Aromatic heterocycle derivatives and aromatic carbocycle derivatives having PDE4d inhibitory activity

Abstract

Provided are compounds having phosphodiesterase 4D inhibitory activity, pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising thereof. A compound represented by Formula (I) wherein R1 is substituted or unsubstituted aromatic heterocyclyl or the like; R2 is substituted or unsubstituted alkyloxy or the like; R3 and R4 are hydrogen atoms or the like; R7 is a group represented by formula (AA) or the like; wherein R8 and R9 are hydrogen atoms or the like; R5 is hydroxy or the like; R6 is a hydrogen atom or the like; a divalent group represented by formula (BB) is a divalent group represented by formula (CC) or the like wherein R21 is each independently substituted or unsubstituted C1-C3 alkyl or the like; n is 0 or the like; the atom marked "a" binds to the group represented by the formula (DD) the atom marked "b" binds to R7; X is N or the like, or a pharmaceutically acceptable salt thereof.

Description

TITLE OF THE INVENTION: AROMATIC HETEROCYCLE DERIVATIVES AND AROMATIC CARBOCYCLE DERIVATIVES HAVING PDE4D INHIBITORY ACTIVITY [TECHNICAL FIELD]

[0001] The present invention relates to a compound having phosphodiesterase 4D ((hereinafter, also referred to as "PDE4D") inhibitory activity and useful in the treatment and / or prevention of a disease caused by PDE4D or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising thereof. [BACKGROUND ART]

[0002] Dementia is a clinical syndrome characterised by several signs such as difficulties in memory, disturbances in language, psychological and psychiatric changes, and impairments in activities of daily living. Dementia is mainly induced by neurodegenerative disorder (ND) such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and Lewy bodies disease (Non-patent Document 1). 10003] For the most common disorders of NDs, including Parkinson's disease and Alzheimer's disease, genetic factors that cause these rare familial diseases have been discovered, but for the majority of sporadic cases, the pathogenesis is not uncovered yet. Therefore, there are few specific therapeutic agents to inhibit the progression of the disease although Ap antibodies such as Aducanumab and Lecanemab have recently approved as the treatment of Alzheimer’s disease. Instead, clinicians utilize a variety of existing agents to achieve symptom relief of several symptoms including dementia.

[0004] To relieve the declined cognitive function, cholinesterase inhibitors and glutamate regulators are often used in the clinic. For example, cholinesterase inhibitors such as donepezil is mainly treated for patients with mild-tomoderate AD, and memantine, which is an NMDA antagonist, is for patients with moderate-to-severe AD. However, these existing therapeutic drugs induce several adverse effects including vomiting, nausea, diarrhea and dizziness (Non-patent Documents 2 and 3). Also, there is no worldwide approved therapeutics drugs for dementia other than AD.

[0005] The cyclic AMP (cAMP)—protein kinase A (PKA)-cAMP-response element binding protein (CREB) pathway is fundamental to early and late stages of memory formation (Non-patent Document 4). Phosphodiesterase 4 (PDE4) is the primary cAMP-specific hydrolase. The inhibition of PDE4 increases cAMP and phosphorylated CREB (Non-patent Document 5). It has been reported that a null mutation of PDE4 disrupted memory by allowing the unregulated accumulation of cAMP within neurons (Non-patent Documents 6 and 7). Therefore, PDE4 is an attractive target for dementia, but no PDE4 inhibitors have been brought to market for central nervous system diseases because of issues related to tolerability, such as emesis and diarrhea.

[0006] PDE4 consists of four isoforms (A, B. C and D). Although the inhibition of PDE4 causes emesis, the selective inhibition of Phosphodiesterase 4D (PDE4D) can avoid it (Non-patent Document 8). In addition, the selective inhibition of PDE4D improves memory deficit (Non-patent Documents 8 and 9). Therefore, selective PDE4D inhibitors can be a therapeutic target for dementia with reduced side effects which are related to the non-selective inhibition of PDE4.

[0007] Patent Documents 1 to 1 8 and non Patent Documents 10 to 28 disclose compounds having PDE4D inhibitory activity, but any of the documents neither disclose nor suggest the compounds related to the present invention. [PRIOR ART REFERENCES] [Patent Document]

[0008] [Patent Document 1] International Publication WO2006 / 123639 [Patent Document 2] International Publication WO2009 / 067600 [Patent Document 3] International Publication WO2009 / 067621 [Patent Document 4] International Publication WO2013 / 123766 [Patent Document 5] International Publication WO2014 / 066659 [Patent Document 6] International Publication WO2020 / 219615 [Patent Document 7] China Patent Application Publication CN108997122 [Patent Document 8] International Publication WO2015 / 048407 [Patent Document 9] International Publication WO2016 / 049595 [Patent Document 10] International Publication WO2010 / 059836 [Patent Document 11] International Publication WO2010 / 059838 [Patent Document 12] International Publication WO03 / 078397 [Patent Document 13] International Publication WO2014 / 158998 [Patent Document 14] International Publication WO94 / 22852 [Patent Document 15] International Publication WO97 / 18208 [Patent Document 16] International Publication WO2007 / 084560 [Patent Document 17] International Publication WO2009 / 067604 [Patent Document 18] International Publication WO2009 / 067618 [Non-patent Document] 10009] [Non-patent Document 1] BMJ, 338: b75 (2009) [Non-patent Document 2] CNS Neurosci Ther, 2018 Oct; 24(10): 876 ■ 888. [Non-patent Document 3] Gurr Alzheimer Res. 2018 Oct; 15(10): 964 ■ 974. [Non patent Document 4] Am J Hum Genet. 2012; 90: 746 - 751. [Non-patent Document 5] Neuropsychopharmacology. 2009 Oct;34(l 1):2404-2419. [Non-patent Document 6] Neuron. 2010; 65: 516 ■ 529. [Non-patent Document 7] Neuron. 2009: 64: 510 - 521. [Non-patent Document 8] Neuropsychopharmacology. 2018; 43: 2299 ■ 2309. [Non-patent Document 9] J Neurosci. 2011 Jan 5; 31(1): 172 - 183. [Non-patent Document 10] J. Med. Chem. 2015, 58, 6747 ■ 6752. [Non-patent Document 11] British Journal of Pharmacology (2002) 135, 113 ■ 118. [Non-patent Document 12] J. Med. Chem. 2000, 43, 3820 ■ 3823. [Non-patent Document 13] Mol. Inf. 2016, 35. 369 ■ 381. [Non-patent Document 14] J. Med. Chem. 2023, 66, 1543 ■ 1561. [Non-patent Document 15] J. Med. Chem. 2019, 62, 4884 - 4901. [Non-patent Document 161 Nature Biotechnology. 2010, 28, 63 ■ 70. [Non-patent Document 17] ACS Chem. Neurosci. 2020, 11, 1311 ■ 1323. [Non-patent Document 18] Structure, Vol. 12, 2233 ■ 2247, December, 2004. [Non-patent Document 19] J. Med. Chem. 2022, 65, 4238 ■ 4254. [Non-patent Document 20] European Journal of Medicinal Chemistry 124 (2016) 82-102. [Non-patent Document 21] European Journal of Medicinal Chemistry 223 (2021) 113638. [Non-patent Document 22] Scientific Deports volume 7. Article number- 46320 (2017). [Non-patent Document 23] Biochemistry 2018, 57, 2876 - 2888. [Non-patent Document 24] Molecules 2022, 27(15), 4964. [Non-patent Document 25] J.Med.Chem.2020, 63, 10594 - 10617. [Non-patent Document 26] J.Med.Chem. 2001, 44, 2511'2522. [Non-patent Document 27] Bioorg. Med. Chem. Lett. 2010, 20, 5502’5505. [Non-patent Document 28] Int. J. Mol. Sci. 2024, 25, 8052. [SUMMARY OF THE INVENTION] [PROBLEMS TO BE SOLVED BY THE INVENTION]

[0010] An object of the present invention is to provide novel compounds having PDE4D inhibitory activity or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising thereof. Preferably the present invention is to provide novel compounds having an effect on PDE4D-related disease such as Alzheimer’s disease, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising thereof. [MEANS FOR SOLVING THE PROBLEM]

[0011] The present invention relates to the following items (1) to (24), (3'), (13'), (19’) and (21') to (24'). (1) A compound represented by Formula (I): wherein R1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl. or substituted or unsubstituted non-aromatic carbocyclyl; R2 is halogen, or substituted or unsubstituted alkyloxy; R3 and R4 are each independently a hydrogen atom, or halogen; R7 is a group represented by formula: wherein R8 and R9 are (i-1) or (ii-1) shown below; (i-1) Rs and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl: (ii-1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3’ to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen; R10 is substituted or unsubstituted alkyl (provided that dimethylamino methyl is excluded), substituted or unsubstituted non aromatic carbocyclyl. substituted or unsubstituted tetrahydrofuryl, or substituted or unsubstituted oxetanyl; R17 is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl; R11 is a hydrogen atom or substituted or unsubstituted alkyl; R12 is a hydrogen atom or substituted or unsubstituted alkyl; R13 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkvloxy, or substituted or unsubstituted alkylamino; R14 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R15 is a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylamino; R16 is a hydrogen atom, or substituted or unsubstituted alkyl; R31 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl. substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino; R32 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl: R33 is a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino; R34 is a hydrogen atom, or substituted or unsubstituted alkyl; R30 is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl; R3B is a hydrogen atom or substituted or unsubstituted alkyl; R30 is a hydrogen atom or substituted or unsubstituted alkyl; R37 is a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino; R38 is a hydrogen atom, or substituted or unsubstituted alkyl; R39 is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl; R40 is a hydrogen atom or substituted or unsubstituted alkyl; R41 is a hydrogen atom or substituted or unsubstituted alkyl; R26 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkvloxy, or substituted or unsubstituted alkylamino; R27 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R22 is a hydrogen atom or substituted or unsubstituted alkyl; R23 is a hydrogen atom or substituted or unsubstituted alkyl; R24 is a hydrogen atom or substituted or unsubstituted alkyl; R2B is a hydrogen atom or substituted or unsubstituted alkyl; Y is 0 or NR18; R18 is a hydrogen atom, or substituted or unsubstituted alkyl; RB and R6 are (i-2) or (ii-2) shown below: (i-2) R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; RB is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl; (provided that when R7 is a group represented by formula: wherein each symbol is as defined above, R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl: and RB is hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl); (ii-2) RB and R 6 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z: a divalent group represented by formula: is a divalent group represented by formula: wherein R21 is each independently substituted or unsubstituted C1-C3 alkyl, or halogen; m is 0 or 1; n is an integer from 0 to 2; p is an integer from 0 to 4 (provided that when R10 is methyl, p is 0); q is an integer from 0 to 3; the atom marked “a” binds to the group represented by the formula: R1 ; the atom marked “b” binds to R7; X is CR19 or N; R19 is a hydrogen atom, or halogen: or a pharmaceutically acceptable salt thereof. (2) The compound according to the item (1), wherein R7 is a group represented by formula: wherein each symbol is as defined in the item (1), or a pharmaceutically acceptable salt thereof. (3) The compound according to the item (1), wherein Formula (l) is a formula represented by Formula (II): R4 OH wherein R1 is substituted or unsubstituted aromatic heterocyclyl. substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic carbocyclyl; R2 is halogen, or substituted or unsubstituted alkyloxy; R3 and R4 are each independently a hydrogen atom, or halogen; R8 and R9 are (i-1) or (ii-1) shown below; (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1C3 alkyl; (ii- 1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3- to 6-membered non aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1C3 alkyl and halogen; a divalent group represented by formula: is a divalent group represented by formula: wherein R21 is each independently substituted or unsubstituted C1-C3 alkyl or halogen; m is 0 or 1; n is an integer from 0 to 2: p is an integer from 0 to 4; q is an integer from 0 to 3; the atom marked “a" binds to the group represented by the formula: R4 OH R1 • the atom marked “b” binds to the group represented by the formula: X is CR19 or N; R19 is a hydrogen atom, or halogen; or a pharmaceutically acceptable salt thereof. (3 ). The compound according to the item (1), wherein Formula (l) is a formula represented by Formula (II ): R4 OH wherein each symbol has the same meaning as defined in the item (3) or a pharmaceutically acceptable salt thereof. (4) The compound according to any one of the items (1) to (3) and (3’), wherein a divalent group represented by formula: is a divalent group represented by formula: wherein each symbol is as defined in the item (1), or a pharmaceutically acceptable salt thereof. (5) The compound according to any one of the items (1) to (4) and (3’), wherein m is 0, n is 0 and q is 0. or a pharmaceutically acceptable salt thereof. (6) The compound according to the item (1), wherein Formula (I) is a formula represented by Formula (III): wherein R1 is substituted or unsubstituted aromatic heterocyclyl. substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic carbocyclyl; R2 is halogen, or substituted or unsubstituted alkyloxy! R3 and R4 are each independently a hydrogen atom, or halogen; R8 and R9 are (i-1) or (ii-1) shown below; (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1C3 alkyl; (ii- 1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3’ to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1C3 alkyl and halogen: R10 is substituted or unsubstituted alkyl (provided that methyl and dimethylamino methyl are excluded); R17 is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl; Re and R6 are (i-2) or (ii-2) shown below; (1-2) RB is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl; R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl: (ii-2) Rc and R6 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z; a divalent group represented by formula: is a divalent group represented by formula: wherein R21 is each independently substituted or unsubstituted C1-C3 alkyl, or halogen: m is 0 or 1! n is an integer from 0 to 2; p is an integer from 0 to 4: q is an integer from 0 to 3; the atom marked “a'’ binds to the group represented by the formula: R1 ; the atom marked “b” binds to the group represented by the formula: R17 X is CR19 or N; R19 is a hydrogen atom or halogen! or a pharmaceutically acceptable salt thereof. (7) The compound according to any one of the items (1) to (6) and (3’), wherein R10 is alkyl substituted with hydroxy! or a pharmaceutically acceptable salt thereof. (8) The compound according to any one of the items (1) to (7) and (3’), wherein RB is a hydrogen atom, or hydroxy! andR6 is a hydrogen atom! or a pharmaceutically acceptable salt thereof. (9) The compound according to any one of the items (1) to (8) and (3’), wherein a divalent group represented by formula: is a divalent group represented by formula: wherein each symbol is as defined in the item (1), or a pharmaceutically acceptable salt thereof. (10) The compound according to the item (9), wherein p is 0, n is 0, and q is 0, or a pharmaceutically acceptable salt thereof. (11) The compound according to any one of the items (1) to (10) and (3’), wherein R17 is a hydrogen atom, or substituted or unsubstituted C1'C3 alkyl, or a pharmaceutically acceptable salt thereof. (12) The compound according to any one of the items (1) to (10) and (3’), wherein R17 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. (13) The compound according to any one of the items (1) to (12) and (3’). wherein R8 and R9 are (i'3) or (ii'3) shown below; (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl; (ii-3) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle, or a 3- to 6-membered non-aromatic heterocycle, or a pharmaceutically acceptable salt thereof. (13 ) The compound according to any one of items (1) to (12) and (3’), wherein R8 and R9 are (i-3) shown below; (i-3) R8 and R9 may be each independently a hydrogen atom, or C1-C3 alkyl, or a pharmaceutically acceptable salt thereof. (14) The compound according to any one of items (1) to (12) and (3’), wherein R8 and R9 are (i-4) shown below: (1-4) R8 is a hydrogen atom and R9 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. (15) The compound according to any one of the items (1) to (14), (3’) and (13’). wherein R2 is substituted or unsubstituted methyloxy, or a pharmaceutically acceptable salt thereof. (16) The compound according to any one of the items (1) to (14), (3’) and (13’), wherein R2 is halomethyloxy or unsubstituted methyloxy, or a pharmaceutically acceptable salt thereof. (17) The compound according to any one of the items (1) to (16). (3’) and (13 ), wherein R1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non aromatic heterocyclyl. or substituted or unsubstituted aromatic carbocyclyl, or a pharmaceutically acceptable salt thereof. (18) The compound according to any one of the items (1) to (16). (3’) and (13’), wherein R1 is substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, or a pharmaceutically acceptable salt thereof. (19) The compound according to the item (1), wherein the compound is selected from the group consisting of compounds 1-014, 1-026. 1 041. 1-046, 1-099, I-107, 1'116, 1'152, 1'153, 1 155 and 1'168, or a pharmaceutically acceptable salt thereof. (19 ) The compound according to the item (1). wherein the compound is selected from the group consisting of OH OH or a pharmaceutically acceptable salt thereof. (20) A pharmaceutical composition comprising the compound according to any one of the items (1) to (19), (3 ), (13’) and (19), or a pharmaceutically acceptable salt thereof. (21) The pharmaceutical composition according to the item (20), for the treatment and / or prevention a disease associated with PDE4D and / or cAMP signaling, or a symptom of a disease related to PDE4D and / or cAMP signaling. (21’) The pharmaceutical composition according to the item (20) or (21), wherein the compound or a pharmaceutically acceptable salt thereof have 10-fold or more selectivity for a human PDE4D inhibitory activity over a human PDE4B inhibitory activity. (22) A method for treating and / or preventing a disease associated with PDE4D and / or cAMP signaling, or a symptom of a disease related to PDE4D and / or cAMP signaling, comprising administering an effective amount of the compound according to any one of the items (1) to (19), (3 ), (13’) and (19 ), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. (22 ) The method according to the item (22), wherein the compound or a pharmaceutically acceptable salt thereof have 10-fold or more selectivity for a human PDE4D inhibitory activity over a human PDE4B inhibitory activity. (23) The compound according to any one of the items (1) to (19). (3’), (13 ) and (19’). or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention a disease associated with PDE4D and / or cAMP signaling, or a symptom of a disease related to PDE4D and / or cAMP signaling. (23 ) The compound according to the item (23), wherein the compound or a pharmaceutically acceptable salt thereof have 10-fold or more selectivity for a human PDE4D inhibitory activity over a human PDE4B inhibitory activity. (24) Use of the compound according to any one of the items (1) to (19), (3’), (13 ) and (19’), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating and / or preventing a disease associated with PDE4D and / or cAMP signaling, or a symptom of a disease related to PDE4D and / or cAMP signaling. (24’) The use according to the item (24), wherein the compound or a pharmaceutically acceptable salt thereof have 10-fold or more selectivity for a human PDE4D inhibitory activity over a human PDE4B inhibitory activity. [EFFECT OF THE INVENTION]

[0012] The compound according to the present invention has PDE4D inhibitory activity, and is useful as a therapeutic agent and / or prophylactic agent for PDE4D-related disease. [MODE FOR CARRYING OUT THE INVENTION]

[0013] Terms used in this description are explained below. Each term, unless otherwise indicated, has the same meaning when it is used alone or together with other terms. The term of “consisting of means having only components. The term of “comprising” means not restricting with components and not excluding undescribed factors. Hereinafter, the present invention is described with reference to embodiments. It should be understood that, throughout the present description, the expression of a singular form includes the concept of its plural form unless specified otherwise. Accordingly, it should be understood that an article in singular form (for example, in the English language, “a”, “an”, and “the”) includes the concept of its plural form unless specified otherwise. Furthermore, it should be understood that the terms used herein are used in a meaning normally used in the art unless specified otherwise. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field to which the present invention pertains. If there is a contradiction, the present description (including definitions) precedes.

[0014] The term “halogen” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A fluorine atom and a chlorine atom are especially preferable.

[0015] The term “alkyl” includes a Cl to C15, preferably Cl to CIO, more preferably Cl to C6, further preferably Cl to C4, and particularly preferably Cl to C3 linear or branched hydrocarbon group. Examples include methyl, ethyl, npropyl. isopropyl, nbutyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n nonyl. and n-decyl. Preferred embodiments of “alkyl” include methyl, ethyl, n propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n pentyl. More preferred embodiments include methyl, ethyl, n propyl. isopropyl, and tert butyl.

[0016] The term “haloalkyl” means the above alkyl substituted with one or more halogen(s). When substituted with two or more halogens, the halogens may be the same or different. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2,2'difluoroethyl, 2.2,2-trifluoroethyl, 2,2'difluoropropyl, 3,3,3’ trifluoropropyl, 2,2,3,3 tetrafluoropropyl, and 2,2,3,3,3-pentafluoropropyl.

[0017] The term “alkenyl” includes a C2 to C15, preferably C2 to CIO, more preferably C2 to C6, and further preferably C2 to C4 linear or branched hydrocarbon group having one or more double bond(s) at any position(s). Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl and n-propenyl.

[0018] The term “alkynyl” includes a C2 to CIO, preferably C2 to C8, more preferably C2 to C6, and further preferably C2 to C4 linear or branched hydrocarbon group having one or more triple bond(s) at any position(s). Furthermore, it may have double bond(s) at any position(s). Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Preferred embodiments of “alkynyl” include ethynyl. propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl and propynyl.

[0019] The term “aromatic carbocyclyl” means a cyclic aromatic hydrocarbon group, which is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. Preferred embodiments of the “aromatic carbocyclyl" include phenyl.

[0020] The term “aromatic carbocycle” means a ring derived from the above “aromatic carbocyclyl”.

[0021] The term “non-aromatic carbocyclyl” means a cyclic saturated hydrocarbon group or a cyclic non aromatic unsaturated hydrocarbon group, which is monocyclic or polycyclic having two or more rings. The “non-aromatic carbocyclyl” which is polycyclic having two or more rings includes a fused ring group wherein a nonaromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”. In addition, examples of the “non-aromatic carbocyclyl" also include a group having a bridge or a group to form a spiro ring as follows: The non-aromatic carbocyclyl which is monocyclic is preferably C3 to C16, more preferably C3 to C12, and further preferably C3 to C6 carbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The non-aromatic carbocyclyl which is polycyclic having two or more rings is preferably C8 to C20, more preferably C8 to C16 carbocyclyl. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0022] The term “non aromatic carbocycle” means a ring derived from the above “nonaromatic carbocyclyl”.

[0023] The term “3- to 6 membered non-aromatic carbocycle that Rs and R9 are taken together with the carbon atom to which they are attached to form” mean rings as follows as examples.

[0024] The term “3- to 6 membered non-aromatic carbocycle that RB and R6 are taken together with the carbon atom to which they are attached to form” means nonaromatic carbocycles as follows as examples.

[0025] The term “aromatic heterocyclyl” means an aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected optionally from O, S. and N. The aromatic heterocyclyl which is polycyclic having two or more rings includes a fused ring group wherein an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”, the bond may be held in any ring. The aromatic heterocyclyl which is monocyclic is preferably a 5- to 8-membered ring and more preferably a 5- or 6-membered ring. Examples of the 5-membered aromatic heterocyclyl include pyrrolyl. imidazolyl, pyrazolyl, triazolyl. tetrazolyl, furyl, thienyl, isoxazolyl. oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of the 6-membered aromatic heterocyclyl include pyridyl, pyridazinyl, pyrimidinyl. pyrazinyl, and triazinyl. The aromatic heterocyclyl which is bicyclic is preferably an 8' to lO membered ring and more preferably a 9- or 10-membered ring. Examples of the aromatic heterocyclyl which is bicyclic include indolyl. isoindolyl, indazolyl, indolizinyl. quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl. quinazolinyl, naphthyridinyl. quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl. benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. Examples of the 9-membered aromatic heterocyclyl include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl. benzimidazolyl, benzisoxazolyl. benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl. benzotriazolyl, benzofuranyl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, and thiazolopyridyl. Examples of the 10-membered aromatic heterocyclyl include quinolinyl. isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, and pyrazinopyridazinyl. The aromatic heterocyclyl which is polycyclic having three or more rings is preferably a 13- to 15-membered ring. Examples of the aromatic heterocyclyl which is polycyclic having three or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0026] The term “aromatic heterocycle” means a ring derived from the above “aromatic heterocyclyl”.

[0027] The term “non-aromatic heterocyclyl” means a non-aromatic cyclyl. which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected optionally from 0, S, and N. The “non-aromatic heterocyclyl” which is polycyclic having two or more rings includes a non-aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl”, and / or “aromatic heterocyclyl”. and further includes a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, fused with a ring of the above “aromatic heterocyclyl”, the bond may be held in any ring. In addition, examples of the “non-aromatic heterocyclyl” also include a group having a bridge or a group to form a spiro ring as follows^ The non-aromatic heterocyclyl which is monocyclic is preferably a 3’ to 8’ membered ring and more preferably a 5- or 6-membered ring. Examples of the 3membered non-aromatic heterocyclyl include thiiranyl. oxiranyl, and aziridinyl. Examples of the 4 membered non aromatic heterocyclyl include oxetanyl and azetidinyl. Examples of the 5-membered non-aromatic heterocyclyl include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of the 6-membered non-aromatic heterocyclyl include dioxanyl, thianyl. piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl. tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of the 7-membered non-aromatic heterocyclyl include hexahydroazepinyl. tetrahydrodiazepinyl. and oxepanyl. Examples of the 8 membered non-aromatic heterocyclyl include azocane, thiocane, and oxocane. The non-aromatic heterocyclyl which is polycyclic having two or more rings is preferably an 8- to 20membered ring and more preferably an 8- to lO membered ring. Examples of the non-aromatic heterocyclyl which is polycyclic having two or more rings include indolinyl. isoindolinyl, chromanyl, 1,3-benzodioxolyl and isochromanyl.

[0028] The term “non-aromatic heterocycle” means a ring derived from the above “nonaromatic heterocyclyl”.

[0029] The term “3- to 6-membered non-aromatic heterocycle that R8 and R9 are taken together with the carbon atom to which they are attached to form” mean rings as follows as examples.

[0030] The term “trialkylsilyl” means a group in which the above three “alkyls” are bound to a silicon atom. The three alkyls may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert butyldimethylsilyl. [00311 In the present description, the phrase “may be substituted with substituent group a’' means that “may be substituted with one or more group(s) selected from substituent group a". The same also applies to substituent groups B, y, and Y •

[0032] Substituents for “substituted alkyl’, “substituted alkenyl”, “substituted alkynyT, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylcarbonyloxy”, “substituted alkenylcarbonyloxy”, “substituted alkynylcarbonyloxy”, “substituted alkylcarbonyl", “substituted alkenylcarbonyl”, “substituted alkynylcarbonyl”, “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonvl”, “substituted alkynyloxycarbonyl”. “substituted alkylsulfanyl”, “substituted alkenylsulfanyl”. “substituted alkynylsulfanyl”, “substituted alkylsulfinyl”, “substituted alkenylsulfinyl”, “substituted alkynylsulfinyl”, “substituted alkylsulfonyl”, “substituted alkenylsulfonyl”, “substituted alkynylsulfonyl”, and the like include the following substituent group A. A carbon atom at any position may be bonded to one or more group(s) selected from the following substituent group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl. alkyloxy which may be substituted with substituent group a, alkenyloxy which may be substituted with substituent group a, alkynyloxy which may be substituted with substituent group a, alkylcarbonyloxy which may be substituted with substituent group a. alkenylcarbonyloxy which may be substituted with substituent group a. alkynylcarbonyloxy which may be substituted with substituent group a, alkylcarbonyl which may be substituted with substituent group a, alkenylcarbonyl which may be substituted with substituent group a, alkynylcarbonyl which may be substituted with substituent group a, alkyloxycarbonyl which may be substituted with substituent group a. alkenyloxycarbonyl which may be substituted with substituent group a, alkynyloxycarbonyl which may be substituted with substituent group a, alkylsulfanyl which may be substituted with substituent group a, alkenylsulfanyl which may be substituted with substituent group a, alkynylsulfanyl which may be substituted with substituent group a. alkylsulfinyl which may be substituted with substituent group a, alkenylsulfinyl which may be substituted with substituent group a, alkynylsulfinyl which may be substituted with substituent group a, alkylsulfonyl which may be substituted with substituent group a, alkenylsulfonyl which may be substituted with substituent group a, alkynylsulfonyl which may be substituted with substituent group a, amino which may be substituted with substituent group B, imino which may be substituted with substituent group B, carbamoyl which may be substituted with substituent group B, sulfamoyl which may be substituted with substituent group B, aromatic carbocyclyl which may be substituted with substituent group y, nonaromatic carbocyclyl which may be substituted with substituent group y’. aromatic heterocyclyl which may be substituted with substituent group y, non-aromatic heterocyclyl which may be substituted with substituent group y’, aromatic carbocyclyloxy which may be substituted with substituent group y. non aromatic carbocyclyloxy which may be substituted with substituent group y’, aromatic heterocyclyloxy which may be substituted with substituent group y, non-aromatic heterocyclyloxy which may be substituted with substituent group y’, aromatic carbocyclylcarbonyloxy which may be substituted with substituent group y, nonaromatic carbocyclylcarbonyloxy which may be substituted with substituent group y . aromatic heterocyclylcarbonyloxy which may be substituted with substituent group y, non-aromatic heterocyclylcarbonyloxy which may be substituted with substituent group y’, aromatic carbocyclylcarbonyl which may be substituted with substituent group y, non-aromatic carbocyclylcarbonyl which may be substituted with substituent group y', aromatic heterocyclylcarbonyl which may be substituted with substituent group y, non-aromatic heterocyclylcarbonyl which may be substituted with substituent group y , aromatic carbocyclyloxycarbonyl which may be substituted with substituent group y, nonaromatic carbocyclyloxycarbonyl which may be substituted with substituent group y, aromatic heterocyclyloxycarbonyl which may be substituted with substituent group y, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group y’, aromatic carbocyclylalkyloxy which may be substituted with substituent group y, non-aromatic carbocyclylalkyloxy which may be substituted with substituent group y’, aromatic heterocyclylalkyloxy which may be substituted with substituent group y, non-aromatic heterocyclylalkyloxy which may be substituted with substituent group y', aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group y, non aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group y', aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group y, non-aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group y , aromatic carbocyclylsulfanyl which may be substituted with substituent group y, non aromatic carbocyclylsulfanyl which may be substituted with substituent group y', aromatic heterocyclylsulfanyl which may be substituted with substituent group y, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group y’, aromatic carbocyclylsulfinyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group y’, aromatic heterocyclylsulfinyl which may be substituted with substituent group y. non-aromatic heterocyclylsulfinyl which may be substituted with substituent group y', aromatic carbocyclylsulfonyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group y', aromatic heterocyclylsulfonyl which may be substituted with substituent group y, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group y’.

[0033] Substituent group a: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0034] Substituent group B- halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with substituent group a, alkenyl which may be substituted with substituent group a, alkynyl which may be substituted with substituent group a, alkylcarbonyl which may be substituted with substituent group a, alkenylcarbonyl which may be substituted with substituent group a. alkynylcarbonyl which may be substituted with substituent group a, alkylsulfanyl which may be substituted with substituent group a. alkenylsulfanyl which may be substituted with substituent group a, alkynylsulfanyl which may be substituted with substituent group a. alkylsulfinyl which may be substituted with substituent group a, alkenylsulfinyl which may be substituted with substituent group a. alkynylsulfinyl which may be substituted with substituent group a, alkylsulfonyl which may be substituted with substituent group a, alkenylsulfonyl which may be substituted with substituent group u, alkynylsulfonyl which may be substituted with substituent group u, aromatic carbocyclyl which may be substituted with substituent group y, nonaromatic carbocyclyl which may be substituted with substituent group y • aromatic heterocyclyl which may be substituted with substituent group y, nonaromatic heterocyclyl which may be substituted with substituent group y’, aromatic carbocyclylalkyl which may be substituted with substituent group y. non aromatic carbocyclylalkyl which may be substituted with substituent group y’, aromatic heterocyclylalkyl which may be substituted with substituent group y, non-aromatic heterocyclylalkyl which may be substituted with substituent group y’, aromatic carbocyclylcarbonyl which may be substituted with substituent group y, non aromatic carbocyclylcarbonyl which may be substituted with substituent group y’, aromatic heterocyclylcarbonyl which may be substituted with substituent group y, nonaromatic heterocyclylcarbonyl which may be substituted with substituent group y’, aromatic carbocyclyloxycarbonyl which may be substituted with substituent group y, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group y’, aromatic heterocyclyloxycarbonyl which may be substituted with substituent group y, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group y', aromatic carbocyclylsulfanyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfanyl which may be substituted with substituent group y’, aromatic heterocyclylsulfanyl which may be substituted with substituent group y, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group y’, aromatic carbocyclylsulfinyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group y , aromatic heterocyclylsulfinyl which may be substituted with substituent group y, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group y", aromatic carbocyclylsulfonyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group y", aromatic heterocyclylsulfonyl which may be substituted with substituent group y, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group y’.

[0035] Substituent group y: substituent group a, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0036] Substituent group y’: substituent group y and oxo.

[0037] The substituents on the rings of “aromatic carbocycle’’ and “aromatic heterocycle", such as “substituted aromatic carbocyclyl"’. “substituted aromatic heterocyclyl”, “substituted aromatic nitrogen-containing heterocyclyl”, “substituted aromatic carbocyclyloxy”. “substituted aromatic heterocyclyloxy”. “substituted aromatic carbocyclylcarbonyloxy”, “substituted aromatic heterocyclylcarbonyloxy”, “substituted aromatic carbocyclylcarbonyl”, “substituted aromatic heterocyclylcarbonyl”. “substituted aromatic carbocyclyloxycarbonyl”, “substituted aromatic heterocyclyloxycarbonyl”, “substituted aromatic carbocyclylsulfanyl”. “substituted aromatic heterocyclylsulfanyl”, “substituted aromatic carbocyclylsulfinyl", “substituted aromatic heterocyclylsulfinyl", “substituted aromatic carbocyclylsulfonyl”, and “substituted aromatic heterocyclylsulfonyl” include the following substituent group B. An atom at any position on the ring may be bonded to one or more group(s) selected from the following substituent group B. Substituent group B- halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyl which may be substituted with substituent group a. alkenyl which may be substituted with substituent group a, alkynyl which may be substituted with substituent group a, alkyloxy which may be substituted with substituent group a, alkenyloxy which may be substituted with substituent group a. alkynyloxy which may be substituted with substituent group a, alkylcarbonyloxy which may be substituted with substituent group a. alkenylcarbonyloxy which may be substituted with substituent group a, alkynylcarbonyloxy which may be substituted with substituent group a, alkylcarbonyl which may be substituted with substituent group a, alkenylcarbonyl which may be substituted with substituent group a, alkynylcarbonyl which may be substituted with substituent group a. alkyloxycarbonyl which may be substituted with substituent group a, alkenyloxycarbonyl which may be substituted with substituent group a, alkynyloxycarbonyl which may be substituted with substituent group a, alkylsulfanyl which may be substituted with substituent group a. alkenylsulfanyl which may be substituted with substituent group a. alkynylsulfanyl which may be substituted with substituent group a, alkylsulfinyl which may be substituted with substituent group a, alkenylsulfinyl which may be substituted with substituent group a, alkynylsulfinyl which may be substituted with substituent group a, alkylsulfonyl which may be substituted with substituent group a. alkenylsulfonyl which may be substituted with substituent group a, alkynylsulfanyl which may be substituted with substituent group a, amino which may be substituted with substituent group B, imino which may be substituted with substituent group B, carbamoyl which may be substituted with substituent group B, sulfamoyl which may be substituted with substituent group B, aromatic carbocyclyl which may be substituted with substituent group y, nonaromatic carbocyclyl which may be substituted with substituent group y’. aromatic heterocyclyl which may be substituted with substituent group y, non-aromatic heterocyclyl which may be substituted with substituent group y’, aromatic carbocyclyloxy which may be substituted with substituent group y. non aromatic carbocyclyloxy which may be substituted with substituent group y’, aromatic heterocyclyloxy which may be substituted with substituent group y, non-aromatic heterocyclyloxy which may be substituted with substituent group y’, aromatic carbocyclylcarbonyloxy which may be substituted with substituent group y. nonaromatic carbocyclylcarbonyloxy which may be substituted with substituent group y', aromatic heterocyclylcarbonyloxy which may be substituted with substituent group y, and non-aromatic heterocyclylcarbonyloxy which may be substituted with substituent group y', aromatic carbocyclylcarbonyl which may be substituted with substituent group y, non-aromatic carbocyclylcarbonyl which may be substituted with substituent group y’, aromatic heterocyclylcarbonyl which may be substituted with substituent group y, non-aromatic heterocyclylcarbonyl which may be substituted with substituent group y • aromatic carbocyclyloxycarbonyl which may be substituted with substituent group y, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group y’, aromatic heterocyclyloxycarbonyl which may be substituted 20 with substituent group y, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group y’, aromatic carbocyclylalkyl which may be substituted with substituent group y, non-aromatic carbocyclylalkyl which may be substituted with substituent group y’, aromatic heterocyclylalkyl which may be substituted with substituent group y, non-aromatic heterocyclylalkyl which may be substituted with substituent group y > aromatic carbocyclylalkyloxy which may be substituted with substituent group y, non-aromatic carbocyclylalkyloxy which may be substituted with substituent group y’, aromatic heterocyclylalkyloxy which may be substituted with substituent group y, non-aromatic heterocyclylalkyloxy which may be substituted with substituent group y’, aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group y, non aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group y’, aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group y. non-aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group y’, aromatic carbocyclylalkyloxyalkyl which may be substituted with substituent group y, non-aromatic carbocyclylalkyloxyalkyl which may be substituted with substituent group y’, aromatic heterocyclylalkyloxyalkyl which may be substituted with substituent group y, non-aromatic heterocyclylalkyloxyalkyl which may be substituted with substituent group y’, aromatic carbocyclylsulfanyl which may be substituted with substituent group y, non aromatic carbocyclylsulfanyl which may be substituted with substituent group y’. aromatic heterocyclylsulfanyl which may be substituted with substituent group y. non aromatic heterocyclylsulfanyl which may be substituted with substituent group y’, aromatic carbocyclylsulfinyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group y’, aromatic heterocyclylsulfinyl which may be substituted with substituent group y, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group y’, aromatic carbocyclylsulfonyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group y’, aromatic heterocyclylsulfonyl which may be substituted with substituent group y, and nonaromatic heterocyclylsulfonyl which may be substituted with substituent group y’.

[0038] The substituents on the ring of “non aromatic carbocycle” and “non-aromatic heterocycle” of “substituted non-aromatic carbocyclyl”, “substituted non-aromatic heterocyclyl”, “substituted non-aromatic carbocycle that R5 and RG are taken together with the carbon atom to which they are attached to form”, “substituted non-aromatic heterocycle that R8 and R9 are taken together with the carbon atom to which they are attached to form”, “substituted nonaromatic carbocycle that R® and R9 are taken together with the carbon atom to which they are attached to form”, “substituted nonaromatic carbocyclyloxy”, “substituted non-aromatic heterocyclyloxy”, “substituted non-aromatic carbocyclylcarbonyloxy”, “substituted non-aromatic heterocyclylcarbonyloxy”, “substituted non aromatic carbocvclylcarbonyl”, “substituted non-aromatic heterocyclylcarbonyl”, “substituted non aromatic carbocyclyloxycarbonyl”, “substituted non-aromatic heterocyclyloxycarbonyl”, “substituted non-aromatic carbocyclylsulfanyl”, “substituted non-aromatic heterocyclylsulfanyl”, “substituted non-aromatic carbocyclylsulfinyl”, “substituted non-aromatic heterocyclylsulfinyl”, “substituted non-aromatic carbocyclylsulfonyl”, and “substituted non-aromatic heterocyclylsulfonyl” include the following substituent group C. An atom at any position on the ring may be bonded to one or more group(s) 21 selected from the following substituent group C. Substituent group C' substituent group B and oxo. [00391 When the “non-aromatic carbocycle”, and the “non-aromatic heterocycle” are substituted with “oxo”, this means a ring in which two hydrogen atoms on a carbon atom are substituted as follows-

[0040] The substituents for “substituted amino”, “substituted imino”, “substituted carbamoyl”, and “substituted sulfamoyl” include the following substituent group D. These moieties may be substituted with one or two group(s) selected from substituent group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with substituent group a, alkenyl which may be substituted with substituent group a, alkynyl which may be substituted with substituent group a, alkylcarbonyl which may be substituted with substituent group a, alkenylcarbonyl which may be substituted with substituent group a. alkynylcarbonyl which may be substituted with substituent group a, alkylsulfanyl which may be substituted with substituent group a. alkenylsulfanyl which may be substituted with substituent group a. alkynylsulfanyl which may be substituted with substituent group a. alkylsulfinyl which may be substituted with substituent group a, alkenylsulfinyl which may be substituted with substituent group a, alkynylsulfinyl which may be substituted with substituent group u, alkylsulfonyl which may be substituted with substituent group a. alkenylsulfonyl which may be substituted with substituent group a, alkynylsulfonyl which may be substituted with substituent group a, amino which may be substituted with substituent group B, imino which may be substituted with substituent group B, carbamoyl which maybe substituted with substituent group B, sulfamoyl which may be substituted with substituent group B, aromatic carbocyclyl which may be substituted with substituent group y, nonaromatic carbocyclyl which may be substituted with substituent group y'. aromatic heterocyclyl which may be substituted with substituent group y, nonaromatic heterocyclyl which may be substituted with substituent group y', aromatic carbocyclylalkyl which may be substituted with substituent group y. non aromatic carbocyclylalkyl which may be substituted with substituent group y', aromatic heterocyclylalkyl which may be substituted with substituent group y, non-aromatic heterocyclylalkyl which may be substituted with substituent group y', aromatic carbocyclylcarbonyl which may be substituted with substituent group y. non aromatic carbocyclylcarbonyl which may be substituted with substituent group y', aromatic heterocyclylcarbonyl which may be substituted with substituent group y, nonaromatic heterocyclylcarbonyl which may be substituted with substituent group y', aromatic carbocyclyloxycarbonyl which may be substituted with substituent group y, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group y', aromatic heterocyclyloxycarbonyl which may be substituted with substituent group y, non aromatic heterocyclyloxycarbonyl which may be substituted with substituent group y', aromatic carbocyclylsulfanyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfanyl which may be substituted with substituent group y', aromatic heterocyclylsulfanyl which may be substituted with substituent group y, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group y', aromatic carbocyclylsulfinyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group y', aromatic heterocyclylsulfinyl which may be substituted with substituent group y, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group y', aromatic carbocyclylsulfonyl which may be substituted with substituent group y, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group y', aromatic heterocyclylsulfonyl which may be substituted with substituent group y, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group y'.

[0041] The substituents of "substituted aromatic carbocyclyl" and "substituted aromatic heterocyclyl" in R1 include, for example, halogen, alkyl, haloalkyl. alkyloxy, haloalkyloxy. and cyano. The atoms at any positions on the ring may be substituted with one or more groups selected from these substituents. The substituents of "substituted non-aromatic carbocyclyl" and "substituted non-aromatic heterocyclyl" in R1 include, for example, halogen.

[0042] The substituents of "substituted alkyloxy" in R2 include, for example, halogen.

[0043] The substituents of "substituted C1-C3 alkyl" in R8 and R9 include, for example, halogen. The substituents of "3- to 6-membered non-aromatic carbocycle that R8 and R9 are taken together with the carbon atom to which they are attached to form” and "3-to 6-membered non-aromatic heterocycle that R8 and R9 are taken together with the carbon atom to which they are attached to form” include, for example, halogen.

[0044] The substituents of "substituted alkyl" in R10 include, for example, halogen, hydroxy, alkyloxy, aromatic heterocyclyl, and aromatic heterocyclyl substituted with alkyl. The carbon atoms at any positions may be substituted with one or more groups selected from these substituents.

[0045] The substituents of "substituted non-aromatic carbocyclyl", "substituted tetrahydrofuryl" and "substituted oxetanyl" in R10 include, for example, halogen, and hydroxy. The atoms at any positions on the ring may be substituted with one or more groups selected from these substituents.

[0046] The substituents of "substituted C1-C3 alkyl" in R17 include. for example, halogen.

[0047] The substituents of "substituted cyclopropyl" and "substituted cyclobutyl" in R17 include, for example, halogen.

[0048] The substituents of "substituted alkyl" in R11 and R12 include, for example, halogen. The substituents of "substituted alkyl" in R13 and R14 include, for example, halogen. The substituents of "substituted alkyloxy” and "substituted alkylamino" in R13 include, for example, halogen.

[0050] The substituents of "substituted alkyl" in R1B and R16 include, for example, halogen. The substituents of "substituted alkyloxy” and "substituted alkylamino" in R15 include, for example, halogen.

[0051] The substituents of "substituted alkyl" in R31 and R32 include, for example, halogen. The substituents of "substituted alkyloxy” and "substituted alkylamino" in R31 include, for example, halogen.

[0052] The substituents of "substituted alkyl" in R3S and R34 include, for example, halogen. The substituents of "substituted alkyloxy” and "substituted alkylamino" in R33 include, for example, halogen.

[0053] The substituents of "substituted C1-C3 alkyl" in R30 include, for example, halogen. The substituents of "substituted cyclopropyl" and "substituted cyclobutyl" in R30 include, for example, halogen.

[0054] The substituents of "substituted alkyl" in R3B and R36 include, for example, halogen.

[0055] The substituents of "substituted alkyl" in R37 and R38 include, for example, halogen. The substituents of "substituted alkyloxy” and "substituted alkylamino" in R37 include, for example, halogen.

[0056] The substituents of "substituted C1-C3 alkyl" in R39 include, for example, halogen. The substituents of "substituted cyclopropyl" and "substituted cyclobutyl" in R39 include, for example, halogen.

[0057] The substituents of "substituted alkyl" in R40 and R41 include, for example, halogen.

[0058] The substituents of "substituted alkyl" in R26 and R27 include, for example, halogen. The substituents of "substituted alkyloxy” and "substituted alkylamino" in R26 include, for example, halogen.

[0059] The substituents of "substituted alkyl" in R22 and R23 include, for example, halogen. The substituents of "substituted alkyl" in R24 and R2B include, for example, halogen.

[0061] The substituents of "substituted alkyl" in R18 include. for example, halogen.

[0062] The substituents of "substituted alkyl" in RB and R6 include, for example, halogen. The substituents of "3- to 6-membered non-aromatic carbocycle that RB and R6 are taken together with the carbon atom to which they are attached to form” include, for example, halogen. The substituents of "substituted alkyloxy" in RB include, for example, halogen.

[0063] The substituents of "substituted C1-C3 alkyl" in R21 include, for example, halogen.

[0064] With regard to a compound represented by Formula (I), preferred embodiments of R1, R2, R3, R4, R7, R8, R9, R10, R17, R11, R12, R13, R14, R1B, R16, R31, R32, R33, R34, R30, R3B, R36, R37, R3S, R39, R40, R41. R28, R27, R22, R23, R24, R2B, Y, R18. RB, R8, ring A, R21, m, n. p, q. X and R19 are shown below. Regarding the compound represented by Formula (I), embodiments of all the combinations of specific examples shown below are mentioned as examples. R1 may be substituted or unsubstituted aromatic heterocyclyl. substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic carbocyclyl (hereinafter, referred to as A-1). R1 may be substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted aromatic carbocyclyl (hereinafter, referred to as A-2). R1 may be substituted or unsubstituted aromatic heterocyclyl. or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as A-3). R1 may be substituted or unsubstituted 6 membered aromatic heterocyclyl, or substituted or unsubstituted 9-membered non-aromatic heterocyclyl (hereinafter, referred to as A-4). R1 may be substituted or unsubstituted pyridyl, or substituted or unsubstituted l,3benzodioxolyl (hereinafter, referred to as A-5). R1 may be pyridyl substituted with haloalkyloxy, pyridyl substituted with alkyloxy,or 1.3-benzodioxolyl substituted with halogen (hereinafter, referred to as A-6). R1 may be pyridyl substituted with halomethyloxy, pyridyl substituted with methyloxv,or 1.3-benzodioxolyl substituted with halogen (hereinafter, referred to as A-7). R1 may be 2 difluoromethyloxypyridin-4 yl, 2 methyloxypyridin-4-yl, or 2.2-difluoro-l,3-benzodioxol-5 yl (hereinafter, referred to as A-8). R1 may be 2-difluoromethyloxypyridin-4-yl (hereinafter, referred to as A9). R1 may be 2-methvloxypyridin-4-yl (hereinafter, referred to as A-10). R1 may be 2,2-difluoro-l,3benzodioxol-5-yl (hereinafter, referred to as A-11). R1 may be aromatic heterocyclyl substituted with haloalkyloxy or unsubstituted alkyloxy. or non-aromatic heterocyclyl substituted with halogen (hereinafter, referred to as A-12).

[0065] R2 may be halogen, or substituted or unsubstituted alkyloxy (hereinafter, referred to as B-l). R2 may be halogen, or substituted or unsubstituted methyloxy (hereinafter, referred to as B-2). R2 may be substituted or unsubstituted methyloxy (hereinafter, referred to as B-3). R2 may be halomethyloxy, or unsubstituted methyloxy (hereinafter, referred to as B-4). R2 may be difluoromethyloxy, or unsubstituted methyloxy (hereinafter, referred to as B'5). R2 may be halomethyloxy (hereinafter, referred to as B-6). R2 may be methyloxy (hereinafter, referred to as B 7). R2 may be difluoromethyloxv (hereinafter, referred to as B-8).

[0066] R3 may be a hydrogen atom, or halogen (hereinafter, referred to as Ol). R3 may be a hydrogen atom (hereinafter, referred to as 02). R3 may be halogen (hereinafter, referred to as 03).

[0067] R4 may be a hydrogen atom, or halogen (hereinafter, referred to as D-l). R4 may be a hydrogen atom (hereinafter, referred to as D-2). R4 may be halogen (hereinafter, referred to as D-3).

[0068] R7 may be a group represented by formula: R17 R8 Ra o or wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as E-l). R7 may be a group represented by formula: R8 Ra O or wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as E-2). R7 may be a group represented by formula: or wherein R8 and R9 are (i-1) or (ii-1) shown below; (r 1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1C3 alkyl; (ii- 1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, 27 or a 3’ to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen; R10 is substituted alkyl (provided that dimethylamino methyl is excluded); R17 is a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl; R15 is a hydrogen atom, or hydroxy; Y is 0 (hereinafter, referred to as E-3). R7 may be a group represented by formula: or wherein R8 and R9 may be (i-3) shown below! (r3) Rs and R9 may be each independently a hydrogen atom, or C1C3 alkyl; R10 is alkyl substituted with hydroxy: R17 is a hydrogen atom; R1B is a hydrogen atom, or hydroxy; Y is 0 (hereinafter, referred to as E-4). R7 may be a group represented by formula: wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as E-5). R7 may be a group represented by formula: R8 Ry o 10 wherein R8 and R9 are (i-1) or (ii-1) shown below: (il) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl; (ii-1) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3' to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3’ to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen; R10 is substituted alkyl (provided that dimethylamino methyl is excluded); R17 is a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl (hereinafter, referred to as E G). R7 may be a group represented by formula; .                               R17 R8 R9 or r8 r9 o wherein R8 and R9 are (i 3) shown below; (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkvl; R10 is alkyl substituted with hydroxy; R17 is a hydrogen atom (hereinafter, referred to as E-7). R7 may be a group represented by formula; R8 R9 wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as E-8). R7 may be a group represented by formula: R8 R9 wherein R8 and R9 are (i-1) or (ii-1) shown below; (i-1) Rs and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl; (ii-1) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3’ to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen (hereinafter, referred to as E-9). R7 may be a group represented by formula: R8 R9 wherein R8 and R9 are (i-3) shown below: (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl (hereinafter, referred to as E-10). R7 may be a group represented by formula: R17 AJY" R8 R9 0 wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as E-ll). R7 may be a group represented by formula: R17 / xy" R8 R9 0 wherein R8 and R9 are (i-1) or (ii-1) shown below; (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1’C3 alkyl; (ii-1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3- to 6-membered non aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen; R10 is substituted alkyl (provided that dimethylamino methyl is excluded); R17 is a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl (hereinafter, referred to as E-12). R7 may be a group represented by formula: R17 A A ^R10 r8 R9 o wherein R8 and R9 may be (i-3) shown below; (i-3) R8 and R9 may be each independently a hydrogen atom, or C1C3 alkyl: R10 is alkyl substituted with hydroxy! R17 is a hydrogen atom (hereinafter, referred to as E13). R7 may be a group represented by formula: R17 A ^R10 r8 R9 0 wherein R8 and R9 may be (i-4) shown below; (i-4) R 8 may be a hydrogen atom and R9 may be a hydrogen atom: R10 is alkyl substituted with hydroxy; R17 is a hydrogen atom (hereinafter, referred to as E-14). Rs and R9 may be (i l) or (ii l) shown below; (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl; (ii-1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3- to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen (hereinafter, referred to as F-l). R8 and R9 may be (i-3) or (ii-3) shown below; (i-3) R8 and R9are each independently a hydrogen atom, or C1C3 alkyl; (ii- 3) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non aromatic carbocycle, or a 3- to 6-membered non-aromatic heterocycle (hereinafter, referred to as F-2). R8 and R9 may be (i-3) shown below; (i-3) R8 and R9 are each independently a hydrogen atom, or 01’03 alkyl (hereinafter, referred to as F-3). Rs and R9 may be (i-4) shown below; (i-4) R8 is a hydrogen atom and R9 is a hydrogen atom (hereinafter, referred to as F4).

[0070] R10 may be substituted or unsubstituted alkyl (provided that dimethylamino methyl is excluded), substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted tetrahydrofuryl, or substituted or unsubstituted oxetanyl (hereinafter, referred to as G-l). R10 may be substituted or unsubstituted alkyl (provided that methyl and dimethylamino methyl are excluded), substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted tetrahydrofuryl, or substituted or unsubstituted oxetanyl (hereinafter, referred to as G 2). R10 may be substituted or unsubstituted alkyl (provided that methyl and dimethylamino methyl are excluded) (hereinafter, referred to as G‘3). R10 may be substituted alkyl (provided that dimethylamino methyl is excluded) (hereinafter, referred to as G-4). R10 may be alkyl substituted with hydroxy (hereinafter, referred to as G’5). R10 may be methyl substituted with hydroxy (hereinafter, referred to as G'6). R10 may be isopropyl substituted with hydroxy (hereinafter, referred to as G’7). R10 may be C1C3 alkyl substituted with hydroxy (hereinafter, referred to as G-8).

[0071] R17 may be a hydrogen atom, substituted or unsubstituted 01-03 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl (hereinafter, referred to as H-l). R17 may be a hydrogen atom, or substituted or unsubstituted 01'03 alkyl (hereinafter, referred to as H-2). R17 may be a hydrogen atom (hereinafter, referred to as H 3).

[0072] R11 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as J-l). R11 may be a hydrogen atom, or alkyl (hereinafter, referred to as J-2). R11 may be a hydrogen atom (hereinafter, referred to as J-3). [00731 R12 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as K-l). R12 may be a hydrogen atom, or alkyl (hereinafter, referred to as K-2). R12 may be a hydrogen atom (hereinafter, referred to as K 3).

[0074] R1S may be a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylamino (hereinafter, referred to as L-l). R13 may be a hydrogen atom, hydroxy, halogen, alkyl, alkyloxy, or alkylamino (hereinafter, referred to as L-2). R13 may be a hydrogen atom, hydroxy, or halogen (hereinafter, referred to as L-3). R13 may be a hydrogen atom (hereinafter, referred to as L-4).

[0075] R14 may be a hydrogen atom, halogen, or substituted or unsubstituted alkyl (hereinafter, referred to as M l). R14 may be a hydrogen atom, or halogen (hereinafter, referred to as M-2). R14 may be a hydrogen atom (hereinafter, referred to as M-3).

[0076] R15 may be a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino (hereinafter, referred to as N l). R1B may be a hydrogen atom, hydroxy, alkyl, alkyloxy, alkylamino (hereinafter, referred to as N-2). R15 may be a hydrogen atom, or hydroxy (hereinafter, referred to as N-3). R1B may be a hydrogen atom (hereinafter, referred to as N4). R1B may be hydroxy (hereinafter, referred to as N’5).

[0077] R16 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as O-l). R16 may be a hydrogen atom, or alkyl (hereinafter, referred to as O-2). R1G may be a hydrogen atom (hereinafter, referred to as 03).

[0078] R31 may be a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylamino (hereinafter, referred to as P-1). R31 may be a hydrogen atom, hydroxy, halogen, alkyl, alkyloxy, or alkylamino (hereinafter, referred to as P-2). R31 may be a hydrogen atom, hydroxy, or halogen (hereinafter, referred to as P3). R31 may be a hydrogen atom (hereinafter, referred to as P-4).

[0079] R32 may be a hydrogen atom, halogen, or substituted or unsubstituted alkyl (hereinafter, referred to as Q-l). R32 may be a hydrogen atom, or halogen (hereinafter, referred to as Q2). R32 may be a hydrogen atom (hereinafter, referred to as Q-3).

[0080] R33 may be a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylamino (hereinafter, referred to as R-l). R33 may be a hydrogen atom, hydroxy, alkyl, alkyloxy, alkylamino (hereinafter, referred to as R-2). R33 may be a hydrogen atom, or hydroxy (hereinafter, referred to as R 3). R33 may be a hydrogen atom (hereinafter, referred to as R-4). R33 may be hydroxy (hereinafter, referred to as R-5).

[0081] R34 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as S i). R34 may be a hydrogen atom, or alkyl (hereinafter, referred to as S'2). R34 may be a hydrogen atom (hereinafter, referred to as S’3).

[0082] R30 may be a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl (hereinafter, referred to as T-l). R30 may be a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl (hereinafter, referred to as T-2). R30 may be a hydrogen atom (hereinafter, referred to as T-3).

[0083] R35 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as U-1). R3B may be a hydrogen atom, or alkyl (hereinafter, referred to as U2). R3B may be a hydrogen atom (hereinafter, referred to as U 3).

[0084] R36 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as V-1). R3S may be a hydrogen atom, or alkyl (hereinafter, referred to as V’2). R36 may be a hydrogen atom (hereinafter, referred to as V 3).

[0085] R37 may be a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkvloxy, or substituted or unsubstituted alkylamino (hereinafter, referred to as Wl). R37 may be a hydrogen atom, hydroxy, alkyl, alkyloxy, alkylamino (hereinafter, referred to as W-2). R37 may be a hydrogen atom, or hydroxy (hereinafter, referred to as W 3). R37 may be a hydrogen atom (hereinafter, referred to as W-4). R37 may be hydroxy (hereinafter, referred to as W5).

[0086] R38 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as X-l). R38 may be a hydrogen atom, or alkyl (hereinafter, referred to as X-2). R38 may be a hydrogen atom (hereinafter, referred to as X-3).

[0087] R3S may be a hydrogen atom, substituted or unsubstituted C1C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl (hereinafter, referred to as Yl). R39 may be a hydrogen atom, or substituted or unsubstituted CDC3 alkyl (hereinafter, referred to as Y-2). R39 may be a hydrogen atom (hereinafter, referred to as Y-3).

[0088] R40 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as Z-1). R40 may be a hydrogen atom, or alkyl (hereinafter, referred to as Z-2). R40 may be a hydrogen atom (hereinafter, referred to as Z-3).

[0089] R41 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as AA-1). R41 may be a hydrogen atom, or alkyl (hereinafter, referred to as AA 2). R41 may be a hydrogen atom (hereinafter, referred to as AA-3).

[0090] R26 may be a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylamino (hereinafter, referred to as AB’l). R26 may be a hydrogen atom, hydroxy, halogen, alkyl, alkyloxy, or alkylamino (hereinafter, referred to as AB-2). R26 may be a hydrogen atom, hydroxy, or halogen (hereinafter, referred to as AB-3). R2G may be a hydrogen atom (hereinafter, referred to as AB-4).

[0091] R27 may be a hydrogen atom, halogen, or substituted or unsubstituted alkyl (hereinafter, referred to as AC1). R27 may be a hydrogen atom, or halogen (hereinafter, referred to as AC-2). R27 may be a hydrogen atom (hereinafter, referred to as AC-3).

[0092] R22 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as AD-1). R22 may be a hydrogen atom, or alkyl (hereinafter, referred to as AD-2). R22 may be a hydrogen atom (hereinafter, referred to as AD-3).

[0093] R23 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as AE-1). R23 may be a hydrogen atom, or alkyl (hereinafter, referred to as AE-2). R23 may be a hydrogen atom (hereinafter, referred to as AE-3).

[0094] R24 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as AF-1). R24 may be a hydrogen atom, or alkyl (hereinafter, referred to as AF-2). R24 may be a hydrogen atom (hereinafter, referred to as AF-3).

[0095] R2B may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as AG-1). R2B may be a hydrogen atom, or alkyl (hereinafter, referred to as AG-2). R2B may be a hydrogen atom (hereinafter, referred to as AG-3).

[0096] Y may be O or NR18 (hereinafter, referred to as AH-1). Y may be 0 (hereinafter, referred to as AH2). Y may be NR18 (hereinafter, referred to as AH-3). [00971 R18 may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as AI-1). R18 may be a hydrogen atom, or alkyl (hereinafter, referred to as AI-2). R18 may be a hydrogen atom (hereinafter, referred to as AI-3).

[0098] RB and R 6 may be (i-2) or (ii-2) shown below; (i-2) R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; RB is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl; (provided that when R7 is a group represented by formula: wherein R8 and R9 are (i-1) or (ii-1) shown below: (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl; (ii-1) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3' to 6-membered non aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen: R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl! and R5 is hydroxy, halogen substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkyl); (ii-2) RB and R6 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z (hereinafter, referred to as AJ-1). RB and R6 may be (i-2) shown below; (1-2) R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl: RB is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl: (provided that when R7 is a group represented by formula: wherein R8 and R9 are (i l) or (ii l) shown below! (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl; (ii- 1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3- to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen: R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; and R5 is hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl) (hereinafter, referred to as AJ-2). RB and R 6 may be (i-6) shown below; (i-6) R6 is a hydrogen atom; RB is a hydrogen atom, or hydroxy: (provided that when R7 is a group represented by formula: wherein R8 and R9 are (i-1) or (ii-1) shown below; (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl; (il l) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z. or a 3- to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen; R8 is a hydrogen atom; and RB is hydroxy) (hereinafter, referred to as AJ-3).

[0099] A divalent group represented by formula: may be a divalent group represented by formula: wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as AK-1). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 is each independently C1-C3 alkyl, or halogen! m is 0; n is 0 or 1! p is 0 or 1! q is 0 or 1! the atom marked “a'’ binds to the group represented by the formula: R1            ; the atom marked “b" binds to R7 (hereinafter, referred to as AK 1’). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a'’ binds to the group represented by the formula: R1            ; the atom marked “b” binds to R7 (hereinafter, referred to as AK 1”). A divalent group represented by formula: may be a divalent group represented by formula: wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as AK-2). A divalent group represented by formula may be a divalent group represented by formula: wherein R21 is each independently substituted or unsubstituted C1C3 alkyl or halogen; m is 0; n is 0 or 1; q is 0 or 1: the atom marked “a" binds to the group represented by the formula: R1            ; the atom marked “b” binds to R7 (hereinafter, referred to as AK-3). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 is each independently C1C3 alkyl or halogen; m is 0; n is 0 or 1; q is 0 or 1: the atom marked “a'’ binds to the group represented by the formula: R1            ; the atom marked “b'’ binds to R7 (hereinafter, referred to as AK-3 ). A divalent group represented by formula: may be a divalent group represented by formula- wherein the atom marked “a” binds to the group represented by the formula: r1 ; the atom marked “b" binds to R7 (hereinafter, referred to as AK 4). A divalent group represented by formula may be a divalent group represented by formula- wherein each symbol has the same meaning as defined in the item (1) (hereinafter, referred to as AK-5). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 is each independently substituted or unsubstituted C1’C3 alkyl, halogen; n is 0 or 1; p is 0 or 1; q is 0 or 1; the atom marked “a” binds to the group represented by the formula: or r1 ; the atom marked “b" binds to R7 (hereinafter, referred to as AK-6). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 is each independently C1-C3 alkyl, or halogen: n is 0 or 1; p is 0 or 1: q is 0 or 1; the atom marked “a” binds to the group represented by the formula: R1 ; the atom marked “b" binds to R7 (hereinafter, referred to as AK-6 ). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a” binds to the group represented by the formula: R1 ; the atom marked “b" binds to R7 (hereinafter, referred to as AK-7). A divalent group represented by formula: may be a divalent group represented by formula- wherein R21 is each independently substituted or unsubstituted C1-C3 alkyl, or halogen; p is 0 or 1; the atom marked “a” binds to the group represented by the formula: R1 ; the atom marked “b” binds to R7 (hereinafter, referred to as AK-8). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a"’ binds to the group represented by the formula: R1            ; the atom marked “b” binds to R7 (hereinafter, referred to as AK-9). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 is each independently substituted or unsubstituted C1-C3 alkyl, or halogen; q is 0 or 1; the atom marked “a” binds to the group represented by the formula: R1 : the atom marked “b" binds to R7 (hereinafter, referred to as AK-IO). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a" binds to the group represented by the formula: R1 ; the atom marked “b” binds to R7 (hereinafter, referred to as AK-11). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 is each independently substituted or unsubstituted C1-C3 alkyl, or halogen; n is 0 or 1: the atom marked “a" binds to the group represented by the formula: R1            ; the atom marked “b” binds to R7 (hereinafter, referred to as AK-12). A divalent group represented by formula: may be a divalent group represented by formula- wherein the atom marked “a” binds to the group represented by the formula: R1 ; the atom marked “b" binds to R7 (hereinafter, referred to as AK-13). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a" binds to the group represented by the formula: R1 ; the atom marked “b” binds to R7 (hereinafter, referred to as AK-14).

[0100] R21 may be each independently substituted or unsubstituted C1-C3 alkyl, or halogen (hereinafter, referred to as AL-1). R21 may be each independently C1C3 alkyl or halogen (hereinafter, referred to as AL-2). R21 may be C1-C3 alkyl (hereinafter, referred to as AL-3). R21 may be halogen (hereinafter, referred to as AL-4).

[0101] m may be 0 or 1 (hereinafter, referred to as AM-1). m may be 0 (hereinafter, referred to as AM-2). m may be 1 (hereinafter, referred to as AM-3).

[0102] n may be an integer from 0 to 2 (hereinafter, referred to as AN-1). n may be 0 or 1 (hereinafter, referred to as AN-2). n may be 0 (hereinafter, referred to as AN-3). n may be 1 (hereinafter, referred to as AN-4). n may be 2 (hereinafter, referred to as AN-5).

[0103] p may be an integer from 0 to 4 (provided that when R10 is methyl, p is 0) (hereinafter, referred to as AO4). p may be an integer from 0 to 2 (provided that when R10 is methyl, p is 0) (hereinafter, referred to as AO-2). p may be 0 or 1 (provided that when R10 is methyl, p is 0) (hereinafter, referred to as AO-3). p may be 0 (hereinafter, referred to as AO-4). p may be 1 (hereinafter, referred to as AO-5). p may be 2 (hereinafter, referred to as AO-6).

[0104] q may be an integer from 0 to 3 (hereinafter, referred to as AP-1). q may be an integer from 0 to 2 (hereinafter, referred to as AP-2). q may be 0 or 1 (hereinafter, referred to as AP 3). q may be 0 (hereinafter, referred to as AP-4). q may be 1 (hereinafter, referred to as AP 5). q may be 2 (hereinafter, referred to as AP-6).

[0105] X may be CR19 or N (hereinafter, referred to as AQ-1). X may be OR19 (hereinafter, referred to as AQ-2). X may be N (hereinafter, referred to as AQ-3).

[0106] R19 may be. a hydrogen atom or halogen (hereinafter, referred to as AR-1). R19 may be a hydrogen atom (hereinafter, referred to as AR-2). R19 may be halogen (hereinafter, referred to as AR-3).

[0107] With regard to a compound represented by Formula (II), preferred embodiments of R1, R2, R3, R4, R8, R9, ring A, R21, m, n, p, q, X and R19 are shown below. Regarding the compound represented by Formula (II), embodiments of all the combinations of specific examples shown below are mentioned as examples. R1 may be substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic carbocyclyl (hereinafter, referred to as BA-1). R1 may be substituted or unsubstituted aromatic heterocyclyl. substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted aromatic carbocyclyl (hereinafter, referred to as BA-2). R1 may be substituted or unsubstituted aromatic heterocyclyl. or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as BA-3). R1 may be substituted or unsubstituted 6 membered aromatic heterocyclyl, or substituted or unsubstituted 9-membered non-aromatic heterocyclyl (hereinafter, referred to as BA-4). R1 may be substituted or unsubstituted pyridyl, or substituted or unsubstituted 1.3benzodioxolyl (hereinafter, referred to as BA-5). R1 may be pyridyl substituted with haloalkyloxy, pyridyl substituted with alkyloxy.or 1.3-benzodioxolyl substituted with halogen (hereinafter, referred to as BA-6). B R1 may be pyridyl substituted with halomethyloxy, pyridyl substituted with methyloxy,or 1,3'benzodioxolyl substituted with halogen (hereinafter, referred to as BA-7). R1 may be 2-difluoromethyloxypyridin-4-yl, 2-methyloxypyridin-4-yl, or 2,2-difluoro-1,3-benzodioxol’5yl (hereinafter, referred to as BA-8). R1 may be 2-difluoromethyloxypyridin-4-yl (hereinafter, referred to as BA-9). R1 may be 2-methyloxypyridin-4-yl (hereinafter, referred to as BA-10). R1 may be 2,2 difluoro-l,3-benzodioxol-5-yl (hereinafter, referred to as BA-11). R1 may be aromatic heterocyclyl substituted with haloalkyloxy or alkyloxy. or non-aromatic heterocyclyl substituted with halogen (hereinafter, referred to as BA-12).

[0108] R2 may be halogen, or substituted or unsubstituted alkyloxy (hereinafter, referred to as BB-1). R2 may be halogen, or substituted or unsubstituted methyloxy (hereinafter, referred to as BB-2). R2 may be substituted or unsubstituted methyloxy (hereinafter, referred to as BB-3). R2 may be halomethyloxy, or unsubstituted methyloxy (hereinafter, referred to as BB-4). R2 may be difluoromethyloxy, or unsubstituted methyloxy (hereinafter, referred to as BB-5). R2 may be halomethyloxy (hereinafter, referred to as BB 6). R2 may be methyloxy (hereinafter, referred to as BB-7). R2 may be difluoromethyloxy (hereinafter, referred to as BB-8).

[0109] R3 may be a hydrogen atom, or halogen (hereinafter, referred to as BOI). Rs may be a hydrogen atom (hereinafter, referred to as BO2). R3 may be halogen (hereinafter, referred to as BOS).

[0110] R4 may be a hydrogen atom, or halogen (hereinafter, referred to as BD-1). R4 may be a hydrogen atom (hereinafter, referred to as BD-2). R4 may be halogen (hereinafter, referred to as BD 3).

[0111] R8 and R9 may be (il) or (ii-1) shown below! (il) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1C3 alkyl: (ii-1) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6membered non aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z. or a 3’ to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen (hereinafter, referred to as BE-1). R8 and R9 may be (i-3) or (ii-3) shown below: (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl: (ii-3) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle, or a 3- to 6-membered non-aromatic heterocycle (hereinafter, referred to as BE 2). R8 and R9 may be (i-3) shown below! (i-3) R8 and R9 may be each independently a hydrogen atom, or C1-C3 alkyl (hereinafter, referred to as BE-3). R8 and R9 may be (i d) shown below! (i-4) R8 may be a hydrogen atom and R9 may be a hydrogen atom (hereinafter, referred to as BE-4).

[0112] A divalent group represented by formula: may be a divalent group represented by formula: wherein each symbol has the same meaning as defined in the item (3) (hereinafter, referred to as BF-1). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21, m, n and q have the same meaning as defined in the AK3! the atom marked “a” binds to the group represented by the formula: R4 OH R1             : the atom marked “b” binds to the group represented by the formula: (hereinafter, referred to as BF-2). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a"’ binds to the group represented by the formula: R4 OH R1             • the atom marked “b'’ binds to the group represented by the formula: (hereinafter, referred to as BF-3). A divalent group represented by formula: may be a divalent group represented by formula: Mu b / wherein R21 and q have the same meaning as defined in the AK IO: the atom marked “a" binds to the group represented by the formula: R4 OH R1             • the atom marked “b'’ binds to the group represented by the formula: (hereinafter, referred to as BF-4). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a"’ binds to the group represented by the formula: R4 OH R1 • the atom marked “b'’ binds to the group represented by the formula: (hereinafter, referred to as BF-5). A divalent group represented by formula: b r may be a divalent group represented by formula: wherein R21 and n have the same meaning as defined in the AK12: the atom marked “a" binds to the group represented by the formula: R4 OH R1             • the atom marked “b'’ binds to the group represented by the formula: (hereinafter, referred to as BF-6). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a"’ binds to the group represented by the formula: R4 OH R1 • the atom marked “b'’ binds to the group represented by the formula: (hereinafter, referred to as BF-7). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a” binds to the group represented by the formula: R4 OH R1 the atom marked “b” binds to the group represented by the formula: (hereinafter, referred to as BF 8).

[0113] R21 may be each independently substituted or unsubstituted C1-C3 alkyl, or halogen (hereinafter, referred to as BG-1). R21 may be each independently C1-C3 alkyl or halogen (hereinafter, referred to as BG-2). R21 may be C1-C3 alkyl (hereinafter, referred to as BG 3). R21 may be halogen (hereinafter, referred to as BG-4).

[0114] m may be 0 or 1 (hereinafter, referred to as BH-1). m may be 0 (hereinafter, referred to as BH-2). m may be 1 (hereinafter, referred to as BH-3).

[0115] n may be an integer from 0 to 2 (hereinafter, referred to as BI-1). n may be 0 or 1 (hereinafter, referred to as BI-2). n may be 0 (hereinafter, referred to as BBS). n may be 1 (hereinafter, referred to as BI 4). n may be 2 (hereinafter, referred to as BI-5).

[0116] p may be an integer from 0 to 4 (hereinafter, referred to as BJ-1). p may be an integer from 0 to 2 (hereinafter, referred to as BJ-2). p may be 0 or 1 (hereinafter, referred to as BJ-3). p may be 0 (hereinafter, referred to as BJ-4). p may be 1 (hereinafter, referred to as BJ-5). p may be 2 (hereinafter, referred to as BJ-6).

[0117] q may be an integer from 0 to 3 (hereinafter, referred to as BK-1). q may be an integer from 0 to 2 (hereinafter, referred to as BK-2). q may be 0 or 1 (hereinafter, referred to as BK-3). q may be 0 (hereinafter, referred to as BK-4). q may be 1 (hereinafter, referred to as BK-5). q may be 2 (hereinafter, referred to as BK-6). 10118] X may be CR19 or N(hereinafter, referred to as BL-1). X may be CR19 (hereinafter, referred to as BL-2). X may be N (hereinafter, referred to as BL-3).

[0119] R19 may be, a hydrogen atom or halogen (hereinafter, referred to as BM1). R19 may be a hydrogen atom (hereinafter, referred to as BM2). R19 may be halogen (hereinafter, referred to as BM-3).

[0120] With regard to a compound represented by Formula (IT), preferred embodiments of R1, R2, R3, R4, R8, R9, ring A, R21, m, n, p, q, X and R19 are shown below. Regarding the compound represented by Formula (IF), embodiments of all the combinations of specific examples shown below are mentioned as examples. R1 may be substituted or unsubstituted aromatic heterocyclyl. substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic carbocyclyl (hereinafter, referred to as CA-1). R1 may be substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted aromatic carbocyclyl (hereinafter, referred to as CA-2). R1 may be substituted or unsubstituted aromatic heterocyclyl. or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as CA-3). R1 may be substituted or unsubstituted 6 membered aromatic heterocyclyl, or substituted or unsubstituted 9-membered non-aromatic heterocyclyl (hereinafter, referred to as CA-4). R1 may be substituted or unsubstituted pyridyl, or substituted or unsubstituted l,3benzodioxolyl (hereinafter, referred to as CA-5). R1 may be pyridyl substituted with haloalkyloxy, pyridyl substituted with alkyloxy,or 1.3'benzodioxolyl substituted with halogen (hereinafter, referred to as CA-6). B R1 may be pyridyl substituted with halomethyloxy, pyridyl substituted with methyloxy,or 1,3'benzodioxolyl substituted with halogen (hereinafter, referred to as CA-7). R1 may be 2-difluoromethyloxypyridin-4-yl, 2-methyloxypyridin-4-yl, or 2.2-difluoro-1,3-benzodioxol-5yl (hereinafter, referred to as CA 8). R1 may be 2-difluoromethyloxypyridin-4-yl (hereinafter, referred to as CA'9). R1 may be 2-methyloxypyridin-4-yl (hereinafter, referred to as CA-10). R1 may be 2,2-difluoro-l,3’benzodioxol‘5-yl (hereinafter, referred to as CA-11). R1 may be aromatic heterocyclyl substituted with haloalkyloxy or alkyloxy, or non-aromatic heterocyclyl substituted with halogen (hereinafter, referred to as CA-12).

[0121] R2 may be halogen, or substituted or unsubstituted alkyloxy (hereinafter, referred to as CB-1). R2 may be halogen, or substituted or unsubstituted methyloxy (hereinafter, referred to as CB-2). R2 may be substituted or unsubstituted methyloxy (hereinafter, referred to as CB-3). R2 may be halomethyloxy, or unsubstituted methyloxy (hereinafter, referred to as CB-4). R2 may be difluoromethyloxy, or unsubstituted methyloxy (hereinafter, referred to as CB-5). R2 may be halomethyloxy (hereinafter, referred to as CB 6). R2 may be methyloxy (hereinafter, referred to as CB7). R2 may be difluoromethyloxv (hereinafter, referred to as CB-8).

[0122] R3 may be a hydrogen atom, or halogen (hereinafter, referred to as CC-1). R3 may be a hydrogen atom (hereinafter, referred to as CC-2). R3 may be halogen (hereinafter, referred to as CO3).

[0123] R4 may be a hydrogen atom, or halogen (hereinafter, referred to as CD-1). R4 may be a hydrogen atom (hereinafter, referred to as CD-2). R4 may be halogen (hereinafter, referred to as CD-3).

[0124] R8 and R9 may be (i l) or (ii l) shown below; (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1C3 alkyl; (ii- 1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z. or a 3- to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1C3 alkyl and halogen (hereinafter, referred to as CE-1). R8 and R9 may be (i-3) or (ii-3) shown below; (i-3) R8 and R9 are each independently a hydrogen atom, or CDC3 alkyl; (ii-3) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle, or a 3- to 6-membered non-aromatic heterocycle (hereinafter, referred to as CE-2). R8 and R9 may be (i 3) shown below; (i-3) R8 and R9 may be each independently a hydrogen atom, or C1C3 alkyl (hereinafter, referred to as CE-3). R8 and R9 may be (i-4) shown below; (i-4) R8 may be a hydrogen atom and R9 may be a hydrogen atom (hereinafter, referred to as CE-4).

[0125] A divalent group represented by formula may be a divalent group represented by formula: wherein each symbol has the same meaning as defined in the item (3’) (hereinafter, referred to as CF-1). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21, m. n and q have the same meaning as defined in the AK3; the atom marked “a” binds to the group represented by the formula: R4 OH R1 • the atom marked “b'’ binds to the group represented by the formula: (hereinafter, referred to as CF-2). A divalent group represented by formula: may be a divalent group represented by formula- wherein the atom marked “a” binds to the group represented by the formula: R4 OH R1             • the atom marked “b" binds to the group represented by the formula: (hereinafter, referred to as CF-3). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 and q have the same meaning as defined in the AK-10: the atom marked “a” binds to the group represented by the formula: R4 OH R1             • the atom marked “b" binds to the group represented by the formula: (hereinafter, referred to as CF-4). A divalent group represented by formula: may be a divalent group represented by formula- wherein the atom marked “a” binds to the group represented by the formula: R4 OH R1             • the atom marked “b" binds to the group represented by the formula: (hereinafter, referred to as CF-5). A divalent group represented by formula: b s’ may be a divalent group represented by formula: / »21\ wherein R21 and n have the same meaning as defined in the AK-12; the atom marked “a” binds to the group represented by the formula: R4 OH R1 • the atom marked “b" binds to the group represented by the formula: (hereinafter, referred to as OF-6). A divalent group represented by formula: may be a divalent group represented by formula- wherein the atom marked “a” binds to the group represented by the formula: R4 OH R1             • the atom marked “b" binds to the group represented by the formula: (hereinafter, referred to as CF-7). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a”’ binds to the group represented by the formula: R4 OH R1             • the atom marked “b” binds to the group represented by the formula: (hereinafter, referred to as CF-8).

[0126] R21 may be each independently substituted or unsubstituted C1-C3 alkyl, or halogen (hereinafter, referred to as CG-1). R21 may be each independently C1-C3 alkyl or halogen (hereinafter, referred to as CG-2). R21 may be C1-C3 alkyl (hereinafter, referred to as CG 3). R21 may be halogen (hereinafter, referred to as CG-4).

[0127] m may be 0 or 1 (hereinafter, referred to as CH-1). m may be 0 (hereinafter, referred to as CH-2). m may be 1 (hereinafter, referred to as CH-3).

[0128] n may be an integer from 0 to 2 (hereinafter, referred to as CI-1). n may be 0 or 1 (hereinafter, referred to as CI-2). n may be 0 (hereinafter, referred to as CD 3). n may be 1 (hereinafter, referred to as CI-4). n may be 2 (hereinafter, referred to as CI-5).

[0129] p may be an integer from 0 to 4 (hereinafter, referred to as CJ-1). p may be an integer from 0 to 2 (hereinafter, referred to as CJ-2). p may be 0 or 1 (hereinafter, referred to as CJ-3). p may be 0 (hereinafter, referred to as CJ-4). p may be 1 (hereinafter, referred to as CJ-5). p may be 2 (hereinafter, referred to as CJ-6).

[0130] q may be an integer from 0 to 3 (hereinafter, referred to as CK-1). q may be an integer from 0 to 2 (hereinafter, referred to as CK-2). q may be 0 or 1 (hereinafter, referred to as CK-3). q may be 0 (hereinafter, referred to as CK-4). q may be 1 (hereinafter, referred to as CK-5). q may be 2 (hereinafter, referred to as CK 6).

[0131] X may be CR19 or N(hereinafter, referred to as CL-1). X may be CR19 (hereinafter, referred to as CL-2). X may be N (hereinafter, referred to as CL-3).

[0132] R19 may be, a hydrogen atom or halogen (hereinafter, referred to as CM1). R19 may be a hydrogen atom (hereinafter, referred to as CM 2). R19 may be halogen (hereinafter, referred to as CM-3). 10133] With regard to a compound represented by Formula (III), preferred embodiments of R1, R2, R3, R4, R8. R9, R10, R17, Re, R6, ring A, R21, m, n, p, q, X and R19 are shown below. Regarding the compound represented by Formula (HI), embodiments of all the combinations of specific examples shown below are mentioned as examples. R1 may be substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic carbocyclyl (hereinafter, referred to as DA-1). R1 may be substituted or unsubstituted aromatic heterocyclyl. substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted aromatic carbocyclyl (hereinafter, referred to as DA-2). R1 may be substituted or unsubstituted aromatic heterocyclyl. or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as DA-3). R1 may be substituted or unsubstituted 6-membered aromatic heterocyclyl, or substituted or unsubstituted 9-membered non-aromatic heterocyclyl (hereinafter, referred to as DA-4). R1 may be substituted or unsubstituted pyridyl, or substituted or unsubstituted l,3benzodioxolyl (hereinafter, referred to as DA-5). R1 may be pyridyl substituted with haloalkyloxy. pyridyl substituted with unsubstituted alkyloxy,or 1.3 benzodioxolyl substituted with halogen (hereinafter, referred to as DA-6). R1 may be pyridyl substituted with halomethyloxy. pyridyl substituted with unsubstituted methyloxy,or 1,3-benzodioxolyl substituted with halogen (hereinafter, referred to as DA-7). R1 may be 2-difluoromethyloxypyridin-4-yl. 2-methyloxypyridin-4-yl. or 2,2-difluoro-l,3 benzodioxol'5 yl (hereinafter, referred to as DA-8). R1 may be 2-difluoromethyloxypyridin-4-yl (hereinafter, referred to as DA-9). R1 may be 2-methyloxypyridin-4-yl (hereinafter, referred to as DA-10). R1 may be 2,2-difluoro-l,3-benzodioxol-5-yl (hereinafter, referred to as DA-11). R1 may be aromatic heterocyclyl substituted with haloalkyloxy or unsubstituted alkyloxy, or non-aromatic heterocyclyl substituted with halogen (hereinafter, referred to as DA-12).

[0134] R2 may be halogen, or substituted or unsubstituted alkyloxy (hereinafter, referred to as DB-1). R2 may be halogen, or substituted or unsubstituted methyloxy (hereinafter, referred to as DB-2). R2 may be substituted or unsubstituted methyloxy (hereinafter, referred to as DB-3). R2 may be halomethyloxy, or unsubstituted methyloxy (hereinafter, referred to as DB4). R2 may be difluoromethyloxy, or unsubstituted methyloxy (hereinafter, referred to as DB-5). R2 may be halomethyloxy (hereinafter, referred to as DB‘6). R2 may be methyloxy (hereinafter, referred to as DB-7). R2 may be difluoromethyloxy (hereinafter, referred to as DB-8).

[0135] R3 may be a hydrogen atom, or halogen (hereinafter, referred to as DC-1). R3 may be a hydrogen atom (hereinafter, referred to as DC-2). R3 may be halogen (hereinafter, referred to as DC-3).

[0136] R4 may be a hydrogen atom, or halogen (hereinafter, referred to as DD1). R4 may be a hydrogen atom (hereinafter, referred to as DD-2). R4 may be halogen (hereinafter, referred to as DD-3).

[0137] R8 and R9 may be (i l) or (ii l) shown below; (i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1C3 alkyl; (ii-1) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z. or a 3- to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, wherein the Substituent group Z is the group consisting of C1C3 alkyl and halogen (hereinafter, referred to as DE-1). R8 and R9 may be (i-3) or (ii 3) shown below! (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl; (ii- 3) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle, or a 3- to 6-membered non-aromatic heterocycle (hereinafter, referred to as DE-2). R8 and R9 may be (i-3) shown below! (i-3) R8 and R9 may be each independently a hydrogen atom, or C1C3 alkyl (hereinafter, referred to as DE 3). R8 and R9 may be (i-4) shown below! (i-4) R8 may be a hydrogen atom and R9 may be a hydrogen atom (hereinafter, referred to as DE-4).

[0138] R10 may be substituted or unsubstituted alkyl (provided that methyl and dimethylamino methyl are excluded) (hereinafter, referred to as DF1). R10 may be substituted alkyl (provided that dimethylamino methyl is excluded) (hereinafter, referred to as DF-2). R10 may be alkyl substituted with hydroxy (hereinafter, referred to as DF-3). R10 may be methyl substituted with hydroxy (hereinafter, referred to as DF-4). L0139J R17 may be a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl (hereinafter, referred to as DG-1). R17 may be a hydrogen atom, or substituted or unsubstituted C1C3 alkyl (hereinafter, referred to as DG-2). R17 may be a hydrogen atom (hereinafter, referred to as DG3).

[0140] RB and R 6 may be (i-5) or (ii-2) shown below! (i-5) RB is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl! R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl! (ii-2) RB and R6 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z (hereinafter, referred to as DH1). RB and R 6 may be (i-5) shown below! (i-5) R5 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl: R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl (hereinafter, referred to as DH-2). RB and R 6 may be (i-7) shown below! (i-7) RB is a hydrogen atom, or hydroxy! R6 is a hydrogen atom (hereinafter, referred to as DH-3).

[0141] A divalent group represented by formula: may be a divalent group represented by formula- wherein each symbol has the same meaning as defined in the item (6) (hereinafter, referred to as Dl-1). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21, p, n and q have the same meaning as defined in the AK-6; the atom marked “a'’ binds to the group represented by the formula: R1            ; the atom marked “b” binds to the group represented by the formula: R17 R10 A Y R8 R9 0 (hereinafter, referred to as DI-2). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a” binds to the group represented by the formula: R1 ; the atom marked “b” binds to the group represented by the formula: R17 R10 A 0 Y R8 R9 0 (hereinafter, referred to as DI-3). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 and p have the same meaning as defined in the AK-8: the atom marked “a" binds to the group represented by the formula: R1 ; the atom marked “b” binds to the group represented by the formula: R17 (hereinafter, referred to as DI-4). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a"’ binds to the group represented by the formula: R1 ; the atom marked “b” binds to the group represented by the formula: R17 R10 A 0 Y R8 R9 0 (hereinafter, referred to as DI-5). A divalent group represented by formula: may be a divalent group represented by formula: wherein R21 and q have the same meaning as defined in the AK-10: the atom marked “a" binds to the group represented by the formula: R1 ; the atom marked “b” binds to the group represented by the formula: R17 (hereinafter, referred to as DI-6). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a"’ binds to the group represented by the formula: the atom marked “b” binds to the group represented by the formula: R17 .bL .R10 R8 R9 0 (hereinafter, referred to as DI-7). A divalent group represented by formula- may be a divalent group represented by formula: (R21)n wherein R21 and n have the same meaning as defined in the AK-12: the atom marked “a" binds to the group represented by the formula: the atom marked “b” binds to the group represented by the formula: R17 ,bL ^R10 R8 R9 0 (hereinafter, referred to as DI-8). A divalent group represented by formula: may be a divalent group represented by formula: wherein the atom marked “a"’ binds to the group represented by the formula- the atom marked “b” binds to the group represented by the formula: R17 ,N^ .R10 R8 R9 0 (hereinafter, referred to as DI-9).

[0142] R21 may be each independently substituted or unsubstituted C1-C3 alkyl, or halogen (hereinafter, referred to as DJ-1). R21 may be each independently C1’C3 alkyl or halogen (hereinafter, referred to as DJ-2). R21 may be CDC3 alkyl (hereinafter, referred to as DJ-3). R21 may be halogen (hereinafter, referred to as DJ-4). 10143] m may be 0 or 1 (hereinafter, referred to as DK-1). m may be 0 (hereinafter, referred to as DK-2). m may be 1 (hereinafter, referred to as DK-3).

[0144] n may be an integer from 0 to 2 (hereinafter, referred to as DL-1). n may be 0 or 1 (hereinafter, referred to as DL-2). n may be 0 (hereinafter, referred to as DL-3). n may be 1 (hereinafter, referred to as DL-4). n may be 2 (hereinafter, referred to as DL-5).

[0145] p may be an integer from 0 to 4 (provided that when R10 is methyl, p is 0) (hereinafter, referred to as DM1). p may be an integer from 0 to 2 (provided that when R10 is methyl, p is 0) (hereinafter, referred to as DM 2). p may be 0 or 1 (provided that when R10 is methyl, p is 0) (hereinafter, referred to as DM-3). p may be 0 (hereinafter, referred to as DM4). p may be 1 (hereinafter, referred to as DM-5). p may be 2 (hereinafter, referred to as DM-6).

[0146] q may be an integer from 0 to 3 (hereinafter, referred to as DN-1). q may be an integer from 0 to 2 (hereinafter, referred to as DN-2). q may be 0 or 1 (hereinafter, referred to as DN-3). q may be 0 (hereinafter, referred to as DN-4). q may be 1 (hereinafter, referred to as DN-5). q may be 2 (hereinafter, referred to as DN-6).

[0147] X may be CR19 or N (hereinafter, referred to as DO-1). X may be CR19 (hereinafter, referred to as DO-2). X may be N (hereinafter, referred to as DO-3).

[0148] R1S may be, a hydrogen atom or halogen (hereinafter, referred to as DP-1). R19 may be a hydrogen atom (hereinafter, referred to as DP-2). R19 may be halogen (hereinafter, referred to as DP-3).

[0149] In the compound represented by Formula (l), for example, the following embodiments are included. (i) A compound represented by Formula (I)- wherein R1 is aromatic heterocyclyl substituted with haloalkyloxy or unsubstituted alkyloxy, or non-aromatic heterocyclyl substituted with halogen; R2 is haloalkyloxy or unsubstituted alkyloxyi R3 and R4 are each a hydrogen atom; R7 is a group represented by formula- R17 A Q A Y R8 R9 or R8 R9 0 wherein R8 and R9 are(i-3) shown below; (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl; R10 is alkyl substituted with hydroxy; R17 is a hydrogen atom; Re and R6 are (i-6) shown below: (i-6) R6 is a hydrogen atom; Re is a hydrogen atom, or hydroxy; (provided that when R7 is a group represented by formula: R8 R9 wherein each symbol is as defined above, R6 is a hydrogen atom; and R5 is hydroxy); a divalent group represented by formula- is a divalent group represented by formula: wherein R21 is each independently C1-C3 alkyl, or halogen! m is 0: n is 0 or 1; p is 0 or 1: q is 0 or 1! the atom marked “a” binds to the group represented by the formula: R1 the atom marked “b” binds to R7! X is CR19 or NJ R19 is a hydrogen atom, or halogen: or a pharmaceutically acceptable salt thereof. (i ) A compound represented by Formula (I): wherein R1 is pyridyl substituted with haloalkyloxy, pyridyl substituted with unsubstituted alkyloxy, or 1,3'benzodioxolyl substituted with halogen! R2 is haloalkyloxy or unsubstituted alkyloxy! R3 and R4 are each a hydrogen atom! R7 is a group represented by formula: R17 Z___N___R10 A A T R8 R9 or R8 R9 O wherein R8 and R9 are (i-3) shown below! (i-3) Rs and R9 are each independently a hydrogen atom, or C1-C3 alkyl: R10 is C1-C3 alkyl substituted with hydroxy! R17 is a hydrogen atom: R5 and R6 are (i-6) shown below! (i-6) R6 is a hydrogen atom! RB is a hydrogen atom, or hydroxy: (provided that when R7 is a group represented by formula: wherein each symbol is as defined above, R6 is a hydrogen atom; and R5 is hydroxy); a divalent group represented by formula: is a divalent group represented by formula: wherein the atom marked “a” binds to the group represented by the formula: R1 : the atom marked “b” binds to R7; X is CR19 or N; R19 is a hydrogen atom, or halogen: or a pharmaceutically acceptable salt thereof.

[0150] In the compound represented by Formula (II), for example, the following embodiments are included. (ii) A compound represented by Formula (II): R4 OH wherein R1 is aromatic heterocyclyl substituted with haloalkyloxy or unsubstituted alkyloxy, or non-aromatic heterocyclyl substituted with halogen; R2 is haloalkyloxy or unsubstituted alkyloxy; R3 and R4 are each a hydrogen atom: R8 and R9 are (i-3) shown below; (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl: a divalent group represented by formula: is a divalent group represented by formula: wherein R21 is each independently C1-C3 alkyl or halogen; m is 0; nisOor 1; q is 0 or 1; the atom marked “a” binds to the group represented by the formula: R4 OH R1            ; the atom marked “b" binds to the group represented by the formula: X is CR19 or N; R19 is a hydrogen atom, or halogen: or a pharmaceutically acceptable salt thereof. (ii ) A compound represented by Formula (II): R4 OH wherein R1 is pyridyl substituted with haloalkyloxy, pyridyl substituted with unsubstituted alkyloxy, or 1,3'benzodioxolyl substituted with halogen; R2 is haloalkyloxy or unsubstituted alkyloxy; R3 and R4 are each a hydrogen atom: R8 and R9 are (i-3) shown below; (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl: a divalent group represented by formula: is a divalent group represented by formula: wherein the atom marked “a” binds to the group represented by the formula: R4 OH R1             ; the atom marked “b” binds to the group represented by the formula: X is CR19 or N; R19 is a hydrogen atom, or halogen; or a pharmaceutically acceptable salt thereof.

[0151] In the compound represented by Formula (II ), for example, the following embodiments are included. (iii) A compound represented by Formula (II’): R4 OH wherein R1 is aromatic heterocyclyl substituted with haloalkyloxy or unsubstituted alkyloxy. or non-aromatic heterocyclyl substituted with halogen; R2 is haloalkyloxy or unsubstituted alkyloxy; R3 and R4 are each a hydrogen atom; R8 and R9 are (i-3) shown below: (i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyl: a divalent group represented by formula: is a divalent group represented by formula: wherein R21 is each independently C1-C3 alkyl or halogen; m is 0: n is 0 or 1; q is 0 or 1: the atom marked “a" binds to the group represented by the formula: R4 OH R1 • the atom marked “b'’ binds to the group represented by the formula: X is CR19 or N; R19 is a hydrogen atom, or halogen: or a pharmaceutically acceptable salt thereof. (iii ) A compound represented by Formula (II ): R4 OH wherein R1 is pyridyl substituted with haloalkyloxy, pyridyl substituted with unsubstituted alkyloxy. or 1.3-benzodioxolyl substituted with halogen: R2 is haloalkyloxy or unsubstituted alkyloxy; R3 and R4 are each a hydrogen atom; R8 and R9 may are (i-3) shown below: (i-3) Rs and R9 are each independently a hydrogen atom, or C1’C3 alkyl: a divalent group represented by formula: is a divalent group represented by formula: wherein the atom marked “a” binds to the group represented by the formula: R4 OH R1 the atom marked “b” binds to the group represented by the formula: X is CR19 or N; R19 is a hydrogen atom, or halogen; or a pharmaceutically acceptable salt thereof.

[0152] In the compound represented by Formula (III), for example, the following embodiments are included. (iv) A compound represented by Formula (III): wherein R1 is aromatic heterocyclyl substituted with haloalkyloxy or unsubstituted alkyloxy, or non-aromatic heterocyclyl substituted with halogen; R2 is haloalkyloxy or unsubstituted alkyloxy! R3 and R4 are each a hydrogen atom; R8 and R9 are (i-3) shown below; (i-3) Rs and R9 are each independently a hydrogen atom, or C1-C3 alkyl: R10 is alkyl substituted with hydroxy; R17 is a hydrogen atom: Re and R6 may be (i-7) shown below; (i-7) RB is a hydrogen atom, or hydroxy; R6 is a hydrogen atom; a divalent group represented by formula: is a divalent group represented by formula: wherein R21 is each independently C1-C3 alkyl, or halogen: n is 0 or 1; p is 0 or 1: q is 0 or 1; the atom marked “a” binds to the group represented by the formula: R1 the atom marked “b" binds to the group represented by the formula: R17 X is CR19 or N; R19 is a hydrogen atom or halogen; or a pharmaceutically acceptable salt thereof. (iv) A compound represented by Formula (III): wherein R1 is pyridyl substituted with haloalkyloxy, pyridyl substituted with unsubstituted alkyloxy, or 1, Bbenzodioxolyl substituted with halogen; R2 is haloalkyloxy or unsubstituted alkyloxy; R3 and R4 are each a hydrogen atom; R8 and R9 may be (i B) shown below; (i-3) R8 and R9 may be each independently a hydrogen atom, or C1C3 alkyl; R10 is C1’C3 alkyl substituted with hydroxy; R17 is a hydrogen atom; RB and R 6 may be (i-7) shown below; (i-7) R5 is a hydrogen atom, or hydroxy; R6 is a hydrogen atom: a divalent group represented by formula: is a divalent group represented by formula: wherein the atom marked “a” binds to the group represented by the formula: the atom marked “b” binds to the group represented by the formula: R17 R10 A 0 Y R8 R9 0     ■ X is CR19 or N; R19 is a hydrogen atom or halogen! or a pharmaceutically acceptable salt thereof.

[0153] The compounds represented by Formula (I), Formula (II), Formula (IF), or Formula (III) are not limited to specific isomers, but include all possible isomers (e.g., keto enol isomers, imine enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

[0154] One or more hydrogen, carbon, and / or other atom(s) of the compounds represented by Formula (l), Formula (II), Formula (II ), or Formula (III) may be substituted with isotope(s) of hydrogen, carbon, and / or other atom(s), respectively. Examples of such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, as in the cases of 2H, 3H, nC, 13C, 14C, 1BN, 18O, 17O. 31P, 32P. 3BS, 18F, 123I. and 36C1, respectively. The compounds represented by Formula (l), Formula (II), Formula (II ), or Formula (III) also include compounds substituted with such isotopes. The compounds substituted with the isotopes are also useful as pharmaceutical products. The compounds represented by Formula (I), Formula (II), Formula (II ), or Formula (III) include all radiolabeled forms which are substituted with radioisotopes included in the isotope. Furthermore, a “radiolabeling method" for producing the “radiolabeled forms" is also included in the present invention, and the “radiolabeled forms” are useful as tools for metabolic pharmacokinetics studies, studies on binding assay, and / or diagnostics.

[0155] Radiolabeled forms of the compounds represented by Formula (I). Formula (II), Formula (II ), or Formula (III) can be prepared by methods well known in the pertinent art. For example, a tritium-labeled compound represented by Formula (I), Formula (II), Formula (IP), or Formula (III) can be prepared by introducing tritium into a specific compound represented by Formula (l), Formula (II), Formula (II ), or Formula (III), by a catalytic dehalogenation reaction using tritium. This method comprises reacting an appropriately-halogenated precursor of the compound of Formula (I), Formula (II), Formula (II ), or Formula (III) with tritium gas in the presence of an appropriate catalyst, such as Pd / C, and in the presence or absence of a base. The other appropriate method of preparing a tritium-labeled compound can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. A 14C'labeled compound can be prepared by using a raw material having 14C carbon.

[0156] The pharmaceutically acceptable salts of the compounds represented by Formula (I), Formula (II), Formula (IF), or Formula (III) include, for example, salts of compounds represented by Formula (I), Formula (II), Formula (IF), or Formula (III) with alkaline metal (e.g., lithium, sodium, or potassium), alkaline earth metal (e.g., calcium or barium), magnesium, transition metal (e.g., zinc or iron), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, or quinoline), or amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, or hydroiodic acid) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, or trifluoroacetic acid). These salts can be formed by the usual methods.

[0157] The compounds represented by Formula (l), Formula (II), Formula (IF), or Formula (III) of the present invention or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates), co-crystals. and / or crystal polymorphs. The present invention encompasses those various solvates, co-crystals, and crystal polymorphs. The “solvates’’ may have the compounds represented by Formula (I), Formula (II), Formula (IF), or Formula (III) coordinated with any number of solvent molecules (e.g., water molecules). When the compounds represented by Formula (I), Formula (11). Formula (IF), or Formula (ill), or pharmaceutically acceptable salts thereof are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds represented by Formula (I). Formula (II), Formula (IF), or Formula (III), or pharmaceutically acceptable salts thereof may produce crystal polymorphs. The “co crystal” means that a compound represented by Formula (l), Formula (II), Formula (IF), or Formula (III), or a salt thereof and a counter molecule exist in the same crystal lattice, and it can include any number of counter molecules.

[0158] The compounds represented by Formula (I), Formula (II). Formula (IF), or Formula (III) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs. The present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds according to the present invention that have chemically or metabolically degradable groups, and compounds that are converted to the pharmaceutically active compounds according to the present invention through solvolysis or under physiological conditions in vivo. Prodrugs include compounds that are converted to the compounds represented by Formula (I), Formula (II). Formula (IF), or Formula (III) through enzymatic oxidation, reduction, hydrolysis, or the like under physiological conditions in vivo, compounds that are converted to the compounds represented by Formula (I), Formula (II), Formula (II ), or Formula (III) through hydrolysis by gastric acid etc., and the like. Methods for selecting and preparing suitable prodrug derivatives are described in, for example, “Design of Prodrugs. Elsevier, Amsterdam, 1985”. Prodrugs themselves may have some activity.

[0159] When the compounds represented by Formula (I), Formula (II), Formula (IF), or Formula (III) or pharmaceutically acceptable salts thereof have hydroxyl group(s), prodrugs include acyloxy derivatives and sulfonyloxy derivatives that are prepared by, for example, reacting compounds having hydroxyl group(s) with suitable acyl halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonyl anhydride, and mixed anhydride, or with a condensing agent. For example, they include CHsCOO-, C2H5COO-, tert-BuCOO-, C15H31COO-, PhCOO-, (m-NaOOC)C6H4COO-, NaOOCCH2CH2COO-. CHSCH(NH2)COO-, CH2N(CH3)2COO-. CH3SO3-, CHsCH2SO3-, CFsSOs’, CH2FSO3-, CF3CH2SO3-, p-CH3O-C6H4SO3-, PhSO3-, and p-CH3-C6H4SO3-.

[0160] Since the compound according to the present invention has a PDE4D selective inhibitory activity and activates cAMP pathway, the compound is useful as a therapeutic and / or prophylactic agent for a disease related to PDE4D and / or cAMP signaling. Diseases associated with PDE4D and / or cAMP signaling include Alzheimer's disease and related dementia, Parkinson's disease, Huntington’s disease, traumatic brain injury, schizophrenia, major depressive disorder, Fragile X syndrome, Rett syndrome, down syndrome, Prader Willi Syndrome. Jordan’s syndrome, autism, autism and related autism spectrum disorders, intellectual and learning disabilities, Angelman syndrome, 22qll.2 deletion syndrome, Phelan-McDermid syndrome. Rubinstein Taybi syndrome, tuberous sclerosis, autosomal recessive spastic ataxia of Charlevoix-Saguenay, multiple sclerosis, and progressive supranuclear palsy. Preferable examples include Alzheimer’s disease and related dementia. Parkinson’s disease-related dementia, Huntington’s disease-related dementia, traumatic brain injury-induced dementia, major depressive disorder, fragile X syndrome, rett syndrome and Jordan’s syndrome. More preferable examples include Alzheimer's disease and related dementia and fragile X syndrome. Symptoms of diseases related to PDE4D and / or cAMP signaling include anxiety, cognitive impairment, degraded learning ability, degraded memory ability, memory deficit, depression, pain. The “pain’' includes acute herpes zoster shingles pain, autoimmune neuropathy, carpal tunnel syndrome pain, chronic pain, complex regional pain syndrome, dental pain, dental extraction pain, dermal injury pain, diabetic neuropathy pain, drug-induced peripheral neuropathy, headache pain, Human Immunodeficiency Virus-associated neuropathy, idiopathic neuropathy, lower back pain, mastalgia. membranous neuropathy, menstrual cramps, migraine headaches pain, muscular pain, myasthenia gravis, neuropathic pain, neuropathy, pain resulting from cancer, nociceptive pain, ocular pain associated with postherpetic neuralgia, peripheral neuropathy pain, post-cardiac surgery pain, postherpetic neuralgia, post-surgical pain, causalgia nerve injury pain, and tactile allodynia. Diseases associated with PDE4D and / or cAMP signaling also include acidosis inflammation of the lung, acoustic trauma, acute allograft rejection, acute inflammation, acute mountain sickness, acute pulmonary edema, acute pulmonary hypertension, acute pulmonary thromboembolism, acute respiratory distress syndrome, acute rheumatic arthritis, adenocarcinoma, adenomatous polyps treatment, adjuvant to short-term immunosuppression in transplant therapy, AIDS-related dementia HIV dementia, airway hyperreactivity, alcohol addiction, alcohol withdrawal symptoms, allergen-induced asthma, allergic contact dermatitis, allergic 74 rhinitis, allograft rejections, alopecia areata, anemia, aortic aneurysm, aplastic anemia, arthritis, asthma-related diseases, asthmatic bronchitis, atherosclerosis arteriosclerotic dementia, autoimmune diseases, autoimmune hepatitis, basal cell carcinoma, Behcet's syndrome, benzodiazepine tolerance, bipolar disorder, blast noise injury, bronchiectasis, bronchiolitis, bullous disease, burns, bursitis, cachexia, cardiovascular ischemia, central nervous system disease, cerebral ischemia, cerebral vessel disorder-related impairment, chronic allograft rejection, chronic bronchitis with airway obstruction, chronic obstructive bronchitis, chronic bronchitis with normal airflow, chronic inflammation, chronic sinusitis, cirrhosis, cisplatin-induced ototoxicity, cold-induced asthma, congestive heart failure, cough, Crohn's disease, cystic fibrosis, delayed type hypersensitivity reaction, dermatitis, dermatomyositis, diabetes type I or type II, diarrhea, drug withdrawal symptoms, dysmenorrhea, dyspnea, early transplantation rejection, eating disorders, eczema, emphysema, encephalitis, endometriosis, endotoxic shock, enteropathic arthritis, epilepsy, Eustachian tube itching, exercise-induced asthma, familial adenomatous polyposis prevention, farmer's lung, fat embolism in the lung, fever antipyretic, fibrosis treatment occurring with radiation therapy, gastritis, cancer, gingivitis, global ischemia, glomerulonephritis, Goodpasture's syndrome, gouty arthritis, graft vs. host disease. Gram-negative sepsis, Graves' disease hyperthyroidism. Hashimoto's thyroiditis, hearing loss, hemolytic syndromes, heparin-protamine reactions, hepatitis, Human Immunodeficiency Virus-associated neurodegenerative disorder. Hodgkin's disease, hyaline membrane disease, hyperalgesia, hyperbaric oxygen convulsions, hyperbaric oxygen toxicity, hypercapnea, hyperinflation, hypoglycemia, hypoxemia, hypoxia, IgA neuropathy, IL-1 therapy. IL-2 therapy, inflammatory bowel disease, insulin resistance, interstitial cystitis, irritable bowel syndrome, ischemia secondary to cardiac arrest, ischemic heart disease, juvenile arthritis, Korsakoffs syndrome, Langerhans' cell histiocytosis, lichen planus, metabolic disorders associated with exaggerated inflammatory signaling, multi-organ dysfunction, myocardial ischemia, myocarditis, myositis including polymyositis, necrotizing enterocolitis, nephritis, nephrotic syndrome, nerve degeneration, nerve necrosis, neuromuscular junction disease, neuropathic arthritis, nicotine addiction, ophthalmic disease, opiate analgesic tolerance, opiate withdrawal symptom, organ transplant patients-related condition, osteoarthritis, osteoporosis, otic allergic disorder, otic disease, otitis, pancreatitis, periarteritis nodosa, perinatal aspiration syndrome, periodontitis, peripheral disease, persistent pulmonary hypertension of the newborn, pigeon fancier's disease, pneumonia, pneumonitis, pollution-induced asthma, polymyositis, post-traumatic stress disorder, premature labor, pre senile dementia, pruritus, psoriasis, psoriatic arthritis, pulmonary fibrosis, pulmonary hypertension, pulmonary inflammation, pyogenic arthritis, Reiter's syndrome, reflex sympathetic dystrophy, reflux esophagitis, restenosis, restenosis following coronary bypass surgery, rheumSymtoatic fever, rheumatoid arthritis, sarcoidosis, Schwann cell transplantation for spinal cord injury, scleritis, scleroderma, hemorrhagic shock-induced systemic hypotension, septic shock, small airway disease, spinal cord and head injury, spinal cord injury, spondyloarthropathy, status asthmaticus. stem cell transplantation for spinal cord injury, sunburn, surgical analgesia, swelling occurring after injury, Sydenham's chorea, systemic lupus erythematosus, lupus nephritis, tendonitis, thrombotic stroke, thyroiditis, tissue damage in vascular disease, tobacco addiction, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, type 1 diabetes, ulcerative colitis, viral-induced-asthma. vitiligo, autoimmune thyroiditis, obesity and weight gain. The “cancer” includes adenocarcinoma, basal cell carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, esophageal carcinoma, epithelial carcinoma, epithelial cell-derived neoplasia, gastrointestinal cancer, leukemia, lip cancer, liver cancer, lung cancer, lymphoma, mouth cancer, neoplasia, nervous system cancer, ovarian cancer, pancreas cancer, prostate cancer, renal cell carcinoma, skin cancer, small bowel cancer, squamous cell carcinoma, stomach cancer, testicular cancer, treatment resistant cancer, pancreatic cancer, and melanoma. The “central nervous system disease” includes Alzheimer's disease, central nervous system trauma Huntington's disease, multiple sclerosis. Parkinson's disease, and progressive supranuclear palsy. The “peripheral disease” includes diabetic neuropathy, peripheral neuropathy, and Guillain Barre syndrome.

[0161] The “PDE4D inhibitor” means a pharmaceutical product having a PDE4D inhibitory activity.

[0162] (Method for producing compounds of the present invention) The compounds represented by Formula (l), Formula (II), Formula (II ), or Formula (III) of the present invention can be produced by, for example, the general synthesis method described below. Regarding extraction, purification, and the like, the treatments carried out in ordinary experiments of organic chemistry may be carried out. The compounds of the present invention can be synthesized with reference to methods known in the art.

[0163] Method A A-2 A-7 R4 OH wherein X1 is a chlorine atom, a bromine atom or an iodine atom; M1 is Li, MgCl or MgBE and each of other symbols is as described above. Step 1 Compound A-2 can be obtained by reacting Compound A l with N, (O dimethyl hydroxylamine hydrochloride and a condensing agent in an appropriate solvent in the presence or absence of an amine and 1-hydroxybenzotriazole. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N’hydroxybenzotriazole, EDC, 4 (4,6’ dimethoxy l,3,5 triazin-2-yl)’4-methylmorpholinium chloride and HATU, and the condensing agent can be used in an amount of 1 to 5 molar equivalents relative to Compound A l. Examples of the amine include triethylamine and N, JV’diisopropylethylamine, and the condensing agent can be used in an amount of 1 to 5 molar equivalents relative to Compound Al. The reaction temperature is -20°C to 60°C, preferably 0°C to 30°C. The reaction time is 0.1 hours to 24 hours, and preferably 1 hour to 12 hours. The reaction solvents include DMF, DMA, NMP, tetrahydrofuran, dioxane, dichloromethane and acetonitrile, and each solvent can be used alone or mixed with the others. The obtained desired Compound A-2 can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary. Step 2 Compound A-4 can be obtained by reacting Compound A-2 and Compound A 3 with an appropriate metal catalyst in an appropriate solvent in the presence of a base. Examples of the metal catalyst include [1, l' bis(diphenylphosphino)ferrocene] palladium(TT) dichloride dichloromethane adduct, palladium(n) acetate. bis(dibenzylideneacetone)palladium(0) and tetrakis(triphenylphosphine)palladium(0), and the metal catalyst can be used in an amount of 0.001 to 0.5 molar equivalents or more, preferably 0.01 to 0.2 molar equivalents relative to Compound A-2. Examples of the base include lithium hydroxide, sodium hydroxide, sodium carbonate and tripotassium phosphate, and the base can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents relative to Compound A-2. Compound A3 can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 3.0 molar equivalents relative to Compound A-2. The reaction solvents include ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO. NAIF and water, and each solvent can be used alone or mixed with the others. The reaction temperature is 0 to 150°C, preferably 20 to 100°C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours. The obtained desired Compound A-4 can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary. Step 3 Compound A 6 can be obtained by reacting Compound A-4 and Compound A-5 in an appropriate solvent. Compound A 5 can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents relative to Compound A-4. The reaction solvents include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.) and ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) and each solvent can be used alone or mixed with the others. The reaction temperature is 78 to 50 °C, preferably 45 to 0°C. The reaction time is 0.1 to 24 hours, preferably 1 to 6 hours. The obtained desired Compound A 6 can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary. Compound A 5 can be obtained by reacting an appropriately-halogenated precursor of the Compound A-5 with alkyl lithium such as nbutyllithium. The reaction temperature at lithiation is preferably -78 to 0°C. Step 4 Compound A 7 can be obtained by reacting Compound A-6 with an appropriate reducing agent in an appropriate solvent Examples of the reducing agent include sodium borohydride and lithium borohydride, and the reducing agent can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 3.0 molar equivalents relative to Compound A-6. The reaction solvents include alcohols (e.g., methanol, ethanol, zo / 7-bulanol. isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.) and ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), and each solvent can be used alone or mixed with the others. The reaction temperature is 0 to 80°C, preferably 0 to 20°C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours. The obtained desired Compound A 7 can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary. Step 5 Compound A8 can be obtained by deprotecting TBS group on Compound A-7 in the presence of an TBAF in an appropriate solvent. TBAF can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 5 molar equivalents relative to Compound A-7. The reaction solvents include ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) and halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), and each solvent can be used alone or mixed with the others. The reaction temperature is 0 to 100°C, preferably 20 to 80°C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours. The obtained desired Compound A-8 can be purified by a conventional method (e.g.. column chromatography, recrystallization, etc.) if necessary.

[0164] Method B wherein X1 is a chlorine atom, a bromine atom or an iodine atom; X2 is chlorine, bromine or iodine; and each of other symbols is as described above. Step 1 Compound B-2 can be obtained by reacting Compound B-l and Compound A 3 with an appropriate metal catalyst in an appropriate solvent in the presence of a base. Examples of the metal catalyst include [1, l'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride dichloromethane adduct, palladium(n) acetate, bis(dibenzylideneacetone)palladium(0) and tetrakis(triphenylphosphine)palladium(0), and the metal catalyst can be used in an amount of 0.001 to 0.5 molar equivalents or more, preferably 0.01 to 0.2 molar equivalents relative to Compound B l. Examples of the base include lithium hydroxide, sodium hydroxide, sodium carbonate and tripotassium phosphate, and the base can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents relative to Compound Bl. Compound A3 can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 3.0 molar equivalents relative to Compound B l, The reaction solvents include ethers (e.g.. tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP and water, and each solvent can be used alone or mixed with the others. The reaction temperature is 0 to 150°C, preferably 20 to 100°C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours. The obtained desired Compound B-2 can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary. Step 2 Compound B-3 can be obtained by reacting Compound B-2 with an appropriate halogenated agent in an appropriate solvent. Examples of halogenated agent include phosphorus tribromide and thionyl chloride and can be used in an amount of 0.5 molar equivalents or more, preferably 0.5 to 3 molar equivalents relative to Compound B-2. The reaction solvents include ethers (e.g.. tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) and halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), and each solvent can be used alone or mixed with the others. The reaction temperature is 0 to 100°C, preferably 0 to 40°C. The reaction time is 0.1 to 24 hours, preferably 1 to 20 hours. The obtained desired Compound B-3 can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary. Step 3 Compound B-5 can be obtained by reacting Compound B-3 and Compound B-4 with an appropriate metal catalyst in an appropriate solvent in the presence of a base. Examples of the metal catalyst include [1, r-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride dichloromethane adduct, palladium(n) acetate, bis(dibenzylideneacetone)palladium(0) and tetrakis(triphenylphosphine)palladium(0), and the metal catalyst can be used in an amount of 0.001 to 0.5 molar equivalents or more, preferably 0.01 to 0.2 molar equivalents relative to Compound B-3. Examples of the base include lithium hydroxide, sodium hydroxide, sodium carbonate and tripotassium phosphate, and the base can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents relative to Compound B3. Compound B-4 can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 3.0 molar equivalents relative to Compound B-3. The reaction solvents include ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane. etc.). DMF. DMSO, NMP and water, and each solvent can be used alone or mixed with the others. The reaction temperature is 0 to 150°C, preferably 20 to 100°C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours. The obtained desired Compound B-5 can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary. Step 4 Compound B-6 can be obtained by deprotecting Boc group on Compound B-5 in the presence of an acid in the absence of a solvent. Examples of the acid include hydrochloric acid, sulfuric acid, TFA and formic acid, and the acid can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 100 molar equivalents relative to Compound B-5. The reaction solvents include alcohols (e.g., methanol, ethanol, £ert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g.. toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP and acetonitrile, and each solvent can be used alone or mixed with the others. The reaction temperature is 0 to 80°C, preferably 0 to 50°C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours. The obtained desired Compound B-6 can be purified by a conventional method (e.g.. column chromatography, recrystallization, etc.) if necessary. Step 5 Compound B-8 can be obtained by reacting Compound B-6 with Compound B7 and a condensing agent in the presence or absence of an amine and 1-hydroxybenzotriazole. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-JVhydroxybenzotriazole, EDC, 4 (4,6' dimethoxy-1,3,5 triazin-2-yl)-4-methylmorpholinium chloride and HATU, and the condensing agent can be used in an amount of 1 to 5 molar equivalents relative to Compound B6. Examples of the amine include triethylamine and A / TV'diisopropylethylamine, and the amine can be used in an amount of 1 to 5 molar equivalents relative to Compound B6. Compound B-7 can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 3.0 molar equivalents relative to Compound B-6. The reaction temperature is -20°C to 60°C, preferably 0°C to 30°C. The reaction time is 0.1 hours to 24 hours, and preferably 1 hour to 12 hours. The reaction solvents include DMF, DMA, NMP, tetrahydrofuran, dioxane, dichloromethane and acetonitrile, and each solvent can be used alone or mixed with the others. The obtained desired Compound B-8 can be purified by a conventional method (e.g.. column chromatography, recrystallization, etc.) if necessary.

[0165] Since the compound of the present invention has PDE4D inhibitory activity, the compound is useful as a therapeutic and / or prophylactic agent for a disease associated with PDE4D and / or cAMP signaling, or symptoms of diseases related to PDE4D and / or cAMP signaling, for example Alzheimer's disease and related dementia and fragile X syndrome. Furthermore, the compound of the present invention has utility as a pharmaceutical, and preferably, the compound has any one or a plurality of the following excellent features. a) Inhibitory activity against CYP enzymes (for example. CYP1A2, CYP2C9, CYP2C19. CYP2D6, and CYP3A4) is weak. b) Satisfactory pharmacokinetics such as high bioavailability and adequate clearance are exhibited. c) Metabolic stability is high. d) Irreversible inhibitory activity is not exhibited against CYP enzymes (for example, CYP3A4) within the concentration range of the measurement conditions described in the present description. e) Mutagenicity is not exhibited. f) The cardiovascular risk is low. g) High solubility is exhibited. h) High PDE4D inhibitory activity is exhibit. i) A selectivity for PDE4D over PDE4B is high. j) Brain distribution ability is high. k) P-gp and BCRP (Breast cancer resistance protein) substrate property is low. 1) The hepatotoxicity risk is low.

[0166] A pharmaceutical composition of the present invention can be administered orally or parenterally. Methods for parenteral administration include dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, inner ear. or vaginal administration.

[0167] In the case of oral administration, any dosage forms, which are usually used, such as oral solid preparations (e.g., tablets, powders, granules, capsules, pills, or films), and oral liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic water, extracts, decoctions, or tinctures) may be prepared according to a conventional method and administered. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets. The powders and the granules may be dry syrups. The capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0168] In the case of parenteral administration, any dosage forms, which are usually used, such as injections, drips, and external preparations (e.g., ophthalmic drops, nasal drops, ear drops, aerosols, inhalations, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, cataplasms, external powders, or suppositories) can be preferably administered. Injections may be emulsions whose type is O / W, W / O, O / W / O, W / O / W, or the like.

[0169] A pharmaceutical composition can be obtained by mixing an effective amount of the compound of the present invention with various pharmaceutical additives appropriate for the dosage form, such as an excipient, a binder, a disintegrant, and a lubricant, as necessary. Furthermore, the pharmaceutical composition can be prepared into a pharmaceutical composition for use for a child, an elderly, a patient with a serious case, or a surgical operation, by appropriately changing the effective amount of the compound of the present invention, the dosage form, and / or various pharmaceutical additives. For example, a pharmaceutical composition for use for a child may be administered to a neonate (less than 4 weeks after birth), an infant (from 4 weeks after birth to less than 1 year), a preschool child (from 1 year to less than 7 years), a child (from 7 years to less than 15 years), or a patient 15 years to 18 years of age. For example, a pharmaceutical composition for an elderly may be administered to a patient 65 years of age or older.

[0170] It is desirable to set the amount of administration of the pharmaceutical composition of the present invention, after considering the age and body weight of the patient, the type and degree of the disease, the route of administration, and the like: however, in the case of oral administration, the amount of administration is usually 0.05 to 300 mg / kg / day and is preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, the amount of administration may vary greatly depending on the route of administration: however, the amount of administration is usually 0.005 to 10 mg / kg / day and is preferably in the range of 0.01 to 1 mg / kg / day. This may be administered once a day or several times a day.

[0171] The compound of the present invention can be used in combination with another therapeutic agent for Alzheimer’s disease and related dementia or fragile X syndrome (hereinafter, referred to as concomitant drug), for the purpose of enhancing the action of the compound, reducing the amount of administration of the compound, or the like. At this time, the timing of administration for the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the target of administration or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more kinds of preparations each including active ingredients, or may be administered as a single preparation including those active ingredients.

[0172] The amount of administration of the concomitant drug can be appropriately selected based on the clinically used dosage. Furthermore, the blending ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to the target of administration, the route of administration, the target disease, symptoms, combination, and the like. For example, when the target of administration is a human being, 0.01 to 100 parts by weight of the concomitant drug may be used relative to 1 part by weight of the compound of the present invention. [EXAMPLES]

[0173] Hereinafter, the present invention will be described in more detail by way of Examples, Reference Examples, and Test Examples; however, the present invention is not intended to be limited by these.

[0174] Furthermore, abbreviations used in the present description denote the following meanings. TBS: ZeiTButyldimethylsilyl EDC: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: O(7-Azabenzotriazol- 1-yl)-1, l,3.3tetramethyluronium hexafluorophosphate PdCL(dppf) • CH2CI2: [1, l'-bis(Diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct n BuLi- nButyllithium TBAF: Tetra-zr butylammonium fluoride DMF: N, N-Dimethylformamide DMA: N,N-Dimethylacetamide NMP: N-Methylpyrrolidone DMSQ: Dimethyl sulfoxide THF: Tetrahydrofuran TFA: Trifluoroacetic acid EtOAc: Ethyl acetate MeOH: Methanol CDCls: Chloroform-di SFC: Supercritical Fluid Chromatography DEA: Diethylamine IPE: Diisopropyl ether RT: Retention time ee: Enantiomeric excess nM: nmol / L pM: pmol / L mM: mmol / L ESC Electrospray ionization 10175J (Method for identifying compound) The NMR analysis obtained in each Example was performed at 400 MHz, and measurement was made using DMSO-de and CDCls. Furthermore, when NMR data are shown, there are occasions in which all the measured peaks are not described. "MS (m / z)" represents the mass of a molecule observed by LC / MS: liquid chromatography / mass spectrometry(ESl). Measurement conditions for LC / MS include the conditions shown below, but are not limited to these conditions. Note that "MS (m / z)" represents [M+H]+ unless otherwise specified. (Measurement condition 1) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 pm, i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, and [B] was 0.1% formic acid containing acetonitrile solution. Gradient: A linear gradient of 5% to 100% solvent [B] was carried out for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. Incidentally, in the description, the description of MS (m / z) indicates a value observed by mass spectrometry. (Measurement condition 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 pm. i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] was lOmM ammonium carbonate-containing aqueous solution, and [B] was acetonitrile. Gradient: A linear gradient of 5% to 100% solvent [B] was carried out for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.

[0176] Example 1 Synthesis of Compound 1'067 O Br 2 °                                              1-067 Step 1 Synthesis of Compound 2 Sodium 2-chloro'2,2-difluoroacetate (1.65 g, 10.8 mmol) was added to a solution of methyl 3bromo-4-hydroxybenzoate (1000 mg, 4.33 mmol) and K2CO3 (1.50 g, 10.8 mmol) in DMF (20.0 mL) and HaO (1.0 mb) at 0 °C. The reaction mixture was heated at 100 °C for 2.5 hours, allowed to cool to room temperature. Saturated aqueous sodium hydrogen carbonate (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3x 10 mL). The organic layer was distilled off under reduced pressure, and then the residue was immediately used in the next step without further purification. The residue was dissolved in THF (6.1 mL) and MeOH (6.1 mL). To the solution was added sodium hydroxide solution (2 mol / L in H2O, 8.68 ml, 17.4 mmol) at room temperature. The reaction mixture was maintained for 5 hours at room temperature. Hydrochloric acid solution (2 mol / L in HaO. 9.0 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2x 50 mL). The solvent was distilled off under reduced pressure, and then the residue was immediately used in the next step without further purification. The residue was dissolved in DMF (8.1 mL). To the solution was added HATU (2.15 g, 5.65 mmol), N, Odimethylhydroxylamine hydrochloride (0.85 g, 8.69 mmol) and A / JV-diisopropylethylamine (2.28 mL, 13.0 mmol) at room temperature. The solution was maintained for 1.0 h at room temperature, saturated aqueous ammonium chloride solution (30.0 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2x 60 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (30.0 mL) and water (30 mL). The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (EtOAc / Hexane L0) to afford Compound 2 (1.23 g, yield 91%) as a colorless oil. iH-NMR (CDCls) 8: 3.38 (3H, s), 3.57 (3H, s), 6.60 (1H, t, J= 72.9 Hz), 7.25 (1H, d, J= 8.4 Hz), 7.71 (1H, dd, J= 8.4, 2.1 Hz), 8.02 (1H, d, J= 2.1 Hz) Step 2 Synthesis of Compound 3 PdCla(dppf) • CH2CI2 (184 mg, 10 mol%) was added to a solution of Compound 2 (700 mg, 2.26 mmol), (3'(difluoromethoxy)phenyl)boronic acid (636 mg, 3.39 mmol). K3PO4 (1.44 g, 6.77 mmol), H2O (1.2 mL) and l,4 dioxane (7.0 mL) at room temperature. The reaction mixture was heated at 100°C for 5.5 hours and was then allowed to cool to room temperature. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2x 10 mL). The organic layer was washed with 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 (EtOAc / Hexane El) to afford Compound 3 (630 mg, yield 75%) as a colorless oil. iH-NMR (CDCls) 8: 3.39 (3H, s), 3.59 (3H, s), 6.44 (1H, t, J= ISA Hz), 6.56 (1H, t, J= 72.8 Hz), 7.77-7.19 (7H, m), Step 3 Synthesis of Compound 5 nBuLi (1.55 mol / L solution in hexane, 778 pL, 1.21 mmol) was added to a solution of Compound 3 (150 mg, 0.402 mmol), 5'bromo'2-(((ferf-butyldimethylsilyl)oxy) methyl)pyridine (364 mg, 1.21 mmol) {J.Am. Chern.Soc. 2013, 135, 14052-14055) in toluene (2.4 mL) and THF (0.9 mL) at -78 °C. After stirring for 1 hour at '78 °C. rrBuLi (1.55 mol / L solution in hexane, 778 pL, 1.21 mmol) was added to the reaction mixture. The solution was maintained for 2 h at -78 °C, saturated aqueous ammonium chloride solution (20.0 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2x 50 mL). The organic layer was washed with 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 (EtOAc / hexane El), and then the residue was immediately used in next step without further purification. The residue was dissolved in MeOH (4.3 mL). To the solution was added NaBH4 (30.4 mg, 0.803 mmol) at room temperature. The solution was maintained for 1.5 h at room temperature, saturated aqueous ammonium chloride solution (2.0 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2x 30 mL). The organic layer was washed with 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 (EtOAc / Hexane El) to afford Compound 5 (47 mg, yield 22%) as a colorless oil. HINMR (CDCls) 8: 0.12 (611, s), 0.96 (911, s), 2.35 (HI, brs), 4.83 (211, s), 5.93 (1H, d. J = 5.93 Hz). 6.35 (1H, t. J= 74.0 Hz). 6.54 (1H. t, J= 73.8 Hz), 7.72-6.98 (9H, m). 8.54 (1H, br-s) Step 4 Synthesis of Compound 1'067 TBAF (1.0 mol / L solution in THF, 156 pL. 0.156 mmol) was added to a solution of Compound 5 (42 mg, 0.078 mmol) in THF (0.84 mL) at room temperature. The solution was maintained for 2.0 h at room temperature, saturated aqueous ammonium chloride solution (5.0 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2x 5 mL). The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative chiral SFC method A to afford Compound 1 067 (7 mg, yield 21%) as a colorless oil. Enantiometric purity determination of Compound 1-067 was carried out using analytical chiral SFC method B. Compound I-067: RT = 5.84 min, >99.5% ee, isomer of Compound 1'067: RT = 5.27 min, >99.5% ee. !H-NMR (CDCls) 8: 2.38 (1H, d, J= 2.1 Hz). 3.54 (1H, br s), 4.76 (2H, s), 5.95 (1H, d. J= 2.1 Hz), 6.36 (1H, t, J= 73.7 Hz), 6.55 (1H, t, J= 74.0 Hz), 7.31'7.13 (5H, m). 7.44-7.37 (3H. m), 7.71 (1H. d, J= 8.2, 2.3 Hz), 8.60 (1H, br-s) Preparative chiral SFC method A Column: Two CHTRALPAK TA / SFC (5 pm. cp20 x 250 mm) (DAICEL) Flow rate: 30mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient: MeOH + 0.1% DEA / CO2 = 15 / 85 composition ratio was maintained and sent for 30 minutes. Sample Solution: 22.0 mg I mL MeOH / CHCls(l / l) Injection Volume: 0.1 mL Analytical chiral SFC method B Column: CHIRALPAK IA / SFC (5 pm, cp4.6 x 250 mm) (DAICEL) Flow rate: 2.0 mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient,: MeOH + 0.1% DEA / CO2 = 20 / 80 composition ratio was maintained, and the solution was sent for 15 minutes. Sample Solution: 0.5 mg / mL in methanol Injection Volume: 10 pL

[0177] Example 2 Synthesis of Compound I-101 1-101 Step 1 Synthesis of Compound 8 zrBuLi (1.56 mol / L solution in hexane. 2.54 mL, 3.95 mmol) was added to a solution of Compound 6 (492 mg, 1.32 mmol). 5-bromo-2-((( / erC butyldimethylsilyl)oxy)methyl)thiazole (1.22 g. 3.95 mmol) (WO2022155941A) in toluene (7.4 mL) and THF (2.5 mL) at -78 °C. After stirring for 1.0 hour at -78 °C, saturated aqueous ammonium chloride solution (4.0 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (2x 50 mL). The organic layer was washed with 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 (EtOAc / hexane E4) to afford Compound 8 (380 mg, yield 53%) as a brown oil. !H-NMR (CDCls) 8- 0.17 (6H, s). 0.91 (9H. s), 4.50 (2H, s), 6.52 (1H, t, J= 73.3 Hz), 6.57 (1H, t, J= 74.2 Hz), 7.49-7.17 (5H, m), 7.95-7.90 (2H, m), 8.19 (1H, s) Step 2 Synthesis of Compound 1-101 NaBH4 (52.8 mg. 1.40 mmol) was added to a solution of Compound 8 (378 mg, 0.70 mmol) in MeOH (3.8 mL) at 0 °C. The solution was allowed to warm to room temperature and maintained for 1.0 h. Saturated aqueous ammonium chloride solution (4 mL) was added to the reaction mixture, and the mixture was extracted with CHCls (2x 20 mL). The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was immediately used in the next step without further purification. TBAF (1.0 mol / L solution in THF,1.40 mL, 1.40 mmol) was added to the residue and the mixture was stirred for 20 min at room temperature. The mixture was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (EtOAc / hexane 3:7 to 1 / 0), and preparative chiral SFC method C to afford Compound I-101 (58.6 mg. yield 20%) as a colorless oil. Enantiometric purity determination of Compound I-101 was carried out using analytical SFC method D. Compound LIOL RT = 3.89 min, >99.5% ee. isomer of Compound 1-10L RT = 3.36 min, >99.5% ee. !HNMR (CDCls) 8: 7.55 (1H, s). 7.48 7.41 (2H, m), 7.33 7.13 (5H, m), 6.55 (1H, t, J= 73.8 Hz), 6.37 (1H, t. J= 73.6 Hz). 6.13 (1H, d, J= 3.6 Hz), 4.89 (2H, d. J= 5.5 Hz), 2.67 (1H, d. J= 3.6 Hz), 2.61 (1H, t, J= 6.0 Hz) Preparative chiral SFC method C Column: Two CHIRALPAK IF / SFC (5 pm, <p20 x 250 mm) (DAICEL) Flow rate: 30mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient: MeOH + 0.1% DEA / CO2 = 10 / 90 composition ratio was maintained and sent for 40 minutes. Sample Solution: 45.0 mg / mL MeOH / CHC13(l / l) Injection Volume: 0.2 mL Analytical chiral SFC method D Column: CHIRALPAK IF / SFC (5 pm, ¢4.6 x 250 mm) (DAICEL) Flow rate: 2.0 mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient: MeOH + 0.1% DEA / CO2 = 20 / 80 composition ratio was maintained, and the solution was sent for 10 minutes. Sample Solution: 0.5 mg / mL in methanol Injection Volume: 10 pL

[0178] Example 3 Synthesis of Compound 1-116 1-116 Step 1 Synthesis of Compound 10 Compound 9 (10.3 g, 44.2 mmol) was dissolved in dichloromethane (103 mL). and aluminium chloride (29.4 g, 221 mmol) was added. Then the mixture was refluxed for 3 hours. Aluminium chloride (17.7 g. 132 mmol) was added, and the mixture was refluxed for 16 hours. Aluminium chloride (17.7 g, 132 mmol) was added, and the mixture was refluxed for 2 hours. Under ice cooling, a solution of sodium acetate (120 g, 1457 mmol) in HaO (300 mL) was added, and ethyl acetate (100 mL) was added. The mixture was filtered through celite and was extracted two times with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure. The obtained residue was washed by ethyl acetate (8 mL) and hexane (8 mL) to afford Compound 10 (6.17 g, 64%) as a pink solid. !H-NMR (CDCls) 8: 6.24 (br-s, 1H), 6.95 (d, J= 8.7 Hz, 1H), 7.80 (dd. J= 8.7, 7.7 Hz, 1H), 10.21 (s, 1H). Step 2 Synthesis of Compound 11 Compound 10 (6.17 g, 28.2 mmol) was dissolved in DMF (63 mL) and II2O (6.3 mL), and potassium carbonate (9.73 g, 70.4 mmol) and chlorodifluoroacetic acid sodium salt (10.7 g, 70.4 mmol) were added. The mixture was stirred at 100 °C for 1 hour. Water (300 mL) was added, and the mixture was extracted two times with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 11 (6.12 g, 81%) as a colorless oil. 'H-NMR (CDCls) 8: 6.67 (t.    71.8 Hz, 1H), 7.15 (d, J= 8.7 Hz, 1H), 7.87 (dd, J= 8.7, 7.7 Hz. 1H), 10.30 (s, 1H). Step 3 Synthesis of Compound 12 Compound 11 (6.12 g, 22.7 mmol) was dissolved in acetonitrile (30.6 mL) and HaO (9.2 mL). and 30% hydrogen peroxide solution (2.55 mL, 25.0 mmol), potassium dihydrogen phosphate (0.773 g, 5.68 mmol) and a solution of sodium chlorite (2.88 g, 31.8 mmol) in HaO (18.4 mL) were added under ice cooling. Then the mixture was stirred at room temperature for 2 hours. A solution of sodium hypochlorite pentahydrate (5 g) in HaO (25 mL) was added, and the mixture was extracted two times with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure, and then the residue was immediately used in the next step without further purification. The residue was dissolved in DMF (66 mL), and A( (9-dimethylhydroxylamine hydrochloride (2.71 g, 27.8 mmol), Ihydroxybenzotriazole (0.31g, 2.32 mmol), triethvlamine (4.82 mL, 34.8 mmol) and l-ethyL3-(3-dimethylaminopropyl) carbodiimide monohydrochloride (5.33 g, 27.8 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. Water (300 mL) was added, and the mixture was extracted two times with ethyl acetate (100 mL). The organic layer was washed with water (300 mL) and brine (100 mL). and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 12 (5.05 g, 66%) as a colorless oil. iH-NMR (CDCls) 8: 3.37 (s, 3H), 3.56 (br-s, 3H), 6.60 (t, J= 72.5 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 7.41 (dd. J= 8.5, 7.7 Hz, 1H). Step 4 Synthesis of Compound 13 Compound 12 (202 mg, 0.616 mmol) was dissolved in l,4 dioxane (2.0 mL) and HaO (0.4 mL), and 2-(difluoromethoxy)-4-(4,4,5,5’tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (200 mg. 0.739 mmol), tripotassium phosphate (392 mg, 1.85 mmol), and [1, l'bis(diphenylphosphino)ferrocene]palladium(H) dichloride dichloromethane adduct (50 mg, 0.062 mmol) were added. Then the mixture was stirred at 100 °C for 40 minutes under a nitrogen atmosphere. Water (10 mL) was added, and the mixture was extracted two times with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 13 (231 mg. 96%) as a yellow oil. !H-NMR (CDCls) 8: 3.37 (s, 3H). 3.59 (br-s, 3H), 6.46 (t, J= 72.2 Hz, 1H), 6.95 (s, 1H), 7.12-7.18 (m, 2H), 7.52 (t, J= 72.8 Hz, 1H), 7.53 (dd, J= 8.8, 7.0 Hz, 2H), 8.28 (dd, J= 5.3, 0.5 Hz, 1H). Step 5 Synthesis of Compound 15 Compound 13 (764 mg, 1.95 mmol) and Compound 14 (909 mg. 2.70 mmol) were dissolved in toluene (11.5 mL) and THF (3.8 mL), and zrbutyllithium (2.66 mol / L in hexane, 1.02 mL, 2.70 mmol) was added at -78°C. The mixture was stirred at -78°C for 1 hour. A saturated aqueous solution of ammonium chloride (10 mL) was added, and the mixture was extracted three times with chloroform (5 mL). The organic layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off 91 under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 15 (344 mg, 30%) as a yellow oil. 'H-NMR (CDCh) 8: 0.20 (s. 6H). 0.98 (s, 9H), 1.68 (s, 6H), 6.53 (t.     71.9 Hz, 1H), 6.97 (s, 1H), 7.15 (d. J= 5.2 Hz, 1H), 7.23 (d, J= 8.5 Hz, 1H), 7.52 (t, J= 72.5 Hz, 1H), 7.69 (dd, J= 8.5, 7.7 Hz, 1H). 8.01 (d. J= 1.8 Hz, 1H), 8.29 (d, J= 5.2 Hz, 1H). Step 6 Synthesis of Compound TH 16 Compound 15 (340 mg, 0.578 mmol) was dissolved in methanol (3.4 mL), and sodium borohydride (43.7 mg, 1.16 mmol) was added. The mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL). and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the residue of crude compound (330 mg), which was immediately used in the next step without further purification. The residue of crude compound (328 mg) was dissolved in THF (1.6 mL), and tetrabutylammonium fluoride (1 mol / L in THF, 1.11 mL, 1.11 mmol) was added. The mixture was stirred at 60 °C for 1 hour. A saturated aqueous solution of ammonium chloride (5 mL) was added, and the mixture was extracted three times with chloroform (5 mL). The organic layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), and the obtained product was purified by preparative chiral SFC method E to afford Compound 1116 (101 mg, 38%) as a yellow oil. Enantiometric purity determination of Compound F116 was carried out using analytical chiral SFC method F. Compound 1-116- RT = 4.42 min, >99.5% ee, isomer of Compound Fl 16: RT = 2.74 min, >99.5% ee. !H-NMR (CDCh) 6: 1.65 (s, 6H), 2.60 (d, J= 4.0 Hz, 1H), 2.72 (s. 1H), 6.37 (d, J = 4.0 Hz, 1H), 6.43 (t. J= 72.5 Hz, 1H), 6.93 (s, 1H), 7.12 (d, J= 5.2 Hz, 1H), 7.17 (d, J= 8.5 Hz, 1H), 7.51 (t. J= 72.5 Hz, 1H), 7.54 (s, 1H), 7.73 (t, J= 8.5 Hz, 1H), 8.26 (d, J= 5.2 Hz, 1H). Preparative chiral SFC method E Column: Two CHIRALPAK IF / SFC (5 pm, cp20 x 250 mm) (DAICEL) Flow rate: 30mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient: MeOII + 0.1% DEA / CO2 = 20 / 80 composition ratio was maintained and sent for 20 minutes. Sample Solution: 57.5 mg I mL MeOH / CHCls(l / l) Injection Volume: 0.8 mL Analytical chiral SFC method F Column: CHIRALPAK IF / SFC (5 pm, cp4.6 x 250 mm) (DAICEL) Flow rate: 2.0 mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient: MeOH + 0.1% DEA / CO2 = 20 / 80 composition ratio was maintained, and the solution was sent for 15 minutes. Sample Solution: 0.5 mg / mL in methanol Injection Volume- 10 pL

[0179] Reference Example 1 Synthesis of Compound 14 16                                          14 Compound 16 (1.00 g. 4.50 mmol) (WO2011075515A) was dissolved in dichloromethane (15 mL), and triethylamine (3.74 mL, 27.0 mmol) and tert~ butyldimethylsilyl trifluoromethane sulfonate (4.96 mL, 21.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. A saturated NaHCOs aq. was added, and the mixture was extracted two times with ethyl acetate (20 mL). The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 14 (1.50 g. 99%) as colorless oil. !H-NMR (CDCh) 8: 0.17 (6H, s), 0.95 (9H, s), 1.63 (6H, s), 7.54 (1H, s).

[0180] Example 4 Synthesis of Compound L168 17                                       18 19 21                                       1-168 Step 1 Synthesis of Compound 18 Compound 17 (4.30 g, 16.9 mmol) was dissolved in 1,4'dioxane (43 mL) and H2O (8.6 mL), and 2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-LS^-dioxaborolan^-yDpyridine (5.50 g, 20.3 mmol), tripotassium phosphate (10.8 g, 50.7 mmol), and [1.1'-bis(diphenylphosphino)ferrocenelpalladium(II) dichloride dichloromethane adduct (1.38 g, 1.69 mmol) were added. Then the mixture was stirred at 80°C for 2.5 hours under a nitrogen atmosphere. Water (100 mL) was added, and the mixture was extracted two times with chloroform (100 mL). The organic layer was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 18 (4.95 g, 92%) as a beige solid. iH-NMR (CDCls) 8: 3.24 (t, J= 5.3 Hz, 1H), 4.84 (d, J= 5.3 Hz, 2H), 6.51 (t. J= 72.1 Hz. 1H). 7.40 (d. J= 8.5 Hz, 1H), 7.43 (d, J= 1.3 Hz, 1H), 7.52 (t. J= 72.1 Hz, 1H), 7.62 (dd, J= 5.3, 1.3 Hz, 1H), 7.69 (d, J= 8.5 Hz, 1H), 8.30 (d, J= 5.3 Hz, 1H). Step 2 Synthesis of Compound 19 Compound 18 (2.0 g, 6.28 mmol) was dissolved in dichloromethane (30 mL), and phosphorus tribromide (0.296 mL. 3.14 mmol) was added under ice cooling. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted two times with chloroform (30 mL). The organic layer was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 19 (1.52 g, 64%) as a colorless oil. iH-NMR (CDCls) 6: 4.59 (s. 2H). 6.52 (t, J= 72.0 Hz, 1H), 7.44 (s. 1H), 7.52 (t, J = 73.0 Hz. 1H). 7.55 (d, J= 8.5 Hz, 1H), 7.64 (d, J= 5.3 Hz, 1H), 7.66 (d, J= 8.5 Hz, 1H), 8.30 (d, J= 5.3 Hz, 1H). Step 3 Synthesis of Compound 20 Compound 19 (1.52 g, 3.99 mmol) was dissolved in THF (22.8 mL) and H2O (7.6 mL), and tert-butyl N-[[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridyl]methyl]carbamate (1.60 g, 4.79 mmol)(WO2013147214), tripotassium phosphate (3.39 g, 16.0 mmol), and [1,l'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride dichloromethane adduct (0.163 g, 0.19 mmol) were added. Then the mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. Water (100 mL) was added, and the mixture was extracted two times with ethyl acetate (100, 50 mL). The organic layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (hexane / ethyl acetate) to afford Compound 20 (1.58 g, 78%) as a brown oil. iH-NMR (CDCls) 6: 1.46 (s. 9H). 4.18 (s. 2H), 4.42 (d, J= 5.0 Hz, 2H), 5.48 (br-s, HI), 6.47 (t, J= 72.2 Hz, III), 7.20 (d, J= 8.4 Hz, III), 7.24 (d, J= 8.7 IIz, HI), 7.42 (s, 1H), 7.51 (t, J= 73.0 Hz, 1H), 7.56 (d, J= 8.4 Hz. 1H). 7.58-7.63 (m, 2H), 8.28 (d. J = 5.3 Hz, 1H), 8.50 (s, 1H). Step 4 Synthesis of Compound 21 Compound 20 (1.58 g, 3.11 mmol) was dissolved in dichloromethane (21 mL). and trifluoroacetic acid (15.8 mL. 206 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL) and chloroform (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) and amino silica gel column chromatography 94 (chloroform / methanol) to afford Compound 21 (1.18 g, 93%) as a brown oil. iH-NMR (CDCls) 8: 3.97 (s, 2H), 4.19 (s, 2H), 6.47 (t, J= 72.2 Hz, 1H), 7.20 (d, J= 8.5 Hz, 1H), 7.25 (d, J= 7.7 Hz, 1H), 7.43 (d, J= 1.2 Hz, 1H), 7.52 (t, J= 73.0 Hz, 1H), 7.56 (d, J= 8.5 Hz, 1H), 7.60 (dd, J= 7.7, 1.9 Hz, 1H), 7.62 (dd, J= 5.3, 1.2 Hz, 1H), 8.28 (d, J= 5.3 Hz, 1H), 8.53 (d. J= 1.9 Hz, 1H). Step 5 Synthesis of Compound 1'168 Compound 21 (100 mg, 0.245 mmol) was dissolved in l,2 dichloroethane (2.0 mL), and 2-hydroxy-2-methylpropanoic acid (30.6 mg. 0.294 mmol). HATU (121 mg, 0.318 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.318 mmol) were added. Then the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride (20 mL) was added, and the mixture was extracted two times with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure. The obtained residue was purified by diol silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (chloroform / methanol) to afford Compound 1'168 (56.4 mg, 47%) as a colorless oil. iH-NMR (CDCls) 8: 1.49 (s. 6H). 4.19 (s, 2H), 4.55 (d, J= 5.3 Hz, 2H), 6.47 (t. J = 72.2 Hz. 1H). 7.21 (d, J= 8.4 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 7.42 (s. 1H). 7.52 (t, J= 73.0 Hz, 1H), 7.57 (d. J= 8.4 Hz. 1H). 7.60'7.67 (m, 3H). 8.28 (d. J= 5.3 Hz, 1H), 8.52 (s, 1H). 10181J Example 5 Synthesis of Compound 1'014 28 1-014 Step 1 Synthesis of Compound 23 6 bromo-5-methoxypicolinic acid (6.88 g, 29.7 mmol) was dissolved in DMF (34 mL), and N, O-dimethylhydroxylamine hydrochloride (3.47 g, 35.6 mmol). 1-hydroxybenzotriazole (0.40 g, 2.97 mmol), triethylamine (6.17 ml. 44.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (6.82 g, 35.6 mmol) were added thereto, then the mixture was stirred at room temperature for 3 hours. Water was added to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous disodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to afford Compound 23 (6.88 g, yield 84%). !H-NMR (CDCls) 8: 3.40 (3H, s), 3.85 (3H, s), 3.96 (3H, s), 7.20 (1H, d, J= 8.4 Hz), 7.74 (1H, br-s). Step 2 Synthesis of Compound 25 A solution of Compound 23 (1.00 g, 3.64 mmol) in dioxane (10 mL) and water (1 mL) was added to (2,2-difluorobenzo[d][l,3]dioxol 5-yl)boronic acid (0.881 g, 4.36 mmol). 11, r-bis(diphenylphosphino)ferrocenelpalladium(II) dichloride dichloromethane adduct (0.148 g. 0.182 mmol), tripotassium phosphate (2.32 g, 10.91 mmol) at room temperature. The reaction solution was stirred at 80°C for 2.2 hours. Water was added to stop the reaction. The mixture was extracted with chloroform. The organic layer was dried over anhydrous disodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to afford Compound 25 (1.06 g, yield 83%). ‘H-NMR (CDCh) 3: 3.46 (3H, s), 3.80 (3H, s), 3.94 (3H, s), 7.12 (1H, d, J = 8.4 Hz), 7.36 (1H, d. J= 8.5 Hz). 7.72-7.76 (3H, m). Step 3 Synthesis of Compound 27 Compound 25 (479 mg, 1.36 mmol) and Compound 26 (743 mg. 2.45 mmol) (WO2011093501) were dissolved in toluene (7.7 mb) and tetrahydrofuran (1.9 mL), and then 2.66 mol / L n-butyllithium hexane solution (0.921 mL, 2.45 mmol) was added at 78 °C and the mixture was stirred at the same temperature for 1.5 hours. Saturated NH4Q aq. was added to stop the reaction, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCI aq., and then dried over anhydrous disodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 27 (679 mg, yield 97%). 'H-NMR (CDCh) 6: 0.15 (6H, s), 0.95 (9H, s), 4.03 (3H, s), 5.03 (2H. s), 7.13 (1H, d, J= 8.4 Hz), 7.50 (1H, d, J= 8.7 Hz), 7.69-7.75 (2H, m), 8.26 (1H, d, J= 8.5 Hz), 9.50 (2H, s). Step 4 Synthesis of Compound 28 Compound 27 (10.0 g, 19.4 mmol) was dissolved in MeOH (200 mL). and then sodium borohydride (1.47 g, 38.8 mmol) was added at room temperature and the mixture was stirred at the same temperature for 1.0 hours. Saturated NH4CI aq. (50 mL) was added to stop the reaction, and then the mixture was extracted with ethyl acetate. 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) to afford Compound 28 (8.27 g, yield 82%). !H-NMR (CDCh) 8: 0.13 (6H, s), 0.94 (9H, s), 3.90 (3H, s), 4.92-4.93 (3H, m), 5.81 (1H, d. J= 4.6 Hz), 7.10 (1H, d, J= 8.5 Hz). 7.15 (1H, d, J= 8.4 Hz), 7.32 (1H, d, J= 8.4 Hz), 7.73-7.76 (2H, m). 8.76 (2H, s). Step 5 Synthesis of Compound 1'014 Compound 28 (8.27 g, 16.0 mmol) was dissolved in tetrahydrofuran (83 mL), and then 1.0 mol / L tetra zrbutylammonium fluoride tetrahydrofuran solution (19.2 mL, 19.2 mmol) was added at room temperature. After the mixture was stirred at the same temperature for 0.5 hours, 1.0 mol / L tetranbutylammonium fluoride tetrahydrofuran solution (12.8 mL. 12.8 mmol) was added at room temperature. After the mixture was stirred at the same temperature for 0.5 hours, saturated NH4CI aq. (50 mL) was added to stop the reaction, and then the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was solidified by adding IPE. After filtration, the residue was purified by preparative chiral SFC method G to afford Compound L014 (2.54 g, yield 39%) as a white solid. Enantiometric purity determination of Compound 1-014 was carried out using analytical SFC method H. Compound 1-014^ RT = 5.38 min. >99.5% ee, isomer of Compound 1-014: RT = 6.52 min, >99.5% ee. !H-NMR (CDCh) 6: 3.60 (1H. t, J= 5.0 Hz), 3.90 (3H, s), 4.84 (2H. d, J= 5.0 Hz), 4.93 (1H, d, J= 4.6 Hz), 5.84 (1H, d, J= 4.6 Hz), 7.11-7.17 (2H, m). 7.33 (1H, d, J = 8.5 Hz), 7.73-7.77 (2H, m), 8.77 (2H, s). Preparative chiral SFC method G Column: Two CHIRALPAK IE / SFC (5 pm, cp20 x 250 mm) (DAICEL) Flow rate: 30mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient: MeOH + 0.1% DEA / CO2 = 36 / 65 composition ratio was maintained and sent for 19 minutes. Sample Solution: 67 mg / mL MeOH / CHC13(l / l) Injection Volume: 0.55 mL Analytical chiral SFC method H Column: Two CHIRALPAK IE / SFC (5 pm, (p4.6 x 250 mm) (DAICEL) Flow rate: 2.0 mL / min UV detection wavelength: 220nm Mobile phase: [A] was MeOH + 0.1% DEA, and [B] was CO2. Gradient: MeOH + 0.1% DEA / CO2 = 30 / 70 composition ratio was maintained, and the solution was sent for 15 minutes. Sample Solution: 0.5 mg / mL in methanol Injection Volume: 10 pL

[0182] Example 6 Synthesis of Compound L046 33 34                                                                    1-046 Step 1 Synthesis of Compound 30 Compound 17 (1.18 g, 4.66 mmol), 2(2,2-difluorobenzo[d][l,3]dioxol-5yl)-4.4,5,5-tetramethyl-1.3,2-dioxaborolane (1.98 g, 6.98 mmol), [1,1’-bis(diphenylphosphino)ferrocene]palladium(H) dichloride dichloromethane adduct (0.38 g, 0.466 mmol) and tripotassium phosphate (2.97 g, 13.97 mmol) were dissolved in dioxane (11.8 mL) and water (1.2 mL), then the mixture was stirred at 80°C for 2 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (0 to 70% ethyl acetate-hexane) to afford Compound 30 (1.43 g, 4.32 mmol, yield 93%) as a brown oil. iH-NMR (CDCls) 6: 3.37 (1H, t, J= 5.2 Hz), 4.81 (2H, d, 5.2 Hz), 6.43 (1H, t, J= 72.8 Hz), 7.15 (1H, d, J= 8.4 Hz), 7.29 (1H, d, J= 8.4 Hz), 7.63 (1H, m), 7.63 (1H, d. 8.4 Hz), 7.66 (1H. m). Step 2 Synthesis of Compound 31 Phosphorus Tribromide (0.201 mL, 2.13 mmol) was dropwised to a solution of Compound 30 (1.41 g. 4.26 mmol) in dichloromethane (14 mL) at 0°C, and the mixture was stirred at room temperature for 3 hours. Water was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford crude Compound 31 (1.74 g) as a brown oil. The crude Compound 31 (1.0 g) was purified by silica gel column chromatography (0 to 50% ethyl acetate-hexane) to afford Compound 31 (836.5 mg, 2.12 mmol, yield 50%) as a colorless oil. !H-NMR (CDCls) b: 4.58 (2H, s). 6.45 (1H. t, J= 72.5 Hz), 7.15 (1H, d, J= 8.4 Hz), 7.46 (1H, d, J= 8.4 Hz), 7.60 (1H. d, J= 8.4 Hz), 7.64 (1H, d, J= 1.6 Hz), 7.68 (1H, dd, J= 8.4, 1.6 Hz). Step 3 Synthesis of Compound 33 Compound 31 (383 mg, 0.973 mmol), (4-(((tert'butoxycarbonyl)amino) methyl)phenyl)boronic acid (293 mg. 1.17 mmol), [1, l'-bis(diphenylphosphino) ferrocene]palladium(ll) dichloride dichloromethane adduct (39.7 mg, 0.049 mmol) and tripotassium phosphate (826 mg, 3.89 mmol) were dissolved in tetrahydrofuran (5.75 mL) and water (1.92 mL), then the mixture was stirred at 80°C for 3.5 hours. Water (2 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (100 mL) twice. 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 (0 to 20% ethyl acetatehexane) to afford Compound 33 (344.9 mg, 0.663 mmol, yield 68%) as a pale yellow oil. !H-NMR (CDCh) 8: 1.46 (9H. s), 4.17 (2H, s), 4.30 (2H, d, J= 5.9 Hz). 4.81 (1H. br-s), 6.38 (1H, t, J= 73.0 Hz), 7.06 (1H, d, J= 8.4 Hz), 7.14 (1H. d, J= 8.4 Hz), 7.227.29 (4H, m), 7.47 (1H, d, J= 8.4 Hz), 7.64 (1H, m), 7.67 (1H, m). Step 4 Synthesis of Compound 34 Trifluoroacetic acid (3.5 ml, 45.4 mmol) was added to a solution of Compound 33 (344.9 mg. 0.663 mmol) in dichloromethane (3.5 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was added to saturated aqueous sodium hydrogen carbonate (5 mL). The mixture was extracted with ethyl acetate (100 mL) twice, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was solidified (ethyl acetate-hexane) to afford Compound 34 (57.9 mg, 0.138 mmol, yield 21%) as a white solid. !H-NMR (CDCh) 6: 3.86 (2H. s), 4.18 (2H, s), 6.37 (1H, t, J= 73.0 Hz), 7.07 (1H, d, J= 8.4 Hz), 7.14 (1H, d, J= 8.4 Hz), 7.28 (4H. m), 7.47 (1H, d, J= 8.4 Hz). 7.64 (1H, m), 7.67 (1H, m). Step 5 Synthesis of Compound 1'046 HATH (33.9 mg, 0.089 mmol) was added to a solution of Compound 34 (25.0 mg. 0.059 mmol). 2-hydroxyacetic acid 70% solution in water (6.78 mg. 0.062 mmol) and N,W'diisopropylethylamine (0.016 mL, 0.089 mmol) in N,N-dimethylformamide (0.5 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water (2 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (50 mL) twice. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (0 to 100% ethyl acetate-hexane) to afford crude Compound L046, which was containing dimethylformamide and tetramethylurea. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was solidified by adding hexane to afford Compound 1 046 (15.7 mg, 0.033 mmol, yield 55%) as a white solid. !H-NMR (CDCls) 8: 2.29 (1H, t, J= 5.2 Hz), 4.17 (2H, d, J= 5.2 Hz), 4.18 (2H, s), 4.49 (2H, d, J= 5.9 Hz), 6.38 (1H. t, J= 73.0 Hz), 6.66 (1H, br-s), 7.07 (1H, d, J= 8.4 Hz), 7.14 (1H, d. J= 8.4 Hz), 7.23-7.31 (4H, m), 7.47 (1H, d, J= 8.4 Hz), 7.63 (1H. m). 7.67 (1H. m).

[0183] The following compounds were synthesized according to the above general synthesis method and the method described in Examples. The structure and physical properties (LC / MS data, NMR spectra) are shown in the table below. The MS (m / z) of Compound 1-262 was observed as [M+Na]+. Incidentally, in the structural formula, “wedge shape” and “dashed line” indicate the steric configuration. Particularly, with regard to compounds whose configurations are described, a compound described as “a” in the item of “Steric configuration” indicates that the configuration is determined as shown in the chemical structure. In addition, with regard to compounds in which the bonds forming an asymmetric carbon are described by solid lines, a compound described as “b” in the item of “Steric configuration” is a racemic compound. A compound described as “c” in the item of “Steric configuration” is a single enantiomer whose configuration has not been specified. Compound 1'023 is the enantiomer of Compound T024. Compound 1-033 is the enantiomer of Compound 1-034. Compound 1'036 is the enantiomer of Compound 1'037. Compound 1 074 is the enantiomer of Compound 1 075. Compound 1'076 is the enantiomer of Compound 1'077. Compound 1'129 is the enantiomer of Compound 1'130. Compound 1'138 is the enantiomer of Compound 1'139. Compound 1'146 is the enantiomer of Compound 1'147. Compound 1-192 is the enantiomer of Compound 1'193. Compound 1'206 is the enantiomer of Compound 1'207. Compound 1'218 is the enantiomer of Compound T219. Compound 1-221 is the enantiomer of Compound 1-222. Compound 1-223 is the enantiomer of Compound 1-224. Compound 1-253 is the enantiomer of Compound T254. Compound 1-258 is the enantiomer of Compound 1-259. Compound 1-260 is the enantiomer of Compound 1261.

[0184] [Table 1] Compound No. Structure MS (m / zj Steric configuration T001 / o Xo    X __ / u 0 I 390.2 1002 o \   / —V # o I 368.2 1003 o / / z       / =\ z / > \\ / / o I 367.1 1004 I o A XX / o 368.1 1005 F F kiK 0H Xl ^•N^O fXf 410.1

[0185] [Table 2] Compound No. Structure MS (m / z) Steric configuration 1006 I O A 348.1 b 1007 0'1   < 'v'0 p o I 352.1 1008 F F 1        OH r i 383.1 c 1009 / O \ / —# / / 71 o      X __ / m z V 'r o I 378.1 1010 OH <Yr N ^^■ci 357.1 c

[0186] [Table 3] Compound No. Structure MS (m / z) Steric configuration I Oil F F (|Xr^N A 386.1 1012 T o a w IJ_ / _ / "O zy / v p 385.1 1013 I O A tyry o / 365.1 b 1014 OH ^nA_OH fj F"^ 404.1 a 1015 o 'z\ / 0 0 o I 377.2

[0187] [Table 4] Compound No. Structure MS (m / z) Steric configuration 1016 V / o T 432.2 1017 D D Ql 376.2 1018 X01 pb '3 o ZE 432.2 c 1019 o” Z d--c 7 \\ / / T Jb o I 391.2 c 1020 D D xoz y    n A bb 394.2

[0188] [Table 5] Compound No. Structure MS (m / z) Steric configuration 1021 D D fXq F^F 419.1 1022 I o A X Q )—Z 1---( Il chQ o / 377.1 1023 X z —V y / / \ / / — ° o       X )— / =v " Vf o ZE 391.2 c 1024 o 2    / )---V 7 / —     \ O o       X )-- / =X° - v i o ZE 391.2 c 1025 m ) m o <"0^   >*O o I 4 39 a

[0189] [Table 6] Compound No. Structure MS (m / z) Steric configuration 1026 OH Ml be 438 a 1027 OH fW A M 401 a 1028 I o o / 414 1029 OH i cyM? A / A A,™ N N-d 400 a 1030 / N 0 I 430.1 b

[0190] [Table 7] Compound No. Structure MS (m / z) Steric configuration 1031 F OH Ml 457 a 1032 I o IZ 492.15 1033 I o —\      °-4 o / 402 c 1034 / o ,:m-o I 402 c 1035 ti \«o o I 441j a

[0191] [Table 8] Compound No. Structure MS (m / z) Steric configuration 1036 > m o Z^O        \-- o I 438 c 1037 I imC 438 c 1038 T 4 °        Z"O p o ZE 439 a 1039 Tl O w o ZE 439 a 1040 I o w LL 437 b

[0192] [Table 9] Compound No. Structure MS Steric configuration 1041 OH I f J mi Vf 444 a I 042 OH Ml Vf 444 a 1043 T o O                       ' M LL 456 a 1044 Y'O        )"IO 1                ___ / I CO 445 a 1045 OH F AoJO^ Ml Vf 445 a

[0193] [Table 10] Compound No. Structure MS (m / z) Steric configuration 1046 F^O^V       N^OH 479.15 1047 F               N ^-^.0 H fl 493.1 1048 ‘n IZ (     _P-^. O’ 530.15 1049 ZI 2 544.15 1050 OH iTySt^ fA^JNn ll^OH a

[0194] [Table 11] Compound No. Structure MS (m / z) Steric configuration 1051 OH " frY1,1 378 a 1052 X o Z— / 1 on <         o Y-Z / = / # J__ / \ u- 443 a 1053 i o z — / / ^7     U- o* /        o Y-Z    / = / # _ / \ O    x ‘Z -143 a 1054 X o 1 /   "A on /       o Y-z / = / # _ / \ O      U- “-N Ml a 1055 m    O \   / —V # 5==7 z— / o        >*o )- 7-C1 - p o X 444 a

[0195] [Table 12] Compound No. Structure MS (m / z) Steric configuration 1056 I ll- I /       V Oh /       p # _z \ 449 a 1057 OH XX1 449 a 1058 / o "X" o      m > 110 X o ZE 421 a 1059 OH ri NF 421 a 1-060 i jqVx^ 437 c

[0196] [Table 13] Compound No. Structure MS (m / z) Steric configuration 1061 I 0 LL. /                               . -A o / 420 b 1062 I o o I / Oi /         ll _o 395 a 1063 T| o -H         \<O o o I 395 a 1064 oh । rYYX CX x F 425 a 1065 OH F A'VN fAoAN ^,.A-oh QI 425 a

[0197] [Table 14] Compound No. Structure MS (m / z) Steric configuration 1066 oh i [PAC? CL x 424 a 1067 o~ o I 424 a 1068 OH F a / yV faXT X^h Pn 389 a 1069 OH F zvVv F AoJUJ      \dh Cl 389 a 1-070 I O L C   Z      u. T / 7 Oil /          o V-Z    / = / o A 426 a

[0198] [Table 15] Compound No. Structure MS (m / z) Steric configuration 1071 OH i rvVx A1 426 a 1072 OH Ql ? 431 a 1073 o o? -n I 431 a 1074 o / =\ z\ / / o       )— ' r o ZE Q * Q c 1075 I o (4 X / / —\      ° 2   / =\ C         2 \__ / X. / / o 4 ‘4 c

[0199] [Table 16] Compound No. Structure MS (m / z) Steric configuration 1076 I O C Z      u- —\ ~° z   / =( \ \ z \— / / / b 389 c I 077 ZE o —\      ° V-Z    / =\ V         z \ / / / o 389 c 1078 I o N z  f=\ ( / __ / \ o 347 c 1079 OH i LJ OH 431 a 1080 I u_ X /      °"  \ o \           / V V---(\ \__ / / / 431 a 1081 / O r o I 348 c

[0200] [Table 17] Compound No. Structure MS (m / z) Steric configuration I 082 X O N Xs / / -T  \ \—-z.     / =\ v          z \— / X / / 378 c 1083 I o z — / / / X         LI. 1 / ^ Ol"(          o Z    / = / # X_ / \ o 425 a 1084 OH Ml I f 425 a 1085 OH F CL 1 420 a 1086 I o L ( /   Z        U- °*\      P V 7----(\ \__ /       / / O 426 a

[0201] [Table 18] Compound No. Structure MS (m / z) Steric configuration 1087 o” o I a 1088 OH pA^X^ A 395.1 a 1089 OH pA^N ll^OH 396.1 a 1090 OH । iTySp? fAJUn ll^OH 396.1 a 1091 OH 394 a

[0202] [Table 19] Compound No. Structure MS (m / z) Steric configuration 1092 T| o o O ZE 394 a 1093 ZE o / 426 a 1094 OH QH Q >'' O r 426 a 1095 oh 1 1 J TAYh OH jA r 448 a 1096 OH jlI r f'^AoNf 448 a

[0203] [Table 20] Compound No. Structure MS (m / z) Steric configuration 1097 1XXXX n F^O-^V"   \N\ / 'y^'OH Ok 424.15 1098 ixyoi F^'O^y'         -y^OH 1 430.15 1099 OH F                     / OH I XT LX'S F / xo / \^ (S X ^N^O^F 459.1 a I-100 o~ o       \no N-" H 1 m             co I 430.2 a I-101 OH ▼ e OH FW\r Q A 430.2 a

[0204] [Table 21] Compound No. Structure MS (m / z) Steric configuration I-102 T o 4 IZ \ / QwQ 425.2 I 103 I o IZ p 430.15 I-104 o O    m >HO y- 1 “0 I 412.3 a 1105 OH \cAAF    OH UL a 412.1 a I-106 I o > d /        / __o o LL 4'36.2

[0205] [Table 22] Compound No. Structure MS (m / z) Steric configuration I-107 ZE o / / A ty-Cy o LL 467.15 I 108 F                       h F^O-^y-         y OH rii 0 ^■N^O^F 468.15 I-109 Tl o \ ” m p ZI 481.2 I-110 ^N^O-^F 451.2 mi i O Oli / U- O LL 401.1 a

[0206] [Table 23] Compound No. Structure MS (m / z) Steric configuration 1112 ZE O oY^C _ o Ll_ 401.1 a 1113 OH Ok 430.1 a 1114 OH YY^YY x A       J. OH 0l 347.1 a 1115 u CO                 U_ x Y7 Y On-( u-      O v v—G z \__ / \\ / / 477 a 1116 OH _ T e OH iixxrs Ml J. ^N-^O-^F 477 a

[0207] [Table 24] Compound No. Structure MS (m / z) Steric configuration I 117 1 394 1118 oh kkkfk 0k 402.15 a 1119 OH 0k 402.1 a I-120 T o ...... TZ k^ \ ° k^o o LL 481.15 a I-121 I TZ o - H Q-£y o LL 481.15 a

[0208] [Table 25] Compound No. Structure MS (m / z) Steric configuration T122 OH T   o   OH XCAcr Cl ^N^O 1 395.2 a I 123 OH T o   OH Cl ^N^O 1 395.2 a I-124 (C ti          Z^O ___ / ZE ^O ZE 400.1 a T125 OH _   -   „ OH inv F                 N Cl 400.1 a I-126 < / p-b ZI T I 388

[0209] [Table 26] Compound No. Structure MS (m / z) Steric configuration I-127 IKI 419 I 128 o / / ” / 2       / =\ o=^ ZE 389 I-129 I ll u- —< X /        V O —f   u-      0 V 7--G Z 413.05 c I-130 X O CD V           Ll- X O-(   U-     O v  v— \__ / / / 413.05 c I-131 CD -7-            U_ I / ^ Ob /   u-     O V   7--z O 441.1 a

[0210] [Table 27] Compound No. Structure MS (m / z) Steric configuration I-132 O / =\ z n—\\ n )-- M X 441.1 a I 133 I O z — / I / =^ OlH u.     O \__ / \\ / / o 407.1 a I-134 I o z — / Z IM o* / U-     O V 7----(\ \__ / / / o 407.1 a I-135 on \ X. JL IL JI n 463.15 a I-136 OH nrY^i h Jk IL JL n Ml X 463.15 a

[0211] [Table 28] Compound No. Structure MS (m / z) Steric configuration I-137 Ml X 477.15 I 138 OH 409.05 c I-139 OH ^oJyN      ^OH 409.05 c I-140 ti       O O      "n      O y- M o X 453.1 a I 141 oh oh £1 I 430.1 a

[0212] [Table 29] Compound No. Structure MS (m / z) Steric configuration I-142 OH IJL L / XXh A. i F              F 430.1 a I 143 oh A a ^N-^cr^F 482.15 a I-144 )- -n o    o -n      m      O __ / I Q o I 489.2 a 1145 OH 1          n / . F^O^V        '^XOH OX 482.15 a I-146 OH । oAci fAqA^A-f X,;:;^^oh A Xj 471.2 c

[0213] [Table 30] Compound No. Structure MS Steric configuration I-147 X O ri' X / O—f u- o    o “-N- 471.2 c I 148 o O      -n      o ■ X o I 435.2 a I-149 o / A Z 7--\ # O    m YhO N" / =< 1 ' p o I 444.1 a I-150 OH aIXTa oh Cl I 444.05 a I-151 I O x / -^ “-N Oh / u-     O \__ / X / / O “-p 472.1 a

[0214] [Table 31] Compound No. Structure MS (m / z) Steric configuration I-152 I O zX  ( o* / U-     O V 7--G   Z O 472.1 a I 153 N"" o / A Z 7--X   / / O    m  \<O m      X   / ) / z o T 471.15 a I-154 )-■" )-■" o    o O / ^X z 2—X m >"IO __ / I 4 / / / —z o T 443.15 a 1155 )—" )—" o    o z 2—# n \*O __ / I / z o I 443.1 a I-156 T o z        “■-( O*<   U-     O V    7 L ^- \__ / X / / o 436.15 a

[0215] [Table 32] Compound No. Structure MS (m / z) Steric configuration I-157 OH iXlUL n F^cr^     '.N -,--   ' -QH Cl 'P'O Cf 495.1 a I 158 N'> P’ ZI o ZE 495.1 a I-159 o z y—p A O     -n >UO y- / =<1 - p o I 408.1 a I-160 1 Z p--P A O    T    O o I 408.1 a I-161 X O"C     O-NIl 0 / 408.05 a

[0216] [Table 33] Compound No. Structure MS (m / z) Steric configuration I-162 OH W OH Q ^F 408.05 a I 163 / O O        )HO / =<1 ZI “> o I 445 a I-164 I o o / ° -145 a 1165 i r T li i h r \ 1 Jk N <      N ,.1 2 F “I F ^N^cP'F 507.3 a I-166 O " \ -° O<7 o LL 493.2

[0217] [Table 34] Compound No. Structure MS (m / z) Steric configuration I-167 O-^ ( "1 o LL 507.1 a I 168 o o -o LL 495.15 I-169 / o -n      -n YhC _ / i co 382 a 1170 OH ^'''p^F N °H Cl 382 a H7i T o p M M o    o u. Y LL         LL 493

[0218] [Table 35] Compound No. Structure MS (m / z) Steric configuration 1172 % A A LL         LL 507 a 1173 i 1 J li i h r \ A. n < A. n / CL JL -n-'o-f 507 a 1174 -i; 1---)-7 ^nA0Af 527 1-175 । rcTi h Cl Cf 481.25 1-176 X O > 466.15

[0219] [Table 36] Compound No. Structure MS (m / z) Steric configuration 1177 । nee, h Cl 465.3 1178 z— / \ -° _O LL 450.15 1179 I O "ft IZ / / A LL A / u.^ \ ° CaO o LL 535.1 a I-180 T < / \y$ IZ / / A C t CaO o A LL 507.15 I-181 I OH- / LL     O — ~ \_ / / / / 377.U5 a

[0220] [Table 37] Compound No. Structure MS (m / z) Steric configuration I-182 O — O    n    O _ / I T 377.05 a I 183 oh f J lZa™ ^oAXf n oh ul o / 1 a I-184 OH ■"oMM    oh Ok b7 i a 1185 OH ^N'^'CC^F 446.2 a I-186 OH hYhi H ^o^yn ^s:::^^ny,xoh Ml X 446.2 a

[0221] [Table 38] Compound No. Structure MS (m / z) Steric configuration I-187 I O x 5 ' o o 417.15 a I 188 478.15 I-189 1 XPXTa n ' ”? i.........4" ^■N^O-^F 467.1 I-190 । HOPi h AJA LA N / A 451.2 I-191 A JOPTaJ niXdAf 477.2

[0222] [Table 39] Compound No. Structure MS (m / z) Steric configuration I-192 I O / "X V 2        ll. --\ ° b 387 c I 193 ZE o O " —\ /   ~o C   V—-¼  2 \__ / / / b 387 c I-194 ZE o <z z        LU IX / V-z / =\ / \\—4 \__ / / / b 400 1195 o o ZE 434.05 I-196 T o —2 / / A     u. W / u.^( \ ° o~O O LL 481.2

[0223] [Table 40] Compound No. Structure MS (m / z) Steric configuration I-197 LL     0 IZ -\ ° _o LL 505.2 I 198 o Z 2--C O    -n p o N-" / =(1 / z o I 435.15 a I-199 T o / z O 483 3 1-200 H - \        ° o LL 479.15 1-201 p v z       U- \= /  u_-( \ ° o LL 491.15

[0224] [Table 41] Compound No. Structure MS (m / z) Steric configuration 1-202 ZE o / / A \= / \ ° o LL 480.2 a 1203 I O IZ C3 o LL 480.2 a 1204 i non1 h Ml I       " 517.2 1205 I O C Z       U- ex ° Mz z=\ \__ / / / o 401 1-206 \ JlJn ILkZL oh Ml X 388 c

[0225] [Table 42] Compound No. Structure MS (m / z) Steric configuration 1-207 ZE o <z 2        U- —\      ° 4 2    / =\ v  —G  2 \_ /   4 o 388 c 1208 / o — O      X] ZI I 420 1209 —z \ 3 o LL 509.3 1-210 o 493.1 a 1-211 N o I 418

[0226] [Table 43] Compound No. Structure MS (m / z) Steric configuration 1212 480.2 1213 ^N-^O^F 494.2 1-214 nor? h n cii NJ-'N-'N 492.15 1215 \ ° o LL 477.15 T216 T o IZ o /                 LL LL 480.15

[0227] [Table 44] Compound No. Structure MS (m / z) Steric configuration 1-217 NJ       F 491.2 1218 ZE V V        LL —\      ° o / 444 c 1219 / o o      2— o ZE -144 c 1-220 o / \ / v # O          2-- )—"   / =\ o I 417 c 1-221 -XXVxjv- CP 1 408 c

[0228] [Table 45] Compound No. Structure MS (m / z) Steric configuration 1-222 I 0 —\      ° — 0 / 408 c 1223 I U. X o—<        o \ / —c / Z o “-N 432.2 c 1-224 X Ll I O—<        O V 7--C 2 \_Z     / / o U- 432 c 1225 F OH UL1 443.1 a 1226 435

[0229] [Table 46] Compound No. Structure MS (m / z) Steric configuration 1227 X O TZ LL     \ /                  LL \        ° Vh LL 497 1228 F (MH j H 1 I. , N U J. N .-. A 497 1229 Xr~N.»vl. 447 1-230 d T!                     ) 463.1 1-231 ......q IZ _b LL 493.1 a

[0230] [Table 47] Compound No. Structure MS (m / z) Steric configuration 1232 A I Z\° IZ /                  LL \             °--7-1 LL 505.1 1233 T IZ o LL 493.1 a 1-234 JI .N [1          N 431 1235 Mois 453.1 1-236 j o LL 417.1

[0231] [Table 48] Compound No. Structure MS (m / z) Steric configuration 1-237 F^O^y       y^OH ^>^F 417.1 1238 451.1 1239 ti ZI o ZE 483.1 1-240 F^c^y       y^oH 469 1-241 LXXXXj^ F'^O'^y-          -y^OH t^YF 4'37.1

[0232] [Table 49] Compound No. Structure MS (m / z) Steric configuration 1-242 465.1 I 243 1 k. n U J. n F-Q'Y       Y°F J FZ' / -'O'F 483.1 1-244 1XTXX n 447.1 1245 1 F-^x-O-^Y'            Y^-OH Ci ° 457.1 1-246 o IZ o LL 413.1

[0233] [Table 50] Compound No. Structure MS (m / z) Steric configuration 1-247 1 jOOCcc- 433.1 I 248 f aa^ h 1 L. n U J. n F’O'Y       y oH Cl 429.1 1249 1XTXX n cl 1 465 1-250 a jOTTX n CL af 483.1 1251 c 0 o LL 497.1

[0234] [Table 51] Compound No. Structure MS (m / z) Steric configuration 1252 449.1 1253 OH f.nX^ u. X 445 c T254 o Xc0'        J c -145 c 1-255 362.2 c 1256 H O Y         y \=:O UL 475 b

[0235] [Table 52] Compound No. Structure MS (m / z) Steric configuration 1257 420 b 1258 o C) (_ _P'^L. 475 c 1259 j YOH h F CT y UL 475 c 1-260 o z — / / / /                 LL (      __f0''^ O LL 476 c 1-261 o ) m              / 4 / / o 476 c

[0236] [Table 53] Compound No. Structure zvIS (m / z) Steric configuration T262 I o—4 PF 496.1 b 1-263 ZE o ,4 G    Z       LL o 391.1 a 1-264 / o \ / —V # / =7 z \ cf         ><o H H 1 T1        Z    ') c o ZE 390.1 a 1-265 OH "0-^“ F 376 a 1-266 OH kj. X .OH O          N F F 360 a

[0237] [Table 54] Compound No. Structure MS (m / z) Steric configuration T-267 -n       a / V —\ __ / I r o ZE 378 a 1-268 -n       O 2=7  z—y o        >*o -n        z ') r o I 408.1 a 1-269 / o 0¾. ' A ’ rz o I 394.2

[0238] [Table 55] Compound No. Structure MS (m / z) Steric configuration T-270 D D Ok Ml 334.15 I-271 I O A 0  __ / \ / O 335.1 1-272 I o A \ / / Q /         — X         Cl q-A z / # __ / \ o 344.1

[0239] [Table 56] Compound No. NMR I 099 ^-NMR (CDC]3) 8: 1.65 (6H. s), 2.56 (1H, br-s), 2.72 (1H. s), 6.12 (1H, s), 6.44 (1H, t. J = 73.0 Hz), 7.02 (1H, s), 7.23-7.30 (2H. m). 7.33-7.69 (4H, m), 8.24 (1H, d, J = 5.3 Hz). 1-152 ^-NMR (CDCI3) 8: 1.58 (6H, s), 2.57 (1H. d, J = 4.1 Hz). 4.60 (1H, s), 6.22 (1H, d, J = 4.1 Hz), 6.43 (1H, t, J = 72.3 Hz), 6.92 (1H, s), 7.10 (1H, d. J = 5.1 Hz). 7.20 (1H. d, J = 8.7 Hz), 7.33-7.72 (2H. m). 8.26 (1H, d, J = 5.3 Hz), 8.75 (2H, s). 1-155 ^-NMR (CDCI3) 8: 2.51 (1H, d, J= 3.5 Hz). 3.56 (1H, t, 5.0 Hz), 4.75 (2H, d. 5.0 Hz), 6.19 (1H, br-s). 6.41 (1H, t, J= 72.5 Hz), 6.90 (1H, s), 7.09 (1H, d, J = 5.3 Hz), 7.16 (1H, d, J = 9.0 Hz), 7.25-7.26 (1H, m), 7.32-7.69 (2H. m). 7.73 (1H, dd, J= 8.0 Hz, J= 1.8 Hz), 8.25 (1H, d. J = 5.3 Hz), 8.61 (1H, br-s).

[0240] The following is a description of biological test examples of the compound of the present invention. In the biological test of the compound according to the present invention, the test procedure described in the following biological test examples or essentially the same test procedure can be used. The compound represented by Formula (I), Formula (II), Formula (II ), or Formula (III) according to the present invention may have PDE4D inhibitory activity, and may inhibit PDE4D. Specifically, in the evaluation method described below, the ECso value is preferably 5 pM or less, more preferably 1 pM or less, and even more preferably 0.1 pM or less, and the Ki value is preferably 5 pM or less, more preferably 1 pM or less, and even more preferably 0.1 pM or less.

[0241] Test Example L Human active PDE4D7 (S129D mutant) functional inhibition test (Each experimental condition) Recombinant enzyme: human active PDE4D7 (S129D mut) Assay buffer: Tris HCl 50 mmol / L (pH 8.0) containing MgCH 10 mmol / L, KC1 50 mmol / L, tris(2-carboxyethyl)phosphine (TCEP) 1 mmol / L, phosphenolpyruvate (PEP) 0.4 mmol / L, NADH 0.01 mmol / L, adenosine triphosphate (ATP) 0.04 mmol / L, myokinase from yeast or rabbit 7.5 units / mL, pyruvate kinase / lactate dehydrogenase 2 units / mL, BSA 0.1 mg / ml, and active PDE4D7 (S129D mut) 0.2nmol / L (Functional test of the compound of the present invention) In advance, 0.05 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the Assay buffer containing the enzyme is dispensed into a microplate at 40 pL / well. Then, it is allowed to stand at room temperature (25°C) for 5 minutes. Then, cAMP 0.02 mmol / L is dispensed into a microplate at 10 pL / well. After mixing, reaction rates are immediately measured by monitoring the decrease in fluorescence using excitation at 350 nm and emission at 450 nm for a period of 10 min in a fluorescence plate reader. Initial rates (slopes) are determined from linear portions of the progress curves. The slope of positive control is calculated from the reaction rate in the absence of the compound of the present invention, and the slope of negative control is calculated from the reaction rate in the absence of the compound of the present invention and enzymes. Finally, the ECso value is calculated from the concentration-response curve. (The functional activity of the compound of the present invention is calculated from the following inhibition rate (%).) Inhibition rate (%) = [ (c ■ b) / (a ■ b)l x 100 a; mean slope of positive control b; mean slope of negative control c: slope in the presence of the test compound

[0242] The compounds of the present invention were tested essentially as described above. Results are shown below. (Results)

[0243] [Table 57] Compound No. Human active PDE4D7_ ECso (pM) Compound No. Human active PDE4D7_ ECso (pM) Compound No. Human active PDE4D7_ ECso (pM) TOOl 0.0012 I 031 0.07 P061 0.0087 1-002 0.0013 1-032 0.0045 1-062 0.075 T003 0,00054 T033 0,058 P063 0.012 1-004 0.0015 1-034 0.0016 1-064 0.026 T005 < 0.00051 T035 0.013 P065 < 0.00051 1-006 0.008 1-036 0.036 1-066 0.04 T007 0.0012 I 037 < 0.00051 P067 0.00057 1-008 0.038 I 038 0.062 1-068 0.068 T009 < 0.00051 T039 0.0088 P069 0.0013 1-010 0.0015 1-040 0.0017 1-070 0.028 1-011 0.0016 1-041 0.0015 P071 0.0023 1-012 0.003 1-042 0.016 1-072 0.022 T013 0.012 T043 0.019 P073 0.0032 1-014 0.013 1-044 0.018 1-074 0 O 18 T015 0.027 1-045 0.0066 P075 0.0014 1-016 0.003 1-046 0.00044 1-076 0.0082 T017 0.0084 T047 0.0076 P077 0.001 1-018 0.082 1-048 0.0047 1-078 0.0026 T019 0.012 1-049 0.024 P079 0.0041 1-020 0.012 1-050 0.082 1-080 < 0.00051 1-021 0,0033 1051 0.033 P081 0.016 1-022 <0.00051 1-052 0.046 1-082 0.018 T023 0.0084 T053 0.011 P083 0.027 1-024 0.0095 1-054 0,087 1-084 0.0089 T025 0.0046 T055 0.012 P085 0.084 1-026 0.0066 1-056 0.065 1-086 < 0.00051 T027 0.0054 T057 0.01 P087 0.0011 1-028 0.017 1-058 0.026 1-088 0.0027 T029 0.004 I 059 0.0023 P089 0.093 1-030 0.081 1-060 0.0021 1-090 0.013

[0244] [Table 58] Compound No. Human active PDE4D7_ ECso (pM) Compound No. Human active PDE4D7_ ECso (pM) Compound No. Human active PDE4D7_ ECso (pM) T091 0.1 I 121 0.0017 1-151 0.071 1-092 0.0017 1-122 0.029 1-152 0.019 1-093 0.009 1-123 0.00076 1-153 0.017 1-094 0.0012 1124 0.0018 1-154 0.0035 T095 0.032 1125 0.018 1-155 < 0.00051 1-096 0.0019 1126 <0.00051 1-156 0.029 T097 < 0.00051 1127 0.0035 1-157 0.005 1-098 < 0.00051 1128 0.02 1-158 0.013 T099 0.0077 1-129 0.001 1-159 0.0034 TWO 0.0058 1-130 < 0.0005! 1-160 < 0.00051 1-101 < O.OOOol 1-131 0.042 1-161 0.018 1-102 0.0069 1-132 0.0038 1-162 0.0022 T103 < 0.00051 1133 0.002 1-163 0.0045 1-104 0.0015 1134 < 0.00051 1-164 < 0.00051 T105 < 0.00051 1135 0.00067 1-165 0.01 1-106 < 0.00051 1-136 < 0.00051 1-166 0.0059 T107 < 0.00051 1-137 < 0.00051 1-167 0.016 1-108 0.00052 1-138 0.024 1-168 0.0043 T109 0.0017 T139 0.032 1-169 0.016 1110 < 0.00051 1-140 0.044 1-170 0.0015 Till 0.0041 I 141 0,0052 1-171 0.0012 1-112 <0.00051 1-142 0.00071 1-172 0.012 1113 0.06 1143 0.0026 1-173 0.0038 1-114 0.004 1-144 0.0 c>6 1-174 0.0065 1115 0.024 1-145 0.00056 1-175 0.0037 1-116 0.0029 1-146 0.066 1-176 < 0.00051 1-117 0.00073 1-147 0.025 1-177 0.0095 1-118 0.0048 1-148 0.015 1-178 < 0,00051 1-119 < 0.00051 1-149 0.0023 1-179 0.031 1-120 0.0007 1-150 < 0.00051 1-180 0.0068

[0245] [Table 59] Compound No. Human active PDE4D7_ ECso (pM) Compound No. Human active PDE4D7_ ECso (pM) Compound No. Human active PDE4D7_ EC50 (pM) 1181 0.0057 1211 0.0031 1-241 0.00095 1-182 0.0015 1-212 0.019 1-242 0.0024 1-183 0.012 1-213 0.06 1-243 < 0.00051 1-184 0.00097 1-214 0.012 1-244 < 0.00051 1-185 0.007 1-215 0.0008 1-245 < 0.00051 1-186 0.0028 1-216 0.00052 1-246 0.0011 1-187 0.055 I 217 < 0.00051 1-247 < 0.00051 1-188 0.003 1-218 < 0.00051 1-248 < 0.00051 1-189 < 0.00051 1-219 0.0013 1-249 < 0.00051 1-190 0.0015 1-220 0.0072 1-250 0.0011 1191 0.0023 1-221 <0.00051 1-251 0.00057 1-192 0.0017 1-222 0.0063 1-252 0.00096 1-193 < 0.00051 1-223 0.0036 1-253 0.028 1-194 0.0026 1-224 0.0081 1-254 0.023 1-195 0.0033 1-225 0.0037 1-255 0.0029 1-196 < 0.00051 1-226 < 0.00051 1-256 0.012 1-197 0.01 1-227 0,00053 1-257 0.0031 1-198 0.023 1-228 <0.00051 1-258 0.052 1-199 0.00097 1-229 0.031 1-259 0.076 1-200 0.039 1-230 0.002 1-260 0.015 1-201 0.039 1-231 0,0022 1-261 0.017 1-202 <0.00051 1-232 0,0069 1-262 0.041 1-203 0.00093 1-233 0.0038 1-263 0.0043 1-204 < 0.00051 1-234 0.0073 1-264 0.0061 1-205 0.0054 1-235 <0.00051 1-265 0.01 1-206 0.0037 1-236 0.0016 1-266 0.028 1-207 < 0.00051 1-237 < 0.00051 1-267 0.042 1-208 0.011 1-238 <0.00051 1-268 0.027 1-209 0.017 1-239 0.0013 1-269 0.018 1-210 0.0019 1-240 0.0008

[0246] [Table 60] Compound No. Human active PDE4D7_ ECso (pM) 1-270 0.003 T-271 0.0044 1-272 0.0017

[0247] Test Example 1-2: Human active PDE4D7 (S129D mutant) functional inhibition test (Each experimental condition) Recombinant enzyme: human active PDE4D7 (S129D mut) Master mix buffer: Tris-HCl 50 mmol / L (pH 8.0) containing MgCh 10 mmol / L, KC1 50 mmol / L, tris(2-carboxyethyl)phosphine (TCEP) 1 mmol / L, phosphenolpyruvate (PEP) 0.4 mmol / L, NADH 0.01 mmol / L, adenosine triphosphate (ATP) 0.04 mmol / L, myokinase from yeast or rabbit 7.5 units / mL, pyruvate kinase 1.6 units / mL, lactate dehydrogenase 2.2 units / mL, BSA 0.1 mg / ml, and active PDE4D7 (S129D mut) 0.06 nmol / L (Functional test of the compound of the present invention) In advance, 5 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the Master mix buffer containing the enzyme is dispensed into a microplate at 40 pL / well. Then, it is allowed to stand at room temperature (25°C) for 10 minutes. Then, cAMP 0.04 mmol / L is dispensed into a microplate at 5 pL / well. After mixing, reaction rates are immediately measured by monitoring the decrease in fluorescence using excitation at 337 nm and emission at 460 nm for a period of 13 min in a fluorescence plate reader. Initial rates (slopes) are determined from linear portions of the progress curves. The slope of positive control is calculated from the reaction rate in the absence of the compound of the present invention, and the slope of negative control is calculated from the reaction rate in the absence of the compound of the present invention and enzymes. Finally, the ECso value is calculated from the concentration-response curve. (The functional activity of the compound of the present invention is calculated from the following inhibition rate (%).) Inhibition rate (%) = [ (c ■ b) / (a ■ b)] x 100 a; mean slope of positive control b; mean slope of negative control cl slope in the presence of the test compound The compounds of the present invention can be tested essentially as described above.

[0248] Test Example 2: Human basal PDE4D7 (wild type) functional inhibition test (Each experimental condition) Recombinant enzyme: human basal PDE4D7 (wild type) Assay buffer: Tris HCl 50 mmol / L (pH 8.0) containing MgCh 10 mmol / L. KC1 50 mmol / L, tris(2-carboxyethyl)phosphine (TCEP) 1 mmol / L, phosphenolpyruvate (PEP) 0.4 mmol / L, NADH 0.01 mmol / L, adenosine triphosphate (ATP) 0.04 mmol / L, myokinase from yeast or rabbit 7.5 units / mL, pyruvate kinase / lactate dehydrogenase 2 units / mL, BSA 0.1 mg / ml, and basal PDE4D7 (wild type) 1.2 nmol / L (Functional test of the compound of the present invention) In advance. 0.05 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the Assay buffer containing the enzyme is dispensed into a microplate at 40 pL / well. Then, it is allowed to stand at room temperature (25°C) for 5 minutes. Then, cAMP 0.02 mmol / L is dispensed into a microplate at 10 pL / well. After mixing, reaction rates are immediately measured by monitoring the decrease in fluorescence using excitation at 350 nm and emission at 450 nm for a period of 10 min in a fluorescence plate reader. Initial rates (slopes) are determined from linear portions of the progress curves. The slope of positive control is calculated from the reaction rate in the absence of the compound of the present invention, and the slope of negative control is calculated from the reaction rate in the absence of the compound of the present invention and enzymes. Finally, the ECso value is calculated from the concentration-response curve. (The functional activity of the compound of the present invention is calculated from the following inhibition rate (%).) Inhibition rate (%) = [ (c - b) / (a • b)] x 100 a: mean slope of positive control b; mean slope of negative control ci slope in the presence of the test compound

[0249] The compounds of the present invention were tested essentially as described above. Results are shown below. (Results)

[0250] [Table 61]______________________________________________________________________________ Compound No. Human basal PDE4D7_ ECso (pM) Compound No. Human basal PDE4D7_ ECso (pM) Compound No. Human basal PDE4D7_ ECso (pM) 1-001 0.018 1-031 0.92 1-061 0.056 T002 0.014 T032 0.063 1-062 0.32 1-003 0.013 1-033 0.38 1-063 0.088 1-004 0.023 T034 0.013 1-064 0.27 1-005 0.0059 1-035 0.19 1-065 0.0058 1-006 0.073 T036 0.54 1-066 0.38 1-007 0.015 1-037 0.0055 1-067 0.017 1-008 0.21 1-038 0.58 1-068 0.46 1-009 0.0078 1-039 0.14 1-069 0.022 1-010 0.023 1-040 0.021 1-070 0.21 1-011 0.015 1-041 0.05 1-071 0.036 1-012 0.039 1-042 0.27 1-072 0.11 1-013 0.11 1-043 0.36 1-073 0.038 1-014 0.16 1-044 0.22 1-074 0.39 1-015 0.17 1-045 0.092 1-075 0.017 1-016 0.043 1-046 0.0043 1-076 0.08 1-017 0.088 1-047 0.081 1-077 0.0081 1-018 0.34 T048 0.028 1-078 0.015 1-019 0.18 1-049 0.13 1-079 0.06 1-020 0.27 1-050 0.42 1-080 0.011 1-021 0.038 1-051 0.17 1-081 0.13 1-022 0.008 T052 0.37 1-082 0.14 1-023 0.089 1-053 0.11 1-083 0.23 1-024 0.1 1-054 0.63 1-084 0.081 1-025 0.046 1-055 0.12 1-085 0.86 1-026 0.089 1-056 0.36 1-086 0.011 1-027 0.077 1-057 0.14 1-087 0.013 1-028 0.16 1058 0.37 1-088 0.024 1-029 0.082 1-059 0.017 1-089 0.97 1-030 0.64 1-060 0.013 1-090 0.14

[0251] [Table 62] Compound No. Human basal PDE4D7_ ECso (pM) Compound No. Human basal PDE4D7_ ECso (pM) Compound No. Human basal PDE4D7_ ECso (pM) 1-091 0.57 1-121 0.017 1-151 0.62 1-092 0.025 1122 0.23 1-152 0.13 1-093 0.13 1123 0.011 1-153 0.16 1-094 0.03 1124 0.022 1-154 0.055 1-095 0.16 1125 0.14 1-155 0.0089 1-096 0.022 1126 0.0081 1-156 0.18 1-097 0.0019 1127 0.065 1-157 0.071 1-098 0.0033 1128 0.097 1-158 0.3 1-099 0.1 1129 0.024 1-159 0.024 1-100 0.069 1-130 0.0035 1-160 0.0029 1101 0.0043 1131 0.29 1-161 0.11 1-102 0.1 1-132 0.1 1-162 0.021 1-103 0.0016 1-133 0.031 1-163 0.043 1-104 0.016 1-134 0.023 1-164 0.0015 1-105 0.0055 1-135 0.017 1-165 0.079 1-106 0.00072 1136 0.0055 1-166 0.023 1-107 0.0054 1137 0.002 1-167 0.062 1-108 0.0075 1138 0.15 1-168 0.031 1-109 0.018 1139 0.3 1-169 0.11 1110 0.0037 1-140 0.55 1-170 0.02 Till 0.036 1-141 0.07 1-171 0.014 1-112 0.008 1-142 0.018 1-172 0.052 1-113 0.39 1-143 0.045 1-173 0.016 1-114 0.045 1-144 0.37 1-174 0.023 1-115 0.31 1-145 0.066 1-175 0.03 1-116 0.033 1-146 0.43 1-176 0.0012 1-117 0.011 1-147 0.24 1-177 0.036 1-118 0.059 1-148 0.12 1-178 0.0022 1-119 0.015 1-149 0.046 1-179 0.13 1-120 0.011 1-150 0.0046 1-180 0.067

[0252] [Table 63] Compound No. Human basal PDE4D7_ ECao (pM) Compound No. Human basal PDE4D7_ ECao (pM) Compound No. Human basal PDE4D7_ ECao (pM) 1181 0.068 1-211 0.054 1-241 0.0088 1-182 0.012 1-212 0.11 1-242 0.019 1-183 0.14 1-213 0.4 1-243 0.0032 1-184 0.014 1-214 0.1 1-244 0.0058 1-185 0.092 1-215 0.0096 1-245 0.0055 1-186 0.048 1-216 0.0069 1-246 0.011 1-187 0.38 1-217 0.0031 1-247 0.0017 1188 0.022 1-218 0.0015 1-248 0.0029 1-189 0.0052 1-219 0.013 1-249 0.00092 1-190 0.027 1-220 0.046 1-250 0.009 1191 0.032 1-221 0.0038 1-251 0.0062 1-192 0.013 1-222 0.041 1-252 0.011 1-193 0.0016 1-223 0.036 1-253 0.31 1-194 0.02 1-224 0.039 1-254 0.2 1-195 0.066 1-225 0.052 1-255 0.004 1-196 0.014 1-226 0.0024 1-256 0.06 1-197 0.037 1-227 0.0072 1-257 0.02 1-198 0.2 1-228 0.0046 1-258 0.51 1-199 0.011 1-229 0.15 1-259 0.77 1-200 0.25 1-230 0.012 1-260 0.16 1-201 0.16 1-231 0.02 1-261 0.15 1-202 0.0091 1-232 0.034 1-262 0.13 1-203 0.01 1-233 0.029 1-263 0.055 1-204 0.0034 1-234 0.077 1-264 0.058 1-205 0.039 1-235 0.0052 1-265 0.13 1-206 0.039 1-236 0.014 1-266 0.53 1-207 0.003 1-237 0.0053 1-267 0.37 1-208 0.067 1-238 0.005 1-268 0.37 1-209 0.16 1-239 0.005 1-269 0.12 1-210 0.013 1-240 0.012

[0253] [Table 64] Compound No. Human basal PDE4D7_ ECao (pM) 1-270 0.053 1-271 0.07 1-272 0.021

[0254] Test Example 2’2: Human basal PDE4D7 (wild type) functional inhibition test (Each experimental condition) Recombinant enzyme: human basal PDE4D7 (wild type) Master mix buffer: Tris-HCl 50 mmol / L (pH 8.0) containing MgCh 10 mmol / L, KC1 50 mmol / L, tris(2-carboxyethyl)phosphine (TCEP) 1 mmol / L, phosphenolpyruvate (PEP) 0.4 mmol / L, NADH 0.01 mmol / L, adenosine triphosphate (ATP) 0.04 mmol / L, myokinase from yeast or rabbit 7.5 units / mL, pyruvate kinase 1.6 units / mL, lactate dehydrogenase 2.2 units / mL, BSA 0.1 mg / ml, and basal PDE4D7 (wild type) 0.75 nmol / L (Functional test of the compound of the present invention) In advance, 5 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the master mix buffer containing the enzyme is dispensed into a microplate at 40 pL / well. Then, it is allowed to stand at room temperature (25°C) for 10 minutes. Then, cAMP 0.04 mmol / L is dispensed into a microplate at 5 pL / well. After mixing, reaction rates are immediately measured by monitoring the decrease in fluorescence using excitation at 337 nm and emission at 460 nm for a period of 13 min in a fluorescence plate reader. Initial rates (slopes) are determined from linear portions of the progress curves. The slope of positive control is calculated from the reaction rate in the absence of the compound of the present invention, and the slope of negative control is calculated from the reaction rate in the absence of the compound of the present invention and enzymes. Finally, the ECso value is calculated from the concentration-response curve. (The functional activity of the compound of the present invention is calculated from the following inhibition rate (%).) Inhibition rate (%) = [ (c ■ b) / (a ■ b)] x 100 a; mean slope of positive control b; mean slope of negative control cl slope in the presence of the test compound The compounds of the present invention can be tested essentially as described above.

[0255] Test Example 3: Human active PDE4B1 (S133D mutant) functional inhibition test (Each experimental condition) Recombinant enzyme: human active PDE4B1 (S133D mut) Assay buffer: Tris HCl 50 mmol / L (pH 8.0) containing MgCh 10 mmol / L. KC1 50 mmol / L, tris(2-carboxyethyl)phosphine (TCEP) 1 mmol / L, phosphenolpyruvate (PEP) 0.4 mmol / L, NADH 0.01 mmol / L, adenosine triphosphate (ATP) 0.04 mmol / L, myokinase from yeast or rabbit 7.5 units / mL, pyruvate kinase / lactate dehydrogenase 2 units / mL, BSA 0.1 mg / ml, and active PDE4B1 (S133D mut) 0.7 nmol / L (Functional test of the compound of the present invention) In advance. 0.05 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the Assay buffer containing the enzyme is dispensed into a microplate at 40 pL / well. Then, it is allowed to stand at room temperature (25°C) for 5 minutes. Then, cAMP 0.02 mmol / L is dispensed into a microplate at 10 pL / well. After mixing, reaction rates are immediately measured by monitoring the decrease in fluorescence using excitation at 350 nm and emission at 450 nm for a period of 10 min in a fluorescence plate reader. Initial rates (slopes) are determined from linear portions of the progress curves. The slope of positive control is calculated from the reaction rate in the absence of the compound of the present invention, and the slope of negative control is calculated from the reaction rate in the absence of the compound of the present invention and enzymes. Finally, the ECso value is calculated from the concentration-response curve. (The functional activity of the compound of the present invention is calculated from the following inhibition rate (%).) Inhibition rate (%) = [ (c - b) / (a • b)] x 100 a: mean slope of positive control b; mean slope of negative control ci slope in the presence of the test compound

[0256] The compounds of the present invention were tested essentially as described above. Results are shown below. (Results)

[0257] [Table 65]______________________________________________________________________________ Compound No. Human active PDE4B1_ ECso (pM) Compound No. Human active PDE4B1_ ECso (pM) Compound No. Human active PDE4B1_ ECso (pM) 1-001 0.18 1031 2.8 1-061 1.7 1-002 0.38 1-032 0.28 1-062 2.5 1-003 0.18 1-033 6.7 1-063 0.62 1-004 0.15 1-034 0.12 1-064 2.7 1-005 0.022 1-035 1 1-065 0.068 1-006 1.3 1-036 3.2 1-066 3.2 1-007 0.27 1-037 0.047 1-067 0.12 1-008 2.3 1-038 4.3 1-068 4.8 1-009 0.075 1-039 0.99 1-069 0.43 1-010 0.22 1-040 0.077 1-070 3.7 1-011 0.37 1-041 0.7 1-071 0.6 1-012 0.16 1-042 4.8 1-072 3.5 1-013 1.3 1-043 2.1 1-073 1 1-014 2.6 1-044 1.9 1-074 3.5 1-015 3.1 1-045 1.1 1-075 0.25 1-016 4.6 1-046 0.12 1-076 1.2 1-017 0.47 1-047 0.57 1-077 0.083 1-018 2.2 1-048 0.4 1-078 0.2 1-019 1.7 1-049 10 1-079 1.7 1-020 10 1-050 1.1 1-080 0.11 1-021 1.2 1051 0.51 1-081 1.1 1-022 0.18 1-052 6 1-082 2.9 1-023 1.6 1-053 2.8 1-083 3.6 1-024 1 1-054 7.7 1-084 1.3 1-025 0.6 1-055 1.4 1-085 4.1 1-026 0.7 1-056 4.2 1-086 0.08 1-027 0.28 1-057 2.2 1-087 0.098 1-028 2.7 1-058 10 1-088 0.1 1-029 0.43 1-059 1.1 1-089 2.5 1-030 10 1-060 0.13 1-090 0.35

[0258] [Table 66] Compound No. Human active PDE4B1_ ECso (pM) Compound No. Human active PDE4B1_ ECso (pM) Compound No. Human active PDE4B1_ ECso (pM) 1-091 2.5 1121 0.31 1-151 10 1092 0.12 I 122 5.5 I 152 3.7 1-093 7.8 1123 0.43 1-153 1.4 1-094 2 1124 0.095 1-154 1.5 1-095 3.1 1125 0.52 1-155 0.16 1-096 0.5 I 126 0.23 I 156 6.4 1-097 0.084 1127 1.5 1-157 1.7 1-098 0.099 I 128 0.37 I 158 6.5 1-099 0.97 1129 1.6 1-159 1.5 1100 1.9 I 130 0.19 1-160 0.12 1-101 0.12 1131 6.5 1-161 5 1-102 1.8 1-132 2 1-162 0.71 1-103 0.093 P133 1.7 1-163 0.78 1-104 2.9 1-134 0.22 1-164 0.048 1-105 0.38 1-135 0.5 1-165 1.8 1-106 0.02 1-136 0.056 1-166 0.51 1-107 0.079 1-137 0.041 1-167 0.82 1-108 0.21 1-138 2.5 1-168 0.76 1-109 0.31 1-139 2.7 1-169 2.9 1110 0.14 1-140 9.7 1-170 0.4 1-111 3.7 1-141 3.5 1-171 0.29 1-112 0.56 1-142 0.49 1-172 0.34 1-113 10 1143 1.7 1-173 0.75 1-114 0.87 1-144 9 1-174 2.1 1-115 8 1145 0.57 1-175 0.4 1-116 1.7 1-146 10 1-176 0.0085 1-117 0.41 1147 4.1 1-177 0.79 1-118 3.2 1-148 10 1-178 0.013 1-119 0.21 1-149 1.2 1-179 1 1-120 0.26 1-150 0.072 1-180 0.81

[0259] [Table 67] Compound No. Human active PDE4B1_ ECbo (pM) Compound No. Human active PDE4B1_ ECbo (pM) Compound No. Human active PDE4B1_ ECbo (pM) 1-181 7.5 1211 2.1 1-241 0.13 1182 1.3 I 212 1.5 1-242 0.25 1-183 7 1-213 1 1-243 0.063 1184 1.2 1-214 3.1 1-244 0.12 1-185 5.4 1-215 0.14 1-245 0.19 1-186 1.9 I 216 0.23 1-246 0.13 1-187 3.4 1-217 0.044 1-247 0.023 1-188 0.44 I 218 0.1 1-248 0.071 1-189 0.025 1-219 0.43 1-249 0.023 1-190 0.042 1-220 0.44 1-250 0.12 1191 0.029 1-221 0.56 1-251 0.056 1-192 0.33 P222 1.8 1-252 0.15 1-193 0.017 P223 0.96 1-253 3.6 1-194 0.8 P224 1.2 1-254 3.3 1-195 2 1-225 0.38 1-255 0.47 P196 0.53 P226 0.024 P256 1.9 1-197 10 1-227 0.2 1-257 1.2 P198 1.3 P228 0.12 P258 4.4 1-199 0.11 1-229 7.9 1-259 3.7 P200 0.32 P230 0.3 P260 3.5 1-201 1.1 1-231 0.73 1-261 2.1 1-202 0.031 P232 0.89 1-262 2.2 1-203 0.06 P233 1.2 1-263 2 1-204 0.002 1-234 4.2 1-264 1.5 1-205 0.68 P235 0.059 1-265 0.64 P206 0.56 P236 0.054 P266 0.96 1-207 0.074 P237 0.037 1-267 1.8 P208 2.6 P238 0.024 P268 2.4 1-209 1.1 P239 0.087 1-269 1.7 1-210 0.48 P240 0.11

[0260] [Table 68] Compound No. Human active PDE4B1_ ECbo (pM) P270 0.46 I 271 0.55 P272 0.088

[0261] The selectivity for a human PDE4D inhibitory activity over a human PDE4B inhibitory activity is calculated from the following formula. Selectivity = [Human active PDE4B1 ECbo value] / [Human active PDE4D7 ECbo value]

[0262] The selectivity of the compounds of the present invention is shown below. The ECbo values in Tables 62 to 64 were used as Human active PDE4B1 ECbo value, and the ECbo values in Tables 56 to 58 were used as Human active PDE4D7 ECbo value.

[0263] [Table 69] Compound No. Selectivity (PDE4B1 / PDE4D7) Compound No. Selectivity (PDE4B1 / PDE4D7) Compound No. Selectivity (PDE4B1 / PDE4D7) 1-001 150.0 1-031 40.0 1-061 195.4 1-002 292.3 1-032 62.2 1-062 33.3 1-003 333.3 1-033 115.5 1-063 51.7 1-004 100.0 1-034 75.0 1-064 103.8 1-005 >43.1 1-035 76.9 1-065 >133.3 1-006 162.5 1-036 88.9 1-066 80.0 1-007 225.0 1-037 >92.1 1-067 210.5 1-008 60.5 1-038 69.4 1-068 70.6 1-009 >147.0 1-039 112.5 1-069 330.8 1010 146.7 1-040 45.3 1-070 132.1 1011 231.3 1-041 466.7 1-071 260.9 1-012 53.3 1-042 300.0 1-072 159.1 1-013 108.3 1-043 110.5 1-073 312.5 1-014 200.0 1-044 105.6 1-074 72.9 1-015 114.8 1-045 166.7 1-075 178.6 1-016 1533.3 1-046 272.7 1-076 146.3 1-017 56.0 1-047 75.0 1-077 83.0 1-018 26.8 1-048 85.1 1-078 76.9 1-019 141.7 1-049 416.7 1-079 414.6 1-020 833.3 1-050 13.4 1-080 >215.6 1-021 363.6 1-051 15.5 1-081 68.8 1-022 >352.9 1-052 130.4 1-082 161.1 1-023 190.5 1-053 254.5 1-083 133.3 1-024 105.3 1-054 88.5 1-084 146.1 1-025 130.4 1-055 116.7 1-085 48.8 1-026 106.1 1-056 64.6 1-086 >156.8 1-027 51.9 1-057 220.0 1-087 89.1 1-028 158.8 1-058 384.6 1-088 37.0 1-029 107.5 1-059 478.3 1-089 26.9 1-030 123.5 1-060 61.9 1-090 26.9

[0264] [Table 70] Compound No. Selectivity (PDE4B1 / PDE4D7) Compound No. Selectivity (PDE4B1 / PDE4D7) Compound No. Selectivity (PDE4B1 / PDE4D7) 1-091 25.0 1-121 182.4 1-151 140.8 1-092 70.6 1-122 189.7 1-152 194.7 1-093 866.7 1-123 565.8 1-153 82.4 1-094 1666.7 1-124 52.8 1-154 428.6 1-095 96.9 1-125 28.9 1-155 >313.7 1-096 263.2 1-126 >450.9 1-156 220.7 1-097 >164.7 1-127 428.6 1-157 340.0 1-098 >194.1 1-128 18.5 1-158 500.0 1-099 126.0 1-129 1600.0 1-159 441.2 IT00 327.6 1-130 >372.5 1-160 >235.2 ITOI >235.2 1-131 154.8 1-161 277.8 1-102 260.9 1-132 526.3 1-162 322.7 1-103 >182.3 1-133 850.0 1-163 173.3 1-104 1933.3 1-134 >431.3 1-164 >94.1 1-105 >745 1-135 746.3 1-165 180.0 1-106 >39.2 1-136 >109.8 1-166 86.4 1-107 >154.9 1-137 >80.3 1-167 51.3 1-108 403.8 1-138 104.2 1-168 176.7 1-109 182.4 1-139 84.4 1-169 181.3 1-110 >274.5 1-140 220.5 1-170 266.7 Illi 902.4 1-141 673.1 1-171 241.7 1-112 >1098 1-142 690.1 1-172 28.3 1-113 166.7 1-143 653.8 1-173 197.4 1114 217.5 1-144 160.7 1-174 323.1 1-115 333.3 1-145 1017.9 1-175 108.1 1-116 586.2 1-146 151.5 1-176 >16.6 1-117 561.6 1-147 164.0 1-177 83.2 1-118 666.7 1-148 666.7 1-178 >25.4 IT19 >411.7 1-149 521.7 1-179 32.3 1-120 371.4 1-150 >141.1 1-180 119.1

[0265] [Table 71] Compound No. Selectivity (PDE4B1 / PDE4D7) Compound No. Selectivity (PDE4B1 / PDE4D7) Compound No. Selectivity (PDE4B1 / PDE4D7) 1-181 1315.8 1-211 677.4 1-241 136.8 1-182 866.7 1-212 78.9 1-242 104.2 1-183 583.3 1-213 16.7 1-243 >123.5 1-184 1237.1 1-214 258.3 1-244 >235.2 1-185 771.4 1-215 175.0 1-245 >372.5 1-186 678.6 1-216 442.3 1-246 118.2 1-187 61.8 1-217 >86.2 1-247 >45 1-188 146.7 1-218 >196 1-248 >139.2 1-189 >49 1-219 330.8 1-249 >45 1-190 28.0 1-220 61.1 1-250 109.1 1-191 12.6 1-221 >1098 1-251 98.2 1-192 194.1 1-222 285.7 1-252 156.3 1-193 >33.3 1-223 266.7 1-253 128.6 1194 307.7 1-224 148.1 1-254 143.5 1-195 606.1 1-225 102.7 1-255 162.1 1-196 >33.3 1-226 >47 1-256 158.3 1-197 1000.0 1-227 377.4 1-257 387.1 1-198 54.2 1-228 >235.2 1-258 84.6 1-199 113.4 1-229 254.8 1-259 48.7 1-200 8.2 1-230 150.0 1-260 233.3 1-201 28.2 1-231 331.8 1-261 123.5 1-202 >60.7 1-232 129.0 1-262 53.7 1-203 64.5 1-233 315.8 1-263 465.1 1-204 >3.9 1-234 575.3 1-264 245.9 1-205 125.9 1-235 >115.6 1-265 64.0 1-206 151.4 1-236 33.8 1-266 34.3 1-207 >145 1-237 >72.5 F267 42.9 1-208 236.4 1-238 >47 1-268 88.9 1-209 64.7 1-239 66.9 1-269 94.4 1-210 252.6 1-240 137.5

[0266] [Table 72] Compound No. Selectivity (PDE4B1 / PDE4D7) 1-270 153.3 1-271 125.0 1-272 51.8

[0267] Test Example 3’2: Human active PDE4B1 (S133D mutant) functional inhibition test (Each experimental condition) Recombinant enzyme: human active PDE4B1 (S133D mut) Assay buffer: Tris HCl 50 mmol / L (pH 8.0) containing MgCh 10 mmol / L, KC1 50 mmol / L, tris(2-carboxyethyl)phosphine (TCEP) 1 mmol / L, phosphenolpyruvate (PEP) 0.4 mmol / L, NADH 0.01 mmol / L, adenosine triphosphate (ATP) 0.04 mmol / L, myokinase from yeast or rabbit 7.5 units / mL. pyruvate kinase 1.6 units / mL, lactate dehydrogenase 2.2 units / mL, BSA 0.1 mg / ml. and active PDE4B1 (S133D mut) 0.5nmol / L (Functional test of the compound of the present invention) In advance, 5 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the master mix buffer containing the enzyme is dispensed into a microplate at 40 pL / well. Then, it is allowed to stand at room temperature (25°C) for 10 minutes. Then, cAMP 0.04 mmol / L is dispensed into a microplate at 5 pL / well. After mixing, reaction rates are immediately measured by monitoring the decrease in fluorescence using excitation at 337 nm and emission at 460 nm for a period of 13 min in a fluorescence plate reader. Initial rates (slopes) are determined from linear portions of the progress curves. The slope of positive control is calculated from the reaction rate in the absence of the compound of the present invention, and the slope of negative control is calculated from the reaction rate in the absence of the compound of the present invention and enzymes. Finally, the ECao value is calculated from the concentration-response curve. (The functional activity of the compound of the present invention is calculated from the following inhibition rate (%).) Inhibition rate (%) = [ (c ■ b) / (a - b)] x 100 a: mean slope of positive control b; mean slope of negative control c- slope in the presence of the test compound The compounds of the present invention can be tested essentially as described above.

[0268] Test Example 4: Human active PDE4D7 (S129D mutant) binding inhibition test (Each experimental condition) Recombinant enzyme: human active PDE4D7 (S129D mut) Assay buffer: TrisHCl 50 mmol / L (pH 7.4) containing NaCI 120 mmol / L, MgCL GHaO 1 mmol / L, KC1 5 mmol / L. 0.1% BSA, and CaCh 2 mmol / L Radioactive ligand: Compound X 3 nmol / L Non-specific ligand: Compound Y (Binding test of the compound of the present invention) In advance, 0.3 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the enzyme and the radioactive ligand are diluted with Assay buffer, respectively. Then, the radioactive ligand solution is dispensed into a microplate at 50 pL / well. Then, the Assay buffer containing the diluted enzyme is dispensed into a microplate at 0.3 ug / 50 pL / well, and the plate is sealed. Then, it is allowed to stand at room temperature (25°C) for 2 hours. During this period, 25 mmol / L Tris'HCl (pH 7.4) is dispensed into a GF / C UniFilter plate at 50 pL / well and allowed to stand at 4°C for 1 hour or longer. After that, filtration is performed with Cell harvester (PerkinElmer). After the GF / C UniFilter plate is dried at room temperature. MicroScinti 20 is dispensed into the GF / C UniFilter plate at 50 pL / well, and the plate is sealed. The GF / C UniFilter plate is allowed to stand for 12 hours or longer at room temperature. The radioactivity of Compound X bound to the active PDE4D7 (S129D mut) is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. The non-specific binding is calculated from the radioactivity of Compound X in the presence of 90 pmol / L Compound Y with the unlabeled ligand, and the total binding is calculated from the radioactivity of Compound X in the absence of the compound of the present invention (Vehicle). Finally, the Ki value is calculated from the concentration-response curve. (The binding activity of the compound of the present invention is calculated from the following binding inhibition rate (%).) Inhibition rate (%) = [1 ■ (c - a) / (b ■ a)] x 100 a! mean cpm of non-specific binding 172 b: mean cpm of total binding ci cpm in the presence of the test compound The structure of Compound X is shown below. D D The structure of Compound ¥ is shown below. The compounds of the present invention can be tested essentially as described above.

[0269] Test Example 5: Human basal PDE4D7 (wild type) binding inhibition test (Each experimental condition) Recombinant enzyme: human basal PDE4D7 (wild type) Assay buffer: Tris HCl 50 mmol / L (pH 7.4) containing NaCI 120 mmol / L, MgCh-GHaO 1 mmol / L, KC1 5 mmol / L, 0.1% BSA, and CaCh 2 mmol / L Radioactive ligand: Compound X 5 nmol / L Non-specific ligand: Compound Y (Binding test of the compound of the present invention) In advance, 0.3 pL of the compound solution dissolved in DMSO is dispensed into a microplate, and the enzyme and the radioactive ligand are diluted with Assay buffer, respectively. Then, the radioactive ligand solution is dispensed into a microplate at 50 pL / well. Then, the assay buffer containing the diluted enzyme is dispensed into a microplate at 0.12 ug / 50 pL / well. and the plate is sealed. Then, it is allowed to stand at room temperature (25°C) for 2 hours. During this period, 25 mmol / L Tris-HCl (pH 7.4) is dispensed into a GF / C UniFilter plate at 50 pL / well and allowed to stand at 4°C for 1 hour or longer. After that, filtration is performed with Cell harvester (PerkinElmer). After the GF / C UniFilter plate is dried at room temperature. MicroScinti 20 is dispensed into the GF / C UniFilter plate at 50 pL / well, and the plate is sealed. The GF / C UniFilter plate is allowed to stand for 12 hours or longer at room temperature. The radioactivity of Compound X bound to the basal PDE4D7 (wild type) is measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min / well. The non-specific binding is calculated from the radioactivity of Compound X in the presence of 90 pmol / L Compound Y with the unlabeled ligand, and the total binding is calculated from the radioactivity of Compound X in the absence of the compound of the present invention (Vehicle). Finally, the Ki value is calculated from the concentration-response curve. (The binding activity of the compound of the present invention is calculated from the following binding inhibition rate (%).) Inhibition rate (%) = [1 ■ (c - a) / (b - a)] x 100 a^ mean cpm of non-specific binding b; mean cpm of total binding ci cpm in the presence of the test compound The structure of Compound X is shown below. D D The structure of Compound Y is shown below. The compounds of the present invention can be tested essentially as described above.

[0270] Test Example 6: Y-Maze spontaneous alteration test This test consisted of a single 7-min trial in which a mouse is allowed to explore all three arms of the Y-maze. 10 to 15-week-old humanized PDE4D knock-in mice are used. For preparation of a test compound administration solution, saline with 50% polyethylene glycol is used as a vehicle by dissolving the test compound, and for preparation of a scopolamine administration solution, saline is used as a vehicle by dissolving scopolamine. The test compound is orally administered to mice 1 h before the experiment. Additionally, scopolamine (0.1 mg / kg) or saline is injected intraperitoneally 30 min before the experiment. Spontaneous alternation (%) is defined as the consecutive entries into the three different arms, divided by the number of possible alternations (total arm entries -2). Analysis of the test results is performed as follows. The data are analyzed by one way analysis of variance with treatment (dose of the test compound) as the intersubject factors, followed by Dunnett’s multiple comparison test. A value of P<0.05 is considered significant. The compounds of the present invention can be tested essentially as described above.

[0271] Test Example 7- Ketamine / xylazine anesthesia test 10 to 19 week-old humanized PDE4D knock-in mice are used. The animals are orally administered the test compound or vehicle. After 30 min, a mixture of ketamine (80 mg / kg) and xylazine (10 mg / kg) is injected to mice intraperitoneally. Anesthesia duration is determined as the time between the loss and return of locomotor activity, measured using SCANET (Scanet MV-40: MELQUEST, Toyama, Japan). Analysis of the test results is performed as follows. The data are analyzed by one way analysis of variance with treatment (dose of the test compound) as the intersubject factors, followed by Dunnett’s multiple comparison test. A value of P<0.05 is considered significant. When significant suppression of the duration time of anesthesia is shown in the test compound administration group as compared with the vehicle administration group, it is determined that the test compound has an emetic potential because the duration of ketamine / xylazine-induced anesthesia in rodents is used as a pharmacological surrogate for assessment of emetic potential as commonly seen in other species (Nonpatent document 7). The compounds of the present invention can be tested essentially as described above.

[0272] Test Example 8: Metabolic stability test with liver microsomal fraction Using commercially available pooled liver microsomes, a compound of the present invention is reacted for a constant time, a remaining rate is calculated by comparing a reacted sample with an unreacted sample, thereby, a degree of metabolism in liver is assessed. A compound of the present invention is incubated (oxidative reaction) at 37 °C for 0 minute or 30 minutes in the presence of 1 mmol / L NADPH in an aliquot of a buffer (50 mmol / L TrisHCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL of liver microsomes. After the reaction, an aliquot of the reaction solution is added to a doubled volume of a methanol / acetonitrile = 1 / 1 (v / v), mixed and centrifuged. The compound of the present invention in the supernatant is analyzed by LC-MS / MS or solid phase extraction (SPE) / MS, and a remaining amount of the compound of the present invention after the reaction is calculated, letting a compound amount at 0-minute reaction time to be 100%. The compounds of the present invention were tested essentially as described above. Results are shown below. (Results) Remaining rate of the compound of the present invention at a concentration of 0.5 pmol / L: Compound 1'014: 90% Compound 1'026: 93% Compound 1'043: 99% Compound 1 046: 84% Compound L086: 97% Compound 1'090: 99% Compound I-116: 97% Compound I-153: 100% Compound 1-155: 85% Compound L189: 98%

[0273] Test Example 9: Metabolic stability test with hepatocytes Using hepatocytes which are commercially available or prepared in-house, a compound of the present invention is reacted for a constant time, a remaining rate is calculated by comparing a reacted sample with an unreacted sample, thereby, a degree of metabolism in liver is assessed. A compound of the present invention is incubated (oxidative reaction) at 37 °C for 0 minute, 60 or 120 minutes with 1.0 million cells / mL hepatocytes suspended in William’s E medium containing 0.292 g / L Lglutamine. After the reaction, an aliquot of the reaction solution is added to four times volume of a methanol / acetonitrile = 1 / 1 (v / v), mixed and centrifuged. The compound of the present invention in the supernatant is analyzed by LOMS / MS or solid phase extraction (SPE) / MS, and a remaining amount of the compound of the present invention after the reaction is calculated, letting a compound amount at 0 minute reaction time to be 100%. The compounds of the present invention were tested essentially as described above. Results are shown below. (Results) Remaining rate after reacting the compound of the present invention at a concentration of 0.5 pmol / L for 120 minutes: Compound I-026: 88% Compound 1'041: 84% Remaining rate after reacting the compound of the present invention at a concentration of 0.05 pmol / L for 120 minutes: Compound 1-102: 94% Compound 1'113: 90% Compound 1'116: 89% Compound 1-152: 95% Compound 1-155: 82% Compound I 156: 89% Compound 1-162: 89% Compound 1'168: 92%

[0274] Test Example 10: CYP inhibition test Using commercially available pooled human liver microsomes, an inhibitory degree of each metabolite production amount by the compound of the present invention is assessed, as marker reactions of human main five CYP isoforms (CYP1A2, 2C9, 2C19, 2D6, and 3A4), 7 ethoxyresorufin Odeethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9). mephenytoin 4'hydroxylation (CYP2C19). dextromethorphan O'demethylation (CYP2D6), and terfenadine hydroxylation. The reaction conditions are as follows: substrate, 0.5 pmol / L ethoxyresorufin (CYP1A2), 100 pmol / L tolbutamide (CYP2C9), 30 pmol / L S mephenytoin (CYP2C19), 5 pmol / L dextromethorphan (CYP2D6), 1 pmol / L terfenadine (CYP3A4): reaction time, 15 minutes; reaction temperature. 37°C; enzyme, pooled human liver microsomes 0.2 mg protein / mL; concentrations of the compound of the present invention, 1, 5, 10, 20 pmol / L (4 points). Five kinds of substrates, human liver microsomes, and a compound of the present invention in 50 mmol / L Hepes buffer are added to a 96 well plate at the composition as described above, and NADPH, as a cofactor is added to initiate metabolism reactions. After the incubation at 37°C for 15 minutes, a methanol / acetonitrile = 1 / 1 (V / V) solution is added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant is quantified by a fluorescent multilabel counter or LC'MS / MS and hydroxytolbutamide (CYP2C9 metabolite), 4' hydroxymephenytoin (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol metabolite (CYP3A4 metabolite) are quantified by LOMS / MS. The sample adding only DMSO as a solvent to a reaction system instead of a solution dissolving a compound of the present invention is adopted as a control (100%). Remaining activity (%) is calculated and ICbo is calculated by reverse presumption by a logistic model using a concentration and an inhibition rate. The compounds of the present invention were tested essentially as described above. Results are shown below. (Results) ICbo values towards CYP 1A2: Compound 1025 ICbo > 20 pM Compound 1'027 ICbo > 20 pM Compound 1'046 ICbo > 20 pM Compound 1'055 ICbo > 20 pM Compound 1'063 ICbo > 20 pM Compound 1'071 ICbo = 18 pM Compound 1' 108 ICbo > 20 pM Compound 1' 152 ICbo > 20 pM Compound 1' 153 ICbo > 20 pM ICbo values towards CYP 2C19: Compound 1'025: ICbo > 20 pM Compound 1'027: ICbo > 20 pM Compound I 046: ICbo > 20 pM Compound 1'055: ICbo > 20 pM Compound 1'063: ICbo > 20 pM Compound 1'071: ICbo > 20 pM Compound 1' 108: ICbo > 20 pM Compound 1' 152: ICbo > 20 pM Compound 1'153: ICbo > 20 pM ICbo values towards CYP 2C9: Compound 1'025: ICbo > 20 pM Compound 1'027: ICbo > 20 pM Compound I'046: ICbo = 16 pM Compound 1'055: ICbo > 20 pM Compound 1 063: ICbo > 20 pM Compound 1'071: ICbo > 20 pM Compound 1' 108: ICbo > 20 pM Compound 1' 152: ICbo > 20 pM Compound 1' 153: ICbo = 19 pM ICbo values towards CYP 2D6: Compound 1'025: ICbo > 20 pM Compound 1'027: ICbo > 20 pM Compound 1'046: ICbo > 20 pM Compound 1'055: ICbo > 20 pM Compound 1'063: ICbo > 20 pM Compound I-07L ICso > 20 pM Compound I-108: ICbo > 20 pM Compound 1'152: ICeo = 18 pM Compound 1'153: ICbo > 20 pM ICso values towards CYP 3C4: Compound I'025: ICbo > 20 pM Compound T-027: ICso > 20 pM Compound 1'046: ICso > 20 pM Compound 1'055: ICao > 20 pM Compound 1'063: ICso > 20 pM Compound 1071: ICeo > 20 pM Compound 1'108: ICso > 20 pM Compound 1'152: ICso > 20 pM Compound I-153: ICbo > 20 pM

[0275] Test Example 11: CYP3A4 (MDZ) MBI test CYP3A4 (MDZ) MBI test is a test of investigating MBI potential on CYP3A4 by the enhancement of inhibitory degree of a metabolic reaction caused by the compound of the present invention. CYP3A4 inhibition is evaluated using pooled human liver microsomes by 1-hydroxylation reaction of midazolam (MDZ) as a marker reaction. The reaction conditions are as follows: substrate, 10 pmol / L MDZ; pre-reaction time, 0 or 30 minutes! substrate reaction time. 2 minutes! reaction temperature, 37°C; protein content of pooled human liver microsomes, at pre reaction time 0.5 mg / mL, at reaction time 0.05 mg / mL (at 10'fold dilution): concentrations of the compound of the present invention, 0.83, 5. 10, 20 pmol / L (4 points). Pooled human liver microsomes and a solution of the compound of the present invention in K Pi buffer (pH 7.4) as a pre-reaction solution are added to a 96'well plate at the composition of the pre reaction. A part of pre-reaction solution is transferred to another 96-well plate and diluted lOfold by K Pi buffer containing a substrate. NADPH as a co-factor is added to initiate a reaction as a marker reaction (preincubation 0 minutes). After a predetermined time of a reaction, methanol / acetonitrile=l / l (V / V) solution is added to stop the reaction. In addition. NADPH is added to a remaining pre reaction solution to initiate a pre-reaction (preincubation 30 minutes). After a predetermined time of a pre-reaction, a part is transferred to another 96-well plate and diluted lO fold by K-Pi buffer containing a substrate to initiate a reaction as a marker reaction. After a predetermined time of a reaction, methanol / acetonitrile=l / l (V / V) solution is added to stop the reaction. After centrifuged at 3000 rpm for 15 minutes, 1 ■ hydroxymidazolam in the supernatant is quantified by LC-MS / MS. The sample adding DMSO as a solvent to a reaction system instead of a solution dissolving the compound of the present invention is adopted as a control (100 %). Remaining activity (%) is calculated at each concentration of the compound of the present invention compared to a control, and IC value is calculated by reversepresumption by a logistic model using a concentration and an inhibition rate. Shifted IC value is calculated as "IC of preincubation at 0 minutes / IC of preincubation at 30minutes". When a shifted IC is 1.5 or more, this is defined as positive. When a shifted IC is 1.0 or less, this is defined as negative. The compounds of the present invention were tested essentially as described above. Results are shown below. (Results) Compound 1'025: Negative Compound 1-027: Negative Compound 1'046: Negative Compound 1'055: Negative Compound 1'063: Negative Compound 1'071: Negative Compound 1'108: Negative Compound 1'152: Negative Compound 1153: Negative

[0276] Test Example 12: P-gp substrate test The compound of the present invention is added to one side of a Transwell (registered trademark, CORNING) in which human MDRl-expressing cells or parent cells are cultured in a single layer and reacted for a certain period of time. For MDRl-expressing cells and parent cells, the membrane permeability coefficients from the Apical side to the Basolateral side (A —> B) and from the Basolateral side to the Apical side (B —> A) are calculated, and Efflux Ratio (ER; ratio of membrane permeability coefficients of B —> A and A —> B) value of the MDRl-expressing cells and the parent cells are calculated. The Efflux Ratio (ER value) of the MDRl-expressing cells and the parent cells are compared to determine whether the compound of the present invention is a P’gp substrate or not. The compounds of the present invention can be tested essentially as described above.

[0277] Test Example 13: BCRP substrate test The compound of the present invention is added to one side of a Transwell (registered trademark, CORNING) in which human ABCG2 expressing cells or parent cells are cultured in a single layer and reacted for a certain period of time. For ABCG2-expressing cells and parent cells, the membrane permeability coefficients from the Apical side to the Basolateral side (A —> B) and from the Basolateral side to the Apical side (B —► A) are calculated, and Efflux Ratio (ER; ratio of membrane permeability coefficients of B —> A and A —> B) value of the ABCG2-expressing cells and the parent cells are calculated. The Efflux Ratio (ER value) of the ABCG2-expressing cells and the parent cells are compared to determine whether the compound of the present invention is a BCRP substrate or not. The compounds of the present invention can be tested essentially as described above.

[0278] Test Example 14: Bioavailability, clearance and brain penetration evaluation in rats Materials and methods for experiments to evaluate pharmacokinetic parameters (bioavailability (BA), total clearance (CLtot) and brain-to-plasma concentration ratio (Kp,brain)) (1) Experimental animals: SD rats are used. (2) Rearing condition: SD rats are allowed free access to solid feed and sterilized tap water. (3) Setting of dosage and grouping: Oral administration and intravenous administration are performed with the predetermined dosage. Grouping is set as below. The dosage is changed per compound as necessary. Oral administration 2 pmol / kg (n = 2 to 3) Intravenous administration 1 pmol / kg (n = 2 to 3) (4) Preparation of administration solutions: Oral administration is performed as solution or suspension. Intravenous administration is performed after solubilization. (5) Routes of administration: Oral administration is performed mandatory into the stomach by oral sonde. Intravenous administration is performed from caudal vein by syringes with needle. (6) Evaluation items: Blood is collected serially and concentration of a compound of the present invention in plasma is measured by LC MS / MS. Brain is also collected and concentration of a compound of the present invention in brain is measured by LCMS / MS. (7) Statistical analysis: About transition of concentration of a compound of the present invention in plasma, the area under the plasma concentration versus time curve (AUG) is calculated by moment analysis method, and BA of a compound of the present invention is calculated from the dosage ratio and the AUG ratio between oral and intravenous administration group. CLtot of a compound of the present invention is calculated by the moment analysis method. The dilution concentration or the dilution solvent are changed as necessary. Kp,brain is calculated from the ratio between plasma and brain concentration. The compounds of the present invention were tested essentially as described above. Results are shown below. (Results) CLtot: Compound 1'014: 5.25 mL / min / kg Compound I'046: 3.59 mL / min / kg Compound 1'080: 4.36 mL / min / kg Compound I'099: 1.90 mL / min / kg Compound 1'107: 3.03 mL / min / kg Compound 1'116: 1.86 mL / min / kg Compound I-152: 0.858 mL / min / kg Compound 1'153: 2.52 mL / min / kg Compound 1'168: 3.23 mL / min / kg Compound 1'175: 1.66 mL / min / kg BA: Compound 1-014: 78.8% Compound 1'039: 93.5% Compound 1'041: 96.5% Compound 1'045: 92.8% Compound I'097: 55.5% Compound L099: 83.7% Compound I-128: 63.3% Compound 1'168: 51.4% Compound 1'175: 51.0% Compound 1'203: 58.8% Test Example 15- hERG test (Screening hERG) For the purpose of evaluating risk of an electrocardiogram QT interval prolongation of the compound of the present invention, effects of the compound of the present invention on delayed rectifier K+ current (iKr), which plays an important role in the ventricular repolarization process, are studied using CHO cells expressing human ether-a-gogo related gene (hERG) channel. After a cell is retained at a membrane potential of -80 mV by whole cell patch clamp method using an automated patch clamp system (QPatch; Sophion Bioscience A / S) and given a leak potential of -50 mV, IKr induced by depolarization pulse stimulation at +20 mV for 2 seconds, and further, repolarization pulse stimulation at ■50 mV for 2 seconds, is recorded. A vehicle, which is the 0.1% dimethyl sulfoxide solution in extracellular solution (NaCl: 145 mmol / L, KCF 4 mmol / L, CaChd 2 mmol / L, MgCR: 1 mmol / L, glucose-10 mmol / L, HEPES (4-(2hydroxyethyl)-l-piperazineethanesulfonic acid)- 10 mmol / L, pH = 7.4), or the compound of the present invention is dissolved at an objective concentration in the extracellular solution, and each of the extracellular solution is applied to the cell at room temperature for 7 minutes or more. From the obtained IKr, an absolute value of the tail peak current is measured based on the current value at the resting membrane potential using analysis software (QPatch Assay software or Sophion Analyzer: Sophion Bioscience A / S). The inhibition rate of the tail peak current after application of the compound of the present invention relative to the tail peak current after application of the vehicle is calculated, and further correction is performed using the inhibition rate result of the negative control to evaluate influence of the compound of the present invention on IKr. The dilution concentration is changed as necessary. The compounds of the present invention can be tested essentially as described above.

[0280] Test Example 16: hERG test (Preliminary hERG) For the purpose of evaluating risk of an electrocardiogram QT interval prolongation of the compound of the present invention, effects of the compound of the present invention on delayed rectifier K+ current (IKr), which plays an important role in the ventricular repolarization process, are studied using CHO cells expressing human ether-a-go go related gene (hERG) channel. After a cell is retained at a membrane potential of -80 mV by whole cell patch clamp method using an automated patch clamp system (QPatch; Sophion Bioscience A / S) and given a leak potential of -50 mV. IKr induced by depolarization pulse stimulation at +20 mV for 2 seconds, and further, repolarization pulse stimulation at 50 mV for 2 seconds, is recorded. A vehicle, which is the 0.3% or less dimethyl sulfoxide solution in extracellular solution (NaCL 145 mmol / L, KCL 4 mmol / L, CaCh: 2 mmol / L. MgCR: 1 mmol / L, glucoseHO mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4), or the compound of the present invention is dissolved at an objective concentration in the extracellular solution, and each of the extracellular solution is applied to the cell at room temperature for 7 minutes or more. From the obtained IKr, an absolute value of the tail peak current is measured based on the current value at the resting membrane potential using analysis software (Sophion Analyzer; Sophion Bioscience A / S). The inhibition rate of the tail peak current after application of the compound of the present invention relative to the tail peak current after application of the vehicle is calculated, and further correction is performed using the inhibition rate result of the negative control 181 to evaluate influence of the compound of the present invention on IKr. In this assay, up to 5 concentrations of the compound of the present invention are cumulatively applied starting from the lowest concentration, and the 50% inhibitory concentration (ICso) is estimated from the inhibition rate at each concentration based on a logistic model. The compounds of the present invention can be tested essentially as described above.

[0281] Test Example 17- 3D Hepatotoxicity Assay Using HepaRG spheroids For the purpose of evaluating risk of the hepatotoxicity of the compound of the present invention, these compounds are treated long-term in liver spheroids and assessed their cytotoxicity. HepaRG spheroids are formed by seeding HepaRG cells into round bottom ultra-low adhesion spheroid plates and allowed to form 3D structures over the following 7 days. Cells are incubated at 37 °C, 5% CO2 until spheroid formation with media changes every three to four days. HepaRG spheroids are dosed with these compounds (0.04 - lOOpM) for 336 hrs. Spheroids are dosed in triplicates per test concentration and the final DMSO concentration in each incubation is 0.5%. DMSO vehicle controls are included in all experiments. Over the course of the experiment, compound exposure media is renewed with fresh, compound containing media every three to four days (Days 0, 3, 7, 10 and 13). Appropriate controls, L-buthionine-sulfoximine (BSO: 0.4 - lOOOpM) and carbonyl cyanide 3-chlorophenylhydrazone (CCCP: 0.04 - lOOgM) are run alongside the assay. The acceptance criteria is based on historical data, using the AC50 values for cellular ATP (BSO: 30-525pM CCCP: 0.4-3pM) and glutathione content (BSO; 15'lOOpM and CCCP; 0.85-4.5pM). At the end of the incubation period, the cells are loaded with the relevant dye for each cell health marker. These are spheroid count, spheroid size, DNA structure (Sytoll), GSH content (mBCL), ROS formation (DHE), mitochondrial dysfunction (MitoTracker). The cells are incubated for 30 mins at 37°C, 5% CO2. The dye is removed and the spheroids are carefully washed before the plate is scanned using an automated confocal fluorescent cellular imager, ArrayScan® XTI (Thermo Scientific Cellomics) at 37°C, 5% CO2. The data is acquired using HCS Studio2 software and a validated algorithm. Features measured include ring spot intensity and circ intensity. Following which cellular ATP content is measured using CellTiter-Glo ® 3D Cell Viability Assay (Promega), according to the manufacturer’s instructions then read using BioTek Cytation 3 platereader. The minimum effective concentration (MEC) is determined from the lowest concentration whose mean value exceeds the significance level, provided either a clear dose response relationship is observed, or at least two consecutive concentration points are above the significance level. ACbo values are also determined provided a clear concentration-response relationship is observed. The compounds of the present invention can be tested essentially as described above.

[0282] Test Example 18: Functional Mitochondrial Toxicity Assay: Seahorse Mitochondrial Profiling For the purpose of evaluating risk of the hepatotoxicity of the compound of the present invention, the effects of the compounds on mitochondrial function in HepaRG cells using the Agilent Seahorse XFe96 flux analyzer is also assessed. HepaRG cells are plated on collagen coated XFe96-well tissue culture polystyrene plates and incubated overnight. These are maintained for 7 days with media changes every 3'4 days prior to the assay being performed. One hour prior to the assay the growth media is removed and replaced with unbuffered, serum free media supplemented with glucose, glutamine and pyruvate (assay media). The cells are incubated for 1 hr in a CO2 free incubator before they are moved into the XFe96 flux analyser. Compounds are prepared in DMSO then further diluted in assay media and loaded directly into port A of the XFe9G Seahorse cartridge, which contains 4 individual injection ports. The remaining ports contain the stress test solutions Oligomycin, FCCP and Rotenone / Antimycin A. The cartridge is loaded into the flux analyzer and left to calibrate before the cell plate is added. Four baseline Oxygen Consumption Rate (OCR) and ExtraCellular Acidification Rate (ECAR) readings are taken prior to the injection of test compound. OCR and ECAR readings are taken immediately, and for five further cycles. The cells are then sequentially injected with the stress test components followed by two measurement cycles after each injection. The stress test components are injected in the following order: Oligomycin (allows determination of ATP turnover and proton leak), FCCP (determination of reserve capacity) and Rotenone / Antimycin (determination of nonmitochondrial OCR). HepaRG cells are exposed to the compounds (0.1 to lOOpM) in duplicate per test concentration and the final DMSO concentration is 0.5 %. DMSO vehicle controls are included and rotenone is used a quality control at concentrations of 0.003, 0.01, 0.03, 0.1. 0.3 and 1 pM. OCR and ECAR are determined and normalized as the effect of the test compound on baseline values for each well. The vehicle control wells are used to determine significance limits. OCR changes can be bi-directional, with increases and decreases in OCR indicative of mitochondrial toxicity. Reserve capacity and ECAR changes can also be bi-directional, however these are used more for assessing the potential mechanism of toxicity. The minimum effective concentration (MEC) is determined from the lowest concentration whose mean value exceeds the significance level, provided either a clear concentration-response relationship is observed, or at least two consecutive concentration points are above the significance level. ACso values are also determined provided a clear concentration-response relationship is observed. The compounds of the present invention can be tested essentially as described above.

[0283] Test Example 19: Single dose toxicity study in Monkeys This study is conducted to obtain the information of the systemic exposure and to preliminarily evaluate the toxicity, particularly emesis, of the compounds of the present invention when orally administered to monkeys in a single dose. The compounds are orally administered to cynomolgus monkeys (5 animals, 4 to 7 years old) at several doses by dose escalation or dose de-escalation method at 7-day intervals. 0.5 w / v% methylcellulose (MC) aqueous solution is used for vehicle. The following items are examined: clinical signs, food consumption, and toxicokinetics. The compounds of the present invention can be tested essentially as described above.

[0284] Test Example 20- Solubility test 1 The solubility of a compound is determined under the condition in which 1% DMSO is added. 10 mmol / L compound solution is prepared using DMSO, and then 2 pL of the compound solution is added to 198 pL of artificial intestinal fluid in JP-1 solution (water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL), or JP-2 solution (500 mL of water is added to 500 mL of phosphate buffer (pH 6.8)). After shaking at 25°C over 1 hour, the solution is filtrated using suction. The filtrate is diluted 100 times with acetonitrile / methanol / water (1 / 1 / 2), and then the concentration is measured using LC / MS / MS with the absolute calibration curve method. The compounds of the present invention were tested essentially as described above. Results are shown below. (Results) Solubility in JP-2 solution: Compound 1'014: >50 pL Compound 1'025: >50 pL Compound L065: >50 pL Compound 1'087: >50 pL Compound 1'099: 42.7pL Compound 1'108: >50 pL Compound I119: >50 pL Compound 1-152: >50 pL Compound 1'155: 41.9 pL Compound 1'160: >50 pL

[0285] Test Example 21: Solubility test 2 Appropriate quantity of a compound of the present invention is put in suitable containers. 200 pL of JP1 solution (water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL), 200 pL of JP-2 solution (500 mL of water is added to 500 mL of phosphate buffer (pH 6.8)) or 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to reach 100 mL) is independently added to each container. If the compound is completely dissolved after adding the test reagent, the compound of the present invention is added appropriately. After sealing and shaking at 37°C for 1 hour, the solution is filtrated and 100 pL of methanol is added to 100 pL of each filtrate to achieve a twofold dilution. The dilution rate is adjusted as necessary. After checking that there are no bubbles or deposits, the containers are sealed and shaken. The compound of the present invention is measured using HPLC with the absolute calibration curve method. The compounds of the present invention can be tested essentially as described above.

[0286] The following formulation examples are merely examples, and are not intended to limit the scope of the invention. The compound according to the present invention can be administered as a pharmaceutical composition by any conventional route, in particular enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions, topically, for example, in the form of lotions, gels, ointments, or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating, or coating methods. For example, oral compositions can be tablets, granules, or capsules containing excipients, disintegrants. binders, lubricants, and the like, and active ingredients. Compositions for injection can be solutions or suspension, may be sterilized, and may contain preservatives, stabilizers, buffering agents, and the like. [INDUSTRIAL APPLICABILITY]

[0287] The compound of the present invention has PDE4D inhibitory activity, and the compound is considered to be useful as a therapeutic and / or prophylactic agent for a disease or condition related to PDE4D or cAMP signaling.

Claims

[Document Name] Claims1. A compound represented by Formula (I):R4 R5 R6whereinR1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl. or substituted or unsubstituted non-aromatic carbocyclyl;R2 is halogen, or substituted or unsubstituted alkyloxy;R3 and R4 are each independently a hydrogen atom, or halogen;R7 is a group represented by formula:whereinRs and R9 are (i-1) or (ii-1) shown below:(i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl;(ii-1) R8 and R9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3' to 6-membered non aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z,wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen:R10 is substituted or unsubstituted alkyl (provided that dimethylamino methyl is excluded), substituted or unsubstituted non aromatic carbocyclyl, substituted or unsubstituted tetrahydrofuryl, or substituted or unsubstituted oxetanyl;R17 is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl;R11 is a hydrogen atom or substituted or unsubstituted alkyl;R12 is a hydrogen atom or substituted or unsubstituted alkyl;R13 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino;R14 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl;R1B is a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino;R16 is a hydrogen atom, or substituted or unsubstituted alkyl;R31 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino;R32 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl:R33 is a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylamino;R34 is a hydrogen atom, or substituted or unsubstituted alkyl:R30 is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl;R3B is a hydrogen atom or substituted or unsubstituted alkyl;R36 is a hydrogen atom or substituted or unsubstituted alkyl;R37 is a hydrogen atom, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy. or substituted or unsubstituted alkylamino;R38 is a hydrogen atom, or substituted or unsubstituted alkyl;R3S is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl;R40 is a hydrogen atom or substituted or unsubstituted alkyl;R41 is a hydrogen atom or substituted or unsubstituted alkyl;R26 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkvloxy, or substituted or unsubstituted alkylamino;R27 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl;R22 is a hydrogen atom or substituted or unsubstituted alkyl;R23 is a hydrogen atom or substituted or unsubstituted alkyl;R24 is a hydrogen atom or substituted or unsubstituted alkyl;R2B is a hydrogen atom or substituted or unsubstituted alkyl:Y is 0 or NR18;R18 is a hydrogen atom, or substituted or unsubstituted alkyl;RB and R 6 are (i-2) or (ii-2) shown below!(i-2) R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl;RB is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl; (provided that when R7 is a group represented by formula:wherein each symbol is as defined above,R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; and RB is hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl);(ii-2) RB and R6 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z;a divalent group represented by formula:is a divalent group represented by formula:whereinR21 is each independently substituted or unsubstituted C1-C3 alkyl, or halogen; m is 0 or 1;n is an integer from 0 to 2;p is an integer from 0 to 4 (provided that when R10 is methyl, p is 0);q is an integer from 0 to 3;the atom marked “a” binds to the group represented by the formula:R1 ;the atom marked “b" binds to R7;X is CR19 or N;R19 is a hydrogen atom, or halogen:or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R7 is a group represented by formula:R8 Ry oR10wherein each symbol is as defined in claim 1. or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein Formula (I) is a formula represented by Formula (ll):R4 OHwhereinR1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl. or substituted or unsubstituted non-aromatic carbocyclyl;R2 is halogen, or substituted or unsubstituted alkyloxy;R3 and R4 are each independently a hydrogen atom, or halogen;R8 and R9 are (i-1) or (ii-1) shown below:(i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl;(ii- 1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3- to 6-membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z,wherein the Substituent group Z is the group consisting of C1'C3 alkyl and halogen:a divalent group represented by formula:is a divalent group represented by formula:whereinR21 is each independently substituted or unsubstituted C1-C3 alkyl or halogen; m is 0 or 1;n is an integer from 0 to 2:p is an integer from 0 to 4;q is an integer from 0 to 3:the atom marked “a” binds to the group represented by the formula:R4 OHR1             •the atom marked “b" binds to the group represented by the formula:X is CR19 or N;R19 is a hydrogen atom, or halogen;or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein a divalent group represented by formula^is a divalent group represented by formula^wherein each symbol is as defined in claim 1. or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, wherein m is 0, n is 0 and q is 0, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein Formula (I) is a formula represented by Formula (ITT):whereinR1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl. substituted or unsubstituted aromatic carbocyclyl. or substituted or unsubstituted nonaromatic carbocyclyl;R2 is halogen, or substituted or unsubstituted alkyloxy;R3 and R4 are each independently a hydrogen atom, or halogen;R8 and R9 are (i-1) or (ii-1) shown below!(i-1) R8 and R9 are each independently a hydrogen atom, or substituted or unsubstituted C1’C3 alkyl;(ii- 1) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z, or a 3- to G membered non-aromatic heterocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z,wherein the Substituent group Z is the group consisting of C1-C3 alkyl and halogen;R10 is substituted or unsubstituted alkyl (provided that methyl and dimethylamino methyl are excluded);R17 is a hydrogen atom, substituted or unsubstituted C1C3 alkyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl;R5 and R6 are (i-2) or (ii-2) shown below;(i-2) R5 is a hydrogen atom, hydroxy, halogen, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkyl;R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl:(11-2) RB and R6 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non aromatic carbocycle which is unsubstituted or substituted with one or more substituent(s) selected from the Substituent group Z:a divalent group represented by formula:is a divalent group represented by formula:whereinR21 is each independently substituted or unsubstituted C1-C3 alkyl, or halogen; m is 0 or 1;n is an integer from 0 to 2:p is an integer from 0 to 4;q is an integer from 0 to 3;the atom marked “a" binds to the group represented by the formula:R1 ;the atom marked “b'’ binds to the group represented by the formula:R17 I N?9X is CR19 or N:R19 is a hydrogen atom or halogen;or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1, 2, 4, 5 and G, wherein R10 is alkyl substituted with hydroxy:or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1, 2, 6 and 7, whereinRe is a hydrogen atom, or hydroxy; andR6 is a hydrogen atom:or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1. 2 and 6 to 8, wherein a divalent group represented by formula:b ris a divalent group represented by formulawherein each symbol is as defined in claim 1.or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, wherein p is 0, n is 0 and q is 0, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1, 2 and 6 to 10, wherein R17 is a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl.or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1, 2 and 6 to 10. wherein R17 is a hydrogen atom,or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 12, wherein R8 and R9 are (i-3) or (ii-3) shown below:(i-3) R8 and R9 are each independently a hydrogen atom, or C1-C3 alkyh(ii- 3) R8 and R 9 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered non-aromatic carbocycle, or a 3- to 6-membered non-aromatic heterocycle,or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 12, wherein R8 and R9 are (i-4) shown below:(i-4) R8 is a hydrogen atom and R9 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1 to 14, wherein R2 is substituted or unsubstituted methyloxy,or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 14, wherein R2 ishalomethyloxy or unsubstituted methyloxy,or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 16, wherein R1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted nonaromatic heterocyclyl, or substituted or unsubstituted aromatic carbocyclyl, or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1 to 16, wherein R1 is substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl.or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds 1-014, 1 026, 1-041, 1-046, 1-099, 1'107. I-116, I-152, 1-153, 1-155 and 1-168, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition according to claim 20, for the treatment and / or prevention a disease associated with PDE4D and / or cAMP signaling, or a symptom of a disease related to PDE4D and / or cAMP signaling.

22. A method for preventing and / or treating a disease associated with PDE4D and / or cAMP signaling, or a symptom of a disease related to PDE4D and / or cAMP signaling, comprising administering an effective amount of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

23. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention a disease associated with PDE4D and / or cAMP signaling, or a symptom of disease related to PDE4D and / or cAMP signaling.