations and delusions associated with schizophrenia, hallucinations and delusions associated with depression, hallucinations and delusions associated with neurodegenerative diseases, depression, schizophrenia, autism, addiction, dyskinesia, sleep disorders, irritability associated with Parkinson's disease, irritability associated with dementia, irritability associated with schizophrenia, and sexual dysfunction. Preferred examples include hallucinations and delusions associated with Parkinson's disease, hallucinations and delusions associated with dementia, hallucinations and delusions associated with schizophrenia, hallucinations and delusions associated with depression, irritability associated with Parkinson's disease, irritability associated with dementia, and irritability associated with schizophrenia. More preferred examples include hallucinations and delusions associated with Parkinson's disease and hallucinations and delusions associated with dementia. The term "serotonin 5-HT2A receptor antagonist and / or inverse agonist" refers to a pharmaceutical product having serotonin 5-HT2A receptor antagonistic and / or inverse agonist activity. The term "serotonin 5-HT2A receptor antagonist and / or inverse agonist composition" refers to a composition having serotonin 5-HT2A receptor antagonistic and / or inverse agonist activity, and is not limited to pharmaceutical use.

[0059] (Method for Producing the Compound of the Present Invention) The compound of the present invention represented by formula (I), formula (I') or formula (II') can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments carried out in ordinary organic chemistry experiments. The compound of the present invention can be synthesized by referring to methods known in the art.

[0060] A method (wherein each symbol has the same meaning as in the above item (1'), R １’ - is R １ - or R １ - (CR ２ R ３ ) ｎ－１-.) Step 1 Compound (a-3) can be obtained by reacting compound (a-1) and compound (a-2) in the presence or absence of acetic acid in a suitable reducing agent and a suitable solvent. Alternatively, compound (a-3) can be obtained in the same manner by using compound (a'-1) and compound (a'-2) instead of compound (a-1) and compound (a-2). Examples of reducing agents include sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride, and can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents, relative to compound (a-1). Acetic acid can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents, relative to compound (a-1). Examples of reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., and these can be used alone or in combination. The reaction temperature is 0 to 80°C, preferably 0 to 20°C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours. The resulting desired compound (a-3) can be purified, if necessary, by a conventional method (e.g., column chromatography, recrystallization, etc.).

[0061] Step 2: Compound (a-4) and CDI are reacted in a suitable solvent, followed by reaction with compound (a-3) in a suitable solvent to obtain compound (I-a). CDI can be used in an amount of 1.0 molar equivalent or more, preferably 1.2 molar equivalents, relative to compound (a-4). Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination. The reaction temperature is 0 to 80°C, preferably 0 to 20°C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours. The resulting desired compound (Ia) can be purified by a conventional method (eg, column chromatography, recrystallization, etc.) if necessary.

[0062] A' method (wherein each symbol is as defined in the above item (1'), PG is a suitable protecting group for an amino group (e.g., Boc, Cbz, etc.), Y １ and Y ２ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, etc.) Step 1 Compound (I-a'') can be obtained by deprotecting PG from compound (I-a') in the presence of an acid, without a solvent or in a suitable solvent, or by reacting compound (I-a') with hydrogen gas in the presence of a metal catalyst, without a solvent or in a suitable solvent, to deprotect PG. Examples of acids include hydrochloric acid, sulfuric acid, TFA, and formic acid, which can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 30 molar equivalents, relative to compound (I-a'). Examples of metal catalysts include palladium-carbon (Pd / C), Adams' catalyst (PtO ２ ), Pearlman's catalyst (Pd(OH) ２), rhodium-aluminum oxide, chlorotris(triphenylphosphine)rhodium(I), etc., can be used in a range of 0.01 to 100 weight percent based on Compound (I-a'). The hydrogen pressure can be 1 to 50 atmospheres. Cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, etc. can also be used as a hydrogen source. Examples of reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination. The reaction temperature is 0 to 80°C, preferably 0 to 20°C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours. The resulting desired compound (Ia'') can be purified by a conventional method (eg, column chromatography, recrystallization, etc.) if necessary.

[0063] Step 2 Compound (I-a'') can be obtained by reacting compound (I-a'') and compound (a-5) with an appropriate reducing agent, and optionally acetic acid, in an appropriate solvent. Examples of the reducing agent include sodium triacetoxyborohydride and sodium cyanoborohydride, which can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents, relative to compound (I-a''). Acetic acid can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents, relative to compound (I-a''). Examples of reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., and these can be used alone or in combination. The reaction temperature is 0 to 80°C, preferably 0 to 20°C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours. The resulting desired compound (I-a''') can be purified, if necessary, by a conventional method (e.g., column chromatography, recrystallization, etc.).

[0064] B method (In the formula, each symbol has the same meaning as in item (1') above.) Compound (I-b) can be obtained by reacting compound (a-3) with compound (b-1) in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, and HATU, and these can be used in an amount of 1 to 5 molar equivalents relative to compound (a-3). The reaction temperature is −20° C. to 60° C., preferably 0° C. to 30° C. The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours. Examples of the reaction solvent include DMF, DMA, NMP, tetrahydrofuran, dioxane, dichloromethane, and acetonitrile, and these can be used alone or in combination. The desired compound (Ib) obtained can be purified by a conventional method (eg, column chromatography, recrystallization, etc.) if necessary.

[0065] C method (In the formula, each symbol has the same meaning as in item (1') above.) Compound (I-c) can be obtained by reacting compound (a-3) with compound (c-1) or a salt thereof in the presence of a base. Examples of the base include pyridine, 2,6-lutidine, triethylamine, and NMM, and 2 to 10 molar equivalents can be used relative to compound (a-3). The reaction temperature is −20° C. to 60° C., preferably 0° C. to 30° C. The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours. Examples of the reaction solvent include dichloromethane, DMF, DMA, NMP, tetrahydrofuran, dioxane, and acetonitrile, and these can be used alone or in combination. The obtained desired compound (I-c) can be purified, if necessary, by a conventional method (e.g., column chromatography, recrystallization, etc.).

[0066] The compounds of the present invention have serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and are therefore useful as therapeutic and / or preventive agents for hallucinations and delusions associated with Parkinson's disease and / or dementia. Furthermore, the compounds of the present invention are useful as pharmaceuticals and preferably have one or more of the following excellent characteristics: a) weak inhibitory activity against CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.); b) good pharmacokinetics, such as high bioavailability and moderate clearance; c) high metabolic stability; d) no irreversible inhibitory activity against CYP enzymes (e.g., CYP3A4) within the concentration ranges of the measurement conditions described herein; e) no mutagenicity; f) low cardiovascular risk; g) high solubility; and h) high serotonin 5-HT2A receptor binding ability. i) High serotonin 5-HT2C receptor binding ability, j) High brain penetration, k) Low P-gp substrate.

[0067] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0068] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0069] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0070] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0071] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but when administered orally, it is usually 0.05 to 300 mg / kg / day, preferably 0.1 to 10 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage can be administered once or in divided doses several times a day.

[0072] The compound according to the present invention can be used in combination with an anti-Parkinson's drug, an anti-Alzheimer's drug, an antipsychotic drug, or an antidepressant drug (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration timing of the compound according to the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound according to the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing these active ingredients.

[0073] The dose of the concomitant drug can be appropriately selected based on the dose used clinically. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0074] Examples of anti-Parkinson's disease drugs include levodopa preparations, etc. Examples of anti-Alzheimer's drugs include donepezil, etc. Examples of antipsychotic drugs include quetiapine, etc. Examples of antidepressants include escitalopram, etc.

[0075] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0076] The abbreviations used herein have the following meanings: Boc: tert-butoxycarbonyl, CDCl3: deuterated chloroform, CDI: carbonyldiimidazole, Cbz: benzyloxycarbonyl, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, NMP: N-methylpyrrolidone, TFA: trifluoroacetic acid, NMM: N-methylmorpholine, THF: tetrahydrofuran, PdCl ２ (dppf): [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0077] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ , CDCl ３ Measurement was performed using a solvent other than 100% solvent [B]. NMR data may not include all measured peaks. The retention time (RT) in the specification represents the retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Measurement Condition 1) Column: Shim-pack XR-ODS (2.2 μm i.d. 3.0 x 50 mm) (Shimadzu) Flow rate: 1.6 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10%-100% solvent [B] was performed over 3 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Measurement Condition 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. In the specification, the term MS (m / z) refers to a value observed by mass spectrometry.

[0078] Synthesis of compound (I-016) Step 1 Synthesis of Compound 2 5-Fluoropicolinaldehyde (1.54 g, 12.3 mmol) was dissolved in ethanol (20 mL), and compound 1 (2.00 g, 11.2 mmol) (the synthesis method is described in Bioorganic and Medicinal Chemistry Letters, 2015, Vol. 25, No. 5, pp. 1053-1056) was added, followed by stirring at 80°C for 30 minutes. Sodium borohydride (506 mg, 13.4 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction. Ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature for a while. Water (10 mL) and potassium carbonate (2 g) were added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL). The solvent was evaporated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (20-100% ethyl acetate-hexane) and diol silica gel column chromatography (20-100% ethyl acetate-hexane) to give compound 2 (2.11 g, 7.30 mmol, yield 66%) as a yellow oil. 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.8 Hz), 2.02-2.12 (1H, m), 3.71 (2H, d, J = 6.5 Hz), 3.76 (2H, s), 3.89 (2H, s), 6.86 (2H, d, J = 8.5 Hz), 7.25 (2H, d, J = 8.5 Hz), 7.29-7.40 (2H, m), 8.41 (1H, d, J = 2.0 Hz).

[0079] Step 2: Synthesis of Compound (I-016) To a suspension of carbonyldiimidazole (0.843 g, 5.20 mmol) in acetonitrile (3.0 mL), a solution of 1-methylpiperidin-4-amine (0.634 g, 5.55 mmol) in acetonitrile (2 mL) was added dropwise over 2 minutes at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. A solution of compound 2 (1.00 g, 3.47 mmol) in acetonitrile (5.0 mL) and triethylamine (0.961 mL, 6.94 mmol) were added, and the mixture was stirred at 80°C for 1.5 hours. In a separate reaction vessel, to a suspension of carbonyldiimidazole (0.843 g, 5.20 mmol) in acetonitrile (3.0 mL), a solution of 1-methylpiperidin-4-amine (0.634 g, 5.55 mmol) in acetonitrile (2 mL) was added dropwise over 2 minutes at room temperature, and the mixture was stirred at room temperature for 30 minutes. This reaction solution was added to the reaction solution of compound 2 and stirred at 80°C for 1.5 hours. Water (10 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (100 mL). The organic layer was washed three times with a mixture of water (45 mL) and saturated aqueous sodium chloride solution (5 mL) and once with water (10 mL). The solvent was evaporated under reduced pressure, and the resulting residue was purified by diol silica gel column chromatography (0-5% methanol-chloroform) to obtain compound (I-016) (1.27 g, 2.97 mmol, yield 86%) as a colorless oil. 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.8 Hz), 1.35-1.48 (2H, m), 1.86-2.00 (2H, m), 2.00-2.17 (3H, m), 2.25 (3H, s), 2.54-2.83 (2H, m), 3.61-3.73 (1H, m), 3.70 (2H, d, J = 6.5 Hz), 4.42 (2H, s), 4.49 (2H, s), 5.78 (1H, s), 6.84 (2H, d, J = 8.4 Hz), 7.03 (1H, dd, J = 8.5, 4.0 Hz), 7.16 (2H, d, J = [Reference example 1]

[0080] Synthesis of Compound 3 Step 1: Synthesis of Compound 3 Compound 1 (3.39 g, 18.92 mmol) was added to a solution of 1-methyl-1-pyrazole-3-carbaldehyde (2.50 g, 22.70 mmol) in ethanol (25 mL), and the mixture was stirred at 80°C for 1 hour. After cooling to 0°C, sodium borohydride (0.71 g, 18.92 mmol) was added, and the mixture was stirred at 0°C for 1.5 hours. Saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was stirred for 15 minutes. 20% aqueous potassium carbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate) to give compound 3 (4.5 g, 87% yield). 1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.8 Hz), 2.04-2.10 (1H, m), 3.72 (2H, d, J = 10.2 Hz), 3.76 (2H, s), 3.80 (2H, s), 3.86 (3H, s), 6.17 (1H, d, J = 1.8 Hz), 6.85 (2H, d, J = 8.5 Hz), 7.23-7.28 (4H, m).

[0081] Synthesis of compound (I-043) Step 1 Synthesis of Compound (I-043) Using 1-methylpiperidin-4-amine and Compound 3, compound (I-043) (126 mg, 0.304 mmol, yield 56%) was obtained as a yellow oil using the same procedure as in Step 2 of Example 1. 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.8 Hz), 1.30-1.49 (2H, m), 1.85-1.96 (2H, m), 2.01-2.17 (3H, m), 2.25 (3H, s), 2.54-2.80 (2H, m), 3.61-3.74 (1H, m), 3.71 (2H, d, J = 6.5 Hz), 3.83 (3H, s), 4.26 (2H, s), 4.48 (2H, s), 5.36 (1H, d, J = 5.3 Hz), 5.89 (1H, d, J = 1.5 Hz), 6.85 (2H, d, J = 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.23 (1H, d, J = 1.8 Hz).

[0082] Synthesis of compound (I-028) Step 1: Synthesis of Compound 5 Compound 4 (3.39 g, 18.92 mmol) was added to (S)-1-phenethyl-1-amine (1.29 g, 10.7 mmol) under ice cooling, and the mixture was stirred at room temperature for 18 hours. Diethyl ether (60 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting solid was removed by filtration, and the solvent was removed under reduced pressure to obtain Compound 5 (2.8 g, yield 96%).

[0083] Step 2: Synthesis of Compound 6 Sodium borohydride (0.16 g, 4.26 mmol) was added to a solution of compound 5 (2.8 g, 8.52 mmol) in ethanol (28 mL) at −78°C, and the mixture was stirred at −78°C for 2 hours. Saturated aqueous sodium bicarbonate (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate) to give compound 6 (2.1 g, yield 75%). 1H-NMR (CDCl3) δ: 0.29-0.50 (m, 4H), 1.30 (d, J = 6.4 Hz, 2H), 1.42 (s, 9H), 1.45-1.70 (m, 2H), 2.18 (s, 1H), 2.92-3.06 (s, 1H), 3.28-3.49 (m, 3H), 3.83 (q, J = 6.6 Hz, 1H), 7.22 (dd, J = 8.7, 4.5 Hz, 1H), 7.30 (d, J = 4.3 Hz, 4H).

[0084] Step 3: Synthesis of Compound 7 Compound 6 (157 mg, 0.48 mmol) was added with methanol (1.6 mL), ammonium formate (150 mg, 2.38 mmol), and palladium hydroxide on carbon (40 mg, 0.14 mmol), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was filtered to remove the palladium hydroxide on carbon. The solvent was removed under reduced pressure to give compound 7 (102 mg, 95% yield). 1H-NMR (CDCl3) δ: 0.32-0.50 (m, 4H), 1.45 (s, 9H), 1.50-1.62 (m, 1H), 1.80-1.88 (m, 1H), 2.62 (dd, J = 10.0, 6.4 Hz, 1H), 3.05 (d, J = 12.2 Hz, 1H), 3.41 (d, J = 13.6 Hz, 1H), 3.45-3.62 (m, 2H).

[0085] Step 4: Synthesis of Compound 8 Compound 8 was synthesized using Compound 7 and Compound 3 in the same manner as in Step 2 of Example 1. 1H-NMR (CDCl3) δ: 0.30 (1H, s), 0.42 (4H, s), 1.01 (3H, s), 1.03 (3H, s), 1.44 (9H, s), 1.61-1.64 (1H, m), 1.79 (1H, br s), 2.08-2.09 (1H, m), 3.14-3.17 (1H, m), 3.27-3.31 (1H, m), 3.47 (2H, br s), 3.70 (1H, s), 3.72 (1H, s), 3.82 (3H, s), 4.23 (2H, s), 4.47 (1H, d, J = 14.7 Hz), 4.52 (1H, d, J = 14.7 Hz), 5.65 (1H, s), 5.83 (1H, s), 6.86 (2H, d, J = 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.24 (1H, s).

[0086] Step 5: Synthesis of Compound (I-028) Dichloromethane (1.1 mL) and trifluoroacetic acid (230 μL, 2.99 mmol) were added to Compound 8, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate, ethyl acetate-methanol) to give Compound (I-028) (38.8 mg, yield 41%) as a colorless oil. 1H-NMR (CDCl3) δ: 0.14-0.18 (1H, m), 0.27-0.31 (1H, m), 0.35-0.37 (1H, m), 0.44-0.46 (1H, m), 1.02 (6H, d, J = 6.5 Hz), 1.56-1.57 (2H, m), 1.75-1.80 (1H, m), 2.08-2.09 (1H, m), 2.53 (1H, d, J = 13.0 Hz), 2.66 (1H, d, J = 13.0 Hz), 2.81-2.86 (1H, m), 2.91-2.93 (1H, m), 3.71 (3H, d, J = 6.5 Hz), 3.85 (3H, s), 4.25 (2H, s), 4.46 (1H, d, J = 15.1 Hz), 4.53 (1H, d, J = 15.3 Hz), 5.51 (1H, s), 5.85 (1H, s), 6.86 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz), 7.24 (1H, s).

[0087] Synthesis of compound (I-037) Step 1: Synthesis of (I-037) To compound (I-028) (186.2 mg, 0.43 mmol), tetrahydrofuran (1.1 mL), methanol (1.1 mL), formaldehyde (36.2 μL, 1.31 mmol), and sodium triacetoxyborohydride (186.0 g, 0.87 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate, ethyl acetate-methanol) to give compound (I-037) (4.9 mg, yield 3%) as a colorless oil. 1H-NMR (CDCl3) δ: 0.20-0.24 (1H, m), 0.33-0.36 (1H, br m), 0.40 (1H, dd, J = 8.8, 4.1 Hz), 0.46 (1H, dd, J = 8.8, 4.1 Hz), 1.01 (3H, s), 1.03 (3H, s), 1.85 (3H, s), 2.07-2.10 (2H, m), 2.15-2.18 (1H, br m), 2.23 (3H, s), 2.38-2.40 (2H, br m), 3.70 (1H, s), 3.72 (1H, s), 3.84 (3H, s), 4.26 (2H, s), 4.45 (1H, d, J = 15.2 Hz), 4.51 (1H, d, J = 15.2 Hz), 5.36 (1H, br s), 5.87 (1H, d, J = 1.9 Hz), 6.86 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.24 (1H, d, J = 1.9 Hz).

[0088] Synthesis of compound (I-030) Step 1: Synthesis of Compound 9 To a solution of 4-fluorobenzonitrile (5.00 g, 41.3 mmol) in dimethyl sulfoxide (50.0 mL), isobutylamine (20.7 mL, 206 mmol) and cesium carbonate (16.1 g, 49.5 mmol) were added and stirred at 70°C for 4 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed three times with water (100 mL), and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methylene chloride (37 mL), and di-tert-butyl dicarbonate (9.86 mL, 42.5 mmol) and 4-dimethylaminopyridine (0.519 g, 4.25 mmol) were added, followed by stirring at room temperature for 30 minutes. 4-Dimethylaminopyridine (5.19 g, 42.5 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Di-t-butyl dicarbonate (9.86 mL, 42.5 mmol) was added, and the mixture was allowed to stand at room temperature for 5 days. N-methylpiperidine (9.45 mL, 85.0 mmol) was added under ice-cooling to quench the reaction. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (0-30% ethyl acetate-hexane) to give compound 9 (2.32 g, 8.45 mmol, 20% yield) as a white solid. H-NMR (CDCl) δ: 0.87 (6H, d, J = 6.8 Hz), 1.45 (9H, s), 1.74-1.81 (1H, m), 3.54 (2H, d, J = 7.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz).

[0089] Step 2: Synthesis of Compound 10 Compound 9 (750 mg, 2.73 mmol) was dissolved in methanol (7.5 mL) and acetic acid (0.75 mL). 10% palladium carbon (375 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 19 hours. 30 mL of ethyl acetate was added, and the mixture was filtered through Celite. 10% aqueous potassium carbonate solution (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed twice with water (20 mL), and the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (30-100% ethyl acetate-hexane) to give compound 10 (488 g, 1.75 mmol, yield 64%) as a colorless oil. 1H-NMR (CDCl3) δ: 0.88 (6H, d, J = 6.5 Hz), 1.43 (9H, s), 1.50-1.61 (2H, m), 1.72-1.79 (1H, m), 3.47 (2H, d, J = 7.3 Hz), 3.86 (2H, s), 7.16 (2H, d, J = 8.0 Hz), 7.27 (2H, d, J = 9.8 Hz).

[0090] Step 3, Step 4, and Step 5: Synthesis of Compound (I-030) Compound 11 was synthesized using 1-methyl-1-pyrazole-3-carbaldehyde and compound 10 in the same manner as in Reference Example 1, compound 12 was synthesized in the same manner as in Step 1 of Example 2, and then compound (I-030) was obtained as a colorless oil in the same manner as in Step 5 of Example 3. 1H-NMR (CDCl3) δ: 0.97 (3H, s), 0.99 (3H, s), 1.39-1.41 (2H, m), 1.87-1.91 (3H, m), 2.08-2.11 (2H, br m), 2.24 (3H, s), 2.65 (2H, br s), 2.92 (2H, d, J = 4.3 Hz), 3.67 (2H, br s), 3.83 (3H, s), 4.28 (2H, s), 4.41 (2H, s), 5.28 (1H, br s), 5.92 (1H, d, J = 1.9 Hz), 6.56 (2H, d, J = 8.3 Hz), 7.10 (2H, d, J = 8.3 Hz), 7.23 (1H, d, J = 1.9 Hz).

[0091] Synthesis of compound (I-012) Step 1: Synthesis of Compound (I-012) To a solution of compound 3 (48.9 mg, 0.18 mmol) in dimethylformamide (489 μL), 1-methylpiperidine-4-carboxylic acid (56.2 mg, 0.36 mmol), HATU (102.0 mg, 0.27 mmol), and diisopropylethylamine (62.5 μL, 0.36 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (chloroform-methanol) to give compound (I-012) (44.9 mg, yield 61%) as a yellow oil. 1H-NMR (CDCl3) δ: 1.02 (12H, t, J = 6.5 Hz), 1.19-1.31 (4H, m), 1.76 (4H, s), 1.94 (6H, d, J = 10.3 Hz), 2.03-2.09 (2H, m), 2.24-2.28 (7H, m), 2.38 (2H, d, J = 6.8 Hz), 2.79-2.82 (5H, br m), 3.70 (4H, t, J = 3.3 Hz), 3.84 (3H, s), 3.87 (3H, s), 4.36 (2H, s), 4.47 (2H, s), 4.55 (4H, s), 6.00 (1H, s), 6.18 (1H, s), 6.84 (4H, t, J = 8.5 Hz), 7.06 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.27 (1H, s), 7.28 (1H, s).

[0092] Synthesis of compound (I-112)

[0093] Step 1: Synthesis of Compound 13 2-Fluoro-4-hydroxybenzonitrile (5.00 g, 36.5 mmol) was dissolved in DMF (50 mL), potassium carbonate (15.12 g, 109 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.52 mL, 38.3 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed three times with water (100 mL) and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give Compound 13 (7.90 g, 98% yield) as a crude product. 1 H-NMR (CDCl3) δ: 4.41 (2H, q, J = 7.8 Hz), 6.72-6.89 (2H, m), 7.58-7.64 (1H, m).

[0094] Step 2: Compound 13 (4.17 g, 19.0 mmol) was dissolved in THF (41.7 mL), and 0.89 mol / L borane-THF solution (32.1 mL, 28.5 mmol) was added. The mixture was heated to reflux for 70 minutes. Under ice-cooling, 2 mol / L hydrochloric acid (28.5 mL, 57.1 mmol) was added, followed by heating to reflux for 1 hour. Ethyl acetate (100 mL) was added, and the layers were separated. A 2 mol / L aqueous sodium hydroxide solution (28.5 mL, 57.1 mmol) was added to the resulting aqueous layer, and the mixture was extracted twice with chloroform (100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 14 (1.46 g, yield 34%). 1 H-NMR (CDCl3) δ: 3.85 (2H, s), 4.33 (2H, q, J = 8.1 Hz), 6.65-6.70 (2H, m), 7.23-7.29 (1H, m).

[0095] Step 3: Synthesis of Compound 15 Using compound 14 and 2-cyclopropyl-4-oxazole-carbaldehyde, compound 15 (614 mg, yield 61%) was synthesized in the same manner as in Step 1 of Example 1. 1H-NMR (CDCl3) δ: 0.98-1.08 (4H, m), 1.98-2.06 (1H, m), 3.65 (2H, s), 3.80 (2H, s), 4.29-4.36 (2H, m), 6.64-6.74 (2H, m), 7.30 (1H, t, J = 8.4 Hz), 7.35 (1H, s).

[0096] Step 4 Synthesis of Compound (I-112) Compound (I-112) (219 mg, yield 72%) was synthesized using compound 15 and 1-methylpiperidin-4-amine in the same manner as in Step 2 of Example 1. 1H-NMR (CDCl3) δ: 1.00-1.05 (4H, m), 1.45-1.57 (2H, m), 1.93-2.03 (3H, m), 2.08-2.17 (2H, m), 2.28 (3H, s), 2.72-2.81 (2H, m), 3.61-3.72 (1H, m), 4.09 (2H, s), 4.33 (2H, q, J = 8.0 Hz), 4.46 (2H, s), 6.07 (1H, d, J = 7.5 Hz), 6.63-6.73 (2H, m), 7.23 (1H, s), 7.39 (1H, t, J = 8.6 Hz).

[0097] Synthesis of compound (I-086) Step 1: Synthesis of Compound 16 1-Butanol (9.00 g, 121 mmol) was dissolved in DMF (56 mL) and THF (14 mL). Sodium hydride (60 w / w%, 4.62 g, 116 mmol) was added under ice-cooling, and the mixture was stirred for 30 minutes. A solution of 4-fluorobenzonitrile (7.00 g, 57.8 mmol) in DMF (14 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (300 mL) and extracted twice with ethyl acetate (60 mL). The organic layer was washed with water (300 mL) and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound 16 (12.1 g) as a crude product. 1H-NMR (CDCl3) δ: 0.98 (3H, t, J = 7.4 Hz), 1.44-1.55 (2H, m), 1.74-1.83 (2H, m), 4.00 (2H, t, J = 6.5 Hz), 6.93 (2H, d, J = 8.9 Hz), 7.57 (2H, d, J = 8.9 Hz).

[0098] Step 2: Synthesis of Compound 17 Compound 16 (12.1 g, 68.9 mmol) was dissolved in methanol (217 mL), and acetic acid (7.89 mL, 138 mmol) and 10 wt% palladium on carbon (1.47 g) were added. The mixture was stirred under 1 atmosphere of hydrogen for 2.5 hours. The reaction mixture was filtered through Celite, and the solvent in the filtrate was evaporated under reduced pressure. A 1 mol / L aqueous sodium hydroxide solution (150 mL) was added to the resulting residue, and the mixture was extracted twice with ethyl acetate (150 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound 17 (12.1 g, 98% yield). 1H-NMR (CDCl3) δ: 0.97 (3H, t, J = 7.3 Hz), 1.44-1.53 ​​(2H, m), 1.71-1.81 (2H, m), 3.80 (2H, s), 3.95 (2H, t, J = 6.5 Hz), 6.87 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz).

[0099] Step 3: Synthesis of Compound 18 Compound 18 (2.79 g, 90% yield) was synthesized using compound 17 and 2-methyl-4-oxazolecarbaldehyde in the same manner as in Step 1 of Example 1. H-NMR (CDCl) δ: 0.97 (3H, t, J = 7.4 Hz), 1.42-1.55 (2H, m), 1.72-1.80 (2H, m), 2.44 (3H, s), 3.66 (2H, s), 3.74 (2H, s), 3.95 (2H, t, J = 6.5 Hz), 6.85 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.40 (1H, s).

[0100] Step 4 Synthesis of Compound (I-086) Compound (I-086) (0.125 g, yield 40%) was synthesized using compound 18 and 1-methylpiperidin-4-amine in the same manner as in Step 2 of Example 1. 1H-NMR (CDCl3) δ: 7.20 (1H, s), 7.18 (2H, d, J = 9.2 Hz), 6.84 (2H, d, J = 9.2 Hz), 5.60 (1H, s), 4.43 (2H, s), 4.16 (2H, s), 3.95 (2H, t, J = 6.5 Hz), 3.67 (1H, br s), 2.69 (2H, br s), 2.41 (3H, s), 2.26 (3H, s), 2.11 (2H, t, J = 9.4 Hz), 1.96-1.92 (2H, m), 1.78-1.74 (2H, m), 1.54-1.40 (4H, m), 0.98 (3H, t, J = 7.4 Hz).

[0101] Synthesis of compound (I-082) Step 1: Synthesis of Compound (I-082) Compound 3 (49.3 mg, 0.230 mmol) and pyridine (0.053 mL, 0.658 mL) were dissolved in dichloromethane (0.6 mL), and compound 19 (49.3 mg, 0.048 mmol) (the synthesis method is described in Journal of Medicinal Chemistry, 1990, Vol. 33, No. 8, pp. 2101-2108) was added, followed by stirring at room temperature for 8 hours. The reaction solution was purified by aminosilica gel column chromatography to obtain compound (I-082) (20.0 mg, 0.048 mmol, 22% yield) as a colorless oil. 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.8 Hz), 1.76 (2H, br s), 1.94 (2H, br s), 2.02-2.12 (1H, m), 2.25 (5H, br s), 2.56 (2H, br s), 3.70 (2H, d, J = 6.7 Hz), 3.86 (3H, s), 4.38 (4H, dd, J = 26.2, 9.7 Hz), 4.79 (1H, br s), 6.08-6.18 (1H, br m), 6.83 (2H, d, J = 8.4 Hz), 7.14-7.26 (3H, m).

[0102] Synthesis of compound (I-108) Step 1 Synthesis of Compound 20 4-Bromobenzonitrile (2.0 g, 11 mmol) was dissolved in toluene (10 mL), and propylboronic acid (1.45 g, 16.5 mmol), cesium carbonate (8.95 g, 27.5 mmol), and PdCl ２(dppf) (0.40 g, 0.55 mmol) was added, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 8 hours. The reaction mixture was filtered through Celite, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 20 (1.40 g, 88%) as a pale yellow oil. 1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.4 Hz), 1.66 (2H, sextet, J = 7.4 Hz), 2.64 (2H, J = 7.4 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).

[0103] Step 2: Synthesis of Compound 21. Compound 20 (1.39 g) was dissolved in THF (13.9 mL), and 16.1 mL of a borane-THF complex THF solution (0.89 mol / L) was added at room temperature under a nitrogen atmosphere. The mixture was refluxed for 3 hours. After cooling in an ice bath, 2 mol / L hydrochloric acid (14.4 mL) was slowly added, followed by reflux for 2.5 hours. The reaction mixture was cooled and extracted with ethyl acetate (20 mL). The organic layer was extracted twice with 2 mol / L hydrochloric acid (5 mL). The combined aqueous layers were made basic with 2 mol / L aqueous sodium hydroxide solution and extracted three times with chloroform (20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 21 (1.39 g, 97%) as a colorless oil. 1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.3 Hz), 1.63 (2H, sextet, J = 7.7 Hz), 2.57 (2H, t, J = 7.7 Hz), 3.83 (2H, s), 7.15 (2H, d, J = 8.0 Hz), 7.22 (2H, d, J = 8.0 Hz).

[0104] Step 3: Synthesis of Compound 22 Compound 22 (680 mg, 83% yield) was synthesized using compound 21 and 2-methyl-4-oxazole-carbaldehyde in the same manner as in Step 1 of Example 1. H-NMR (CDCl) δ: 0.93 (3H, t, J = 7.5 Hz), 1.63 (2H, sextet, J = 7.5 Hz), 2.43 (3H, s), 2.57 (2H, t, J = 7.5 Hz), 3.67 (2H, s), 3.78 (2H, s), 7.13 (2H, d, J = 8.0 Hz), 7.24 (2H, d, J = 8.0 Hz).

[0105] Step 4 Synthesis of Compound (I-108) Compound (I-108) (374 mg, yield 95%) was synthesized using compound 22 and 1-methylpiperidin-4-amine in the same manner as in Step 2 of Example 1. 1H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.3 Hz), 1.40-1.50 (2H, m), 1.58-1.71 (2H, m), 1.92-1.96 (2H, m), 2.11 (2H, t, J = 10.2 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.57 (2H, t, J = 7.6 Hz), 2.68 (2H, br), 3.69 (1H, br), 4.18 (2H, s), 4.47 (2H, s), 5.59 (1H, br), 7.13 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz), 7.18 (1H, s).

[0106] The following compounds were synthesized according to the general synthesis method and the methods described in the Examples. The structures and physical properties (LC / MS data, NMR spectra) are shown in the table below. In the structural formulas, a "wedge" and a "dashed line" indicate the configuration. In particular, among compounds for which the configuration is described, compounds with "a" in the "S" column are racemic compounds with a specified relative configuration. Compounds with "b" in the "S" column are single enantiomers with a specified relative configuration but with an unknown absolute configuration. Compounds with "c" in the "S" column indicate that the configuration is determined as shown in the chemical structure. Furthermore, among compounds in which the bond forming the asymmetric carbon is described with a solid line, compounds with "d" in the "S" column are racemic compounds. Compounds with "e" in the "S" column are racemic compounds and diastereomeric mixtures thereof. Compounds with "f" in the "S" column are single enantiomers with an unspecified configuration.

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[0141] Examples of biological tests for the compounds according to the present invention are described below. Biological tests for the compounds according to the present invention can be performed using the test procedures described in the following biological test examples or essentially the same test procedures. The compounds represented by formula (I), (I'), or (II') according to the present invention have serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity, and antagonize the human serotonin 5-HT2A receptor. The compounds represented by formula (I), (I'), or (II') according to the present invention have serotonin 5-HT2A and 2C receptor antagonistic and / or inverse agonistic activity, and antagonize the human serotonin 5-HT2A and 2C receptors. Specifically, in the evaluation methods described below, the Ki value is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.

[0142] Test Example 1: 5-HT2A receptor binding inhibition test (Experimental conditions) Cell membrane: Jump-In HEK cell membrane (expressing human recombinant 5-HT2A receptor) Assay buffer: NaCl 120 mmol / L, MgCl ２ ・6H ２ O 1 mmol / L, KCl 5 mmol / L, 0.1% BSA and CaCl ２ 2 mmol / L Tris-HCl 50 mmol / L (pH 7.4) Radioactive ligand: [ ３[H]-Ketanserin Nonspecific Ligand: Serotonin HCl The Kd value was calculated when the cell membrane lot was changed. 0.5 μL of 1 mmol / L nonspecific binding calculation compound or DMSO dissolved in DMSO was dispensed into a microplate, and the cell membrane was diluted with assay buffer. The radioactive ligand solution was serially diluted and counted using a liquid scintillator. 50 μL / well of the assay buffer containing the diluted cell membrane was dispensed into the microplate. 50 μL / well of the radioactive ligand solution was then dispensed into the microplate, and the plate was sealed. The plate was left to stand at room temperature (25°C) for 1.5 hours. During this time, 50 μL / well of 50 mmol / L Tris-HCl (pH 7.4) was dispensed into a GF / B UniFilter plate and left to stand at 4°C for at least 1 hour. Then, filtration was performed using a Cell Harvester (PerkinElmer). 10 μL / well of the radioactive ligand solution was dispensed into empty wells of the GF / B UniFilter plate. After the GF / B UniFilter plate was dried at room temperature, 50 μL / well of MicroScinti20 was dispensed into the GF / B UniFilter plate, and the plate was sealed. The GF / B UniFilter plate was left standing overnight at room temperature. [ ３The radioactivity of [H]-Ketanserin was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve was plotted from the measured values, and the Kd value was calculated from the slope of the Scatchard plot. (Binding test of the compound according to the present invention) 0.5 μL of compound solution dissolved in DMSO was dispensed into a microplate in advance, and the cell membrane and hot ligand were each diluted with assay buffer. Then, 50 μL / well of the assay buffer containing the diluted cell membrane was dispensed into the microplate. Then, 50 μL / well of the radioactive ligand solution was dispensed into the microplate, and the plate was sealed. The plate was then left to stand at room temperature (25°C) for 1.5 hours. During this time, 50 μL / well of 50 mmol / L Tris-HCl (pH 7.4) was dispensed into the GF / B UniFilter plate and left to stand at 4°C for at least 1 hour. Then, filtration was performed using a Cell Harvester (PerkinElmer). After the GF / B UniFilter plate was dried at room temperature, 50 μL / well of MicroScinti20 was dispensed into the GF / B UniFilter plate and the plate was sealed. The GF / B UniFilter plate was left to stand overnight at room temperature. The 5-HT2A receptor-bound [ ３ The radioactivity of [H]-Ketanserin was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Non-specific binding was measured in the presence of 500 μmol / L unlabeled ligand Serotonin HCl, and total binding was measured in the absence of the compound of the present invention (vehicle). ３The binding activity of the compound according to the present invention was calculated from the radioactivity of [H]-Ketanserin. Finally, the Ki value was calculated from the dose-response curve. (The binding activity of the compound according to the present invention was calculated from the binding inhibition rate (%) below.) Inhibition rate (%) = [1 - (ca) / (ba)] x 100 a; mean cpm of non-specific binding b; mean cpm of total binding c; cpm in the presence of test compound (Results) The evaluation results for the binding activity of the compound according to the present invention to human serotonin 5-HT2A receptor are shown below. Note that Ki values ​​are categorized as "A" for less than 10 nM, "B" for 10 nM or more but less than 100 nM, and "C" for 100 nM or more but less than 5000 nM. Compound I-003: 9.93nM Compound I-004: 4.51nM Compound I-006: 0.968nM Compound I-012: 6.02nM Compound I-015: 45.5nM Compound I-029: 4.33nM Compound I-030: 2.17nM Compound I-031: 0.709nM Compound I-033: 4.01nM Compound I-037: 4.70nM Compound I-043: 2.14nM Compound I-046: 3.09nM Compound I-084: 2.61nM Compound I-086: 0.503nM Compound I-101: 0.683nM Compound I-102: 0.642nM Compound I-103: 1.89nM Compound I-104: 0.952nM Compound I-107: 0.549nM Compound I-109: 0.430nM Compound I-110: 0.537nM Compound I-117: 0.820nM Compound I-118: 1.03nM Compound I-122: 0.824nM Compound I-123: 0.506nM Compound I-126: 1.24nM

[0143] Test Example 2: 5-HT2C receptor binding inhibition test (Experimental conditions) Cell membrane: Jump-In HEK cell membrane (expressing human recombinant 5-HT2C receptor) Assay buffer: NaCl 120 mmol / L, MgCl ２ ・6H ２ O 1 mmol / L, KCl 5 mmol / L, 0.1% BSA and CaCl ２2 mmol / L Tris-HCl 50 mmol / L (pH 7.4) Radioactive ligand: [ ３ [H]-Mesulergine Nonspecific Ligand: Serotonin HCl The Kd value was calculated when the cell membrane lot was changed. 0.5 μL of 1 mmol / L nonspecific binding calculation compound or DMSO dissolved in DMSO was dispensed into a microplate, and the cell membrane was diluted with assay buffer. The radioactive ligand solution was serially diluted and counted using a liquid scintillator. 50 μL / well of the assay buffer containing the diluted cell membrane was dispensed into the microplate. 50 μL / well of the radioactive ligand solution was then dispensed into the microplate, and the plate was sealed. The plate was left to stand at room temperature (25°C) for 1.5 hours. During this time, 50 μL / well of 50 mmol / L Tris-HCl (pH 7.4) was dispensed into a GF / B UniFilter plate and left to stand at 4°C for at least 1 hour. Then, filtration was performed using a Cell Harvester (PerkinElmer). 10 μL / well of the radioactive ligand solution was dispensed into empty wells of the GF / B UniFilter plate. After the GF / B UniFilter plate was dried at room temperature, 50 μL / well of MicroScinti20 was dispensed into the GF / B UniFilter plate, and the plate was sealed. The GF / B UniFilter plate was left standing overnight at room temperature. [ ３The radioactivity of [H]-Ketanserin was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve was plotted from the measured values, and the Kd value was calculated from the slope of the Scatchard plot. (Binding test of the compound according to the present invention) 0.5 μL of compound solution dissolved in DMSO was dispensed into a microplate in advance, and the cell membrane and hot ligand were each diluted with assay buffer. Then, 50 μL / well of the assay buffer containing the diluted cell membrane was dispensed into the microplate. Then, 50 μL / well of the radioactive ligand solution was dispensed into the microplate, and the plate was sealed. Then, the plate was left to stand at 37°C for 2 hours. During this time, 50 mmol / L Tris-HCl (pH 7.4) was dispensed into the GF / B UniFilter plate at 50 μL / well and left to stand at 4°C for at least 1 hour. Then, filtration was performed using a Cell Harvester (PerkinElmer). After the GF / B UniFilter plate was dried at room temperature, 50 μL / well of MicroScinti20 was dispensed into the GF / B UniFilter plate and sealed. The GF / B UniFilter plate was left to stand overnight at room temperature. The 5-HT2A receptor-bound [ ３ The radioactivity of [H]-Mesulergine was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Nonspecific binding was measured in the presence of 500 μmol / L unlabeled ligand Serotonin HCl, and total binding was measured in the absence of the compound of the present invention (vehicle). ３The binding activity of the compound according to the present invention was calculated from the radioactivity of [H]-mesulergine. Finally, the Ki value was calculated from the dose-response curve. (The binding activity of the compound according to the present invention was calculated from the binding inhibition rate (%) below.) Inhibition rate (%) = [1 - (ca) / (ba)] x 100 a; mean cpm of non-specific binding b; mean cpm of total binding c; cpm in the presence of test compound (Results) The evaluation results of the human serotonin 5-HT2C receptor binding inhibitory activity of the compound according to the present invention are shown below. Note that the Ki value is rated as "A" for less than 10 nM, "B" for 10 nM or more but less than 100 nM, and "C" for 100 nM or more but less than 5000 nM. Compound I-003: 8.39nM Compound I-004: 11.5nM Compound I-006: 2.47nM Compound I-012: 33.0nM Compound I-015: 136nM Compound I-029: 20.5nM Compound I-030: 7.76nM Compound I-031: 1.89nM Compound I-033: 28.9nM Compound I-037: 2.11nM Compound I-043: 3.07nM Compound I-046: 14.5nM Compound I-084: 5.78nM Compound I-086: 0.241nM Compound I-101: 0.461nM Compound I-102: 0.412nM Compound I-103: 0.634nM Compound I-104: 0.484nM Compound I-107: 0.340nM Compound I-109: 0.463nM Compound I-110: 0.301nM Compound I-117: 0.315nM Compound I-118: 0.371nM Compound I-122: 0.281nM Compound I-123: 1.39nM Compound I-126: 6.25nM

[0144] Test Example 3: hERG Test For the purpose of evaluating the risk of electrocardiogram QT interval prolongation of the compound according to the present invention, a delayed rectifier K channel, which plays an important role in the ventricular repolarization process, was measured using CHO cells expressing the human ether-a-go-go related gene (hERG) channel. ＋ Current (I ＫｒThe effect of the compound of the present invention on the I-cell response was investigated using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S) by the whole-cell patch clamp method. The cells were held at a membrane potential of −80 mV, and a leak potential of −50 mV was applied. Then, a depolarizing stimulus of +20 mV was applied for 2 seconds, followed by a repolarizing stimulus of −50 mV for 2 seconds. Ｋｒ The extracellular solution was adjusted to 0.1% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ２ :2 mmol / L, MgCl ２ The vehicle used was a mixture of 1 mmol / L of ATP, 10 mmol / L of glucose, and 10 mmol / L of HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), pH 7.4. The vehicle and the extracellular solution containing the compound according to the present invention dissolved at the desired concentration were applied to the cells at room temperature for 15 minutes or more. Ｋｒ The absolute value of the maximum tail current was measured using analysis software (QPatch Assay software; Sophion Bioscience A / S) based on the current value at the resting membrane potential. The maximum tail current after application of the compound according to the present invention relative to the maximum tail current after application of the vehicle was calculated as an inhibition rate, and further correction was made using the inhibition rate result of the negative control to determine the I of the compound according to the present invention. Ｋｒ The dilution concentration will be changed as necessary.

[0145] Test Example 3-2: hERG Test For the purpose of evaluating the risk of electrocardiogram QT interval prolongation of the compound according to the present invention, the action of the compound was examined by evaluating potassium channel activity using CHO cells expressing the human ether-a-go-go related gene (hERG) channel. Evaluation was carried out using a FluxORII Green Potassium Ion Channel Assay Kit (Invitrogen: Molecular Probes). Cells were seeded in a 384 assay plate (8000 cells / well / 40 μL) and incubated overnight (37°C, 5% CO ２ After replacing the medium with wash buffer (1xHBSS, 20 mM HEPES) using a microplate washer, a fluorescent indicator dye was added to the medium and incubated for 1 hour (37°C, 5% CO2) to allow the fluorescent indicator dye to be incorporated into the cells. ２ ) was placed on a cell-based kinetic assay system FLIPR (Molecular Devices), and the compound was added to the cells to the desired concentration and allowed to react for 10 minutes. When a mixture of potassium and thallium, which are stimulants, was added thereto, the potassium channel opened, and the thallium that flowed into the cells bound to the fluorescent indicator dye, increasing the intracellular fluorescent signal, and the potassium channel current was detected as a fluorescent signal. The inhibition rate at each concentration was calculated from the signal intensity at each concentration, with the signal intensity when E-4031 was added to the cells at a final concentration of 10.3 μmol / L defined as 100% inhibition, and the signal intensity when DMSO was added to the cells at a final concentration of 0.7% defined as 0% inhibition. The inhibition rate was calculated from the signal intensity at each concentration. The IC ５０ was calculated. (Results) Compound I-081: IC ５０ >52.0 μM Compound I-082: IC ５０ >52.0 μM Compound I-083: IC ５０ >52.0 μM Compound I-084: IC ５０ >52.0 μM Compound I-099: IC ５０ = 46.8 μM

[0146] Test Example 4: BA Test Materials and Methods for Experiments to Examine Oral Absorbability (1) Animals Used: Mice or rats are used. (2) Breeding Conditions: Mice or rats are allowed free access to solid feed and sterilized tap water. (3) Dosage and Grouping: Oral and intravenous administration is performed at the specified dosage. Groups are set up as follows. The dosage is changed for each compound as necessary. Oral Administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous Administration: 1-30 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of Dosage Solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization. (5) Administration Method: Oral administration is administered by forced administration into the stomach using an oral probe. Intravenous administration is administered via the tail vein using a syringe with an injection needle attached. (6) Evaluation item: Blood is collected over time, and the plasma concentration of the compound according to the present invention is measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound according to the present invention is calculated by moment analysis for the change in plasma concentration of the compound according to the present invention, and the bioavailability (BA) of the compound according to the present invention is calculated from the dose ratio and AUC ratio between the oral administration group and the intravenous administration group. The dilution concentration and dilution solvent are changed as necessary.

[0147] Test Example 5: Clearance Evaluation Test Experimental Materials and Methods (1) Animals: SD rats were used. (2) Breeding Conditions: SD rats were allowed free access to solid feed and sterilized tap water. (3) Dosage and Grouping: Intravenous administration was performed at a predetermined dose. Groups were set up as follows: Intravenous administration: 1 μmol / kg (n=2) (4) Preparation of Dosage Solution: Solubilized and administered using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent. (5) Administration Method: Administered via the tail vein using a syringe with an injection needle. (6) Evaluation Items: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical Analysis: The total body clearance (CLtot) was calculated using moment analysis of the plasma concentration of the compound of the present invention. The dilution concentration and dilution solvent were changed as necessary.

[0148] Test Example 6: Metabolic Stability Test Commercially available pooled human liver microsomes were reacted with the compound of the present invention for a certain period of time, and the residual rate was calculated by comparing the reacted sample with the unreacted sample to evaluate the extent of hepatic metabolism of the compound of the present invention. Human liver microsomes were reacted in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction mixture was added to 100 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifuged supernatant was quantified by LC / MS / MS or solid-phase extraction (SPE) / MS, and the amount of compound remaining after the reaction was calculated, assuming the amount of compound at 0 minutes of reaction as 100%. The hydrolysis reaction is carried out in the absence of NADPH, and the glucuronidation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the subsequent procedures are the same. The dilution concentration and dilution solvent are changed as necessary.

[0149] Test Example 6-2: Metabolic Stability Test Commercially available pooled human liver microsomes were reacted with the compound of the present invention for a set period of time, and the residual percentage was calculated by comparing the reacted sample with the unreacted sample to evaluate the extent of hepatic metabolism of the compound of the present invention. Human liver microsomes were reacted in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidative reaction). After the reaction, 70 μL of the reaction mixture was added to 140 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3,000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC / MS / MS or solid-phase extraction (SPE) / MS, and the residual percentage of the compound of the present invention after the reaction was calculated, with the amount of compound at 0 minutes of reaction defined as 100%. (Results) The residual rates at a compound concentration of 0.5 μmol / L are shown below. Compound I-016: 99.6% Compound I-028: 90.2% Compound I-043: 85.0% Compound I-077: 85.3% Compound I-086: 75.5% Compound I-088: 80.0% Compound I-102: 97.3%

[0150] Test Example 7: P-gp substrate test A compound according to the present invention is added to one side of a Transwell (registered trademark, Corning) containing monolayer cultures of human MDR1-expressing cells or parent cells, and allowed to react for a certain period of time. The membrane permeability coefficients for the MDR1-expressing cells and parent cells in the apical-to-basolateral direction (A→B) and the basolateral-to-apical direction (B→A) are calculated, and the efflux ratio (ER; ratio of the membrane permeability coefficients B→A and A→B) values ​​for the MDR1-expressing cells and parent cells are calculated. The efflux ratios (ER values) of the MDR1-expressing cells and parent cells are compared to determine whether the compound according to the present invention is a P-gp substrate.

[0151] Test Example 8: MK801-Induced Hyperlocomotion Inhibition Test 6-10 week-old Wistar male rats were used. Test compound administration solutions were prepared by dissolving the compound in 30 mmol / L HCl as a solvent, and MK801 administration solutions were prepared by dissolving the compound in physiological saline as a solvent. The MK801-induced hyperlocomotion inhibition test was carried out using SCANET (Melquest), the data acquisition program SCL-40, and transparent plastic cages, as follows: In the breeding room, the compound administration solution (solvent or test compound solution) was administered subcutaneously, and the animals were returned to their breeding cages. Thirty minutes later, the animals were brought into the laboratory and allowed to acclimate to the laboratory. Fifteen minutes later, the rats were gently removed, and MK801 administration solution (solvent or MK801 solution) was administered intraperitoneally, followed by returning them to their breeding cages. Fifteen minutes after intraperitoneal administration, the rats were removed and gently placed in the SCANET, and locomotion measurement was initiated. Measurements were completed 30 minutes after the start of the measurements, and the amount of locomotion for each individual animal over the 30 minutes was totaled. Analysis of the test results was performed as follows. One-way ANOVA (significance level: two-sided 5%) was performed for the test compound and vehicle-administered groups. If the test compound-administered group showed a significant suppression of locomotion compared to the vehicle-administered group, it was determined to have an antipsychotic effect. The results of the above test are shown in Figures 1 and 2. In the figures, ● indicates the total spontaneous motor activity of rats when the vehicle was administered, ■ indicates the total spontaneous motor activity of rats when the Example compound of the present application (3 mg / kg) was administered, and ▲ indicates the total spontaneous motor activity of rats when the Example compound of the present application (10 mg / kg) was administered.

[0152] The following formulation examples are illustrative only and are not intended to limit the scope of the invention. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments, or creams, or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0153] The compounds according to the present invention have serotonin 5-HT2A receptor antagonistic and / or inverse agonistic activity and are considered to be useful as therapeutic and / or preventive agents for diseases or conditions associated with the serotonin 5-HT2A receptor.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R ３ are each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; n is 1 or 2; (L 1 , L ２ ) combination is (NH,N) or (CH 2 ,N); R ４ is the formula: 【Chemistry 2】 wherein p and q are 2; p″ and q″ are each independently 1 or 2; R ａ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ａ’’ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; X ｂ are each independently ｂ R ｂ’ and X ｃ are each independently ｃ R ｃ’ and R ｂ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｂ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ’ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｂ’’ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; R ｃ’’ is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy; X ｄ is CR ｄ or N; X ｄ’’ is CR ｄ or N; R ｄ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl; R ｂ and R ｂ’ And R ｃ and R ｃ’ may, together with the same carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｂ is R ａ and a nitrogen atom to which R ｂ together with the carbon atom to which it is attached may form a substituted or unsubstituted non-aromatic heterocycle; or R ａ And, R ａ R bonded to the carbon atom adjacent to the nitrogen atom to which ｃ is R ａ and a nitrogen atom to which R ｃ together with the carbon atom to which it is attached may form a substituted or unsubstituted non-aromatic heterocycle; R ｂ and R ｃ together form a (C1-C3) bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom; R ａ and R ｄ is a group represented by the formula (C1-C3) (which together form a bridge, one of the carbon atoms constituting the bridge may be replaced by an oxygen atom); R ５ and R ６ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R ５ and R ６ may, together with the same carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring; R ７ is the formula: 【Chemistry 3】 (In the formula, A is CR １１ or N; R ９ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted amino, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group or a cyano; R １０ is a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R ９ and R １０ may be joined together to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle; R １１ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group) (provided that the compound represented by the following formula: 【Chemistry 4】 ) or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is CH.

3. X ｄ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is CH.

4. R ２ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ３ The compound according to any one of claims 1 to 3, wherein each is independently a hydrogen atom or a substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof.

5. R ５ and R ６ The compound according to any one of claims 1 to 4, wherein each is independently a hydrogen atom or a substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof.

6. R １ is a substituted or unsubstituted 5-membered aromatic heterocyclic group, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-3-yl, substituted or unsubstituted pyridazin-3-yl, substituted or unsubstituted pyrimidin-2-yl, substituted or unsubstituted pyrimidin-5-yl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted 9-membered aromatic heterocyclic group, substituted or unsubstituted 10-membered aromatic heterocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group, or a pharma- ceutical acceptable salt thereof.

7. R １ The compound according to any one of claims 1 to 6, wherein is a substituted or unsubstituted 5-membered aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof.

8. A compound comprising: 【Chemistry 5】 【Chemistry 6】 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist.

11. The pharmaceutical composition according to claim 9, which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist and a 5-HT2C receptor antagonist and / or inverse agonist.

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