Nitrogen-containing heterocyclic and carbocyclic derivatives having serotonin receptor binding activity

Abstract

The present invention provides a compound having a serotonin 5-HT2A receptor antagonistic and / or inverse agonist effect and a serotonin 5-HT2C receptor antagonistic and / or inverse agonist effect, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: # imgabs0, in which R1 is a substituted or unsubstituted six-membered aromatic heterocyclic group or the like, A1 is CR2 or the like, A2 is CR3 or the like, A3 is CR4 or the like, R2, R3 and R4 are each independently a hydrogen atom or the like, R5 is a substituted or unsubstituted aromatic heterocyclic group or the like, R15 and R16 are each independently a hydrogen atom or the like, and R17 and R18 are each independently a hydrogen atom or the like.

Description

Technical Field

[0001] The present invention relates to compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic actions and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic actions, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.

[0002] Furthermore, it relates to compounds having serotonin 5-HT2A receptor and / or serotonin 5-HT2C receptor antagonistic and / or inverse agonistic actions, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, which are useful for the treatment and / or prevention of diseases caused by serotonin 5-HT2A receptor and / or serotonin 5-HT2C receptor. Background Art

[0003] Neurodegenerative diseases (ND) are a group of related human diseases that exhibit common pathophysiological characteristics, namely, the progressive degeneration of selective neuronal populations over time. These neurodegenerative diseases include, for example, Alzheimer's disease and related dementias, Parkinson's disease, Huntington's disease, Lewy body disease and related movement disorders, etc., but are not limited to these. Each of these disorders has unique clinical symptoms in terms of onset age, time course of progression, neurological signs and symptoms, neuropsychiatric symptoms, and susceptibility to known therapeutic agents. In addition, the pathophysiological basis of each of these disorders is caused by genetic mechanisms specific to each disease (Non-Patent Document 1).

[0004] Although there has been considerable progress in elucidating the genetic causes underlying these essentially different disorders, less is known about all of these common biochemical mechanisms that cause selective neuronal degeneration. In addition, among these disorders, regarding the most common diseases including Parkinson's disease and Alzheimer's disease, although rare familial genetic factors causing these diseases have been discovered, the pathophysiological basis for most sporadic cases is unknown. Therefore, there is still no specific therapeutic agent that can directly alter disease progression and completely prevent onset. Instead, clinicians have utilized various existing agents to achieve alleviation of the motor manifestations, cognitive manifestations, and neuropsychiatric manifestation symptoms characteristic of these disorders (Non-Patent Documents 2 and 3).

[0005] Among the various neurological symptoms that characterize ND, common symptoms include abnormalities in motor function such as bradykinesia, dyskinesia, and chorea, as well as the emergence of neuropsychiatric symptoms including psychosis and mood symptoms such as anxiety or depression, which have a significant impact on the functional status and quality of life of patients (Non-Patent Documents 4 and 5). Almost all existing therapeutic agents, including antipsychotics and antidepressants, although generally effective for these patients, have very low acceptability (Non-Patent Document 6). In addition, available Parkinson's disease therapeutic agents include L-dopa and dopamine agonists, which, although generally effective, cause serious treatment-limiting side effects that are still not treatable by drug therapy at present.

[0006] Although there has long been no approved drug dedicated to ND, in 2016, the 5-HT2A receptor inverse agonist drug pimavanserin was first approved in the United States for hallucinations and delusions associated with Parkinson's disease (Non-Patent Document 7). This agent has not been reported to have side effects such as exacerbation of motor symptoms or reduction of cognitive function like existing antipsychotics. The main pharmacological action of pimavanserin is serotonin 5-HT2A receptor inverse agonism / antagonism, and it also has serotonin 5-HT2C receptor inverse agonism (Non-Patent Document 8). Based on the 5-HT2A occupancy results measured in human PET trials of pimavanserin and the clinical trial results of pimavanserin, it is suggested that pimavanserin exerts its efficacy through 5-HT2A and 2C (Non-Patent Document 9). In addition, pimavanserin has a greater adverse impact on the cardiovascular system, and the dosage is limited.

[0007] These insights highlight the need to develop new therapeutic agents that should not only show efficacy against these specific symptoms that cause physical disabilities but also be specifically designed in a way that is acceptable for these specific patient groups. This can be achieved by improving the selectivity of the drug-target interaction of the new therapeutic agent. Specifically, it is achieved by having strong activity and selectivity against the targeted 5-HT2A and 2C and reducing the adverse impact on the cardiovascular system.

[0008] Compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonist effects are described in Patent Documents 1 to 16 and Non-Patent Documents 10 to 13, but no compound related to the present invention is described or suggested in any of the documents.

[0009] Patent Document 17 discloses benzamide derivatives having interleukin-6 inhibitory activity, but does not describe serotonin 5-HT2A receptor antagonistic and / or inverse agonist effects and the therapeutic effect of hallucinations and delusions, nor does it describe or suggest a compound related to the present invention.

[0010] Patent Documents 18 to 20 disclose pyrimidine derivatives having protein kinase C inhibitory activity, but do not describe the serotonin 5-HT2A receptor antagonistic and / or inverse agonistic effects and the therapeutic effects on hallucinations and delusions, nor do they describe or imply compounds related to the present invention.

[0011] Prior art documents

[0012] Patent documents

[0013] Patent Document 1: WO 2005 / 012254;

[0014] Patent Document 2: WO 2006 / 078610;

[0015] Patent Document 3: WO 2007 / 136703;

[0016] Patent Document 4: WO 2007 / 136680;

[0017] Patent Document 5: WO 2022 / 093850;

[0018] Patent Document 6: WO 2022 / 093849;

[0019] Patent Document 7: WO 2007 / 120600;

[0020] Patent Document 8: WO 2006 / 055734;

[0021] Patent Document 9: WO 2004 / 058722;

[0022] Patent Document 10: WO 2004 / 028450;

[0023] Patent Document 11: WO 01 / 29008;

[0024] Patent Document 12: WO 2013 / 171641;

[0025] Patent Document 13: WO 2008 / 027483;

[0026] Patent Document 14: WO 2007 / 136875;

[0027] Patent Document 15: WO 99 / 52927;

[0028] Patent Document 16: WO 03 / 062206;

[0029] Patent Document 17: WO 2019 / 165158;

[0030] Patent Document 18: International Publication No. WO 2013 / 152198

[0031] Patent Document 19: International Publication No. WO 2014 / 089112

[0032] Patent Document 20: International Publication No. WO 2014 / 151900

[0033] Non - Patent Literature

[0034] Non - Patent Literature 1: Nature Reviews Neurology, Vol. 10, pp. 620 - 633, 2014

[0035] Non - Patent Literature 2: Progress in Neurology and Psychiatry, Vol. 22, No. 1, pp. 30 - 35, 2018

[0036] Non - Patent Literature 3: Movement Disorders, Vol. 24, No. 11, pp. 1641 - 1649, 2009

[0037] Non - Patent Literature 4: Parkisonism and Related Disorders, Vol. 15, Supplement 3, pp. S105 - S109, 2009

[0038] Non - Patent Literature 5: Neurology, 2004; Vol. 63, No. 2, pp. 293 - 300, 2004

[0039] Non - Patent Literature 6: JAMA Neurology, Vol. 73, No. 5, pp. 535 - 541, 2016

[0040] Non - Patent Literature 7: The Lancet, Vol. 383, pp. 533 - 540, 2014

[0041] Non - Patent Literature 8: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 2, pp. 910 - 918, 2006

[0042] Non - Patent Literature 9: CNS Spectrums, Vol. 21, pp. 271 - 275, 2016

[0043] Non-Patent Document 10: Bioorganic & Medicinal Chemistry Letters, Vol. 19, pp. 5486 - 5489, 2009;

[0044] Non-Patent Document 11: Journal of Medicinal Chemistry, Vol. 53, pp. 4412 - 4421, 2010;

[0045] Non-Patent Document 12: Journal of Medicinal Chemistry, Vol. 53, pp. 1923 - 1936, 2010;

[0046] Non-Patent Document 13: Journal of Medicinal Chemistry, Vol. 53, pp. 5696 - 5706, 2010. Summary of the Invention

[0047] Problems to be Solved by the Invention

[0048] An object of the present invention is to provide a novel compound having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic action and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic action. More preferably, the present invention provides a novel compound or a pharmaceutically acceptable salt thereof, which has an effect on serotonin-related diseases represented by hallucinations and delusions accompanying Parkinson's disease and / or dementia by having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic action and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic action, and a drug containing them.

[0049] Means for Solving the Problems

[0050] The present invention relates to the following items (1) to (24) and (1') to (26').

[0051] (1) A compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof:

[0052]

[0053] In the formula,

[0054] R 1 is a substituted or unsubstituted six-membered aromatic carbocyclic group, a substituted or unsubstituted six-membered aromatic heterocyclic group, or a substituted or unsubstituted five-membered aromatic heterocyclic group;

[0055] A 1 is CR 2 or N;

[0056] A 2 is CR3 or N;

[0057] A 3 is CR 4 or N;

[0058] R 2 , R 3 and R 4 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group; or

[0059] R 2 and R 3 may together with the carbon atom to which they are bonded form a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle, or a substituted or unsubstituted non-aromatic heterocycle;

[0060] R 5 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;

[0061] R 15 and R 16 each independently is a hydrogen atom, or a substituted or unsubstituted alkyl group; or

[0062] R 15 and R 16 may together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocycle,

[0063] wherein, the compound represented by the formula (I-1) does not include the following compounds:

[0064] (i) a compound in which R 1 is a substituted or unsubstituted tetrazolyl group and (ii) a compound in which R 1 is a substituted or unsubstituted tetrazolonyl group.

[0065] (2) The compound as described in (1) above or a pharmaceutically acceptable salt thereof, wherein, R 15 and R 16 each independently is a hydrogen atom or an alkyl group.

[0066] (3) The compound as described in (1) above or a pharmaceutically acceptable salt thereof, wherein, R15 and R 16 is a hydrogen atom.

[0067] (4) The compound according to any one of (1) to (3) above, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group represented by the following formula:

[0068]

[0069] In the formula,

[0070] R 6 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0071] R 7 is a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a cyano group;

[0072] R 8 is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0073] R 9 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkoxy group.

[0074] (5) The compound according to (4) above, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group represented by the following formula:

[0075]

[0076] In the formula, R 6 , R 7 and R 8 are synonymous with those in (4) above.

[0077] (6) The compound according to any one of (1) to (5) above, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.

[0078] (7) The compound according to any one of (1) to (6) above, or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group.

[0079] (8) The compound according to any one of (1) to (6) above, or a pharmaceutically acceptable salt thereof, wherein A 1 is CH.

[0080] (9) The compound according to any one of (1) to (8) above, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group.

[0081] (10) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (8), wherein A 2 is CR 3 ;

[0082] R 3 is halogen, or substituted or unsubstituted alkyl.

[0083] (11) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (10), wherein R 5 is substituted or unsubstituted aromatic carbocyclic group, or substituted or unsubstituted aromatic heterocyclic group.

[0084] (12) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (10), wherein R 5 is substituted or unsubstituted phenyl, or substituted or unsubstituted six-membered aromatic heterocyclic group.

[0085] (13) The compound or a pharmaceutically acceptable salt thereof according to the above (1) to (10), wherein R 5 is a group represented by the following formula:

[0086]

[0087] In the formula,

[0088] R 10 and R 13 are each independently a hydrogen atom, or substituted or unsubstituted alkyl;

[0089] R 14 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl or cyano;

[0090] B 1 is CR 11 or N;

[0091] B 2 is CR 12 or N;

[0092] R 11 and R 12 are each independently a hydrogen atom or halogen.

[0093] (14) The compound or a pharmaceutically acceptable salt thereof according to the above (13), wherein B 1 is N, and B 2 is CR 12 .

[0094] (15) The compound or its pharmaceutically acceptable salt as described in (13) or (14) above, wherein R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group.

[0095] (16) A pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt as described in any one of (1) to (15) above.

[0096] (17) The pharmaceutical composition as described in (16) above, which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist.

[0097] (18) The pharmaceutical composition as described in (16) above, which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist and a serotonin 5-HT2C receptor antagonist and / or inverse agonist.

[0098] (19) A method for treating and / or preventing a disease related to the serotonin 5-HT2A receptor, characterized by administering the compound or its pharmaceutically acceptable salt as described in any one of (1) to (15) above.

[0099] (20) A method for treating and / or preventing a disease related to the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor, characterized by administering the compound or its pharmaceutically acceptable salt as described in any one of (1) to (15) above.

[0100] (21) The compound or its pharmaceutically acceptable salt as described in any one of (1) to (15) above, which is used for treating and / or preventing a disease related to the serotonin 5-HT2A receptor.

[0101] (22) The compound or its pharmaceutically acceptable salt as described in any one of (1) to (15) above, which is used for treating and / or preventing a disease related to the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor.

[0102] (23) Use of the compound or its pharmaceutically acceptable salt as described in any one of (1) to (15) above in the manufacture of a therapeutic and / or prophylactic agent for a disease related to the serotonin 5-HT2A receptor.

[0103] (24) Use of the compound or its pharmaceutically acceptable salt as described in any one of (1) to (15) above in the manufacture of a therapeutic and / or prophylactic agent for a disease related to the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor.

[0104] (1’) The compound or its pharmaceutically acceptable salt represented by formula (I):

[0105]

[0106] In the formula,

[0107] R 1 is a substituted or unsubstituted six-membered aromatic heterocyclic group, a substituted or unsubstituted five-membered aromatic heterocyclic group (wherein, a substituted or unsubstituted tetrazolyl group and a substituted or unsubstituted tetrazolone group are excluded), a substituted or unsubstituted six-membered aromatic carbocyclic group, a substituted or unsubstituted bicyclic nine-membered non-aromatic heterocyclic group, or a substituted or unsubstituted bicyclic ten-membered non-aromatic heterocyclic group;

[0108] A 1 is CR 2 or N;

[0109] A 2 is CR 3 or N;

[0110] A 3 is CR 4 or N;

[0111] R 2 、R 3 and R 4 are (i) or (ii) below:

[0112] (i) R 2 、R 3 and R 4 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic heterocyclic epoxy group, or a substituted or unsubstituted non-aromatic heterocyclic epoxy group;

[0113] (ii) When A 1 is CR 2 、A 2 is CR 3 、A 3 is CR 4 or N, R 2 and R 3 together with the carbon atom to which they are bonded form a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle, R 4Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group;

[0114] R 5 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0115] R 15 and R 16 Each independently is a hydrogen atom, or a substituted or unsubstituted alkyl group; or

[0116] R 15 and R 16 may together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocycle;

[0117] R 17 and R 18 Each independently is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group; or

[0118] R 17 and R 18 may together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocycle.

[0119] (2’) The compound described in (1’) above or a pharmaceutically acceptable salt thereof, wherein R 15 and R 16 are hydrogen atoms, and R 17 and R 18 Each independently is a hydrogen atom, a halogen or an alkyl group.

[0120] (3’) The compound described in (1’) above or a pharmaceutically acceptable salt thereof, wherein R 15 、R 16 、R 17 and R 18 are hydrogen atoms.

[0121] (4’) The compound described in any one of (1’) to (3’) above or a pharmaceutically acceptable salt thereof, wherein R 1 is a group represented by the following formula:

[0122]

[0123] In the formula,

[0124] R 6 and R 7 each independently represents a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a cyano group, or a substituted or unsubstituted non-aromatic carbocyclic group (wherein, when R 6 is a hydrogen atom, R 7 is a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a cyano group, or a substituted or unsubstituted non-aromatic carbocyclic group);

[0125] R 8 and R 9 each independently represents a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a cyano group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted non-aromatic heterocyclic epoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;

[0126] R 31 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0127] R 32 and R 33 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group.

[0128] (5’) The compound according to any one of (1’) to (4’) above or a pharmaceutically acceptable salt thereof, wherein R 1 is a group represented by the following formula:

[0129]

[0130] In the formula,

[0131] R 6 and R 7 each independently represents a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a cyano group;

[0132] R 8 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted non-aromatic heterocyclic epoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;

[0133] R 31is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group.

[0134] (6’) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1’) to (5’), wherein A 1 is CR 2 or N;

[0135] A 2 is CR 3 or N;

[0136] A 3 is CR 4 or N;

[0137] R 2 、R 3 and R 4 are the following (i-1):

[0138] (i-1) R 2 and R 3 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group, and R 4 is a hydrogen atom.

[0139] (7’) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1’) to (6’), wherein A 1 is CR 2 or N;

[0140] A 2 is CR 3 or N;

[0141] A 3 is CR 4 or N;

[0142] R 2 、R 3 and R 4 are the following (i-2):

[0143] (i-2) R 2 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, and R 3 and R 4Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group.

[0144] (8’) The compound according to any one of the above (1’) to (7’) or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 2 or N;

[0145] A 2 is CR 3 or N;

[0146] A 3 is CR 4 or N;

[0147] R 2 、R 3 and R 4 are the following (i-3):

[0148] (i-3) R 2 is a hydrogen atom, R 3 and R 4 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group.

[0149] (9’) The compound according to any one of the above (1’) to (8’) or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 2 or N;

[0150] A 2 is CR 3 or N;

[0151] A 3 is CR 4 or N;

[0152] R 2 、R 3 and R 4 are the following (i-4):

[0153] (i-4)R 3 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, R 2 and R 4 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic heterocyclic epoxy group, or a substituted or unsubstituted non-aromatic heterocyclic epoxy group.

[0154] (10’) The compound according to any one of the above (1’) to (9’), or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 2 or N;

[0155] A 2 is CR 3 or N;

[0156] A 3 is CR 4 or N;

[0157] R 2 、R 3 and R 4 are as follows (i-5):

[0158] (i-5)R 3 is a hydrogen atom or a halogen, R 2 and R 4 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic heterocyclic epoxy group, or a substituted or unsubstituted non-aromatic heterocyclic epoxy group.

[0159] (11’) The compound according to any one of the above (1’) to (10’), or a pharmaceutically acceptable salt thereof, wherein, (i’) A 1 is CH, A 2 is N, and A 3 is CH; or

[0160] (ii’) A 1 is CH, A 2 is CR 3, R 3 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, and A 3 is N.

[0161] (12’) The compound according to any one of the above (1’) to (11’), or a pharmaceutically acceptable salt thereof, wherein R 5 is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic group.

[0162] (13’) The compound according to any one of the above (1’) to (12’), or a pharmaceutically acceptable salt thereof, wherein R 5 is a substituted or unsubstituted six-membered aromatic heterocyclic group, or a substituted or unsubstituted phenyl group.

[0163] (14’) The compound according to any one of the above (1’) to (13’), or a pharmaceutically acceptable salt thereof, wherein R 5 is a group represented by the following formula:

[0164]

[0165] In the formula,

[0166] R 10 and R 13 are each independently a hydrogen atom, a cyano group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group;

[0167] R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyl group or a cyano group;

[0168] B 1 is CR 11 or N;

[0169] B 2 is CR 12 or N;

[0170] R 11 and R 12 are each independently a hydrogen atom, a halogen, a methoxy group, a methyl group or a halomethyl group.

[0171] (15’) The compound according to the above (14’), or a pharmaceutically acceptable salt thereof, wherein

[0172] (i”) B 1is N, and B 2 is CR 12 ; or

[0173] (ii”) B 1 and B 2 are N.

[0174] (16’) The compound or a pharmaceutically acceptable salt thereof as described in (14’) or (15’) above, wherein R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group.

[0175] (17’) The compound or a pharmaceutically acceptable salt thereof as described in (1’) above, which is selected from Compound I-006, I-062, I-063, I-073, I-127, I-200, I-211, I-247, I-257, I-266, I-267, I-271, I-359, I-376 and I-378.

[0176] (18’) A pharmaceutical composition, which contains the compound or a pharmaceutically acceptable salt thereof as described in any one of (1’) to (17’) above.

[0177] (19’) The pharmaceutical composition as described in (18’) above, which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist.

[0178] (20’) The pharmaceutical composition as described in (18’) above, which is an antagonist and / or inverse agonist of serotonin 5-HT2A receptor and serotonin 5-HT2C receptor.

[0179] (21’) A method for treating and / or preventing a disease related to serotonin 5-HT2A receptor, characterized by administering the compound or a pharmaceutically acceptable salt thereof as described in any one of (1’) to (17’) above.

[0180] (22’) A method for treating and / or preventing a disease related to serotonin 5-HT2A and serotonin 5-HT2C receptors, characterized by administering the compound or a pharmaceutically acceptable salt thereof as described in any one of (1’) to (17’) above.

[0181] (23’) The compound or a pharmaceutically acceptable salt thereof as described in any one of (1’) to (17’) above, which is used for treating and / or preventing a disease related to an antagonist and / or inverse agonist of serotonin 5-HT2A receptor.

[0182] (24’) The compound or a pharmaceutically acceptable salt thereof as described in any one of (1’) to (17’) above is used for treating and / or preventing diseases related to antagonists and / or inverse agonists of serotonin 5-HT2A receptor and serotonin 5-HT2C receptor.

[0183] (25’) Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of (1’) to (17’) above in the manufacture of a therapeutic agent and / or prophylactic agent for diseases related to serotonin 5-HT2A receptor.

[0184] (26’) Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of (1’) to (17’) above in the manufacture of a therapeutic agent and / or prophylactic agent for diseases related to serotonin 5-HT2A receptor and serotonin 5-HT2C receptor.

[0185] Advantages of the Invention

[0186] The compound involved in the present invention has antagonist and / or inverse agonist effects on serotonin 5-HT2A receptor and antagonist and / or inverse agonist effects on serotonin 5-HT2C receptor, and is useful as a therapeutic agent and / or prophylactic agent for hallucinations and delusions accompanied by Parkinson's disease and / or dementia. Detailed Embodiments

[0187] The meanings of the terms used in this specification are described below. For each term, unless otherwise specified, it has the same meaning when used alone or in combination with other terms.

[0188] The term "consisting of" means having only the constituent elements.

[0189] The term "comprising" means not limited to the constituent elements and does not exclude elements not described.

[0190] Hereinafter, embodiments of the present invention will be described with illustrations. It should be understood that throughout this specification, unless otherwise specifically mentioned, the singular form of an expression also includes the concept of its plural form. Therefore, unless otherwise specifically mentioned, it should be understood that the singular form of an article (for example, "a", "an", "the", etc. in English) also includes the concept of its plural form.

[0191] In addition, unless otherwise specifically mentioned, it should be understood that the terms used in this specification are used with the meanings commonly used in the art as described above. Therefore, without additional definition, all the technical terms and scientific and technological terms used in this specification have the same meanings as those generally understood by those skilled in the technical field to which the present invention belongs. In case of contradiction, this specification (including definitions) shall prevail.

[0192] "Halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Fluorine atoms and chlorine atoms are particularly preferred.

[0193] As the "halogen" in R 7 chlorine atoms and bromine atoms are preferred.

[0194] "Alkyl" includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and further preferably 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl, etc.

[0195] Preferred examples of "alkyl" include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl. Further preferred examples include: methyl, ethyl, n-propyl, isopropyl, tert-butyl.

[0196] "C1-C3 alkyl" includes methyl, ethyl, n-propyl, and isopropyl.

[0197] "Halogenated alkyl" refers to the above alkyl group substituted by one or more halogens. When substituted by two or more halogens, the halogens may be the same or different. Examples include: fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl, 3,3,3-trifluoro-2-(trifluoromethyl)propyl, etc.

[0198] Preferred examples of "halogenated alkyl" include: difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 2,2,3,3,3-pentafluoropropyl. Further preferred examples include: difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl.

[0199] "Alkoxy" refers to a group in which the above "alkyl" is bonded to an oxygen atom. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, etc.

[0200] As preferred embodiments of the "alkoxy group", there may be mentioned: methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group. As more preferred embodiments, there may be mentioned: methoxy group, ethoxy group, n-propoxy group, isopropoxy group.

[0201] The "haloalkoxy group" refers to a group in which the above-mentioned "haloalkyl group" is bonded to an oxygen atom. For example, there may be mentioned: difluoromethoxy group, 2-monofluoroethoxy group, 3-monofluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2-difluoroethoxy group, 3,3,3-trifluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 2,2,3,3,4,4,4-heptafluorobutoxy group, etc.

[0202] As preferred embodiments of the "haloalkoxy group", there may be mentioned: difluoromethoxy group, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, 2,2-difluoroethoxy group, 3,3,3-trifluoropropoxy group. As more preferred embodiments, there may be mentioned: difluoromethoxy group, trifluoromethoxy group, 2,2,2-trifluoroethoxy group.

[0203] The "alkenyl group" includes a linear or branched hydrocarbon group having 1 or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms. For example, there may be mentioned: vinyl group, allyl group, propenyl group, isopropenyl group, butenyl group, isobutenyl group, isoprenyl group, butadienyl group, pentenyl group, isopentenyl group, pentadienyl group, hexenyl group, isohexenyl group, hexadienyl group, heptenyl group, octenyl group, nonenyl group, decenyl group, undecenyl group, dodecenyl group, tridecenyl group, tetradecenyl group, pentadecenyl group, etc.

[0204] As preferred embodiments of the "alkenyl group", there may be mentioned: vinyl group, allyl group, propenyl group, isopropenyl group, butenyl group. As more preferred embodiments, there may be mentioned: vinyl group, n-propenyl group, etc.

[0205] The "alkynyl group" includes a linear or branched hydrocarbon group having 1 or more triple bonds at any position and having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms. It may also have a double bond at any position. For example, it includes: ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, nonynyl group, decynyl group, etc.

[0206] As preferred embodiments of the "alkynyl group", there may be mentioned: ethynyl group, propynyl group, butynyl group, pentynyl group. As more preferred embodiments, there may be mentioned: ethynyl group, propynyl group, etc.

[0207] "Aromatic carbocyclic group" refers to a monocyclic or polycyclic (two or more rings) cyclic aromatic hydrocarbon group. Examples include: phenyl, naphthyl, anthryl, phenanthryl, etc.

[0208] As a preferred embodiment of the "aromatic carbocyclic group", phenyl can be cited.

[0209] As the "six-membered aromatic carbocyclic group", phenyl can be cited.

[0210] "Aromatic carbocycle" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0211] As the "R 2 and R 3 together with the carbon to which they are bonded to form an aromatic carbocycle", the following rings are exemplified.

[0212]

[0213] "Non-aromatic carbocyclic group" refers to a monocyclic or polycyclic (two or more rings) cyclic saturated hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group. The polycyclic (two or more rings) "non-aromatic carbocyclic group" includes a group formed by condensing a ring in the above-mentioned "aromatic carbocyclic group" onto a monocyclic or polycyclic (two or more rings) non-aromatic carbocyclic group.

[0214] Moreover, the "non-aromatic carbocyclic group" also includes groups crosslinked in the following manner or groups forming a spiro ring.

[0215]

[0216] As the monocyclic non-aromatic carbocyclic group, the number of carbon atoms is preferably 3 to 16, more preferably 3 to 12, and further preferably 4 to 8. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, etc.

[0217] As the polycyclic (two or more rings) non-aromatic carbocyclic group, the number of carbon atoms is preferably 8 to 20, more preferably 8 to 16. Examples include: indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, etc.

[0218] "Non-aromatic carbocycle" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0219] As the "R 2 and R 3 together with the carbon to which they are bonded to form a non-aromatic carbocycle", the following rings are exemplified.

[0220]

[0221] As the "R 15 and R 16"Non-aromatic carbocyclic rings formed together with the carbon to which they are bonded", for example, the following rings are shown.

[0222]

[0223] As "R 17 and R 18 "Non-aromatic carbocyclic rings formed together with the carbon to which they are bonded", for example, the following rings are shown.

[0224]

[0225] "Aromatic heterocyclic group" means a monocyclic or polycyclic aromatic ring group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N within the ring.

[0226] Polycyclic aromatic heterocyclic groups also include groups obtained by condensing a ring of the above "aromatic carbocyclic group" onto a monocyclic or polycyclic aromatic heterocyclic group, and the bonding bond can be present on any ring.

[0227] As the monocyclic aromatic heterocyclic group, it is preferably five- to eight-membered, more preferably five- or six-membered. As the five-membered aromatic heterocyclic group, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, is azolyl, azolyl, diazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. As the six-membered aromatic heterocyclic group, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.

[0228] As the bicyclic aromatic heterocyclic group, it is preferably eight- to ten-membered, more preferably nine- or ten-membered. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzois azolyl, benzo azolyl, benzo diazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, azolopyridyl, thiazolopyridyl, etc.

[0229] As the nine-membered aromatic heterocyclic group, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzois azolyl, benzo azolyl, benzo Diazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, Oxazolopyridyl, thiazolopyridyl, etc.

[0230] As the ten-membered aromatic heterocyclic group, examples include: quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, etc.

[0231] As the aromatic heterocyclic group having 3 or more rings, preferably 13 to 15 members. For example, examples include: carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phen Thienyl, phen Phenazinyl, dibenzofuranyl, etc.

[0232] "Aromatic heterocycle" means a ring derived from the above "aromatic heterocyclic group".

[0233] As "R 2 and R 3 The aromatic heterocycle formed together with the carbon to which they are bonded", for example, the following rings are shown.

[0234]

[0235] "Non-aromatic heterocyclic group" means a monocyclic or polycyclic non-aromatic ring group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N in the ring. The polycyclic non-aromatic heterocyclic group includes a group obtained by condensing each of the above "aromatic carbocyclic group", "non-aromatic carbocyclic group", and / or "aromatic heterocyclic group" on the monocyclic or polycyclic non-aromatic heterocyclic group, and also includes a group obtained by condensing the ring of the above "aromatic heterocyclic group" on the monocyclic or polycyclic non-aromatic carbocyclic group, and the bonding bond can be present in any ring.

[0236] Moreover, the "non-aromatic heterocyclic group" also includes a crosslinked group or a group forming a spiro ring as follows.

[0237]

[0238] As the monocyclic non-aromatic heterocyclic group, preferably 3 to 8 members, more preferably 5 or 6 members.

[0239] As a ternary non-aromatic heterocyclic group, for example, thiiranyl, oxiranyl, and aziridinyl can be mentioned. As a quaternary non-aromatic heterocyclic group, for example, oxetanyl and azetidinyl can be mentioned. As a five-membered non-aromatic heterocyclic group, for example, oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, etc. can be mentioned. As a six-membered non-aromatic heterocyclic group, for example, di alkyl, thianyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyranyl, di azinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, di azinyl, thiinyl, thiazinyl, etc. can be mentioned. As a seven-membered non-aromatic heterocyclic group, for example, hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl can be mentioned. As an eight-membered non-aromatic heterocyclic group, for example, azocane, thiocane, oxocane, etc. can be mentioned.

[0240] As a non-aromatic heterocyclic group having two or more rings, it is preferably an eight- to twenty-membered ring, more preferably an eight- to ten-membered ring. For example, dihydroindolyl, iso-dihydroindolyl, chromanyl, isochromanyl, etc. can be mentioned.

[0241] As a bicyclic nine-membered non-aromatic heterocyclic group, groups shown below can be mentioned, etc.

[0242]

[0243] As a bicyclic ten-membered non-aromatic heterocyclic group, groups shown below can be mentioned, etc.

[0244]

[0245] "Non-aromatic heterocycle" means a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0246] As the "non-aromatic heterocycle formed by R 2 and R 3 together with the carbon to which they are bonded", for example, the following rings are shown.

[0247]

[0248] "Trialkylsilyl" refers to a group formed by bonding three of the above-mentioned "alkyl groups" to a silicon atom. The three alkyl groups may be the same or different. Examples include: trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, etc.

[0249] In this specification, "being capable of being substituted by substituent group α" means "being capable of being substituted by one or more groups selected from substituent group α". The same applies to substituent groups β, γ, and γ'.

[0250] As substituents for "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkoxy", "substituted alkenyloxy", "substituted alkynyloxy", "substituted alkylcarbonyloxy", "substituted alkenylcarbonyloxy", "substituted alkynylcarbonyloxy", "substituted alkylcarbonyl", "substituted alkenylcarbonyl", "substituted alkynylcarbonyl", "substituted alkoxycarbonyl", "substituted alkenyloxycarbonyl", "substituted alkynyloxycarbonyl", "substituted alkylthio", "substituted alkenylthio", "substituted alkynylthio", "substituted alkylsulfinyl", "substituted alkenylsulfinyl", "substituted alkynylsulfinyl", "substituted alkylsulfonyl", "substituted alkenylsulfonyl", "substituted alkynylsulfonyl", etc., the following substituent group A can be cited. A carbon atom at any position can be bonded to one or more groups selected from the following substituent group A.

[0251] Substituent group A: halogen, hydroxyl, carboxyl, formyl, formyloxy, thio, sulfino, sulfo, thioaldehyde, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl,

[0252] alkoxy that can be substituted by substituent group α, alkenyloxy that can be substituted by substituent group α, alkynyloxy that can be substituted by substituent group α, alkylcarbonyloxy that can be substituted by substituent group α, alkenylcarbonyloxy that can be substituted by substituent group α, alkynylcarbonyloxy that can be substituted by substituent group α, alkylcarbonyl that can be substituted by substituent group α, alkenylcarbonyl that can be substituted by substituent group α, alkynylcarbonyl that can be substituted by substituent group α, alkoxycarbonyl that can be substituted by substituent group α, alkenyloxycarbonyl that can be substituted by substituent group α, alkynyloxycarbonyl that can be substituted by substituent group α, alkylthio that can be substituted by substituent group α, alkenylthio that can be substituted by substituent group α, alkynylthio that can be substituted by substituent group α, alkylsulfinyl that can be substituted by substituent group α, alkenylsulfinyl that can be substituted by substituent group α, alkynylsulfinyl that can be substituted by substituent group α, alkylsulfonyl that can be substituted by substituent group α, alkenylsulfonyl that can be substituted by substituent group α, alkynylsulfonyl that can be substituted by substituent group α,

[0253] An amino group that can be substituted by substituent group β, an imino group that can be substituted by substituent group β, a carbamoyl group that can be substituted by substituent group β, a sulfamoyl group that can be substituted by substituent group β,

[0254] An aromatic carbocyclic group that can be substituted by substituent group γ, a non-aromatic carbocyclic group that can be substituted by substituent group γ’, an aromatic heterocyclic group that can be substituted by substituent group γ, a non-aromatic heterocyclic group that can be substituted by substituent group γ’, an aromatic carbocyclic oxy group that can be substituted by substituent group γ, a non-aromatic carbocyclic oxy group that can be substituted by substituent group γ’, an aromatic heterocyclic oxy group that can be substituted by substituent group γ, a non-aromatic heterocyclic oxy group that can be substituted by substituent group γ’, an aromatic carbocyclic carbonyl oxy group that can be substituted by substituent group γ, a non-aromatic carbocyclic carbonyl oxy group that can be substituted by substituent group γ’, an aromatic heterocyclic carbonyl oxy group that can be substituted by substituent group γ, a non-aromatic heterocyclic carbonyl oxy group that can be substituted by substituent group γ, an aromatic carbocyclic carbonyl group that can be substituted by substituent group γ, a non-aromatic carbocyclic carbonyl group that can be substituted by substituent group γ’, an aromatic heterocyclic carbonyl group that can be substituted by substituent group γ, a non-aromatic heterocyclic carbonyl group that can be substituted by substituent group γ, an aromatic carbocyclic oxy carbonyl group that can be substituted by substituent group γ, a non-aromatic carbocyclic oxy carbonyl group that can be substituted by substituent group γ’, an aromatic heterocyclic oxy carbonyl group that can be substituted by substituent group γ, a non-aromatic heterocyclic oxy carbonyl group that can be substituted by substituent group γ, an aromatic carbocyclic alkoxy group that can be substituted by substituent group γ, a non-aromatic carbocyclic alkoxy group that can be substituted by substituent group γ’, an aromatic heterocyclic alkoxy group that can be substituted by substituent group γ, a non-aromatic heterocyclic alkoxy group that can be substituted by substituent group γ, an aromatic carbocyclic alkoxy carbonyl group that can be substituted by substituent group γ, a non-aromatic carbocyclic alkoxy carbonyl group that can be substituted by substituent group γ’, an aromatic heterocyclic alkoxy carbonyl group that can be substituted by substituent group γ, a non-aromatic heterocyclic alkoxy carbonyl group that can be substituted by substituent group γ, an aromatic carbocyclic thio group that can be substituted by substituent group γ, a non-aromatic carbocyclic thio group that can be substituted by substituent group γ’, an aromatic heterocyclic thio group that can be substituted by substituent group γ, a non-aromatic heterocyclic thio group that can be substituted by substituent group γ, an aromatic carbocyclic sulfinyl group that can be substituted by substituent group γ, a non-aromatic carbocyclic sulfinyl group that can be substituted by substituent group γ’, an aromatic heterocyclic sulfinyl group that can be substituted by substituent group γ, a non-aromatic heterocyclic sulfinyl group that can be substituted by substituent group γ, an aromatic carbocyclic sulfonyl group that can be substituted by substituent group γ, a non-aromatic carbocyclic sulfonyl group that can be substituted by substituent group γ’, an aromatic heterocyclic sulfonyl group that can be substituted by substituent group γ and a non-aromatic heterocyclic sulfonyl group that can be substituted by substituent group γ’.

[0255] Substituent group α: halogen, hydroxy, carboxy, alkoxy, alkoxy substituted by alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, thio and cyano.

[0256] Substituent group β: halogen, hydroxyl, carboxyl, cyano, alkyl which may be substituted by substituent group α, alkenyl which may be substituted by substituent group α, alkynyl which may be substituted by substituent group α, alkylcarbonyl which may be substituted by substituent group α, alkenylcarbonyl which may be substituted by substituent group α, alkynylcarbonyl which may be substituted by substituent group α, alkylthio which may be substituted by substituent group α, alkenylthio which may be substituted by substituent group α, alkynylthio which may be substituted by substituent group α, alkanesulfinyl which may be substituted by substituent group α, alkenesulfinyl which may be substituted by substituent group α, alkynesulfinyl which may be substituted by substituent group α, alkanesulfonyl which may be substituted by substituent group α, alkenesulfonyl which may be substituted by substituent group α, alkynesulfonyl which may be substituted by substituent group α,

[0257] aromatic carbocyclic group which may be substituted by substituent group γ, non-aromatic carbocyclic group which may be substituted by substituent group γ’, aromatic heterocyclic group which may be substituted by substituent group γ, non-aromatic heterocyclic group which may be substituted by substituent group γ’, aromatic carbocyclic alkyl group which may be substituted by substituent group γ, non-aromatic carbocyclic alkyl group which may be substituted by substituent group γ’, aromatic heterocyclic alkyl group which may be substituted by substituent group γ, non-aromatic heterocyclic alkyl group which may be substituted by substituent group γ’, aromatic carbocyclic carbonyl group which may be substituted by substituent group γ, non-aromatic carbocyclic carbonyl group which may be substituted by substituent group γ’, aromatic heterocyclic carbonyl group which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyl group which may be substituted by substituent group γ, aromatic carbocyclic epoxycarbonyl group which may be substituted by substituent group γ, non-aromatic carbocyclic epoxycarbonyl group which may be substituted by substituent group γ’, aromatic heterocyclic epoxycarbonyl group which may be substituted by substituent group γ, non-aromatic heterocyclic epoxycarbonyl group which may be substituted by substituent group γ, aromatic carbocyclic thio group which may be substituted by substituent group γ, non-aromatic carbocyclic thio group which may be substituted by substituent group γ’, aromatic heterocyclic thio group which may be substituted by substituent group γ, non-aromatic heterocyclic thio group which may be substituted by substituent group γ, aromatic carbocyclic sulfinyl group which may be substituted by substituent group γ, non-aromatic carbocyclic sulfinyl group which may be substituted by substituent group γ’, aromatic heterocyclic sulfinyl group which may be substituted by substituent group γ, non-aromatic heterocyclic sulfinyl group which may be substituted by substituent group γ, aromatic carbocyclic sulfonyl group which may be substituted by substituent group γ, non-aromatic carbocyclic sulfonyl group which may be substituted by substituent group γ’, aromatic heterocyclic sulfonyl group which may be substituted by substituent group γ and non-aromatic heterocyclic sulfonyl group which may be substituted by substituent group γ’.

[0258] Substituent group γ: substituent group α, alkyl, alkyl substituted by alkoxy, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.

[0259] Substituent group γ’: substituent group γ and oxo group.

[0260] As “substituted aromatic carbocyclic group”, “substituted aromatic heterocyclic group”, “R 2 and R 3"Substituted aromatic carbocyclic ring formed together with the bonded carbon", "R" 2 and R 3 "Substituted aromatic heterocyclic ring formed together with the bonded carbon", "substituted aromatic carbocyclic epoxy group", "substituted aromatic heterocyclic epoxy group", "substituted aromatic carbocyclic carbonyl oxy group", "substituted aromatic heterocyclic carbonyl oxy group", "substituted aromatic carbocyclic carbonyl group", "substituted aromatic heterocyclic carbonyl group", "substituted aromatic carbocyclic epoxy carbonyl group", "substituted aromatic heterocyclic epoxy carbonyl group", "substituted aromatic carbocyclic thio group", "substituted aromatic heterocyclic thio group", "substituted aromatic carbocyclic sulfinyl group", "substituted aromatic heterocyclic sulfinyl group", "substituted aromatic carbocyclic sulfonyl group", and "substituted aromatic heterocyclic sulfonyl group", etc., substituents on the rings of "aromatic carbocyclic ring" and "aromatic heterocyclic ring" include: 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.

[0261] Substituent group B: halogen, hydroxyl group, carboxyl group, formyl group, formyloxy group, thio group, sulfino group, sulfo group, thiocarbonyl group, thiocarboxyl group, dithiocarboxyl group, thiocarbamoyl group, cyano group, nitro group, nitroso group, azide group, hydrazino group, ureido group, amidino group, guanidino group, pentafluorothio group, trialkylsilyl group

[0262] 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, alkoxy group that can be substituted by substituent group α, alkenyloxy group that can be substituted by substituent group α, alkynyloxy group that can be substituted by substituent group α, alkylcarbonyloxy group that can be substituted by substituent group α, alkenylcarbonyloxy group that can be substituted by substituent group α, alkynylcarbonyloxy group that can be substituted by substituent group α, alkylcarbonyl group that can be substituted by substituent group α, alkenylcarbonyl group that can be substituted by substituent group α, alkynylcarbonyl group that can be substituted by substituent group α, alkoxycarbonyl group that can be substituted by substituent group α, alkenyloxycarbonyl group that can be substituted by substituent group α, alkynyloxycarbonyl group that can be substituted by substituent group α, alkylthio group that can be substituted by substituent group α, alkenylthio group that can be substituted by substituent group α, alkynylthio group that can be substituted by substituent group α, alkanesulfinyl group that can be substituted by substituent group α, alkenesulfinyl group that can be substituted by substituent group α, alkynesulfinyl group that can be substituted by substituent group α, alkylsulfonyl group that can be substituted by substituent group α, alkenylsulfonyl group that can be substituted by substituent group α, alkynylsulfonyl group that can be substituted by substituent group α

[0263] amino group that can be substituted by substituent group β, imino group that can be substituted by substituent group β, carbamoyl group that can be substituted by substituent group β, sulfamoyl group that can be substituted by substituent group β

[0264] An aromatic carbocyclic group which may be substituted by a substituent group γ, a non-aromatic carbocyclic group which may be substituted by a substituent group γ', an aromatic heterocyclic group which may be substituted by a substituent group γ, a non-aromatic heterocyclic group which may be substituted by a substituent group γ', an aromatic carbocyclic oxy group which may be substituted by a substituent group γ, a non-aromatic carbocyclic oxy group which may be substituted by a substituent group γ', an aromatic heterocyclic oxy group which may be substituted by a substituent group γ, a non-aromatic heterocyclic oxy group which may be substituted by a substituent group γ', an aromatic carbocyclic carbonyl oxy group which may be substituted by a substituent group γ, a non-aromatic carbocyclic carbonyl oxy group which may be substituted by a substituent group γ', an aromatic heterocyclic carbonyl oxy group which may be substituted by a substituent group γ and a non-aromatic heterocyclic carbonyl oxy group which may be substituted by a substituent group γ', an aromatic carbocyclic carbonyl group which may be substituted by a substituent group γ, a non-aromatic carbocyclic carbonyl group which may be substituted by a substituent group γ', an aromatic heterocyclic carbonyl group which may be substituted by a substituent group γ, a non-aromatic heterocyclic carbonyl group which may be substituted by a substituent group γ', an aromatic carbocyclic oxy group carbonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic oxy group carbonyl which may be substituted by a substituent group γ', an aromatic heterocyclic oxy group carbonyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic oxy group carbonyl which may be substituted by a substituent group γ', an aromatic carbocyclic alkyl group which may be substituted by a substituent group γ, a non-aromatic carbocyclic alkyl group which may be substituted by a substituent group γ', an aromatic heterocyclic alkyl group which may be substituted by a substituent group γ, a non-aromatic heterocyclic alkyl group which may be substituted by a substituent group γ', an aromatic carbocyclic alkoxy group which may be substituted by a substituent group γ, a non-aromatic carbocyclic alkoxy group which may be substituted by a substituent group γ', an aromatic heterocyclic alkoxy group which may be substituted by a substituent group γ, a non-aromatic heterocyclic alkoxy group which may be substituted by a substituent group γ', an aromatic carbocyclic oxy group alkyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic oxy group alkyl which may be substituted by a substituent group γ', an aromatic heterocyclic oxy group alkyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic oxy group alkyl which may be substituted by a substituent group γ', an aromatic carbocyclic alkoxy group carbonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic alkoxy group carbonyl which may be substituted by a substituent group γ', an aromatic heterocyclic alkoxy group carbonyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic alkoxy group carbonyl which may be substituted by a substituent group γ', an aromatic carbocyclic alkoxy group alkyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic alkoxy group alkyl which may be substituted by a substituent group γ', an aromatic heterocyclic alkoxy group alkyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic alkoxy group alkyl which may be substituted by a substituent group γ', an aromatic carbocyclic thio group which may be substituted by a substituent group γ, a non-aromatic carbocyclic thio group which may be substituted by a substituent group γ', an aromatic heterocyclic thio group which may be substituted by a substituent group γ, a non-aromatic heterocyclic thio group which may be substituted by a substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted by a substituent group γ, a non-aromatic carbocyclic sulfinyl group which may be substituted by a substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted by a substituent group γ, a non-aromatic heterocyclic sulfinyl group which may be substituted by a substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted by a substituent group γ, a non-aromatic carbocyclic sulfonyl group which may be substituted by a substituent group γ', an aromatic heterocyclic sulfonyl group which may be substituted by a substituent group γ and a non-aromatic heterocyclic sulfonyl group which may be substituted by a substituent group γ'.

[0265] As the "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "R 2 and R 3 substituted non-aromatic carbocyclic formed together with the bonded carbon", "R 2 and R 3 substituted non-aromatic heterocyclic formed together with the bonded carbon", "R 2 and R 3 substituted aromatic carbocyclic formed together with the bonded carbon", "R 2 and R 3 substituted aromatic heterocyclic formed together with the bonded carbon", "R 15 and R 16 substituted non-aromatic carbocyclic formed together with the bonded carbon", "R 17 and R 18 substituted non-aromatic carbocyclic formed together with the bonded carbon", "substituted non-aromatic carbocyclic oxy group", "substituted non-aromatic heterocyclic oxy group", "substituted non-aromatic carbocyclic carbonyl oxy group", "substituted non-aromatic heterocyclic carbonyl oxy group", "substituted non-aromatic carbocyclic carbonyl group", "substituted non-aromatic heterocyclic carbonyl group", "substituted non-aromatic carbocyclic oxy carbonyl group", "substituted non-aromatic heterocyclic oxy 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", the substituents on the rings of the "non-aromatic carbocyclic" and "non-aromatic heterocyclic" include 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.

[0266] Substituent group C: Substituent group B and oxo group.

[0267] When the "non-aromatic carbocyclic" and "non-aromatic heterocyclic" are substituted by the "oxo group", as shown below, it means a ring in which two hydrogen atoms on the carbon atom are substituted.

[0268]

[0269] As the substituents of "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl", the following substituent group D can be cited. It can be substituted by 1 or 2 groups selected from substituent group D.

[0270] Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted by substituent group α, alkenyl which may be substituted by substituent group α, alkynyl which may be substituted by substituent group α, alkylcarbonyl which may be substituted by substituent group α, alkenylcarbonyl which may be substituted by substituent group α, alkynylcarbonyl which may be substituted by substituent group α, alkylthio which may be substituted by substituent group α, alkenylthio which may be substituted by substituent group α, alkynylthio which may be substituted by substituent group α, alkylsulfinyl which may be substituted by substituent group α, alkenylsulfinyl which may be substituted by substituent group α, alkynylsulfinyl which may be substituted by substituent group α, alkylsulfonyl which may be substituted by substituent group α, alkenylsulfonyl which may be substituted by substituent group α, alkynylsulfonyl which may be substituted by substituent group α,

[0271] amino which may be substituted by substituent group β, imino which may be substituted by substituent group β, carbamoyl which may be substituted by substituent group β, sulfamoyl which may be substituted by substituent group β,

[0272] aromatic carbocyclic group which may be substituted by substituent group γ, non-aromatic carbocyclic group which may be substituted by substituent group γ', aromatic heterocyclic group which may be substituted by substituent group γ, non-aromatic heterocyclic group which may be substituted by substituent group γ', aromatic carbocyclic alkyl group which may be substituted by substituent group γ, non-aromatic carbocyclic alkyl group which may be substituted by substituent group γ', aromatic heterocyclic alkyl group which may be substituted by substituent group γ, non-aromatic heterocyclic alkyl group which may be substituted by substituent group γ', aromatic carbocyclic carbonyl group which may be substituted by substituent group γ, non-aromatic carbocyclic carbonyl group which may be substituted by substituent group γ', aromatic heterocyclic carbonyl group which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyl group which may be substituted by substituent group γ, aromatic carbocyclic epoxycarbonyl group which may be substituted by substituent group γ, non-aromatic carbocyclic epoxycarbonyl group which may be substituted by substituent group γ', aromatic heterocyclic epoxycarbonyl group which may be substituted by substituent group γ, non-aromatic heterocyclic epoxycarbonyl group which may be substituted by substituent group γ, aromatic carbocyclic thio group which may be substituted by substituent group γ, non-aromatic carbocyclic thio group which may be substituted by substituent group γ', aromatic heterocyclic thio group which may be substituted by substituent group γ, non-aromatic heterocyclic thio group which may be substituted by substituent group γ, aromatic carbocyclic sulfinyl group which may be substituted by substituent group γ, non-aromatic carbocyclic sulfinyl group which may be substituted by substituent group γ', aromatic heterocyclic sulfinyl group which may be substituted by substituent group γ, non-aromatic heterocyclic sulfinyl group which may be substituted by substituent group γ, aromatic carbocyclic sulfonyl group which may be substituted by substituent group γ, non-aromatic carbocyclic sulfonyl group which may be substituted by substituent group γ', aromatic heterocyclic sulfonyl group which may be substituted by substituent group γ and non-aromatic heterocyclic sulfonyl group which may be substituted by substituent group γ'.

[0273] as R 1The substituents on the rings of "substituted six-membered aromatic heterocyclic group", "substituted five-membered aromatic heterocyclic group", "substituted six-membered aromatic carbocyclic group", "substituted bicyclic nine-membered non-aromatic heterocyclic group" and "substituted bicyclic ten-membered non-aromatic heterocyclic group" include, for example: alkyl, haloalkyl, alkyl substituted by alkoxy, alkyl substituted by haloalkoxy, alkyl substituted by alkoxy-substituted alkoxy, hydroxyalkyl, carbamoyl substituted by alkyl, alkyl substituted by non-aromatic heterocyclic oxy group, alkyl substituted by non-aromatic carbocyclic oxy group, alkyl substituted by aromatic heterocyclic group, alkyl substituted by alkyl-substituted aromatic heterocyclic group, alkyl substituted by aromatic carbocyclic group, alkyl substituted by alkyl-substituted aromatic carbocyclic group, alkoxy, haloalkoxy, alkoxy substituted by alkoxy, haloalkoxy substituted by alkoxy, alkoxy substituted by non-aromatic heterocyclic group, alkoxy substituted by non-aromatic carbocyclic group, non-aromatic heterocyclic oxy group, non-aromatic carbocyclic oxy group, non-aromatic heterocyclic group, non-aromatic carbocyclic group, halogen, cyano, alkenyl, alkynyl. Atoms at any position on the ring can be substituted by one or more groups selected from these.

[0274] As R 6 and R 7 The substituents of "substituted alkyl", "substituted alkoxy", "substituted alkenyl" and "substituted alkynyl" in include, for example: halogen.

[0275] As R 6 and R 7 The substituents on the ring of "substituted non-aromatic carbocyclic group" in include, for example: halogen.

[0276] As R 8 and R 9 The substituents of "substituted alkyl", "substituted alkoxy" and "substituted alkoxycarbonyl" in include, for example: halogen, alkoxy, alkoxy substituted by alkoxy, haloalkoxy, hydroxy, non-aromatic heterocyclic oxy group, non-aromatic carbocyclic oxy group, aromatic heterocyclic group, aromatic heterocyclic group substituted by alkyl, aromatic carbocyclic group, aromatic carbocyclic group substituted by alkyl, non-aromatic heterocyclic group, non-aromatic carbocyclic group. Carbon atoms at any position can be substituted by one or more groups selected from these.

[0277] As R 8 and R 9 The substituents of "substituted carbamoyl" in include, for example: alkyl, non-aromatic carbocyclic group. Carbon atoms at any position can be substituted by one or more groups selected from these.

[0278] As R 8 and R 9Substituents on the rings of "substituted non-aromatic carbon epoxy groups", "substituted non-aromatic hetero epoxy groups", "substituted non-aromatic carbocyclic groups" and "substituted non-aromatic heterocyclic groups" include, for example: alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and halogens. Atoms at any position on the ring can be substituted by one or more groups selected from these.

[0279] As R 31 Substituents of "substituted alkyl groups" in

[0280] As R 31 Substituents on the ring of "substituted non-aromatic carbocyclic groups" in

[0281] As R 32 And R 33 Substituents of "substituted alkyl groups" in

[0282] As R 32 And R 33 Substituents on the ring of "substituted non-aromatic carbocyclic groups" in

[0283] As R 2 、R 3 And R 4 Substituents of "substituted alkyl groups" and "substituted alkoxy groups" in

[0284] As R 2 、R 3 And R 4 Substituents of "substituted carbamoyl groups" in

[0285] As R 2 、R 3 And R 4 Substituents on the rings of "substituted aromatic carbocyclic groups", "substituted non-aromatic carbocyclic groups", "substituted aromatic heterocyclic groups", "substituted non-aromatic heterocyclic groups", "substituted aromatic carbon epoxy groups", "substituted non-aromatic carbon epoxy groups", "substituted aromatic hetero epoxy groups" and "substituted non-aromatic hetero epoxy groups" include, for example: halogens, alkyl groups. Atoms at any position on the ring can be substituted by one or more groups selected from these.

[0286] As R 2 And R 3Substituents on the rings of "substituted aromatic carbocyclic rings", "substituted non-aromatic carbocyclic rings", "substituted aromatic heterocyclic rings" and "substituted non-aromatic heterocyclic rings" formed together with the carbon atoms to which they are bonded, for example, include: halogen.

[0287] As R 5 Substituents on the rings of "substituted aromatic heterocyclic groups", "substituted six-membered aromatic heterocyclic groups", "substituted aromatic carbocyclic groups", "substituted phenyl groups", "substituted non-aromatic heterocyclic groups" and "substituted non-aromatic carbocyclic groups" in R, for example, include: alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxy substituted by an aromatic carbocyclic group, alkoxy substituted by a non-aromatic carbocyclic group, aromatic carbocyclic oxy group, aromatic carbocyclic oxy group substituted by halogen, non-aromatic carbocyclic oxy group, non-aromatic carbocyclic oxy group substituted by halogen, aromatic carbocyclic group, aromatic carbocyclic group substituted by an alkyl substituted by an alkoxy group, aromatic carbocyclic group substituted by halogen, aromatic carbocyclic group substituted by an alkyl group, aromatic carbocyclic group substituted by a haloalkyl group, aromatic heterocyclic group substituted by an alkoxy group, aromatic carbocyclic group substituted by a haloalkoxy group, aromatic carbocyclic group substituted by a cyano group, aromatic carbocyclic group substituted by a cyano group and halogen, aromatic carbocyclic group substituted by a non-aromatic carbocyclic group, aromatic carbocyclic group substituted by an aromatic carbocyclic group, non-aromatic carbocyclic group, non-aromatic carbocyclic group substituted by halogen, non-aromatic carbocyclic group substituted by an alkyl group, non-aromatic carbocyclic group substituted by a haloalkyl group, non-aromatic carbocyclic group substituted by a haloalkoxy group, aromatic heterocyclic group, aromatic heterocyclic group substituted by an alkyl substituted by an alkoxy group, aromatic heterocyclic group substituted by halogen, aromatic heterocyclic group substituted by an alkyl group, aromatic heterocyclic group substituted by a haloalkyl group, aromatic heterocyclic group substituted by an alkoxy group, aromatic heterocyclic group substituted by a haloalkoxy group, aromatic heterocyclic group substituted by a cyano group, aromatic heterocyclic group substituted by a cyano group and halogen, aromatic heterocyclic group substituted by a non-aromatic carbocyclic group, aromatic heterocyclic group substituted by an aromatic carbocyclic group, halogen, cyano, alkoxycarbonyl, alkylcarbamoyl. Atoms at any position on the ring can be substituted by one or more groups selected from these.

[0288] As R 10 and R 13 Substituents on the "substituted alkoxy" and "substituted alkyl" in R, for example, include: halogen.

[0289] As R 14 Substituents on the "substituted alkyl", "substituted alkoxy", "substituted alkoxycarbonyl" and "substituted alkylcarbonyl" in R, for example, include: halogen, non-aromatic carbocyclic group, aromatic carbocyclic group. Carbon atoms at any position can be substituted by one or more groups selected from these.

[0290] As R 14The substituents on the rings of "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted non-aromatic carbocyclic epoxy group" and "substituted aromatic carbocyclic epoxy group" include, for example: alkyl, halogen, alkoxy, haloalkyl, haloalkoxy, cyano. Atoms at any position on the ring can be substituted by one or more groups selected from these.

[0291] As R 15 and R 16 The substituents of "substituted alkyl" include, for example: halogen.

[0292] As R 15 and R 16 The substituents on the ring of "substituted non-aromatic carbocyclic ring" formed by R

[0293] 17 and R 18 18 The substituents of "substituted alkyl" include, for example: halogen.

[0294] As R 17 and R 18 The substituents on the ring of "substituted non-aromatic carbocyclic ring" formed by R

[0295] In the compound represented by formula (I), R 1 、R 6 、R 7 、R 8 、R 9 、R 31 、R 32 、R 33 、A 1 、A 2 、A 3 、R 2 、R 3 、R 4 、R 5 、B 1 、B 2 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 and R 18 The preferred embodiments of and are as follows. As the compound represented by formula (I), examples include: all combinations of the specific examples shown below.

[0296] R 1Examples include: a substituted or unsubstituted six-membered aromatic heterocyclic group, or a substituted or unsubstituted five-membered aromatic heterocyclic group (wherein, a substituted or unsubstituted tetrazolyl group and a substituted or unsubstituted tetrazolone group are excluded), a substituted or unsubstituted six-membered aromatic carbocyclic group, a substituted or unsubstituted bicyclic nine-membered non-aromatic heterocyclic group, or a substituted or unsubstituted bicyclic ten-membered non-aromatic heterocyclic group (hereinafter referred to as A-1).

[0297] R 1 Examples include: a substituted or unsubstituted six-membered aromatic carbocyclic group, a substituted or unsubstituted six-membered aromatic heterocyclic group, or a substituted or unsubstituted five-membered aromatic heterocyclic group (wherein, a substituted or unsubstituted tetrazolyl group and a substituted or unsubstituted tetrazolone group are excluded) (hereinafter referred to as A-2).

[0298] R 1 Examples include the group represented by the following formula (hereinafter referred to as A-3):

[0299]

[0300] R 1 Examples include the group represented by the following formula (hereinafter referred to as A-4):

[0301]

[0302] R 1 Examples include the group represented by the following formula (hereinafter referred to as A-5):

[0303]

[0304] R 1 Examples include the group represented by the following formula (hereinafter referred to as A-6):

[0305]

[0306] R 1 Examples include the group represented by the following formula (hereinafter referred to as A-7):

[0307]

[0308] R 6 Examples include: a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a cyano group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as B-1).

[0309] R 6 Examples include: a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a cyano group (hereinafter referred to as B-2).

[0310] R6 Examples include: substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy (hereinafter referred to as B-3).

[0311] R 6 Examples include: alkyl or alkoxy (hereinafter referred to as B-4).

[0312] R 6 Examples include: methyl or methoxy (hereinafter referred to as B-5).

[0313] R 6 Examples include: methyl (hereinafter referred to as B-6).

[0314] R 7 Examples include: a hydrogen atom, a halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a cyano group, or substituted or unsubstituted non-aromatic carbocyclic group (wherein, when R 6 is a hydrogen atom, R 7 is a halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a cyano group) (hereinafter referred to as C-1).

[0315] R 7 Examples include: a halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a cyano group (hereinafter referred to as C-2).

[0316] R 7 Examples include: a halogen, substituted or unsubstituted alkyl or a cyano group (hereinafter referred to as C-3).

[0317] R 7 Examples include: a halogen, alkyl, haloalkyl or a cyano group (hereinafter referred to as C-4).

[0318] R 7 Examples include: a halogen, alkyl or a cyano group (hereinafter referred to as C-5).

[0319] R 7 Examples include: a halogen, methyl, ethyl, isopropyl or a cyano group (hereinafter referred to as C-6).

[0320] R 7 Examples include: a halogen, methyl or a cyano group (hereinafter referred to as C-7).

[0321] R 7 Examples include: a halogen or alkyl (hereinafter referred to as C-8).

[0322] R 7 Examples include: a halogen or methyl (hereinafter referred to as C-9).

[0323] R7 Examples include: alkyl (hereinafter referred to as C-10).

[0324] R 7 Examples include: methyl (hereinafter referred to as C-11).

[0325] R 7 Examples include: halogen (hereinafter referred to as C-12).

[0326] R 8 Examples include: a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a cyano group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic ring group, or a substituted or unsubstituted non-aromatic heterocyclic ring group (hereinafter referred to as D-1).

[0327] R 8 Examples include: a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic ring group, or a substituted or unsubstituted non-aromatic heterocyclic ring group (hereinafter referred to as D-2).

[0328] R 8 Examples include: a hydrogen atom, or a substituted or unsubstituted alkyl group (hereinafter referred to as D-3).

[0329] R 8 Examples include: a substituted or unsubstituted alkyl group (hereinafter referred to as D-4).

[0330] R 8 Examples include: an alkyl group, an alkyl group substituted with an alkoxy group, or an alkyl group substituted with a non-aromatic heterocyclic group (hereinafter referred to as D-5).

[0331] R 8 Examples include: methyl, methyl substituted with an alkoxy group, or methyl substituted with a non-aromatic heterocyclic group (hereinafter referred to as D-6).

[0332] R 9 Examples include: a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a cyano group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic ring group, or a substituted or unsubstituted non-aromatic heterocyclic ring group (hereinafter referred to as E-1).

[0333] R 9 Examples include: a hydrogen atom, a halogen, or a substituted or unsubstituted alkoxy group (hereinafter referred to as E-2).

[0334] R 9 Examples include: a hydrogen atom, a halogen, or an alkoxy group (hereinafter referred to as E-3).

[0335] R 9 Examples include: a hydrogen atom or a halogen (hereinafter referred to as E-4).

[0336] R 31 Examples include: a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as E'-1).

[0337] R 31 Examples include: an alkyl group or a non-aromatic carbocyclic group (hereinafter referred to as E'-2).

[0338] R 31 Examples include: methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl (hereinafter referred to as E'-3).

[0339] R 31 Examples include: methyl, ethyl, or cyclopropyl (hereinafter referred to as E'-4).

[0340] R 31 Examples include: an alkyl group (hereinafter referred to as E'-5).

[0341] R 31 Examples include: methyl (hereinafter referred to as E'-6).

[0342] R 32 Examples include: a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as E''-1).

[0343] R 32 Examples include: a hydrogen atom, or a substituted or unsubstituted alkyl group (hereinafter referred to as E''-2).

[0344] R 32 Examples include: a hydrogen atom or an alkyl group (hereinafter referred to as E''-3).

[0345] R 32 Examples include: a hydrogen atom (hereinafter referred to as E''-4).

[0346] R 32 Examples include: an alkyl group (hereinafter referred to as E''-5).

[0347] R 33 Examples include: a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as E'''-1).

[0348] R 33 Examples include: a hydrogen atom, or a substituted or unsubstituted alkyl group (hereinafter referred to as E'''-2).

[0349] R 33 Examples include: a hydrogen atom or an alkyl group (hereinafter referred to as E”’-3).

[0350] R 33 Examples include: a hydrogen atom (hereinafter referred to as E”’-4).

[0351] R 33 Examples include: an alkyl group (hereinafter referred to as E”’-5).

[0352] A 1 Examples include: CR 2 or N (hereinafter referred to as F-1).

[0353] A 1 Examples include: CR 2 (hereinafter referred to as F-2).

[0354] A 1 Examples include: N (hereinafter referred to as F-3).

[0355] R 2 Examples include: a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group (hereinafter referred to as G-1).

[0356] R 2 Examples include: a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (hereinafter referred to as G-2).

[0357] R 2 Examples include: a hydrogen atom, a halogen, or an alkyl group (hereinafter referred to as G-3).

[0358] R 2 Examples include: a hydrogen atom or a halogen (hereinafter referred to as G-4).

[0359] R 2 Examples include: a hydrogen atom (hereinafter referred to as G-5).

[0360] A 2 Examples include: CR 3 or N (hereinafter referred to as H-1).

[0361] A 2 Examples include: CR 3 (hereinafter referred to as H-2).

[0362] A 2Examples include: N (hereinafter referred to as H-3).

[0363] R 3 Examples include: a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group (hereinafter referred to as J-1).

[0364] R 3 Examples include: a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (hereinafter referred to as J-2).

[0365] R 3 Examples include: a halogen, or a substituted or unsubstituted alkyl group (hereinafter referred to as J-3).

[0366] R 3 Examples include: a halogen or an alkyl group (hereinafter referred to as J-4).

[0367] R 3 Examples include: a hydrogen atom or a halogen (hereinafter referred to as J-5).

[0368] R 3 Examples include: a hydrogen atom (hereinafter referred to as J-6).

[0369] R 3 Examples include: a halogen (hereinafter referred to as J-7).

[0370] R 2 and R 3 may together with the carbon atom to which they are attached form a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle, or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as J-8).

[0371] R 2 and R 3 may together with the carbon atom to which they are attached form an aromatic carbocycle, a non-aromatic carbocycle, an aromatic heterocycle or a non-aromatic heterocycle (hereinafter referred to as J-9).

[0372] A 3 Examples include: CR 4 or N (hereinafter referred to as K-1).

[0373] A 3 Examples include: CR 4 (hereinafter referred to as K-2).

[0374] A3 Examples include: N (hereinafter referred to as K-3).

[0375] R 4 Examples include: a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group (hereinafter referred to as L-1).

[0376] R 4 Examples include: a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkoxy group (hereinafter referred to as L-2).

[0377] R 4 Examples include: a hydrogen atom, a halogen, a cyano group, an alkyl group or an alkoxy group (hereinafter referred to as L-3).

[0378] R 4 Examples include: a hydrogen atom, a halogen, a cyano group (hereinafter referred to as L-4).

[0379] R 4 Examples include: a hydrogen atom (hereinafter referred to as L-5).

[0380] R 5 Examples include: a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as M-1).

[0381] R 5 Examples include: a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as M-2).

[0382] R 5 Examples include: a substituted or unsubstituted six-membered aromatic heterocyclic group, or a substituted or unsubstituted phenyl group (hereinafter referred to as M-3).

[0383] R 5 Examples include: a group represented by the following formula (hereinafter referred to as M-4):

[0384]

[0385] R 10 Examples include: a hydrogen atom, a cyano group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group (hereinafter referred to as N-1’).

[0386] R 10Examples include: a hydrogen atom, or a substituted or unsubstituted alkyl group (hereinafter referred to as N-1).

[0387] R 10 Examples include: a hydrogen atom, an alkyl group or a haloalkyl group (hereinafter referred to as N-2).

[0388] R 10 Examples include: a hydrogen atom or a haloalkyl group (hereinafter referred to as N-3).

[0389] R 10 Examples include: a hydrogen atom (hereinafter referred to as N-4).

[0390] R 13 Examples include: a hydrogen atom, a cyano group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group (hereinafter referred to as O-1’).

[0391] R 13 Examples include: a hydrogen atom, or a substituted or unsubstituted alkyl group (hereinafter referred to as O-1).

[0392] R 13 Examples include: a hydrogen atom, an alkyl group or a haloalkyl group (hereinafter referred to as O-2).

[0393] R 13 Examples include: a hydrogen atom or a haloalkyl group (hereinafter referred to as O-3).

[0394] R 13 Examples include: a hydrogen atom (hereinafter referred to as O-4).

[0395] R 14 Examples include: a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyl group or a cyano group (hereinafter referred to as P-1’).

[0396] R 14 Examples include: a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyl group or a cyano group (hereinafter referred to as P-1).

[0397] R 14 Examples include: a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as P-2’).

[0398] R 14 Examples include: halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted non-aromatic carbocyclic group, or cyano (hereinafter referred to as P-2).

[0399] R 14 Examples include: halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as P-3).

[0400] R 14 Examples include: halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or non-aromatic carbocyclic group (hereinafter referred to as P-4).

[0401] R 14 Examples include: halogen, haloalkyl, haloalkoxy, or non-aromatic carbocyclic group (hereinafter referred to as P-5).

[0402] R 14 Examples include: halogen or haloalkyl (hereinafter referred to as P-6).

[0403] B 1 Examples include: CR 11 or N (hereinafter referred to as Q-1).

[0404] B 1 Examples include: CR 11 (hereinafter referred to as Q-2).

[0405] B 1 Examples include: N (hereinafter referred to as Q-3).

[0406] R 11 Examples include: hydrogen atom, halogen, methoxy, methyl, or halomethyl (hereinafter referred to as R-1’).

[0407] R 11 Examples include: hydrogen atom or halogen (hereinafter referred to as R-1).

[0408] R 11 Examples include: halogen (hereinafter referred to as R-2).

[0409] R 11 Examples include: hydrogen atom (hereinafter referred to as R-3).

[0410] B 2 Examples include: CR 12 or N (hereinafter referred to as S-1).

[0411] B 2 Examples include: CR 12 (hereinafter referred to as S-2).

[0412] B 2 Examples include: N (hereinafter referred to as S-3).

[0413] R 12 Examples include: a hydrogen atom, a halogen, a methoxy group, a methyl group or a halogenated methyl group (hereinafter referred to as T-1').

[0414] R 12 Examples include: a hydrogen atom or a halogen (hereinafter referred to as T-1).

[0415] R 12 Examples include: a halogen (hereinafter referred to as T-2).

[0416] R 12 Examples include: a hydrogen atom (hereinafter referred to as T-3).

[0417] R 15 Examples include: a hydrogen atom, or a substituted or unsubstituted alkyl group (hereinafter referred to as U-1).

[0418] R 15 Examples include: a hydrogen atom or an alkyl group (hereinafter referred to as U-2).

[0419] R 15 Examples include: a hydrogen atom (hereinafter referred to as U-3).

[0420] R 16 Examples include: a hydrogen atom, or a substituted or unsubstituted alkyl group (hereinafter referred to as V-1).

[0421] R 16 Examples include: a hydrogen atom or an alkyl group (hereinafter referred to as V-2).

[0422] R 16 Examples include: a hydrogen atom (hereinafter referred to as V-3).

[0423] R 15 and R 16 can together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic ring (hereinafter referred to as V-4).

[0424] R 15 and R 16 can together with the carbon atom to which they are attached form a non-aromatic carbocyclic ring (hereinafter referred to as V-5).

[0425] R 17 Examples include: a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (hereinafter referred to as W-1).

[0426] R 17 Examples include: a hydrogen atom, a halogen or an alkyl group (hereinafter referred to as W-2).

[0427] R17 Examples include: a hydrogen atom (hereinafter referred to as W-3).

[0428] R 18 Examples include: a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (hereinafter referred to as X-1).

[0429] R 18 Examples include: a hydrogen atom, a halogen, or an alkyl group (hereinafter referred to as X-2).

[0430] R 18 Examples include: a hydrogen atom (hereinafter referred to as X-3).

[0431] R 17 and R 18 may together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic ring (hereinafter referred to as X-4).

[0432] R 17 and R 18 may together with the carbon atom to which they are attached form a non-aromatic carbocyclic ring (hereinafter referred to as X-5).

[0433] As one embodiment, the following scheme may be cited.

[0434] (i) A compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof:

[0435]

[0436] In the formula,

[0437] R 1 is a group represented by the following formula:

[0438]

[0439] (In the formula,

[0440] R 6 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0441] R 7 is a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a cyano group;

[0442] R 8 is a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0443] R 9 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkoxy group);

[0444] A 1 is CR 2 or N;

[0445] R 2 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0446] A 2 is CR 3 or N;

[0447] R 3 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0448] A 3 is CR 4 or N;

[0449] R 4 is a hydrogen atom;

[0450] R 5 is a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group;

[0451] R 15 and R 16 are hydrogen atoms.

[0452] (ii) A compound of formula (I-1) or a pharmaceutically acceptable salt thereof:

[0453]

[0454] In the formula,

[0455] R 1 is a group represented by the following formula:

[0456]

[0457] (In the formula,

[0458] R 6 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0459] R 7 is a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a cyano group;

[0460] R 8 is a hydrogen atom, or a substituted or unsubstituted alkyl group);

[0461] A 1 is CR 2 or N;

[0462] R 2 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0463] A2 is CR 3 or N;

[0464] R 3 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0465] A 3 is CR 4 or N;

[0466] R 4 is a hydrogen atom;

[0467] R 5 is a group represented by the following formula:

[0468]

[0469] (wherein,

[0470] R 10 and R 13 are each independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0471] R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyl group or a cyano group;

[0472] B 1 is CR 11 or N;

[0473] B 2 is CR 12 or N;

[0474] R 11 and R 12 are each independently a hydrogen atom or a halogen);

[0475] R 15 and R 16 are hydrogen atoms.

[0476] (iii) a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof:

[0477]

[0478] wherein,

[0479] R 1 is a group represented by the following formula:

[0480]

[0481] (wherein,

[0482] R 6 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0483] R 7 is a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a cyano group;

[0484] R 8 is a hydrogen atom, or a substituted or unsubstituted alkyl group);

[0485] A 1 is CR 2 ;

[0486] R 2 is a hydrogen atom;

[0487] A 2 is CR 3 ;

[0488] R 3 is a halogen, or a substituted or unsubstituted alkyl group;

[0489] A 3 is CR 4 or N;

[0490] R 4 is a hydrogen atom;

[0491] R 5 is a group represented by the following formula:

[0492]

[0493] (wherein,

[0494] R 10 and R 13 are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0495] R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0496] B 1 is N;

[0497] B 2 is CR 12 ;

[0498] R 12 is a hydrogen atom or a halogen);

[0499] R 15 and R 16 are hydrogen atoms.

[0500] (iv) The compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof:

[0501]

[0502] Wherein,

[0503] R 1 is a group represented by the following formula:

[0504]

[0505] (Wherein,

[0506] R 6 is alkyl or non-aromatic carbocyclic group;

[0507] R 7 is halogen, alkyl, haloalkyl, alkenyl, alkynyl or cyano;

[0508] R 8 is a hydrogen atom or alkyl);

[0509] A 1 is CR 2 ;

[0510] R 2 is a hydrogen atom;

[0511] A 2 is CR 3 ;

[0512] R 3 is halogen or alkyl;

[0513] A 3 is CR 4 or N;

[0514] R 4 is a hydrogen atom;

[0515] R 5 is a group represented by the following formula:

[0516]

[0517] (Wherein,

[0518] R 10 and R 13 are each independently a hydrogen atom, alkyl or haloalkyl;

[0519] R 14 is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or non-aromatic carbocyclic group;

[0520] B1 is N;

[0521] B 2 is CR 12 ;

[0522] R 12 is a hydrogen atom or a halogen);

[0523] R 15 and R 16 are hydrogen atoms.

[0524] (v) The compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0525]

[0526] In the formula,

[0527] R 1 is a group represented by the following formula:

[0528]

[0529] (In the formula,

[0530] R 6 is a substituted or unsubstituted alkyl;

[0531] R 7 is a halogen, or a substituted or unsubstituted alkyl;

[0532] R 8 is a substituted or unsubstituted alkyl;

[0533] R 31 is a substituted or unsubstituted alkyl));

[0534] (The combination of A 1 , A 2 , A 3 ) is (CH, N, CH) or (CH, CR 3 , N);

[0535] R 3 is a hydrogen atom or a halogen;

[0536] R 5 is a group represented by the following formula:

[0537]

[0538] (In the formula,

[0539] R 10 and R 13 are each independently a hydrogen atom, a substituted or unsubstituted alkoxy, or a substituted or unsubstituted alkyl;

[0540] R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0541] B 1 is CR 11 or N;

[0542] R 11 is a hydrogen atom or a halogen;

[0543] B 2 is N);

[0544] R 15 、R 16 、R 17 and R 18 are hydrogen atoms.

[0545] (vi) The compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0546]

[0547] In the formula,

[0548] R 1 is a group represented by the following formula:

[0549]

[0550] (In the formula,

[0551] R 6 is a substituted or unsubstituted alkyl group;

[0552] R 7 is a halogen, or a substituted or unsubstituted alkyl group;

[0553] R 8 is a substituted or unsubstituted alkyl group;

[0554] R 31 is a substituted or unsubstituted alkyl group);

[0555] A 1 is CH;

[0556] A 2 is CR 3 ;

[0557] A 3 is N;

[0558] R 3 is a hydrogen atom or a halogen;

[0559] R 5 is a group represented by the following formula:

[0560]

[0561] (wherein,

[0562] R 10 and R 13 are each independently a hydrogen atom, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group;

[0563] R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0564] B 1 is CH;

[0565] B 2 is N);

[0566] R 15 、R 16 、R 17 and R 18 are hydrogen atoms.

[0567] (vii) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0568]

[0569] wherein,

[0570] R 1 is a group represented by the following formula:

[0571]

[0572] (wherein,

[0573] R 6 is an alkyl group;

[0574] R 7 is a halogen or an alkyl group;

[0575] R 8 is an alkyl group substituted with an alkoxy group, an alkyl group substituted with a non-aromatic heterocyclic group, or an unsubstituted alkyl group;

[0576] R 31 is an alkyl group);

[0577] A 1 is CH;

[0578] A 2 is CR 3 ;

[0579] A 3 is N;

[0580] R 3 is a hydrogen atom or a halogen;

[0581] R 5 is a group represented by the following formula:

[0582]

[0583] (wherein,

[0584] R 10 and R 13 are each independently a hydrogen atom, an alkoxy group or an alkyl group,

[0585] R 14 is a hydrogen atom, a halogen, a haloalkyl group, an alkyl group, a haloalkoxy group, an alkoxy group, an aromatic carbocyclic group substituted with one or more groups selected from substituent group Z, an unsubstituted aromatic carbocyclic group, an aromatic heterocyclic group substituted with one or more groups selected from substituent group Z, an unsubstituted aromatic heterocyclic group, a non-aromatic carbocyclic epoxy group substituted with a halogen, an unsubstituted non-aromatic carbocyclic epoxy group, a non-aromatic carbocyclic group substituted with a halogen, or an unsubstituted non-aromatic carbocyclic group;

[0586] Substituent group Z: halogen, haloalkyl, alkyl substituted with an alkoxy group, alkyl, haloalkoxy, alkoxy and cyano

[0587] B 1 is CH,

[0588] B 2 is N);

[0589] R 15 、R 16 、R 17 and R 18 are hydrogen atoms.

[0590] (viii) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0591]

[0592] wherein,

[0593] R 1 is a group represented by the following formula:

[0594]

[0595] (wherein,

[0596] R 6 is a substituted or unsubstituted alkyl group,

[0597] R 7 is a halogen, or a substituted or unsubstituted alkyl group;

[0598] R 8 is a substituted or unsubstituted alkyl group;

[0599] R 31 is a substituted or unsubstituted alkyl group);

[0600] A 1 is CH;

[0601] A 2 is N;

[0602] A 3 is CH;

[0603] R 3 is a hydrogen atom or a halogen;

[0604] R 5 is a group represented by the following formula:

[0605]

[0606] (wherein,

[0607] R 10 and R 13 are each independently a hydrogen atom, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group;

[0608] R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0609] B 1 is CR 11 or N;

[0610] R 11 is a hydrogen atom or a halogen;

[0611] B 2 is N);

[0612] R 15 、R 16 、R 17 and R 18 are hydrogen atoms.

[0613] (ix) The compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0614]

[0615] Wherein,

[0616] R 1 is a group represented by the following formula:

[0617]

[0618] (Wherein,

[0619] R 6 is alkyl,

[0620] R 7 is halogen or alkyl;

[0621] R 8 is alkyl substituted with alkoxy, alkyl substituted with a non-aromatic heterocyclic group, or unsubstituted alkyl;

[0622] R 31 is alkyl);

[0623] A 1 is CH;

[0624] A 2 is N;

[0625] A 3 is CH;

[0626] R 3 is a hydrogen atom or halogen;

[0627] R 5 is a group represented by the following formula:

[0628]

[0629] (Wherein,

[0630] R 10 and R 13 are each independently a hydrogen atom, alkoxy or alkyl;

[0631] R 14 is a hydrogen atom, halogen, haloalkyl, alkyl, haloalkoxy, alkoxy, an aromatic carbocyclic group substituted with one or more groups selected from substituent group Z, an unsubstituted aromatic carbocyclic group, an aromatic heterocyclic group substituted with one or more groups selected from substituent group Z, an unsubstituted aromatic heterocyclic group, a non-aromatic carbocyclic epoxy group substituted with halogen, an unsubstituted non-aromatic carbocyclic epoxy group, a non-aromatic carbocyclic group substituted with halogen, or an unsubstituted non-aromatic carbocyclic group;

[0632] Substituent group Z: halogen, haloalkyl, alkyl substituted by alkoxy, alkyl, haloalkoxy, alkoxy and cyano;

[0633] B 1 is CR 11 or N;

[0634] R 11 is a hydrogen atom or halogen;

[0635] B 2 is N);

[0636] R 15 , R 16 , R 17 and R 18 are hydrogen atoms.

[0637] The compounds represented by formula (I) or formula (I-1) are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates or mixtures thereof.

[0638] One or more of the hydrogen, carbon and / or other atoms in the compounds represented by formula (I) or formula (I-1) may be replaced by isotopes of hydrogen, carbon and / or other atoms. As examples of such isotopes, 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 include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine in the form of. The compounds represented by formula (I) or formula (I-1) also include compounds substituted by such isotopes. The compounds substituted by the isotopes are also useful as pharmaceuticals. The compounds represented by formula (I) or formula (I-1) include all radiolabeled forms of the compounds represented by formula (I) or formula (I-1) substituted by the radioactive isotopes contained in the isotopes. In addition, the "radiolabeling method" for producing the "radiolabeled compound" is also included in the present invention, and the "radiolabeled compound" is useful as a tool for pharmacokinetic studies, studies in binding assays and / or diagnosis.

[0639] The radiolabel of the compound represented by formula (I) or formula (I-1) can be modulated by methods well-known in the art. For example, the tritium-labeled compound represented by formula (I) or formula (I-1) can be modulated by introducing tritium into the specific compound represented by formula (I) or formula (I-1) through a catalytic dehalogenation reaction of tritium. This method includes: reacting the compound represented by formula (I) or formula (I-1) appropriately with a halogen-substituted precursor and tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, and in the presence of a base. Other suitable methods for preparing tritium-labeled compounds can be referred to "Isotopes in the Physical and Biomedical Sciences, Vol.1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 The C-labeled compound can be modulated by using a raw material having 14 C carbon.

[0640] Examples of the pharmaceutically acceptable salts of the compound represented by formula (I) or formula (I-1) include salts of the compound represented by formula (I) or formula (I-1) with alkali metals (such as lithium, sodium, potassium, etc.), alkaline earth metals (such as calcium, barium, etc.), magnesium, transition metals (such as zinc, iron, etc.), ammonia, organic bases (such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, glucosamine, ethylenediamine, pyridine, methylpyridine, quinoline, etc.), and amino acids; or salts with 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 commonly used methods.

[0641] The compounds of formula (I) or formula (I-1) of the present invention or their pharmaceutically acceptable salts sometimes form solvates (e.g., hydrates, etc.), co-crystals and / or polymorphs, and the present invention also includes such various solvates, co-crystals and polymorphs. For "solvate", the compounds of formula (I) or formula (I-1) can be coordinated with any number of solvent molecules (e.g., water molecules, etc.). There are cases where the compounds of formula (I) or formula (I-1) or their pharmaceutically acceptable salts absorb moisture and adsorb water by being placed in the atmosphere, or cases where hydrates are formed. In addition, there are cases where the compounds of formula (I) or formula (I-1) or their pharmaceutically acceptable salts form polymorphs by recrystallization. "Co-crystal" means that the compound or salt of formula (I) or formula (I-1) and the co-crystal forming molecule are present in the same crystal lattice and can contain any number of co-crystal forming molecules.

[0642] The compounds of formula (I) or formula (I-1) of the present invention or their pharmaceutically acceptable salts sometimes form prodrugs, and the present invention also includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically decomposed or metabolically decomposed, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or in vivo under physiological conditions. Prodrugs include compounds that are converted into the compounds of formula (I) or formula (I-1) by undergoing enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in the body; compounds that are hydrolyzed by gastric acid, etc. to be converted into the compounds of formula (I) or formula (I-1), etc. Methods for selecting appropriate prodrug derivatives and methods for their preparation are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug itself can have activity.

[0643] When the compounds of formula (I) or formula (I-1) or their pharmaceutically acceptable salts have a hydroxyl group, for example, prodrugs such as acyloxy derivatives or sulfonyloxy derivatives prepared by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed acid anhydride or by reacting using a condensing agent can be exemplified. For example, CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, p-CH3PhSO3-.

[0644] Due to the serotonin 5-HT2A receptor antagonistic and / or inverse agonistic effects and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic effects of the compounds involved in the present invention, they are useful as therapeutic agents and / or prophylactic agents for diseases related to the serotonin 5-HT2A receptor and / or serotonin 5-HT2C receptor. Examples of diseases related to the serotonin 5-HT2A receptor and / or serotonin 5-HT2C 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, dependence, movement disorders, sleep disorders, obstructive sleep apnea syndrome, irritability associated with Parkinson's disease, irritability associated with dementia, irritability associated with schizophrenia, sexual dysfunction and 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, sleep disorders, obstructive sleep apnea syndrome, irritability associated with Parkinson's disease, irritability associated with dementia, irritability associated with schizophrenia, etc. More preferably, examples include: hallucinations and delusions associated with Parkinson's disease, hallucinations and delusions associated with dementia, obstructive sleep apnea syndrome, etc.

[0645] (Method for manufacturing the compounds of the present invention)

[0646] The compounds represented by formula (I) or formula (I-1) involved in the present invention can be manufactured, for example, by the general synthesis methods shown below. Extraction, purification, etc. can be carried out by the treatments carried out in ordinary organic chemistry experiments.

[0647] The compounds of the present invention can be synthesized with reference to the methods known in the art.

[0648] General synthesis method 1

[0649] (Method A)

[0650]

[0651] (In the formula, R 20 is a hydrogen atom or a C1-C3 alkyl group, X 1 is a leaving group such as a chlorine atom or a bromine atom, X2 is a halogen, and other symbols have the same meanings as those in (1) above)

[0652] Process 1

[0653] Compound (a-2) can be obtained by reacting compound (a-7) with compound (a-1) in the presence of a base.

[0654] The reaction temperature is 0°C to 150°C, preferably 0°C to 50°C.

[0655] The reaction time is 0.5 hour to 12 hours, preferably 1 hour to 6 hours.

[0656] Examples of the base include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP, etc., and 1 to 5 molar equivalents can be used relative to compound (a-1).

[0657] Examples of the reaction solvent include dichloromethane, acetonitrile, tetrahydrofuran, di ane, DMF, DMA, DMSO, etc., and they can be used alone or in combination.

[0658] Process 2

[0659] Compound (a-3) can be obtained by reacting a halogenating agent with compound (a-2).

[0660] Examples of the halogenating agent include N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, Selectfluor (registered trademark), silver(II) fluoride, etc., and 1 to 5 molar equivalents can be used relative to compound (a-2).

[0661] The reaction temperature is -20°C to 50°C, preferably 0°C to 20°C.

[0662] The reaction time is 0.5 hour to 24 hours, preferably 0.5 hour to 6 hours.

[0663] Examples of the reaction solvent include acetonitrile, tetrahydrofuran, toluene, dichloromethane, DMF, etc., and they can be used alone or in combination.

[0664] Process 3

[0665] Compound (a-4) can be obtained by reacting a reducing agent with compound (a-3).

[0666] Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, etc., and 1 to 10 molar equivalents can be used relative to compound (a-3).

[0667] The reaction temperature is 0°C to the reflux temperature, preferably 20°C to the reflux temperature.

[0668] The reaction time is from 0.2 hours to 48 hours, preferably from 1 hour to 24 hours.

[0669] Examples of the reaction solvent include: methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane, water, etc., which can be used alone or in combination.

[0670] Process 4

[0671] Compound (a-5) can be obtained by reacting ammonium chloride and iron with compound (a-4).

[0672] The reaction temperature is from 50 °C to the reflux temperature.

[0673] The reaction time is from 0.2 hours to 12 hours, preferably from 1 hour to 4 hours.

[0674] Examples of the reaction solvent include: methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, water, etc., which can be used alone or in combination.

[0675] Process 5

[0676] Compound (a-6) can be obtained by reacting compound (a-5) with compound (a-8) in the presence of a metal catalyst and a base.

[0677] Examples of the metal catalyst include: copper acetate, etc., and 0.01 to 1 molar equivalent can be used relative to compound (a-5).

[0678] Examples of the base include: pyridine, triethylamine, etc., and 1 to 10 molar equivalents can be used relative to compound (a-5).

[0679] 1 to 10 molar equivalents of compound (a-8) can be used relative to compound (a-5).

[0680] The reaction time is from 4 to 72 hours, preferably from 12 hours to 24 hours.

[0681] Examples of the reaction solvent include: dichloromethane, tetrahydrofuran, toluene, DMF, di alkane, etc., which can be used alone or in combination.

[0682] General synthesis method 2

[0683] (Method B)

[0684]

[0685] (In the formula, X 3 is a leaving group such as a chlorine atom or a fluorine atom, and other symbols have the same meanings as those in (1) above)

[0686] Process 1

[0687] Compound (b-2) can be obtained by reacting compound (b-6) with compound (b-1) in the presence of NaH.

[0688] The reaction temperature is 0°C to 100°C, preferably 0°C to 50°C.

[0689] The reaction time is 0.5 hour to 12 hours, preferably 0.5 hour to 2 hours.

[0690] Examples of the reaction solvent include: dichloromethane, acetonitrile, tetrahydrofuran, di ane, DMF, DMA, DMSO, etc., which can be used alone or in combination.

[0691] Process 2

[0692] Compound (b-3) can be obtained by reacting compound (b-2) with compound (b-7) in the presence of a metal catalyst and a base.

[0693] Examples of the metal catalyst include: palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, XPhos Pd G3, etc., and 0.001 to 0.5 molar equivalents can be used relative to compound (b-2).

[0694] Examples of the base include: lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, etc., and 1 to 10 molar equivalents can be used relative to compound (b-2).

[0695] 1 to 10 molar equivalents of compound (b-7) can be used relative to compound (b-2).

[0696] The reaction temperature is 20°C to the reflux temperature of the solvent, and depending on the situation, it is carried out at the temperature under microwave irradiation.

[0697] The reaction time is 0.1 to 48 hours, preferably 0.5 hour to 12 hours.

[0698] Examples of the reaction solvent include: tetrahydrofuran, toluene, DMF, di ane, water, etc., which can be used alone or in combination.

[0699] Process 3

[0700] Using compound (b-3) as the raw material, compound (b-4) can be obtained by the same method as in Process 4 of A above.

[0701] Process 4

[0702] Compound (b-5) can be obtained by reacting compound (b-8) with compound (b-4) in the presence of an acid.

[0703] The reaction temperature is 30 °C to 150 °C, preferably 100 °C to 130 °C.

[0704] The reaction time is 0.5 hour to 24 hours, preferably 1 hour to 18 hours.

[0705] Examples of the acid include: hydrochloric acid, sulfuric acid, TFA, formic acid, boron trifluoride, p-TsOH, PPTS, etc. 0.1 molar equivalent or more, preferably 0.1 to 1 molar equivalent, can be used relative to compound (b-4).

[0706] Examples of the reaction solvent include: methanol, ethanol, 2-propanol, tert-butanol, water, acetone, acetonitrile, tetrahydrofuran, di alkane, etc., which can be used alone or in combination.

[0707] Process 4'

[0708] Compound (b-5) can be obtained by reacting compound (b-8) with compound (b-4) in the presence of a base and then reacting with an acid.

[0709] Reaction with compound (b-8):

[0710] The reaction temperature is 0 °C to 30 °C.

[0711] The reaction time is 10 minutes to 6 hours, preferably 10 minutes to 1 hour.

[0712] Examples of the base include: NaH, potassium tert-butoxide. 0.1 molar equivalent or more, preferably 1 to 5 molar equivalents, can be used relative to compound (b-4).

[0713] Examples of the reaction solvent include: DMF, acetone, acetonitrile, tetrahydrofuran, di alkane, etc., which can be used alone or in combination.

[0714] Reaction with the acid:

[0715] The reaction temperature is 30 °C to 150 °C, preferably 100 °C to 130 °C.

[0716] The reaction time is 0.5 hour to 24 hours, preferably 1 hour to 18 hours.

[0717] Examples of the acid include: hydrochloric acid, sulfuric acid, TFA, formic acid, boron trifluoride, p-TsOH, PPTS, etc. 0.1 molar equivalent or more can be used relative to compound (b-4), preferably 0.1 to 1 molar equivalent.

[0718] Examples of the reaction solvent include: methanol, ethanol, 2-propanol, tert-butanol, water, acetone, acetonitrile, tetrahydrofuran, hexane, etc., which can be used alone or in combination.

[0719] General synthesis method 3

[0720] (Method C)

[0721]

[0722] (In the formula, each symbol has the same meaning as in the above (1))

[0723] Step 1

[0724] Compound (c-2) can be obtained by reacting compound (c-1) with compound (c-3) in the presence of a metal catalyst and a base.

[0725] Examples of the metal catalyst include: palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, XPhos Pd G3, PdCl2(dtbpf), etc., and 0.001 to 0.5 molar equivalents can be used relative to compound (c-1).

[0726] Examples of the base include: lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, etc., and 1 to 10 molar equivalents can be used relative to compound (c-1).

[0727] 1 to 10 molar equivalents of compound (c-3) can be used relative to compound (c-1).

[0728] The reaction temperature is 20°C to the reflux temperature of the solvent, and in some cases, it is carried out at the temperature under microwave irradiation.

[0729] The reaction time is 0.1 to 48 hours, preferably 0.5 hours to 12 hours.

[0730] Examples of the reaction solvent include: tetrahydrofuran, toluene, DMF, hexane, water, etc., which can be used alone or in combination.

[0731] General synthesis method 4

[0732] (Method D)

[0733]

[0734] (In the formula, each symbol has the same meaning as in the above (1))

[0735] Step 1

[0736] Compound (d-1) can be obtained by reacting hydrogen with compound (c-2) in the presence of a metal catalyst.

[0737] Examples of the metal catalyst include palladium-carbon, platinum oxide, rhodium-aluminum oxide, rhodium(I) chloride tris(triphenylphosphine), etc., and 0.01 to 100% by weight can be used relative to compound (c-2).

[0738] Examples of the hydrogen pressure include 1 to 50 atmospheres. It should be noted that cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, etc. can also be used as the hydrogen source instead of hydrogen.

[0739] The reaction temperature is 0 °C to the reflux temperature of the solvent, preferably 20 °C to 40 °C.

[0740] The reaction time is 0.5 to 72 hours, preferably 1 to 12 hours.

[0741] Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, acetic acid, water, etc., which can be used alone or in combination.

[0742] General synthesis method 5

[0743] (Method E)

[0744]

[0745] (In the formula, X 4 , X 5 and X 6 are each independently a leaving group such as a chlorine atom, a bromine atom or an iodine atom, PG is a protecting group such as TBS, and other symbols are synonymous with those in (1) above)

[0746] Step 1

[0747] Compound (e-2) can be obtained by reacting compound (e-6) with compound (e-1) in the presence of a base.

[0748] The reaction temperature is 0 °C to the reflux temperature, preferably 60 °C to 80 °C.

[0749] The reaction time is 0.5 hours to 12 hours, preferably 1 hour to 6 hours.

[0750] Examples of the base include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP, etc., and 1 to 5 molar equivalents can be used relative to compound (e-1).

[0751] Examples of the reaction solvent include dichloromethane, acetonitrile, tetrahydrofuran, di Alkanes, DMF, DMA, DMSO, etc. can be used alone or in combination.

[0752] Process 2

[0753] Compound (e-3) can be obtained by reacting compound (e-2) with compound (b-7) in the presence of a metal catalyst and a base.

[0754] Examples of the metal catalyst include palladium acetate, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)dichloropalladium(II), bis(tritert-butylphosphine)palladium, XPhos Pd G3, etc. 0.001 to 0.5 molar equivalents can be used relative to compound (e-2).

[0755] Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, etc. 1 to 5 molar equivalents can be used relative to compound (e-2).

[0756] 1 to 5 molar equivalents of compound (b-7) can be used relative to compound (e-2).

[0757] The reaction temperature is 20°C to the reflux temperature of the solvent, and in some cases, it is carried out at the temperature under microwave irradiation.

[0758] The reaction time is 0.1 to 48 hours, preferably 0.5 hours to 12 hours.

[0759] Examples of the reaction solvent include tetrahydrofuran, toluene, DMF, di alkanes, water, etc. They can be used alone or in combination.

[0760] Process 3

[0761] Compound (e-4) can be obtained by reacting compound (e-3) with compound (e-7) in the presence of a metal catalyst, a ligand, and a base.

[0762] As the metal catalyst, examples include combinations of (dibenzylideneacetone)palladium, palladium acetate, palladium chloride, etc. with Xantphos, BINAP, X-Phos, BrettPhos, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, etc., and 0.001 to 0.5 molar equivalents can be used relative to each compound (e-3). Alternatively, examples include tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, PdCl2(dtbpf), bis(triphenylphosphine)palladium(II) dichloride, bis(tritert-butylphosphine)palladium, Xantphos Pd G3, XPhos Pd G3, Brettphos Pd G3, etc., and 0.001 to 0.5 molar equivalents can be used relative to compound (e-3).

[0763] As the base, examples include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, etc., and 1 to 5 molar equivalents can be used relative to compound (e-3).

[0764] 1 to 5 molar equivalents of compound (e-7) can be used relative to compound (e-3).

[0765] The reaction temperature is 50°C to the reflux temperature of the solvent, and in some cases, it is carried out at the temperature under microwave irradiation.

[0766] The reaction time is 1 to 48 hours, preferably 1 hour to 12 hours.

[0767] As the reaction solvent, examples include tetrahydrofuran, toluene, hexane, etc., which can be used alone or in combination. and can be used alone or in combination.

[0768] Step 4

[0769] By reacting the deprotecting agent with compound (e-4), compound (e-5) can be obtained.

[0770] As the deprotecting agent, examples include tetrabutylammonium fluoride, pyridine hydrofluoride, trifluoroacetic acid, hydrochloric acid, etc., and 0.2 to 10 molar equivalents can be used relative to compound (e-4).

[0771] The reaction temperature is 0°C to 60°C, preferably 20°C to 60°C.

[0772] The reaction time is 0.5 hour to 24 hours, preferably 0.5 hour to 2 hours.

[0773] As the reaction solvent, examples include tetrahydrofuran, dichloromethane, dichloroethane, methanol, etc., which can be used alone or in combination.

[0774] General synthesis method 6

[0775] (Method F)

[0776]

[0777] (In the formula, R 40 、R 41 are each independently a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted aromatic carbocyclic group, X 4 and X 6 are each independently a leaving group such as a chlorine atom, a bromine atom or an iodine atom, PG is a protecting group such as TBS, and other symbols are as defined in (1) above)

[0778] Step 1

[0779] Compound (f-2) can be obtained by reacting compound (f-1) with compound (e-3) in the presence of a metal catalyst and a base.

[0780] Examples of the metal catalyst include combinations of bis(dibenzylideneacetone)palladium, palladium acetate, palladium chloride, etc. with Xantphos, BINAP, X-Phos, BrettPhos, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, etc., and 0.001 to 0.5 molar equivalents can be used relative to each compound (e-3). Alternatively, examples also include Xantphos Pd G3, XPhos Pd G3, Brettphos Pd G3, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, PdCl2(dtbpf), bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, etc., and 0.001 to 0.5 molar equivalents can be used relative to compound (e-3).

[0781] Examples of the base include cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium acetate, sodium acetate, sodium tert-butoxide, potassium tert-butoxide, etc., and 1 to 10 molar equivalents can be used relative to compound (e-3).

[0782] 1 to 10 molar equivalents of compound (f-1) can be used relative to compound (e-3).

[0783] The reaction temperature is 20°C to the reflux temperature of the solvent, and it is carried out at the temperature under microwave irradiation if necessary.

[0784] The reaction time is 0.1 to 72 hours, preferably 0.5 hours to 48 hours.

[0785] Examples of the reaction solvent include alkane, toluene, tetrahydrofuran, etc., which can be used alone or in combination.

[0786] Process 2

[0787] Compound (f-3) can be obtained by reacting hydroxylamine hydrochloride and a base with compound (f-2).

[0788] 1 to 5 molar equivalents of hydroxylamine hydrochloride can be used relative to compound (f-2).

[0789] Examples of the base include: triethylamine, pyridine, sodium acetate, potassium acetate, etc., and 1 - 10 molar equivalents can be used relative to compound (f-2).

[0790] The reaction temperature is carried out at 20°C to the reflux temperature of the solvent.

[0791] The reaction time is 0.1 hour to 10 hours, preferably 0.1 hour to 5 hours.

[0792] Examples of the reaction solvent include: ethanol, methanol, 2-propanol, etc., which can be used alone or in combination.

[0793] Process 3

[0794] Compound (e-4) can be obtained by reacting compound (f-3) with compound (f-4) in the presence of a metal catalyst and a base.

[0795] Examples of the metal catalyst include: combinations of (dibenzylideneacetone)palladium, palladium acetate, palladium chloride, etc. with Xantphos, BINAP, X-Phos, BrettPhos, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, etc., and 0.001 to 0.5 molar equivalents can be used relative to each compound (f-3). Or, examples include: tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, PdCl2(dtbpf), bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, Xantphos Pd G3, XPhos Pd G3, Brettphos Pd G3, etc., and 0.001 to 0.5 molar equivalents can be used relative to compound (f-3).

[0796] Examples of the base include: cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium acetate, sodium acetate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, etc., and 1 to 5 molar equivalents can be used relative to compound (f-3).

[0797] 1 to 5 molar equivalents of compound (f-4) can be used relative to compound (f-3).

[0798] The reaction temperature is 50°C to the reflux temperature of the solvent, and in some cases, it is carried out at the temperature under microwave irradiation.

[0799] The reaction time is 0.5 to 48 hours, preferably 0.5 to 12 hours.

[0800] As the reaction solvent, examples include: toluene, di alkane, tetrahydrofuran, etc., which can be used alone or in combination.

[0801] Step 5

[0802] Compound (e-5) can be obtained by reacting a deprotecting agent with compound (e-4).

[0803] As the deprotecting agent, examples include: tetrabutylammonium fluoride, pyridine hydrofluoride, trifluoroacetic acid, p-toluenesulfonic acid, etc., and 0.2 to 10 molar equivalents can be used relative to compound (e-4).

[0804] The reaction temperature is 0°C to 60°C, preferably 20°C to 60°C.

[0805] The reaction time is 0.5 hours to 24 hours, preferably 0.5 hours to 2 hours.

[0806] As the reaction solvent, examples include: tetrahydrofuran, dichloromethane, dichloroethane, methanol, etc., which can be used alone or in combination.

[0807] General synthesis method 7

[0808] (Method G)

[0809]

[0810] (In the formula, R 22 , R 23 , R 24 are each independently a C1-C3 alkyl group, X 7 is iodine or bromine, etc., PG is a protecting group such as TBS, and other symbols are as defined in (1) above)

[0811] Step 1

[0812] Compound (g-2) can be obtained by reacting compound (g-7) with compound (g-1) in the presence of a base.

[0813] The reaction temperature is 0°C to the reflux temperature, preferably 60°C to 80°C.

[0814] The reaction time is 0.5 hours to 12 hours, preferably 1 hour to 6 hours.

[0815] As the base, examples include: sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP, etc., and 1 to 5 molar equivalents can be used relative to compound (g-1).

[0816] Examples of the reaction solvent include: dichloromethane, acetonitrile, tetrahydrofuran, di ane, DMF, DMA, DMSO, etc., which can be used alone or in combination.

[0817] Step 2

[0818] Compound (g-3) can be obtained by reacting a base with compound (g-2), then reacting with compound (g-8), and adding an acid.

[0819] The reaction temperature is carried out at -78°C to 20°C.

[0820] The reaction time is 0.1 hour to 10 hours, preferably 0.1 hour to 5 hours.

[0821] Examples of the reaction solvent include: diethyl ether, tetrahydrofuran, toluene, etc., which can be used alone or in combination.

[0822] Examples of the base include: n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, and 1 to 2 molar equivalents can be used relative to compound (g-2).

[0823] Step 3

[0824] Compound (g-4) can be obtained by reacting compound (g-9) with compound (g-3) in the presence of a metal catalyst and a base.

[0825] The reaction temperature is 20°C to the reflux temperature of the solvent, and is carried out at the temperature under microwave irradiation as appropriate.

[0826] The reaction time is 0.1 to 72 hours, preferably 0.5 hour to 48 hours.

[0827] Examples of the reaction solvent include: di ane, toluene, tetrahydrofuran, etc., which can be used alone or in combination.

[0828] As the metal catalyst, examples include combinations of bis(dibenzylideneacetone)palladium, palladium acetate, palladium chloride, etc. with Xantphos, BINAP, X-Phos, BrettPhos, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, etc., and 0.001 to 0.5 molar equivalents can be used relative to each compound (g-3). Alternatively, examples also include: Xantphos Pd G3, XPhos Pd G3, Brettphos Pd G3, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, PdCl2(dtbpf), bis(triphenylphosphine)palladium(II) dichloride, bis(tritert-butylphosphine)palladium, etc., and 0.001 to 0.5 molar equivalents can be used relative to compound (g-3).

[0829] As the base, examples include: cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium acetate, sodium acetate, sodium tert-butoxide, potassium tert-butoxide, etc., and 1 to 10 molar equivalents can be used relative to compound (g-3).

[0830] 1 to 10 molar equivalents of compound (g-9) can be used relative to compound (g-3).

[0831] The reaction temperature is 20°C to the reflux temperature of the solvent, and it is carried out at the temperature under microwave irradiation as appropriate.

[0832] The reaction time is 0.1 to 72 hours, preferably 0.5 hours to 48 hours.

[0833] As the reaction solvent, examples include: di alkane, toluene, tetrahydrofuran, etc., which can be used alone or in combination.

[0834] Step 4

[0835] Compound (g-5) can be obtained from compound (g-4) by the method described in Step 3 of Method E.

[0836] Step 5

[0837] Compound (g-6) can be obtained from compound (g-5) by the method described in Step 4 of Method E.

[0838] The compound according to the present invention has serotonin 5-HT2A receptor antagonistic and / or inverse agonist effects and serotonin 5-HT2C receptor antagonistic and / or inverse agonist effects, and thus is useful as a therapeutic and / or prophylactic agent for hallucinations and delusions accompanying Parkinson's disease and / or dementia.

[0839] Moreover, the compound according to the present invention has the usefulness as a drug and preferably has any one or more of the following excellent characteristics.

[0840] a) Weak inhibition of CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.).

[0841] b) Exhibits good pharmacokinetics such as high bioavailability and moderate clearance.

[0842] c) High metabolic stability.

[0843] d) For CYP enzymes (e.g., CYP3A4), does not exhibit irreversible inhibition within the concentration range of the measurement conditions described in this specification.

[0844] e) Does not have mutagenicity.

[0845] f) Low risk to the cardiovascular system.

[0846] g) Exhibits high solubility.

[0847] h) Has high serotonin 5-HT2A receptor binding ability.

[0848] i) Has high serotonin 5-HT2C receptor binding ability.

[0849] j) High brain metastasis.

[0850] k) Low P-gp substrate property.

[0851] l) Low substrate property of BCRP (breast cancer resistance protein).

[0852] The pharmaceutical composition of the present invention can be administered by either oral or parenteral methods. As methods of parenteral administration, the following can be mentioned: transdermal, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, intranasal, eye drops, ear drops, intravaginal administration, etc.

[0853] In the case of oral administration, it can be formulated into any of the following commonly used dosage forms according to common methods for administration: internal solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.), internal liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonade preparations, alcoholic preparations, aromatic water preparations, extract preparations, decoctions, tinctures, etc.). Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, buccal tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets in the mouth. Powders and granules can be dry syrups, and capsules can be soft capsules, microcapsules or sustained-release capsules.

[0854] In the case of parenteral administration, appropriate administration can also be carried out using any of the following commonly used dosage forms: injections, drip infusions, external preparations (such as eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, mouthwashes, enemas, ointments, plasters, gels, creams, patches, cataplasms, external powders, suppositories, etc.). The injection can also be an emulsion such as O / W, W / O, O / W / O, W / O / W type, etc.

[0855] For an effective amount of the compound of the present invention, various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for its dosage form can be mixed as needed to prepare a pharmaceutical composition. Moreover, in this pharmaceutical composition, the effective amount, dosage form, and / or various pharmaceutical additives of the compound of the present invention can be appropriately changed, whereby a pharmaceutical composition for pediatric use, elderly use, critically ill patients, or surgical use can be prepared. For example, the pharmaceutical composition for pediatric use can be administered to neonates (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old), toddlers (1 year old or older and less than 7 years old), children (7 years old or older and less than 15 years old), or patients aged 15 to 18 years. For example, the pharmaceutical composition for elderly use can be administered to patients aged 65 years or older.

[0856] The dosage of the pharmaceutical composition of the present invention is preferably set considering the patient's age, weight, type or degree of disease, administration route, etc. In the case of oral administration, it is usually in the range of 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of parenteral administration, there are significant differences depending on the administration route, but it is usually in the range of 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. It can be administered once to several times a day.

[0857] Regarding the compound of the present invention, it can be used in combination with an antiparkinsonian drug, an anti-Alzheimer's drug, an antipsychotic drug, an antidepressant drug (hereinafter referred to as a concomitant drug) for the purpose of enhancing the action of the compound or reducing the dosage of the compound. At this time, there is no limitation on the administration timing of the compound of the present invention and the concomitant drug. For the administration object, these can be administered simultaneously or at an interval. Moreover, the compound of the present invention and the concomitant drug can be administered as two or more preparations containing their respective active ingredients, or can be administered as a single preparation containing these active ingredients.

[0858] The dosage of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to the administration object, administration route, target disease, symptoms, combination, etc. For example, in the case of a human administration object, 0.01 to 100 parts by weight of the concomitant drug can be used relative to 1 part by weight of the compound of the present invention.

[0859] As an antiparkinsonian drug, for example, levodopa preparations, etc. can be cited.

[0860] As an anti-Alzheimer's drug, for example, donepezil, etc. can be cited.

[0861] As an antipsychotic drug, for example, quetiapine, etc. can be cited.

[0862] As an antidepressant drug, for example, escitalopram, etc. can be cited.

[0863] Examples

[0864] Hereinafter, examples, reference examples, and test examples will be listed to further illustrate the present invention in detail, but the present invention is not limited by these examples.

[0865] In addition, the abbreviations used in this specification represent the following meanings.

[0866] BINAP: (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene

[0867] BrettPhos: 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl

[0868] BrettPhos Pd G3: Palladium(II) [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] methanesulfonate

[0869] CDCl3: Deuterochloroform

[0870] DMSO-d6: Deuterated dimethyl sulfoxide

[0871] DMF: N,N-Dimethylformamide

[0872] DMSO: Dimethyl sulfoxide

[0873] DMA: N,N-Dimethylacetamide

[0874] DMAP: 4-(Dimethylamino)pyridine

[0875] HCl: Hydrogen chloride

[0876] IPE: Diisopropyl ether

[0877] NaH: Sodium hydride

[0878] PdCl2(dtbpf): Dichloropalladium(II) [1,1'-bis(di-tert-butylphosphino)ferrocene]

[0879] p-TsOH: p-Toluenesulfonic acid

[0880] PPTS: Pyridinium p-toluenesulfonate

[0881] TBS: Tert-butyldimethylsilyl

[0882] TFA: Trifluoroacetic acid

[0883] THF: Tetrahydrofuran

[0884] THP: 2-Tetrahydropyranyl

[0885] TMS: Trimethylsilyl

[0886] Tr: Triphenylmethyl

[0887] X-Phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0888] XPhos Pd G3: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate

[0889] Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethyloxanthene

[0890] Xantphos Pd G3: [(4,5-Bis(diphenylphosphino)-9,9-dimethyloxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate

[0891] HPLC: High performance liquid chromatography

[0892] nM: nmol / L

[0893] μM: μmol / L

[0894] (Method for identifying compounds)

[0895] The NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d6 and CDCl3. In addition, when NMR data are shown, there are cases where not all peaks measured are recorded.

[0896] In the specification, "RT" represents the retention time in LC / MS: Liquid chromatography / mass spectrometry, and the measurement was performed under the following conditions. The unit of "RT" is minutes.

[0897] (Measurement condition 1)

[0898] Column: Shim-pack XR-ODS (2.2 μm i.d. 3.0 x 50 mm) (Shimadzu)

[0899] Flow rate: 1.6 mL / min

[0900] UV detection wavelength: 254 nm

[0901] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0902] Gradient: After performing a linear gradient of 10% - 100% solvent [B] over 3 minutes, maintain at 100% solvent [B] for 0.5 minutes.

[0903] (Measurement condition 2)

[0904] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters)

[0905] Flow rate: 0.8 mL / min

[0906] UV detection wavelength: 254 nm

[0907] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0908] Gradient: After performing a linear gradient of 5% - 100% solvent [B] over 3.5 minutes, maintain at 100% solvent [B] for 0.5 minutes.

[0909] (Measurement condition 3)

[0910] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters)

[0911] Flow rate: 0.8 mL / min

[0912] UV detection wavelength: 254 nm

[0913] Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile

[0914] Gradient: After performing a linear gradient of 5% - 100% solvent [B] over 3.5 minutes, maintain at 100% solvent [B] for 0.5 minutes.

[0915] (Measurement condition 4)

[0916] Column: Shim-pack Scepter (1.9um i.d. 2.1x50mm) (Shimadzu)

[0917] Flow rate: 0.8 mL / min

[0918] UV detection wavelength: 254 nm

[0919] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, and [B] is an acetonitrile solution containing 0.1% formic acid

[0920] Gradient: After performing a linear gradient of 5% - 100% solvent [B] over 3.5 minutes, maintain at 100% solvent [B] for 0.5 minutes.

[0921] It should be noted that in the specification, the recorded value of MS (m / z) represents the value observed by mass spectrometry. If not otherwise specified, it represents [M+H] + value.

[0922] In addition, in the specification, "Compound No." represents the compound number, "Structure" represents the chemical structure, and "LC / MS method" represents the above-mentioned LC / MS measurement conditions.

[0923] Synthesis of Compound I-002 in Example 1

[0924]

[0925] Step 1 Synthesis of Compound 2

[0926] Under a nitrogen atmosphere, dissolve Compound 1 (the synthesis method is described in WO200501225) (5.00 g, 22.8 mmol) in dimethylformamide (50 mL), add potassium carbonate (3.47 g, 25.1 mmol) and methyl bromoacetate (2.31 mL, 25.1 mmol), and stir at room temperature for 2 hours and 30 minutes. Add ethyl acetate (120 mL), water (120 mL), and 2 mol / L hydrochloric acid, and extract with ethyl acetate. After washing the organic layer with 1 mol / L hydrochloric acid, saturated sodium bicarbonate solution, water, and saturated brine, dry it over anhydrous sodium sulfate. Distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 2 (4.90 g, yield 74%).

[0927] 11H-NMR (CDCl3) δ: 3.82 (s, 3H), 3.82 (s, 3H), 4.78 (s, 2H), 6.35 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.30 (dd, J = 9.0, 2.8 Hz, 1H).

[0928] Synthesis of Compound 3 in Step 2

[0929] Under a nitrogen atmosphere, dissolve Compound 2 (4.19 g, 14.4 mmol) in dimethylformamide (42 mL). Add N-bromosuccinimide (2.56 g, 14.4 mmol) under ice-cooling and stir at room temperature for 1 hour. Add an additional N-bromosuccinimide (512 mg, 2.88 mmol) under ice-cooling and stir at room temperature for 1 hour and 45 minutes. Add ethyl acetate (100 mL), sodium thiosulfate (2 g), and water (50 mL), and extract with ethyl acetate. Wash the organic layer with 1 mol / L hydrochloric acid, saturated sodium bicarbonate solution, water, and saturated brine, and then dry over anhydrous sodium sulfate. Distill off the solvent under reduced pressure. Wash the resulting solid with hexane (20 mL) - ethyl acetate (10 mL), and then filter to obtain Compound 3 (5.23 g, yield 98%).

[0930] 1 1H-NMR (CDCl3) δ: 3.81 (s, 3H), 3.82 (s, 3H), 4.79 (s, 2H), 6.93 (d, J = 9.3 Hz, 1H), 7.57 (s, 1H), 8.25 (d, J = 2.8 Hz, 1H), 8.36 (dd, J = 9.2, 2.9 Hz, 1H).

[0931] Synthesis of Compound 4 in Step 3

[0932] Under a nitrogen atmosphere, dissolve Compound 3 (5.08 g, 13.7 mmol) in methanol (36 mL) - dichloromethane (72 mL). Add sodium borohydride (1.04 g, 27.4 mmol) under ice-cooling and stir at room temperature for 1 hour. Add an additional sodium borohydride (1.04 g, 27.4 mmol) under ice-cooling and stir at room temperature for 1 hour. Add an additional sodium borohydride (260 mg, 6.86 mmol) under ice-cooling and stir at room temperature for 1 hour. Add 1 mol / L hydrochloric acid (70 mL) under ice-cooling and extract with ethyl acetate (200 mL). Wash the organic layer with saturated sodium bicarbonate solution, water, and saturated brine, and then dry over anhydrous sodium sulfate. Distill off the solvent under reduced pressure. Purify the resulting residue by silica gel column chromatography (chloroform - methanol) to obtain Compound 4 (2.66 g, yield 57%).

[0933] 1 1H-NMR (CDCl3) δ: 1.96 (t, J = 6.1 Hz, 1H), 3.77 (s, 3H), 3.92 - 3.96 (m, 2H), 4.19 - 4.29 (m, 2H), 7.14 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.39 (dd, J = 9.2, 2.9 Hz, 1H).

[0934] Synthesis of Compound 5 in Step 4

[0935] Compound 4 (2.66 g, 7.77 mmol), iron (1.30 g, 23.3 mmol), and ammonium chloride (4.16 g, 78 mmol) were suspended in ethanol (53 mL) - water (13 mL), and stirred at 70 °C for 1 hour. Iron (217 mg, 3.89 mmol) was added, and the mixture was stirred at 70 °C for 50 minutes. After cooling, ethyl acetate (70 mL) and water (50 mL) were added, and the insoluble matter was filtered through Celite (registered trademark), and the mother liquor was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform - methanol) to obtain Compound 5 (1.89 g, yield 78%).

[0936] 1 1H-NMR (CDCl3) δ: 1.85 (br s, 1H), 3.58 (br s, 2H), 3.73 (s, 3H), 3.73 - 3.79 (m, 2H), 3.90 - 4.02 (m, 2H), 6.60 (d, J = 3.0 Hz, 1H), 6.78 (dd, J = 8.7, 2.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H).

[0937] Synthesis of Compound I-002 in Step 5

[0938] Compound 5 (30.0 mg, 0.096 mmol) was dissolved in dichloromethane (2.7 mL), and (6-trifluoromethylpyridin-3-yl)boronic acid (36.7 mg, 0.192 mmol), copper(II) acetate (17.5 mg, 0.096 mmol), and triethylamine (0.027 mL, 0.192 mmol) were added. The mixture was stirred at room temperature for 20 hours and 40 minutes. (6-Trifluoromethylpyridin-3-yl)boronic acid (36.7 mg, 0.192 mmol), copper(II) acetate (17.5 mg, 0.096 mmol), and triethylamine (0.027 mL, 0.192 mmol) were added additionally, and the mixture was stirred at room temperature for 23 hours and 45 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (amino silica gel, chloroform - methanol) to obtain Compound I-002 (24.4 mg, yield 56%).

[0939] 1 1H-NMR (CDCl3) δ: 1.96 (br s, 1H), 3.77 (s, 3H), 3.87 (br s, 2H), 4.06 - 4.14 (m, 2H), 5.98 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 7.28 (dd, J = 9.0, 2.8 Hz, 1H), 7.32 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H).

[0940] Example 2 Synthesis of Compound I-006

[0941]

[0942] Step 1 Synthesis of Compound I-006

[0943] Under a nitrogen atmosphere, Compound 5 (255 mg, 0.817 mmol) was dissolved in 2-propanol (2.5 mL), 2,3-difluoro-5-trifluoromethylpyridine (122 μL, 0.981 mmol) and p-toluenesulfonic acid monohydrate (78 mg, 0.409 mmol) were added, and the mixture was stirred at 100 °C for 18 hours. After cooling, saturated sodium bicarbonate solution (0.5 mL) and water (0.5 mL) were added, and the mixture was stirred for 5 minutes. The precipitated solid was filtered and dried to obtain Compound I-006 (252 mg, yield 65%).

[0944] 1H-NMR (CDCl3) δ: 8.26 (1H, s), 7.76 (1H, dd, J = 9.0, 2.8 Hz), 7.56 (1H, d, J = 2.8 Hz), 7.55 (1H, s), 7.47 (1H, dd, J = 10.8, 1.9 Hz), 7.07 (1H, d, J = 9.0 Hz), 6.81 (1H, s), 4.10 (2H, ddd, J = 19.7, 9.9, 4.1 Hz), 3.87 - 3.85 (2H, br m), 3.79 (3H, s), 1.87 (1H, t, J = 6.3 Hz).

[0945] Synthesis of Compound I-062 in Example 3

[0946]

[0947] Step 1 Synthesis of Compound 7

[0948] Under a nitrogen atmosphere, Compound 6 (1.00 g, 6.32 mmol) and 2,3-difluoro-5-trifluoromethylpyridine (1.16 g, 6.32 mmol) were dissolved in dimethylformamide (10 mL). A solution of potassium tert-butoxide (3.47 g, 25.1 mmol) in tetrahydrofuran (5 mL) was added under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling. Saturated ammonium chloride aqueous solution (15 mL) and water (5 mL) were added, and the mixture was stirred for 5 minutes. The precipitated solid was filtered and dried to obtain Compound 7 (2.03 g, yield 63%).

[0949] 1H-NMR (CDCl3) δ: 8.64 (1H, s), 8.37 (1H, s), 7.96 (1H, s), 7.59 (1H, s), 7.51 (1H, d, J = 10.5 Hz), 3.98 (3H, s).

[0950] Step 2 Synthesis of Compound 8

[0951] Under a nitrogen atmosphere, Compound 7 (1.29 g, 4.00 mmol) was dissolved in dichloromethane (13 mL). A 1 mol / L boron tribromide-dichloromethane solution (28 mL, 28.0 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 15 hours. A 1 mol / L sodium hydroxide aqueous solution (60 mL) was added under ice-cooling, and the mixture was stirred for 5 minutes. The precipitated solid was filtered and dried to obtain Compound 8 (1.22 g, yield 99%).

[0952] 1H-NMR (CDCl3) δ: 8.64 (1H, s), 8.37 (1H, d, J = 1.0 Hz), 8.09 (1H, s), 7.63 (1H, s), 7.52 (1H, dd, J = 10.5, 1.0 Hz), 5.35 (1H, br s).

[0953] Synthesis of Compound 9 in Step 3

[0954] Under a nitrogen atmosphere, dissolve Compound 8 (1.02 g, 3.30 mmol) in dimethylformamide (50 mL), add potassium carbonate (0.48 g, 3.47 mmol) and methyl bromoacetate (0.31 mL, 3.34 mmol), and stir at room temperature for 1 hour. Add water (15 mL) under ice-cooling and stir for 5 minutes. Filter the precipitated solid and dry it to obtain Compound 9 (1.11 g, yield 89%).

[0955] 1H-NMR (CDCl3) δ: 8.68 (1H, s), 8.38 (1H, s), 7.98 (1H, s), 7.63 (1H, s), 7.53 (1H, d, J = 9.9 Hz), 4.74 (2H, s), 3.83 (3H, s).

[0956] Synthesis of Compound 10 in Step 4

[0957] Under a nitrogen atmosphere, dissolve Compound 9 (1.11 g, 2.93 mmol) in methanol (11 mL) - tetrahydrofuran (11 mL), add sodium borohydride (0.55 g, 14.6 mmol) under ice-cooling, and stir at room temperature for 15 hours. Add saturated ammonium chloride aqueous solution (10 mL) and water (10 mL) under ice-cooling and stir for 5 minutes. Filter the precipitated solid and dry it to obtain Compound 10 (0.953 g, yield 93%).

[0958] 1H-NMR (CDCl3) 8: 8.66 (1H, s), 8.38 (1H, s), 8.01 (1H, s), 7.62 (1H, s), 7.52 (1H, d, J = 10.4 Hz), 4.23 - 4.21 (2H, br m), 4.03 - 4.01 (2H, br m), 2.17 (1H, br s).

[0959] Synthesis of Compound 11 in Step 5

[0960] Dissolve Compound 10 (379 mg, 1.08 mmol) in 1,4 - bis Alkane (3.8 mL) - water (0.80 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (449 mg, 2.16 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (70.3 mg, 0.11 mmol), and potassium carbonate (298 mg, 2.16 mmol) were added and stirred at 100 °C for 4 hours. Ethyl acetate (10 mL) and water (5 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (5 mL) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 11 (222 mg, yield 52%).

[0961] 1H-NMR (CDCl3) δ: 8.52 (1H, s), 8.31 (1H, s), 8.11 (1H, s), 7.67 (1H, s), 7.59 (1H, d, J = 1.9 Hz), 7.52 (1H, d, J = 10.5 Hz), 6.46 (1H, d, J = 1.9 Hz), 4.15 - 4.14 (2H, br m), 3.89 - 3.87 (5H, br m), 1.77 (1H, t, J = 6.1 Hz).

[0962] Step 6 Synthesis of Compound I-062

[0963] Compound 11 (77.2 mg, 0.194 mmol) was dissolved in dimethylformamide (0.77 mL), and N-bromosuccinimide (38.0 mg, 0.214 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. 10% sodium thiosulfate (0.4 mL) and saturated sodium bicarbonate solution (0.4 mL) were added, and the mixture was stirred for 5 minutes. The precipitated solid was filtered and dried to obtain compound I-062 (77.5 mg, yield 84%).

[0964] 1H-NMR (CDCl3) δ: 8.51 (1H, s), 8.32 (1H, s), 8.16 (1H, s), 7.74 (1H, d, J = 1.8 Hz), 7.58 (1H, s), 7.52 (1H, dd, J = 10.5, 1.8 Hz), 4.18 - 4.16 (2H, br m), 3.89 (2H, dd, J = 4.5, 2.3 Hz), 3.84 (3H, s), 2.03 (1H, br s).

[0965] Example 4 Synthesis of Compound I-063

[0966]

[0967] Step 1 Synthesis of Compound I-063

[0968] Compound 10 (1.02 g, 2.89 mmol) was dissolved in 1,4-dihydrochloric acid. 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.28 g, 5.78 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (188 mg, 0.29 mmol), potassium carbonate (799 mg, 5.78 mmol) were added, and stirred at 100°C for 4 hours. Ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (10 mL) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, ethyl acetate-methanol) to obtain compound I-063 (740 mg, yield 62%).

[0969] 1H-NMR (CDCl3) δ: 8.43 (1H, s), 8.30 (1H, s), 8.14 (1H, s), 7.68 (1H, s), 7.52 (1H, d, J = 8.7Hz), 7.43 (1H, s), 4.12-4.09 (2H, br m), 3.86-3.84 (2H, m), 3.78 (3H, s), 2.04 (3H, s), 1.77 (1H, t, J=6.3Hz).

[0970] Example 5 Synthesis of Compound I-073

[0971]

[0972] Step 1 Synthesis of Compound 13

[0973] Compound 12 (503 mg, 3.17 mmol) and 2-fluoro-5-trifluoromethylpyridine (374 μL, 3.17 mmol) were dissolved in dimethylformamide (5 mL) under nitrogen atmosphere, and a solution of tert-butoxypotassium (748 mg, 25.1 mmol)-tetrahydrofuran (2.5 mL) was added under ice-cooling, and stirred for 10 minutes under ice-cooling. Saturated aqueous ammonium chloride solution (15 mL) and water (5 mL) were added, and stirred for 5 minutes. The precipitated solid was filtered and dried to obtain compound 13 (638 g, yield 66%).

[0974] 1H-NMR (CDCl3) δ: 8.49 (1H, s), 7.79-7.74 (2H, m), 7.43 (1H, s), 7.30 (2H, d, J=8.8Hz), 3.91 (3H, s).

[0975] Synthesis of Compound 14 in Step 2

[0976] Under a nitrogen atmosphere, compound 13 (617 mg, 2.00 mmol) was dissolved in dichloromethane (6 mL). While cooling with ice, 1 mol / L boron tribromide-dichloromethane solution (16.2 mL, 16.2 mmol) was added, and the mixture was stirred at room temperature for 15 hours. While cooling with ice, 1 mol / L aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred for 5 minutes. The precipitated solid was collected by filtration and dried, thereby obtaining compound 14 (512 mg, yield 86%).

[0977] 1H-NMR (CDCl3) δ: 8.49 (1H, s), 7.79 (1H, dd, J = 8.8, 2.4 Hz), 7.58 (1H, d, J = 8.7 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.38 - 7.35 (2H, m), 5.24 (1H, br s).

[0978] Synthesis of Compound 15 in Step 3

[0979] Under a nitrogen atmosphere, compound 14 (375 mg, 1.29 mmol) was dissolved in dimethylformamide (3.7 mL). Potassium carbonate (197 mg, 1.42 mmol) and methyl bromoacetate (141 μL, 1.31 mmol) were added, and the mixture was stirred at room temperature for 1 hour. While cooling with ice, water (15 mL) was added, and the mixture was stirred for 5 minutes. The precipitated solid was collected by filtration and dried, thereby obtaining compound 15 (436 mg, yield 93%).

[0980] 1H-NMR (CDCl3) δ: 8.50 (1H, s), 7.79 (1H, dd, J = 8.8, 2.4 Hz), 7.71 (1H, d, J = 8.8 Hz), 7.40 (1H, br s), 7.35 - 7.33 (2H, m), 4.70 (2H, s), 3.82 (3H, s).

[0981] Synthesis of Compound 16 in Step 4

[0982] Compound 15 (436 mg, 1.20 mmol) was dissolved in methanol (4.3 mL)-tetrahydrofuran (4.3 mL) under nitrogen atmosphere, sodium borohydride (228 mg, 6.02 mmol) was added under ice-cold, and stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride solution (5 mL) and water (5 mL) were added under ice-cold, and stirred for 5 minutes. Ethyl acetate (10 mL) was added and extracted with ethyl acetate. The organic layer was washed with water (10 mL) and saturated brine (10 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 16 (414 mg, yield 100%).

[0983] 1H-NMR (CDCl3) δ: 8.50 (1H, s), 7.78 (1H, dd, J=8.8, 2.3Hz), 7.74 (1H, d, J=8.8Hz), 7.42 (1H, s), 7.35-7.33 (2H, m), 4.16-4.15 (2H, m), 4.01-3.99 (2H, m), 2.20 (1H, t, J = 6.4Hz).

[0984] Step 5 Synthesis of Compound 17

[0985] Compound 16 (99.6 mg, 0.298 mmol) was dissolved in 1,4-dihydrochloric acid. To the mixture was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (124 mg, 0.60 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (19.5 mg, 0.03 mmol), and potassium carbonate (124 mg, 0.60 mmol), and stirred at 100°C for 4 hours. Ethyl acetate (10 mL) and water (5 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (5 mL) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, ethyl acetate-methanol) to obtain compound 17 (62 mg, yield 55%).

[0986] 1H-NMR (CDCl3) δ: 8.51 (1H, s), 7.77-7.73 (2H, m), 7.56 (2H, d, J=1.9Hz), 7.43-7.40 (2H, m), 6 .68 (1H, d, J=1.9Hz), 4.13-4.11 (2H, m), 4.04 (3H, s), 3.94-3.92 (2H, m), 2.07-2.06 (1H, brm).

[0987] Synthesis of Compound I-073 in Step 6

[0988] Dissolve Compound 17 (56.4 mg, 0.149 mmol) in dimethylformamide (564 μL). Add N-bromosuccinimide (29.1 mg, 0.164 mmol) under ice-cooling and stir at room temperature for 1 hour. Add 10% sodium thiosulfate (0.2 mL), saturated sodium bicarbonate solution (0.2 mL), and ethyl acetate (5 mL). After stirring for 5 minutes, extract with ethyl acetate. Wash the organic layer with water (5 mL) and saturated brine (5 mL), and then dry over anhydrous sodium sulfate. Distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (hexane-ethyl acetate, ethyl acetate-methanol) to obtain Compound I-073 (9.8 mg, yield 14%).

[0989] 1H-NMR (CDCl3) δ: 8.50 (1H, s), 7.81 (1H, d, J = 9.2 Hz), 7.77 (1H, dd, J = 8.8, 2.4 Hz), 7.69 (1H, br s), 7.55 (1H, s), 7.48 - 7.45 (2H, m), 4.12 - 4.11 (2H, m), 3.91 - 3.89 (2H, m), 3.84 (3H, s), 2.14 (1H, t, J = 6.3 Hz).

[0990] Synthesis of Compound I-082 in Example 6

[0991]

[0992] Synthesis of Compound 19 in Step 1

[0993] Dropwise add tetrahydropyranyl ethylene glycol (3.87 mL, 28.5 mmol) to a solution of sodium hydride (1.14 g, 28.5 mmol) in THF (50 mL) under ice-cooling and stir for 10 minutes. Dropwise add a solution of Compound 18 (5.0 g, 25.9 mmol) in THF (25 mL) under ice-cooling and stir at room temperature for 1 hour. Add saturated ammonium chloride aqueous solution (20 mL) and water (10 mL), and stir for 5 minutes. Add ethyl acetate (10 mL) and extract with ethyl acetate. Wash the organic layer with water (20 mL) and saturated brine (20 mL), and then dry over anhydrous sodium sulfate. Distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 19 (6.62 g, yield 84%).

[0994] 1H-NMR (CDCl3) δ: 8.96 (1H, d, J = 2.5Hz), 8.45 (1H, d, J = 2.5Hz), 4.73-4.70 (3H, m), 4.13- 4.10 (1H, m), 3.90-3.87 (2H, m), 3.55-3.52 (1H, m), 1.83-1.71 (2H, m), 1.63-1.62 (2H, br m), 1.54-1.52(2H, br m).

[0995] Step 2 Synthesis of Compound 20

[0996] Compound 19 (3.13 g, 10.3 mmol) was dissolved in distilled water under nitrogen atmosphere. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.30 g, 20.7 mmol), XPhosPd G3 (438 mg, 0.52 mmol), potassium carbonate (4.29 g, 31.0 mmol) were added to the mixture, and the mixture was stirred at 100°C for 2 hours. After cooling, water (10 mL) and ethyl acetate (20 mL) were added, and the mixture was filtered through Celite (registered trademark) and extracted with ethyl acetate. The organic layer was washed with water (20 mL) and saturated brine (20 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 20 (3.6 g, yield 90%).

[0997] 1H-NMR (CDCl3) δ: 9.12 (1H, d, J = 2.8Hz), 8.38 (1H, d, J = 2.8Hz), 7.55 (1H, d, J = 1.8Hz), 6.38 (1H, d, J = 1.8Hz), 4 .69-4.67 (2H, m), 4.61 (1H, t, J = 3.4Hz), 4.08-4.02 (1H, m), 3.84 (3H, s), 3.76-3.74 (2H, m), 3.47-3.44 (1H, br m), 1.73-1.69(3H, m), 1.53-1.51(3H, br m).

[0998] Step 3 Synthesis of Compound 21

[0999] Compound 20 (2.02 g, 5.79 mmol) was dissolved in dimethylformamide (20 mL) under a nitrogen atmosphere. N-Bromosuccinimide (1.13 g, 6.37 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 10% Sodium thiosulfate (20 mL), saturated sodium bicarbonate solution (10 mL), and ethyl acetate (20 mL) were added, and after stirring for 5 minutes, extraction was performed with ethyl acetate. The organic layer was washed with water (20 mL) and saturated brine (10 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 21 (2.52 g).

[1000] Synthesis of Compound 22 in Step 4

[1001] Compound 21 was dissolved in ethanol (50 mL) and water (13 mL) under a nitrogen atmosphere. Iron (1.32 g, 23.6 mmol) and ammonium chloride (3.15 g, 59.0 mmol) were added, and the mixture was stirred at 70 °C for 1 hour. After cooling, water (20 mL) was added, and after filtration through Celite (registered trademark), extraction was performed with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate, ethyl acetate - methanol) to obtain Compound 22 (1.9 g, yield 80%).

[1002] 1H-NMR (CDCl3) δ: 7.76 (1H, d, J = 2.9 Hz), 7.50 (1H, s), 7.06 (1H, d, J = 2.9 Hz), 4.57 (1H, t, J = 3.3 Hz), 4.50 - 4.47 (1H, br m), 4.41 - 4.38 (1H, br m), 3.98 - 3.95 (1H, br m), 3.78 (3H, s), 3.72 - 3.69 (2H, br m), 3.44 - 3.42 (1H, br m), 1.76 - 1.68 (3H, br m), 1.52 - 1.47 (5H, br m).

[1003] Synthesis of Compound I-082 in Step 5

[1004] Compound 22 (436 mg, 1.20 mmol) was dissolved in 2-propanol (381 μL) under a nitrogen atmosphere, 2,3-difluoro-5-trifluoromethylpyridine (13.3 μL, 0.11 mmol) and p-toluenesulfonic acid monohydrate (25.4 mg, 0.13 mmol) were added, and the mixture was stirred at 100 °C for 18 hours. After cooling, saturated sodium bicarbonate solution (0.5 mL) and water (0.5 mL) were added, and the mixture was stirred for 5 minutes. The precipitated solid was collected by filtration and dried to obtain Compound I-082 (9.2 mg, yield 22%).

[1005] 1H-NMR (CDCl3) δ: 8.49 (1H, d, J = 2.8 Hz), 8.26 (1H, s), 8.11 (1H, d, J = 2.8 Hz), 7.56 (1H, s), 7.51 (1H, dd, J = 10.8, 1.9 Hz), 6.89 (1H, d, J = 3.3 Hz), 4.54 - 4.52 (2H, m), 3.94 - 3.92 (2H, m), 3.82 (3H, s), 3.188 (1H, t, J = 5.5 Hz).

[1006] Example 7 Synthesis of Compound I-064

[1007]

[1008] Step 1 Synthesis of Compound I-064

[1009] Compound 5 (25 mg, 0.080 mmol) was dissolved in 2-propanol (0.25 mL), 2,6-dichlorobenzothiazole (18 mg, 0.088 mmol) and p-toluenesulfonic acid monohydrate (7.6 mg, 0.040 mmol) were added, and the mixture was stirred at 80 °C for 1.5 hours. Then it was further stirred at 100 °C for 2.5 hours. After cooling, water (0.25 mL) was added, and the mixture was stirred for 5 minutes. The precipitated solid was washed with 2-propanol and hexane, collected by filtration and dried to obtain Compound I-064 (23 mg, yield 61%).

[1010] 1H-NMR (DMSO-D6) δ: 3.63 - 3.69 (2H, m), 3.71 (3H, s), 4.01 - 4.07 (2H, m), 4.86 (1H, br s), 7.25 (1H, d, J = 9.1 Hz), 7.32 (1H, dd, J = 8.6, 2.2 Hz), 7.53 (1H, d, J = 8.6 Hz), 7.63 (1H, d, J = 2.8 Hz), 7.64 (1H, s), 7.89 (1H, dd, J = 9.1, 2.8 Hz), 7.93 (1H, d, J = 2.2 Hz), 10.56 (1H, s).

[1011] Synthesis of Compound I-031 in Example 8

[1012]

[1013] Step 1 Synthesis of Compound 24

[1014] Using Compound 23 and ethyl bromoacetate, the operation was carried out in the same manner as in Step 1 of Example 1 to synthesize Compound 24 (8.9 g, yield 100%).

[1015] 1 H-NMR(CDCl3)δ: 1.31(3H, t, J = 7.2Hz), 4.29(2H, q, J = 7.2Hz), 4.82(2H, s), 6.83(1H, d, J = 9.2Hz), 8.19(1H, dd, J = 9.2, 2.8Hz), 8.50(1H, d, J = 2.8Hz).

[1016] Step 2 Synthesis of Compound 25

[1017] Using Compound 24, the operation was carried out in the same manner as in Step 4 of Example 1 to synthesize Compound 25 (8.9 g, yield 99%).

[1018] 1 H-NMR(CDCl3)δ: 1.29(3H, t, J = 7.2Hz), 3.52(2H, brs), 4.26(2H, q, J = 7.2Hz), 4.58(2H, s), 6.56(1H, dd, J = 8.7, 2.8Hz), 6.77(1H, d, J = 8.7Hz), 6.92(1H, d, J = 2.8Hz).

[1019] Step 3 Synthesis of Compound 26

[1020] Using Compound 25, the operation was carried out in the same manner as in Step 3 of Example 1 to synthesize Compound 26 (7.5 g, yield 99%).

[1021] 1 H-NMR(CDCl3)2.27(1H, brs), 3.51(2H, brs), 3.92(2H, t, J = 4.3Hz), 4.06(2H, dd, J = 4.8, 4.3Hz), 6.59(1H, dd, J = 8.7, 2.8Hz), 6.80(1H, d, J = 8.7Hz), 6.91(1H, d, J = 2.8Hz).

[1022] Step 4 Synthesis of Compound 27

[1023] Using Compound 26, the same operation as in Step 1 of Example 2 was carried out to synthesize Compound 27 (3.5 g, yield 92%).

[1024] 1 H-NMR (CDCl3) 2.22 (1H, t, J = 6.5Hz), 3.97-4.01 (2H, m), 4.15 (2H, t, J = 4.5Hz), 6.72 (1H, brs), 6.95 (1H, d , J=8.9Hz), 7.46 (1H, dd, J=10.9, 1.9Hz), 7.52 (1H, dd, J=8.8, 2.7Hz), 7.94 (1H, d, J=2.7Hz), 8.28 (1H, s).

[1025] Step 5 Synthesis of Compound I-031

[1026] Compound 27 (20 mg, 0.051 mmol) was dissolved in distilled water under nitrogen atmosphere. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-4-carbonitrile (24 mg, 0.101 mmol), 2 mol / L sodium carbonate aqueous solution (76 μL, 0.152 mmol), PdCl2(dtbpf) (3.3 mg, 5.1 μmol) were added, and stirred at 80°C for 5 hours. After cooling, water was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-031 (11.4 mg, yield 53%).

[1027] 1 H-NMR (CDCl3) δ: 2.18 (1H, t, J=6.3Hz), 3.89 (3H, s), 3.94 (2H, dd, J=9.8, 5.1Hz), 4.17 (2H, t, J=4.3Hz), 6.86 (1H, s), 7.09 ( 1H, d, J=9.0Hz), 7.48 (1H, dd, J=10.7, 1.8Hz), 7.68 (1H, dd, J=8.9, 2.8Hz), 7.75 (1H, d, J=2.8Hz), 7.87 (1H, s), 8.25 (1H, s).

[1028] Example 9 Synthesis of Compound I-058

[1029]

[1030] Step 1 Synthesis of Compound 28

[1031] Under a nitrogen atmosphere, compound I-006 (20 mg, 0.042 mmol) was dissolved in di ane (300 μL), trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane (18.9 mg, 0.084 mmol), 2 mol / L aqueous sodium carbonate solution (63 μL, 0.126 mmol), and PdCl2(dtbpf) (2.7 mg, 4.2 μmol) were added, and the mixture was stirred at 80 °C for 3.5 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 28 (8.1 mg, yield 39%).

[1032] 1 1H-NMR (CDCl3) δ: 0.11 (9H, s), 2.25 (1H, t, J = 6.3 Hz), 3.80 (3H, s), 3.79 - 3.91 (2H, m), 4.11 (2H, t, J = 4.9 Hz), 6.78 (1H, s), 7.04 (1H, d, J = 8.9 Hz), 7.46 (1H, d, J = 10.9 Hz), 7.63 (1H, d, J = 2.8 Hz), 7.66 (1H, s), 7.73 (1H, dd, J = 8.9, 2.8 Hz), 8.26 (1H, s).

[1033] Step 2 Synthesis of compound I-058

[1034] Compound 28 (8.1 mg, 0.042 mmol) was dissolved in tetrahydrofuran (100 μL), 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (32 μL, 0.021 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound I-058 (4.1 mg, yield 60%).

[1035] 1 1H-NMR (CDCl3) δ: 2.13 (1H, t, J = 6.2 Hz), 2.98 (1H, s), 3.79 (3H, s), 3.85 - 3.90 (2H, m), 4.11 (2H, t, J = 4.3 Hz), 6.81 (1H, s), 7.06 (1H, d, J = 8.9 Hz), 7.47 (1H, d, J = 10.7 Hz), 7.61 (1H, d, J = 1.6 Hz), 7.69 (1H, s), 7.74 (1H, t, J = 4.5 Hz), 8.25 (1H, s).

[1036] Example 10 Synthesis of compound I-054

[1037]

[1038] Synthesis of Compound I-054 in Step 1

[1039] Under a nitrogen atmosphere, dissolve Compound I-006 (30 mg, 0.063 mmol) in hexane (600 μL), add 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (21 mg, 0.126 mmol), 2 mol / L aqueous sodium carbonate solution (95 μL, 0.189 mmol), PdCl2(dtbpf) (4.1 mg, 6.3 μmol), and stir at 80 °C for 6.5 hours. After cooling, add water and extract with chloroform. Dry the organic layer over anhydrous magnesium sulfate. Distill off the solvent under reduced pressure, and purify the resulting residue by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound I-054 (18.1 mg, yield 66%).

[1040] 1 1H-NMR (CDCl3) δ: 1.90 (3H, s), 1.92 (1H, t, J = 6.0 Hz), 3.70 (3H, s), 3.76 - 3.81 (2H, m), 4.02 - 4.09 (2H, m), 4.76 (1H, t, J = 1.6 Hz), 4.84 (1H, s), 6.80 (1H, s), 7.03 (1H, d, J = 8.9 Hz), 7.46 (1H, dd, J = 10.8, 2.0 Hz), 7.53 (1H, d, J = 2.8 Hz), 7.59 (1H, s), 7.75 (1H, dd, J = 8.9, 2.8 Hz), 8.25 (1H, s).

[1041] Synthesis of Compound I-056 in Example 11

[1042]

[1043] Synthesis of Compound I-056 in Step 1

[1044] Dissolve Compound I-054 (10 mg, 0.023 mmol) in tetrahydrofuran (1 mL), add 5% palladium on carbon (50% wet) (5 mg, 2.3 μmol), and stir at room temperature for 5 hours under a hydrogen atmosphere. After filtering through Celite (registered trademark), distill off the solvent under reduced pressure, and purify the resulting residue by silica gel column chromatography (chloroform - methanol) to obtain Compound I-056 (9.8 mg, yield 97%).

[1045] 1H-NMR (CDCl3) δ: 1.09 (3H, d, J = 6.9Hz), 1.19 (3H, d, J = 6.9Hz), 1.81 (1H, t, J=6.4Hz), 2.68-2.75(1H, m), 3.68(3H, s), 3.76-3.82(2H, m), 3.98-4.11(2 H, m), 6.82 (1H, s), 7.05 (1H, d, J = 8.8Hz), 7.44 (1H, s), 7.46 (1H, dd, J = 10. 8, 1.6Hz), 7.55 (1H, d, J = 2.8Hz), 7.68 (1H, dd, J = 8.8, 2.8Hz), 8.23 (1H, s).

[1046] Example 12 Synthesis of Compound I-065

[1047]

[1048] Step 1 Synthesis of Compound I-065

[1049] Compound 27 (50 mg, 0.127 mmol) was dissolved in distilled water under nitrogen atmosphere. alkane (1.5mL), bis(pinacolato)diboron (96mg, 0.380mmol), potassium acetate (62mg, 0.633mmol), PdCl2(dppf) (46.3mg, 63μmol) were added, and stirred at 100°C overnight. After cooling, 5-bromo-1-methyl-1H-imidazole-4-carbonitrile (70.6mg, 0.380mmol) and 2mol / L sodium carbonate aqueous solution (380μL, 0.759mmol) were added, and stirred at 100°C for 7 hours. After cooling, water was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC (acetonitrile-water) to obtain compound I-065 (8.9mg, yield 17%).

[1050] 1 H-NMR (DMSO-D6) δ: 3.60 (3H, s), 3.65-3.70 (2H, m), 4.06 (2H, t, J = 4.9Hz), 4.86 (1H, t, J = 5.3Hz), 7.23 (1H, d, J = 9.0Hz), 7.79 (1H, d, J = 2.7Hz), 7.92 (1H, dd, J = 9.0, 2.7Hz), 7.97 (1H, s), 7.98 (1H, dd, J = 11.6, 2.0Hz), 8.30 (1H, s), 9.52 (1H, s).

[1051] Example 13 Synthesis of Compound I-108

[1052]

[1053] Synthesis of Compound 30 in Step 1

[1054] Using Compound 29 and ethyl bromoacetate, Compound 30 (2.6 g, yield 96%) was synthesized in the same manner as in Step 1 of Example 1.

[1055] 1 H-NMR (CDCl3) δ: 1.32 (3H, t, J = 7.2 Hz), 4.31 (2H, q, J = 7.2 Hz), 4.79 (2H, s), 6.64 (1H, d, J = 11.9 Hz), 8.39 (1H, d, J = 8.0 Hz).

[1056] Synthesis of Compound 31 in Step 2

[1057] Using Compound 30, Compound 31 (2.2 g, yield 95%) was synthesized in the same manner as in Step 4 of Example 1.

[1058] 1 H-NMR (CDCl3) δ: 1.30 (3H, t, J = 7.2 Hz), 3.55 (2H, brs), 4.27 (2H, q, J = 7.2 Hz), 4.58 (2H, s), 6.68 (1H, d, J = 11.8 Hz), 7.00 (1H, d, J = 9.2 Hz).

[1059] Synthesis of Compound 32 in Step 3

[1060] Using Compound 31, Compound 32 (1.9 g, yield 100%) was synthesized in the same manner as in Step 3 of Example 1.

[1061] 1 H-NMR (CDCl3) δ: 2.21 (1H, t, J = 6.3 Hz), 3.53 (2H, brs), 3.91 - 3.97 (2H, m), 4.04 (2H, t, J = 4.5 Hz), 6.71 (1H, d, J = 11.9 Hz), 7.00 (1H, d, J = 9.3 Hz).

[1062] Synthesis of Compound 33 in Step 4

[1063] Using Compound 32, Compound 33 (153 mg, yield 82%) was synthesized in the same manner as in Step 1 of Example 2.

[1064] 11H-NMR (CDCl3) δ: 2.18 (1H, t, J = 6.5 Hz), 3.98 - 4.02 (2H, m), 4.12 (2H, t, J = 4.4 Hz), 6.80 (1H, s), 6.83 (1H, s), 7.50 (1H, dd, J = 10.7, 1.9 Hz), 8.32 (1H, s), 8.66 (1H, d, J = 8.7 Hz).

[1065] Synthesis of Compound I-108 in Step 5

[1066] Using Compound 33, the operation was carried out in the same manner as in Step 5 of Example 8 to synthesize Compound I-108 (38 mg, yield 72%).

[1067] 1 1H-NMR (CDCl3) δ: 2.30 (1H, t, J = 6.3 Hz), 3.90 (3H, s), 3.94 - 3.98 (2H, m), 4.16 (2H, t, J = 4.3 Hz), 6.95 (1H, d, J = 12.4 Hz), 6.95 (1H, brs), 7.52 (1H, dd, J = 10.5, 1.9 Hz), 7.87 (1H, s), 8.27 (1H, d, J = 1.9 Hz), 8.48 (1H, d, J = 8.8 Hz).

[1068] Synthesis of Compound I-109 in Example 14

[1069]

[1070] Synthesis of Compound 35 in Step 1

[1071] Under a nitrogen atmosphere, THF (5 mL) was added to NaH (86 mg, 2.167 mmol), and 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (293 μL, 2.162 mmol) was added at 0 °C, and the mixture was stirred at the same temperature for 10 minutes. Compound 34 (500 mg, 1.965 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 35 (596 mg, 80%).

[1072] 11H-NMR (CDCl3) δ: 1.48 - 1.66 (4H, m), 1.70 - 1.86 (2H, m), 3.54 - 3.57 (1H, m), 3.86 - 3.93 (2H, m), 4.10 - 4.16 (1H, m), 4.31 - 4.34 (2H, m), 4.75 (1H, t, J = 3.3 Hz), 7.11 (1H, s), 8.27 (1H, s).

[1073] Synthesis of Compound 36 in Step 2

[1074] Using Compound 35, the operation was carried out in the same manner as in Step 4 of Example 1 to synthesize Compound 36 (525 mg, yield 80%).

[1075] 1 1H-NMR (CDCl3) δ: 1.45 - 1.68 (4H, m), 1.70 - 1.80 (1H, m), 1.80 - 1.90 (1H, m), 3.50 - 3.57 (1H, m), 3.78 - 3.85 (3H, m), 3.89 - 3.96 (1H, m), 4.01 - 4.08 (1H, m), 4.12 (2H, t, J = 5.1 Hz), 4.76 (1H, t, J = 3.5 Hz), 6.95 (1H, s), 6.99 (1H, s).

[1076] Synthesis of Compound 37 in Step 3

[1077] Using Compound 36, the operation was carried out in the same manner as in Step 1 of Example 5 to synthesize Compound 37 (140 mg, yield 48%).

[1078] 1 1H-NMR (CDCl3) δ: 2.18 (1H, t, J = 6.5 Hz), 3.98 - 4.02 (2H, m), 4.12 (2H, t, J = 4.4 Hz), 6.82 (1H, d, J = 12.2 Hz), 6.82 (1H, s), 7.50 (1H, dd, J = 10.7, 1.9 Hz), 8.32 (1H, s), 8.66 (1H, d, J = 8.7 Hz).

[1079] Synthesis of Compound 38 in Step 4

[1080] Using Compound 37, the operation was carried out in the same manner as in Step 5 of Example 8 to synthesize Compound 38 (15.2 mg, yield 32%).

[1081] 1H-NMR (CDCl3) δ: 1.47 - 1.60 (4H, m), 1.65 - 1.80 (2H, m), 3.44 - 3.50 (1H, m), 3.69 - 3.77 (2H, m), 3.86 (3H, s), 3.99 - 4.04 (1H, m), 4.19 - 4.23 (2H, m), 4.59 (1H, t, J = 3.5 Hz), 7.21 (1H, s), 7.52 (1H, dd, J = 10.5, 1.9 Hz), 7.84 (1H, s), 8.29 (1H, s), 8.58 (1H, s).

[1082] Synthesis of Compound I-109 in Step 5

[1083] Dissolve Compound 38 (14.5 mg, 0.027 mmol) in methanol (1 mL), add p-toluenesulfonic acid monohydrate (1.0 mg, 5.4 μmol), and stir overnight at 40 °C. Add saturated sodium bicarbonate solution, extract with chloroform, dry the organic layer over anhydrous magnesium sulfate. Distill off the solvent under reduced pressure, and purify the resulting residue by silica gel column chromatography (chloroform - methanol) to obtain Compound I-109 (10.7 mg, yield 87%).

[1084] 1 H-NMR (CDCl3) δ: 2.31 (1H, t, J = 6.3 Hz), 3.92 (3H, s), 3.94 - 3.98 (2H, m), 4.17 (2H, t, J = 4.3 Hz), 7.18 (1H, s), 7.29 (1H, dd, J = 13.6, 2.2 Hz), 7.53 (1H, dd, J = 11.2, 2.2 Hz), 7.87 (1H, s), 8.27 (1H, s), 8.60 (1H, s).

[1085] Synthesis of Compound 40 in Reference Example 1

[1086]

[1087] Synthesis of Compound 40 in Step 1

[1088] Dissolve Compound 39 (500 mg, 2.79 mmol) in dichloro - Alkane (10 mL), bis(pinacolato)diboron (2.13 g, 8.38 mmol), potassium acetate (1.37 g, 0.633 mmol), and PdCl2(dppf) (204 mg, 0.279 mmol) were added and stirred at 100 °C for 2 hours. After cooling, the mixture was filtered through Celite (registered trademark) to remove insoluble substances. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane - ethyl acetate) to obtain Compound 40 (294 mg, yield 47%).

[1089] 1 1H-NMR (CDCl3) δ: 1.35 (12H, s), 3.98 (3H, s), 7.29 (1H, d, J = 4.4 Hz).

[1090] Synthesis of Compound I-127 in Example 15

[1091]

[1092] Step 1 Synthesis of Compound 41

[1093] Using Compound 19 obtained in Step 1 of Example 6, the same operations as in Step 4 of Example 1 were carried out to synthesize Compound 41 (324 mg, yield 60%).

[1094] 1 1H-NMR (CDCl3) δ: 1.48 - 1.66 (4H, m), 1.68 - 1.77 (1H, m), 1.78 - 1.89 (1H, m), 3.39 (2H, brs), 3.48 - 3.55 (1H, m), 3.79 - 3.86 (1H, m), 3.89 - 3.96 (1H, m), 4.01 - 4.07 (1H, m), 4.45 - 4.48 (2H, m), 4.75 (1H, t, J = 3.4 Hz), 7.11 (1H, d, J = 2.6 Hz), 7.53 (1H, d, J = 2.6 Hz).

[1095] Step 2 Synthesis of Compound 42

[1096] Using Compound 41, the same operations as in Step 1 of Example 2 were carried out to synthesize Compound 42 (133 mg, yield 32%).

[1097] 11H-NMR (CDCl3) δ: 2.95 (1H, t, J = 6.0 Hz), 3.98 - 4.02 (2H, m), 4.54 (2H, t, J = 4.5 Hz), 6.70 (1H, s), 7.50 (1H, dd, J = 10.9, 1.8 Hz), 8.21 (1H, d, J = 2.4 Hz), 8.24 (1H, d, J = 2.4 Hz), 8.288 (1H, s).

[1098] Synthesis of Compound 43 in Step 3

[1099] Dissolve Compound 42 (125 mg, 0.355 mmol) in THF (2.5 mL), add 3,4-dihydro-2H-pyran (49 μL, 0.533 mmol) and p-toluenesulfonic acid monohydrate (3.33 mg, 0.018 mmol), and stir at room temperature for 19 hours. Further add 3,4-dihydro-2H-pyran (49 μL, 0.533 mmol) and stir at room temperature for 27 hours. Add saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the organic layer with anhydrous magnesium sulfate. Distill off the solvent under reduced pressure and purify the obtained residue by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 43 (155 mg, yield 100%).

[1100] 1 1H-NMR (CDCl3) δ: 1.48 - 1.68 (4H, m), 1.70 - 1.79 (1H, m), 1.80 - 1.90 (1H, m), 3.50 - 3.57 (1H, m), 3.84 - 3.89 (1H, m), 3.91 - 3.97 (1H, m), 4.06 - 4.13 (1H, m), 4.55 - 4.59 (2H, m), 4.77 (1H, t, J = 3.5 Hz), 6.67 (1H, s), 7.49 (1H, dd, J = 10.7, 1.8 Hz), 8.18 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 2.4 Hz), 8.27 (1H, s).

[1101] Synthesis of Compound I-127 in Step 4

[1102] Dissolve Compound 43 (50 mg, 0.115 mmol) in dichloro - Alkane (0.5 mL), compound 40 (51.9 mg, 0.229 mmol), 2 mol / L aqueous potassium carbonate solution (172 μL, 0.344 mmol) and XPhos Pd G3 (4.88 mg, 5.74 mmol) were added, and the mixture was stirred at 100 °C for 3.3 hours. After cooling, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate). The obtained residue was dissolved in MeOH (1 mL), p-toluenesulfonic acid monohydrate (3.96 mg, 0.021 mmol) was added, and the mixture was stirred at 40 °C for 16 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound I-127 (10.4 mg, yield 22%).

[1103] 1 1H-NMR (CDCl3) δ: 1.91 (3H, s), 3.02 (1H, t, J = 5.8 Hz), 3.81 (3H, s), 3.92 - 3.96 (2H, m), 4.53 (2H, t, J = 4.3 Hz), 6.78 (1H, s), 7.42 (1H, d, J = 4.4 Hz), 7.51 (1H, d, J = 10.4 Hz), 8.11 (1H, d, J = 2.6 Hz), 8.25 (1H, s), 8.44 (1H, d, J = 2.6 Hz).

[1104] Synthesis of Compound 45 in Reference Example 2

[1105]

[1106] Step 1 Synthesis of Compound 45

[1107] Compound 44 (34.0 g, 182 mmol) was dissolved in dichloromethane (340 mL) and water (340 mL). Methoxyacetic acid (32.7 g, 364 mmol), silver nitrate (3.09 g, 18.2 mmol) and ammonium persulfate (83.0 g, 364 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 1 hour. Water (100 mL) and potassium carbonate (75.0 g, 545 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After adding saturated brine (100 mL), the mixture was filtered through Celite (registered trademark), and extracted with chloroform (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 45 (34.6 g, yield 82%).

[1108] 11H-NMR (CDCl3) δ: 2.66 (s, 6H), 3.53 (s, 3H), 4.58 (s, 2H).

[1109] Synthesis of Compound 47 in Reference Example 3

[1110]

[1111] Step 1 Synthesis of Compound 46

[1112] Dissolve 5,6-dichloro-3-pyridinol (100 mg, 0.61 mmol) in DMF (1 mL) and cool to 0 °C. Add sodium hydride (60%, dispersed in liquid paraffin) (80 mg, 1.83 mmol) to the reaction solution and stir at 0 °C for a further 30 minutes. Moreover, add dibromodifluoromethane (384 mg, 1.83 mmol) and heat and stir in a sealed container at 60 °C for 1 hour. After cooling, quench with saturated aqueous ammonium chloride solution and extract with ethyl acetate. Wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. Distill off the solvent under reduced pressure and purify the resulting residue by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 46 (125.6 mg, yield 70%).

[1113] 1H-NMR (CDCl3) δ: 7.74 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H).

[1114] Step 2 Synthesis of Compound 47

[1115] Dissolve Compound 46 (116 mg, 0.395 mmol) in dichloromethane (1.2 mL) and cool to -78 °C. Add silver tetrafluoroborate (154 mg, 0.791 mmol) to the reaction solution and warm to room temperature. After stirring for 1 hour, allow to stand overnight as it is. Filter the reaction solution through Celite (registered trademark) to remove insoluble matters. Distill off the solvent of the filtrate under reduced pressure and purify the resulting residue by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 47 (68 mg, yield 74%).

[1116] 1H-NMR (CDCl3) δ: 7.71 - 7.72 (m, 1H), 8.29 (d, J = 1.6 Hz, 1H).

[1117] Synthesis of Compound I-200 in Example 16

[1118]

[1119] Step 1 Synthesis of Compound 49

[1120] Compound 48 (25.0 g, 193 mmol) was dissolved in N,N-dimethylformamide (125 mL), cesium carbonate (82.0 g, 251 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (50.8 g, 212 mmol) were added, and the mixture was stirred at 80 °C for 1 hour. After cooling, water was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 49 (54.1 g, yield 97%).

[1121] 1 1H-NMR (CDCl3) δ: 0.09 (s, 6H), 0.90 (s, 9H), 3.96 - 3.98 (m, 2H), 4.07 - 4.09 (m, 2H), 7.21 - 7.22 (m, 2H), 8.06 - 8.07 (m, 1H).

[1122] Step 2: Synthesis of Compound 50

[1123] Compound 49 (54.0 g, 188 mmol) and triisopropyl borate (70.6 g, 375 mmol) were dissolved in THF (540 mL), and then 2 mol / L lithium diisopropylamide (tetrahydrofuran / heptane / ethylbenzene solution, 122 mL, 244 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 30 minutes. Then, after stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added, and after the solid precipitated, filtration was carried out to obtain Compound 50 (35.6 g, yield 57%).

[1124] 1 1H-NMR (CDCl3) δ: 0.11 (s, 6H), 0.91 (s, 9H), 3.98 - 4.00 (m, 2H), 4.21 - 4.23 (m, 2H), 5.94 (br s, 2H), 7.68 (s, 1H), 8.08 (s, 1H).

[1125] Step 3: Synthesis of Compound 51

[1126] To Compound 45 (19.5 g, 84.0 mmol), Compound 50 (30.8 g, 93.0 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (5.50 g, 8.44 mmol) and potassium carbonate (23.3 g, 169 mmol), 1,4-di Alkane (195 mL) - water (39.0 mL), stirred at 80 °C for 1 hour. After cooling, water was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 51 (27.3 g, yield 74%).

[1127] 1 H-NMR (CDCl3) δ: -0.10 (s, 6H), 0.80 (s, 9H), 2.28 (s, 6H), 3.58 (s, 3H), 3.80 (t, J = 4.6 Hz, 2H), 4.11 (t, J = 4.8 Hz, 2H), 4.67 (s, 2H), 7.07 (s, 1H), 8.19 (s, 1H).

[1128] Step 4 Synthesis of Compound 62

[1129] Under a nitrogen atmosphere, Compound 51 (10.00 g, 22.8 mmol), xantphos (2.64 g, 4.57 mmol), and cesium carbonate (29.8 g, 91 mmol) were suspended in di alkane (150 mL). Diphenylmethanimine (4.60 ml, 27.4 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2.09 g, 2.28 mmol) were added, and the mixture was stirred at 100 °C for 8 hours and 25 minutes, and then left standing at room temperature for 14 hours and 40 minutes. Xantphos (2.64 g, 4.57 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2.09 g, 2.28 mmol) were added, and the mixture was further stirred at 100 °C for 8 hours and 45 minutes. The insoluble matter was filtered through Celite (registered trademark), and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 62 (10.34 g, yield 78%).

[1130] 1 H-NMR (DMSO-d6) δ: -0.21 (s, 6H), 0.73 (s, 9H), 1.91 (s, 6H), 3.37 (s, 3H), 3.70 - 3.71 (m, 2H), 4.04 - 4.05 (m, 2H), 4.45 (s, 2H), 6.43 (s, 1H), 7.10 - 7.17 (m, 2H), 7.30 - 7.36 (m, 3H), 7.44 - 7.60 (m, 3H), 7.68 - 7.70 (m, 2H), 8.20 (s, 1H).

[1131] Step 5 Synthesis of Compound 63

[1132] Compound 62 (10.30 g, 17.7 mmol) was suspended in ethanol (154 mL) under a nitrogen atmosphere. Triethylamine (5.14 mL, 37.1 mmol) and hydroxylamine hydrochloride (2.46 g, 35.3 mmol) were added, and the mixture was stirred at 100 °C for 1 hour and 10 minutes. After cooling, ethyl acetate (300 mL) and water (200 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound 63 (6.58 g, yield 89%).

[1133] 1 H-NMR (CDCl3) δ: -0.14 (s, 6H), 0.80 (s, 9H), 2.30 (s, 6H), 3.57 (s, 3H), 3.74 (t, J = 4.8 Hz, 2H), 3.95 (t, J = 4.8 Hz, 2H), 4.27 (s, 2H), 4.65 (s, 2H), 6.28 (s, 1H), 7.89 (s, 1H).

[1134] Step 6 Synthesis of Compound 52

[1135] Compound 63 (600 mg, 1.43 mmol) was dissolved in methanol (6 mL), trifluoroacetic acid (817 mg, 7.17 mmol) was added, and the mixture was stirred at 60 °C for 2 hours. After cooling, the solvent was distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (ethyl acetate - methanol), and solidified from a mixed solvent system of ethyl acetate - hexane to obtain compound 52 (382 mg, yield 88%).

[1136] 1 H-NMR (CDCl3) δ: 1.55 - 1.60 (m, 1H), 2.31 (s, 6H), 3.59 (s, 3H), 3.72 - 3.76 (m, 2H), 3.99 (t, J = 4.4 Hz, 2H), 4.31 (brs, 2H), 4.67 (s, 2H), 6.30 (s, 1H), 7.90 (s, 1H).

[1137] Step 7 Synthesis of Compound I-200

[1138] To compound 52 (135 mg, 0.44 mmol), compound 47 (103 mg, 0.44 mmol), bis(dibenzylideneacetone)palladium (25.5 mg, 0.044 mmol), BINAP (55.2 mg, 0.089 mmol) and cesium carbonate (289 mg, 0.89 mmol) were added, and then toluene (3.4 mL) was added. The mixture was heated with stirring at 100 °C for 4 hours. After cooling, the reaction solution was filtered through Celite (registered trademark), and rinsed with ethyl acetate. The solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound I-200 (43.3 mg, yield 20%).

[1139] 1 1H-NMR (CDCl3) δ: 1.59 (t, J = 6.4 Hz, 1H), 2.35 (s, 6H), 3.61 (s, 3H), 3.79 - 3.83 (m, 2H), 4.12 (t, J = 4.8 Hz, 2H), 4.70 (s, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.11 (s, 1H), 8.24 (s, 1H).

[1140] Synthesis of Compound 56 in Reference Example 4

[1141]

[1142] Step 1 Synthesis of Compound 56

[1143] To compound 45 (30 g, 130 mmol), bis(pinacolato)diboron (65.9 g, 260 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (9.5 g, 13 mmol) and potassium acetate (31.9 g, 325 mmol) were added, and then di ane (300 mL) was added. The mixture was stirred at 100 °C for 8 hours. After cooling, it was filtered through Celite (registered trademark) to remove insoluble matters, and then the solvent was distilled off under reduced pressure. Hexane was added to the resulting residue, and after filtering off the precipitated insoluble matters again and removing them, the solvent was distilled off under reduced pressure. The resulting residue was roughly purified by silica gel column chromatography (hexane - ethyl acetate). The obtained roughly purified product was purified by silica gel column chromatography (chloroform - methanol) to obtain compound 56 (26.1 g, yield 72%).

[1144] 1H-NMR (CDCl3) δ: 1.40 (s, 12H), 2.61 (s, 6H), 3.52 (s, 3H), 4.61 (s, 2H).

[1145] Synthesis of Compound I-247 in Example 17

[1146]

[1147] Synthesis of Compound 55 in Step 1

[1148] Suspend Compound 53 (10 g, 36.6 mmol), potassium carbonate (7.58 g, 54.9 mmol), sodium iodide (5.48 g, 36.6 mmol), and Compound 54 (10.5 g, 43.9 mmol) in N,N-dimethylformamide (100 mL), stir at 60 °C for 2 hours, and then stir at 70 °C for 3 hours. After cooling, add water and ethyl acetate, and extract with ethyl acetate. Wash the organic layer with water and saturated brine, and then dry over anhydrous sodium sulfate. Distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 55 (15.35 g, yield 97%).

[1149] 1 1H-NMR (CDCl3) δ: 0.11 (s, 6H), 0.90 (s, 9H), 4.02 (t, J = 4.8 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H), 7.04 (d, J = 9.2 Hz, 1H).

[1150] Synthesis of Compound 57 in Step 2

[1151] Suspend Compound 55 (12.7 g, 29.4 mmol), Compound 56 (12.27 g, 44.1 mmol), PdCl2(dtbpf) (1.92 g, 2.94 mmol), and potassium carbonate (8.13 g, 58.8 mmol) in di ane (127 mL) and water (25.4 mL), and stir at 100 °C for 6 hours under a nitrogen atmosphere. Add ethyl acetate and water, and extract with ethyl acetate. Wash with saturated brine, and then dry over anhydrous magnesium sulfate. Distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 57 (8.92 g, yield 67%).

[1152] 1 1H-NMR (CDCl3) δ: -0.07 (s, 6H), 0.81 (s, 9H), 2.28 (s, 6H), 3.55 (s, 3H), 3.83 (t, J = 4.6 Hz, 2H), 4.07 (t, J = 4.6 Hz, 2H), 4.67 (s, 2H), 7.34 (d, J = 9.2 Hz, 1H).

[1153] Synthesis of Compound 58 in Step 3

[1154] Compound 57 (500 mg, 1.10 mmol) was dissolved in dichloromethane (10 mL) under a nitrogen atmosphere, and diphenylmethanimine (0.22 mL, 1.32 mmol), xantphos (63.4 mg, 0.110 mmol), cesium carbonate (1.07 g, 3.29 mmol), and palladium acetate (49.2 mg, 0.219 mmol) were added. The mixture was stirred at 100 °C for 5 hours and 20 minutes, and then allowed to stand at room temperature for 12 hours and 30 minutes. Palladium acetate (49.2 mg, 0.219 mmol) and xantphos (63.4 mg, 0.110 mmol) were added, and the mixture was further stirred at 100 °C for 8 hours and 40 minutes. The insoluble material was filtered through Celite (registered trademark) and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 58 (386 mg, yield 59%).

[1155] 1 1H-NMR (CDCl3) δ: -0.11 (s, 6H), 0.80 (s, 9H), 2.04 (s, 6H), 3.52 (s, 3H), 3.75 (t, J = 4.7 Hz, 2H), 3.94 (t, J = 4.8 Hz, 2H), 4.62 (s, 2H), 7.13 (d, J = 10.8 Hz, 1H), 7.19 - 7.23 (m, 2H), 7.27 - 7.32 (m, 3H), 7.37 - 7.43 (m, 2H), 7.46 - 7.53 (m, 1H), 7.77 - 7.82 (m, 2H).

[1156] Step 4 Synthesis of Compound 59

[1157] Compound 58 (385 mg, 0.641 mmol) was dissolved in ethanol (3.9 mL) under a nitrogen atmosphere, and hydroxylamine hydrochloride (89 mg, 1.28 mmol) and triethylamine (0.187 mL, 1.35 mmol) were added. The mixture was stirred at 100 °C for 2 hours. After cooling, chloroform and water were added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 59 (141 mg, yield 51%).

[1158] 1 1H-NMR (CDCl3) δ: -0.70 (s, 6H), 0.82 (s, 9H), 2.29 (s, 6H), 3.54 (s, 3H), 3.75 (t, J = 4.8 Hz, 2H), 3.90 (t, J = 4.8 Hz, 2H), 4.37 (br s, 2H), 4.66 (s, 2H), 7.22 (d, J = 11.2 Hz, 1H).​

[1159] Synthesis of Compound 61 in Step 5

[1160] Under a nitrogen atmosphere, Compound 59 (40 mg, 0.092 mmol) and Compound 60 (26.9 mg, 0.137 mmol) were suspended in toluene (1 mL), and BINAP (11.4 mg, 0.018 mmol), cesium carbonate (90 mg, 0.275 mmol), and tris(dibenzylideneacetone)dipalladium (8.4 mg, 0.0092 mmol) were added. The mixture was stirred at 100 °C for 7 hours and 45 minutes. The insoluble matter was filtered through Celite (registered trademark) and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 61 (41.7 mg, yield 76%).

[1161] 1 H-NMR (CDCl3) δ: -0.62 (s, 6H), 0.82 (s, 9H), 2.32 (s, 6H), 2.58 (s, 3H), 3.60 (s, 3H), 3.80 (t, J = 4.6 Hz, 2H), 4.00 (t, J = 4.6 Hz, 2H), 4.69 (s, 2H), 7.34 (d, J = 11.5 Hz, 1H), 7.52 (br s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H).

[1162] Synthesis of Compound I-247 in Step 6

[1163] Under a nitrogen atmosphere, Compound 61 (39.1 mg, 0.066 mmol) was dissolved in tetrahydrofuran (0.8 mL), and 1 mol / L tetrabutylammonium fluoride - tetrahydrofuran solution (0.079 mL, 0.079 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 50 minutes. Water and ethyl acetate were added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform - methanol) to obtain Compound I-247 (25.0 mg, yield 79%).

[1164] 11H-NMR (CDCl3) δ: 1.70 (t, J = 6.0 Hz, 1H), 2.32 (s, 6H), 2.58 (s, 3H), 3.61 (s, 3H), 3.78 - 3.84 (m, 2H), 4.03 (t, J = 4.5 Hz, 2H), 4.70 (s, 2H), 7.29 (d, J = 11.6 Hz, 1H), 7.55 (brs, 1H), 7.74 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H).

[1165] Synthesis of Compound I-257 in Example 18

[1166]

[1167] Step 1 Synthesis of Compound 62

[1168] Under a nitrogen atmosphere, Compound 51 (10.00 g, 22.8 mmol), xantphos (2.64 g, 4.57 mmol), and cesium carbonate (29.8 g, 91 mmol) were suspended in dodecane (150 mL). Diphenylmethanimine (4.60 ml, 27.4 mmol) and tris(dibenzylideneacetone)dipalladium (2.09 g, 2.28 mmol) were added, and the mixture was stirred at 100 °C for 8 hours and 25 minutes, and then allowed to stand at room temperature for 14 hours and 40 minutes. Xantphos (2.64 g, 4.57 mmol) and tris(dibenzylideneacetone)dipalladium (2.09 g, 2.28 mmol) were added, and the mixture was further stirred at 100 °C for 8 hours and 45 minutes. The insoluble matter was filtered through Celite (registered trademark) and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 62 (10.34 g, yield 78%).

[1169] 1 1H-NMR (DMSO-d6) δ: -0.21 (s, 6H), 0.73 (s, 9H), 1.91 (s, 6H), 3.37 (s, 3H), 3.70 - 3.71 (m, 2H), 4.04 - 4.05 (m, 2H), 4.45 (s, 2H), 6.43 (s, 1H), 7.10 - 7.17 (m, 2H), 7.30 - 7.36 (m, 3H), 7.44 - 7.60 (m, 3H), 7.68 - 7.70 (m, 2H), 8.20 (s, 1H).

[1170] Step 2 Synthesis of Compound 63

[1171] Compound 62 (10.30 g, 17.7 mmol) was suspended in ethanol (154 mL) under a nitrogen atmosphere. Triethylamine (5.14 mL, 37.1 mmol) and hydroxylamine hydrochloride (2.46 g, 35.3 mmol) were added, and the mixture was stirred at 100 °C for 1 hour and 10 minutes. After cooling, ethyl acetate (300 mL) and water (200 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound 63 (6.58 g, yield 89%).

[1172] 1 H-NMR (CDCl3) δ: -0.14 (s, 6H), 0.80 (s, 9H), 2.30 (s, 6H), 3.57 (s, 3H), 3.74 (t, J = 4.8 Hz, 2H), 3.95 (t, J = 4.8 Hz, 2H), 4.27 (s, 2H), 4.65 (s, 2H), 6.28 (s, 1H), 7.89 (s, 1H).

[1173] Step 3 Synthesis of Compound 65

[1174] Compound 63 (1.00 g, 2.39 mmol) and compound 64 (603 mg, 2.87 mmol) were dissolved in N,N-dimethylformamide (20 mL) under a nitrogen atmosphere. A solution of potassium tert-butoxide (670 mg, 5.97 mmol) in tetrahydrofuran (12 mL) was added under ice-cooling, and the mixture was stirred at ice-cooling for 40 minutes. Water (50 mL) and ethyl acetate (30 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 65 (858 mg, yield 59%).

[1175] 1 H-NMR (CDCl3) δ: -0.09 (s, 6H), 0.81 (s, 9H), 2.33 (s, 6H), 3.60 (s, 3H), 3.80 (t, J = 4.8 Hz, 2H), 4.07 (t, J = 4.8 Hz, 2H), 4.68 (s, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 8.09 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.17 (s, 1H).

[1176] Step 4 Synthesis of Compound 66

[1177] Compound 65 (858 mg, 1.41 mmol) was dissolved in tetrahydrofuran (8.6 mL) under a nitrogen atmosphere, 1 mol / L tetrabutylammonium fluoride - tetrahydrofuran solution (2.1 mL, 2.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was solidified with diisopropyl ether to obtain compound 66 (617 mg, yield 89%).

[1178] 1 1H-NMR (CDCl3) δ: 1.63 (t, J = 6.3 Hz, 1H), 2.35 (s, 6H), 3.61 (s, 3H), 3.77 - 3.83 (m, 2H), 4.11 (t, J = 4.5 Hz, 2H), 4.70 (s, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 8.10 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H).

[1179] Step 5 Synthesis of Compound I-257

[1180] A solution of compound 67 (11 mg, 0.076 mmol) and compound 66 (25 mg, 0.051 mmol) in dichloromethane (0.5 mL), PdCl2(dtbpf) (3.3 mg, 0.0051 mmol), and an aqueous solution of potassium carbonate (21 mg, 0.152 mmol) in water (0.10 mL) were mixed. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. Chloroform and water were added, and the mixture was extracted with chloroform. The insoluble matter was filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dimethyl sulfoxide. It was purified by reverse-phase liquid column chromatography (aqueous ammonium carbonate solution, acetonitrile) to obtain compound I-257 (4.2 mg, yield 16%).

[1181] 1 1H-NMR (CDCl3) δ: 1.67 (t, J = 5.5 Hz, 1H), 2.37 (s, 6H), 3.61 (s, 3H), 3.78 - 3.85 (m, 2H), 4.12 (t, J = 4.5 Hz, 2H), 4.70 (s, 2H), 7.05 (dt, J = 8.4, 5.9 Hz, 1H), 7.18 - 7.28 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.37 - 7.44 (m, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.89 (s, 1H), 8.12 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.37 (s, 1H).

[1182] Synthesis of Compound 69 in Reference Example 5

[1183]

[1184] Step 1: Synthesis of Compound 69

[1185] Under a nitrogen atmosphere, xenon fluoride (535 mg, 3.16 mmol) was suspended in dichloromethane (6 mL), and compound 68 (300 mg, 1.58 mmol) and 70% hydrogen fluoride pyridine (1.32 mL, 10.3 mmol) were added. The mixture was stirred at room temperature for 25 hours and 55 minutes. The reaction solution was poured into an aqueous solution (30 mL) of sodium bicarbonate (5.31 g, 63.2 mmol), and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 69 (146 mg, yield 40%).

[1186] 1 1H-NMR (CDCl3) δ: 1.98 (t, J = 13.5 Hz, 3H), 7.67 (d, J = 1.8 Hz, 1H), 8.17 - 8.23 (m, 1H).

[1187] Synthesis of Compound I-266 in Example 19

[1188]

[1189] Step 1: Synthesis of Compound 70

[1190] Under a nitrogen atmosphere, compound 63 (40 mg, 0.096 mmol) and compound 69 (32.7 mg, 0.143 mmol) were suspended in toluene (0.8 mL), and BINAP (11.9 mg, 0.019 mmol), cesium carbonate (93 mg, 0.287 mmol), and tris(dibenzylideneacetone)dipalladium (8.8 mg, 0.0096 mmol) were added. The mixture was stirred at 100 °C for 3 hours and 30 minutes. The insoluble matter was filtered through Celite (registered trademark) and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 70 (45.9 mg, yield 79%).

[1191] 11H-NMR (CDCl3) δ: -0.08 (s, 6H), 0.82 (s, 9H), 1.92 (t, J = 13.3 Hz, 3H), 2.34 (s, 6H), 3.59 (s, 3H), 3.80 (t, J = 4.8 Hz, 2H), 4.06 (t, J = 4.8 Hz, 2H), 4.68 (s, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.97 - 7.98 (m, 1H), 8.08 (s, 1H), 8.22 (s, 1H).

[1192] Synthesis of Compound I-266 in Step 2

[1193] Under a nitrogen atmosphere, compound 70 (43.6 mg, 0.071 mmol) was dissolved in tetrahydrofuran (0.9 mL). A 1 mol / L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.086 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 50 minutes. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound I-266 (18.5 mg, yield 52%).

[1194] 1 1H-NMR (CDCl3) δ: 1.66 (t, J = 6.1 Hz, 1H), 1.93 (t, J = 13.3 Hz, 3H), 2.35 (s, 6H), 3.61 (s, 3H), 3.78 - 3.83 (m, 2H), 4.10 (t, J = 4.4 Hz, 2H), 4.69 (s, 2H), 7.54 (d, J = 1.8 Hz, 1H), 7.77 (s, 1H), 7.97 - 8.00 (m, 1H), 8.09 (s, 1H), 8.25 (s, 1H).

[1195] Synthesis of Compound I-271 in Example 20

[1196]

[1197] Synthesis of Compound 72 in Step 1

[1198] Compound 71 (3.00 g, 14.3 mmol) was suspended in N,N-dimethylacetamide (30 mL), potassium carbonate (2.96 g, 21.4 mmol) and (R)-1-(trityloxy)propan-2-ol (5.45 g, 17.1 mmol) were added, and the mixture was stirred at 150 °C for 8 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). Methanol was added to precipitate the solid, and then filtration was carried out to obtain Compound 72 (6.42 g, yield 89%).

[1199] 1 1H-NMR (CDCl3) δ: 1.35 (d, J = 6.5 Hz, 3H), 3.16 (dd, J = 9.7, 3.6 Hz, 1H), 3.34 (dd, J = 9.8, 6.3 Hz, 1H), 5.43 - 5.50 (m, 1H), 7.20 - 7.29 (m, 9H), 7.44 (d, J = 7.5 Hz, 6H), 7.82 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H).

[1200] Step 2 Synthesis of Compound 73

[1201] To Compound 72 (3.00 g, 5.90 mmol), 2,4,6-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (2.19 g, 8.84 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (384 mg, 0.590 mmol) and potassium carbonate (2.44 g, 17.7 mmol), 1,4-d ane (30 mL)-water (6 mL) was added, and the mixture was stirred at 80 °C for 4 hours. After cooling, filtration was carried out through Celite (registered trademark), and the solvent was distilled off under reduced pressure. Water was added to the resulting residue, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 73 (2.21 g, yield 68%).

[1202] 11H-NMR (CDCl3) δ: 1.21 (d, J = 6.5 Hz, 3H), 2.16 (s, 3H), 2.24 (s, 3H), 2.68 (s, 3H), 3.05 (dd, J = 9.5, 4.0 Hz, 1H), 3.11 (dd, J = 9.7, 6.7 Hz, 1H), 5.49 - 5.52 (m, 1H), 7.18 - 7.30 (m, 15H), 7.38 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H).

[1203] Synthesis of Compound 74 in Step 3

[1204] Dissolve Compound 73 (1.10 g, 2.00 mmol) in dichloromethane (11 mL) - methanol (11 mL), add p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol), and stir at room temperature for 24 hours. Add saturated sodium bicarbonate solution and extract with chloroform (20 mL). After washing the organic layer with saturated brine, dry it over anhydrous magnesium sulfate. Distill off the solvent under reduced pressure, and purify the resulting residue by silica gel column chromatography (chloroform - methanol) to obtain Compound 74 (572 mg, yield 93%).

[1205] 1 1H-NMR (CDCl3) δ: 1.22 (d, J = 6.5 Hz, 3H), 2.22 (s, 3H), 2.24 (s, 3H), 2.57 (t, J = 5.9 Hz, 1H), 2.71 (s, 3H), 3.57 - 3.72 (m, 2H), 5.22 - 5.27 (m, 1H), 7.40 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H).

[1206] Synthesis of Compound I-271 in Step 4

[1207] To a solution of compound 74 (50 mg, 0.162 mmol), 5-(4-fluorophenyl)pyridin-2-amine (33.6 mg, 0.179 mmol), cesium carbonate (106 mg, 0.325 mmol), X-Phos (15.5 mg, 0.032 mmol) and tris(dibenzylideneacetone)dipalladium(0) (14.9 mg, 0.016 mmol) in toluene (500 μL) was added, and the mixture was stirred at 110 °C for 9.5 h. After cooling, X-Phos (15.5 mg, 0.032 mmol) and tris(dibenzylideneacetone)dipalladium(0) (14.9 mg, 0.016 mmol) were added, and the mixture was further stirred at 110 °C for 26 h. After cooling, the reaction mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. The resulting residue was purified by diol silica gel column chromatography (hexane - ethyl acetate). Diisopropyl ether - hexane was added to precipitate the solid, and then the solid was collected by filtration to obtain compound I-271 (2.0 mg, yield 3%).

[1208] 1 1H-NMR (CDCl3) δ: 1.22 (d, J = 6.5 Hz, 3H), 2.28 (s, 3H), 2.31 (s, 3H), 2.73 (s, 3H), 3.49 - 3.52 (m, 1H), 3.62 - 3.73 (m, 2H), 5.16 - 5.21 (m, 1H), 6.36 (br s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 7.11 - 7.15 (m, 2H), 7.45 - 7.48 (m, 2H), 7.68 - 7.72 (m, 2H), 8.27 (d, J = 2.8 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H).

[1209] Example 21 Synthesis of Compound I-276

[1210]

[1211] Step 1 Synthesis of Compound 75

[1212] 6-Chloro-5-fluoro-2-iodopyridin-3-ol (300 mg, 1.10 mmol) was dissolved in DMF (3 mL), potassium carbonate (227 mg, 1.65 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (199 μL, 1.32 mmol) were added, and the mixture was stirred at 75 °C for 4 h. After cooling, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with water (30 mL) and saturated brine (20 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound 75 (456 mg) as a crude product. The obtained compound 75 could be used in the next step without further purification.

[1213] Step 2 Synthesis of Compound 76

[1214] The crude product of compound 75 (424 mg) was dissolved in 1,4-dihydrochloric acid under nitrogen atmosphere. alkane (8.5 mL)-water (1.7 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (242 mg, 1.16 mmol), XPhosPdG3 (89 mg, 0.11 mmol), potassium carbonate (175 mg, 1.27 mmol) were added, and stirred at 100°C for 1 hour. After cooling, extraction was performed with water (30 mL) and chloroform (30 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 76 (226 mg, yield 60%).

[1215] 1H-NMR(CDCl3)δ: 1.56-1.85(m, 6H), 3.47-3.55(m, 1H), 3.77-3.85(m, 2H), 4.07-4.15(m, 1H), 4.10(s, 3H ), 4.22-4.26 (m, 2H), 4.66-4.68 (m, 1H), 6.83 (d, J = 1.6Hz, 1H), 7.25-7.28 (m, 1H), 7.50 (d, J = 1.6Hz, 1H).

[1216] Step 3 Synthesis of Compound 77

[1217] Compound 76 (194 mg, 0.546 mmol) was dissolved in N, N-dimethylformamide (2 mL) under a nitrogen atmosphere, and N-bromosuccinimide (117 mg, 0.655 mmol) was added and stirred at room temperature for 6 hours. Saturated sodium bicarbonate solution (20 mL) was added and extracted with ethyl acetate (10 mL). The organic layer was washed with water (20 mL) and saturated brine (10 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 77 (208 mg, yield 88%).

[1218] 1H-NMR (CDCl3) δ: 1.45-1.78 (m, 6H), 3.42-3.49 (m, 1H), 3.68-3.79 (m, 2H), 3.81 (s, 3H), 4. 01-4.07 (m, 1H), 4.20-4.25 (m, 2H). 4.57-4.59 (m, 1H), 7.37 (d, J=9.2Hz, 1H), 7.50 (s, 1H).

[1219] Synthesis of Compound 78 in Step 4

[1220] Under a nitrogen atmosphere, dissolve Compound 77 (22 mg, 0.051 mmol) in toluene (0.5 mL), add 4-(trifluoromethyl)aniline (10 mg, 0.064 mmol), Pd2(dba)3 (4.7 mg, 5.1 μmol), BINAP (6.3 mg, 10.2 μmol), and cesium carbonate (33 mg, 0.102 mmol), and stir at 100 °C for 3 hours. After cooling, add water (10 mL), and extract with chloroform (10 mL). Distill off the solvent under reduced pressure, and purify the obtained residue by thin-layer chromatography (hexane - ethyl acetate) to obtain Compound 78 (19.6 mg, yield 69%).

[1221] 1H-NMR (CDCl3) δ: 1.56 - 1.78 (m, 6H), 3.43 - 3.50 (m, 1H), 3.68 - 3.78 (m, 2H), 3.82 (s, 3H), 3.97 - 4.03 (m, 1H), 4.13 - 4.17 (m, 2H), 4.57 - 4.60 (m, 1H), 6.71 (s, 1H), 7.35 (d, J = 11.7 Hz, 1H), 7.53 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 9.0 Hz, 2H).

[1222] Synthesis of I-276 in Step 5

[1223] Dissolve Compound 78 (19.6 mg, 0.035 mmol) in methanol (500 μL), add p-toluenesulfonic acid monohydrate (1.4 mg, 7.0 μmol), and stir at 50 °C for 1 hour. After cooling, add water (1 mL), and stir for 5 minutes. Filter and dry the precipitated solid to obtain I-276 (14.3 mg, yield 86%).

[1224] 1H-NMR (CDCl3) δ: 2.00 (t, J = 5.9 Hz, 1H), 3.84 (s, 3H), 3.88 - 3.93 (m, 2H), 4.08 (t, J = 4.2 Hz, 2H), 6.73 (s, 1H), 7.29 (d, J = 11.4 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.56 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H).

[1225] Synthesis of Compound I-329 in Example 22

[1226]

[1227] Synthesis of Compound 66 in Step 1

[1228] Dissolve Compound 65 (858 mg, 1.41 mmol) in THF (8.6 mL), add 1 mol / L tetrabutylammonium fluoride - THF solution (2.11 mL, 2.11 mmol), and stir at room temperature for 1 hour. Add saturated aqueous ammonium chloride solution (30 mL), and extract with ethyl acetate (30 mL). After washing the organic layer with saturated brine (30 mL), dry it over anhydrous sodium sulfate. Distill off the solvent under reduced pressure, add IPE (5 mL) to the obtained residue. Wash the precipitated solid with IPE (6 mL), then filter and dry it to obtain Compound 66 (617 mg, yield 89%).

[1229] 1 1H - NMR (CDCl3) δ: 1.63 (t, J = 6.3 Hz, 1H), 2.35 (s, 6H), 3.61 (s, 3H), 3.77 - 3.83 (m, 2H), 4.11 (t, J = 4.5 Hz, 2H), 4.70 (s, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 8.10 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H).

[1230] Synthesis of Compound 80 in Step 2

[1231] Under a nitrogen atmosphere, dissolve Compound 66 (100 mg, 0.202 mmol) in 1,4 - di ane (1 mL), add bis(pinacolato)diboron (61.6 mg, 0.243 mmol), PdCl2(dppf) (16.5 mg, 0.020 mmol), potassium acetate (39.7 mg, 0.404 mmol), and stir at 80 °C for 2 hours. After cooling, add bis(pinacolato)diboron (26 mg, 0.102 mmol), and stir at 80 °C for an additional 1.5 hours. After cooling, add bis(pinacolato)diboron (30 mg, 0.118 mmol), and stir at 80 °C for an additional 1 hour. After cooling, add water (10 mL), and extract with ethyl acetate (10 mL). Dry the organic layer over anhydrous sodium sulfate and distill off the solvent under reduced pressure. Purify the obtained residue by silica gel column chromatography (chloroform - methanol) to obtain Compound 80 (62 mg, yield 57%).

[1232] 1H-NMR (CDCl3) δ: 1.32 (s, 12H), 1.61 - 1.68 (m, 1H), 2.36 (s, 6H), 3.60 (s, 3H), 3.77 - 3.83 (m, 2H), 4.10 (t, J = 4.5 Hz, 2H), 4.70 (s, 2H), 7.92 (s, 1H), 7.94 (s, 1H), 8.10 (s, 1H), 8.37 (s, 1H), 8.43 (s, 1H).

[1233] Synthesis of Compound I-329 in Step 3

[1234] Dissolve Compound 80 (16.5 mg, 0.030 mmol) in 1,4-d ane (0.33 mL) - water (0.07 mL), add 2-bromo-4-(trifluoromethyl)thiazole (10.6 mg, 0.046 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (2.0 mg, 3.0 μmol), potassium carbonate (12.6 mg, 0.091 mmol), and stir at 100 °C for 4 hours. Add chloroform (10 mL) and water (5 mL), and extract with chloroform. Dry the organic layer over anhydrous sodium sulfate and distill off the solvent under reduced pressure. Purify the resulting residue by thin-layer chromatography (chloroform - methanol) and reverse-phase liquid chromatography (acetonitrile - water) to obtain Compound I-329 (6.6 mg, yield 38%).

[1235] 1H-NMR (CDCl3) δ: 1.63 (t, J = 6.3 Hz, 1H), 2.37 (s, 6H), 3.61 (s, 3H), 3.79 - 3.84 (m, 2H), 4.13 (t, J = 4.4 Hz, 2H), 4.71 (s, 2H), 7.71 (s, 1H), 8.04 (s, 1H), 8.13 (s, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H).

[1236] Synthesis of Compound 82 in Reference Example 6

[1237]

[1238] Synthesis of Compound 82 in Step 1

[1239] Compound 44 (5.00 g, 26.7 mmol) was dissolved in dichloromethane (50 mL) and water (50 mL). Glycolic acid (4.07 g, 53.5 mmol), silver nitrate (454 mg, 2.67 mmol), and ammonium persulfate (12.2 g, 53.5 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 1 hour. After adding 2 mol / L aqueous potassium carbonate solution and saturated brine, the mixture was filtered through Celite (registered trademark) and extracted twice with chloroform (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 82 (1.69 g, yield 29%).

[1240] 1H-NMR (CDCl3) δ: 2.65 (6H, s), 3.59 (1H, br s), 4.71 (2H, d, J = 3.0 Hz).

[1241] Example 23 Synthesis of Compound I-376

[1242]

[1243] Step 1 Synthesis of Compound 84

[1244] To compound 50 (2.84 g, 8.56 mmol), compound 82 (1.69 g, 7.79 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (507 mg, 0.779 mmol), and potassium carbonate (2.15 g, 15.6 mmol), 1,4-d ane (17 mL) - water (3.4 mL) was added, and the mixture was stirred at 80 °C for 1 hour. After cooling, water was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 84 (1.36 g, yield 41%).

[1245] 1H-NMR (CDCl3) δ: -0.12 (6H, s), 0.79 (9H, s), 2.28 (6H, s), 3.81 (2H, t, J = 4.6 Hz), 3.84 (1H, br s), 4.12 (2H, t, J = 4.6 Hz), 4.79 (2H, s), 7.09 (1H, s), 8.19 (1H, s).

[1246] Step 2 Synthesis of Compound 85

[1247] Compound 84 (546 mg, 1.29 mmol) was dissolved in dichloromethane (5.46 mL). Triethylamine (268 μL, 1.93 mmol) and methanesulfonyl chloride (120 μL, 1.55 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was cooled to 0 °C, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane (5 mL). The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 85 (638 mg, yield 99%).

[1248] 1H-NMR (CDCl3) δ: -0.11 (6H, s), 0.79 (9H, s), 2.27 (6H, s), 3.28 (3H, s), 3.81 (2H, t, J = 4.8 Hz), 4.12 (2H, t, J = 4.8 Hz), 5.39 (2H, s), 7.07 (1H, s), 8.20 (1H, s).

[1249] Synthesis of Compound 86 in Step 3

[1250] Compound 85 (60.0 mg, 0.119 mmol) was dissolved in THF (600 μL). Sodium hydride (60%, dispersed in liquid paraffin) (7.65 mg, 0.191 mmol) and 3 - oxetanol (11.4 μL, 0.179 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 15 minutes. Water was added, and the mixture was extracted with dichloromethane (4 mL). The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 86 (50 mg) as a crude product. The obtained Compound 86 could be used in the next step without further purification.

[1251] Synthesis of Compound 87 in Step 4

[1252] To the crude product of Compound 86 (50 mg), 3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - amine (30.7 mg, 0.156 mmol), cesium carbonate (67.9 mg, 0.208 mmol), BINAP (13.0 mg, 0.021 mmol), and tris(dibenzylideneacetone)dipalladium (9.54 mg, 0.010 mmol), toluene (500 μL) was added, and the mixture was stirred at 100 °C for 15 hours. After cooling, the reaction solution was roughly purified by silica gel column chromatography (hexane - ethyl acetate, ethyl acetate - methanol) to obtain Compound 87 as a crude product. The obtained Compound 87 (43.8 mg) could be used in the next step without further purification.

[1253] Synthesis of Compound I - 376 in Step 5

[1254] The crude product of compound 87 (43.8 mg) was dissolved in THF (438 μL), and 1 mol / L tetrabutylammonium fluoride - tetrahydrofuran solution (137 μL, 0.137 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate, ethyl acetate - methanol) to obtain compound I - 376 (28.0 mg, yield 78%).

[1255] 1H - NMR (CDCl3) δ: 1.63 (1H, br s), 2.34 (6H, s), 3.82 (2H, dd, J = 9.7, 5.4 Hz), 4.14 (2H, t, J = 4.5 Hz), 4.69 (2H, s), 4.81 - 4.84 (5H, m), 7.83 (1H, d, J = 2.1 Hz), 8.03 (1H, s), 8.13 (1H, s), 8.32 (1H, s), 8.36 (1H, s).

[1256] According to the general synthesis method described above and the method described in the examples, the following compounds were synthesized. The structures and physical properties (LC / MS data) are shown in the following table. It should be noted that compound I - 224 and compound I - 225 in the table are chiral compounds with undetermined absolute configurations, and the enantiomer of compound I - 224 is compound I - 225. In addition, compounds I - 194, I - 198, I - 214, I - 216, and I - 382 in the table are racemates.

[1257] [Table 1]

[1258]

[1259] [Table 2]

[1260]

[1261] [Table 3]

[1262]

[1263] [Table 4]

[1264]

[1265] [Table 5]

[1266]

[1267] [Table 6]

[1268]

[1269] [Table 7]

[1270]

[1271] [Table 8]

[1272]

[1273] [Table 9]

[1274]

[1275] [Table 10]

[1276]

[1277] [Table 11]

[1278]

[1279] [Table 12]

[1280]

[1281] [Table 13]

[1282]

[1283] [Table 14]

[1284]

[1285] [Table 15]

[1286]

[1287] [Table 16]

[1288]

[1289] [Table 17]

[1290]

[1291] [Table 18]

[1292]

[1293] [Table 19]

[1294]

[1295] [Table 20]

[1296]

[1297] [Table 21]

[1298]

[1299] [Table 22]

[1300]

[1301] [Table 23]

[1302]

[1303] [Table 24]

[1304]

[1305] [Table 25]

[1306]

[1307] [Table 26]

[1308]

[1309] [Table 27]

[1310]

[1311] [Table 28]

[1312]

[1313] [Table 29]

[1314]

[1315] [Table 30]

[1316]

[1317] [Table 31]

[1318]

[1319] [Table 32]

[1320]

[1321] [Table 33]

[1322]

[1323] [Table 34]

[1324]

[1325] [Table 35]

[1326]

[1327] [Table 36]

[1328]

[1329] [Table 37]

[1330]

[1331] [Table 38]

[1332]

[1333] [Table 39]

[1334]

[1335] [Table 40]

[1336]

[1337] [Table 41]

[1338]

[1339] [Table 42]

[1340]

[1341] [Table 43]

[1342]

[1343] [Table 44]

[1344]

[1345] [Table 45]

[1346]

[1347] [Table 46]

[1348]

[1349] [Table 47]

[1350]

[1351] [Table 48]

[1352]

[1353] [Table 49]

[1354]

[1355] [Table 50]

[1356]

[1357] [Table 51]

[1358]

[1359] [Table 52]

[1360]

[1361] [Table 53]

[1362]

[1363] [Table 54]

[1364]

[1365] [Table 55]

[1366]

[1367] [Table 56]

[1368]

[1369] [Table 57]

[1370]

[1371] [Table 58]

[1372]

[1373] [Table 59]

[1374]

[1375] [Table 60]

[1376]

[1377] [Table 61]

[1378]

[1379] [Table 62]

[1380]

[1381] [Table 63]

[1382]

[1383] [Table 64]

[1384]

[1385] [Table 65]

[1386]

[1387] [Table 66]

[1388]

[1389] [Table 67]

[1390]

[1391] [Table 68]

[1392]

[1393] [Table 69]

[1394]

[1395] [Table 70]

[1396]

[1397] The following are the biological test examples of the compounds of the present invention. The compounds of the present invention can be tested substantially as described in the following test examples.

[1398] The compounds represented by formula (I) or formula (I-1) according to the present invention may be compounds having serotonin 5-HT2A receptor antagonistic and / or inverse agonistic effects and serotonin 5-HT2C receptor antagonistic and / or inverse agonistic effects.

[1399] Specifically, in the evaluation methods described below, the Ki value is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.

[1400] Test Example 1: 5-HT2A Receptor Binding Inhibition Test

[1401] (Each experimental condition)

[1402] Cell membrane: 15 μg of Jump-In HEK cell membrane (expressing human recombinant 5-HT2A receptor) per well

[1403] 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

[1404] Radioactive ligand: at a final concentration near the Kd value calculated by the following method 3 [[H]]-Ketanserin

[1405] Non-specific ligand: Serotonin HCl at a final concentration of 500 μmol / L

[1406] The Kd value is calculated when the lot of the cell membrane is changed. 1 mmol / L non-specific binding calculation compound pre-dissolved in DMSO or DMSO is dispensed in 0.5 μL aliquots into a microtiter plate, and the cell membrane is diluted with the assay buffer. The radioactive ligand solution is serially diluted, and the counts are confirmed using a liquid scintillator. The diluted assay buffer containing the cell membrane is dispensed in 50 μL aliquots per well into the microtiter plate. Then, the radioactive ligand solution is dispensed in 50 μL aliquots per well into the microtiter plate, and the plate is sealed. It is left standing at room temperature (25 °C) for 1.5 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) is dispensed in 50 μL aliquots per well into the GF / B UniFilter plate and left standing at 4 °C for 1 hour or more. Then, filtration is performed using a cell harvester (PerkinElmer). The radioactive ligand solution is dispensed in 10 μL aliquots per well into the empty wells of the GF / B UniFilter plate. After drying the GF / B UniFilter plate at room temperature, MicroScinti20 is dispensed in 50 μL aliquots per well into the GF / B UniFilter plate, and the plate is sealed. The GF / B UniFilter plate is left standing at room temperature overnight. The radioactivity of 3 [[H]]-Ketanserin bound to the 5-HT2A receptor is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min per well. A saturation curve is plotted based on the measured values, and the Kd value is calculated from the slope of the Scatchard Plot.

[1407] (Binding assay of the compound of the present invention)

[1408] A compound solution pre-dissolved in DMSO was dispensed at 0.5 μL into a microtiter plate. The cell membrane and the hot ligand were diluted separately with the assay buffer. Subsequently, the diluted assay buffer containing the cell membrane was dispensed at 50 μL / well into the microtiter plate. Then, the radiolabeled ligand solution was dispensed at 50 μL / well into the microtiter plate, and the plate was sealed. Then, it was left standing at room temperature (25 °C) for 1.5 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) was dispensed at 50 μL / well into a GF / B UniFilter plate and left standing at 4 °C for over 1 hour. Then, filtration was performed using a cell harvester (PerkinElmer). After the GF / B UniFilter plate was dried at room temperature, MicroScinti 20 was dispensed at 50 μL / well into the GF / B UniFilter plate, and the plate was sealed. The GF / B UniFilter plate was left standing at room temperature overnight. The radioactivity of 3 [3H]-ketanserin bound to the 5-HT2A receptor was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Nonspecific binding was calculated from the radioactivity of 3 [3H]-ketanserin in the presence of 500 μmol / L serotonin hydrochloride without ligand labeling, and total binding was calculated from the radioactivity of 3 [3H]-ketanserin in the absence of the compound of the present invention (Vehicle). Finally, the Ki value was calculated from the dose-response curve.

[1409] (The binding activity of the compound of the present invention was calculated from the following binding inhibition rate (%))

[1410] Inhibition rate (%) = [1 - (c - a) / (b - a)] × 100

[1411] a: Average cpm of nonspecific binding

[1412] b: Average cpm of total binding

[1413] c: Cpm in the presence of the test compound

[1414] The compound of the present invention was basically tested as described above. The test results of the human serotonin 5-HT2A receptor binding activity (h 5-HT2A Ki) of the compound of the present invention are shown below.

[1415] (Results)

[1416] [Table 71]

[1417]

[1418] Test Example 1-2: 5-HT2A Receptor Binding Inhibition Test

[1419] (Each experimental condition)

[1420] Cell membrane: 15 μg of Jump-In HEK cell membrane (expressing human recombinant 5-HT2A receptor) per well

[1421] 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

[1422] Radioactive ligand: The final concentration is near the Kd value calculated by the following method 3 [3H]-Ketanserin

[1423] Non-specific ligand: Ketanserin at a final concentration of 500 μmol / L

[1424] The Kd value was calculated when the batch of the cell membrane was changed. 1 mmol / L non-specific binding calculation compound pre-dissolved in DMSO or DMSO was dispensed at 0.5 μL into a microplate, and the cell membrane was diluted with the assay buffer. The radioactive ligand solution was serially diluted, and the counts were confirmed using a liquid scintillator. The diluted assay buffer containing the cell membrane was dispensed at 50 μL / well into the microplate. Then, the radioactive ligand solution was dispensed at 50 μL / well into the microplate, and the plate was sealed. It was left standing at room temperature (25 °C) for 1.5 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) was dispensed at 50 μL / well into the UniFilter plate and left standing at 4 °C for 1 hour or more. Then, filtration was performed using a cell harvester (PerkinElmer). The radioactive ligand solution was dispensed at 10 μL / well into the empty wells of the UniFilter plate. After the UniFilter plate was dried at room temperature, MicroScinti20 was dispensed at 50 μL / well into the UniFilter plate, and the plate was sealed. The UniFilter plate was left standing at room temperature overnight. The radioactivity of 3 [3H]-Ketanserin bound to the 5-HT2A receptor was measured 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.

[1425] (Binding assay of the compound of the present invention)

[1426] A compound solution pre-dissolved in DMSO was dispensed at 0.5 μL per well into a microtiter plate. The cell membrane and the hot ligand were each diluted with the assay buffer. Subsequently, the diluted assay buffer containing the cell membrane was dispensed at 50 μL per well into the microtiter plate. Then, the radiolabeled ligand solution was dispensed at 50 μL per well into the microtiter plate, and the plate was sealed. Thereafter, it was left standing at room temperature (25 °C) for 1.5 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) was dispensed at 50 μL per well into the UniFilter plate and left standing at 4 °C for 1 hour or more. Then, filtration was performed using a cell harvester (PerkinElmer). After allowing the UniFilter plate to dry at room temperature, MicroScinti20 was dispensed at 50 μL per well into the UniFilter plate, and the plate was sealed. The UniFilter plate was left standing at room temperature overnight. The radioactivity of 3 [H]-ketanserin bound to the 5-HT2A receptor was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min per well. Nonspecific binding was calculated from the radioactivity of 3 [H]-ketanserin in the presence of 500 μmol / L ketanserin without ligand labeling, and total binding was calculated from the radioactivity of 3 [H]-ketanserin in the absence of the compound of the present invention (Vehicle). Finally, the Ki value was calculated from the dose-response curve.

[1427] (The binding activity of the compound of the present invention was calculated from the following binding inhibition rate (%))

[1428] Inhibition rate (%) = [1 - (c - a) / (b - a)] × 100

[1429] a: Average cpm of nonspecific binding

[1430] b: Average cpm of total binding

[1431] c: Cpm in the presence of the test compound

[1432] The compound of the present invention was tested substantially as described above. The test results of the human serotonin 5-HT2A receptor binding activity (h 5-HT2A Ki) of the compound of the present invention are shown below.

[1433] (Results)

[1434] [Table 72]

[1435]

[1436] [Table 73]

[1437]

[1438] [Table 74]

[1439]

[1440] [Table 75]

[1441]

[1442] [Table 76]

[1443]

[1444] Test Example 2: 5-HT2C Receptor Binding Inhibition Test (Each Experimental Condition)

[1445] Cell membrane: 0.5 μg of Jump-In HEK cell membrane (expressing human recombinant 5-HT2C receptor) per well

[1446] 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

[1447] Radioactive ligand: The final concentration is near the Kd value calculated by the following method 3 [3H]-Mesulergine

[1448] Non-specific ligand: Serotonin hydrochloride at a final concentration of 500 μmol / L

[1449] The Kd value is calculated when there is a batch change in the cell membrane. 0.5 μL of a 1 mmol / L non-specific binding calculation compound pre-dissolved in DMSO or DMSO is dispensed into a microplate, and the cell membrane is diluted with the assay buffer. The radioligand solution is serially diluted, and the counts are confirmed using a liquid scintillator. 50 μL / well of the diluted assay buffer containing the cell membrane is dispensed into the microplate. Subsequently, 50 μL / well of the radioligand solution is dispensed into the microplate, and the plate is sealed. It is left standing at 37 °C for 2 hours. During this period, 50 μL / well of 50 mmol / L Tris-HCl (pH 7.4) is dispensed into the GF / B UniFilter plate and left standing at 4 °C for 1 hour or more. Then, filtration is performed using a cell harvester (PerkinElmer). 10 μL / well of the radioligand solution is dispensed into the empty wells of the GF / B UniFilter plate. After the GF / B UniFilter plate is dried at room temperature, 50 μL / well of MicroScinti20 is dispensed into the GF / B UniFilter plate, and the plate is sealed. The GF / B UniFilter plate is left standing overnight at room temperature. The radioactivity of 3 [[H]]-methysergide bound to the 5-HT2C receptor is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve is plotted based on the measured values, and the Kd value is calculated from the slope of the Scatchard plot.

[1450] (Binding assay of the compound of the present invention)

[1451] 0.5 μL of the compound solution pre-dissolved in DMSO is dispensed into a microplate, and the cell membrane and the hot ligand are respectively diluted with the assay buffer. Subsequently, 50 μL / well of the diluted assay buffer containing the cell membrane is dispensed into the microplate. Then, 50 μL / well of the radioligand solution is dispensed into the microplate, and the plate is sealed. Then, it is left standing at 37 °C for 2 hours. During this period, 50 μL / well of 50 mmol / L Tris-HCl (pH 7.4) is dispensed into the GF / B UniFilter plate and left standing at 4 °C for 1 hour or more. Then, filtration is performed using a cell harvester (PerkinElmer). After the GF / B UniFilter plate is dried at room temperature, 50 μL / well of MicroScinti20 is dispensed into the GF / B UniFilter plate and sealed. The GF / B UniFilter plate is left standing overnight at room temperature. The 3The radioactivity of [³H]-methysergide was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 minute / well. Nonspecific binding was calculated from the radioactivity of [³H]-methysergide in the presence of 500 μmol / L serotonin hydrochloride without ligand labeling. 3 The radioactivity of [³H]-methysergide was calculated, and the total binding was calculated from the radioactivity of [³H]-methysergide in the absence of the compound of the present invention (Vehicle). 3 Finally, the Ki value was calculated from the dose-response curve.

[1452] (The binding activity of the compound of the present invention was calculated from the following binding inhibition rate (%))

[1453] Inhibition rate (%) = [1 - (c - a) / (b - a)] × 100

[1454] a: Average cpm of nonspecific binding

[1455] b: Average cpm of total binding

[1456] c: Cpm in the presence of the test compound

[1457] The compound of the present invention was basically tested as described above. The test results of the human serotonin 5-HT2C receptor binding activity (h 5-HT2C Ki) of the compound of the present invention are shown below.

[1458] (Results)

[1459] [Table 77]

[1460]

[1461] Test Example 2-2: 5-HT2C Receptor Binding Inhibition Test

[1462] (Each experimental condition)

[1463] Cell membrane: 0.5 μg of Jump-In HEK cell membrane per well (expressing human recombinant 5-HT2C receptor)

[1464] 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

[1465] Radioactive ligand: [³H]-methysergide near the Kd value calculated by the following method at the final concentration 3 [³H]-methysergide

[1466] Nonspecific ligand: Ketanserin at a final concentration of 500 μmol / L

[1467] The Kd value is calculated when there is a batch change in the cell membrane. 1 mmol / L of the compound for calculating non-specific binding or DMSO pre-dissolved in DMSO is dispensed in 0.5 μL aliquots into a microplate, and the cell membrane is diluted with the assay buffer. The radioligand solution is serially diluted, and the counts are confirmed using a liquid scintillator. The diluted assay buffer containing the cell membrane is dispensed into the microplate at 50 μL / well. Subsequently, the radioligand solution is dispensed into the microplate at 50 μL / well, and the plate is sealed. It is left standing at 37 °C for 2 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) is dispensed into the UniFilter plate at 50 μL / well and left standing at 4 °C for 1 hour or more. Subsequently, filtration is carried out using a cell harvester (PerkinElmer). The radioligand solution is dispensed into the empty wells of the UniFilter plate at 10 μL / well. After the UniFilter plate is dried at room temperature, MicroScinti20 is dispensed into the UniFilter plate at 50 μL / well, and the plate is sealed. The UniFilter plate is left standing overnight at room temperature. The radioactivity of 3 [[H]]-methysergide bound to the 5-HT2C receptor is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. A saturation curve is plotted based on the measured values, and the Kd value is calculated from the slope of the Scatchard plot.

[1468] (Binding assay of the compound of the present invention)

[1469] The compound solution pre-dissolved in DMSO is dispensed in 0.5 μL aliquots into a microplate, and the cell membrane and the hot ligand are each diluted with the assay buffer. Subsequently, the diluted assay buffer containing the cell membrane is dispensed into the microplate at 50 μL / well. Subsequently, the radioligand solution is dispensed into the microplate at 50 μL / well, and the plate is sealed. Subsequently, it is left standing at 37 °C for 2 hours. During this period, 50 mmol / L Tris-HCl (pH 7.4) is dispensed into the UniFilter plate at 50 μL / well and left standing at 4 °C for 1 hour or more. Subsequently, filtration is carried out using a cell harvester (PerkinElmer). After the UniFilter plate is dried at room temperature, MicroScinti20 is dispensed into the UniFilter plate at 50 μL / well and sealed. The UniFilter plate is left standing overnight at room temperature. The radioactivity of 3 [[H]]-methysergide bound to the 5-HT2C receptor is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. Non-specific binding is from in the presence of 500 μmol / L ketanserin without ligand labeling3 The radioactivity of [³H]-methysergide was calculated, and the total result was calculated from the radioactivity of [³H]-methysergide in the absence of the compound of the present invention (Vehicle). 3 The radioactivity of [³H]-methysergide was calculated. Finally, the Ki value was calculated from the dose-response curve.

[1470] (The binding activity of the compound of the present invention was calculated from the following binding inhibition rate (%))

[1471] Inhibition rate (%) = [1 - (c - a) / (b - a)] × 100

[1472] a: Average cpm of non-specific binding

[1473] b: Average cpm of total binding

[1474] c: Cpm in the presence of the test compound

[1475] The compound of the present invention was basically tested as described above. The test results of the human serotonin 5-HT2C receptor binding activity (h 5-HT2C Ki) of the compound of the present invention are shown below.

[1476] (Results)

[1477] [Table 78]

[1478]

[1479] [Table 79]

[1480]

[1481] [Table 80]

[1482]

[1483] [Table 81]

[1484]

[1485] [Table 82]

[1486]

[1487] Test Example 3: hERG Test

[1488] For the purpose of evaluating the risk of prolonging the QT interval of the electrocardiogram of the compound of the present invention, CHO cells expressing the human ether-a-go-go related gene (hERG) channel were used, and the effect of the compound was studied by evaluating the activity of potassium channels.

[1489] Evaluation was carried out using the FluxOR II Green Potassium Ion Channel Assay kit (Invitrogen: Molecular Probe).

[1490] Cells were seeded in a 384-well assay plate (8000 cells / well / 40 μL) and incubated overnight (37 °C, 5% CO2). After replacing the medium with wash buffer (1x HBSS, 20 mM HEPES) using a microplate washer, a fluorescent indicator dye was added to the medium and incubated for 1 hour (37 °C, 5% CO2) to allow the fluorescent indicator dye to be taken up by the cells.

[1491] The cell plate was placed in a cell-based kinetic assay system FLIPR (Molecular Devices), and the compound was added to the cells to reach the target concentration and reacted for 10 minutes. When a mixture of potassium and thallium, which is a stimulant, was added thereto, the potassium channel opened, and the thallium flowing into the cell bound to the fluorescent indicator dye, thereby increasing the fluorescent signal in the cell, and the potassium channel current was detected as the fluorescent signal. For the inhibition rate at each concentration, the signal intensity when E-4031 was added to the cells at a final concentration of 10.3 μmol / L was defined as 100% inhibition rate, and the signal intensity when DMSO was added to the cells at a final concentration of 0.5% was defined as 0% inhibition rate, and the inhibition rate was calculated from the signal intensity at each concentration. The IC 50 。

[1492] The compounds of the present invention were tested substantially as described above. The results are shown below.

[1493] (Results)

[1494] Compound I-062: IC 50 > 52.0 μM

[1495] Compound I-063: IC 50 > 52.0 μM

[1496] Test Example 3-2: hERG Test

[1497] For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compounds of the present invention, CHO cells expressing the human ether-a-go-go related gene (hERG) channel were used, and the effect of the compounds was studied by evaluating the activity of the potassium channel.

[1498] Evaluation was performed using the FluxOR II Green Potassium Ion Channel Assay kit (Invitrogen: Molecular Probe).

[1499] Cells were seeded in a 384-well assay plate (4000 cells / well / 40 μL) and incubated overnight (37 °C, 5% CO2). After replacing the medium with wash buffer (1x HBSS, 20 mM HEPES) using a microplate washer, a fluorescent indicator dye was added to the medium and incubated for 1 hour (37 °C, 5% CO2) to allow the fluorescent indicator dye to be taken up by the cells.

[1500] The cell plate was placed in a cell-based kinetic analysis system FLIPR (Molecular Device), and the compound was added to the cells to reach the target concentration and reacted for 10 minutes. When a mixed solution of potassium and thallium as a stimulant was added thereto, the potassium channel opened, and thallium flowing into the cells bound to the fluorescent indicator dye, thereby increasing the fluorescent signal in the cells. The potassium channel current was detected as a fluorescent signal. For the inhibition rate at each concentration, the signal intensity when E-4031 was added to the cells at a final concentration of 10.3 μmol / L was defined as 100% inhibition rate, and the signal intensity when DMSO was added to the cells at a final concentration of 0.5% was defined as 0% inhibition rate. The inhibition rate was calculated from the signal intensity at each concentration. The IC 50 .

[1501] The compounds of the present invention were tested substantially as described above. The results are shown below.

[1502] (Results)

[1503] Compound I-006: IC 50 > 52.0 μM

[1504] Compound I-127: IC 50 > 52.0 μM

[1505] Compound I-200: IC 50 > 52.0 μM

[1506] Compound I-228: IC 50 = 50.6 μM

[1507] Compound I-267: IC 50 > 52.0 μM

[1508] Compound I-271: IC 50 > 52.0 μM

[1509] Compound I-359: IC 50 > 52.0 μM

[1510] Test Example 4: Study on Oral Absorbability in BA Test

[1511] Experimental Materials and Methods

[1512] (1) Animals used: Mice or rats are used.

[1513] (2) Breeding conditions: Mice or rats are allowed to freely ingest solid feed and sterilized tap water.

[1514] (3) Dosage and grouping settings: Oral administration and intravenous administration are performed at a specified dosage. The grouping is set as follows. The dosage of each compound is changed as needed.

[1515] Oral administration: 2 - 60 μmol / kg or 1 - 30 mg / kg (n = 2 - 3)

[1516] Intravenous administration: 1 - 30 μmol / kg or 0.5 - 10 mg / kg (n = 2 - 3)

[1517] (4) Preparation of the administration solution: Oral administration is performed in the form of a solution or suspension. Intravenous administration is performed after solubilization.

[1518] (5) Administration method: Oral administration is forcibly administered into the stomach through an oral probe. Intravenous administration is administered from the tail vein using a syringe with a needle.

[1519] (6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.

[1520] (7) Statistical analysis: For the change in the concentration of the compound of the present invention in plasma, the area under the plasma concentration-time curve (AUC) is calculated by the moment analysis method, and the bioavailability (BA) of the compound of the present invention is calculated from the dosage ratio and AUC ratio between the oral administration group and the intravenous administration group.

[1521] It should be noted that the dilution concentration or dilution solvent is changed as needed.

[1522] The compound of the present invention can be basically tested as described above.

[1523] Test Example 5: Clearance Evaluation Test

[1524] Experimental Materials and Methods

[1525] (1) Animals used: SD rats are used.

[1526] (2) Breeding conditions: Allow SD rats to freely ingest solid feed and sterilized tap water.

[1527] (3) Dosage and grouping settings: Intravenous administration is performed at the specified dosage. The grouping is set as follows.

[1528] Intravenous administration at 1 μmol / kg (n = 2)

[1529] (4) Preparation of the administration solution: The compound is solubilized using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent for administration.

[1530] (5) Administration method: Administration is performed via the tail vein using a syringe with a needle.

[1531] (6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.

[1532] (7) Statistical analysis: For the change in the concentration of the compound of the present invention in plasma, the total body clearance (CLtot) is calculated by the moment analysis method. It should be noted that the dilution concentration or dilution solvent is changed as needed.

[1533] The compound of the present invention can be basically tested as described above.

[1534] Test Example 6: Metabolic stability test

[1535] The commercially available pooled human liver microsome is reacted with the compound of the present invention for a certain period of time, and the residual rate is calculated by comparing the reaction sample and the unreacted sample to evaluate the degree of metabolism of the compound of the present invention by the liver.

[1536] In a 0.2 mL buffer solution (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL of human liver microsome, the reaction is carried out at 37 °C for 0 minutes or 30 minutes (oxidation reaction) in the presence of 1 mmol / L NADPH. After the reaction, 70 μL of the reaction solution is added to 140 μL of a methanol / acetonitrile = 1 / 1 (v / v) solution and mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifuged supernatant is quantified using LC / MS / MS or solid phase extraction (SPE) / MS. The amount of the compound of the present invention at 0 minutes of reaction is expressed as 100%, and the ratio to the amount of the compound after the reaction is expressed as the residual rate. It should be noted that the hydrolysis reaction is carried out in the absence of NADPH, and the glucuronide conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is performed thereafter. The dilution concentration or dilution solvent is changed as needed.

[1537] The compounds of the present invention can be tested substantially as described above.

[1538] Test Example 7: P-gp Substrate Test

[1539] The compound of the present invention was added unidirectionally to a Transwell (registered trademark, CORNING) monolayer culture of human MDR1-expressing cells or parental cells, and allowed to react for a certain period of time. For MDR1-expressing cells and parental cells, the membrane permeability coefficients in the direction from the apical side to the basolateral side (A→B) and from the basolateral side to the apical side (B→A) were calculated, and the efflux ratio (Efflux Ratio, ER; the ratio of the membrane permeability coefficients of B→A and A→B) value was calculated. The efflux ratios (ER values) of MDR1-expressing cells and parental cells were compared to determine whether the compound of the present invention is a P-gp substrate.

[1540] The compounds of the present invention can be tested substantially as described above.

[1541] Test Example 8: CYP3A4 (MDZ) MBI Test

[1542] Regarding the CYP3A4 inhibition of the compounds of the present invention, a test for evaluating the mechanism-based inhibition (MBI) ability based on the enhancement of metabolic reactions was performed. Using pooled human liver microsomes, the 1-hydroxylation reaction of midazolam (MDZ) was used as an index to evaluate CYP3A4 inhibition.

[1543] The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL during pre-reaction, 0.05 mg / mL during reaction (when diluted 10-fold); concentration of the compound of the present invention during pre-reaction, 0.83, 5, 10, 20 μmol / L (4 points).

[1544] Add the pre-reaction solution to a 96-well plate. The pre-reaction solution is prepared by adding a mixture of human liver microsomes and the solution of the compound of the present invention in the above-mentioned pre-reaction composition to K-Pi buffer (pH 7.4). Transfer a portion of it to another 96-well plate, dilute it to 1 / 10 with the substrate and K-Pi buffer, add NADPH as a coenzyme as an indicator, and start the reaction (without pre-reaction). After the specified reaction time, stop the reaction by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. Additionally, add NADPH to the remaining pre-reaction solution, start the pre-reaction (with pre-reaction). After the specified pre-reaction time, transfer a portion to another plate, dilute it to 1 / 10 with the substrate and K-Pi buffer as an indicator, and start the reaction. After the specified reaction time, stop the reaction by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifuging the plates that have undergone their respective indicator reactions at 3000 rpm for 15 minutes, quantify 1-hydroxydiazepam in the centrifuged supernatant using LC / MS / MS.

[1545] Use the reaction system that only adds the solvent DMSO in which the compound of the present invention is dissolved as a control (100%), calculate the residual activity (%) when adding the compound of the present invention at each concentration, and use the concentration and inhibition rate to calculate the IC by inverse extrapolation using the Logistic model. Take the IC of pre-incubation for 0 minutes / IC of pre-incubation for 30 minutes as the Shifted IC value. If the Shifted IC is 1.5 or more, it is positive; if the Shifted IC is 1.0 or less, it is negative.

[1546] The compound of the present invention was basically tested as described above. The results are shown below.

[1547] (Results)

[1548] Compound I-073: Negative

[1549] Compound I-109: Negative

[1550] Compound I-127: Negative

[1551] Compound I-200: Negative

[1552] Compound I-247: Negative

[1553] Compound I-376: Negative

[1554] Compound I-378: Negative

[1555] Test Example 9: Solubility Test

[1556] The solubility of the compound of the present invention was determined under the condition of adding 1% DMSO. A 10 mmol / L compound solution was prepared with DMSO, and 2 μL of the compound solution of the present invention was added to 198 μL of the first dissolution test solution of the 18th edition of the Japanese Pharmacopoeia (prepared by adding water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL) or the second dissolution test solution (prepared by dissolving 1.7 g of potassium dihydrogen phosphate and 1.775 g of disodium hydrogen phosphate anhydrous in water to make 1000 mL). After shaking at room temperature for 3 hours, the mixture was suction filtered. The filtrate was diluted 100 times with methanol / acetonitrile / water = 1 / 1 / 2 (V / V / V), and the concentration in the filtrate was measured by LC / MS / MS using the absolute calibration curve method.

[1557] The compound of the present invention can be basically tested as described above.

[1558] Description in the 18th edition of the Japanese Pharmacopoeia

[1559] First dissolution test solution

[1560] Dissolve 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to make 1000 mL. This solution is colorless and transparent, and its pH is about 1.2.

[1561] Second dissolution test solution

[1562] Add 1 volume of water to 1 volume of phosphate buffer solution with pH 6.8.

[1563] Phosphate buffer solution with pH 6.8

[1564] Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of disodium hydrogen phosphate anhydrous in water to make 1000 mL.

[1565] Test example 10: MK801-induced hyperkinesia inhibition test

[1566] Male Wistar rats aged 6 - 10 weeks were used. When preparing the administration solution of the test compound, 30 mmol / L HCl was used as the solvent for dissolution, and when preparing the administration solution of MK801, physiological saline was used as the solvent for dissolution. Using SCANET manufactured by Melquest Co., Ltd., the data collection program SCL-40, and a cage made of transparent plastic, the MK801-induced hyperkinesia inhibition test was carried out as follows.

[1567] In the breeding room, a compound administration solution (solvent or test compound solution) is administered subcutaneously or orally, and then the animal is returned to the breeding cage. After 30 minutes, the animal is transferred to the laboratory for laboratory acclimation. After 15 minutes, the rat is quietly taken out, and an MK801 administration solution (solvent or MK801 solution) is administered intraperitoneally or subcutaneously, and then the rat is returned to the breeding cage. The rat is taken out 15 minutes after intraperitoneal administration, quietly placed in the SCANET, and the measurement of the exercise amount is started. The measurement is ended 30 minutes after the start of the measurement, and the exercise amount of each individual for 30 minutes is statistically analyzed respectively.

[1568] The analysis of the test results is carried out as follows.

[1569] In the test compound administration group and the solvent administration group, a Student-T Test (significance level: two-sided 5%) is performed. When the test compound administration group shows significant exercise amount inhibition compared with the solvent administration group, it is judged to have an antipsychotic effect.

[1570] The compound of the present invention can be basically tested as described above.

[1571] The following preparation examples are only exemplary and are not intended to limit the scope of the invention in any way.

[1572] The compound of the present invention can be formulated into a pharmaceutical composition for administration according to any conventional route, especially: enterally, such as orally, for example, in the form of tablets or capsules; or parenterally, such as in the form of injections or suspensions; topically, such as in the form of lotions, gels, ointments or creams, or in the form of nasal administration or suppositories. A pharmaceutical composition containing the compound of the present invention in free form or in a pharmaceutically acceptable salt form, together with at least one pharmaceutically acceptable carrier or diluent, can be manufactured by conventional methods by mixing, granulating or coating methods. For example, as an oral composition, it can be made into tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and the active ingredient, etc. In addition, as an injection composition, it can be made into a solution or suspension, can also be sterilized, and can also contain preservatives, stabilizers, buffers, etc.

[1573] Industrial Applicability

[1574] The compound according to the present invention has serotonin 5-HT2A receptor antagonist and / or inverse agonist activity and serotonin 5-HT2C receptor antagonist and / or inverse agonist activity, and is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions related to serotonin 5-HT2A receptor and / or serotonin 5-HT2C receptor.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein, R 1 is a substituted or unsubstituted six-membered aromatic heterocyclic group, or a substituted or unsubstituted five-membered aromatic heterocyclic group (excluding substituted or unsubstituted tetrazolyl groups and substituted or unsubstituted tetrazolone groups), a substituted or unsubstituted six-membered aromatic carbocyclic group, a substituted or unsubstituted bicyclic nine-membered non-aromatic heterocyclic group, or a substituted or unsubstituted bicyclic ten-membered non-aromatic heterocyclic group; A 1 is CR 2 or N; A 2 is CR 3 or N; A 3 is CR 4 or N; R 2 , R 3 and R 4 are one of the following (i) or (ii): (i)R 2 、R 3 and R 4 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group; (ii) In the case of A 1 being CR 2 , A 2 being CR 3 , A 3 being CR 4 or N, R 2 and R 3 , together with the carbon atom to which they are bonded, form a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring, and R 4 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic heterocyclic epoxy group, or a substituted or unsubstituted non-aromatic heterocyclic epoxy group; R 5 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R 15 and R 16 each independently represents a hydrogen atom, or a substituted or unsubstituted alkyl group; or R 15 and R 16 may together with the carbon atoms to which they are bonded form a substituted or unsubstituted non-aromatic carbocyclic ring; R 17 and R 18 each independently is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group; or R 17 and R 18 may together with the carbon atoms to which they are bonded form a substituted or unsubstituted non-aromatic carbocyclic ring.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 15 and R 16 is a hydrogen atom, and R 17 and R 18 are each independently a hydrogen atom, a halogen, or an alkyl group.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 15 、R 16 、R 17 and R 18 are hydrogen atoms.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein, R 1 is a group represented by the following formula: Wherein, R 6 and R 7 each independently represents a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a cyano group, or a substituted or unsubstituted non-aromatic carbocyclic group (wherein, R 6 When R is a hydrogen atom 7 R is a halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, or substituted or unsubstituted non-aromatic carbocyclic group); R 8 and R 9 each independently represents a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a cyano group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, or a substituted or unsubstituted non-aromatic heterocyclic epoxy group; R 31 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group; R 32 and R 33 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein, R 1 is a group represented by the following formula: Wherein, R 6 and R 7 each independently is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or cyano; R 8 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic radical, or a substituted or unsubstituted non-aromatic heterocyclic radical; R 31 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted non-aromatic carbocyclic group.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein, A 1 is CR 2 or N; A 2 is CR 3 or N; A 3 is CR 4 or N; R 2 , R 3 and R 4 is the following (i-1): (i-1)R 2 and R 3 each independently represents a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group, and R 4 is a hydrogen atom.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein, A 1 is CR 2 or N; A 2 is CR 3 or N; A 3 is CR 4 or N; R 2 , R 3 and R 4 are the following (i - 2): (i-2)R 2 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, R 3 and R 4 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, A 1 is CR 2 or N; A 2 is CR 3 or N; A 3 is CR 4 or N; R 2 , R 3 and R 4 are as follows for (i - 3): (i-3)R 2 is a hydrogen atom, R 3 and R 4 each independently represents a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic heterocyclic epoxy group, or a substituted or unsubstituted non-aromatic heterocyclic epoxy group.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein, A 1 is CR 2 or N; A 2 is CR 3 or N; A 3 is CR 4 or N; R 2 、R 3 and R 4 are the following (i - 4): (i-4)R 3 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, R 2 and R 4 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein, A 1 is CR 2 or N; A 2 is CR 3 or N; A 3 is CR 4 or N; R 2 、R 3 and R 4 are as follows (i - 5): (i-5)R 3 is a hydrogen atom or a halogen, R 2 and R 4 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic oxy group, a substituted or unsubstituted non-aromatic carbocyclic oxy group, a substituted or unsubstituted aromatic heterocyclic oxy group, or a substituted or unsubstituted non-aromatic heterocyclic oxy group.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein, (i’)A 1 is CH, A 2 is N, and A 3 is CH; or (ii’)A 1 is CH, and A 2 is CR 3 , where R 3 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group, and A 3 is N.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein, R 5 is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic group.

13. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein, R 5 is a substituted or unsubstituted six-membered aromatic heterocyclic group, or a substituted or unsubstituted phenyl group.

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein, R 5 is a group represented by the following formula: Wherein, R 10 and R 13 each independently represents a hydrogen atom, a cyano group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkyl group; R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkylcarbonyl group or a cyano group; B 1 is CR 11 or N; B 2 is CR 12 or N; R 11 and R 12 each independently represents a hydrogen atom, a halogen, a methoxy group, a methyl group or a halomethyl group.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein, (i”)B 1 is N, and B 2 is CR 12 ; or (ii”)B 1 and B 2 is N.

16. The compound according to claim 14 or 15, or a pharmaceutically acceptable salt thereof, wherein, R 14 is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, or a substituted or unsubstituted non-aromatic carbocyclic group.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from Compound I-006, I-062, I-063, I-073, I-127, I-200, I-211, I-247, I-257, I-266, I-267, I-271, I-359, I-376 and I-378.

18. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

19. The pharmaceutical composition according to claim 18, which is a serotonin 5-HT2A receptor antagonist and / or inverse agonist.

20. The pharmaceutical composition according to claim 18, which is an antagonist and / or inverse agonist of serotonin 5-HT2A receptor and serotonin 5-HT2C receptor.

21. A method for treating and / or preventing a disease associated with the serotonin 5-HT2A receptor, characterized in that, Administering the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

22. A method for treating and / or preventing a disease associated with serotonin 5-HT2A and serotonin 5-HT2C receptors, characterized in that, Administering the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, which is used for treating and / or preventing diseases related to an antagonist and / or inverse agonist of serotonin 5-HT2A receptor.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, which is used for treating and / or preventing diseases related to an antagonist and / or inverse agonist of serotonin 5-HT2A receptor and serotonin 5-HT2C receptor.

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