Aromatic heterocyclic derivatives with serotonin receptor binding activity

Abstract

This invention provides compounds having serotonin 5-HT2A receptor inverse agonist activity or pharmaceutically permissible salts thereof, and compositions for serotonin 5-HT2A receptor inverse agonist containing the like. The compositions for serotonin 5-HT2A receptor inverse agonist contain a compound represented by formula (I) or a pharmaceutically permissible salt thereof, wherein in formula (I), R... 1 It is a substituted or unsubstituted aromatic heterocyclic group, etc., R 2 Each is independently a hydrogen atom, etc., R 3 Each is independently a hydrogen atom, etc., n is 1 or 2, R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group, and L is -NR. 8 - etc., R 8 It is a hydrogen atom, etc., R 5 Each is independently a hydrogen atom, etc., R 6 Each is independently a hydrogen atom, etc., p is 1 or 2, R 7 It is a basis expressed by the following formula, where R 9 It is a substituted or unsubstituted alkoxy group, etc., R 10 It is a hydrogen atom, etc., R 11 It is a halogen, etc., where m is 0 or 1.

Description

Technical Field

[0001] This invention relates to a compound or a pharmaceutically permissible salt thereof, and pharmaceutical compositions containing the same, the compound having a reverse agonist effect on the serotonin 5-HT2A receptor, useful for the treatment and / or prevention of diseases caused by the serotonin 5-HT2A receptor. Background Technology

[0002] Neurodegenerative diseases (NDs) are a group of related human diseases characterized by a common pathophysiological feature: the progressive degeneration of selective groups of neurons over time. These neurodegenerative diseases include, but are not limited to, Alzheimer's disease and related dementias, Parkinson's disease, Huntington's disease, Lewy body disease and related motor disorders. Each disorder has its own unique clinical symptoms, including age of onset, time of progression, neurological signs and symptoms, neuropsychiatric symptoms, and susceptibility to known treatments. Furthermore, the pathophysiological basis of each disorder is caused by disease-specific genetic mechanisms (Non-Patent Literature 1).

[0003] Despite considerable progress in elucidating the underlying genetic causes of these fundamentally different disorders, little is known about the common biochemical mechanisms leading to selective neuronal degeneration. Furthermore, for the most general diseases, including Parkinson's and Alzheimer's, while rare familial genetic factors have been identified, the pathophysiological basis for the majority of sporadic cases remains unknown. Therefore, no specific therapeutic agents exist that can directly alter disease progression. As an alternative, clinicians utilize a variety of existing medications to alleviate the motor, cognitive, and neuropsychiatric symptoms characteristic of these disorders (Non-Patent Literature 2, 3).

[0004] Among the various neurological symptoms characteristic of Parkinson's disease (ND), common symptoms include motor dysfunction such as bradykinesia, dyskinesia, and hopscotch, as well as neuropsychiatric symptoms including psychosis and mood symptoms such as anxiety or depression, which significantly impact patients' functional status and quality of life (Non-Patent Literature 4, 5). Almost all existing treatments, including antipsychotics and antidepressants, while generally effective for these patients, have very low acceptance rates (Non-Patent Literature 6). Furthermore, available Parkinson's disease treatments include L-dopa and dopamine agonists, which, although generally effective, cause management-limiting side effects that are currently unmanageable by pharmacological therapy.

[0005] Although there have been no approved drugs specifically for Parkinson's disease (ND) for a long time, in 2016 the United States approved pipemaserin as a 5-HT2A receptor inverse agonist for hallucinations and delusions associated with Parkinson's disease (Non-Patent Literature 7). This drug has not been reported to cause side effects such as nausea of ​​motor symptoms or cognitive decline as with existing antipsychotics. The primary pharmacological action of pipemaserin is serotonin 5-HT2A receptor inverse agonist / antagonist, and it also has serotonin 5-HT2C receptor inverse agonist activity (Non-Patent Literature 8). Results of 5-HT2A occupancy measured in human PET studies and clinical trials suggest that pipemaserin exerts its effects through 5-HT2A and 2C (Non-Patent Literature 9). However, pipemaserin has significant adverse effects on the cardiovascular system, limiting its use.

[0006] These findings underscore the necessity of developing new therapeutic agents that not only demonstrate efficacy against the specific symptoms leading to physical impairment but are also specifically designed in a way that is inclusive of these particular patient populations. This can be achieved by improving the selectivity of the drug-target interactions of the new therapeutic agents. Specifically, this is achieved by exhibiting potent activity and selectivity against the targeted 5-HT2A and 2C, while reducing adverse effects on the cardiovascular system.

[0007] Patent documents 3 to 14 describe compounds with inverse agonist activity against serotonin 5-HT2A receptors; however, none of these documents describe or imply compounds related to the present invention.

[0008] Existing technical documents

[0009] Patent documents

[0010] Patent Document 1: International Publication No. 2018 / 131672

[0011] Patent Document 2: US Patent No. 8,377,959

[0012] Patent Document 3: International Publication No. 2001 / 066521

[0013] Patent Document 4: International Publication No. 2004 / 064738

[0014] Patent Document 5: International Publication No. 2019 / 040104

[0015] Patent Document 6: International Publication No. 2019 / 040105

[0016] Patent Document 7: International Publication No. 2019 / 040106

[0017] Patent Document 8: International Publication No. 2019 / 040107

[0018] Patent Document 9: International Publication No. 2010 / 111353

[0019] Patent Document 10: International Publication No. 2004 / 000808

[0020] Patent Document 11: International Publication No. 2003 / 057698

[0021] Patent Document 12: Chinese Patent Publication No. 109111385

[0022] Patent Document 13: International Publication No. 2009 / 039461

[0023] Patent Document 14: International Publication No. 2007 / 124136

[0024] Non-patent literature

[0025] Non-patent literature 1: Nature Reviews Neurology, volume 10, pages 620-633 (2014)

[0026] Non-Patent Literature 2: Progress in Neurology and Psychiatry I Vol.22Iss.12018

[0027] Non-patent literature 3: Movement Disorders Vol.24, No.11, 2009, pp.1641-1649

[0028] Non-Patent Literature 4: Parkisonism and related disorder 155.2009.S105-110

[0029] Non-patent literature 5: Neurology. 2004; 63(2):293-300.

[0030] Non-patent literature 6: JAMANeurol. 2016; 73(5): 535-541.

[0031] Non-patent literature 7: Lancet; 383:533-40 (2014)

[0032] Non-patent literature 8: Journal of Pharmacology and Experimental Therapeutics, May 2006, 317(2): 910-918

[0033] Non-patent literature 9: CNS Spectrums (2016), 21, 271-275. Summary of the Invention

[0034] The problem that the invention aims to solve

[0035] The object of this invention is to provide a novel compound having a serotonin 5-HT2A receptor inverse agonist activity and a composition for serotonin 5-HT2A receptor inverse agonist activity. More preferably, this invention provides a novel compound and a medicament containing these compounds that are effective against serotonin-related diseases, such as hallucinations and delusions associated with Parkinson's disease and / or dementia, by having a serotonin 5-HT2A receptor inverse agonist activity.

[0036] Methods for solving problems

[0037] The present invention relates to the following items (1α) to (20α), (1) to (17), (1'), (3'), (7'), (9'), (7”) and (7”').

[0038] (1α) The compound represented by formula (II) or its pharmaceutically permissible salt,

[0039] [Chemistry 1]

[0040]

[0041] (in the formula,

[0042] R 1 Substituted or unsubstituted aromatic heterocyclic groups;

[0043] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0044] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0045] n is 1 or 2;

[0046] R 4 Substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic groups;

[0047] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0048] R 5 It can be a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0049] R6 It can be a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0050] R 7 The basis is as shown in the following formula:

[0051] [Chemistry 2]

[0052]

[0053] (in the formula,

[0054] R 9 The substituted or unsubstituted alkoxy group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted amino group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted alkenyl group, or the substituted or unsubstituted alkyl group;

[0055] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0056] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0057] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0058] m is 0 or 1);

[0059] Except for the following compounds:

[0060] [Chemistry 3]

[0061]

[0062] (2α) The compound or its pharmaceutically permissible salt as described in item (1α) above, wherein R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group.

[0063] (3α) The compound or its pharmaceutically permissible salt as described in item (1α) or (2α) above, wherein R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0064] (4α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (3α) above, wherein R 2 and R 3 It is a hydrogen atom.

[0065] (5α) The compound or its pharmaceutically permissible salt as described in any of the above items (1α) to (4α), wherein n is 1.

[0066] (6α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (5α) above, wherein R 4 It is a substituted or unsubstituted 4 to 7 membered nonaromatic nitrogen-containing heterocyclic group.

[0067] (7α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (6α) above, wherein R 4 It is either substituted or unsubstituted piperidinyl.

[0068] (8α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (7α) above, wherein R 4 It is the basis shown in the following formula:

[0069] [Chemistry 4]

[0070]

[0071] (in the formula,

[0072] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0073] R 22 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0074] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0075] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0076] (9α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (8α) above, wherein R 4 It is the basis shown in the following formula:

[0077] [Chemistry 5]

[0078]

[0079] (where R is in the formula) 21 R 22 and R 23 (Synonymous with the above item (8α)).

[0080] (10α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (9α) above, wherein R 22 It is a halogen, or a substituted or unsubstituted alkyl group;

[0081] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0082] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0083] (11α) The compound or its pharmaceutically permissible salt as described in any of the above items (1α) to (10α), wherein R 8 It is a hydrogen atom.

[0084] (12α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (11α) above, wherein R 5 and R 6 It is a hydrogen atom.

[0085] (13α) The compound or its pharmaceutically permissible salt as described in any of items (1α) to (12α) above, wherein R 7 It is the basis shown in the following formula:

[0086] [Chemistry 6]

[0087]

[0088] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0089] (14α) The compounds described in item (1α) above, or their pharmaceutically permissible salts, are represented by the following formula (III):

[0090] [Chemistry 7]

[0091]

[0092] (in the formula,

[0093] R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group;

[0094] R 4 It is the basis shown in the following formula:

[0095] [Chemistry 8]

[0096]

[0097] (where R is in the formula) 21 (It is a hydrogen atom, or a substituted or unsubstituted alkyl group),

[0098] R 7 It is the basis shown in the following formula:

[0099] [Chemistry 9]

[0100]

[0101] (in the formula,

[0102] R 9 It is a substituted or unsubstituted C2-C4 alkoxy group, or a substituted or unsubstituted amino group.

[0103] (15α) The compound or its pharmaceutically permissible salt as described in item (14α) above, wherein R 1 It is a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0104] (16α) The compound or its pharmaceutically permissible salt as described in item (1α) above, selected from compounds I-008, I-027, I-047, I-102, I-112, I-114, I-115, I-124, I-126, I-129, I-133, I-134, I-138, I-139, I-140, I-141, I-144 and I-145.

[0105] (17α) A pharmaceutical composition containing a compound described in any one of items (1α) to (16α) above, or a pharmaceutically permissible salt thereof.

[0106] (18α) The pharmaceutical composition described in item (17α) above is a serotonin 5-HT2A receptor inverse agonist.

[0107] (19α) A method for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor, characterized by administration of a compound described in any one of the above items (1α) to (16α) or a pharmaceutically permissible salt thereof.

[0108] (20α) The compound or pharmaceutically permissible salt thereof described in any of the above items (1α) to (16α) for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor.

[0109] (21α) Use of the compound described in any of items (1α) to (16α) above, or a pharmaceutically permissible salt thereof, in the manufacture of a treatment and / or preventive agent for diseases involving the serotonin 5-HT2A receptor.

[0110] (1) The compound represented by formula (I) or its pharmaceutically permitted salt,

[0111] [Chemistry 10]

[0112]

[0113] (in the formula,

[0114] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0115] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; n is 1 or 2;

[0116] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0117] L is -NR 8 -, -O- or a single bond;

[0118] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0119] R 5 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; R 6 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; p is 1 or 2;

[0120] R 7 It is the basis represented by the following formula:

[0121] [Chemistry 11]

[0122]

[0123] (in the formula,

[0124] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkyl group;

[0125] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0126] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0127] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0128] m is 0 or 1);

[0129] Except for the compounds shown below,

[0130] [Chemistry 12]

[0131]

[0132] (1') The compound represented by formula (II) or its pharmaceutically permitted salt,

[0133] [Chemistry 13]

[0134]

[0135] (in the formula,

[0136] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0137] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; n is 1 or 2;

[0138] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0139] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0140] R 5 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0141] R 6 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0142] R 7 It is the basis represented by the following formula:

[0143] [Chemistry 14]

[0144]

[0145] (in the formula,

[0146] R 9It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkyl group;

[0147] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0148] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0149] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0150] m is 0 or 1);

[0151] Except for the compounds shown below,

[0152] [Chemistry 15]

[0153]

[0154] (2) The compound or its pharmaceutically permissible salt as described in item (1) or (1') above, wherein R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group.

[0155] (3) The compound or its pharmaceutically permissible salt as described in any of items (1), (2) and (1') above, wherein R 1 It is a substituted or unsubstituted 6-membered aromatic heterocyclic group, or a substituted or unsubstituted 5-membered aromatic heterocyclic group.

[0156] (3') The compound or its pharmaceutically permissible salt as described in item (1) or (1') above, wherein R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0157] (4) The compound or its pharmaceutically permissible salt described in any of the above items (1) to (3), (1') and (3'), wherein R 2 and R 3 It is a hydrogen atom.

[0158] (5) The compound or its pharmaceutically permissible salt described in any of the above items (1) to (4), (1') and (3'), wherein n is 1.

[0159] (6) The compound or its pharmaceutically permissible salt described in any of the above items (1) to (5), (1') and (3'), wherein R 4 It is a substituted or unsubstituted 4 to 7 membered nonaromatic nitrogen-containing heterocyclic group.

[0160] (7) The compound or its pharmaceutically permissible salt described in any of the above items (1) to (6), (1') and (3'), wherein R 4 It is either substituted or unsubstituted piperidinyl.

[0161] (7') The compound or its pharmaceutically permissible salt described in any of the above items (1) to (7), (1') and (3'), wherein R 4 It is the basis represented by the following formula:

[0162] [Chemistry 16]

[0163]

[0164] (in the formula,

[0165] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0166] R 22 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0167] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0168] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0169] (7”) The compound or pharmaceutically permissible salt thereof described in any of the above items (1) to (7), (1'), (3') and (7'), wherein R 4 It is the basis represented by the following formula:

[0170] [Chemistry 17]

[0171]

[0172] (in the formula,

[0173] R 21 R 22 and R 23 It is synonymous with the above item (7').

[0174] (7”') The compound or its pharmaceutically permissible salt as described in item (7”) above, wherein R22 It is a halogen, or a substituted or unsubstituted alkyl group;

[0175] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0176] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0177] (8) The compound or its pharmaceutically permissible salt as described in any of items (1) to (7) above, wherein L is -NR 8 - or -O-.

[0178] (9) The compound or its pharmaceutically permissible salt described in any of the above items (1) to (8), wherein L is -NH-.

[0179] (9') The compound or its pharmaceutically permissible salt described in any of the above items (1'), (3'), (7'), (7”) and (7”'), wherein R 8 It is a hydrogen atom.

[0180] (10) The compound or its pharmaceutically permissible salt described in any of the above items (1) to (9), (1'), (3'), (7'), (9'), (7”) and (7”'), wherein R 5 and R 6 It is a hydrogen atom.

[0181] (11) The compound or its pharmaceutically permissible salt as described in any of the above items (1) to (10), wherein p is 1.

[0182] (12) The compound or its pharmaceutically permissible salt described in any of the above items (1) to (11), (1'), (3'), (7'), (9'), (7”) and (7”'), wherein R 7 It is the basis represented by the following formula:

[0183] [Chemistry 18]

[0184]

[0185] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0186] (13) A pharmaceutical composition comprising a compound described in any one of the above items (1) to (12), (1'), (3'), (7'), (9'), (7”) and (7”') or a pharmaceutically permissible salt thereof.

[0187] (14) The pharmaceutical composition described in item (13) above is a serotonin 5-HT2A receptor inverse agonist.

[0188] (15) A method for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor, characterized in that the compound described in any one of the above items (1) to (12), (1'), (3'), (7'), (9'), (7”) and (7”') or a pharmaceutically permissible salt thereof is administered.

[0189] (16) The compound or pharmaceutically permissible salt thereof described in any of the above items (1) to (12), (1'), (3'), (7'), (9'), (7”) and (7”'), for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor.

[0190] (17) The use of any of the compounds described in any of the items (1) to (12), (1'), (3'), (7'), (9'), (7”) and (7”') above, or pharmaceutically permissible salts thereof, for the manufacture of therapeutic and / or preventive agents for diseases involving the serotonin 5-HT2A receptor.

[0191] In addition, the present invention relates to the following items (1αA) to (22αA), (1A) to (15A), (1'A) to (7'A), (9'A), (10'A), (12'A), (1”A), (7”A), (1”'A), (7”'A) and (7””A).

[0192] (1αA) A serotonin 5-HT2A receptor inverse agonist containing a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0193] [Chemistry 19]

[0194]

[0195] (in the formula,

[0196] R 1 It is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;

[0197] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0198] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0199] n is 1 or 2;

[0200] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0201] L is -NR 8 -, -O- or a single bond;

[0202] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0203] R 5 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0204] R 6 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0205] p is 1 or 2;

[0206] R 7 It is the basis represented by the following formula:

[0207] [Chemistry 20]

[0208]

[0209] (in the formula,

[0210] R 9 It is a hydrogen atom, halogen, substituted or unsubstituted alkoxy group, substituted or unsubstituted non-aromatic carboxy group, substituted or unsubstituted amino group, substituted or unsubstituted non-aromatic carbcyclic group, substituted or unsubstituted alkenyl group, or substituted or unsubstituted alkyl group;

[0211] R 10 It is a hydrogen atom, a hydroxyl group, a halogen, or a substituted or unsubstituted alkyl group;

[0212] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0213] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0214] m is 0 or 1);

[0215] Except for the following compounds (i) and (ii):

[0216] (i) L is a single bond and R 1 It is a compound with substituted or unsubstituted furanyl or substituted or unsubstituted thiopheneyl groups;

[0217] (ii) L is -NR 8 -and R 1 It is a compound of substituted or unsubstituted 2,3-dihydrobenzofuranyl groups.

[0218] (2αA) The serotonin 5-HT2A receptor inverse agonist as described in item (1αA) above, which contains: R 1 It is a substituted or unsubstituted aromatic heterocyclic group and L is -NR 8 - or -O- compounds or their pharmaceutically permissible salts.

[0219] (3αA) A serotonin 5-HT2A receptor inverse agonist containing a compound represented by formula (II) or a pharmaceutically permissible salt thereof.

[0220] [Chemistry 21]

[0221]

[0222] (in the formula,

[0223] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0224] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0225] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0226] n is 1 or 2;

[0227] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0228] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0229] R 5 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0230] R 6 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0231] R 7 It is the basis represented by the following formula:

[0232] [Chemistry 22]

[0233]

[0234] (in the formula,

[0235] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkyl group;

[0236] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0237] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0238] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0239] m is 0 or 1);

[0240] Except for the compounds shown below,

[0241] [Chemistry 23]

[0242]

[0243] (4αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (3αA), wherein R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group.

[0244] (5αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (4αA), wherein R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0245] (6αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (5αA), wherein R 2 and R 3 It is a hydrogen atom.

[0246] (7αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (6αA), where n is 1.

[0247] (8αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (7αA), wherein R4 It is a substituted or unsubstituted 4 to 7 membered nonaromatic nitrogen-containing heterocyclic group.

[0248] (9αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (8αA), wherein R 4 It is either substituted or unsubstituted piperidinyl.

[0249] (10αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (9αA), wherein R 4 It is the basis represented by the following formula.

[0250] [Chemistry 24]

[0251]

[0252] (in the formula,

[0253] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0254] R 22 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0255] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0256] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0257] (11αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (10αA), wherein R 4 It is the basis represented by the following formula.

[0258] [Chemistry 25]

[0259]

[0260] (where R is in the formula) 21 R 22 and R 23 (Synonymous with the above item (10αA)).

[0261] (12αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (11αA), wherein,

[0262] R 22 It is a halogen, or a substituted or unsubstituted alkyl group;

[0263] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0264] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0265] (13αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (12αA), wherein R 8 It is a hydrogen atom.

[0266] (14αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (13αA), wherein R 5 and R 6 It is a hydrogen atom.

[0267] (15αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (14αA), wherein R 7 It is the basis represented by the following formula.

[0268] [Chemistry 26]

[0269]

[0270] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0271] (16αA) The serotonin 5-HT2A receptor inverse agonist described in item (3αA) above is represented by the following formula (III).

[0272] [Chemistry 27]

[0273]

[0274] (in the formula,

[0275] R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group;

[0276] R 4 It is the basis represented by the following formula:

[0277] [Chemistry 28]

[0278]

[0279] (where R is in the formula) 21 (It is a hydrogen atom, or a substituted or unsubstituted alkyl group),

[0280] R 7 It is the basis represented by the following formula:

[0281] [Chemistry 29]

[0282]

[0283] (in the formula,

[0284] R 9 (It is a substituted or unsubstituted C2-C4 alkoxy group, or a substituted or unsubstituted amino group).

[0285] (17αA) A serotonin 5-HT2A receptor inverse agonist as described in item (16αA) above, wherein R 1 It is a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0286] (18αA) A serotonin 5-HT2A receptor inverse agonist as described in item (3αA) above, selected from compounds I-008, I-027, I-047, I-102, I-112, I-114, I-115, I-124, I-126, I-129, I-133, I-134, I-138, I-139, I-140, I-141, I-144 and I-145.

[0287] (19αA) A method for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor, characterized by administration of a serotonin 5-HT2A receptor inverse agonist as described in any one of the above items (1αA) to (18αA).

[0288] (20αA) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1αA) to (18αA), for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor.

[0289] (21αA) The use of the serotonin 5-HT2A receptor inverse agonist described in any of the above items (1αA) to (18αA) for the manufacture of a treatment and / or preventive agent for diseases involving the serotonin 5-HT2A receptor.

[0290] (1A) A serotonin 5-HT2A receptor inverse agonist, comprising a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0291] [Chemistry 30]

[0292]

[0293] (in the formula,

[0294] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0295] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0296] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0297] n is 1 or 2;

[0298] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0299] L is -NR 8 -, -O- or a single bond;

[0300] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0301] R 5 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0302] R 6 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0303] p is 1 or 2;

[0304] R 7 It is the basis represented by the following formula:

[0305] [Chemistry 31]

[0306]

[0307] (in the formula,

[0308] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkyl group;

[0309] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0310] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0311] R 11It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0312] m is 0 or 1).

[0313] (1'A) A serotonin 5-HT2A receptor inverse agonist containing a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0314] [Chemistry 32]

[0315]

[0316] (in the formula,

[0317] R 1 It is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;

[0318] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0319] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0320] n is 1 or 2;

[0321] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0322] L is -NR 8 -, -O- or a single bond;

[0323] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0324] R 5 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0325] R 6 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0326] p is 1 or 2;

[0327] R 7 It is the basis represented by the following formula:

[0328] [Chemistry 33]

[0329]

[0330] (in the formula,

[0331] R 9 It is a hydrogen atom, halogen, substituted or unsubstituted alkoxy group, substituted or unsubstituted non-aromatic carboxy group, substituted or unsubstituted amino group, substituted or unsubstituted non-aromatic carbcyclic group, substituted or unsubstituted alkenyl group, or substituted or unsubstituted alkyl group;

[0332] R 10 It is a hydrogen atom, a hydroxyl group, a halogen, or a substituted or unsubstituted alkyl group;

[0333] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0334] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0335] m is 0 or 1);

[0336] Except for the compounds in columns (i) and (ii) below:

[0337] (i) L is a single bond and R 1 It is a compound with substituted or unsubstituted furanyl or substituted or unsubstituted thiopheneyl groups;

[0338] (ii) L is -NR 8 -and R 1 It is a compound of substituted or unsubstituted 2,3-dihydrobenzofuranyl groups.

[0339] (1”A) A serotonin 5-HT2A receptor inverse agonist as described in item (1'A) above, wherein R 1 It is a substituted or unsubstituted aromatic heterocyclic group.

[0340] L is -NR 8 - or -O-.

[0341] (1”'A) A serotonin 5-HT2A receptor inverse agonist containing a compound represented by formula (II) or a pharmaceutically permissible salt thereof.

[0342] [Chemistry 34]

[0343]

[0344] (in the formula,

[0345] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0346] R 2Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; n is 1 or 2;

[0347] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0348] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0349] R 5 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0350] R 6 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0351] R 7 It is the basis represented by the following formula:

[0352] [Chemistry 35]

[0353]

[0354] (in the formula,

[0355] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkyl group;

[0356] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0357] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0358] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0359] m is 0 or 1);

[0360] Except for the compounds shown below,

[0361] [Chemistry 36]

[0362]

[0363] (2A) A serotonin 5-HT2A receptor inverse agonist as described in item (1A) above, wherein R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group.

[0364] (2'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A), (1”A), and (1”'A), wherein R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group.

[0365] (3A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A), (2A), (1'A), (1”A), and (1”'A), wherein R 1 It is a substituted or unsubstituted 6-membered aromatic heterocyclic group, or a substituted or unsubstituted 5-membered aromatic heterocyclic group.

[0366] (3'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A), (2A), (1'A), (1”A), and (1”'A), wherein R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0367] (4A) A serotonin 5-HT2A receptor inverse agonist as described in any of items (1A) to (3A) above, wherein R 2 and R 3 It is a hydrogen atom.

[0368] (4'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A) to (3'A), (1”A) and (1”'A), containing R 2 and R 3 It is a compound containing hydrogen atoms or a pharmaceutically permissible salt thereof.

[0369] (5A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (4A), wherein n is 1.

[0370] (5'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A) to (4'A), (1”A) and (1”'A) contains a compound in which n is 1 or a pharmaceutically permissible salt thereof.

[0371] (6A) A serotonin 5-HT2A receptor inverse agonist as described in any of items (1A) to (5A) above, wherein R 4 It is a substituted or unsubstituted 4 to 7 membered nonaromatic nitrogen-containing heterocyclic group.

[0372] (6'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A) to (5'A), (1”A) and (1”'A), containing R 4 It is a compound of a non-aromatic nitrogen-containing heterocyclic group, substituted or unsubstituted, of a 4 to 7 member, or a pharmaceutically permissible salt thereof.

[0373] (7A) A serotonin 5-HT2A receptor inverse agonist as described in any of items (1A) to (6A) above, wherein R 4 It is either substituted or unsubstituted piperidinyl.

[0374] (7'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A) to (6'A), (1”A) and (1”'A), containing R 4 It is a compound with or without a substituted piperidinyl group or a pharmaceutically permissible salt thereof.

[0375] (7”A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (7A), (1'A) to (7'A), (1”A) and (1”'A), containing R 4 It is a compound of the base represented by the following formula or a pharmaceutically permissible salt thereof.

[0376] [Chemistry 37]

[0377]

[0378] (in the formula,

[0379] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0380] R 22 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0381] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0382] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0383] (7”'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (7A), (1'A) to (7'A), (1”A), (7”A) and (1”'A), containing R 4 It is a compound of the base represented by the following formula or a pharmaceutically permissible salt thereof.

[0384] [Chemistry 38]

[0385]

[0386] (in the formula,

[0387] R 21 R 22 and R 23 Synonymous with the above item (7”A).

[0388] (7””A) A serotonin 5-HT2A receptor inverse agonist as described in item (7”A) or (7”’A) above, which contains R 22 It is a halogen, or a substituted or unsubstituted alkyl group, R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, or R 22 and R 23 Compounds that form substituted or unsubstituted non-aromatic carbon rings together with the bonded carbon atoms, or pharmaceutically permissible salts thereof.

[0389] (8A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (7A), wherein L is -NR 8 - or -O-.

[0390] (9A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (8A), wherein L is -NH-.

[0391] (9'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A) to (7'A), (1”A), (7”A), (1”'A), (7”') and (7””A), which contains R 8 It is a compound containing hydrogen atoms or a pharmaceutically permissible salt thereof.

[0392] (10A) A serotonin 5-HT2A receptor inverse agonist as described in any of items (1A) to (9A) above, wherein R 5 and R 6 It is a hydrogen atom.

[0393] (10'A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A) to (7'A), (9'A), (1”A), (7”A), (1”'A), (7”'A), and (7””A), containing R 5 and R 6 It is a compound containing hydrogen atoms or a pharmaceutically permissible salt thereof.

[0394] (11A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (10A), wherein p is 1.

[0395] (12A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (11A), wherein R 7 It is the basis represented by the following formula:

[0396] [Chemistry 39]

[0397]

[0398] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0399] (12A') A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1'A) to (7'A), (9'A), (10'A), (1”A), (7”A), (1”'A), (7”'A), and (7””A), containing R 7 It is a compound of the base represented by the following formula or a pharmaceutically permissible salt thereof.

[0400] [Chemistry 40]

[0401]

[0402] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0403] (13A) A method for treating and / or preventing diseases involving the serotonin 5-HT2A receptor, characterized by administering a serotonin 5-HT2A receptor inverse agonist as described in any one of the above items (1A) to (12A), (1'A) to (7'A), (9'A), (10'A), (12'A), (1”A), (7”A), (1”'A), (7”'A), and (7””A).

[0404] (14A) A serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (12A), (1'A) to (7'A), (9'A), (10'A), (12'A), (1”A), (7”A), (1”'A), (7”'A) and (7””A), for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor.

[0405] (15A) Use of the serotonin 5-HT2A receptor inverse agonist as described in any of the above items (1A) to (12A), (1'A) to (7'A), (9'A), (10'A), (12'A), (1”A), (7”A), (1”'A), (7”'A) and (7””A), for the manufacture of a therapeutic and / or preventive agent for diseases involving the serotonin 5-HT2A receptor.

[0406] In addition, the present invention relates to the following items (1αB) to (22αB), (1B) to (15B), (1'B) to (7'B), (9'B), (10'B), (12'B), (1”B), (7”B), (1”'B), (7”'B) and (7””B).

[0407] (1αB) A composition for reverse agonist of serotonin 5-HT2A receptor, comprising a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0408] [Chemistry 41]

[0409]

[0410] (in the formula,

[0411] R 1 It is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;

[0412] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0413] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0414] n is 1 or 2;

[0415] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0416] L is -NR 8 -, -O- or a single bond;

[0417] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0418] R 5 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0419] R 6Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0420] p is 1 or 2;

[0421] R 7 It is the basis represented by the following formula:

[0422] [Chemistry 42]

[0423]

[0424] (in the formula,

[0425] R 9 It is a hydrogen atom, halogen, substituted or unsubstituted alkoxy group, substituted or unsubstituted non-aromatic carboxy group, substituted or unsubstituted amino group, substituted or unsubstituted non-aromatic carbcyclic group, substituted or unsubstituted alkenyl group, or substituted or unsubstituted alkyl group;

[0426] R 10 It is a hydrogen atom, a hydroxyl group, a halogen, or a substituted or unsubstituted alkyl group;

[0427] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0428] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0429] m is 0 or 1);

[0430] Except for the following compounds (i) and (ii):

[0431] (i) L is a single bond and R 1 It is a compound with substituted or unsubstituted furanyl or substituted or unsubstituted thiopheneyl groups;

[0432] (ii) L is -NR 8 -and R 1 It is a compound of substituted or unsubstituted 2,3-dihydrobenzofuranyl groups.

[0433] (2αB) A composition for reverse activating serotonin 5-HT2A receptors as described in item (1αB) above, containing R 1 It is a substituted or unsubstituted aromatic heterocyclic group, where L is -NR. 8 - or -O- compounds or their pharmaceutically permissible salts.

[0434] (3αB) A composition for the reverse agonist of serotonin 5-HT2A receptor, comprising a compound represented by formula (II) or a pharmaceutically permissible salt thereof.

[0435] [Chemistry 43]

[0436]

[0437] (in the formula,

[0438] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0439] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; n is 1 or 2;

[0440] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0441] R 8 It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0442] R 5 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0443] R 6 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0444] R 7 It is the basis represented by the following formula:

[0445] [Chemistry 44]

[0446]

[0447] (in the formula,

[0448] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkyl group;

[0449] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0450] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0451] R 11It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0452] m is 0 or 1);

[0453] Except for the compounds shown below,

[0454] [Chemistry 45]

[0455]

[0456] (4αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of items (1αB) to (3αB) above, wherein R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group.

[0457] (5αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (4αB), wherein R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0458] (6αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (5αB), wherein R 2 and R 3 It is a hydrogen atom.

[0459] (7αB) A composition for reverse activating serotonin 5-HT2A receptor as described in any of the above items (1αB) to (6αB), wherein n is 1.

[0460] (8αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (7αB), wherein R 4 It is a substituted or unsubstituted 4 to 7 membered nonaromatic nitrogen-containing heterocyclic group.

[0461] (9αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (8αB), wherein R 4 It is either substituted or unsubstituted piperidinyl.

[0462] (10αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (9αB), wherein R 4 It is the basis represented by the following formula.

[0463] [Chemistry 46]

[0464]

[0465] (in the formula,

[0466] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0467] R 22 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0468] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0469] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0470] (11αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (10αB), wherein R 4 It is the basis represented by the following formula.

[0471] [Chemistry 47]

[0472]

[0473] (where R is in the formula) 21 R 22 and R 23 (Synonymous with the above item (10αB)).

[0474] (12αB) The serotonin 5-HT2A receptor reverse agonist composition described in any one of items (1αB) to (11αB) above, wherein,

[0475] R 22 It is a halogen, or a substituted or unsubstituted alkyl group;

[0476] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0477] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0478] (13αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (12αB), wherein R 8 It is a hydrogen atom.

[0479] (14αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (13αB), wherein R 5 and R 6 It is a hydrogen atom.

[0480] (15αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1αB) to (14αB), wherein R 7 It is the basis represented by the following formula.

[0481] [Chemistry 48]

[0482]

[0483] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0484] (16αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in item (3αB) above, represented by formula (III),

[0485] [Chemistry 49]

[0486]

[0487] (in the formula,

[0488] R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group;

[0489] R 4 It is a basis for the following expressions:

[0490] [Transformation 50]

[0491]

[0492] (where R is in the formula) 21 (It is a hydrogen atom, or a substituted or unsubstituted alkyl group),

[0493] R 7 It is the basis represented by the following formula:

[0494] [Chemistry 51]

[0495]

[0496] (in the formula,

[0497] R 9 (It is a substituted or unsubstituted C2-C4 alkoxy group, or a substituted or unsubstituted amino group).

[0498] (17αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in item (16αB) above, wherein R 1 It is a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group.

[0499] (18αB) A composition for reverse activating the serotonin 5-HT2A receptor as described in item (3αB) above, selected from compounds I-008, I-027, I-047, I-102, I-112, I-114, I-115, I-124, I-126, I-129, I-133, I-134, I-138, I-139, I-140, I-141, I-144 and I-145.

[0500] (19αB) A method for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor, characterized in that the serotonin 5-HT2A receptor reverse agonist composition described in any one of the above items (1αB) to (18αB) is administered.

[0501] (20αB) A composition for reverse activating serotonin 5-HT2A receptor as described in any of the above items (1αB) to (18αB), which is used for the treatment and / or prevention of diseases involving serotonin 5-HT2A receptor.

[0502] (21αB) The use of the serotonin 5-HT2A receptor reverse agonist composition described in any one of the above items (1αB) to (18αB) for the manufacture of a treatment and / or preventive agent for diseases involving the serotonin 5-HT2A receptor.

[0503] (1B) A composition for inverse agonist of serotonin 5-HT2A receptor, comprising a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0504] [Chemistry 52]

[0505]

[0506] (in the formula,

[0507] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0508] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0509] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0510] n is 1 or 2;

[0511] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0512] L is -NR 8 -, -O- or a single bond;

[0513] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0514] R 5 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0515] R 6 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0516] p is 1 or 2;

[0517] R 7 It is the basis represented by the following formula:

[0518] [Chemistry 53]

[0519]

[0520] (in the formula,

[0521] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkyl group;

[0522] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0523] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0524] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0525] m is 0 or 1).

[0526] (1'B) A composition for reverse activating serotonin 5-HT2A receptors, comprising a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0527] [Chemistry 54]

[0528]

[0529] (in the formula,

[0530] R 1 It is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;

[0531] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0532] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0533] n is 1 or 2;

[0534] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0535] L is -NR 8 -, -O-, or a single bond;

[0536] R 8 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0537] R 5 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0538] R 6 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0539] p is 1 or 2;

[0540] R 7 It is the basis represented by the following formula:

[0541] [Chemistry 55]

[0542]

[0543] (in the formula,

[0544] R 9 It is a hydrogen atom, halogen, substituted or unsubstituted alkoxy group, substituted or unsubstituted non-aromatic carboxy group, substituted or unsubstituted amino group, substituted or unsubstituted non-aromatic carbcyclic group, substituted or unsubstituted alkenyl group, or substituted or unsubstituted alkyl group;

[0545] R 10 It is a hydrogen atom, a hydroxyl group, a halogen, or a substituted or unsubstituted alkyl group;

[0546] Or R 9 and R10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0547] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0548] m is 0 or 1);

[0549] Except for the following compounds (i) and (ii):

[0550] (i) L is a single bond and R 1 It is a compound with substituted or unsubstituted furanyl or substituted or unsubstituted thiopheneyl groups;

[0551] (ii) L is -NR 8 -and R 1 It is a compound of substituted or unsubstituted 2,3-dihydrobenzofuranyl groups.

[0552] (1”B) A composition for reverse activating serotonin 5-HT2A receptors as described in item (1'B) above, comprising: R 1 It is a substituted or unsubstituted aromatic heterocyclic group, where L is -NR. 8 - or -O- compounds or their pharmaceutically permissible salts.

[0553] (1”'B) A composition for reverse agonist of serotonin 5-HT2A receptor, comprising a compound represented by formula (II) or a pharmaceutically permissible salt thereof.

[0554] [Chemistry 56]

[0555]

[0556] (in the formula,

[0557] R 1 It is a substituted or unsubstituted aromatic heterocyclic group;

[0558] R 2 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0559] R 3 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0560] n is 1 or 2;

[0561] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0562] R 8It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0563] R 5 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0564] R 6 It is a hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0565] R 7 It is the basis represented by the following formula:

[0566] [Chemistry 57]

[0567]

[0568] (in the formula,

[0569] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkyl group;

[0570] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0571] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0572] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0573] m is 0 or 1);

[0574] Except for the compounds shown below,

[0575] [Chem.58]

[0576]

[0577] (2B) A composition for reverse activating serotonin 5-HT2A receptors as described in item (1B) above, wherein R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group.

[0578] (2'B) A composition for serotonin 5-HT2A receptor reverse agonism as described in any of the above items (1'B), (1”B) and (1”'B), comprising: R 1 It is a compound of a nitrogen-containing heterocyclic aromatic group, substituted or unsubstituted, or a pharmaceutically permissible salt thereof.

[0579] (3B) A composition for reverse activating the serotonin 5-HT2A receptor as described in any of the above items (1B), (2B), (1'B), (1”B), and (1”'B), wherein R 1 It is a substituted or unsubstituted 6-membered aromatic heterocyclic group, or a substituted or unsubstituted 5-membered aromatic heterocyclic group.

[0580] (3'B) A serotonin 5-HT2A receptor reverse agonist composition as described in any of the above items (1B), (2B), (1'B), (1”B), and (1”'B), comprising: R 1 It is a compound of a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group or a pharmaceutically permissible salt thereof.

[0581] (4B) A composition for reverse activating serotonin 5-HT2A receptors as described in any of items (1B) to (3B) above, wherein R 2 and R 3 It is a hydrogen atom.

[0582] (4'B) A serotonin 5-HT2A receptor reverse agonist composition as described in any of the above items (1'B) to (3'B), (1”B) and (1”'B), comprising: R 2 and R 3 It is a compound containing hydrogen atoms or a pharmaceutically permissible salt thereof.

[0583] (5B) A composition for reverse activating serotonin 5-HT2A receptor as described in any of the above items (1B) to (4B), wherein n is 1.

[0584] (5'B) A composition for reverse activating serotonin 5-HT2A receptor as described in any of the above items (1'B) to (4'B), (1”B) and (1”'B) contains: a compound in which n is 1 or a pharmaceutically permissible salt thereof.

[0585] (6B) A composition for reverse activating serotonin 5-HT2A receptors as described in any of items (1B) to (5B) above, wherein R 4 It is a substituted or unsubstituted 4- to 7-membered non-aromatic nitrogen-containing heterocyclic group.

[0586] (6'B) A serotonin 5-HT2A receptor reverse agonist composition as described in any of the above items (1'B) to (5'B), (1”B) and (1”'B), comprising: R 4 It is a compound of a non-aromatic nitrogen-containing heterocyclic group, substituted or unsubstituted, of a 4- to 7-membered group or a pharmaceutically permissible salt thereof.

[0587] (7B) A composition for reverse activating serotonin 5-HT2A receptors as described in any of items (1B) to (6B) above, wherein R 4 It is either substituted or unsubstituted piperidinyl.

[0588] (7'B) A serotonin 5-HT2A receptor reverse agonist composition as described in any of the above items (1'B) to (6'B), (1”B) and (1”'B), comprising: R 4 It is a compound with or without a substituted piperidinyl group or a pharmaceutically permissible salt thereof.

[0589] (7”B) A composition for reverse activating serotonin 5-HT2A receptor as described in any of the above items (1B) to (7B), (1'B) to (7'B), (1”B) and (1”'B), comprising: R 4 It is a compound of the base represented by the following formula or a pharmaceutically permissible salt thereof.

[0590] [Chemistry 59]

[0591]

[0592] (in the formula,

[0593] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0594] R 22 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0595] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0596] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0597] (7”'B) A serotonin 5-HT2A receptor reverse agonist composition as described in any of the above items (1B) to (7B), (1'B) to (7'B), (1”B), (7”B) and (1”'B), comprising: R 4 It is a compound of the base represented by the following formula or a pharmaceutically permissible salt thereof.

[0598] [Transformation 60]

[0599]

[0600] (in the formula,

[0601] R21 R 22 and R 23 Synonymous with the above item (7”B).

[0602] (7””B) A composition for reverse activating serotonin 5-HT2A receptor as described in item (7”B) or (7”’B) above, comprising: R 22 It is a halogen, or a substituted or unsubstituted alkyl group, R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, or R 22 and R 23 Compounds that form substituted or unsubstituted non-aromatic carbon rings together with the bonded carbon atoms, or pharmaceutically permissible salts thereof.

[0603] (8B) A composition for reverse activating serotonin 5-HT2A receptor as described in any of items (1B) to (7B) above, wherein L is -NR 8 - or -O-.

[0604] (9B) A composition for reverse activating serotonin 5-HT2A receptor as described in any of the above items (1B) to (8B), wherein L is -NH-.

[0605] (9'B) A serotonin 5-HT2A receptor reverse agonist composition as described in any of the above items (1'B) to (7'B), (1”B), (7”B), (1”'B), (7”') and (7””B), comprising: R 8 It is a compound containing hydrogen atoms or a pharmaceutically permissible salt thereof.

[0606] (10B) A composition for reverse activating serotonin 5-HT2A receptors as described in any of items (1B) to (9B) above, wherein R 5 and R 6 It is a hydrogen atom.

[0607] (10'B) A serotonin 5-HT2A receptor reverse agonist composition as described in any of the above items (1'B) to (7'B), (9'B), (1”B), (7”B), (1”'B), (7”'B) and (7””B), comprising: R 5 and R 6 It is a compound containing hydrogen atoms or a pharmaceutically permissible salt thereof.

[0608] (11B) A composition for reverse activating serotonin 5-HT2A receptor as described in any of the above items (1B) to (10B), wherein p is 1.

[0609] (12B) A composition for reverse activating serotonin 5-HT2A receptors as described in any of items (1B) to (11B) above, wherein R 7 It is the basis represented by the following formula:

[0610] [Chemistry 61]

[0611]

[0612] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0613] (12B') The serotonin 5-HT2A receptor reverse agonist composition described in any one of items (1'B) to (7'B), (9'B), (10'B), (1”B), (7”B), (1”'B), (7”'B) and (7””B) above, comprising: R 7 It is a compound of the base represented by the following formula or a pharmaceutically permissible salt thereof.

[0614] [Chemistry 62]

[0615]

[0616] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0617] (13B) A method for treating and / or preventing diseases involving the serotonin 5-HT2A receptor, characterized by administering a serotonin 5-HT2A receptor reverse agonist composition as described in any one of the above items (1B) to (12B), (1'B) to (7'B), (9'B), (10'B), (12'B), (1”B), (7”B), (1”'B), (7”'B) and (7””B).

[0618] (14B) The serotonin 5-HT2A receptor reverse agonist composition described in any one of items (1B) to (12B), (1'B) to (7'B), (9'B), (10'B), (12'B), (1”B), (7”B), (1”'B), (7”'B) and (7””B) above, for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor.

[0619] (15B) Use of the serotonin 5-HT2A receptor reverse agonist composition described in any one of items (1B) to (12B), (1'B) to (7'B), (9'B), (10'B), (12'B), (1”B), (7”B), (1”'B), (7”'B) and (7””B) for the manufacture of a therapeutic and / or preventive agent for diseases involving the serotonin 5-HT2A receptor.

[0620] Invention Effects

[0621] The compounds of the present invention (in this specification, "compounds of the present invention" refers to compounds of the present invention, compounds related to the 5-HT2A receptor inverse agonist of the present invention, compounds related to the 5-HT2A receptor inverse agonist composition of the present invention, or compounds related to the pharmaceutical composition of the present invention) have serotonin 5-HT2A receptor inverse agonist activity and are useful as therapeutic and / or preventive agents for hallucinations and delusions associated with Parkinson's disease and / or dementia. Detailed Implementation

[0622] The following explains the meaning of each term used in this specification. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms.

[0623] The term “consisting of” refers to something that only has the constituent elements.

[0624] The term "includes" means that it is not limited to the constituent elements and does not exclude elements not recorded.

[0625] Hereinafter, embodiments of the present invention will be described. It should be understood that, for the purposes of this specification as a whole, unless otherwise specified, the singular form also includes the concept of its plural form. Therefore, unless otherwise specified, the articles of the singular form (e.g., "a", "an", "the", etc. in English) also include the concept of their plural forms.

[0626] Furthermore, unless otherwise specified, it should be understood that the terminology used in this specification is used in the sense commonly understood in the aforementioned fields. 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 pertains. In the event of any conflict, this specification (including definitions) shall prevail.

[0627] "Halogen" contains fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are particularly preferred.

[0628] "alkyl" refers to a hydrocarbon group 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, and is either straight-chain or branched. 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, n-decyl, etc.

[0629] Preferred alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0630] As R 9 The alkyl portion of the alkoxy group is preferably C2-C4 alkyl. Examples include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0631] "Halogenated alkyl" refers to the aforementioned alkyl group that has been 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, etc.

[0632] "Alkenyl" refers to a straight-chain or branched hydrocarbon group 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, having one or more double bonds at any position. Examples include: vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprene, butadienyl, pentenyl, isoprene, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, etc.

[0633] Preferred alternatives to "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred alternatives include vinyl and n-propenyl.

[0634] "Alynyl" refers to 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, with one or more triple bonds at any position. It may also have a double bond at any position. Examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, hepynyl, octyynyl, nonynyl, decynyl, etc.

[0635] Preferred alternatives for "alkynyl" include ethynyl, propynyl, butynyl, and pentyynyl. More preferred alternatives include ethynyl and propynyl.

[0636] "Aromatic carbocyclic groups" refer to cyclic aromatic hydrocarbon groups with one or more rings. Examples include phenyl, naphthyl, anthraceneyl, and phenanthrene.

[0637] Phenyl is a preferred example of an "aromatic carbocyclic group".

[0638] "Aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0639] "Non-aromatic carbocyclic group" refers to a monocyclic or cyclic saturated hydrocarbon group with one or more rings, or a cyclic non-aromatic unsaturated hydrocarbon group. "Non-aromatic carbocyclic group" with two or more rings is a group obtained by fusing the rings of the above-mentioned "aromatic carbocyclic group" onto a monocyclic or cyclic non-aromatic carbocyclic group.

[0640] Furthermore, "non-aromatic carbocyclic groups" also include bridging groups or groups that form spirocycles, as described below.

[0641] [Chemistry 63]

[0642]

[0643] As a monocyclic non-aromatic carbocyclic group, it is preferably composed of 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.

[0644] As a non-aromatic carbocyclic group with two or more rings, it is preferably composed of 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include dihydroindanyl, indanyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, etc.

[0645] "Non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0646] "Aromatic heterocyclic group" refers to an aromatic cyclic group with one or more identical or different heteroatoms selected arbitrarily from O, S and N, or a single ring or two or more rings.

[0647] Aromatic heterocyclic groups with two or more rings also include groups obtained by fusing the rings in the above-mentioned "aromatic carbocyclic groups" onto a monocyclic or aromatic heterocyclic group with two or more rings, and such bonding can be present on any ring.

[0648] The aromatic heterocyclic group, being a monocyclic compound, is preferably 5 to 8-membered, more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophene, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclic groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0649] The aromatic heterocyclic group of the two rings is preferably 8 to 10 quinones, more preferably 9 or 10 quinones. Examples include indolyl, isoindolyl, indazole, inazinyl, quinolinyl, isoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxolinyl, purine, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxoxadiazolyl, benzisoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxazolyl, benzoxazolyl, oxazolyl, thiazolyl, etc.

[0650] The aromatic heterocyclic group with 3 or more rings is preferably 13 to 15 quinones. Examples include carbazolyl, acridinel, xanthonyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, dibenzofuranyl, etc.

[0651] "Aromatic heterocycle" refers to a ring derived from the above-mentioned "aromatic heterocyclic group".

[0652] "Aromatic nitrogen-containing heterocyclic group" refers to a monocyclic or two-ring aromatic heterocyclic group containing one or more nitrogen atoms within the ring, and further, having one or more heteroatoms of the same or different origins selected from O or S within the ring. Aromatic nitrogen-containing heterocyclic groups with two or more rings also include groups obtained by fused to the rings of the aforementioned "aromatic carbocyclic group" on a monocyclic or two-ring aromatic nitrogen-containing heterocyclic group, where the bond can be present in any ring.

[0653] 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 pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic nitrogen-containing heterocyclic groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0654] The aromatic nitrogen-containing heterocyclic group of the two rings is preferably 8 to 10 quinones, more preferably 9 or 10 quinones. Examples include indolyl, isoindolyl, indazole, indazinyl, quinolinyl, isoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxalinyl, purine, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxoxazolyl, benzoxoxadiazolyl, benzisoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxoxazolyl, benzoxazolyl, triazolylpyridinyl, triazolylpyridinyl, imidazopyridinyl, pyrazinylpyridinyl, oxazolylpyridinyl, thiazopyridinyl, etc.

[0655] The aromatic nitrogen-containing heterocyclic group with 3 or more rings is preferably 13 to 15 members. Examples include carbazolyl, acridinel, phenothiazinel, etc.

[0656] "Non-aromatic heterocyclic group" refers to a monocyclic or two-ring non-aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N within the ring. A two-ring or more non-aromatic heterocyclic group includes a group obtained by fused to a monocyclic or two-ring non-aromatic heterocyclic group with each ring from the aforementioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," and further includes a group obtained by fused to a monocyclic or two-ring non-aromatic carbocyclic group with the rings from the aforementioned "aromatic heterocyclic group," where the bond can be present in any ring.

[0657] Furthermore, "non-aromatic heterocyclic groups" include bridging groups as described below, or groups that form spirocycles.

[0658] [Chemistry 64]

[0659]

[0660] As a monocyclic non-aromatic heterocyclic group, it is preferably 3 to 8 quinones, more preferably 5 quinones or 6 quinones.

[0661] 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, tetrahydrothiazolyl, pyrrolyl, pyrrololinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiiranyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxyl, thianyl, piperidinyl, piperazine, morpholinyl, morpholino, thiomorpholino, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroacetyl, tetrahydrodiacetyl, and oxocane. Examples of 8-membered non-aromatic heterocyclic groups include azocane, thiocane, and oxocane.

[0662] As a non-aromatic heterocyclic group with two or more rings, it is preferably 8 to 20 quinones, more preferably 8 to 10 quinones. Examples include dihydroindolyl, isodihydroindolyl, benzodihydropyranyl, isobenzodihydropyranyl, etc.

[0663] "Non-aromatic nitrogen-containing heterocyclic group" refers to a monocyclic or two-ring non-aromatic heterocyclic group having one or more nitrogen atoms within the ring. A two-ring or more non-aromatic heterocyclic group comprises a group obtained by fused to a monocyclic or two-ring non-aromatic nitrogen-containing heterocyclic group with each of the rings described above as "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," and may have this bond in any ring.

[0664] For example, consider the following ring.

[0665] [Chemistry 65]

[0666]

[0667] In addition, "non-aromatic nitrogen-containing heterocyclic groups" also include bridging groups or groups that form spirocycles, as described below.

[0668] [Chemistry 66]

[0669]

[0670] "Non-aromatic heterocycle" refers to a ring derived from the above "non-aromatic heterocyclic group".

[0671] R 9 and R 10 Examples of non-aromatic heterocycles formed together are shown in the following examples.

[0672] [Chemistry 67]

[0673]

[0674] R 22 and R 23 Examples of non-aromatic carbon rings formed together with the bonded carbon atoms are shown below.

[0675] [Chemistry 68]

[0676]

[0677] "Trialkylsilyl" refers to a compound formed by three alkyl groups bonded to silicon atoms. The three alkyl groups can be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0678] In this specification, "can be substituted by substituent group α" means "can be substituted by one or more groups selected from substituent group α". The same applies to substituent groups β, γ, and γ'.

[0679] Substituents such as “substituted alkyl,” “substituted alkenyl,” “substituted alkynyl,” “substituted alkenyloxy,” “substituted alkynyloxy,” “substituted alkyl carbonyloxy,” “substituted alkenyl carbonyloxy,” “substituted alkynyl carbonyloxy,” “substituted alkyl carbonyl,” “substituted alkenyl carbonyl,” “substituted alkynyl carbonyl,” “substituted alkenyloxy carbonyl,” “substituted alkynyloxy carbonyl,” “substituted alkenyloxy carbonyl,” “substituted alkynyloxy carbonyl,” “substituted alkyl thio,” “substituted alkenyl thio,” “substituted alkynyl thio,” “substituted alkynyl thio,” “substituted alkyl sulfinyl,” “substituted alkenyl sulfinyl,” “substituted alkynyl sulfinyl,” “substituted alkyl sulfonyl,” “substituted alkenyl sulfonyl,” “substituted alkynyl sulfonyl,” etc., can be listed as substituent group A below. A carbon atom at any position may be bonded to one or more groups selected from substituent group A below.

[0680] Substituent group A: halogen, hydroxyl, carboxyl, formyl, formyloxy, thio, sulfinyl, sulfonyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitrosyl, azide, hydrazine, urea, amidine, guanidine, pentafluorothio, trialkylsilyl,

[0681] Alkoxy groups that can be substituted with α-substituent group, alkenyloxy groups that can be substituted with α-substituent group, alkynyloxy groups that can be substituted with α-substituent group, alkyl carbonyloxy groups that can be substituted with α-substituent group, alkenyl carbonyloxy groups that can be substituted with α-substituent group, alkoxy carbonyl groups that can be substituted with α-substituent group, alkenyl carbonyl groups that can be substituted with α-substituent group, alkenyl carbonyl groups that can be substituted with α-substituent group, alkenyl carbonyl groups that can be substituted with α-substituent group. α-Oxycarbonyl, α-substituted alkynyloxycarbonyl, α-substituted alkylthio, α-substituted alkenylthio, α-substituted alkynylthio, α-substituted alkylsulfinyl, α-substituted alkenylsulfinyl, α-substituted alkynylsulfinyl, α-substituted alkylsulfinyl, α-substituted alkenylsulfinyl, α-substituted alkynylsulfinyl, α-substituted alkenylsulfinyl, α-substituted alkynylsulfinyl

[0682] Amino groups that can be β-substituted by a substituent group, imino groups that can be β-substituted by a substituent group, carbamoyl groups that can be β-substituted by a substituent group, and aminosulfonyl groups that can be β-substituted by a substituent group.

[0683] Aromatic carbocyclic groups substituted by substituent group γ, non-aromatic carbocyclic groups substituted by substituent group γ', aromatic heterocyclic groups substituted by substituent group γ, non-aromatic heterocyclic groups substituted by substituent group γ', aromatic carbocyclic epoxide groups substituted by substituent group γ', non-aromatic carbocyclic epoxide groups substituted by substituent group γ', aromatic heterocyclic epoxide groups substituted by substituent group γ', non-aromatic heterocyclic epoxide groups substituted by substituent group γ', aromatic carbocyclic carbonyl epoxide groups substituted by substituent group γ', non-aromatic carbocyclic carbonyl epoxide groups substituted by substituent group γ', and so on. Substituted aromatic heterocyclic carbonyloxy group, non-aromatic heterocyclic carbonyloxy group substituted by substituent group γ', aromatic carbocyclic carbonyl group substituted by substituent group γ', non-aromatic carbocyclic carbonyl group substituted by substituent group γ', aromatic heterocyclic carbonyl group substituted by substituent group γ', non-aromatic heterocyclic carbonyl group substituted by substituent group γ', aromatic carbocyclic carbonyl group substituted by substituent group γ', non-aromatic carbocyclic carbonyl group substituted by substituent group γ', aromatic heterocyclic carbonyl group substituted by substituent group γ', non-aromatic heterocyclic carbonyl group substituted by substituent group γ', substituent group γ-substituted aromatic carbocycloalkoxy groups, non-aromatic carbocycloalkoxy groups that can be substituted by a substituent group γ', aromatic heterocyclic alkoxy groups that can be substituted by a substituent group γ', non-aromatic heterocyclic alkoxy groups that can be substituted by a substituent group γ', aromatic carbocycloalkoxy carbonyl groups that can be substituted by a substituent group γ', non-aromatic carbocycloalkoxy carbonyl groups that can be substituted by a substituent group γ', aromatic carbocyclothio groups that can be substituted by a substituent group γ', non-aromatic carbocyclothio groups that can be substituted by a substituent group γ', and so on. Aromatic heterocyclic thio groups substituted with substituent group γ, non-aromatic heterocyclic thio groups substituted with substituent group γ', aromatic carbocyclic sulfinyl groups substituted with substituent group γ, non-aromatic carbocyclic sulfinyl groups substituted with substituent group γ', aromatic heterocyclic sulfinyl groups substituted with substituent group γ', non-aromatic heterocyclic sulfinyl groups substituted with substituent group γ', aromatic carbocyclic sulfinyl groups substituted with substituent group γ', non-aromatic carbocyclic sulfinyl groups substituted with substituent group γ', and non-aromatic heterocyclic sulfinyl groups substituted with substituent group γ'.

[0684] Substituent group α: halogen, hydroxyl, carboxyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, thio, and cyano.

[0685] Substituent group β: halogen, hydroxyl, carboxyl, cyano, alkyl group that can be substituted by substituent group α, alkenyl group that can be substituted by substituent group α, alkynyl group that can be substituted by substituent group α, alkyl carbonyl group that can be substituted by substituent group α, alkenyl carbonyl group that can be substituted by substituent group α, alkyl thio group that can be substituted by substituent group α, alkenyl thio group that can be substituted by substituent group α, alkyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkynyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkynyl sulfinyl group that can be substituted by substituent group α.

[0686] Aromatic carbocyclic groups substituted with γ-substituent group, non-aromatic carbocyclic groups substituted with γ'-substituent group, aromatic heterocyclic groups substituted with γ-substituent group, non-aromatic heterocyclic groups substituted with γ'-substituent group, aromatic carbocyclic alkyl groups substituted with γ'-substituent group, non-aromatic carbocyclic alkyl groups substituted with γ'-substituent group, aromatic heterocyclic alkyl groups substituted with γ'-substituent group, non-aromatic heterocyclic alkyl groups substituted with γ'-substituent group, aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, aromatic heterocyclic carbonyl groups substituted with γ'-substituent group, non-aromatic heterocyclic carbonyl groups substituted with γ'-substituent group, aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, substituent group γ-substituted aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl that can be substituted by substituent group γ', aromatic carbocyclic thioyl that can be substituted by substituent group γ, non-aromatic carbocyclic thioyl that can be substituted by substituent group γ', aromatic heterocyclic thioyl that can be substituted by substituent group γ', non-aromatic heterocyclic thioyl that can be substituted by substituent group γ', aromatic carbocyclic sulfinyl that can be substituted by substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted by substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted by substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by substituent group γ', and non-aromatic heterocyclic sulfinyl that can be substituted by substituent group γ'.

[0687] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.

[0688] Substituent group γ': Substituent group γ and oxo group.

[0689] Substituents on the rings of "substituted aromatic carbocyclic groups", "substituted aromatic heterocyclic groups", "substituted aromatic nitrogen-containing heterocyclic groups", "substituted aromatic carboepoxy groups", "substituted aromatic heteroepoxy groups", "substituted aromatic carbocyclic carbonyloxy groups", "substituted aromatic heterocyclic carbonyloxy groups", "substituted aromatic carbocyclic carbonyl groups", "substituted aromatic heterocyclic carbonyl groups", "substituted aromatic carboepoxy carbonyl groups", "substituted aromatic heteroepoxy carbonyl groups", "substituted aromatic carbocyclic thio groups", "substituted aromatic heterocyclic thio groups", "substituted aromatic carbocyclic sulfinyl groups", "substituted aromatic heterocyclic sulfinyl groups", "substituted aromatic carbocyclic sulfonyl groups", and "substituted aromatic heterocyclic sulfonyl groups", etc., on the "aromatic carbocyclic" and "aromatic heterocyclic" rings can be listed in the following substituent group B. An atom at any position on the ring can be bonded to one or more groups selected from the following substituent group B.

[0690] Substituent group B: halogen, hydroxyl, carboxyl, formyl, formyloxy, thio, sulfinyl, sulfonyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitrosyl, azide, hydrazine, urea, amidine, guanidine, pentafluorothio, trialkylsilyl,

[0691] Alkyl groups that can be substituted with α-substituent group, alkenyl groups that can be substituted with α-substituent group, alkoxy groups that can be substituted with α-substituent group, alkenyloxy groups that can be substituted with α-substituent group, alkynyloxy groups that can be substituted with α-substituent group, alkyl carbonyloxy groups that can be substituted with α-substituent group, alkenyl carbonyloxy groups that can be substituted with α-substituent group, alkynyl carbonyloxy groups that can be substituted with α-substituent group, alkyl carbonyl groups that can be substituted with α-substituent group, alkenyl carbonyl groups that can be substituted with α-substituent group, alkynyl carbonyl groups that can be substituted with α-substituent group. Substituted alkoxycarbonyl, alkenyloxycarbonyl that can be substituted with substituent group α, alkynyloxycarbonyl that can be substituted with substituent group α, alkylthio that can be substituted with substituent group α, alkenylthio that can be substituted with substituent group α, alkylsulfinyl that can be substituted with substituent group α, alkenylsulfinyl that can be substituted with substituent group α, alkylsulfinyl that can be substituted with substituent group α, alkenylsulfinyl that can be substituted with substituent group α, alkynesulfonyl that can be substituted with substituent group α.

[0692] Amino groups that can be β-substituted by a substituent group, imino groups that can be β-substituted by a substituent group, carbamoyl groups that can be β-substituted by a substituent group, and aminosulfonyl groups that can be β-substituted by a substituent group.

[0693] Aromatic carbocyclic groups substituted with γ-substituent group; non-aromatic carbocyclic groups substituted with γ'-substituent group; aromatic heterocyclic groups substituted with γ-substituent group; non-aromatic heterocyclic groups substituted with γ'-substituent group; aromatic carbocyclic oxy groups substituted with γ-substituent group; non-aromatic carbocyclic oxy groups substituted with γ'-substituent group; aromatic heterocyclic oxy groups substituted with γ'-substituent group; non-aromatic heterocyclic oxy groups substituted with γ'-substituent group; "aromatic carbocyclic carbonyloxy group substituted with γ-substituent group"; "non-aromatic carbocyclic carbonyloxy group substituted with γ'-substituent group"; "aromatic heterocyclic carbonyloxy group substituted with γ'-substituent group"; and "non-aromatic heterocyclic carbonyloxy group substituted with γ'-substituent group". Aromatic carbocyclic carbonyl groups substituted with γ-substituent group; non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; aromatic heterocyclic carbonyl groups substituted with γ-substituent group; non-aromatic heterocyclic carbonyl groups substituted with γ'-substituent group; aromatic carbocyclic alkyl groups substituted with γ'-substituent group; non-aromatic carbocyclic alkyl groups substituted with γ'-substituent group; aromatic heterocyclic alkyl groups substituted with γ'-substituent group; non-aromatic heterocyclic alkyl groups substituted with γ'-substituent group; substituted γ ... Substituted aromatic carbocycloalkoxy, non-aromatic carbocycloalkoxy that can be substituted with substituent group γ', aromatic heterocycloalkoxy that can be substituted with substituent group γ', non-aromatic heterocycloalkoxy that can be substituted with substituent group γ', aromatic carbocycloalkoxy carbonyl that can be substituted with substituent group γ', non-aromatic carbocycloalkoxy carbonyl that can be substituted with substituent group γ', aromatic heterocycloalkoxy carbonyl that can be substituted with substituent group γ', non-aromatic carbocycloalkoxy alkyl that can be substituted with substituent group γ', aromatic heterocycloalkoxy alkyl that can be substituted with substituent group γ', non-aromatic heterocycloalkane that can be substituted with substituent group γ' oxyalkyl, aromatic carbocyclic thioyl group substituted with γ-substituent, non-aromatic carbocyclic thioyl group substituted with γ'-substituent, aromatic heterocyclic thioyl group substituted with γ-substituent, non-aromatic heterocyclic thioyl group substituted with γ'-substituent, aromatic carbocyclic sulfinyl group substituted with γ-substituent, non-aromatic carbocyclic sulfinyl group substituted with γ'-substituent, aromatic heterocyclic sulfinyl group substituted with γ-substituent, non-aromatic heterocyclic sulfinyl group substituted with γ'-substituent, aromatic carbocyclic sulfinyl group substituted with γ-substituent, non-aromatic carbocyclic sulfinyl group substituted with γ'-substituent, aromatic heterocyclic sulfinyl group substituted with γ'-substituent, and non-aromatic heterocyclic sulfinyl group substituted with γ'-substituent.

[0694] "Substituted non-aromatic carbocyclic group", "Substituted non-aromatic heterocyclic group", "Substituted non-aromatic nitrogen-containing heterocyclic group", "R" 9 and R 10 "The substituted non-aromatic heterocycles formed together", "R" 22 and R 23 The substituents on the rings of the "non-aromatic carbocyclic ring," "substituted non-aromatic carboepoxy group," "substituted non-aromatic heteroepoxy group," "substituted non-aromatic carbocyclic carbonyloxy group," "substituted non-aromatic heterocyclic carbonyloxy group," "substituted non-aromatic carbocyclic carbonyl group," "substituted non-aromatic heterocyclic carbonyl group," "substituted non-aromatic carboepoxy carbonyl group," "substituted non-aromatic heteroepoxy carbonyl group," "substituted non-aromatic carbocyclic thio group," "substituted non-aromatic heterocyclic thio group," "substituted non-aromatic carbocyclic sulfinyl group," "substituted non-aromatic heterocyclic sulfinyl group," "substituted non-aromatic carbocyclic sulfonyl group," and "substituted non-aromatic heterocyclic sulfonyl group" formed together with the bonded carbon atom on the ring can be listed in the following substituent group C. An atom at any position on the ring can be bonded to one or more groups selected from the following substituent group C.

[0695] Substituent group C: Substituent group B and oxo group.

[0696] When a "non-aromatic carbon ring", "non-aromatic heterocycle" and "non-aromatic nitrogen-containing heterocycle" are replaced by an "oxo group", it refers to a ring in which two hydrogen atoms on the carbon atom are replaced as described below.

[0697] [Chemistry 69]

[0698]

[0699] Substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted aminosulfonyl" can be listed in the following substituent group D. They can also be substituted by one or two groups selected from substituent group D.

[0700] Substituent group D: halogen, hydroxyl, carboxyl, cyano, alkyl group that can be substituted by substituent group α, alkenyl group that can be substituted by substituent group α, alkynyl group that can be substituted by substituent group α, alkyl carbonyl group that can be substituted by substituent group α, alkenyl carbonyl group that can be substituted by substituent group α, alkyl thio group that can be substituted by substituent group α, alkenyl thio group that can be substituted by substituent group α, alkyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkynyl sulfinyl group that can be substituted by substituent group α.

[0701] Amino groups that can be β-substituted by a substituent group, imino groups that can be β-substituted by a substituent group, carbamoyl groups that can be β-substituted by a substituent group, and aminosulfonyl groups that can be β-substituted by a substituent group.

[0702] Aromatic carbocyclic groups substituted with γ-substituent group, non-aromatic carbocyclic groups substituted with γ'-substituent group, aromatic heterocyclic groups substituted with γ-substituent group, non-aromatic heterocyclic groups substituted with γ'-substituent group, aromatic carbocyclic alkyl groups substituted with γ'-substituent group, non-aromatic carbocyclic alkyl groups substituted with γ'-substituent group, aromatic heterocyclic alkyl groups substituted with γ'-substituent group, non-aromatic heterocyclic alkyl groups substituted with γ'-substituent group, aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, aromatic heterocyclic carbonyl groups substituted with γ'-substituent group, non-aromatic heterocyclic carbonyl groups substituted with γ'-substituent group, aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group, substituent group γ-substituted aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl that can be substituted by substituent group γ', aromatic carbocyclic thioyl that can be substituted by substituent group γ, non-aromatic carbocyclic thioyl that can be substituted by substituent group γ', aromatic heterocyclic thioyl that can be substituted by substituent group γ', non-aromatic heterocyclic thioyl that can be substituted by substituent group γ', aromatic carbocyclic sulfinyl that can be substituted by substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted by substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted by substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by substituent group γ', and non-aromatic heterocyclic sulfinyl that can be substituted by substituent group γ'.

[0703] R in the compound represented by formula (I) or formula (II) 1 R 2 R 3 n, R 4 L, R 8 R 5 R 6 p, R 7 R 9 R 10 R 11 R 21 R 22 R 23 The preferred configurations of m are shown below. All combinations of the specific examples shown below can be illustrated as compounds represented by formula (I) or formula (II).

[0704] R1 Examples include substituted or unsubstituted aromatic heterocyclic groups, or substituted or unsubstituted non-aromatic heterocyclic groups (hereinafter also referred to as A-1).

[0705] R 1 Examples include substituted or unsubstituted aromatic heterocyclic groups (hereinafter also referred to as A-2).

[0706] R 1 Examples include substituted or unsubstituted aromatic nitrogen-containing heterocyclic groups (hereinafter also referred to as A-3).

[0707] R 1 Examples include substituted or unsubstituted 5-membered aromatic heterocyclic groups, substituted or unsubstituted 6-membered aromatic heterocyclic groups, or substituted or unsubstituted 10-membered aromatic heterocyclic groups (hereinafter also referred to as A-4).

[0708] R 1 Examples include substituted or unsubstituted 6-membered aromatic heterocyclic groups, or substituted or unsubstituted 5-membered aromatic heterocyclic groups (hereinafter also referred to as A-5).

[0709] R 1 Examples include 5-membered aromatic heterocyclic groups substituted with alkyl groups; unsubstituted 5-membered aromatic heterocyclic groups; and 6-membered aromatic heterocyclic groups substituted with one or more groups selected from the group consisting of halogens, alkoxy groups, cyano groups, haloalkyl groups and alkyl groups, or unsubstituted 6-membered aromatic heterocyclic groups (hereinafter also referred to as A-6).

[0710] R 1 Examples of substituted or unsubstituted 5-membered aromatic heterocyclic groups (hereinafter also referred to as A-7) can be given.

[0711] R 1 Examples include alkyl-substituted 5-membered aromatic heterocyclic groups or unsubstituted 5-membered aromatic heterocyclic groups (hereinafter also referred to as A-8).

[0712] R 1 Examples of substituted or unsubstituted 6-membered aromatic heterocyclic groups (hereinafter also referred to as A-9) can be given.

[0713] R 1 Examples include 6-membered aromatic heterocyclic groups substituted with one or more groups selected from the group consisting of halogens, alkoxy groups, cyano groups, haloalkyl groups and alkyl groups, or unsubstituted 6-membered aromatic heterocyclic groups (hereinafter also referred to as A-10).

[0714] R 1 Examples of substituted or unsubstituted 10-membered aromatic heterocyclic groups (hereinafter also referred to as A-11) can be given.

[0715] R 1Examples include unsubstituted 10-membered aromatic heterocyclic groups (hereinafter also referred to as A-12).

[0716] R 1 Examples include substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrroleyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indoleyl (hereinafter also referred to as A-13).

[0717] R 1 Examples include substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrroleyl, or substituted or unsubstituted pyrazolyl (hereinafter also referred to as A-14).

[0718] R 1 Examples include substituted or unsubstituted pyridyl groups, substituted or unsubstituted pyrrole groups, or substituted or unsubstituted pyrazolyl groups (hereinafter also referred to as A-15).

[0719] R 1 Examples include substituted or unsubstituted pyrrole groups, or substituted or unsubstituted pyrazol groups (hereinafter also referred to as A-16).

[0720] R 1 Examples include substituted or unsubstituted pyridinyl groups (hereinafter also referred to as A-17).

[0721] R 1 Examples include pyridinyl groups substituted with one or more groups selected from the group consisting of halogens, alkoxy groups, cyano groups, haloalkyl groups and alkyl groups, or unsubstituted pyridinyl groups (hereinafter also referred to as A-18).

[0722] R 1 Examples include pyridinyl groups substituted with halogens and / or haloalkyl groups, or unsubstituted pyridinyl groups (hereinafter also referred to as A-19).

[0723] R 1 Examples include halogen-substituted pyridinyl groups or unsubstituted pyridinyl groups (hereinafter also referred to as A-20).

[0724] R 1 Examples include pyridinium groups substituted with halogens (hereinafter also referred to as A-21).

[0725] R 1Examples include pyridinyl groups substituted with haloalkyl groups or unsubstituted pyridinyl groups (hereinafter also referred to as A-22).

[0726] R 1 Examples include pyridinyl groups substituted with haloalkyl groups (hereinafter also referred to as A-23).

[0727] R 1 Examples include substituted or unsubstituted pyrazolyl groups (hereinafter also referred to as A-24).

[0728] R 1 Examples include pyrazolyl groups substituted with haloalkyl and / or alkyl groups, or unsubstituted pyrazolyl groups (hereinafter also referred to as A-25).

[0729] R 1 Examples include alkyl-substituted pyrazolyl groups or unsubstituted pyrazolyl groups (hereinafter also referred to as A-26).

[0730] R 1 Examples include alkyl-substituted pyrazolyl groups (hereinafter also referred to as A-27).

[0731] R 1 Examples include substituted or unsubstituted pyrrole groups (hereinafter also referred to as A-28).

[0732] R 1 Examples include pyrrole groups substituted with haloalkyl and / or alkyl groups, or unsubstituted pyrrole groups (hereinafter also referred to as A-29).

[0733] R 1 Examples include alkyl-substituted pyrazolyl groups or unsubstituted pyrroleyl groups (hereinafter also referred to as A-30).

[0734] R 1 Examples include alkyl-substituted pyrrole groups (hereinafter also referred to as A-31).

[0735] R 2 Each of the following can be independently named: hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group (hereinafter also referred to as B-1).

[0736] R 2 Each hydrogen atom (hereinafter also referred to as B-2) can be listed independently.

[0737] R 3 Each of the following can be independently named: hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group (hereinafter also referred to as C-1).

[0738] R 3 Each of the hydrogen atoms (hereinafter also referred to as C-2) can be listed independently.

[0739] n can be either 1 or 2 (hereinafter also referred to as D-1).

[0740] n can be 1 (hereinafter also referred to as D-2).

[0741] R 4 Examples include substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic groups (hereinafter also referred to as E-1).

[0742] R 4 Examples include substituted or unsubstituted 4- to 7-membered non-aromatic nitrogen-containing heterocyclic groups (hereinafter also referred to as E-2).

[0743] R 4 Examples include substituted or unsubstituted 6-membered non-aromatic nitrogen-containing heterocyclic groups (hereinafter also referred to as E-3).

[0744] R 4 Examples include substituted or unsubstituted piperidinyl groups (hereinafter also referred to as E-4).

[0745] R 4 The following basis (hereinafter also referred to as E-5) can be given as an example:

[0746] [Chemistry 70]

[0747]

[0748] (in the formula,

[0749] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0750] R 22 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0751] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0752] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0753] R 4 The following basis (hereinafter also referred to as E-6) can be given as an example:

[0754] [Chemistry 71]

[0755]

[0756] (in the formula,

[0757] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0758] R 22 It is a halogen, or a substituted or unsubstituted alkyl group;

[0759] R 23 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0760] Or R 22 and R 23 Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring.

[0761] R 4 The following basis (hereinafter also referred to as E-7) can be given as an example:

[0762] [Chemistry 72]

[0763]

[0764] (where R is in the formula) 21 (It is a hydrogen atom, or a substituted or unsubstituted alkyl group).

[0765] R 4 The following basis (hereinafter also referred to as E-8) can be given as an example:

[0766] [Chemistry 73]

[0767]

[0768] (where R is in the formula) 21 R 22 and R 23 (Synonymous with E-5).

[0769] R 4 The following basis (hereinafter also referred to as E-9) can be given as an example:

[0770] [Chemistry 74]

[0771]

[0772] (where R is in the formula) 21 R 22 and R 23 It is synonymous with E-6.

[0773] R 4 The following basis (hereinafter also referred to as E-10) can be given as an example:

[0774] [Chemistry 75]

[0775]

[0776] (where R is in the formula) 21 (It is a hydrogen atom, or a substituted or unsubstituted alkyl group).

[0777] The following basis (hereinafter also referred to as E-11) can be given as an example:

[0778] [Chemistry 76]

[0779]

[0780] (in the formula,

[0781] R 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0782] R 22 It is halogen.

[0783] L can be cited as -NR 8 -, -O-, or a single bond (hereinafter also referred to as F-1).

[0784] L can be cited as -NR 8 -(Hereinafter also referred to as F-2).

[0785] L can be cited as -O- (hereinafter also referred to as F-3).

[0786] L can be used to represent a single key (hereinafter also referred to as F-4).

[0787] R 8 Examples include hydrogen atoms, or substituted or unsubstituted alkyl groups (hereinafter also referred to as G-1).

[0788] R 8 The hydrogen atom (hereinafter also referred to as G-2) can be cited as an example.

[0789] R 5 Each of the following can be independently named: hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group (hereinafter also referred to as H-1).

[0790] R 5 Each hydrogen atom (hereinafter also referred to as H-2) can be listed independently.

[0791] R 6 Each of the following can be independently named: hydrogen atom, halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group (hereinafter also referred to as J-1).

[0792] R 6 Each hydrogen atom (hereinafter also referred to as J-2) can be listed independently.

[0793] p can be 1 or 2 (hereinafter also referred to as K-1).

[0794] p can be 1 (hereinafter also referred to as K-2).

[0795] R 7A basis (hereinafter also referred to as L-1) can be represented by the following formula:

[0796] [Chemistry 77]

[0797]

[0798] (in the formula,

[0799] R 9 It is a hydrogen atom, halogen, substituted or unsubstituted alkoxy group, substituted or unsubstituted non-aromatic carboxy group, substituted or unsubstituted amino group, substituted or unsubstituted non-aromatic carbcyclic group, substituted or unsubstituted alkenyl group, or substituted or unsubstituted alkyl group;

[0800] R 10 It is a hydrogen atom, a hydroxyl group, a halogen, or a substituted or unsubstituted alkyl group;

[0801] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0802] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0803] m is 0 or 1).

[0804] R 7 A basis (hereinafter also referred to as L-2) can be given by the following expression:

[0805] [Chemistry 78]

[0806]

[0807] (in the formula,

[0808] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkyl group;

[0809] R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0810] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0811] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group;

[0812] m is 0 or 1).

[0813] R 7 A basis can be given by the following expression (hereinafter also referred to as L-3):

[0814] [Chemistry 79]

[0815]

[0816] (in the formula,

[0817] R 9 It is a substituted or unsubstituted alkoxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkyl group; R 10 It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0818] Or R 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles;

[0819] R 11 It is a halogen, hydroxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkoxy group; m is 0 or 1).

[0820] R 7 The basis can be represented by the following formula:

[0821] [Chemistry 80]

[0822]

[0823] (where R is in the formula) 9 It is a substituted or unsubstituted alkoxy group, R 10 It is a hydrogen atom, m is 0);

[0824] Or the base represented by the following formula (hereinafter also referred to as L-4):

[0825] [Chemistry 81]

[0826]

[0827] (where R is in the formula) 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles, where m is 0).

[0828] R 7 The following basis (hereinafter also referred to as L-5) can be given as an example:

[0829] [Chemistry 82]

[0830]

[0831] (where R is in the formula) 9 It is a substituted or unsubstituted alkoxy group, R10 It is a hydrogen atom, and m is 0).

[0832] R 7 The following basis (hereinafter also referred to as L-6) can be given as an example:

[0833] [Chemistry 83]

[0834]

[0835] (where R is in the formula) 9 It is an alkoxy group that has been substituted with a halogen or is unsubstituted, R 10 It is a hydrogen atom, and m is 0).

[0836] R 7 The following basis (hereinafter also referred to as L-7) can be given as an example:

[0837] [Chemistry 84]

[0838]

[0839] (where R is in the formula) 9 and R 10 Together they form substituted or unsubstituted non-aromatic heterocycles, where m is 0).

[0840] R 7 The following basis (hereinafter also referred to as L-8) can be given as an example:

[0841] [Chemistry 85]

[0842]

[0843] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0844] R 7 The following basis (hereinafter also referred to as L-9) can be given as an example:

[0845] [Chemistry 86]

[0846]

[0847] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted C2-C4 alkoxy group).

[0848] R 7 The following basis (hereinafter also referred to as L-10) can be given as an example:

[0849] [Chemistry 87]

[0850]

[0851] (where R is in the formula)9 (Amino groups that are substituted or unsubstituted alkyl groups).

[0852] R 7 A basis (hereinafter also referred to as L-11) can be represented by the following formula:

[0853] [Chemistry 88]

[0854]

[0855] (where R is in the formula) 9 It is a substituted or unsubstituted C2-C4 alkoxy group, or a substituted or unsubstituted amino group.

[0856] The preferred method is as follows:

[0857] (i) A serotonin 5-HT2A receptor inverse agonist containing a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0858] [Chemistry 89]

[0859]

[0860] (in the formula,

[0861] R 1 It's A-17;

[0862] R 2 It is a hydrogen atom;

[0863] R 3 It is a hydrogen atom;

[0864] n is 1;

[0865] R 4 It's E-4;

[0866] L is -NR 8 -;

[0867] R 8 It is a hydrogen atom;

[0868] R 5 It is a hydrogen atom;

[0869] R 6 It is a hydrogen atom;

[0870] p is 1;

[0871] R 7 It is the basis represented by the following formula:

[0872] [Chemistry 90]

[0873]

[0874] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0875] (ii) A serotonin 5-HT2A receptor inverse agonist containing a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0876] [Chemistry 91]

[0877]

[0878] (in the formula,

[0879] R 1 It's A-24;

[0880] R 2 It is a hydrogen atom;

[0881] R 3 It is a hydrogen atom;

[0882] n is 1;

[0883] R 4 It's E-4;

[0884] L is -NR 8 -;

[0885] R 8 It is a hydrogen atom;

[0886] R 5 It is a hydrogen atom;

[0887] R 6 It is a hydrogen atom;

[0888] p is 1;

[0889] R 7 It is the basis represented by the following formula:

[0890] [Chemistry 92]

[0891]

[0892] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0893] (iii) A serotonin 5-HT2A receptor inverse agonist containing a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0894] [Chemistry 93]

[0895]

[0896] (in the formula,

[0897] R 1 It's A-28;

[0898] R 2 It is a hydrogen atom;

[0899] R 3 It is a hydrogen atom;

[0900] n is 1;

[0901] R 4 It's E-4;

[0902] L is -NR 8 -;

[0903] R 8 It is a hydrogen atom;

[0904] R 5 It is a hydrogen atom;

[0905] R 6 It is a hydrogen atom;

[0906] p is 1;

[0907] R 7 It is the basis represented by the following formula:

[0908] [Chemistry 94]

[0909]

[0910] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0911] (iv) A composition for reverse activating serotonin 5-HT2A receptors, comprising a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0912] [Chemistry 95]

[0913]

[0914] (in the formula,

[0915] R 1 It's A-17;

[0916] R 2 It is a hydrogen atom;

[0917] R 3 It is a hydrogen atom;

[0918] n is 1;

[0919] R 4 It's E-4;

[0920] L is -NR8 -;

[0921] R 8 It is a hydrogen atom;

[0922] R 5 It is a hydrogen atom;

[0923] R 6 It is a hydrogen atom;

[0924] p is 1;

[0925] R 7 It is the basis represented by the following formula:

[0926] [Chemistry 96]

[0927]

[0928] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0929] (v) A composition for reverse agonist of serotonin 5-HT2A receptor, comprising a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0930] [Chemistry 97]

[0931]

[0932] (in the formula,

[0933] R 1 It's A-24;

[0934] R 2 It is a hydrogen atom;

[0935] R 3 It is a hydrogen atom;

[0936] n is 1;

[0937] R 4 It's E-4;

[0938] L is -NR 8 -;

[0939] R 8 It is a hydrogen atom;

[0940] R 5 It is a hydrogen atom;

[0941] R 6 It is a hydrogen atom;

[0942] p is 1;

[0943] R 7 It is the basis represented by the following formula:

[0944] [Chem. 98]

[0945]

[0946] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0947] (vi) A composition for reverse activating serotonin 5-HT2A receptors, comprising a compound represented by formula (I) or a pharmaceutically permissible salt thereof.

[0948] [Chemistry 99]

[0949]

[0950] (in the formula,

[0951] R 1 It's A-28;

[0952] R 2 It is a hydrogen atom;

[0953] R 3 It is a hydrogen atom;

[0954] n is 1;

[0955] R 4 It's E-4;

[0956] L is -NR 8 -;

[0957] R 8 It is a hydrogen atom;

[0958] R 5 It is a hydrogen atom;

[0959] R 6 It is a hydrogen atom;

[0960] p is 1;

[0961] R 7 It is the basis represented by the following formula:

[0962] [Chemistry 100]

[0963]

[0964] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0965] (vii) Compounds represented by formula (II) or pharmaceutically permissible salts thereof,

[0966] [Chemistry 101]

[0967]

[0968] (in the formula,

[0969] R 1 It is a substituted or unsubstituted aromatic nitrogen-containing heterocyclic group;

[0970] R 2 It is a hydrogen atom;

[0971] R 3 It is a hydrogen atom;

[0972] n is 1;

[0973] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0974] R 8 It is a hydrogen atom;

[0975] R 5 It is a hydrogen atom;

[0976] R 6 It is a hydrogen atom;

[0977] R 7 It is the basis represented by the following formula:

[0978] [Chemistry 102]

[0979]

[0980] (where R is in the formula) 9 (It is a substituted or unsubstituted C2-C4 alkoxy group, or a substituted or unsubstituted amino group).

[0981] (viii) The compound represented by formula (II) or its pharmaceutically permitted salt,

[0982] [Chemistry 103]

[0983]

[0984] (in the formula,

[0985] R 1 It's A-17;

[0986] R 2 It is a hydrogen atom;

[0987] R 3 It is a hydrogen atom;

[0988] n is 1;

[0989] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[0990] R 8 It is a hydrogen atom;

[0991] R 5 It is a hydrogen atom;

[0992] R 6 It is a hydrogen atom;

[0993] R 7 It is the basis represented by the following formula:

[0994] [Chemistry 104]

[0995]

[0996] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[0997] (ix) Compounds represented by formula (II) or pharmaceutically permissible salts thereof,

[0998] [Chemistry 105]

[0999]

[1000] (in the formula,

[1001] R 1 It's A-24;

[1002] R 2 It is a hydrogen atom;

[1003] R 3 It is a hydrogen atom;

[1004] n is 1;

[1005] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[1006] R 8 It is a hydrogen atom;

[1007] R 5 It is a hydrogen atom;

[1008] R 6 It is a hydrogen atom;

[1009] R 7 It is the basis represented by the following formula:

[1010] [Chemistry 106]

[1011]

[1012] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[1013] (x) The compound represented by formula (II) or its pharmaceutically permitted salt,

[1014] [Chemistry 107]

[1015]

[1016] (in the formula,

[1017] R 1 It's A-28;

[1018] R 2 It is a hydrogen atom;

[1019] R 3 It is a hydrogen atom;

[1020] n is 1;

[1021] R 4 It is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group;

[1022] R 8 It is a hydrogen atom;

[1023] R 5 It is a hydrogen atom;

[1024] R 6 It is a hydrogen atom;

[1025] R 7 It is the basis represented by the following formula:

[1026] [Chemistry 108]

[1027]

[1028] (where R is in the formula) 9 (Whether it is a substituted or unsubstituted alkoxy group).

[1029] (xi) The compound represented by formula (III) or its pharmaceutically permitted salt,

[1030] [Chemistry 109]

[1031]

[1032] (in the formula,

[1033] R 1 It is a substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclic group;

[1034] R 4 It is the basis represented by the following formula:

[1035] [Chemical 110]

[1036]

[1037] (where R is in the formula) 21 It is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[1038] R 22 and R 23 (Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring);

[1039] R 7 It is the basis represented by the following formula:

[1040] [Chemistry 111]

[1041]

[1042] (in the formula,

[1043] R 9 (It is a substituted or unsubstituted C2-C4 alkoxy group, or a substituted or unsubstituted amino group).

[1044] The compound represented by formula (I) or formula (II) is not limited to a specific isomer, but includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

[1045] In compounds represented by formula (I) or (II), one or more hydrogen, carbon, and / or other atoms may be substituted with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes are as follows: 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 Cl, comprising hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. Compounds represented by formula (I) or (II) also include compounds substituted with such isotopes. Compounds substituted with such isotopes are also useful as pharmaceuticals and comprise all radiolabeled compounds represented by formula (I) or (II). Furthermore, a "radiolabeling method" for manufacturing such "radiolabeled material" is also included in this invention, which is useful as a tool for studying the dynamics of metabolic drugs, for conjugation analysis, and / or for diagnosis.

[1046] Radiolabeled compounds of formula (I) or (II) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) or (II) can be prepared by introducing tritium into a specific compound of formula (I) or (II) using a catalytic dehalogenation reaction of tritium. This method comprises the steps of reacting the compound of formula (I) or (II) appropriately with a halogen-substituted precursor and tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, and a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be used by employing... 14 Preparation of raw materials for carbon C.

[1047] Pharmaceutically permissible salts of compounds represented by formula (I) or (II) include, for example, compounds represented by formula (I) or (II) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, methylpyridine, quinine, etc.). Salts formed from phytocyanines and amino acids; or salts formed from inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (such as 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.

[1048] The compounds represented by formula (I) or formula (II) of the present invention, or their pharmaceutically permissible salts, sometimes form solvates (e.g., hydrates), eutectics, and / or polymorphs, and the present invention also includes such various solvates, eutectics, and polymorphs. A "solvate" refers to a compound represented by formula (I) or formula (II) that can coordinate with any number of solvent molecules (e.g., water molecules). There are cases where compounds represented by formula (I) or formula (II), or their pharmaceutically permissible salts, absorb moisture and adsorb water when placed in the atmosphere, and hydrates may form. Additionally, there are cases where compounds represented by formula (I) or formula (II), or their pharmaceutically permissible salts, form polymorphs through recrystallization. A "eutectic" refers to a compound or salt represented by formula (I) or formula (II) existing in the same crystal lattice as a counter molecule, and may contain any number of counter molecules.

[1049] Compounds represented by formula (I) or formula (II) of the present invention, or their pharmaceutically permissible salts, sometimes form prodrugs, and the present invention also includes various such prodrugs. A prodrug is a derivative of a compound of the present invention having a chemically or metabolically degradable group, or a compound of the present invention that becomes pharmaceutically active in vivo under physiological conditions through solvation or hydrolysis. A prodrug is a compound that is converted into a compound represented by formula (I) or formula (II) under physiological conditions in vivo through enzymatic oxidation, reduction, hydrolysis, etc., or a compound that is converted into a compound represented by formula (I) or formula (II) through hydrolysis by gastric acid, etc. Methods for selecting and manufacturing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs sometimes possess activity themselves.

[1050] Examples of compounds of formula (I) or (II) having a hydroxyl group include: prodrugs such as acyloxy derivatives or sulfonyloxy derivatives, prepared by reacting a hydroxyl-containing compound with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonic anhydride, and a mixture of acid anhydrides, or by using a condensing agent to carry out the reaction. Examples include: CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2 CH2 COO-, CH3 CH(NH2)COO-, CH2 N(CH3)2COO-, CH3SO3-, CH3 CH2 SO3-, CF3SO3-, CH2 FSO3-, CF3 CH2 SO3-, p-CH3 O-PhSO3-, PhSO3-, p-CH3 PhSO3-.

[1051] The compounds of the present invention, due to their inverse agonist effect on the serotonin 5-HT2A receptor, are useful as therapeutic and / or preventative agents for diseases involving the serotonin 5-HT2A receptor. Examples of diseases involving the serotonin 5-HT2A receptor 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, hallucinations and delusions associated with neurodegenerative diseases, depression, schizophrenia, autism, dependency disorders, movement disorders, sleep disorders, irritability associated with Parkinson's disease, irritability associated with dementia, irritability associated with schizophrenia, and sexual dysfunction, among other serotonin-mediated diseases. Preferably, 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 preferably, hallucinations and delusions associated with Parkinson's disease, hallucinations and delusions associated with dementia, etc.

[1052] "Serotonin 5-HT2A receptor inverse agonist" refers to pharmaceutical products that have an inverse agonist effect on serotonin 5-HT2A receptors.

[1053] "Composition for reverse agonist of serotonin 5-HT2A receptor" refers to a composition having reverse agonist activity of serotonin 5-HT2A receptor, and is not limited to pharmaceutical use.

[1054] (Method for manufacturing the compounds of this invention)

[1055] The compounds represented by formula (I) or formula (II) of the present invention can be manufactured by, for example, the general synthetic methods shown below. Extraction, purification, etc., can be performed by ordinary organic chemistry experiments.

[1056] The compounds of the present invention can be synthesized with reference to methods known in the art.

[1057] (R 3 (The case where L is -NH-)

[1058] [Chemistry 112]

[1059]

[1060] (In the formula, each symbol is synonymous with (1) above, R) 1A -is R 1 -or R 1 R 2 CH-).

[1061] Step 1

[1062] Compound (a-2) can be obtained by reacting compound (a-1) and CDI in a suitable solvent.

[1063] The CDI can be used in amounts of 1.0 molar equivalent or more relative to compound (a-1), preferably 1.2 molar equivalent.

[1064] Examples of suitable reaction solvents include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1065] The reaction temperature is 0 to 80°C, preferably 0 to 20°C.

[1066] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.

[1067] The desired compound (a-2) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1068] Step 2

[1069] Compound (a-5) can be obtained by reacting compounds (a-3) and (a-4) with a suitable reducing agent, acetic acid, and a suitable solvent.

[1070] Examples of reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride. The reducing agent can be used in a molar equivalent of 1.0 molar equivalent or more relative to compound (a-3), preferably 1.0 to 2.0 molar equivalents.

[1071] Acetic acid can be used in amounts of 1.0 molar equivalent or more relative to compound (a-3), preferably 1.0 to 2.0 molar equivalent.

[1072] Examples of suitable reaction solvents include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1073] The reaction temperature is 0 to 80°C, preferably 0 to 20°C.

[1074] The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours.

[1075] The desired compound (a-5) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1076] Step 3

[1077] Compound (Ia) can be obtained by reacting compounds (a-5) and (a-2) in a suitable solvent.

[1078] Examples of suitable reaction solvents include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1079] The reaction temperature is 0 to 100°C, preferably 0 to 80°C.

[1080] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.

[1081] The desired compound (Ia) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1082] [Chemistry 113]

[1083]

[1084] (In the formula, PG is a suitable protecting group for the amino group, ring A is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group, and R...) a (Whether it is a substituted or unsubstituted alkyl group).

[1085] Step 1

[1086] Compound (b-3) can be obtained by reacting compounds (b-1) and (b-2) with a suitable reducing agent and, as needed, acetic acid in a suitable solvent.

[1087] Examples of reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride. The reducing agent can be used in a molar equivalent of 1.0 molar equivalent or more relative to compound (b-1), preferably 1.0 to 2.0 molar equivalents.

[1088] Acetic acid can be used in amounts of 1.0 molar equivalent or more relative to compound (b-3), preferably 1.0 to 2.0 molar equivalent.

[1089] Examples of suitable reaction solvents include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1090] The reaction temperature is 0 to 80°C, preferably 0 to 20°C.

[1091] The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours.

[1092] The desired compound (b-3) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1093] Step 2

[1094] Compound (b-4) can be obtained by reacting compound (b-3) and compound (a-2) in a suitable solvent.

[1095] Examples of suitable reaction solvents include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1096] The reaction temperature is 0 to 100°C, preferably 0 to 80°C.

[1097] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.

[1098] The desired compound (b-4) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1099] Step 3

[1100] Compound (b-5) can be obtained by reacting compound (b-4) in the presence of an acid, in the absence of a solvent, or in a suitable solvent.

[1101] Examples of acids include hydrochloric acid, sulfuric acid, TFA, and formic acid. The acid can be used in amounts of 1.0 molar equivalent or more relative to compound (b-4), preferably 1.0 to 30 molar equivalents.

[1102] As reaction solvents, examples include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1103] The reaction temperature is 0 to 80°C, preferably 0 to 20°C.

[1104] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.

[1105] The desired compound (b-5) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1106] Step 4

[1107] Compound (Ib) can be obtained by reacting compounds (b-5) and (b-6) with a suitable reducing agent and, as needed, acetic acid in a suitable solvent.

[1108] Examples of reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride. The reducing agent can be used in an amount of 1.0 molar equivalent or more relative to compound (b-5), preferably 1.0 to 2.0 molar equivalent.

[1109] Acetic acid can be used in amounts of 1.0 molar equivalent or more relative to compound (b-5), preferably 1.0 to 2.0 molar equivalent.

[1110] As reaction solvents, examples include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1111] The reaction temperature is 0 to 80°C, preferably 0 to 20°C.

[1112] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.

[1113] The desired compound (Ib) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1114] [Chemistry 114]

[1115]

[1116] Step 1

[1117] Compound (Ic) can be obtained by reacting compounds (a-5) and (c-1) with a suitable condensing agent and a base as required in a suitable solvent.

[1118] Examples of condensing agents include HOBt, HOAt, DCC, DIC, EDC HCl, HATU, and PyBOP. The condensing agent can be used in an amount of 1.0 molar equivalent or more relative to compound (b-5), preferably 1.0 to 2.0 molar equivalent.

[1119] Examples of bases include triethylamine and DIEA. The base can be used in amounts of 1.0 molar equivalent or more relative to compound (a-5), preferably 1.0 to 2.0 molar equivalents.

[1120] As reaction solvents, examples include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1121] The reaction temperature is 0 to 80°C, preferably 0 to 20°C.

[1122] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.

[1123] The desired compound (Ic) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1124] [Chemistry 115]

[1125]

[1126] Step 1

[1127] Compound (Id) can be obtained by reacting compounds (a-5) and (d-1) with a base in a suitable solvent.

[1128] Examples of bases include triethylamine, DIEA, and pyridine. The base can be used in amounts of 1.0 molar equivalent or more relative to compound (a-5), preferably 1.0 to 5.0 molar equivalents.

[1129] As reaction solvents, examples include alcohols (such as methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (such as toluene, benzene, xylene, etc.), saturated hydrocarbons (such as cyclohexane, hexane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., which can be used alone or in combination.

[1130] The reaction temperature is 0 to 120°C, preferably 0 to 80°C.

[1131] The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.

[1132] The desired compound (Id) obtained can be purified as needed by conventional methods (e.g., column chromatography, recrystallization, etc.).

[1133] The compounds of the present invention are useful as therapeutic and / or preventive agents for hallucinations and delusions associated with Parkinson's disease and / or dementia due to their serotonin 5-HT2A receptor inverse agonist activity.

[1134] Furthermore, the compounds of the present invention possess usefulness as medicines, and preferably have one or more of the following excellent characteristics.

[1135] a) It has a weak inhibitory effect on CYP enzymes (such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.).

[1136] b) It exhibits good drug dynamics, including high bioavailability and moderate clearance.

[1137] c) High metabolic stability.

[1138] d) For CYP enzymes (e.g., CYP3A4), no irreversible inhibition is observed within the concentration range of the assay conditions described in this specification.

[1139] e) It does not have mutagenicity.

[1140] f) Low risk to the cardiovascular system.

[1141] g) shows high solubility.

[1142] h) has a high serotonin 5-HT2A receptor binding capacity.

[1143] i) It has a high serotonin 5-HT2C receptor binding capacity.

[1144] j) High brain migration rate.

[1145] k)P-gp has low matrix properties.

[1146] The pharmaceutical composition of the present invention can be administered by any method, both orally and non-orally. Examples of non-oral administration methods include, for instance, percutaneous, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear, and vaginal administration.

[1147] When administered orally, it can be prepared into any of the following commonly used dosage forms according to conventional methods: 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, limonade, alcoholic preparations, aromatic aqueous solutions, extracts, decoctions, tinctures, etc.). Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets, or intraorally disintegrating tablets; powders and granules can be dry syrups; and capsules can be soft capsules, microcapsules, or sustained-release capsules.

[1148] In cases where administration is not orally, it may be appropriately administered using any of the following commonly used dosage forms: injections, drops, topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalers, lotions, injections, ointments, mouthwashes, enemas, ointments, plasters, gels, creams, patches, mud dressings, powders, suppositories, etc.). Injections may also be in the form of O / W, W / O, O / W / O, or W / O / W emulsions.

[1149] The effective amount of the compound of the present invention can be mixed with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, as needed, to prepare a pharmaceutical composition. Furthermore, the effective amount, dosage form, and / or various pharmaceutical additives of the compound of the present invention can be appropriately modified in this pharmaceutical composition, thereby enabling the preparation of pharmaceutical compositions for pediatric use, elderly use, critically ill patients, or surgical use. For example, the pediatric pharmaceutical composition can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (1 year to less than 7 years), children (7 years to less than 15 years), or patients aged 15 to 18 years. For example, the elderly pharmaceutical composition can be administered to patients aged 65 years and older.

[1150] The dosage of the pharmaceutical composition of the present invention is preferably set considering the patient's age, weight, type and severity of disease, and route of administration. In the case of oral administration, the dosage is typically 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of non-oral administration, the dosage varies considerably depending on the route of administration, but is typically in the range of 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. It can be administered by dividing the dosage into one or more administrations per day.

[1151] The compounds of the present invention can be used in combination with anti-Parkinson's disease drugs, anti-Alzheimer's disease drugs, antipsychotic drugs, and antidepressants (hereinafter also referred to as concomitant drugs) to enhance the effect of the compound or reduce the dosage of the compound. In this case, the timing of administration of the compounds of the present invention and the concomitant drugs is not limited; they can be administered simultaneously or at intervals, depending on the recipient. Furthermore, the compounds of the present invention and the concomitant drugs can be formulated into two or more formulations containing their respective active ingredients for administration, or they can be formulated into a single formulation containing these active ingredients for administration.

[1152] The dosage of the concurrent agent can be appropriately selected based on the dosage used clinically. Furthermore, the mixing ratio of the compound of the present invention to the concurrent agent can be appropriately selected according to the recipient, route of administration, recipient's disease, symptoms, combination, etc. For example, when the recipient is a human, 0.01 to 100 parts by weight of the concurrent agent can be used relative to 1 part by weight of the compound of the present invention.

[1153] Examples of drugs used to treat Parkinson's disease include levodopa preparations.

[1154] Examples of drugs used to treat Alzheimer's disease include donepezil.

[1155] Examples of antipsychotic drugs include quetiapine.

[1156] Examples of antidepressants include edemaproline.

[1157] Example

[1158] The present invention will be further described in detail below with reference to examples, reference examples and experimental examples, but the present invention is not limited to these examples.

[1159] In addition, the abbreviations used in this specification have the following meanings.

[1160] AcOH: Acetic acid

[1161] CDCl3: Deuterated chloroform

[1162] CDI: Carbonyldiimidazole

[1163] DCC: N,N'-Dicyclohexylcarbodiimide

[1164] DIC: N,N'-Diisopropylcarbodiimide

[1165] DIEA: N,N-Diisopropylethylamine

[1166] DMF: N,N-dimethylformamide

[1167] DMSO: Dimethyl sulfoxide

[1168] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1169] HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate

[1170] HOAt: 1-Hydroxy-7-azabenzotriazole

[1171] HOBt: 1-Hydroxybenzotriazole

[1172] NaBH(OAc)3: Sodium triacetoxyborohydride

[1173] NMP: N-methylpyrrolidone

[1174] TFA: Trifluoroacetic acid

[1175] PyBOP (registered trademark): Hexafluorophosphate (benzotriazole-1-yloxy) tripyrrole alkyl phosphate.

[1176] (Methods for identifying compounds)

[1177] The NMR analyses obtained in each embodiment were performed at 400 MHz using DMSO-d6 and CDCl3. Additionally, not all measured peaks were sometimes recorded when displaying the NMR data.

[1178] The RT in the instruction manual represents the retention time in LC / MS: liquid chromatography / mass analysis, determined under the following conditions.

[1179] (Measurement Condition 1)

[1180] Column: Shim-packXR-ODS (2.2μmi.d.3.0x50mm) (Shimadzu)

[1181] Flow rate: 1.6 mL / min

[1182] UV detection wavelength: 254nm

[1183] Mobile phase: [A] aqueous solution containing 0.1% formic acid, [B] acetonitrile solution containing 0.1% formic acid. Gradient: linear gradient of 10%-100% solvent [B] for 3 minutes, followed by 0.5 minutes of 100% solvent [B].

[1184] (Measurement Condition 2)

[1185] Column: ACQUITYUPLC (registered trademark) BEHC18 (1.7μm, d. 2.1 x 50mm) (Waters)

[1186] Flow rate: 0.8 mL / min

[1187] UV detection wavelength: 254nm

[1188] Mobile phase: [A] aqueous solution containing 0.1% formic acid, [B] acetonitrile solution containing 0.1% formic acid. Gradient: After a linear gradient of 5%-100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes.

[1189] Furthermore, the MS(m / z) value stated in the specification refers to the value observed through quality analysis.

[1190] [Example 1]

[1191] Synthesis of compound (I-008)

[1192] [Chemistry 116]

[1193]

[1194] Step 1: Synthesis of Compound 1

[1195] 4-Isobutoxyphenylmethylamine (6.00 g, 33.5 mmol) and CDI (651 mg, 40.2 mmol) were dissolved in acetonitrile (60 mL) and stirred at room temperature for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 1 (7.92 g, yield 87%).

[1196] 1 H-NMR (CDCl3) δ: 1.02 (d, J=6.5Hz, 6H), 2.00-2.14 (m, 1H), 3.68-3.77 (m, 2H), 4.49-4.59 ( m, 2H), 6.03 (brs, 1H), 6.90 (d, J=7.3Hz, 2H), 7.07 (s, 1H), 7.22-7.35 (m, 3H), 8.10 (s, 1H).

[1197] Step 2: Synthesis of Compound 2

[1198] 5-Fluoromethylpyridinaldehyde (1.00 g, 7.99 mmol) and 1-methylpiperidine-4-amine (913 mg, 7.99 mmol) were dissolved in dichloromethane (20 mL), and hydrogenated triacetoxyborohydride (3.39 g, 16.0 mmol) and acetic acid (0.914 mL, 16.0 mmol) were added. The mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give compound 2 (970 mg, 55% yield).

[1199] 1 H-NMR (CDCl3) δ: 1.42-1.53 ​​(m, 2H), 1.81-2.03 (m, 4H), 2.27 (s, 3H), 2.45-2.54 (m, 1H), 2.83 (d, J=11.8Hz, 2H), 3.92 (s, 2H), 7.31-7.40 (m, 2H), 8.40 (d, J=2.5Hz, 1H).

[1200] Synthesis of compound (I-008) in step 3

[1201] Compound 1 (673 mg, 2.46 mmol) and compound 2 (500 mg, 2.24 mmol) were dissolved in toluene (5 mL) and stirred at 80 °C for 1 hour. After cooling, the solvent was removed by vacuum distillation, and the residue was purified by amino column chromatography (hexane-ethyl acetate) to obtain compound (I-008) (525 mg, yield 55%).

[1202] [Example 2]

[1203] Synthesis of compound (I-042)

[1204] [Chemistry 117]

[1205]

[1206] Synthesis of compound (I-042) in step 1

[1207] Compound 2 (74.4 mg, 0.333 mmol) was dissolved in N,N-dimethylformamide (1.15 mL), and 4-isobutoxybenzyl (4-nitrophenyl) carbonate (74.4 mg, 0.333 mmol) and triethylamine (0.14 mL, 1.00 mmol) were added. The mixture was stirred at 70 °C for 8 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound (I-042) (40 mg, yield 28%).

[1208] [Example 3]

[1209] Synthesis of compound (I-050)

[1210] [Chemistry 118]

[1211]

[1212] Step 1: Synthesis of Compound 5

[1213] Dichloromethane (5 mL), (5-fluoropyridin-2-yl)methylamine (202 mg, 1.60 mmol), AcOH (0.07 mL, 1.33 mmol), and sodium triacetoxyborohydride (423 mg, 2.00 mmol) were added to compound 4 (300 mg, 1.33 mmol), and the mixture was stirred at room temperature for 6 hours. Saturated sodium bicarbonate solution (5 mL) was added, and the mixture was stirred at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to give compound 5 (402 mg, 90% yield).

[1214] 1 H-NMR (CDCl3) δ: 0.28-0.33 (m, 1H), 0.40-0.48 (m, 3H), 1.44 (s, 9H), 1.62 -1.68(m, 1H), 1.75-1.82(m, 1H), 2.15(t, J=3.6Hz, 1H), 2.94-3.10(m, 1H) , 3.33-3.42(m, 1H), 3.46-3.53(m, 1H), 3.65-3.82(m, 1H), 3.84(d, J=14.4 Hz, 1H), 3.90 (d, J=14.4Hz, 1H), 7.31-7.39 (m, 2H), 8.40 (d, J=2.6Hz, 1H).

[1215] Step 2: Synthesis of Compound 6

[1216] Acetonitrile (2 mL) and N-(4-isobutoxybenzyl)-1H-imidazol-1-carboxamide (147 mg, 0.54 mmol) were added to compound 5 (150 mg, 0.45 mmol), and the mixture was stirred at 80 °C for 8 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 6 (195 mg, 81% yield).

[1217] 1H-NMR (CDCl3) δ: 0.32-0.50 (m, 3H), 0.52-0.58 (m, 1H), 1.02 (d, J=6.8Hz, 6H), 1.44 (9H, s ),1.56-1.62(m,1H),1.69-1.76(m,1H),1.80-1.91(m,1H),2.04-2.11(m,1H),2.80-3.0 1 (m, 1H), 3.06-3.48 (m, 2H), 3.70 (d, J = 6.7Hz, 2H), 5.80-6.18 (m, 1H), 6.82 (d, J = 8.5Hz, 2H), 7.13 (d, J=8.7Hz, 2H), 7.21-7.25 (m, 1H), 7.35 (td, J=8.3, 2.8Hz, 1H), 8.28 (s, 1H).

[1218] Synthesis of compound (I-051) in step 3

[1219] Dichloromethane (2 mL) and TFA (0.5 mL, 6.49 mmol) were added to compound 6 (195 mg, 0.36 mmol), and the mixture was stirred at room temperature for 3 hours. A 20% aqueous potassium carbonate solution (4 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation to obtain compound (I-051) (152 mg, 96% yield).

[1220] 1H-NMR (CDCl3) δ: 0.28-0.32 (m, 1H), 0.39-0.42 (m, 1H), 0.42-0.48 (m, 1H), 0.57-0.62 (m, 1H), 1.01 ( d, J=6.7Hz, 6H), 1.95-2.10 (m, 3H), 2.35 (d, J=13.6Hz, 1H), 2.87 (t, J=10.8Hz, 1H), 3.17 (d, J=12.2H z, 1H), 3.28 (d, J=12.9Hz, 1H), 3.70 (d, J=6.5Hz, 2H), 4.24-4.57 (m, 6H), 6.05 (s, 1H), 6.82 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5Hz, 2H), 7.22-7.26 (m, 1H), 7.35 (td, J=8.3, 2.9Hz, 1H), 8.27 (d, J=2.8Hz, 1H).

[1221] Synthesis of compound (I-050) in step 4

[1222] To compound (I-051) (85 mg, 0.19 mmol), ethanol (2 mL), 37% formaldehyde solution (0.03 mL, 0.39 mmol), and sodium triacetoxyborohydride (61 mg, 0.29 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (5 mL) was added, and the mixture was stirred at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to obtain compound (I-050) (80 mg, 91% yield).

[1223] [Example 4]

[1224] Synthesis of compound (I-068)

[1225] [Chemistry 119]

[1226]

[1227] Synthesis of compound (I-068) in step 1

[1228] Compound 2 (75.0 mg, 0.336 mmol) was dissolved in N,N-dimethylformamide (0.75 mL), and 2-(4-isobutoxyphenyl)acetic acid (84.0 mg, 0.403 mmol) (synthetic method described in WO2019 / 40104), HOBt (54.5 mg, 0.403 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77.0 mg, 0.403 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. An aqueous solution of potassium carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound (I-068) (104 mg, 75% yield).

[1229] Reference Example 1

[1230] Synthesis of Compound 8

[1231] [Chemistry 120]

[1232]

[1233] Step 1: Synthesis of Compound 8

[1234] CDI (0.97 g, 6.00 mmol) was added to a tetrahydrofuran (14 mL) solution of p-toluylmethylamine (0.6 g, 5.00 mmol), and the mixture was stirred at 45 °C for 3 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 8 (0.66 g, 61% yield).

[1235] 1H-NMR (400MHz, CDCl3) δ: 1.60 (s, 3H), 2.34 (s, 3H), 4.56 (d, J=5.5Hz, 2H), 6.06 (s, 1 H), 7.07 (s, 1H), 7.19 (d, J=7.9Hz, 2H), 7.22-7.26 (m, 2H), 7.31 (s, 1H), 8.09 (s, 1H).

[1236] [Example 5]

[1237] Synthesis of compound (I-120)

[1238] [Chemistry 121]

[1239]

[1240] Step 1: Synthesis of Compound 9

[1241] Under ice cooling, dichloromethane (30 mL), triethylamine (5.39 g, 53.3 mmol), titanium tetrachloride (4.44 mL, 4.44 mmol), and compound 4 (2 g, 8.88 mmol) were added to (S)-1-phenylethyl-1-amine (1.29 g, 10.7 mmol) and stirred at room temperature for 18 hours. Diethyl ether (60 mL) was added and stirred at room temperature for 30 minutes. The resulting solid was filtered off, and the solvent was removed under reduced pressure to give compound 9 (2.8 g, 96% yield).

[1242] Step 2: Synthesis of Compound 10

[1243] In a 28 mL ethanol solution of compound 9 (2.8 g, 8.52 mmol) at -78 °C, sodium borohydride (0.16 g, 4.26 mmol) was added, and the mixture was stirred at -78 °C for 2 hours. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to give compound 10 (2.1 g, 75% yield).

[1244] 1H-NMR (CDCl3) δ: 0.29-0.50 (m, 4H), 1.30 (d, J=6.4Hz, 2H), 1.42 (s, 9H), 1.45-1.70 (m, 2H), 2.18 (s, 1H), 2.9 2-3.06 (s, 1H), 3.28-3.49 (m, 3H), 3.83 (q, J=6.6Hz, 1H), 7.22 (dd, J=8.7, 4.5Hz, 1H), 7.30 (d, J=4.3Hz, 4H).

[1245] Step 3: Synthesis of Compound 11

[1246] Methanol (1.6 mL), ammonium formate (150 mg, 2.38 mmol), and palladium hydroxide on carbon (40 mg, 0.14 mmol) were added to compound 10 (157 mg, 0.48 mmol), and the mixture was stirred at 60°C for 1 hour. After filtering the reaction solution to remove palladium hydroxide on carbon, the solvent was removed under reduced pressure to obtain compound 11 (102 mg, 95% yield).

[1247] 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), 2.6 2 (dd, J=10.o, 6.4Hz, 1H), 3.05 (d, J=12.2Hz, 1H), 3.41 (d, J=13.6Hz, 1H), 3.45-3.62 (m, 2H).

[1248] Step 4: Synthesis of Compound 12

[1249] Compound 12 was obtained by replacing 1-methylpiperidine-4-amine in step 2 of Example 1 with compound 11 (49 mg, 0.22 mmol).

[1250] Step 5: Synthesis of Compound 13

[1251] Compound 13 was obtained by replacing compound 5 in step 2 of Example 3 with compound 12 and replacing N-(4-isobutoxybenzyl)-1H-imidazol-1-carboxamide with compound 8.

[1252] Step 6: Synthesis of Compound 14

[1253] Compound 14 was obtained by replacing compound 6 in step 3 of Example 3 with compound 13.

[1254] Synthesis of step 7I-120

[1255] Compound 14 was used instead of compound (I-051) in step 4 of Example 3, thereby obtaining compound (I-120) (38 mg, 53% overall yield of 4 steps).

[1256] [Example 6]

[1257] Synthesis of compound (I-136)

[1258] [Chemistry 122]

[1259]

[1260] Step 1: Synthesis of Compound 16

[1261] Ethanol (5 mL), methyl acrylate (0.03 mL, 3.02 mmol), and triethylamine (0.42 mL, 3.02 mmol) were added to compound 15 (500 mg, 3.02 mmol), and the mixture was stirred at room temperature for 48 hours. The solvent was removed by vacuum distillation to obtain the crude product of compound 16 (654 mg, 101% yield).

[1262] Step 2: Synthesis of Compound 17

[1263] Methanol (5 mL), 37% formaldehyde solution (0.67 mL, 9.06 mmol), and NaBH(OAc)3 (61 mg, 0.29 mmol) were added to compound 16 (654 mg, 3.02 mmol), and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (5 mL) was added, and the mixture was stirred at room temperature. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation to obtain the crude product of compound 17 (687 mg, 99% yield).

[1264] Step 3: Synthesis of Compound 18

[1265] Toluene (7 mL) and 28% sodium methoxide solution (2.2 mL, 8.87 mmol) were added to compound 17 (195 mg, 0.36 mmol), and the mixture was heated under reflux with stirring for 4 hours. After removing the solvent by vacuum distillation, methanol (3 mL) and water (3 mL) were added, and the mixture was heated under reflux with stirring for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation to obtain the crude product of compound 18 (432 mg, 105% yield).

[1266] Step 4: Synthesis of Compound 19

[1267] Dichloromethane (5 mL), (5-fluoropyridin-2-yl)methylamine (120 mg, 0.95 mmol), AcOH (0.07 mL, 1.14 mmol), and NaBH(OAc)3 (241 mg, 1.14 mmol) were added to compound 18 (132 mg, 0.95 mmol), and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (5 mL) was added, and the mixture was stirred at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation to obtain the crude product of compound 19 (157 mg, 67% yield).

[1268] Synthesis of compound (I-136) in step 5

[1269] Acetonitrile (0.2 mL) and N-(4-isobutoxybenzyl)-1H-imidazol-1-carboxamide (22 mg, 0.08 mmol) were added to compound 19 (18 mg, 0.07 mmol), and the mixture was stirred at 80 °C for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound (I-136) (22 mg, 67% yield).

[1270] 1H-NMR (CDCl3) δ: 0.30-0.36 (m, 1H), 0.43-0.48 (m, 1H), 0.58-0.71 (m, 2H), 1.02 (d, 6H, J=6.5Hz), 1.37-1.47 (m, 1H), 1.86-1.97 (m , 1H), 2.03-2.10(m, 1H), 2.21-2.37(m, 4H), 2.85-2.99(m, 2H), 3.70(d, 2H, J=5.0Hz), 4.33(t, 2H, J=4.5Hz), 4.42(s, 3H), 6.20(br s, 1H), 6.82 (d, 2H, J=8.0Hz), 7.15 (d, 2H, J=8.0Hz), 7.28-7.40 (m, 2H), 8.29 (s, 1H).

[1271] [Example 7]

[1272] Synthesis of compound (I-139)

[1273] [Chemistry 123]

[1274]

[1275] Step 1: Synthesis of Compound 21

[1276] Compound 20 (300 mg, 1.37 mmol) was added with dichloromethane (5 mL), 1,5-dimethyl-1H-pyrazole carbaldehyde (171 mg, 1.37 mmol), AcOH (0.39 mL, 6.87 mmol), and NaBH(OAc)3 (583 mg, 2.75 mmol), and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added, and the mixture was stirred at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to give compound 21 (359 mg, 80% yield).

[1277] 1 H-NMR (CDCl3) δ: 1.45 (s, 9H), 1.59-1.81 (m, 2H), 2.24 (s, 3H), 2.69-3.02 (m, 2H), 3.72 (s, 3H), 3 .72(s,3H), 3.80(s,2H), 3.69-4.20(m,1H), 4.23-4.42(m,1H), 4.69-4.81(m,1H), 5.96(s,1H).

[1278] Step 2: Synthesis of Compound 22

[1279] Acetonitrile (3 mL) and N-(4-n-propoxybenzyl)-1H-imidazol-1-carboxamide (113 mg, 0.44 mmol) were added to compound 21 (142 mg, 0.44 mmol), and the mixture was stirred at 80 °C for 4 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 22 (195 mg, 81% yield).

[1280] 1 H-NMR (CDCl3) δ: 1.03 (t, 3H, J=7.4Hz), 1.47 (s, 9H), 1.56-1.65 (m, 1H), 1 .75-1.84(m, 1H), 2.15-2.24(m, 4H), 2.75-3.1o(m, 2H), 3.56(s, 3H), 3.90 (t, 2H, J=6.6Hz), 4.25-4.42 (m, 5H), 4.74-4.63 (m, 1H), 4.76-4.89 (m, 1H ), 5.92 (s, 1H), 5.92 (s, 1H), 6.82 (d, J = 8.5Hz, 2H), 7.15 (d, J = 8.5Hz, 2H).

[1281] Step 3: Synthesis of Compound 23

[1282] To compound 22 (80 mg, 0.36 mmol), dichloromethane (1 mL), 2,6-dimethylpyridine (0.08 mL, 0.695 mmol), and trimethylsilyl trifluoromethanesulfonate (0.08 mL, 0.695 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. A 20% aqueous potassium carbonate solution (4 mL) was added, and the mixture was extracted with ethyl acetate. The solvent was removed by vacuum distillation, and the residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to give compound 23 (52 mg, 80% yield).

[1283] 1H-NMR (CDCl3) δ: 1.01 (6H, d, J=6.8Hz), 1.62 (1H, br s), 2.02-2.12 (2H, m), 2.21 (3H, s), 2.74-2.92 (2H, m), 3.24 (2H, dd, J = 29.7, 14.9Hz), 3.57 (3H, s), 3.69 (2H, d , J=6.5Hz), 4.30-4.34 (4H, m), 4.57 (1H, dt, J=35.4, 6.4Hz), 4.78 (1H, d, J=50.8Hz), 5.92 (1H, s), 6.82 (1H, br s), 6.81 (2H, d, J = 8.5Hz), 7.14 (2H, d, J = 8.5Hz).

[1284] Synthesis of compound (I-139) in step 4

[1285] Methanol (1 mL), 37% formaldehyde solution (0.03 mL, 0.36 mmol), and NaBH(OAc)3 (45 mg, 0.22 mmol) were added to compound 23 (30 mg, 0.19 mmol), and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added, and the mixture was stirred at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to obtain compound (I-139) (20 mg, 66% yield).

[1286] 1H-NMR (CDCl3) δ: 1.03 (t, 3H, J=7.5Hz), 1.61-1.68 (m, 1H), 1.75-1.84 (m, 2H), 2.15-2.37 (m, 9H), 3.00 (d, 1H, J=1 0.8Hz), 3.14 (t, 1H, J=11.9Hz), 3.56 (s, 3H), 3.90 (t, 2H, J=6.7Hz), 4.26-4.51 (m, 5H), 4.79-4.91 (m, 1H), 5.93 (br s, 1H), 6.70 (br s, 1H), 6.81 (d, 2H, J=8.5Hz), 7.15 (d, 2H, J=8.5Hz).

[1287] The following compounds were synthesized according to the general synthetic method and the methods described in the examples. Their structures and physical properties (LC / MS data) are shown in the table below.

[1288] It should be noted that in the structural formula, "wedge" and "dashed line" indicate stereoconfiguration. Especially in compounds that describe stereoconfiguration, compounds that are described as "racemate" in the "stereo" section are racemic compounds whose relative stereoconfiguration is specified.

[1289] In addition, among the compounds in which the bonds that form asymmetric carbons are recorded with solid lines, the compounds listed as "racemate" in the "stereo" category are racemic compounds.

[1290] The "diastereo mixture" in the "stereo" project refers to a mixture of diastereomers.

[1291] [Table 1]

[1292]

[1293] [Table 2]

[1294]

[1295] [Table 3]

[1296]

[1297] [Table 4]

[1298]

[1299] [Table 5]

[1300]

[1301] [Table 6]

[1302]

[1303] [Table 7]

[1304]

[1305] [Table 8]

[1306]

[1307] [Table 9]

[1308]

[1309] [Table 10]

[1310]

[1311] [Table 11]

[1312]

[1313] [Table 12]

[1314]

[1315] [Table 13]

[1316]

[1317] [Table 14]

[1318]

[1319] [Table 15]

[1320]

[1321] [Table 16]

[1322]

[1323] [Table 17]

[1324]

[1325] [Table 18]

[1326]

[1327] [Table 19]

[1328]

[1329] [Table 20]

[1330]

[1331] [Table 21]

[1332]

[1333] [Table 22]

[1334]

[1335] [Table 23]

[1336]

[1337] [Table 24]

[1338]

[1339] [Table 25]

[1340]

[1341] [Table 26]

[1342]

[1343] [Table 27]

[1344]

[1345] [Table 28]

[1346]

[1347] [Table 29]

[1348]

[1349] [Table 30]

[1350]

[1351] [Table 31]

[1352]

[1353] [Table 32]

[1354]

[1355] [Table 33]

[1356]

[1357] [Table 34]

[1358]

[1359] [Table 35]

[1360]

[1361] [Table 36]

[1362]

[1363] [Table 37]

[1364]

[1365] [Table 38]

[1366]

[1367] [Table 39]

[1368]

[1369] [Table 40]

[1370]

[1371] The following describes examples of biological tests using the compounds of the present invention.

[1372] The compounds represented by formula (I) or formula (II) of the present invention can be those that have reverse agonistic activity against the serotonin 5-HT2A receptor or antagonistic activity against the human serotonin 5-HT2A receptor.

[1373] Specifically, in the evaluation method 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.

[1374] Experimental Example 1: 5-HT2A Receptor Binding Inhibition Assay

[1375] (Experimental conditions)

[1376] Cell membrane: Each well contains 15 μg of Jump-In HEK cell membrane (expressing recombinant human 5-HT2A receptor).

[1377] Assay buffer: 50 mmol / L Tris-HCl (pH 7.4) containing 120 mmol / L NaCl, 1 mmol / L MgCl₂·6H₂O, 5 mmol / L KCl, 0.1% BSA, and 2 mmol / L CaCl₂.

[1378] Radioactive ligand: final concentration 3 nmol / L 3 H]-Ketanserin

[1379] Non-specific ligand: Serotonin hydrochloride at a final concentration of 500 μmol / L.

[1380] The Kd value was calculated during batch (lot) changes of the cell membrane. 0.5 μL of a 1 mmol / L nonspecific binding calculation compound dissolved in DMSO or DMSO was aliquoted into microplates beforehand, and the cell membrane was diluted with assay buffer. Radioactive ligand solutions were staged from 16 nM at a common ratio of 2, and counts were confirmed using a liquid scintillation analyzer. The diluted assay buffer containing the cell membrane was aliquoted into the microplates at 50 μL / well. Then, the radioactive ligand solution was aliquoted into the microplates at 50 μL / well, and the plates were sealed. The plates were incubated at room temperature (25 °C) for 1.5 hours. During this time, 50 mmol / L Tris-HCl (pH 7.4) was aliquoted into GF / B UniFilter plates at 50 μL / well, and the plates were incubated at 4 °C for at least 1 hour. The plates were then filtered using a cell harvester (PerkinElmer). Radioactive ligand solution was aliquoted into the wells of the GF / B UniFilter culture plate at a rate of 10 μL / well. After the GF / B UniFilter culture plate was allowed to dry at room temperature, MicroScinti20 was aliquoted into the GF / B UniFilter culture plate at a rate of 50 μL / well, and the culture plate was sealed. The GF / B UniFilter culture plate was left to stand overnight at room temperature. [The ligand solution binds to the 5-HT2A receptor...] 3 The radioactivity of 1,000 H-ketanserin was determined using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve was plotted based on the measured values, and the Kd value was calculated from the slope of the Scatchard plot.

[1381] (Binding test of the compounds of this invention)

[1382] Pre-dissolved DMSO compound solution was aliquoted into microculture plates at 0.5 μL. Cell membrane and thermal ligand solutions were diluted separately with assay buffer. Then, the diluted assay buffer containing cell membranes was aliquoted into the microculture plates at 50 μL / well. Next, the radioactive ligand solution was aliquoted into the microculture plates at 50 μL / well, and the plates were sealed. The plates were then incubated at room temperature (25°C) for 1.5 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) was aliquoted into the GF / BUniFilter plates at 50 μL / well, and the plates were incubated at 4°C for at least 1 hour. The plates were then filtered using a cell harvester (PerkinElmer). After the GF / B UniFilter plates were dried at room temperature, MicroScinti20 was aliquoted into the GF / B UniFilter plates at 50 μL / well, and the plates were sealed. The GF / BUniFilter plates were incubated at room temperature overnight. [Binding to 5-HT2A receptor] 3 The radioactivity of H-ketanserin was determined using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Nonspecific binding was observed in the presence of ligand-unlabeled 500 μmol / L serotonin hydrochloride (HCl), while total binding was observed in the absence of the compounds of this invention (Vehicle). 3 The radioactivity of 1H-ketanserin was calculated, and the Ki value was calculated from the final dosage response curve.

[1383] (The binding activity of the compounds of the present invention is calculated from the following binding inhibition rate (%))

[1384] Inhibition rate (%) = [1 - (ca) / (ba)] × 100

[1385] a: Average CPM of nonspecific binding

[1386] b: The average CPM of the total combination

[1387] c: cpm in the presence of the test compound.

[1388] (result)

[1389] The following shows the evaluation results of the human serotonin 5-HT2A receptor binding activity of the compounds of the present invention. Furthermore, Ki values ​​are defined as follows: less than 10 nM is designated as "A", 10 nM or more but less than 100 nM as "B", and 100 nM or more as "C".

[1390] Compound I-009: 0.291 nM

[1391] Compound I-021: 0.858 nM

[1392] Compound I-037: 0.654 nM

[1393] Compound I-042: 1.15 nM

[1394] Compound I-043: 2.52 nM

[1395] Compound I-068: 6.52 nM

[1396] Compound I-071: 13.3 nM

[1397] Compound I-072: 219 nM

[1398] Compound I-075: 130 nM

[1399] Compound I-076: 62 nM

[1400] Compound I-082: 3.74 nM

[1401] Compound I-084: 5.61 nM

[1402] Compound I-085: 23.8 nM

[1403] Compound I-088: 25.7 nM

[1404] Compound I-102: 0.919 nM

[1405] Compound I-116: 1.45 nM

[1406] Compound I-124: 0.690 nM

[1407] Compound I-126: 1.92 nM

[1408] Compound I-129: 0.85 nM

[1409] Compound I-130: 15.3 nM

[1410] Compound I-134: 0.475 nM

[1411] Compound I-136: 8.02 nM

[1412] Compound I-139: 2.93 nM

[1413] Compound I-146: 1.94 nM

[1414] Compound I-147: 0.758 nM.

[1415] [Table 41]

[1416]

[1417] [Table 42]

[1418]

[1419] [Table 43]

[1420]

[1421] Experimental Example 2: 5-HT2C Receptor Binding Inhibition Assay

[1422] (Experimental conditions)

[1423] Cell membrane: Each well contains 0.5 μg of Jump-In HEK cell membrane (expressing recombinant human 5-HT2C receptor).

[1424] Assay buffer: 50 mmol / L Tris-HCl (pH 7.4) containing 120 mmol / L NaCl, 1 mmol / L MgCl₂·6H₂O, 5 mmol / L KCl, 0.1% BSA, and 2 mmol / L CaCl₂.

[1425] Radioactive ligand: final concentration of 1 nmol / L [ 3 H]-Mesulergine

[1426] Non-specific ligand: Final concentration 500 μmol / L serotonin hydrochloride (Serotonin HCl).

[1427] The Kd value was calculated during batch changes of the cell membrane. 0.5 μL of the nonspecific binding compound or DMSO dissolved in 1 mmol / L DMSO was aliquoted into microplates beforehand, and the cell membrane was diluted with assay buffer. The radioactive ligand solution was staged from 16 nM at a common ratio of 2, and counts were confirmed using a liquid scintillation analyzer. The diluted assay buffer containing the cell membrane was aliquoted into microplates at 50 μL / well. Then, the radioactive ligand solution was aliquoted into microplates at 50 μL / well, and the plates were sealed. The plates were incubated at room temperature (25 °C) for 1.5 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) was aliquoted into GF / B UniFilter plates at 50 μL / well, and the plates were incubated at 4 °C for at least 1 hour. The plates were then filtered using a cell harvester (PerkinElmer). Radioactive ligand solution was aliquoted into the wells of the GF / B UniFilter culture plate at a rate of 10 μL / well. After the GF / B UniFilter culture plate was allowed to dry at room temperature, MicroScinti20 was aliquoted into the GF / B UniFilter culture plate at a rate of 50 μL / well, and the culture plate was sealed. The GF / B UniFilter culture plate was left to stand overnight at room temperature. [The ligand solution binds to the 5-HT2C receptor...] 3 The radioactivity of H-mesulergine was determined using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve was plotted based on the measured values, and the Kd value was calculated from the slope of the Scatchard plot.

[1428] (Binding test of the compounds of this invention)

[1429] Pre-dissolve the compound solution in DMSO at 0.5 μL in microculture plates. Dilute the cell membrane and thermal ligand separately with assay buffer. Then, aliquot the diluted assay buffer containing the cell membrane into the microculture plates at 50 μL / well. Next, aliquot the radioactive ligand solution into the microculture plates at 50 μL / well and seal the plates. Incubate at 37°C for 2 hours. During this period, aliquot 50 mmol / L Tris-HCl (pH 7.4) into the GF / B UniFilter plates at 50 μL / well and incubate at 4°C for at least 1 hour. Then, filter using a cell harvester (PerkinElmer). After allowing the GF / B UniFilter plates to dry at room temperature, aliquot MicroScinti20 into the GF / B UniFilter plates at 50 μL / well and seal. Incubate the GF / B UniFilter plates overnight at room temperature. [The text abruptly ends here, likely due to an incomplete translation or missing information.] 3 The radioactivity of [H]-mesulergine was determined using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Nonspecific binding occurred in the presence of ligand-unlabeled 500 μmol / L serotonin hydrochloride (HCl), while total binding occurred in the absence of the compounds of this invention (Vehicle). 3 The radioactivity of [H]-mesulergine was calculated. The Ki value was calculated from the final dosage-response curve.

[1430] (The binding activity of the compounds of this invention is calculated from the following binding inhibition rate (%))

[1431] Inhibition rate (%) = [1 - (ca) / (ba)] × 100

[1432] a: Average CPM of nonspecific binding

[1433] b: Average cpm of total binding; cpm in the presence of the test compound.

[1434] (result)

[1435] The following shows the evaluation results of the inhibitory activity of the compounds of the present invention on human serotonin 5-HT2C receptor binding. In addition, the Ki value is set as "A" for less than 10 nM, "B" for more than 10 nM but less than 100 nM, and "C" for more than 100 nM.

[1436] Compound I-009: 7.92 nM

[1437] Compound I-021: 50.7 nM

[1438] Compound I-037: 28.2 nM

[1439] Compound I-042: 2.31 nM

[1440] Compound I-043: 55.7 nM

[1441] Compound I-068: 49.9 nM

[1442] Compound I-071: 60.7 nM

[1443] Compound I-072: 617 nM

[1444] Compound I-075: 1310 nM

[1445] Compound I-076: 263 nM

[1446] Compound I-082: 28.8 nM

[1447] Compound I-084: 65.2 nM

[1448] Compound I-085: 96.2 nM

[1449] Compound I-088: 134 nM

[1450] Compound I-102: 4.01 nM

[1451] Compound I-116: 12.2 nM

[1452] Compound I-124: 2.22 nM

[1453] Compound I-126: 1.09 nM

[1454] Compound I-129: 1.51 nM

[1455] Compound I-130: 348 nM

[1456] Compound I-134: 3.2 nM

[1457] Compound I-136: 148 nM

[1458] Compound I-139: 11.1 nM

[1459] Compound I-146: 4.96 nM

[1460] Compound I-147: 2.12 nM.

[1461] [Table 44]

[1462]

[1463] [Table 45]

[1464]

[1465] [Table 46]

[1466]

[1467] Example 3: hERG Assay To assess the risk of QT interval prolongation caused by the compounds of this invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels were used to investigate the effect of the compounds of this invention on delayed rectifier K, which plays an important role in ventricular repolarization. + The effect of electric current (IKr).

[1468] Using a fully automated patch-clamp system (QPatch; Sophion Bioscience A / S), cells were held at a membrane potential of -80 mV using the whole-cell patch-clamp technique. After applying a -50 mV leakage potential, a +20 mV depolarization stimulus was applied for 2 seconds, followed by a -50 mV repolarization stimulus for another 2 seconds. The induced Ig was recorded. Kr Extracellular fluid (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl2: 2 mmol / L, MgCl2: 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) adjusted to 0.1% was used as a medium. The extracellular fluid containing the medium and the compound of the present invention dissolved at the target concentration was then applied to cells at room temperature for at least 15 minutes. From the obtained I... Kr Using analytical software (QPatc hAssay software; Sophion Bioscience A / S) and with the current value at the maintained membrane potential as a reference, the absolute value of the maximum tail current was measured. The maximum tail current after application of the compound of the present invention relative to the maximum tail current after application to the medium was calculated as the inhibition rate. Further corrections were made for the inhibition rate results using a negative control, thereby evaluating the effect of the compound of the present invention on I... Kr The impact.

[1469] (Results) show the inhibition rate at a compound concentration of 3 μmol / L.

[1470] Compound I-129: 31.4%

[1471] Compound I-133: 6.60%

[1472] Compound I-134: 31.2%

[1473] Compound I-139: 14.2%

[1474] Compound I-141: 49.3%.

[1475] Experimental Example 4: BA Test

[1476] Materials and methods for studying oral absorption

[1477] (1) Use of animals: Use mice or rats.

[1478] (2) Feeding conditions: Allow mice or rats to freely consume solid feed and sterilized tap water.

[1479] (3) Dosage and group setting: Oral and intravenous administration shall be performed at the prescribed dosage. Grouping shall be set as follows.

[1480] (The dosage of each compound has changed)

[1481] Oral administration: 2 to 60 μmol / kg or 1 to 30 mg / kg (n = 2 to 3)

[1482] Intravenous administration: 1 to 20 μmol / kg or 0.5 to 10 mg / kg (n = 2 to 3).

[1483] (4) Preparation of the administration solution: Oral administration is in the form of a solution or suspension. Intravenous administration is administered by liquefaction.

[1484] (5) Administration method: Oral administration is administered by forcibly inserting a probe into the stomach. Intravenous administration is administered via a syringe with a needle through the tail vein.

[1485] (6) Evaluation items: Blood was collected periodically, and the concentration of the compounds of the present invention in the plasma was determined by LC / MS / MS.

[1486] (7) Statistical analysis: The area under the concentration-time curve (AUC) of the compound of the present invention in plasma was calculated by moment analysis method, and the bioavailability (BA) of the compound of the present invention was calculated from the ratio of the oral administration group to the intravenous administration group and the AUC ratio.

[1487] In addition, the dilution concentration and dilution solvent can be changed as needed.

[1488] Experimental Example 5: Sweep Rate Evaluation Experiment

[1489] Experimental Materials and Methods

[1490] (1) Animals used: SD rats were used.

[1491] (2) Feeding conditions: Allow SD rats to freely consume solid feed and sterilized tap water.

[1492] (3) Dosage and group setting: Intravenous administration is performed at the prescribed dosage. Grouping is set as follows.

[1493] Intravenous administration: 1 μmol / kg (n=2).

[1494] (4) Preparation of application solution: The solution is applied by solubilization using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent.

[1495] (5) Administration method: The injection is administered via the tail vein using a syringe with a needle.

[1496] (6) Evaluation items: Blood was collected periodically, and the concentration of the compounds of the present invention in the plasma was determined by LC / MS / MS.

[1497] (7) Statistical analysis: The systemic clearance rate (CLtot) was calculated by moment analysis based on the concentration shift of the compounds of the present invention in plasma. In addition, the dilution concentration and dilution solvent were changed as needed.

[1498] Experimental Example 6: Metabolic Stability Test

[1499] The compound of the present invention was reacted with commercially available pooled human liver microsomes 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 to which the compound of the present invention was metabolized by the liver.

[1500] The reaction was carried out 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 / mL of human liver microsomes at 37 °C for 0 or 30 minutes (oxidation reaction) in the presence of 1 mmol / L NADPH. After the reaction, 50 μL of the reaction solution was added to and mixed with 100 μL of methanol / acetonitrile = 1 / 1 (v / v) solution, and centrifuged at 3000 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 amount of compound at 0 minutes of reaction was set as 100%, and the residual amount of the compound of the present invention after the reaction was calculated.

[1501] Experimental Example 7: P-gp Matrix Test

[1502] The compound of this invention was added to one side of a Transwell (registered trademark, CORNING) monolayer cultured with human MDR1-expressing cells or blast cells, and allowed to react for a certain period of time. For MDR1-expressing cells and blast cells, the membrane permeability coefficients were calculated from the acute side to the basolateral side (A→B) and from the basolateral side to the acute side (B→A), and the efflux ratio (ER; the ratio of the membrane permeability coefficients from B→A to A→B) of MDR1-expressing cells and blast cells was calculated. The efflux ratios (ER values) of MDR1-expressing cells and blast cells were compared to determine whether the compound of this invention is a P-gp matrix.

[1503] The formulation examples shown below are merely illustrative and do not limit the scope of the invention in any way.

[1504] The compounds of the present invention can be administered via any conventional route, particularly via the intestines, for example, orally, in the form of tablets or capsules, or non-oral, for example, in the form of injections or suspensions, topically, for example, in the form of lotions, gels, ointments, or creams, or in the form of nasal suppositories, as pharmaceutical compositions. Pharmaceutical compositions containing the compounds of the present invention in free or pharmaceutically permissible salt forms, together with at least one pharmaceutically permissible carrier or diluent, can be manufactured by conventional methods using mixing, granulation, or coating. For example, oral compositions can be formulated into tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients. In addition, injectable compositions can be formulated as solutions or suspensions, and can be sterilized; furthermore, they may contain preservatives, stabilizers, buffers, etc.

[1505] Industrial practicality

[1506] The compounds of the present invention have a reverse agonist effect on the serotonin 5-HT2A receptor and are considered useful as therapeutic and / or preventative agents for diseases or conditions involving the serotonin 5-HT2A receptor.

Claims

1. A compound or a pharmaceutically permissible salt thereof, said compound being selected from the following compounds: and .

2. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 。 3. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 。 4. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 。 5. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 。 6. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 。 7. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 。 8. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 。 9. A pharmaceutical composition comprising any one of the compounds of claims 1 to 8 or a pharmaceutically permissible salt thereof.

10. The pharmaceutical composition of claim 9, wherein it is a serotonin 5-HT2A receptor inverse agonist.

11. The compound or pharmaceutically permissible salt thereof as claimed in any one of claims 1 to 8, wherein the compound or pharmaceutically permissible salt thereof is used for the treatment and / or prevention of diseases involving the serotonin 5-HT2A receptor.

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