Amide derivatives with antiviral activity.

Abstract

The present invention provides: a compound, or a pharmaceutically acceptable salt thereof, having an antiviral activity and represented by formula (I); and a pharmaceutical composition containing the same. (In the formula, the broken lines indicate the presence or absence of bonding; R1 is a carboxy or the like; L is a substituted or unsubstituted non-aromatic carbocyclic diyl or the like; R2 is a substituted or unsubstituted alkyl; R3 is a hydrogen atom or the like; X is =CRX− or =N−; Y is =CRY− or =N−; U is −CRU= or −N=; V is −CRV= or −N=; W is =CRW− or =N−; ZA is −C= or −N−; ZB is −CR5R6− or the like; ZC is −CR7R8− or the like; RX, RY, RV and RW are each independently a hydrogen atom or the like; RU is a hydrogen atom or the like; R5 and R6 are each independently a hydrogen atom or the like; R7 and R8 are each independently a hydrogen atom or the like; R4 is substituted or unsubstituted alkyloxy or the like.)

Description

Amide derivatives with antiviral activity

[0001] The present invention relates to compounds useful for the treatment and / or prevention of respiratory syncytial virus (RSV) infection and related diseases caused by infection, and pharmaceutical compositions containing them. In particular, the present invention relates to amide derivatives having RSV inhibitory activity.

[0002] Human respiratory syncytial virus (RSV) is a negative-sense, single-stranded RNA virus that is a type of pneumovirus in the Paramyxoviridae family and is the most common cause of bronchiolitis and pneumonia in infants under one year of age. Most children are infected with RSV before their second birthday, and approximately 1-3% of infected individuals require hospitalization. The elderly and those with cardiac, pulmonary, or immune system disorders are particularly susceptible and are at increased risk of severe illness and complications (Non-Patent Document 1).

[0003] RSV has two antigenic subtypes, A and B. Generally, these two types are observed simultaneously during RSV epidemics, but the ratio of these types varies geographically and seasonally, which is thought to be one of the reasons why the clinical impact of each epidemic varies. Therefore, when considering the treatment of RSV, it is considered desirable to have a drug that is effective against both subtypes A and B (Non-Patent Document 1).

[0004] Currently, there is no vaccine that can prevent RSV infection. Palivizumab is a monoclonal antibody used prophylactically to prevent RSV infection in high-risk infants, such as premature infants and infants with heart or lung disease. The high cost of palivizumab treatment limits its use as a general-purpose drug. Ribavirin, a nucleic acid analog, is the only antiviral agent approved in the United States for treating RSV infection, but its side effect profile is a concern and its efficacy is limited. Therefore, there is a need for the development of a safe and effective RSV treatment that can be used widely across all types of RSV and across age groups from infants to the elderly (Non-Patent Document 1).

[0005] RSV therapeutic agents currently under clinical development include Ziresovir, JNJ-53718678, and RV-521, which are inhibitors that act on the F protein involved in RSV membrane fusion, and EDP-938, which is an inhibitor that acts on the N protein involved in genome stabilization. PC786, which inhibits the L protein polymerase, is also under development (Non-Patent Document 2). To date, no amide derivatives with RSV inhibitory activity such as those described in this application have been known.

[0006] Cellular and Molecular Life Sciences, 2020, Jun 16, 1-14Expert Opinion on Investigational Drugs, 2020, Mar 29, 3, 285-294

[0007] An object of the present invention is to provide novel compounds having RSV inhibitory activity. More preferably, the present invention provides compounds useful for the treatment and / or prevention of RSV infection and related diseases caused by infection, and pharmaceuticals containing the same.

[0008] The present invention relates to the following items (1) to (17): (1) Formula (I): (wherein the dashed line indicates the presence or absence of a bond; R １ represents carboxy, cyano, a substituted or unsubstituted aromatic heterocyclic group, —C(═O)—NR １Ｂ R １Ｃ or —CH═CHC(═O)—OH; R １Ｂ and R １Ｃ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aminosulfonyl, or a substituted or unsubstituted non-aromatic heterocyclylsulfonyl; L is a substituted or unsubstituted non-aromatic carbocyclyldiyl, a substituted or unsubstituted non-aromatic heterocyclyldiyl, or a substituted or unsubstituted alkylene; R ２ is substituted or unsubstituted alkyl; R ３is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or substituted or unsubstituted carbamoyl; X is ═CR Ｘ - or ═N—; Y is ═CR Ｙ - or =N-; U is -CR Ｕ = or -N=; V is -CR Ｖ = or -N=; W is =CR Ｗ - or =N-; Z Ａ is —C═ or —N—; Z Ｂ is -CR ５ R ６ -, -CR ５ =, -NR ５ - or -N=; Z Ｃ is -CR ７ R ８ -, -CR ７ =, -NR ７ - or =N-; R Ｘ , R Ｙ , R Ｖ and R Ｗ are each independently a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl; R Ｕ is a hydrogen atom, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted amino, hydroxy, a halogen, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted non-aromatic carbocyclic group; R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl, or R ５ and R ６ may be taken together to form oxo; R ７ and R ８are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted alkylsulfonyl, or R ７ and R ８ may be taken together with the carbon atom to which it is attached to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; or R ５ and R ７ may be taken together with the carbon atom to which it is attached to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted aromatic carbocyclic ring; R ４ is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, hydroxy, halogen, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclylcarbonyl, or R ４ and R Ｕ (2) R may be taken together with the carbon atom to which it is attached to form a substituted or unsubstituted non-aromatic heterocycle, or a pharmaceutically acceptable salt thereof. １ (3) The compound according to the above item (1) or (2), wherein R is substituted or unsubstituted non-aromatic carbocyclic diyl, or a pharmaceutically acceptable salt thereof. ３is a hydrogen atom. (5) The compound according to any one of the above items (1) to (4) or a pharmaceutically acceptable salt thereof, wherein V is -N= and W is =N-. (6) A compound of the formula: The group represented by (7) A compound according to any one of the above items (1) to (5), wherein the compound is a group represented by the formula: (wherein each symbol has the same meaning as in the above item (1)), or a pharmaceutically acceptable salt thereof. The group represented by (8) A compound according to any one of the above items (1) to (6), wherein the compound is a group represented by the formula: (wherein each symbol has the same meaning as in the above item (1)), or a pharmaceutically acceptable salt thereof. The group represented by (9) A compound according to any one of the above items (1) to (7), wherein the compound is a group represented by the formula: (wherein each symbol has the same meaning as in the above item (1)), or a pharmaceutically acceptable salt thereof. The group represented by (In the formula, R ４ is the same as in item (1) above, and R ７ (10) A compound according to any one of the above items (1) to (8), wherein R is a group represented by the formula: The group represented by (In the formula, R ４ is the same as in item (1) above, and R ７ and R ８ are each independently a hydrogen atom, or a substituted or unsubstituted alkyl, or R ７ and R ８(11) The compound according to any one of the above items (1) to (8), wherein R is a group represented by the formula: R is, together with the carbon atom to which it is attached, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring, or a pharmaceutically acceptable salt thereof. ４ (12) The compound according to any one of the above items (1) to (10), wherein R is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, hydroxy, halogen, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted non-aromatic carbocyclic group, or a pharmaceutically acceptable salt thereof. ４ is substituted or unsubstituted non-aromatic heterocyclic oxy or substituted or unsubstituted non-aromatic carbocyclic oxy, or a pharmaceutically acceptable salt thereof. (13) The compound according to item (1) above, which is selected from the group consisting of compounds I-082, I-162, I-481, I-496, I-503, I-506, I-549, I-552, I-568, I-569, I-570, I-571, I-591, I-613, I-617, and I-618, or a pharmaceutically acceptable salt thereof. (14) A pharmaceutical composition comprising the compound according to any of items (1) to (13) above, or a pharmaceutically acceptable salt thereof. (15) The pharmaceutical composition according to item (14) above, which has an anti-RS virus activity. (16) A method for treating and / or preventing RSV infection, comprising administering a compound according to any one of the above items (1) to (13) or a pharmaceutically acceptable salt thereof. (17) A compound according to any one of the above items (1) to (13) or a pharmaceutically acceptable salt thereof for treating and / or preventing RSV infection. (18) Use of a compound according to any one of the above items (1) to (13) or a pharmaceutically acceptable salt thereof for producing a therapeutic and / or prophylactic agent for RSV infection.

[0009] The compounds according to the present invention have RSV inhibitory activity and are useful as therapeutic and / or preventive agents for RSV infection and related diseases caused by infection.

[0010] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprises" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0011] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, fluorine and chlorine atoms are preferred.

[0012] The term "alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0013] The term "alkenyl" encompasses straight-chain or branched hydrocarbon groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include ethenyl and n-propenyl.

[0014] "Alkynyl" includes a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more triple bonds at any position. It may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, etc.

[0015] The term "alkylene" includes a straight-chain or branched divalent hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene.

[0016] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0017] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0018] "R ５ and R ７ Examples of the "substituted or unsubstituted aromatic carbocyclic ring formed by combining with the carbon atom to which it is bonded" include the following rings.

[0019] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated or non-aromatic unsaturated hydrocarbon group. A bicyclic or multicyclic "non-aromatic carbocyclic group" also includes a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group to which the ring of the above-mentioned "aromatic carbocyclic group" is fused. Furthermore, the term "non-aromatic carbocyclic group" also includes bridged groups or groups that form spiro rings as shown below. The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The bicyclic or higher non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0020] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0021] "R ５ and R ７ Examples of the "substituted or unsubstituted non-aromatic carbocyclic ring formed by combining with the carbon atom to which it is attached" include the following rings.

[0022] "R ７ and R ８ Examples of the "substituted or unsubstituted non-aromatic carbocyclic ring formed by combining with the carbon atom to which it is attached" include the following rings.

[0023] "Non-aromatic carbocyclic diyl" means a divalent group derived from the above "non-aromatic carbocyclic ring". Examples include cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, cyclooctanediyl, bicyclo[2.2.2]octanediyl, bicyclo[2.2.1]heptanediyl, adamantanediyl, and the like. One carbon atom may have two bonds. Examples include cyclohexane-1,1-diyl, adamantane-2,2-diyl, and the like.

[0024] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or multicyclic aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or multicyclic aromatic heterocyclic groups also include those in which the rings in the "aromatic carbocyclic group" are fused to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group, and the bond may be on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5- to 8-membered, and more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, and more preferably 9- or 10-membered. Examples 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. The tricyclic or more aromatic heterocyclic group is preferably 13- to 15-membered. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and the like.

[0025] The term "aromatic heterocycle" refers to a ring derived from the above-mentioned "aromatic heterocyclic group".

[0026] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include monocyclic or bicyclic or more non-aromatic heterocyclic groups fused with the respective rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as monocyclic or bicyclic or more non-aromatic carbocyclic groups fused with the rings of the above-mentioned "aromatic heterocyclic group," and the bond may be on any of the rings. Furthermore, the term "non-aromatic heterocyclic group" also includes bridged groups or groups forming spiro rings as described below. The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, aziridinyl, etc. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl, azetidinyl, etc. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, etc. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Non-aromatic heterocyclic groups having two or more rings preferably have 8 to 20 members, and more preferably have 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0027] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0028] "R ７ and R ８ Examples of the "substituted or unsubstituted non-aromatic heterocycle formed by combining with the carbon atom to which it is bonded" include the following rings. (wherein R′ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxycarbonyl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkylcarbonyl).

[0029] "R ４ and R Ｕ Examples of the "substituted or unsubstituted non-aromatic heterocycle formed by combining with the carbon atom to which it is bonded" include the following rings.

[0030] "Non-aromatic heterocyclic diyl" means a divalent group derived from the above "non-aromatic heterocycle". "Non-aromatic heterocyclic diyl" includes non-aromatic ring diyls having 1 to 9 carbon atoms and containing 1 to 4 nitrogen atoms, oxygen atoms, and / or sulfur atoms, such as pyrrolinediyl, pyrrolidinediyl, imidazolinediyl, imidazolidinediyl, pyrazolinediyl, pyrazolidinediyl, piperidinediyl, piperazinediyl, morpholinediyl, and tetrahydropyrandiyl. One carbon atom may have two bonds. Examples include tetrahydropyran-4,4-diyl and piperidine-4,4-diyl.

[0031] "Trialkylsilyl" refers to a group in which three of the above-mentioned "alkyl" groups are bonded to a silicon atom. The three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0032] In this specification, the phrase "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α." The same applies to substituent groups β, γ, γ', etc.

[0033] Examples of substituents such as "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted alkyloxy," "substituted alkenyloxy," "substituted alkynyloxy," "substituted alkylcarbonyloxy," "substituted alkenylcarbonyloxy," "substituted alkynylcarbonyloxy," "substituted alkylcarbonyl," "substituted alkenylcarbonyl," "substituted alkynylcarbonyl," "substituted alkyloxycarbonyl," "substituted alkenyloxycarbonyl," "substituted alkynyloxycarbonyl," "substituted alkylsulfanyl," "substituted alkenylsulfanyl," "substituted alkynylsulfanyl," "substituted alkylsulfinyl," "substituted alkenylsulfinyl," "substituted alkynylsulfinyl," "substituted alkylsulfonyl," "substituted alkenylsulfonyl," and "substituted alkynylsulfonyl" include the following Substituent Group A. A carbon atom at any position may be bonded to one or more groups selected from the following Substituent Group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α,alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic carbocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted by substituent group γ', aromatic heterocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted by substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted by substituent group γ,Non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0034] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0035] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0036] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0037] Substituent group γ': Substituent group γ and oxo.

[0038] "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocycleoxy", "substituted aromatic heterocycleoxy", "substituted aromatic carbocyclecarbonyloxy", "substituted aromatic heterocyclecarbonyloxy", "substituted aromatic carbocyclecarbonyl", "substituted aromatic heterocyclecarbonyl", "substituted aromatic carbocycleoxycarbonyl", "substituted aromatic heterocycleoxycarbonyl", "substituted aromatic carbocyclesulfanyl", "substituted aromatic heterocyclesulfanyl", "substituted aromatic carbocyclesulfinyl", "substituted aromatic heterocyclesulfinyl", "substituted aromatic carbocyclesulfonyl", "substituted aromatic heterocyclesulfonyl" and "R ５ and R ７Substituents on the ring of an "aromatic carbocycle" and an "aromatic heterocycle", such as a "substituted aromatic carbocycle formed by combining a carbon atom to which a group is bonded with a carbon atom to which the group is bonded, include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, substituent group γ' non-aromatic carbocyclic carbonyloxy optionally substituted by substituent group γ, aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ', aromatic carbocyclic carbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by substituent group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ,Non-aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0039] "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocycleoxy", "substituted non-aromatic heterocycleoxy", "substituted non-aromatic carbocyclecarbonyloxy", "substituted non-aromatic heterocyclecarbonyloxy", "substituted non-aromatic carbocyclecarbonyl", "substituted non-aromatic heterocyclecarbonyl", "substituted non-aromatic carbocycleoxycarbonyl", "substituted non-aromatic heterocycleoxycarbonyl", "substituted non-aromatic carbocyclesulfanyl", "substituted non-aromatic heterocyclesulfanyl", "substituted non-aromatic carbocyclesulfinyl", "substituted non-aromatic heterocyclesulfinyl", "substituted non-aromatic carbocyclesulfonyl", "substituted non-aromatic heterocyclesulfonyl", "substituted non-aromatic carbocyclediyl", "substituted non-aromatic heterocyclediyl", "substituted non-aromatic carbocycleoxyimino", "substituted non-aromatic carbocycleiminooxy", "R ５ and R ７ "a substituted non-aromatic carbocyclic ring formed by "R ７ and R ８ "a substituted non-aromatic carbocyclic ring formed by "R ７ and R ８together with the carbon atom to which it is attached" and "R ４ and R Ｕ Substituents on the ring of the "non-aromatic carbocycle" and "non-aromatic heterocycle" of the "substituted non-aromatic heterocycle" formed together with the carbon atom to which it is bonded include the following Substituent Group C. An atom at any position on the ring may be bonded to one or more groups selected from the following Substituent Group C. Substituent Group C: Substituent Group B and oxo.

[0040] When a "non-aromatic carbocycle" or a "non-aromatic heterocycle" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows:

[0041] Substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following Substituent Group D. Each group may be substituted with one or two groups selected from Substituent Group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0042] In the compound of formula (I), R １ , R １Ｂ , R １Ｃ , L, R ２ , R ３ ,X,Y,U,V,W,Z Ａ , Z Ｂ , Z Ｃ , R５ , R ６ , R ７ , R ８ , R Ｘ , R Ｙ , R Ｖ , R Ｗ , R Ｕ and R ４ Preferred embodiments of the formula (I) are shown below: The compounds represented by formula (I) include all combinations of the specific examples shown below.

[0043] R １ represents carboxy, cyano, a substituted or unsubstituted aromatic heterocyclic group, —C(═O)—NR １Ｂ R １Ｃ or —CH═CHC(═O)—OH; R １Ｂ and R １Ｃ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aminosulfonyl, or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl (hereinafter referred to as a-1). １ is carboxy or —C(═O)—NR １Ｂ R １Ｃ and R １Ｂ and R １Ｃ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aminosulfonyl, or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl (hereinafter referred to as a-2). １ is carboxy (hereinafter referred to as a-3).

[0044] L is a substituted or unsubstituted non-aromatic carbocyclic diyl, a substituted or unsubstituted non-aromatic heterocyclic diyl, or a substituted or unsubstituted alkylene (hereinafter referred to as b-1). L is a substituted or unsubstituted non-aromatic carbocyclic diyl or a substituted or unsubstituted non-aromatic heterocyclic diyl (hereinafter referred to as b-2). L is a substituted or unsubstituted non-aromatic carbocyclic diyl (hereinafter referred to as b-3). L is a substituted or unsubstituted adamantanediyl or a substituted or unsubstituted cyclohexanediyl (hereinafter referred to as b-4). L is a substituted or unsubstituted adamantane-2,2-diyl or a substituted or unsubstituted cyclohexane-1,1-diyl (hereinafter referred to as b-5). L is a non-aromatic carbocyclic diyl or an unsubstituted non-aromatic carbocyclic diyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: cyano, alkyloxy, hydroxy, and halogen) (hereinafter referred to as b-6). L is adamantanediyl substituted with one or more substituents selected from substituent group a or unsubstituted adamantanediyl (hereinafter referred to as b-7). L is adamantane-2,2-diyl substituted with one or more substituents selected from substituent group a or unsubstituted adamantane-2,2-diyl (hereinafter referred to as b-8). L is cyclohexanediyl substituted with a halogen or unsubstituted cyclohexanediyl (hereinafter referred to as b-9). L is cyclohexane-1,1-diyl substituted with a halogen or unsubstituted cyclohexane-1,1-diyl (hereinafter referred to as b-10). L is adamantanediyl substituted with one or more substituents selected from substituent group a, unsubstituted adamantanediyl, cyclohexanediyl substituted with a halogen or unsubstituted cyclohexanediyl (hereinafter referred to as b-11). L is adamantane-2,2-diyl substituted with one or more substituents selected from substituent group a, unsubstituted adamantane-2,2-diyl, halogen-substituted cyclohexane-1,1-diyl, or unsubstituted cyclohexane-1,1-diyl (hereinafter referred to as b-12). L is adamantane-2,2-diyl substituted with one or more substituents selected from substituent group a (hereinafter referred to as b-13).L is unsubstituted adamantane-2,2-diyl (hereinafter referred to as b-14), L is cyclohexane-1,1-diyl substituted with halogen (hereinafter referred to as b-15), and L is unsubstituted cyclohexane-1,1-diyl (hereinafter referred to as b-16).

[0045] R ２ is a substituted or unsubstituted alkyl (hereinafter referred to as c-1). ２ is an alkyl substituted with a halogen or an unsubstituted alkyl (hereinafter referred to as c-2). ２ is alkyl substituted with halogen (hereinafter referred to as c-3).

[0046] R ３ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or substituted or unsubstituted carbamoyl (hereinafter referred to as d-1). ３ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted amino (hereinafter referred to as d-2). ３ is a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as d-3). ３ is a hydrogen atom or an alkyl substituted with one or more substituents selected from Substituent Group b (Substituent Group b: dialkylamino, amino, and hydroxy) or an unsubstituted alkyl (hereinafter referred to as d-4). ３ is a hydrogen atom (hereinafter referred to as d-5).

[0047] X is =CR Ｘ - or =N-, and R ｘ is a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl (hereinafter referred to as e-1). Ｘ - or =N-, and R ｘ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as e-2). Ｘ - or =N-, and R ｘis a hydrogen atom, halogen, or unsubstituted alkyl (hereinafter referred to as e-3). X is ═CH— or ═N— (hereinafter referred to as e-4). X is ═CH— (hereinafter referred to as e-5). X is ═N— (hereinafter referred to as e-6).

[0048] Y is =CR Ｙ - or =N-, and R ｙ is a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl (hereinafter referred to as f-1). Ｙ - or =N-, and R ｙ is a hydrogen atom or a halogen (hereinafter referred to as f-2). Y is ═CH— or ═N— (hereinafter referred to as f-3). Y is ═CH— (hereinafter referred to as f-4). Y is ═N— (hereinafter referred to as f-5).

[0049] U is -CR Ｕ = or -N=, and R Ｕ is a hydrogen atom, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted amino, hydroxy, a halogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as g-1). Ｕ = or -N=, and R Ｕ is a hydrogen atom, a halogen atom, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, or a substituted or unsubstituted alkyloxy (hereinafter referred to as g-2). Ｕ = or -N=, and R Ｕis a hydrogen atom, a halogen atom, a non-aromatic carbocyclic oxy or an unsubstituted non-aromatic carbocyclic oxy substituted with pyrazolyl, an oxetanyl-substituted non-aromatic heterocyclic oxy or an unsubstituted non-aromatic heterocyclic oxy, or an unsubstituted alkyloxy (hereinafter referred to as g-3). U is -CH= or -N= (hereinafter referred to as g-4). U is -CH= (hereinafter referred to as g-5). U is -N= (hereinafter referred to as g-6).

[0050] V is -CR Ｖ = or -N=, and R Ｖ is a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl (hereinafter referred to as h-1). Ｖ = or -N=, and R Ｖ is a hydrogen atom, cyano, or substituted or unsubstituted carbamoyl (hereinafter referred to as h-2). Ｖ = or -N=, and R Ｖ is a hydrogen atom, cyano, or unsubstituted carbamoyl (hereinafter referred to as h-3). V is -CH= or -N= (hereinafter referred to as h-4). V is -CH= (hereinafter referred to as h-5). V is -N= (hereinafter referred to as h-6).

[0051] W is = CR Ｗ - or =N-, and R Ｗ is a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl (hereinafter referred to as i-1). W is ═CH— or ═N— (hereinafter referred to as i-2). W is ═CH— (hereinafter referred to as i-3). W is ═N— (hereinafter referred to as i-4).

[0052] Z Ａ is -C= or -N- (hereinafter referred to as j-1). Ａ is -C= (hereinafter referred to as j-2). Z Ａ is -N- (hereinafter referred to as j-3).

[0053] Z Ｂ is -CR ５ R６ -, -CR ５ =, -NR ５ - or -N=, and R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl, or R ５ and R ６ together to form an oxo (hereinafter referred to as k-1). Ｂ is -CR ５ R ６ -, -CR ５ = or -NR ５ - and R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl, or R ５ and R ６ together to form an oxo (hereinafter referred to as k-2). Ｂ is -CR ５ R ６ -or-CR ５ = and R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl, or R ５ and R ６ together to form an oxo (hereinafter referred to as k-3). Ｂ is -CR ５ R ６ - and R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl, or R ５ and R ６ may be taken together to form oxo (hereinafter referred to as k-4). Ｂ is -CR ５ = and R ５is a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl (hereinafter referred to as k-5). Ｂ is -CR ５ R ６ -or-CR ５ = and R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, or R ５ and R ６ together to form an oxo (hereinafter referred to as k-6). Ｂ is -CR ５ R ６ - and R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, or R ５ and R ６ together to form an oxo (hereinafter referred to as k-7). Ｂ is -CR ５ = and R ５ represents a hydrogen atom or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as k-8). Ｂ is -CR ５ R ６ -or-CR ５ = and R ５ and R ６ are each independently a hydrogen atom (hereinafter referred to as k-9). Ｂ is -CR ５ R ６ - and R ５ and R ６ are each independently a hydrogen atom (hereinafter referred to as k-10). Ｂ is -CR ５ = and R ５ is a hydrogen atom (hereinafter referred to as k-11). Ｂ is -CR ５ R ６ -or-CR ５ = and R ５ and R ６are each independently a hydrogen atom, an unsubstituted non-aromatic heterocyclic group, or R ５ and R ６ together to form an oxo (hereinafter referred to as k-12). Ｂ is -CR ５ R ６ - and R ５ and R ６ are each independently a hydrogen atom, an unsubstituted non-aromatic heterocyclic group, or R ５ and R ６ together to form an oxo (hereinafter referred to as k-13). Ｂ is -CR ５ = and R ５ is a hydrogen atom or an unsubstituted non-aromatic heterocyclic group (hereinafter referred to as k-14). Ｂ is -CH ２ - (hereinafter referred to as k-15). Z Ｂ is -CH= (hereinafter referred to as k-16).

[0054] Z Ｃ is -CR ７ R ８ -, -CR ７ =, -NR ７ - or =N-, and R ７ and R ８ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted alkylsulfonyl, or R ７ and R ８ together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as l-1). Ｃ is -CR ７ R ８ -, -CR ７ = or -NR ７ - and R７ and R ８ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted alkylsulfonyl, or R ７ and R ８ may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring together with the carbon atom to which it is attached (hereinafter referred to as l-2). Ｃ is -CR ７ R ８ -or-NR ７ - and R ７ and R ８ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted alkylsulfonyl, or R ７ and R ８ may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring together with the carbon atom to which it is attached (hereinafter referred to as l-3). Ｃ is -CR ７ R ８ - and R ７ and R ８are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted alkylsulfonyl, or R ７ and R ８ may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring together with the carbon atom to which it is attached (hereinafter referred to as l-4). Ｃ is -NR ７ - and R ７ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or a substituted or unsubstituted alkylsulfonyl (hereinafter referred to as l-5). Ｃ is -CR ７ R ８ -or-NR ７ - and R ７ and R ８ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or R ７ and R ８ together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as l-6). Ｃ is -CR７ R ８ - and R ７ and R ８ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or ７ and R ８ together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as l-7). Ｃ is -NR ７ - and R ７ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, or a substituted or unsubstituted non-aromatic carbocyclic sulfonyl (hereinafter referred to as l-8). Ｃ is -CR ７ R ８ -or-NR ７ - and R ７ and R ８are each independently a hydrogen atom, an alkyl substituted with one or more substituents selected from substituent group c (substituent group c: halogen, hydroxy, alkyloxy, a non-aromatic carbocyclic group, a non-aromatic carbocyclic group substituted with a halogen, a non-aromatic heterocyclic group, a non-aromatic heterocyclic carbonyl, and an aromatic carbocyclic group), or an unsubstituted alkyl, a non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group d (substituent group d: halogen, alkyloxy, cyano, hydroxy, haloalkyl, and alkyloxy substituted with phenyl), or an alkyloxy substituted with haloalkyl. an aromatic heterocyclic group or an unsubstituted non-aromatic heterocyclic group, an aromatic carbocyclic group or an unsubstituted aromatic carbocyclic group substituted with one or more substituents selected from substituent group e (substituent group e: halogen, alkyl, haloalkyl, alkyloxy, and cyano), an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from substituent group f (substituent group f: alkyl, halogen, haloalkyl, alkyloxy, hydroxy, and cyano), an unsubstituted non-aromatic carbocyclic oxycarbonyl, an unsubstituted non-aromatic heterocyclic oxycarbonyl, an unsubstituted non-aromatic carbocyclic sulfonyl, or R ７ and R ８ together with the carbon atom to which it is bonded, form a non-aromatic carbocycle or an unsubstituted non-aromatic carbocycle substituted with a halogen, or a non-aromatic heterocycle or an unsubstituted non-aromatic heterocycle substituted with one or more substituents selected from substituent group g (substituent group g: alkyl, haloalkyl, alkylcarbonyl, alkyloxycarbonyl substituted with phenyl, alkyloxycarbonyl, non-aromatic heterocyclic group, alkylcarbamoyl, non-aromatic carbocyclic group, aromatic heterocyclic group, and aromatic heterocyclic group substituted with a halogen) (hereinafter referred to as l-9). Z Ｃ is -CR ７ R ８ - and R ７ and R ８ are each independently a hydrogen atom, an unsubstituted alkyl, an unsubstituted non-aromatic carbocyclic group, an unsubstituted non-aromatic heterocyclic group, or ７ and R ８together with the carbon atom to which it is bonded, form a non-aromatic carbocycle or an unsubstituted non-aromatic carbocycle substituted with a halogen, or a non-aromatic heterocycle or an unsubstituted non-aromatic heterocycle substituted with one or more substituents selected from the substituent group g (hereinafter referred to as l-10). Ｃ is -NR ７ - and R ７ is a hydrogen atom, an alkyl substituted with one or more substituents selected from substituent group c or an unsubstituted alkyl, a non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group d or an unsubstituted non-aromatic carbocyclic group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group e or an unsubstituted aromatic carbocyclic group, an aromatic carbocyclic group substituted with one or more substituents selected from substituent group f or an unsubstituted aromatic heterocyclic group, an unsubstituted non-aromatic carbocyclic oxycarbonyl, an unsubstituted non-aromatic heterocyclic oxycarbonyl, or an unsubstituted non-aromatic carbocyclic sulfonyl (hereinafter referred to as l-11). Z Ｃ is -CR ７ R ８ - and R ７ and R ８ are each independently an unsubstituted alkyl (hereinafter referred to as l-12). Ｃ is -NR ７ - and R ７ is an unsubstituted alkyl (hereinafter referred to as l-13).

[0055] R ４is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, hydroxy, halogen, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclylcarbonyl, or R ４ and R Ｕ R together with the carbon atom to which it is attached forms a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as m-1). ４ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclyloxy, a substituted or unsubstituted non-aromatic carbocyclyloxy, a substituted or unsubstituted aromatic carbocyclyloxy, a substituted or unsubstituted aromatic heterocyclyloxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted amino, a substituted or unsubstituted carbamoyl, hydroxy, a halogen, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclylcarbonyl, or R ４ and R Ｕ R forms a substituted or unsubstituted non-aromatic heterocycle together with the carbon atom to which it is attached (hereinafter referred to as m-2). ４is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted amino, a substituted or unsubstituted carbamoyl, hydroxy, a halogen, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic carbonyl, or R ４ and R Ｕ R forms a substituted or unsubstituted non-aromatic heterocycle together with the carbon atom to which it is attached (hereinafter referred to as m-3). ４represents an alkyloxy substituted with one or more substituents selected from substituent group h (substituent group h: halogen, hydroxy, alkyloxy, cyano, alkylcarbonyloxy, substituted aromatic heterocyclic groups (substituents: alkyl or alkyloxy), non-aromatic heterocyclic groups, substituted non-aromatic heterocyclic groups (substituents: aromatic heterocyclic groups, alkyl or halogen), aromatic heterocyclic amino, aromatic carbocyclic groups, and aromatic carbocyclic groups substituted with alkyloxy) or an unsubstituted alkyloxy; a non-aromatic heterocyclic-oxy ​​or unsubstituted non-aromatic heterocyclic-oxy ​​substituted by one or more substituents selected from substituent group j (substituent group j: alkyl, halogen, haloalkyl, cyanoalkyl, alkylcarbonyl, alkylcarbamoyl, alkyloxycarbonyl, alkyloxyalkyl, alkylsulfonylalkyl, non-aromatic heterocyclic group, substituted aromatic heterocyclic group (substituted by alkyl, alkyloxy, halogen, haloalkyl, or cyano), aromatic heterocyclic group, non-aromatic carbocyclic group, non-aromatic carbocyclic group substituted with halogen, substituted non-aromatic heterocyclic group (substituted by halogen or alkylcarbonyl), non-aromatic heterocyclic-alkyl, non-aromatic carbocyclic-alkyl, non-aromatic carbocyclic-alkyl substituted with halogen, aromatic heterocyclic-alkyl substituted with alkyl, non-aromatic heterocyclic-carbonyl, non-aromatic carbocyclic-carbonyl, aromatic heterocyclic-carbonyl, aromatic carbocyclic-alkyloxycarbonyl, and non-aromatic carbocyclic-sulfonyl); non-aromatic carbocyclic oxy or unsubstituted non-aromatic carbocyclic oxy substituted with one or more substituents selected from substituent group k (substituent group k: alkyl, halogen, haloalkyl, alkyloxy, alkylsulfonyl, haloalkylamino, alkylamino, aromatic heterocyclic group, non-aromatic heterocyclic group substituted with halogen, non-aromatic heterocyclic group, aromatic heterocyclic group substituted with halogen, aromatic heterocyclic amino substituted with halogen, non-aromatic heterocyclic alkyl substituted with halogen, non-aromatic carbocyclic oxy, and non-aromatic carbocyclic iminooxy substituted with halogen); aromatic carbocyclic oxy;alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group l (substituent group l: halogen, aromatic carbocyclic group, aromatic carbocyclic group substituted with alkyloxy, non-aromatic heterocyclic group, and substituted non-aromatic heterocyclic group (substituents: aromatic heterocyclic group, non-aromatic heterocyclic group substituted with alkyl or halogen), and non-aromatic carbocyclic oxyimino substituted with halogen); alkenyl or unsubstituted alkenyl substituted with one or more substituents selected from substituent group m (substituent group m: aromatic carbocyclic group substituted with alkyloxy, non-aromatic heterocyclic group, and non-aromatic heterocyclic group substituted with aromatic carbocyclic alkyloxycarbonyl); an amino substituted with one or more substituents selected from substituent group n (substituent group n: aromatic carbocyclic alkyl substituted with alkyloxy, aromatic carbocyclic carbonyl substituted with alkyloxy, non-aromatic heterocyclic group substituted with aromatic heterocyclic group, aromatic heterocyclic group, aromatic carbocyclic sulfonyl, aromatic carbocyclic carbonyl, alkyl, and aromatic heterocyclic group substituted with haloalkyl) or an unsubstituted amino; a carbamoyl substituted with haloalkyl or an unsubstituted carbamoyl; hydroxy; halogen; an aromatic carbocyclic group substituted with alkyloxyalkyl or an unsubstituted aromatic carbocyclic group; an unsubstituted aromatic heterocyclic group; a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group o (substituent group o: aromatic heterocyclic group, aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, and haloalkyl) or an unsubstituted non-aromatic heterocyclic group; a non-aromatic carbocyclic group or an unsubstituted non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group p (substituent group p: carbamoyl and dialkylcarbamoyl); a non-aromatic heterocyclic carbonyl or an unsubstituted non-aromatic heterocyclic carbonyl substituted with one or more substituents selected from substituent group q (substituent group q: aromatic heterocyclic group, haloalkyl, non-aromatic heterocyclic group substituted with halogen, aromatic heterocyclic group substituted with halogen, halogen, and alkyloxy); a non-aromatic carbocyclic oxyimino substituted with halogen; or R; ４ and R ＵR forms a halogen-substituted non-aromatic heterocycle or an unsubstituted non-aromatic heterocycle together with the carbon atom to which it is bonded (hereinafter referred to as m-4). ４ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbonyl (hereinafter referred to as m-5). ４ is alkyloxy or unsubstituted alkyloxy substituted with one or more substituents selected from substituent group h, non-aromatic heterocyclic oxy or unsubstituted non-aromatic heterocyclic oxy substituted with one or more substituents selected from substituent group j, non-aromatic carbocyclic oxy or unsubstituted non-aromatic carbocyclic oxy substituted with one or more substituents selected from substituent group k, carbamoyl or unsubstituted carbamoyl substituted with haloalkyl, or non-aromatic heterocyclic carbonyl or unsubstituted non-aromatic heterocyclic carbonyl substituted with one or more substituents selected from substituent group q (hereinafter referred to as m-6). ４ is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, or a substituted or unsubstituted non-aromatic carbocyclic oxy (hereinafter referred to as m-7). ４ is an alkyloxy substituted with one or more substituents selected from substituent group h or an unsubstituted alkyloxy, a non-aromatic heterocyclic oxy substituted with one or more substituents selected from substituent group j or an unsubstituted non-aromatic heterocyclic oxy, or a non-aromatic carbocyclic oxy substituted with one or more substituents selected from substituent group k or an unsubstituted non-aromatic carbocyclic oxy (hereinafter referred to as m-8). ４ is a substituted or unsubstituted alkyloxy (hereinafter referred to as m-9). ４ is an alkyloxy substituted with one or more substituents selected from the substituent group h, or an unsubstituted alkyloxy (hereinafter referred to as m-10). ４ is a substituted or unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as m-11). ４is a non-aromatic heterocyclic oxy substituted with one or more substituents selected from the substituent group j, or an unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as m-12). ４ is a substituted or unsubstituted non-aromatic carbocyclic oxy (hereinafter referred to as m-13). ４ is a non-aromatic carbocyclic oxy substituted with one or more substituents selected from the substituent group k, or an unsubstituted non-aromatic carbocyclic oxy (hereinafter referred to as m-14). ４ is a non-aromatic carbocyclic oxy substituted with one or more substituents selected from the substituent group k (hereinafter referred to as m-15). ４ is a substituted non-aromatic carbocyclic oxy (substituent: non-aromatic heterocyclic group substituted with halogen) (hereinafter referred to as m-16). ４ is a substituted non-aromatic heterocyclic oxy (substituent: aromatic heterocyclic group) (hereinafter referred to as m-17). ４ is a substituted non-aromatic heterocyclic oxy (substituent: aromatic heterocyclic group substituted with halogen) (hereinafter referred to as m-18). ４ is a substituted non-aromatic heterocyclic oxy (substituent: haloalkyl) (hereinafter referred to as m-19). ４ is a substituted non-aromatic carbocyclic oxy (substituent: haloalkylamino) (hereinafter referred to as m-20).

[0056] Furthermore, the compound represented by formula (I) includes all combinations of the specific examples shown below. Formula: a group represented by R １ , R １Ｂ , R １Ｃ , L, R ２ , R ３ ,V.,W.,R. ５ , R ６ , R ７ , R ８ , R Ｘ , R Ｙ , R Ｖ , R Ｗ , R Ｕ and R ４ Preferred embodiments of the above are shown below.

[0057] formula: is the following (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii).

[0058] formula: The group represented by is (Ia), (Ib), (Ih) or (Ii).

[0059] formula: The group represented by is (Ia), (Ib) or (Ii).

[0060] formula: The group represented by the formula: is (Ia) or (Ib).

[0061] formula: The group represented by the formula: is (Ia).

[0062] formula: The group represented by the formula: is (Ib).

[0063] R ｘ is a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl (hereinafter referred to as ee-1). ｘ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (hereinafter referred to as ee-2). ｘ is a hydrogen atom, a halogen atom, or an unsubstituted alkyl (hereinafter referred to as ee-3). ｘ is a hydrogen atom (hereinafter referred to as ee-4).

[0064] R ｙ is a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl (hereinafter referred to as ff-1). ｙ is a hydrogen atom or a halogen (hereinafter referred to as ff-2). ｙ is a hydrogen atom (hereinafter referred to as ff-3).

[0065] R Ｕis a hydrogen atom, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted amino, hydroxy, a halogen, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as gg-1). Ｕ is a hydrogen atom, a halogen atom, a substituted or unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, or a substituted or unsubstituted alkyloxy (hereinafter referred to as gg-2). Ｕ is a hydrogen atom, a halogen atom, a non-aromatic carbocyclic oxy substituted with pyrazolyl or an unsubstituted non-aromatic carbocyclic oxy, an oxetanyl-substituted non-aromatic heterocyclic oxy or an unsubstituted non-aromatic heterocyclic oxy, or an unsubstituted alkyloxy (hereinafter referred to as gg-3). Ｕ is a hydrogen atom (hereinafter referred to as gg-4).

[0066] R ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl, or R ５ and R ６ together form an oxo (hereinafter referred to as kk-1). R ５ is a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted alkyl (hereinafter referred to as kk-5). ５ and R ６ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, or R ５ and R ６ together to form an oxo (hereinafter referred to as kk-6). ５ is a hydrogen atom or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as kk-8). ５ and R ６are each independently a hydrogen atom (hereinafter referred to as kk-9). ５ is a hydrogen atom (hereinafter referred to as kk-10). ５ and R ６ are each independently a hydrogen atom, an unsubstituted non-aromatic heterocyclic group, or R ５ and R ６ together to form an oxo (hereinafter referred to as kk-12). ５ represents a hydrogen atom or an unsubstituted non-aromatic heterocyclic group (hereinafter referred to as kk-14).

[0067] R ７ and R ８ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted alkylsulfonyl, or R ７ and R ８ R together with the carbon atom to which it is attached forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-1). ７ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or a substituted or unsubstituted alkylsulfonyl (hereinafter referred to as 11-5). ７ and R ８are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or R ７ and R ８ R together with the carbon atom to which it is attached forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-6). ７ and R ８ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or ７ and R ８ R together with the carbon atom to which it is attached forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-7). ７ is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, or a substituted or unsubstituted non-aromatic carbocyclic sulfonyl (hereinafter referred to as 11-8). ７ and R ８each independently represents a hydrogen atom, an alkyl substituted with one or more substituents selected from substituent group c or an unsubstituted alkyl, a non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group d or an unsubstituted non-aromatic carbocyclic group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group e or an unsubstituted aromatic carbocyclic group, an aromatic carbocyclic group substituted with one or more substituents selected from substituent group f or an unsubstituted aromatic heterocyclic group, an unsubstituted non-aromatic carbocyclic oxycarbonyl, an unsubstituted non-aromatic heterocyclic oxycarbonyl, an unsubstituted non-aromatic carbocyclic sulfonyl, or R ７ and R ８ R together with the carbon atom to which it is attached forms a halogen-substituted non-aromatic carbocycle or an unsubstituted non-aromatic carbocycle, or a non-aromatic heterocycle or an unsubstituted non-aromatic heterocycle substituted with one or more substituents selected from the substituent group g (hereinafter referred to as 11-9). ７ and R ８ are each independently a hydrogen atom, an unsubstituted alkyl, an unsubstituted non-aromatic carbocyclic group, an unsubstituted non-aromatic heterocyclic group, or ７ and R ８ R together with the carbon atom to which it is attached forms a halogen-substituted non-aromatic carbocycle or an unsubstituted non-aromatic carbocycle, or a non-aromatic heterocycle or an unsubstituted non-aromatic heterocycle substituted with one or more substituents selected from the substituent group g (hereinafter referred to as 11-10). ７ and R ８ are each independently an unsubstituted alkyl (hereinafter referred to as 11-11). ７is a hydrogen atom, an alkyl substituted with one or more substituents selected from substituent group c or an unsubstituted alkyl, a non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group d or an unsubstituted non-aromatic carbocyclic group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group e or an unsubstituted aromatic carbocyclic group, an aromatic carbocyclic group substituted with one or more substituents selected from substituent group f or an unsubstituted aromatic heterocyclic group, an unsubstituted non-aromatic carbocyclic oxycarbonyl, an unsubstituted non-aromatic heterocyclic oxycarbonyl, or an unsubstituted non-aromatic carbocyclic sulfonyl (hereinafter referred to as 11-12). ７ is an unsubstituted alkyl (hereinafter referred to as 11-13). ７ and R ８ R together with the carbon atom to which it is attached forms an unsubstituted non-aromatic heterocycle (hereinafter referred to as 11-14). ７ and R ８ R forms a halogen-substituted non-aromatic carbocyclic ring together with the carbon atom to which it is attached (hereinafter referred to as 11-15). ７ is a substituted non-aromatic carbocyclic group (substituent: halogen) (hereinafter referred to as 11-16). ７ is a substituted alkyl (substituent: alkyloxy) (hereinafter referred to as 11-17).

[0068] R １ is the above (a-1), (a-2) or (a-3).

[0069] L is (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (b-11), (b-12), (b-13), (b-14), (b-15) or (b-16) above.

[0070] R ２ is the above (c-1), (c-2) or (c-3).

[0071] R ３ is the above (d-1), (d-2), (d-3), (d-4) or (d-5).

[0072] V is (h-1), (h-2), (h-3), (h-4), (h-5) or (h-6) above.

[0073] W is (i-1), (i-2), (i-3) or (i-4) above.

[0074] R ４ is the above (m-1), (m-2), (m-3), (m-4), (m-5), (m-6), (m-7), (m-8), (m-9), (m-10), (m-11), (m-12), (m-13), (m-14), (m-15), (m-16), (m-17), (m-18), (m-19) or (m-20).

[0075] (1-A) In one embodiment, the compound of formula (I) is represented by the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ５ and R ６ is (kk-9), and R ７ and R ８ is (11-14), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ is (m-17).

[0076] (1-B) In one embodiment, the compound of formula (I) is represented by the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ７ is (11-15), and R １ is (a-3), L is (b-14), and R ２is (c-3), and R ３ is (d-5), V is (h-6), W is (i-3), R ４ is (m-17).

[0077] (1-C) In one embodiment, the compound of formula (I) has the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ７ is (11-15), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ is (m-16).

[0078] (1-D) In ​​one embodiment, the compound of formula (I) has the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ７ is (11-13), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ is (m-16).

[0079] (1-E) In one embodiment, the compound of formula (I) has the formula: is (I-i), and R ｘ is (ee-4), and R ｙ is (ff-3), and R ５ and R ６is (kk-9), and R ７ and R ８ is (11-14), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ is (m-18).

[0080] (1-F) In one embodiment, the compound of formula (I) has the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ５ and R ６ is (kk-9), and R ７ and R ８ is (11-14), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ is (m-16).

[0081] (1-G) In one embodiment, the compound of formula (I) has the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ５ and R ６ is (kk-9), and R ７ and R ８ is (11-14), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３is (d-5), V is (h-6), W is (i-4), R ４ (1-H) In one embodiment, the compound of formula (I) is a compound of formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ５ and R ６ is (kk-9), and R ７ and R ８ is (11-14), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ (1-I) In one embodiment, the compound represented by formula (I) is represented by the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ７ is (11-17), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ is (m-16).

[0082] (1-J) In one embodiment, the compound of formula (I) is represented by the formula: The group represented by R ｘ is (ee-4), and R ｙ is (ff-3), and R Ｕ is (gg-4), and R ５ and R ６is (kk-9), and R ７ and R ８ is (ll-11), and R １ is (a-3), L is (b-14), and R ２ is (c-3), and R ３ is (d-5), V is (h-6), W is (i-4), R ４ is (m-16).

[0083] The compound represented by formula (I) is not limited to a particular isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

[0084] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced by isotopes of the respective hydrogen, carbon and / or other atoms. Examples of such isotopes include: ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. １２３ I and ３６ The isotopes of the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of formula (I) also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals, and include all radiolabeled compounds of formula (I). Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compounds," which are useful as research and / or diagnostic tools in metabolism pharmacokinetic studies and binding assays.

[0085] Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) via catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of formula (I) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0086] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, salts of the compound represented by formula (I) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picolinic acid, methylparaben ... Examples of suitable salts include salts with carboxylic acids (e.g., carboxylic acids such as carboxylic acids, ...

[0087] The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.), a co-crystal, and / or a crystalline polymorph, and the present invention also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with the compound of formula (I) with any number of solvent molecules (e.g., water molecules, etc.). When the compound of formula (I) or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, resulting in the adsorbed water adsorbing, or may form a hydrate. Furthermore, a crystalline polymorph may be formed by recrystallization of the compound of formula (I) or a pharmaceutically acceptable salt thereof. A "co-crystal" means that the compound of formula (I) or a salt thereof and a counter molecule exist in the same crystal lattice, and may contain any number of counter molecules.

[0088] The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of the compound of the present invention having a chemically or metabolically decomposable group, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0089] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH ３ COO-, C ２ H ５ COO-, tert-BuCOO-, C １５ H ３１ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ２ CH ２ COO-, CH ３ CH(NH ２ ) COO-, CH ２ N (CH ３ ) ２ COO-, CH ３ SO ３ -, CH ３ CH ２ SO ３ -, CF ３ SO ３ -, CH ２ FSO ３ -, CF ３ CH ２ SO ３ -, p-CH ３ O-PhSO ３ -, PhSO ３ -, p-CH ３ PhSO ３ - are listed.

[0090] The following formulation examples are illustrative only and are not intended to limit the scope of the invention. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments, or creams, or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0091] The compounds of the present invention are useful for the following symptoms induced by RSV. However, the symptoms induced by RSV vary from mild cold-like symptoms to severe lower respiratory tract diseases such as bronchiolitis and pneumonia. That is, the compounds of the present invention are useful for cold symptoms such as cough, runny nose, and fever, as well as symptoms such as wheezing and retracted breathing that occur when the symptoms become more severe, and are also useful for diseases such as bronchiolitis and pneumonia that occur as a result of the worsening of these symptoms.

[0092] (Method for Producing the Compound of the Present Invention) The compound of formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments performed in ordinary organic chemistry experiments. The compound of the present invention can be synthesized by referring to methods known in the art.

[0093] (Method A) (wherein each symbol has the same meaning as above, R Ａ Ha-B(OH) ２ , —Sn(C1-C6 alkyl) ３ etc., R Ｂis C1-C6 alkyl, etc.) Step 1 Compound (A-1) and compound (A-2) can be reacted in a single or mixed solvent such as tetrahydrofuran, toluene, dimethylformamide, 1,4-dioxane, ethanol, water, etc. with a metal catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, and a base such as potassium carbonate, sodium hydrogencarbonate, sodium phosphate, sodium hydrogenphosphate, potassium phosphate, potassium hydrogenphosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide at 20°C to the reflux temperature of the solvent for 0.1 to 48 hours, preferably 0.5 to 12 hours, to obtain compound (A-3).

[0094] Step 2 The deprotection reaction of the protecting group of the carboxylic acid of compound (A-3) can be carried out by a general method described in, for example, Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons).

[0095] Step 3 Compound (IA) can be obtained by reacting compound (A-4) with compound (A-5) using a dehydration condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, EDC.HCl, or HATU in a single or mixed solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, acetonitrile, or water, in the presence or absence of a base such as triethylamine, pyridine, diisopropylamine, or 1-methylimidazole. Alternatively, compound (IA) can be obtained by adding an acylating reagent such as thionyl chloride or oxalyl chloride to compound (A-4) in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, or dimethylformamide, in the presence or absence of a base such as pyridine, triethylamine, diisopropylamine, or 1-methylimidazole, to generate an acid chloride, adding compound (A-5) thereto, and reacting the resulting mixture at −20° C. to 60° C., preferably −10° C. to 30° C., for 0.1 to 24 hours, preferably 0.5 to 12 hours.

[0096] (Method B) (In the formula, each symbol has the same meaning as above.) Step 1 Compound (A-2) is added to compound (B-1) in a solvent such as 1,4-dioxane, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, or the like, in the presence or absence of a base such as triethylamine, diisopropylamine, cesium carbonate, potassium carbonate, sodium hydride, or the like, or in the presence or absence of an acid such as toluenesulfonic acid, acetic acid, hydrogen chloride, sulfuric acid, or the like, and the reaction is carried out at 20°C to the reflux temperature of the solvent, preferably 40°C to 120°C, for 0.1 to 48 hours, preferably 0.5 to 12 hours, to obtain compound (B-2). Alternatively, compound (B-2) can be obtained by reacting compound (B-1) with compound (A-2) in a single or mixed solvent such as 1,4-dioxane, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, butanol, water, or the like, in the presence or absence of a ligand such as Xantphos, diphenylphosphinoferrocene, X-Phos, a metal catalyst such as palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, or bis(tri-tert-butylphosphine), or a base such as potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydrogenphosphate, lithium hydroxide, or sodium hydroxide, at 20° C. to the reflux temperature of the solvent, and optionally under microwave irradiation, for 0.1 to 48 hours, preferably 0.5 to 12 hours.

[0097] Steps 2 and 3 Compound (IB) can be obtained by carrying out Steps 2 and 3 of Method A using compound (B-2).

[0098] (C method) (wherein each symbol has the same meaning as above) Step 1: Compound (C-1) is added with a dehydration condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, EDC.HCl, HATU, etc. in a single or mixed solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, acetonitrile, water, etc., and then subjected to NMR spectroscopy. １Ｂ R １Ｃ Compound (IC) can be obtained by adding and reacting with a base such as triethylamine, pyridine, diisopropylamine, 1-methylimidazole, sodium hydride, etc.

[0099] (D method) (In the formula, each symbol has the same meaning as above.) Step 1 Compound (ID) can be obtained by reacting compound (D-1) with an azide compound such as azidotrimethylsilane, sodium azide, tributyltin azide, etc. in a single or mixed solvent such as 1,4-dioxane, dimethylformamide, water, etc., in the presence of an additive such as dibutylstannane, zinc chloride, ammonium chloride, etc., at a temperature of 60°C to the reflux temperature of the solvent, optionally under microwave irradiation, for 0.5 to 48 hours, preferably 1 hour to 4 hours.

[0100] (E method) (In the formula, each symbol has the same meaning as above.) Step 1 Compound (E-2) can be obtained by adding hydroxylamine or the like to compound (D-1) in a single or mixed solvent such as methanol, ethanol, tetrahydrofuran, water, or the like, in the presence or absence of a base such as potassium carbonate or triethylamine, and reacting the mixture at a temperature between room temperature and the reflux temperature of the solvent, or in some cases under microwave irradiation.

[0101] Compound (IE) can be obtained by adding a base such as triethylamine, DBU, or potassium carbonate, and 1,1′-carbonyldiimidazole or ethyl chloroformate to compound (E-2) in a single or mixed solvent such as dimethylformamide, chloroform, dichloromethane, tetrahydrofuran, or toluene, and reacting the mixture at room temperature to the reflux temperature of the solvent.

[0102] (F method) (wherein R is a group independently selected from the substituent group n, and the other symbols have the same meanings as above.) Step 1 Compound (F-2) can be obtained by adding a metal catalyst such as palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, or bis(tri-tert-butylphosphine) to compound (F-1) in the presence or absence of a ligand such as Xantphos, diphenylphosphinoferrocene, X-Phos, or BINAP, and a base such as potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydrogenphosphate, lithium hydroxide, or sodium hydroxide, and reacting the resulting mixture with an amine at a temperature from 20° C. to the reflux temperature of the solvent, and optionally under microwave irradiation, for 0.1 to 48 hours, preferably 0.5 to 12 hours.

[0103] Step 2 Compound (IF) can be obtained by carrying out Step 1 of Method A or Step 1 of Method B using compound (F-2).

[0104] (G method) (wherein each symbol is as defined above, Lea is a leaving group, R ｚｚ is a hydrogen atom, C1-C6 alkyl, etc., R ｘｘ and R ｙｙ are each independently a hydrogen atom, a C1-C6 alkyl, or the like, or R ｘｘ and R ｙｙ forms a ring together with the adjacent nitrogen atom.) Step 1 Compound (G-2) can be obtained by subjecting compound (G-1) to step 1 of Method A.

[0105] Compound (G-3) can be obtained by reacting compound (G-2) with sodium periodate or oxone, ruthenium chloride or potassium osmate in a mixed solvent such as 1,4-dioxane, tetrahydrofuran, water, etc. Alternatively, compound (G-3) can be obtained by oxidizing compound (G-2) with ozone to obtain an ozonide, which can then be treated with a reducing agent such as zinc, dimethyl sulfide, or triphenylphosphine.

[0106] Step 3 Compound (G-4) can be obtained by reacting compound (G-3) with sodium dihydrogen phosphate, sodium chlorite, or the like in a single or mixed solvent such as tetrahydrofuran, tert-butanol, or water in the presence of 2-methyl-2-butene, sulfamic acid, or the like.

[0107] Step 4 Compound (IG) can be obtained by subjecting compound (G-4) to the first step of Method C.

[0108] (H method) (wherein each symbol has the same meaning as above, R ｘｘ and R ｙｙ is a hydrogen atom, C1-C6 alkyl, R ｘｘ and R ｙｙ may combine with the adjacent nitrogen atom to form a ring.) Step 1: Compound (G-3) is subjected to NMR spectroscopy in a single or mixed solvent such as chloroform, tetrahydrofuran, acetonitrile, or acetic acid. ｙｙ R ｘｘ and a reducing agent such as sodium triacetoxyborohydride or 2-picoline borane are added, and the reaction is carried out at room temperature to the reflux temperature of the solvent for 0.1 to 48 hours, preferably 0.5 to 8 hours, to obtain compound (I-H).

[0109] (J method) (wherein each symbol has the same meaning as above, R ｚｚ and R ｙｙis a hydrogen atom, a C1-C6 alkyl, an aromatic carbocyclic group, an aromatic heterocyclic group, or the like.) Step 1 Compound (I-J) can be obtained by catalytic hydrogenation of compound (J-1) in a single or mixed solvent such as tetrahydrofuran, methanol, toluene, chloroform, or the like, in the presence of a heterogeneous catalyst such as palladium carbon, palladium hydroxide, Raney nickel, platinum oxide, or the like.

[0110] The compounds of the present invention have an anti-RSV activity, i.e., an inhibitory activity against CPE (cytopathic effect), and are therefore useful as therapeutic and / or preventive agents for diseases such as bronchiolitis and pneumonia. Furthermore, the compounds of the present invention are useful as pharmaceuticals and preferably have one or more of the following excellent characteristics: a) weak inhibitory activity against CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.); b) good pharmacokinetics, such as high bioavailability and moderate clearance; c) high metabolic stability; d) no irreversible inhibitory activity against CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein; e) no mutagenicity; f) low cardiovascular risk; and g) high solubility. h) It has a high inhibitory effect on RSV type A CPE and a high inhibitory effect on RSV type B. i) It reduces the amount of virus in the lungs.

[0111] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, otic, and vaginal administration.

[0112] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0113] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0114] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0115] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but when administered orally, it is usually 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage can be administered once or in divided doses several times a day.

[0116] The compound of the present invention can be used in combination with an L protein inhibitor, an F protein inhibitor, an N protein enzyme inhibitor, etc. (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration timing of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing these active ingredients.

[0117] The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0118] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0119] The abbreviations used in this specification have the following meanings: Boc ２O: Di-tert-butyl dicarbonate DIAD: Diisopropyl azodicarboxylate DMEAD: Bis(2-methoxyethyl) azodicarboxylate DMAP: 4-dimethylaminopyridine HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate Me4tBuXphos: 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl TolBINAP: 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl Ts: Tosyl Pd ２ (dba) ３ : Tris(dibenzylideneacetone)bispalladium PdCl ２ (dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct Pd(PPh ３ ) ４ : Tetrakis(triphenylphosphine)palladium Xantphos Pd G3: [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Xantphos Pd G2: Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) X-Phos: 2,4,6-triisopropyl-2'-(dicyclohexylphosphino)biphenyl

[0120] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ , CDCl ３Measurement was performed using a NMR spectrometer. NMR data may not include all measured peaks. RT in the specification refers to the retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Method 1) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm (detection range 190-500 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Method 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm (detection range 190-400 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Method 3) Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min UV detection wavelength: 254 nm (detection range 190-800 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10%-100% solvent [B] was performed over 3 minutes, and 100% solvent [B] was maintained for 0.5 minutes. (Method 4) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm (detection range 210-500 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes.(Method 5) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 × 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm (detection range 190-500 nm) Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Method 6) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 × 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm (detection range 190-400 nm) Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Method 7) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 × 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm (detection range 190-500 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 70%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Method 8) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 × 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm (detection range 190-500 nm) Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient of 50%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes.(Method 9) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 × 50 mm) (Waters) Flow rate: 0.6 mL / min UV detection wavelength: 254 nm (detection range 190-500 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 25%-95% solvent [B] was performed over 1.5 minutes, followed by maintaining 95% solvent [B] for 1.5 minutes. (Method 10) Column: ACQUITY UPLC® BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.6 mL / min UV detection wavelength: 254 nm (detection range 190-500 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 25% to 95% solvent [B] over 1.5 minutes was performed, followed by a 1.5-minute hold at 95% solvent [B]. (Method 11) Column: ACQUITY UPLC® CSH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.6 mL / min UV detection wavelength: 254 nm (detection range 190-500 nm) Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 25%-95% solvent [B] was performed over 1.5 minutes, followed by maintaining 95% solvent [B] for 1.5 minutes. In the specification, the term MS (m / z) refers to the value observed by mass spectrometry.

[0121] Example 1 Synthesis of Compound (I-023) Step 1: Synthesis of Compound 3 Chloroform (20 mL) and diisopropylethylamine (0.76 mL, 4.34 mmol) were added to Compound 1 (910 mg, 3.62 mmol), and Compound 2 (887 mg, 3.62 mmol) was added under ice-cooling. The mixture was warmed to room temperature and stirred for 2 hours, and then water was added. The mixture was extracted with chloroform and the two layers were separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate-hexane was added to the resulting residue. The solid was collected by filtration to obtain Compound 3 (1.34 g, yield 81%). 1H-NMR (CDCl3) δ: 1.75-1.82 (m, 6H), 1.87-1.97 (m, 4H), 2.15 (m, 2H), 2.60 (s, 2H), 3.78 (s, 3H), 6.00 (s, 1H), 8.98 (s, 1H).

[0122] Step 2: Synthesis of Compound 5 Compound 4 (22.6 g, 76 mmol) was dissolved in 1,4-dioxane (158 mL), bis-pinacolatodiborane (25 g, 98 mmol), and PdCl ２ (dppf) (6.2 g, 7.6 mmol) and potassium acetate (11.1 g, 114 mmol) were added and stirred at 100°C. After 3 hours, the mixture was cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure, and diisopropyl ether was added to the residue to precipitate a solid. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue was dissolved in tetrahydrofuran (226 mL), and 1 mol / L aqueous sodium hydroxide solution (114 mL, 114 mmol) and 30% aqueous hydrogen peroxide (11.6 mL, 114 mmol) were added under ice cooling. After stirring at room temperature for 1 hour, aqueous sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with ethyl acetate to separate the two layers, and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 5 (7.7 g, yield 43%). 1 H-NMR (CDCl3) δ: 1.57 (s, 9H), 3.04 (t, J = 8.8Hz, 2H), 3.96 (m, 2H), 4.58 (s, 1H), 6.61 (d, J = 8.8Hz, 1H), 6.64 (s, 1H), 7.34 (brs, 0.4H), 7.73 (brs, 0.6H).

[0123] Step 3: Synthesis of Compound 7 Dimethylformamide (25 mL), compound 6 (3.08 g, 15.9 mmol), and potassium carbonate (2.94 g, 21.3 mmol) were added to compound 5 (2.5 g, 10.6 mmol), and the mixture was stirred at 60°C for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The two layers were separated, and the organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 7 (2.55 g, yield 69%). 1 H-NMR (CDCl3) δ: 1.35 (m, 2H), 1.57 (s, 9H), 1.60-1.82 (m, 5H), 3.05 (t, J = 8.8Hz, 2H), 3.40 (td, J = 12.0, 1.6Hz, 2H), 3.90-4.00 (m, 6H), 6.68 (d, J = 8.8Hz, 1H), 6.72 (s, 1H), 7.34 (brs, 0.4H), 7.73 (brs, 0.6H).

[0124] Step 4: Synthesis of Compound 8 Dichloromethane (20 mL) and trifluoroacetic acid (10 mL, 130 mmol) were added to Compound 7 (2.55 g, 7.34 mmol). After stirring at room temperature for 1 hour, aqueous sodium bicarbonate solution was added to neutralize the mixture. The mixture was extracted with chloroform to separate the two layers, and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product Compound 8 (1.95 g). 1 H-NMR (CDCl3) δ: 1.35 (m, 2H), 1.61-1.84 (m, 5H), 2.78 (brs, 1H), 3.01 (t, J = 8.4Hz, 2H), 3.40 (td, J = 12.0, 1.6Hz, 2H), 3.54 (t, J = 8.4Hz, 2H), 3.91-4.00 (m, 4H), 6.57-6.61 (m, 2H), 6.76 (s, 1H).

[0125] Step 5 Synthesis of Compound (I-023) To compound 8 (107 mg, 0.43 mmol), 1,4-dioxane (3 mL), triethylamine (0.149 mL, 1.08 mmol), and compound 3 (150 mg, 0.36 mmol) were added, and the mixture was stirred at 50°C for 2 hours. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the resulting residue, tetrahydrofuran (2 mL), ethanol (2 mL), and a 4 mol / L aqueous solution of lithium hydroxide (0.90 mL, 3.6 mmol) were added. The mixture was stirred at 90°C for 8 hours, and then a 10% aqueous solution of citric acid was added. The mixture was extracted with chloroform, and the two layers were separated. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-023) (90 mg, yield 41%). 1 H-NMR (DMSO-d6) δ: 1.22 (m, 2H), 1.53-1.72 (m, 11H), 1.80 (brs, 2H), 2.03-2.16 (m, 4H), 2.54 (s, 2H), 3.19 (t, J = 8.4Hz, 2H), 3.28 (m, 2H), 3.83 (dd, J = 11.2, 0.8Hz, 2H), 4.00 (t, J = 6.4Hz, 2H), 4.21 (t, J = 8.4Hz, 2H), 6.82 (dd, J = 8.8, 1.2Hz, 1H), 6.94 (d, J = 1.2Hz, 1H), 8.16 (d, J = 8.8Hz, 1H), 8.46 (s, 1H), 8.67 (s, 1H), 12.3 (s, 1H).

[0126] Example 2 Synthesis of Compound (I-033) Step 1 Synthesis of Compound (I-033) Compound 8 (41 mg, 0.16 mmol) and compound 9 (40 mg, 0.11 mmol), which was synthesized in the same manner as compound 3, were dissolved in 1,4-dioxane (0.5 mL), and Xantphos Pd G3 (10 mg, 0.01 mmol) and potassium carbonate (38 mg, 0.27 mmol) were added. After stirring at 100°C for 3 hours, water was added. Extraction with chloroform was performed, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. Ethanol (0.5 mL) and tetrahydrofuran (0.5 mL) were added to the resulting residue, and the solution was dissolved. 4 mol / L aqueous lithium hydroxide solution (0.27 mL) was added, and the mixture was stirred at 50°C for 4 hours. Aqueous citric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-033) (20 mg, yield 33%). 1 H-NMR (DMSO-d6) δ: 1.15-1.30 (m, 3H), 1.50-1.78 (m, 12H), 2.03-2.10 (m, 2H), 3.22 (m, 2H), 3.29 (m, 2H), 3.83 (dd, J= 10.8, 3.2Hz, 2H), 3.98 (t, J = 6.4Hz, 2H), 4.06 (t, J = 8.0Hz, 2H), 6.77 (dd, J = 8.8, 3.5Hz, 1H), 6.89 (s, 1H), 7.06 (d, J = 8.8Hz, 1H), 7.72 (d, J = 8.8Hz, 1H), 8.24 (d, J = 8.8Hz, 1H), 8.44 (s, 1H), 12.2 (s, 1H).

[0127] Example 3 Synthesis of Compound (I-082) Step 1: Synthesis of Compound 12 Compound 10 (31 g, 124 mmol) and compound 11 (16.9 g, 148 mmol) were suspended in dichloromethane (600 mL) and cooled on ice. Trifluoroacetic acid (19 mL, 247 mmol) was added, and after 30 minutes, the temperature was raised to 45°C and stirred for 3 hours. After cooling on ice, aqueous sodium carbonate was added for neutralization, and the mixture was filtered through Celite (registered trademark). The two layers of the filtrate were separated, and the organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diethyl ether was added to the resulting residue, and the solid was collected by filtration to obtain compound 12 (9.04 g, yield 25%). 1 H-NMR (CDCl3) δ: 1.63 (m, 2H), 1.93 (ddd, J = 13.6, 10.0, 4.0Hz, 2H), 3.90 (m, 2H), 4.10 (m, 2H), 5.10 (s, 2H), 6.97 (dd, J = 8.4, 2.4Hz, 1H), 7.06 (d, J = 2.4Hz, 1H), 7.34 (m, 1H), 7.40 (m, 2H), 7.45 (m, 2H), 7.56 (d, J = 8.4Hz, 1H), 8.32 (s, 1H). LC / MS(ESI):m / z= 294 [M+H]+, RT=1.96 min, LC / MS method 1

[0128] Step 2: Synthesis of Compound 13 Compound 12 (18 g, 61.4 mmol) was suspended in methanol (180 mL), cooled on ice, and sodium borohydride (2.55 g, 67.5 mmol) was added. After 10 minutes, the temperature was raised to room temperature and the mixture was stirred for 2 hours. Aqueous ammonium chloride solution was added under ice cooling, and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the resulting residue. The solid was collected by filtration to obtain compound 13 (16.1 g, yield 89%). 1H-NMR (CDCl3) δ: 1.65 (d, J = 13.6Hz, 2H), 1.94 (m, 2H), 3.52 (m, 2H), 3.55 (m, 2H), 3.96 (m, 2H), 4.99 (s, 2H), 6.59 (d, J = 8.4Hz, 1H), 6.70 (d, J = 8.4, 2.4Hz, 1H), 6.79 (d, J = 2.4Hz, 1H), 7.26 (s, 1H), 7.31 (m, 1H), 7.38 (m, 2H), 7.43 (m, 2H). LC / MS(ESI):m / z= 296 [M+H]+, RT=1.67 min, LC / MS method 1

[0129] Step 3: Synthesis of Compound 15 Compound 13 (16.1 g, 54.5 mmol) was dissolved in 1,4-dioxane (242 mL), and triethylamine (17.4 mL, 125 mmol) and compound 14 (14.4 g, 60 mmol) were added, followed by stirring at 50°C for 3 hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate-hexane was added to the resulting residue, and the solid was collected by filtration to obtain compound 15 (25.3 g, yield 93%). 1 H-NMR (DMSO-d6) δ: 1.58 (m, 2H), 1.98 (m, 2H), 3.52 (m, 2H), 3.86 (s, 3H), 3.90 (m, 2H), 4.27 (m, 2H), 5.12 (s, 2H), 6.98 (m, 1H), 7.13 (d, J = 2.4Hz, 1H), 7.34 (m, 1H), 7.40 (m, 2H), 7.47 (m, 2H), 8.21 (m, 1H), 9.11 (s, 1H). LC / MS(ESI):m / z= 500 [M+H]+, RT=3.10 min, LC / MS method 1

[0130] Step 4: Synthesis of Compound 16 Compound 15 (25.3 g, 50.7 mmol) was dissolved in chloroform (253 mL) and tetrahydrofuran (127 mL), and 5 wt % palladium hydroxide (5 g, 1.78 mmol) was added. The system was purged with hydrogen and stirred at room temperature and atmospheric pressure for 2 hours. The mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting residue, and the solid was collected by filtration to obtain compound 16 (19.6 g, yield 95%). 1 H-NMR (DMSO-d6) δ: 1.58 (m, 2H), 1.88 (m, 2H), 3.52 (m, 2H), 3.86 (s, 3H), 3.89 (m, 2H), 4.24 (m, 2H), 6.71 (dd, J = 8.8, 2.4Hz, 1H), 6.76 (d, J = 2.4Hz, 1H), 8.13 (m, 1H), 9.09 (s, 1H), 9.42 (s, 1H). LC / MS(ESI):m / z= 410 [M+H]+, RT=2.20 min, LC / MS method 1

[0131] Step 5 Synthesis of Compound 18 Compound 16 (16.1 g, 39.3 mmol), compound 17 (10.6 g, 59.0 mmol), and triphenylphosphine (16.5 g, 62.9 mmol) were dissolved in tetrahydrofuran (217 mL) and cooled on ice, and DIAD (11.47 mL, 59.0 mmol) was added dropwise. After the dropwise addition, the temperature was raised to 40°C and the mixture was stirred for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and ethyl acetate-diisopropyl ether was added and the solid was collected by filtration to obtain compound 18 (20.3 g, yield 91%). 1H-NMR (DMSO-d6) δ: 1.52-1.63 (m, 4H), 1.97-2.05 (m, 4H), 3.46-3.58 (m, 4H), 3.87 (s, 3H), 3.90 (m, 2H), 4.20-4.28 (m, 4H), 4.69 (m, 1H), 6.61 (t, J = 4.8Hz, 1H), 6.96 (m, 1H), 7.11 (d, J = 2.0Hz, 1H), 8.22 (m, 1H), 8.36 (d, J = 4.8Hz, 2H), 9.12 (s, 1H). LC / MS(ESI):m / z= 571 [M+H]+, RT=2.95 min, LC / MS Method 1

[0132] Step 6: Synthesis of Compound 19 Compound 18 (20.3 g, 35.6 mmol) was added with tetrahydrofuran (203 mL), ethanol (203 mL), and a 4 mol / L aqueous solution of lithium hydroxide (44.5 mL, 178 mmol). After stirring at 50°C for 4 hours, the mixture was allowed to cool to room temperature and a 10% aqueous solution of citric acid was added. Water was added, and the precipitated solid was collected by filtration to obtain compound 19 (19 g, yield 96%). 1 H-NMR (DMSO-d6) δ: 1.52-1.61 (m, 4H), 1.97-2.05 (m, 4H), 3.46-3.57 (m, 4H), 3.90 (m, 2H), 4.24 (m, 2H), 4.26 (s, 2H), 4.69 (m, 1H), 6.61 (t, J = 4.4Hz, 1H), 6.96 (dd, J = 8.8, 2.8Hz, 1H), 7.10 (d, J = 2.8Hz, 1H), 8.22 (d, J = 8.8Hz, 1H), 8.36 (d, J = 4.4Hz, 2H), 9.11 (s, 1H), 13.54 (s, 1H). LC / MS(ESI): m / z = 557 [M+H]+, RT = 2.44 min, LC / MS Method 1

[0133] Step 7 Synthesis of Compound (I-082) Dimethylformamide (8 mL), compound 20 (431 mg, 1.71 mmol), HATU (706 mg, 1.86 mmol), and triethylamine (0.495 mL, 3.57 mmol) were added to compound 19 (795 mg, 1.43 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. Dichloromethane (5 mL) and trifluoroacetic acid (5 mL, 65 mmol) were added to the resulting solid, and the mixture was stirred at room temperature for 2 hours. After neutralizing with an aqueous sodium bicarbonate solution, the mixture was acidified again with a 10% aqueous citric acid solution and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-082) (820 mg, yield 78%). 1 H-NMR (DMSO-d6) δ: 1.52-1.60 (m, 6H), 1.65-1.69 (m, 4H), 1.80 (m, 2H), 1.94-2.17 (m, 8H), 2.54 (brs, 2H), 3.46-3.58 (m, 4H), 3.90 (m, 2H), 4.22 (s, 2H), 4.26 (m, 2H), 4.67 (m, 1H), 6.61 (t, J = 4.4Hz, 1H), 6.93 (dd, J = 8.8, 2.0Hz, 1H), 7.08 (d, J = 2.0Hz, 1H), 8.17 (d, J = 8.8Hz, 1H), 8.36 (d, J = 4.4Hz, 2H), 8.46 (s, 1H), 8.68 (s, 1H), 12.34 (s, 1H).

[0134] Example 4 Synthesis of Compound (I-148) Step 1: Synthesis of Compound 22 To a solution of compound 21 (100 mg, 0.20 mmol) (see Example 6 for the synthesis method) in dimethylformamide (1 mL), 60 wt % sodium hydride (11 mg, 0.29 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (49 mg, 0.29 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 22 (74 mg, 59% yield). LC / MS (ESI): m / z = 642 [M+H]+, RT = 1.182 min, LC / MS Method 7

[0135] Step 2: Synthesis of Compound 23 To a solution of compound 22 (74 mg, 0.12 mmol) in ethanol (0.7 mL), 4 mol / L aqueous lithium hydroxide solution (0.28 mL, 1.16 mmol) was added and stirred at 50°C for 1 hour and 40 minutes. 10% aqueous citric acid solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound 23 (73 mg) as a crude product. LC / MS (ESI): m / z = 614 [M+H] +, RT = 3.04 min, LC / MS Method 1

[0136] Step 3: Synthesis of Compound 24 Compound 23 (71 mg, 0.12 mmol) was dissolved in dimethylformamide (1.0 mL), and compound 20 (30 mg, 0.12 mmol), HATU (52 mg, 0.14 mmol), and triethylamine (17 mg, 0.17 mmol) were added. After stirring at room temperature for 17 hours, water was added, and the precipitated solid was collected by filtration to obtain compound 24 (93 mg, 96% yield). LC / MS (ESI): m / z = 847 [M + H] +, RT = 2.80 min, LC / MS Method 7

[0137] Step 4: Synthesis of Compound 25 To a solution of compound 24 (84 mg, 0.10 mmol) in tetrahydrofuran (0.3 mL), 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (0.50 mL, 0.50 mmol) and ethylenediamine (89 mg, 1.50 mmol) were added, and the mixture was stirred under reflux for 8 hours. 10% aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 25 (70 mg, 99% yield). LC / MS (ESI): m / z = 717 [M+H] +, RT = 1.42 min, LC / MS Method 1

[0138] Step 5: Synthesis of Compound 26 To compound 25 (460 mg, 0.64 mmol), 1,4-dioxane (6.9 mL), (1R,2R)-cyclohexane-1,2-diamine (22 mg, 0.19 mmol), tripotassium phosphate (272 mg, 1.28 mmol), iodobenzene (236 mg, 1.16 mmol), and copper(I) iodide (12 mg, 0.06 mmol) were added, and the mixture was stirred under reflux for 8 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 26 (500 mg, 98% yield). LC / MS (ESI): m / z = 793 [M+H] +, RT = 3.71 min, LC / MS Method 1

[0139] Step 6: Synthesis of Compound (I-148) The compound was synthesized in the same manner as in Step 8 of Example 10. 1H -NMR (DMSO-d6) δ: 1.66-1.71 (m, 10H), 2.00-2.13 (m, 6H), 2.59 (s, 2H), 3.53-3.57 (m, 2H), 4.16 (ddd, J = 13.0, 6.4, 3.9 Hz, 2H), 4.66-4.72 (m, 1H), 6.60 (t, J = 4.8 Hz, 1H), 7.07-7.10 (m, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.64-7.66 (m, 2H), 7.70-7.72 (m, 2H), 7.80 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.35 (d, J = 4.8 Hz, 2H), 8.53-8.54 (m, 3H), 12.32 (s, 1H).

[0140] Example 5 Synthesis of Compound (I-159) and Compound (I-182) Step 1: Synthesis of Compound 28 Imidazole (1.53 g, 22.50 mmol) and tert-butyldimethylsilyl chloride (2.71 g, 18.00 mmol) were added to a solution of compound 27 (2.01 g, 15.00 mmol) in dimethylformamide (20.1 mL), and the mixture was stirred at room temperature for 40 minutes. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 28 (3.79 g, 100% yield). LC / MS (ESI): m / z = 249 [M+H]+, RT = 2.66 min, LC / MS Method 1

[0141] Step 2: Synthesis of Compound 29 To a solution of compound 28 (3.73 g, 15.00 mmol) in tetrahydrofuran (74.5 mL), potassium tert-butoxide (3.87 g, 34.50 mmol) and iodine (8.76 g, 34.50 mmol) were added under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. 20% aqueous sodium thiosulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 29 (5.42 g) as a crude product. LC / MS (ESI): m / z = 375 [M+H]+, RT = 3.09 min, LC / MS Method 1

[0142] Step 3: Synthesis of Compound 30. To a solution of compound 29 (5.42 g, 14.48 mmol) in dichloromethane (54.2 mL), triethylamine (2.49 g, 24.61 mmol) and p-toluenesulfonyl chloride (2.49 g, 17.37 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 30 (6.48 g, 82% yield). LC / MS (ESI): m / z = 529 [M+H]+, RT = 3.67 min, LC / MS Method 1.

[0143] Step 4: Synthesis of Compound 31 To a solution of compound 30 (6.39 g, 12.09 mmol) in tetrahydrofuran (31.9 mL), 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (13.3 mL, 13.3 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A 0.4 mol / L aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) and solidified with hexane-ethyl acetate to obtain compound 31 (2.87 g, yield 57%). LC / MS (ESI): m / z = 415 [M+H]+, RT = 2.30 min, LC / MS Method 1

[0144] Step 5: Synthesis of Compound 32 The compound was synthesized in the same manner as in Step 3 of Example 6. LC / MS (ESI): m / z = 576 [M+H] +, RT = 3.03 min, LC / MS Method 1

[0145] Step 6: Synthesis of Compound 33 Ethanol (122 mL), water (146 mL), and 8 mol / L aqueous sodium hydroxide solution (6.61 mL, 52.90 mmol) were added to compound 32 (6.09 g, 10.58 mmol), and the mixture was stirred at 80°C for 80 minutes. The organic solvent was removed by distillation under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was suspended in chloroform and filtered to obtain compound 33 (2.93 g, yield 66%). LC / MS (ESI): m / z = 422 [M+H]+, RT = 2.21 min, LC / MS Method 1

[0146] Step 7 Synthesis of Compound 34 and Compound 35 Compound 33 (3.45 g, 8.19 mmol) was dissolved in dimethylformamide (34.5 mL), and cesium carbonate (5.33 g, 16.36 mmol) and tetrahydro-2H-pyran-4-ylmethanesulfonate (681 mg, 16.36 mmol) were added, followed by stirring at 80°C for 6 hours. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a mixture of approximately 4:1 of Compound 34 and Compound 35 (4.20 g, 100% yield). Compound 34 LC / MS(ESI):m / z= 506[M+H]+, RT=2.65 min, LC / MS method 1 Compound 35 LC / MS(ESI):m / z= 506[M+H]+, RT=2.39 min, LC / MS method 1

[0147] Step 8 Synthesis of Compound 37 Compound 36 (2.00 g, 4.35 mmol), synthesized in the same manner as Compound 3, was suspended in toluene (40 mL), and 1,1,1,2,2,2-hexamethyldistannane (2.00 g, 4.35 mmol) and Pd(PPh ３ ) ４(0.75 g, 0.65 mmol) was added, and the mixture was stirred under reflux for 1 hour. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 37 (1.74 g, yield 68%). LC / MS (ESI): m / z = 590 [M+H]+, RT = 3.34 min, LC / MS Method 1

[0148] Step 9 Synthesis of Compound 40 and Compound 41 A mixture of about 4:1 of Compound 38 and Compound 39 (1.01 g, 2.00 mmol) was dissolved in dimethylformamide (20 mL), and the mixture was added with Compound 37 (1.74 g, 2.96 mmol), Pd(PPh ３ ) ４ (0.35 g, 0.30 mmol), lithium chloride (0.17 g, 4.00 mmol), and copper(I) iodide (38 mg, 0.20 mmol) were added, and the mixture was stirred at 95°C for 8.5 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 40 (505 mg, yield 31%) and compound 41 (120 mg, yield 8%). Compound 40 LC / MS (ESI): m / z = 803 [M+H] +, RT = 3.43 min, LC / MS Method 1 Compound 41 LC / MS (ESI): m / z = 803 [M+H] +, RT = 3.50 min, LC / MS Method 1

[0149] Step 10: Synthesis of Compound (I-159) and Compound (I-182) Compound (I-159) was synthesized in the same manner as in Step 8 of Example 10. 1H-NMR (CDCl3) δ: 1.78-1.83 (m, 6H), 1.92-1.95 (m, 4H), 2.03-2.12 (m, 6H), 2.23 (d, J = 12.4 Hz, 2H), 2.56 (ddd, J = 24.8, 12.4, 4.3 Hz, 2H), 2.67 (s, 2H), 3.64 (t, J = 12.4 Hz, 2H), 3.79-3.85 (m, 2H), 4.14-4.21 (m, 4H), 4.70-4.76 (m, 2H), 6.38 (s, 1H), 6.51 (t, J = 4.8 Hz, 1H), 6.97 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 9.0, 1.8 Hz, 1H), 8.34 (d, J = 4.8 Hz, 2H), 8.49 (d, J = 9.0 Hz, 1H), 9.16 (s, 1H), 12.12 (s, 1H). Compound (I-182) 1 H-NMR (CDCl3) δ: 1.79-2.26 (m, 18H), 2.50 (ddd, J = 24.2, 11.5, 4.2 Hz, 2H), 2.68 (s, 2H), 3.60 (t, J = 11.5 Hz, 2H), 3.68-3.74 (m, 2H), 4.15-4.26 (m, 4H), 4.64-4.69 (m, 1H), 5.95 (tt, J = 11.5, 4.0 Hz, 1H), 6.30 (s, 1H), 6.49 (t, J = 4.8 Hz, 1H), 7.01 (dd, J = 9.2, 1.9 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 8.32-8.33 (m, 3H), 9.15 (s, 1H), 12.12 (s, 1H).

[0150] Example 6 Synthesis of Compound (I-162) Step 1: Synthesis of Compound 44 To compound 42 (10 g, 22.3 mmol), tetrahydrofuran (100 mL) and triisopropyl borate (4.19 g, 22.3 mmol) were added, and the mixture was cooled to −78°C with dry ice-acetone. To this solution, a 1.59 mol / L n-butyllithium-hexane solution (19.6 mL, 31.2 mmol) was added dropwise, and the mixture was stirred at −78°C for 20 minutes. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the mixture was warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the resulting residue, 1,4-dioxane (102 mL), compound 43 (6.2 g, 24.5 mmol), PdCl ２ (dppf) (1.82 g, 2.23 mmol) and 2.2 mol / L aqueous potassium carbonate solution (20.4 mL, 44.5 mmol) were added, and the mixture was stirred at 100°C for 2 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The two layers were separated, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 44 (7.1 g, yield 59%). 1 H-NMR (CDCl3) δ: 1.42 (t, J = 7.2Hz, 3H), 1.70 (s, 9H), 4.44 (q, J = 7.2Hz, 2H), 5.17 (s, 2H), 7.10 (dd, J = 8.8, 2.8Hz, 1H), 7.34 (m, 1H), 7.40 (m, 2H), 7.48 (m, 2H), 7.77-7.90 (m, 2H), 8.11-8.16 (m, 2H), 8.47 (d, J = 8.8Hz, 1H). LC / MS(ESI):m / z= 541[M+H]+, RT=3.21 min, LC / MS method 1

[0151] Step 2: Synthesis of Compound 45 To compound 44 (30.7 g, 56.8 mmol) were added tetrahydrofuran (307 mL) and 20 wt % palladium on carbon (6.34 g, 11.7 mmol). The atmosphere in the system was replaced with hydrogen, and the mixture was stirred at room temperature and atmospheric pressure for 2 hours. The mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting residue, and the solid was collected by filtration to obtain compound 45 (22.0 g, yield 86%). 1 H-NMR (CDCl3) δ: 1.42 (t, J = 7.2Hz, 3H), 1.71 (s, 9H), 4.44 (q, J = 7.2Hz, 2H), 4.94 (s, 1H), 6.93 (dd, J = 8.8, 2.4Hz, 1H), 7.71 (brs, 1H), 7.88 (d, J = 8.4Hz, 1H), 8.11 (s, 1H), 8.14 (d, J = 8.4Hz, 1H), 8.46 (d, J = 8.8Hz, 1H). LC / MS(ESI):m / z= 451 [M+H]+, RT=2.84 min, LC / MS method 1

[0152] Step 3: Synthesis of Compound 46 To compound 45 (3.27 g, 7.26 mmol), tetrahydrofuran (39.2 mL), compound 17 (1.69 g, 9.44 mmol), triphenylphosphine (2.48 g, 9.44 mmol), and DMEAD (2.21 g, 9.44 mmol) were added. After stirring at 50°C for 1 hour, water was added to quench the reaction. Extraction was performed with ethyl acetate, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 46 (4.07 g, yield 92%). 1H-NMR (CDCl3) δ: 1.42 (t, J = 7.2Hz, 3H), 1.72 (s, 9H), 1.90 (m, 2H), 2.06 (m, 2H), 3.76 (m, 2H), 4.19 (m, 2H), 4.44 (q, J = 7.2Hz, 2H), 4.67 (m, 1H), 6.48 (t, J = 4.4Hz, 1H), 7.06 (dd, J = 8.8, 2.0Hz, 1H), 7.83 (brs, 1H), 7.89 (d, J = 8.0Hz, 1H), 8.13-8.16 (m, 2H), 8.32 (d, J = 4.8Hz, 2H), 8.49 (d, J = 8.8 Hz, 1H). LC / MS (ESI): m / z = 612 [M+H]+, RT = 3.59 min, LC / MS Method 1

[0153] Step 4: Synthesis of Compound 21 Dichloromethane (41.7 mL) and trifluoroacetic acid (41.7 mL, 541 mmol) were added to compound 46 (4.17 g, 6.82 mmol), and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure and neutralized by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and chloroform was added to the resulting residue, and the solid was collected by filtration to obtain compound 47 (800 mg, yield 22%). The filtrate was again concentrated under reduced pressure, and toluene was added to the resulting residue, and the solid was collected by filtration to obtain compound 47 (1.73 g, yield 48%). The filtrate was further concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 21 (520 mg, yield 15%). 1H-NMR (CDCl3) δ: 1.42 (t, J = 7.2Hz, 3H), 1.88 (m, 2H), 2.06 (m, 2H), 3.71 (m, 2H), 4.21 (m, 2H), 4.43 (q, J = 7.2Hz, 2H), 4.61 (m, 1H), 6.48 (t, J = 4.8Hz, 1H), 6.98 (d, J = 2.0Hz, 1H), 7.02 (dd, J = 8.8, 2.0Hz, 1H), 7.78-7.84 (m, 2H), 8.11 (d, J = 8.4Hz, 1H), 8.32 (d, J = 4.8Hz, 2H), 8.42-8.48 (m, 2H). LC / MS(ESI): m / z = 512 [M+H]+, RT = 2.80 min, LC / MS Method 1

[0154] Step 5 Synthesis of Compound 49 Dimethylformamide (12 mL) was added to compound 21 (800 mg, 1.56 mmol), and the mixture was cooled on ice and then 60 wt% sodium hydride (94 mg, 2.35 mmol) and compound 48 (681 mg, 2.35 mmol) were added. After stirring at 90°C for 30 minutes, the mixture was cooled on ice again, ... After stirring at 90°C for 30 minutes, the mixture was again cooled on ice, and 60 wt% sodium hydride (94 mg, 2.35 mmol) and compound 48 (681 mg, 2.35 mmol) were added, followed by stirring at 90°C for 30 minutes. The reaction solution was poured into a 10% aqueous citric acid solution to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 49 (900 mg, yield 96%). 1H-NMR (CDCl3) δ: 1.71-2.24 (m, 10H), 2.35 (m, 2H), 3.77 (m, 2H), 4.20 (m, 2H), 4.32 (m, 1H), 4.67 (m, 1H), 6.54 (t, J = 4.8Hz, 1H), 6.96 (d, J = 2.0Hz, 1H), 7.05 (dd, J = 8.8, 2.0Hz, 1H), 7.80 (d, J = 8.4Hz, 1H), 7.82 (s, 1H), 8.23 ​​(d, J = 8.0Hz, 1H), 8.39 (t, J = 4.8Hz, 2H), 8.50 (d, J = 8.8Hz, 1H). LC / MS(ESI):m / z= 602 [M+H]+, RT=2.71 min, LC / MSメソッド1

[0155] Process 6: Synthesis of compound (I-162) was carried out in the same way as Project 7 of Example 3. 1 H-NMR (DMSO-d6) δ: 1.55-1.71 (m, 8H), 1.81 (brs, 2H), 1.98-2.25 (m, 14H), 2.58 (s, 2H), 3.62 (m, 2H), 4.19 (m, 2H), 4.68-4.78 (m, 2H), 6.62 (t, J = 4.8Hz, 1H), 6.98 (dd, J = 8.8, 2.0Hz, 1H), 7.31 (d, J = 2.0Hz, 1H), 7.73 (d, J = 8.4Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 8.37 (d, J = 4.4Hz, 2H), 8.41-8.44 (m, 2H), 8.49 (s, 1H), 12.32 (s, 1H). LC / MS(ESI):m / z= 779 [M+H]+, RT=3.06 min, LC / MSメソッド1

[0156] Example 7 Synthesis of Compound (I-165) Step 1: Synthesis of Compound 51 Compound 50 (49.9 g, 297 mmol) and 2-methyl-2-propanesulfinamide (53.9 g, 445 mmol) were added to tetrahydrofuran (250 mL), and tetraethyl orthotitanate (137 mL, 653 mmol) was added at room temperature. After stirring at 80°C for 1 hour, the mixture was poured into acetonitrile (1 L). Water (53.5 g) was added to quench the reaction. After stirring for 10 minutes, anhydrous magnesium sulfate was added, and the solid was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 51 (58.9 g, 70% yield). LC / MS (ESI): m / z = 272 [M+H]+, RT = 1.81 min, LC / MS Method 2

[0157] Step 2: Synthesis of a mixture of compound 52 and compound 53. Compound 51 (70.3 g, 241 mmol) was dissolved in tetrahydrofuran (211 mL), and 1 mol / L vinylmagnesium bromide (361 mL, 361 mmol) was added dropwise under ice cooling. The reaction was stopped by adding aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. After washing with water, the organic layer was concentrated under reduced pressure. Hexane was added to the resulting solid, and the solid was filtered to obtain a mixture of compound 52 and compound 53 (46.1 g, yield 64%). LC / MS (ESI): m / z = 300 [M+H]+, RT = 2.01 min, LC / MS Method 2

[0158] Step 3: Synthesis of a mixture of compound 54 and compound 55. A 2 mol / L hydrogen chloride methanol solution (354 mL, 708 mmol) was added to a mixture of compound 52 and compound 53 (70.7 g, 236 mmol) and stirred at room temperature for 1 hour. Water and ethyl acetate were added for extraction. The aqueous layer was neutralized with aqueous sodium bicarbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude mixture of compound 54 and compound 55 (55.2 g). LC / MS (ESI): m / z = 196 [M+H]+, RT = 1.01 min, LC / MS Method 2

[0159] Step 4: Synthesis of a mixture of compound 56 and compound 57. A mixture of compound 54 and compound 55 (55.2 g, 223 mmol) was dissolved in tetrahydrofuran (497 mL), and 1-[2-(trimethylsilyl)ethoxycarbonyl]pyrrolidine-2,5-dione (100 g, 387 mmol) was added. After stirring at room temperature for 1 hour, 1-[2-(trimethylsilyl)ethoxycarbonyl]pyrrolidine-2,5-dione (12.5 g, 48.2 mmol) was added. After stirring for 1 hour and 40 minutes, an aqueous citric acid solution was added. Extraction was performed with ethyl acetate, and the organic layer was washed with water. After concentration under reduced pressure, hexane was added to the resulting solid, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a mixture of compound 56 and compound 57 (65.0 g, 86% yield). 1 H-NMR (CDCl3) δ: 0.03 (s, 9H), 0.92-0.98 (m, 2H), 1.49-1.56 (m, 2H), 1.73-1.80 (m, 2H), 1.87-2.01 (m, 4H), 2.13-2.28 (m, 3H), 2.56 (brs, 2H), 4.09 (m, 2H), 4.62 (s, 1H), 5.20-5.31 (m, 2H), 6.10 (dd, J = 17.6, 2.8Hz, 1H).

[0160] Step 5: Synthesis of a Mixture of Compound 58 and Compound 59 A mixture of Compound 56 and Compound 57 (67.0 g, 197 mmol) was dissolved in acetonitrile (1179 mL), and water (395 mL), sodium periodate (127 g, 592 mmol), 2,6-lutidine (63.4 g, 592 mmol), and potassium osmate dihydrate (7.27 g, 19.7 mmol) were added. After stirring at 60°C for 1 hour, sodium periodate (42.2 g, 197 mmol) was added. After 2 hours, the mixture was cooled on ice and the reaction was quenched by adding aqueous sodium thiosulfate. Extraction was performed with ethyl acetate, and the organic layer was washed with 10% aqueous citric acid and 3% aqueous sodium bicarbonate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a mixture of Compound 58 and Compound 59 (32.5 g, 48% yield). 1 H-NMR (CDCl3) δ: 0.03 (s, 9H), 0.92-1.00 (m, 2H), 1.56-1.98 (m, 8H), 2.09-2.28 (m, 3H), 2.63-2.69 (m, 2H), 4.12 (m, 2H), 4.81-4.89 (m, 1H), 9.60-9.74 (m, 2H).

[0161] Step 6: Synthesis of a mixture of compound 60 and compound 61. A mixture of compound 58 and compound 59 (36.1 g, 106 mmol) was dissolved in tert-butyl alcohol (361 mL) and water (65 mL), and 2-methyl-2-butene (63.8 mL, 603 mmol) was added. Potassium dihydrogen phosphate (57.5 g, 423 mmol) and sodium chlorite (76 g, 846 mmol) were dissolved in water (300 mL) and added dropwise under ice-cooling. After stirring for 1 hour under ice-cooling, aqueous sodium thiosulfate solution was added to quench the reaction. Extraction was performed with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a mixture of compound 60 and compound 61 (45 g) as a crude product. LC / MS (ESI): m / z = 356 [MH]-, RT = 2.32 min and 2.41 min, LC / MS Method 2

[0162] Step 7: Synthesis of a mixture of compound 62 and compound 63. A mixture of crude compound 60 and compound 61 (45 g) was dissolved in tetrahydrofuran (227 mL) and methanol (227 mL), and diphenyldiazomethane (61.8 g, 318 mmol) was added. After stirring at room temperature for 2 hours, acetic acid (18.2 mL) was added. After stirring at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The fractions were concentrated, and hexane was added to the resulting residue to solidify it. The solid was collected by filtration to give a mixture of compound 62 and compound 63 (21.5 g, 39% yield). 1 H-NMR (CDCl3) δ: 0.03 (s, 9H), 0.73-0.94 (m, 2H), 1.50-1.56 (m, 2H), 1.75-1.96 (m, 6H), 2.10-2.20 (m, 3H), 2.84 (brs, 2H), 3.95 (m, 2H), 4.83 (brs, 1H), 6.90-6.93 (m, 1H), 7.25-7.31 (m, 10H).

[0163] Step 8: Synthesis of Compound 64 To a mixture of Compound 62 and Compound 63 (43.2 g, 82 mmol), 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (866 mL) and acetic acid (42.4 mL) were added, and the mixture was heated to reflux for 15 hours. Aqueous sodium bicarbonate solution was added to neutralize the mixture, followed by extraction with ethyl acetate. The organic layer was washed three times with aqueous ammonium chloride solution, then with aqueous sodium bicarbonate solution and brine. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to separate the less polar Compound 65 and the more polar Compound 64, yielding Compound 64 (19.5 g, 56% yield). 1H-NMR (DMSO-d6) δ: 1.30-1.35 (m, 2H), 1.65-1.77 (m, 6H), 1.99-2.11 (m, 3H), 2.19-2.27 (m, 2H), 2.35 (brs, 2H), 6.82 (s, 1H), 7.27 (m, 2H), 7.35 (m, 4H), 7.45 (m, 4H).

[0164] Step 9: Synthesis of Compound 66. Compound 66 was synthesized under the same conditions as in Step 3 of Example 4. LC / MS (ESI): m / z = 918 [M+H] +, RT = 3.06 min, LCMS Method 1

[0165] Step 10 Synthesis of Compound (I-165) Compound 66 (66 mg, 0.072 mmol) was dissolved in dichloromethane (4 mL), and anisole (40 mg, 0.37 mmol) and trifluoroacetic acid (2 mL) were added under ice-cooling. After stirring for 30 minutes under ice-cooling, the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and neutralized with an aqueous sodium bicarbonate solution. Aqueous citric acid solution was added to the aqueous layer, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-165) (33 mg, yield 61%). 1 H-NMR (DMSO-d6) δ: 1.45-1.48 (m, 2H), 1.53-1.60 (m, 4H), 1.78-1.84 (m, 4H), 1.97-2.05 (m, 6H), 2.16-2.24 (m, 3H), 2.82 (s, 2H), 3.48-3.56 (m, 4H), 3.88-3.92 (m, 2H), 4.22-4.26 (m, 4H), 4.64-4.70 (m, 1H). 6.61 (t, J = 4.8Hz, 1H), 6.94 (d, J = 8.0Hz, 1H), 7.09 (d, J = 2.4Hz, 1H), 8.17 (d, J = 4.4Hz, 1H), 8.36 (d, J = 4.8Hz, 2H), 8.63 (brs, 1H), 8.71 (s, 1H), 12.67 (brs, 1H).

[0166] Example 8 Synthesis of Compound (I-228) Step 1: Synthesis of Compound 68 To a solution of compound 67 (300 mg, 1.52 mmol) in N-methylpyrrolidone (4.42 mL) was added 60 wt% sodium hydride (61 mg, 1.53 mmol) at room temperature while stirring under an argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Next, compound 48 (442 mg, 1.52 mmol) was added at room temperature. After stirring at 100°C for 3 hours, compound 48 (442 mg, 1.52 mmol) and 60 wt% sodium hydride (61 mg, 1.53 mmol) were added, and the mixture was stirred at 80°C for 5 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 68 (252 mg, yield 53%). LC / MS (DUIS): m / z = 315 [M+H]+, RT = 1.59 min, LC / MS Method 9

[0167] Step 2 Synthesis of Compound 69 Compound 68 (50 mg, 0.16 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.5 mL), and the solution was stirred under an argon atmosphere with 8 mol / L aqueous potassium hydroxide solution (0.06 mL, 0.48 mmol), Pd ２ (dba) ３ (15 mg, 0.02 mmol), 5-(Di-t-butylphosphono)-1',3',5'-triphenyl-1,4'-bi-1H-pyrazole (16 mg, 0.03 mmol) were added at room temperature, and the mixture was stirred at 75°C. After 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the crude product, Compound 69 (51 mg). LC / MS (DUIS): m / z = 253 [M+H]+, RT = 1.04 min, LC / MS Method 9

[0168] Step 3: Synthesis of Compound 70. To a solution of crude compound 69 (49 mg, 0.19 mmol) in tetrahydrofuran (0.98 mL), compound 17 (70 mg, 0.39 mmol), 1.9 mol / L DIAD-toluene solution (145 μL, 0.28 mmol), and triphenylphosphine (74 mg, 0.28 mmol) were added at room temperature under stirring under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 70 (47 mg, 58%). LC / MS (DUIS): m / z = 414 [M+H]+, RT = 1.77 min, LC / MS Method 9

[0169] Step 4: Synthesis of Compound 71 The compound was synthesized in the same manner as in Step 5 of Example 9. LC / MS (DUIS): m / z = 540 [M+H] +, RT = 1.98 min, LC / MS Method 9

[0170] Step 5: Synthesis of Compound 72 The compound was synthesized in the same manner as in Step 6 of Example 9. LC / MS (DUIS): m / z = 540 [M+H] +, RT = 2.00 min, LC / MS Method 9

[0171] Step 6: Synthesis of Compound 73 The compound was synthesized in the same manner as in Step 1 of Example 6. LC / MS (DUIS): m / z = 837 [M+H] +, RT = 2.29 min, LC / MS Method 9

[0172] Step 7: Synthesis of Compound (I-228) The compound was synthesized in the same manner as in Step 8 of Example 10. 1H-NMR (DMSO-d6) δ: 1.55-1.84 (m, 10H), 2.02-2.28 (m, 14H), 2.55-2.58 (m, 2H), 3.45-3.55 (m, 2H), 4.30-4.42 (m, 2H), 4.70-4.83(m, 1H), 5.23-5.33 (m, 1H), 6.63 (t, J = 4.8Hz, 1H), 6.79 (d, J = 8.5Hz, 1H), 8.31 (s, 1H), 8.37 (d, J = 4.6Hz, 2H), 8.61 (d, J = 8.5Hz, 1H), 8.65 (brs, 1H), 8.87 (s, 1H), 12.51 (brs, 1H). LC / MS(ESI): m / z = 781 [M+H]+, RT = 1.86 min, LC / MS Method 10

[0173] Example 9 Synthesis of Compound (I-268) Step 1 Synthesis of Compound 75 To a solution of Compound 17 (760 mg, 4.24 mmol) in toluene (10 mL), 60 wt % sodium hydride (283 mg, 7.08 mmol) was added at room temperature under stirring under an argon atmosphere, and the mixture was stirred at 70° C. for 15 minutes. ２ (dba) ３ (324 mg, 0.354 mmol) and (R)-(+)-TolBINAP (240 mg, 0.354 mmol) were added at room temperature, and the mixture was stirred at 100°C. After 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 75 (899 mg, yield 63%). LC / MS (DUIS): m / z = 398 [M+H]+, RT = 1.17 min, LC / MS Method 9

[0174] Step 2: Synthesis of Compound 76 To a solution of compound 75 (899 mg, 2.26 mmol) in dichloromethane (2 mL), trifluoroacetic acid (2 mL, 26.1 mmol) was added at room temperature under argon atmosphere, and the mixture was stirred for 6 hours. After the reaction was completed, aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound 76 (695 mg, 100% yield). LC / MS (DUIS): m / z = 298 [M+H]+, RT = 0.35 min, LC / MS Method 9

[0175] Step 3: Synthesis of Compound 77 To a solution of compound 76 (530 mg, 1.78 mmol) in toluene (15.9 mL), manganese dioxide (775 mg, 8.91 mmol) was added at room temperature while stirring under an argon atmosphere, and the mixture was stirred at 120°C for 6 hours. After stirring at room temperature for 18 hours, manganese dioxide (775 mg, 8.91 mmol) was added at room temperature while stirring under an argon atmosphere, and the mixture was stirred at 120°C for 2 hours. After completion of the reaction, the reaction solution was filtered through Celite (registered trademark), washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give compound 77 (342 mg, yield 65%). LC / MS (DUIS): m / z = 296 [M+H]+, RT = 0.36 min, LC / MS Method 9

[0176] Step 4 Synthesis of Compound 78 To a solution of compound 77 (370 mg, 1.25 mmol) in N-methylpyrrolidone (7.4 mL) was added cesium carbonate (1.22 g, 3.74 mmol) and compound 48 (1.09 g, 3.75 mmol) at room temperature under argon atmosphere with stirring, and the mixture was stirred at 120°C for 3 hours. Next, cesium carbonate (1.22 g, 3.74 mmol) and compound 48 (1.09 g, 3.75 mmol) were added at room temperature, and the mixture was stirred at 120°C for 2 hours. Further, cesium carbonate (1.22 g, 3.74 mmol) and compound 48 (1.09 g, 3.75 mmol) were added at room temperature, and the mixture was stirred at 120°C for 2 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 78 (520 mg, yield 100%). LC / MS (DUIS): m / z = 414 [M+H] +, RT = 0.91 min, LC / MS Method 9

[0177] Step 5: Synthesis of Compound 79 To a solution of compound 78 (470 mg, 1.14 mmol) in dimethylformamide (4.7 mL) was added N-iodosuccinimide (280 mg, 1.25 mmol) at room temperature while stirring under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 79 (180 mg, yield 29%). LC / MS (ESI): m / z = 540 [M+H]+, RT = 1.43 min, LC / MS Method 10

[0178] Step 6 Synthesis of Compound 80 To a solution of Compound 79 (180 mg, 0.33 mmol) in 1,4-dioxane (3.6 mL) was added triethylamine (185 μL, 1.33 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (195 μL, 1.34 mmol), X-Phos (32 mg, 0.07 mmol), Pd ２(dba) ３ (31 mg, 0.03 mmol) was added at room temperature, and the mixture was stirred at 95°C for 1 hour. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 80 (111 mg, yield 62%). LC / MS (ESI): m / z = 540 [M+H]+, RT = 1.29 min, LC / MS Method 10

[0179] Step 7: Synthesis of Compound 81 The compound was synthesized in the same manner as in Step 1 of Example 6. LC / MS (ESI): m / z = 837 [M+H] +, RT = 1.99 min, LC / MS Method 10

[0180] Step 8: Synthesis of Compound (I-268) The compound was synthesized in the same manner as in Step 8 of Example 10. 1 H-NMR (DMSO-d6) δ: 1.49-1.84 (m, 10H), 2.01-2.22 (m, 14H), 2.56-2.60 (m, 2H), 3.54-3.63 (m, 2H), 4.21-4.31 (m, 2H), 4.60-4.73 (m, 1H), 5.33-5.43 (m, 1H), 6.62 (t, J = 4.8Hz, 1H), 7.15 (s, 1H), 8.37 (d, J = 4.8 Hz, 2H), 8.41 (brs, 1H), 8.51 (brs, 1H), 8.89 (s, 1H), 9.23 (s, 1H), 12.51 (brs, 1H). LC / MS (DUIS): m / z = 781 [M+H]+, RT = 1.56 min, LC / MS Method 9

[0181] Example 10 Synthesis of Compound (I-269) Step 1: Synthesis of Compound 83 2-(Trimethylsilyl)ethan-1-ol (1.08 g, 9.10 mmol) was dissolved in tetrahydrofuran (10 mL), and 60 wt % sodium hydride (218 mg, 5.46 mmol) was added under ice-cooling. After 5 minutes, compound 82 (1.00 g, 4.55 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 83 (1.45 g, 100% yield). 1 H-NMR (CDCl3) δ: 1.10 (s, 9H), 1.16 (t, J = 8.0Hz, 2H), 4.14 (t, J = 8.0Hz, 2H), 6.88 (dd, J = 9.2, 2.8Hz, 1H), 7.18 (d, J = 2.8Hz, 1H), 7.98 (d, J = 9.2Hz, 1H).

[0182] Step 2: Synthesis of Compound 84 Compound 83 (500 mg, 1.57 mmol) was dissolved in ethanol (5 mL), and water (1 mL), ammonium chloride (336 mg, 6.28 mmol), and iron (438 mg, 7.85 mmol) were added, followed by stirring at 90°C for 3 hours. The reaction mixture was allowed to cool, then diluted with ethyl acetate (30 mL), and insoluble matter was removed by filtration using Celite (registered trademark). Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 84 (303 mg, yield 67%). LC / MS (ESI): m / z = 288 [M+H]+, RT = 2.83 min, LC / MS Method 1

[0183] Step 3: Synthesis of Compound 85 Compound 84 (1.93 g, 6.70 mmol) was dissolved in dimethylformamide (10 mL), and cyclopent-1-ene-1-carboxylic acid (1.08 g, 1.44 mmol), triethylamine (3.39 g, 33.5 mmol), and HATU (3.80 g, 10.1 mmol) were added, followed by stirring at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and then with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 85 (816 mg, yield 32%). LC / MS (ESI): m / z = 382 [M+H]+, RT = 3.08 min, LC / MS Method 1

[0184] Step 4 Synthesis of Compound 86 Compound 85 (816 mg, 2.13 mmol) was dissolved in dimethylformamide (6 mL), and triethylamine (1.08 g, 10.6 mmol), PdCl ２ (dppf) (156 mg, 0.213 mmol) was added, and the mixture was stirred at 80°C for 2 hours. After allowing the reaction mixture to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 86 (467 mg, yield 73%). LC / MS (ESI): m / z = 302 [M+H]+, RT = 2.50 min, LC / MS Method 1

[0185] Step 5 Synthesis of Compound 87 Compound 86 (218 mg, 0.723 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 36 (399 mg, 0.868 mmol), cesium carbonate (707 mg, 2.17 mmol), and Xantphos Pd G2 (129 mg, 0.145 mmol) were added. The mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. After cooling, the mixture was diluted with ethyl acetate (10 mL) and insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 87 (404 mg, 77% yield). LC / MS (ESI): m / z = 725 [M+H]+, RT = 3.54 min, LC / MS Method 1

[0186] Step 6: Synthesis of Compound 88 Compound 87 (404 mg, 0.557 mmol) was mixed with a 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (10 mL, 10 mmol) and stirred at 80°C for 1 hour. After cooling, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in dimethylformamide (8 mL), and triethylamine (169 mg, 1.67 mmol) and HATU (318 mg, 0.835 mmol) were added, followed by stirring at room temperature for 30 minutes. Methanol (20 mL) and potassium carbonate (231 mg, 1.67 mmol) were added, followed by stirring at room temperature for 30 minutes. Water was then added to the reaction mixture. Extraction was performed with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 88 (203 mg, yield 58%). LC / MS(ESI): m / z = 625 [M+H]+, RT = 2.77 min, LC / MS Method 1

[0187] Step 7: Synthesis of Compound 89. Compound 89 was synthesized under the same conditions as in Step 5 of Example 3. LC / MS (ESI): m / z = 786 [M+H] +, RT = 3.11 min, LC / MS Method 1

[0188] Step 8 Synthesis of Compound (I-269) Compound 89 (50 mg, 0.064 mmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, then dissolved in dichloromethane and neutralized with saturated aqueous sodium bicarbonate. Aqueous citric acid solution was added to the reaction solution to make it acidic again, and the solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-269) (30 mg, yield 65%). 1 H-NMR (CDCl3) δ: 1.77-2.05 (m, 15H), 2.19-2.27 (m, 3H), 2.61-2.67 (m, 3H), 2.70-2.76 (m, 1H), 2.78-2.87 (m, 1H), 3.69-3.75 (m, 2H), 4.11-4.19 (m, 2H), 4.51-4.57 (m, 1H), 5.53-5.56 (m, 1H), 6.24-6.27 (m, 1H), 6.49 (t, J = 5.2Hz, 1H), 6.55 (brs, 1H), 6.81 (d, J = 2.8Hz, 1H), 6.90 (dd, J = 8.8, 2.4Hz, 1H), 7.88 (d, J = 9.2Hz, 1H), 8.32 (d, J = 4.8Hz, 2H), 9.12 (s, 1H).

[0189] Example 11 Synthesis of Compound (I-270) Step 1: Synthesis of Compound 91 Compound 90 (1.64 g, 5.60 mmol) was dissolved in dichloromethane (16.4 mL), and pyridine (1.33 g, 16.80 mmol) and paratoluenesulfonyl chloride (2.14 g, 11.20 mmol) were added under ice-cooling. After stirring at room temperature for 1.5 hours, triethylamine (1.70 g, 16.80 mmol) and 1-methylpiperazine (1.12 g, 11.20 mmol) were added, and the mixture was stirred for 30 minutes. Concentrated hydrochloric acid was added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 91 (2.08 g, 86% yield). LC / MS (ESI): m / z = 432 [M+H]+, RT = 2.76 min, LC / MS Method 1

[0190] Step 2 Synthesis of Compound 92 Compound 91 (0.45 g, 1.04 mmol) was dissolved in dimethylformamide (2.89 mL) and the solution was added with 4-ethynyltetrahydro-2H-pyran (0.17 g, 1.56 mmol), copper(I) iodide (39 mg, 0.21 mmol), triethylamine (2.11 g, 20.82 mmol) and PdCl ２ (dppf) (76 mg, 0.10 mmol) was added and the mixture was stirred at 100°C for 8 hours. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 92 (0.35 g, yield 73%). LC / MS (ESI): m / z = 462 [M+H]+, RT = 2.99 min, LC / MS Method 1

[0191] Step 3: Synthesis of Compound 93 To a solution of compound 92 (200 mg, 0.43 mmol) in tetrahydrofuran (0.4 mL), 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (8.67 mL, 8.67 mmol) was added, and the mixture was stirred under reflux for 17 hours. 1 mol / L hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 93 (130 mg, 98% yield). LC / MS (ESI): m / z = 308 [M+H]+, RT = 2.35 min, LC / MS Method 1

[0192] Step 4 Synthesis of Compound 94 Compound 93 (130 mg, 0.42 mmol) in tetrahydrofuran (1.3 mL) was dissolved in Boc ２ O (220 mg, 1.01 mmol) and DMAP (5.2 mg, 0.04 mmol) were added, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 94 (160 mg, yield 93%). LC / MS (ESI): m / z = 408 [M+H] +, RT = 3.18 min, LC / MS Method 1

[0193] Step 5 Synthesis of Compound 95 Iodine (62 mg, 0.25 mmol) was dissolved in dichloromethane (0.5 mL), and pyridine (39 mg, 0.49 mmol) and iodobenzene bis(trifluoroacetate (106 mg, 0.25 mmol) were added under ice-cooling, followed by stirring at room temperature for 15 minutes. To this solution was added a solution of compound 94 (100 mg, 0.25 mmol) in dichloromethane (2 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. A 10% aqueous solution of sodium thiosulfate was added, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 95 (115 mg, yield 88%). 1H -NMR (CDCl3) δ: 1.63-1.65 (m, 2H), 1.67 (s, 9H), 2.70 (ddd, J = 25.3, 11.8, 4.1 Hz, 2H), 3.53 (td, J = 11.8, 1.7 Hz, 2H), 3.76-3.82 (m, 1H), 4.11 (dd, J = 11.8, 4.1 Hz, 2H), 5.13 (s, 2H), 6.99 (dd, J = 8.6, 2.2 Hz, 1H), 7.29-7.33 (m, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.45 (d, J = 7.3 Hz, 2H), 7.60 (d, J = 2.2 Hz, 1H).

[0194] Step 6 Synthesis of Compound 96 Compound 95 (113 mg, 0.21 mmol) was dissolved in 1,4-dioxane (2.3 mL), and the solution was added with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (163 mg, 1.27 mmol), X-Phos (30 mg, 0.06 mmol), Pd ２ (dba) ３ (39 mg, 0.04 mmol) and triethylamine (129 mg, 1.27 mmol) were added, and the mixture was stirred at 95°C for 2.5 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 96 (110 mg, yield 97%). 1H-NMR (CDCl3) δ: 1.40 (s, 12H), 1.67 (s, 9H), 1.73 (d, J = 12.0 Hz, 2H), 2.42 (ddd, J = 24.8, 12.0, 4.1 Hz, 2H), 3.50 (t, J = 10.9 Hz, 2H), 3.72-3.77 (m, 1H), 4.07 (dd, J = 10.9, 4.1 Hz, 2H), 5.11 (s, 2H), 6.92 (dd, J = 8.5, 2.3 Hz, 1H), 7.29-7.39 (m, 3H), 7.45 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H).

[0195] Step 7 Synthesis of Compound 97 Compound 96 (108 mg, 0.20 mmol) was dissolved in 1,4-dioxane (1.4 mL), and the solution was mixed with Compound 43 (57 mg, 0.22 mmol) and PdCl ２ (dppf) (17 mg, 0.02 mmol), water (0.3 mL), and cesium carbonate (132 mg, 0.41 mmol) were added, and the mixture was stirred under reflux for 1 hour. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 97 (92 mg, yield 73%). LC / MS (ESI): m / z = 625 [M+H] +, RT = 3.45 min, LC / MS Method 1

[0196] Step 8 Synthesis of Compound 98 Compound 97 (90 mg, 0.14 mmol) was added with tetrahydrofuran (0.63 mL), ethanol (0.63 mL), and 20 wt% palladium on carbon (18 mg, 0.17 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 2.5 hours. After filtration through Celite®, the filtrate was concentrated under reduced pressure to give compound 98 (100 mg) as a crude product. LC / MS (ESI): m / z = 535 [M+H] +, RT = 2.72 min, LC / MS Method 1

[0197] Step 9: Synthesis of Compound 99. The compound was synthesized in the same manner as in Step 3 of Example 6. LC / MS (ESI): m / z = 696 [M+H] +, RT = 3.08 min, LC / MS Method 1

[0198] Step 10: Synthesis of Compound 100 The compound was synthesized in the same manner as in Step 4 of Example 6. LC / MS (ESI): m / z = 596 [M+H] +, RT = 2.61 min, LC / MS Method 1

[0199] Step 11 Synthesis of Compound 101 To a solution of Compound 100 (34 mg, 0.06 mmol) in dimethylformamide (0.5 mL), 60 wt % sodium hydride (3.4 mg, 0.09 mmol) and methyl iodide (16 mg, 0.11 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 101 (26 mg, 75% yield). LC / MS (ESI): m / z = 610 [M+H] +, RT = 3.04 min, LC / MS Method 1

[0200] Step 12: Synthesis of Compound 102: The compound was synthesized in the same manner as in Step 2 of Example 4. LC / MS (ESI): m / z = 582 [M+H] +, RT = 2.25 min, LC / MS Method 1

[0201] Step 13: Synthesis of Compound (I-270) Synthesis was carried out in the same manner as in Step 6 of Example 6. 1H-NMR (CDCl3)δ: 1.78-2.32 (m, 20H), 2.70 (s, 2H), 3.48 (t, J = 11.0 Hz, 2H), 3.73 (ddd, J = 13.2, 8.3, 4.1 Hz, 2H), 3.91-3.94 (m, 4H), 4.08-4.15 (m, 2H), 4.19 (dq, J = 13.2, 4.1 Hz, 2H), 4.59-4.65 (m, 1H), 6.14 (s, 1H), 6.49 (t, J = 4.7 Hz, 1H), 6.90-6.91 (m, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 4.7 Hz, 2H), 12.12 (s, 1H).

[0202] Example 12 Synthesis of Compound (I-486) Step 1: Synthesis of Compound 104 A solution of triethylsilane (1.7 mL, 10.75 mmol) and trichloroacetic acid (1.1 g, 6.72 mmol) in toluene (5 mL) was stirred at 70°C, and a solution of compound 103 (1 g, 4.48 mmol) and cyclopentanone (414 mg, 4.93 mmol) in toluene (10 mL) was added dropwise to the solution. After the dropwise addition, the mixture was stirred at 70°C for 40 minutes. The mixture was cooled to room temperature and a 10% aqueous sodium carbonate solution was added. Extraction was performed with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 104 (600 mg, yield 46%). LC / MS (ESI): m / z = 292 [M+H]+, RT = 2.98 min, LC / MS Method 1

[0203] Step 2: Synthesis of Compound 105 Compound 104 (570 mg, 1.96 mmol) was dissolved in acetic acid (2 mL), and sodium cyanoborohydride (246 mg, 3.91 mmol) was added under ice-cooling. After stirring at room temperature for 50 minutes, aqueous potassium carbonate solution was added for neutralization. Extraction was performed with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 105 (340 mg, yield 59%). LC / MS (ESI): m / z = 294 [M+H]+, RT = 1.74 min, LC / MS Method 1

[0204] Step 3: Synthesis of Compound 106 Compound 36 (266 mg, 0.58 mmol), diisopropylamine (0.2 mL, 1.16 mmol), and compound 105 (170 mg, 0.58 mmol) were dissolved in 1,4-dioxane (2.55 mL) and stirred at 90°C for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by amino column chromatography (hexane-ethyl acetate) to give compound 106 (330 mg, 80% yield). LC / MS (ESI): m / z = 717 [M+H]+, RT = 2.96 min, LC / MS Method 7

[0205] Step 4: Synthesis of Compound 107 Compound 107 was synthesized under the same conditions as in Step 4 of Example 3. LC / MS (ESI): m / z = 627 [M+H] +, RT = 3.42 min, LC / MS Method 1

[0206] Step 5: Synthesis of Compound 108. Compound 108 was synthesized under the same conditions as in Step 5 of Example 3. LC / MS (ESI): m / z = 806 [M+H] +, RT = 3.12 min, LC / MS Method 7

[0207] Step 6: Synthesis of Compound (I-486) The compound was synthesized in the same manner as in Step 8 of Example 10. 1H-NMR (CDCl3) δ: 1.23-1.72 (m, 5H), 1.81 (dd, J = 14.9, 7.5 Hz, 9H), 1.95-1.99 (m, 8H), 2.15-2.21 (m, 3H), 2.68 (s, 2H), 3.38-3.41 (m, 1H), 3.66-3.68 (m, 2H), 4.09-4.14 (m, 3H), 4.28 (t, J = 10.5 Hz, 1H), 4.50-4.53 (m, 1H), 6.02 (s, 1H), 6.86-6.92 (m, 2H), 8.20 (s, 2H), 8.28 (d, J = 8.3 Hz, 1H), 8.78 (s, 1H), 12.34 (s, 1H). LC / MS(ESI): m / z = 750 [M+H]+, RT = 3.56 min, LC / MS Method 1

[0208] Example 13 Synthesis of Compound (I-591) Step 1: Synthesis of Compound 110 Compound 10 (42 g, 166 mmol) and compound 109 (16.6 g, 166 mmol) were suspended in dichloromethane (250 mL) and cooled on ice. Trifluoroacetic acid (25.6 mL, 332 mmol) was added, and the mixture was heated to 45°C and stirred for 5 hours. After cooling on ice, aqueous sodium carbonate solution was added for neutralization, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 110 (8.9 g, yield 19%). LC / MS (ESI): m / z = 280 [M+H]+, RT = 2.59 min, LC / MS Method 1

[0209] Step 2: Synthesis of Compound 111. Compound 111 was synthesized under the same conditions as in Step 2 of Example 3. LC / MS (ESI): m / z = 282 [M+H] +, RT = 1.57 min, LC / MS Method 1

[0210] Step 3: Synthesis of Compound 113 Compound 113 was synthesized under the same conditions as in Step 3 of Example 3. LC / MS (ESI): m / z = 496 [M+H] +, RT = 3.60 min, LC / MS Method 1

[0211] Step 4: Synthesis of Compound 114 Compound 114 was synthesized under the same conditions as in Step 6 of Example 3. LC / MS (ESI): m / z = 468 [M+H] +, RT = 3.14 min, LC / MS Method 1

[0212] Step 5 Synthesis of Compound 115 Compound 114 (570 mg, 1.22 mmol) and compound 20 (429 mg, 1.71 mmol) were dissolved in dimethylformamide (8.6 mL), and HATU (788 mg, 2.07 mmol) and triethylamine (0.39 mL, 2.8 mmol) were added. After stirring at room temperature for 15 hours, water was added. The precipitated solid was collected by filtration and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 115 (740 mg, 87% yield). LC / MS (ESI): m / z = 701 [M+H]+, RT = 3.88 min, LC / MS Method 1

[0213] Step 6: Synthesis of Compound 116. Compound 116 was synthesized under the same conditions as in Step 4 of Example 3. LC / MS (ESI): m / z = 611 [M+H] +, RT = 1.42 min, LC / MS Method 7

[0214] Step 7 Synthesis of Compound 118 Compound 116 (70 mg, 0.115 mmol) was dissolved in dimethylformamide (1.05 mL). Cesium carbonate (45 mg, 0.14 mmol) and compound 117 (31 mg, 0.11 mmol) were added, and the mixture was stirred at 90°C for 1 hour. The same amounts of cesium carbonate and compound 117 were added four times every 30 minutes. After confirming the disappearance of the raw materials, water was added to quench the reaction. Extraction was performed with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by amino column chromatography (hexane-ethyl acetate) to give compound 118 (63 mg, 70% yield). LC / MS (ESI): m / z = 784 [M+H]+, RT = 3.17 min, LC / MS Method 1

[0215] Step 8: Synthesis of Compound (I-591) The compound was synthesized under the same conditions as in Step 8 of Example 10. 1H -NMR (DMSO-d6) δ: 0.70 (t, J = 7.3 Hz, 6H), 1.12-1.24 (m, 2H), 1.29-1.39 (m, 2H), 1.53-1.78 (m, 14H), 1.98-2.24 (m, 10H), 2.50-2.55 (m, 2H), 3.54 (t, J = 12.4 Hz, 4H), 3.95 (s, 2H), 4.26-4.29 (m, 1H), 6.81-6.83 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H), 8.29 (s, 1H), 8.47 (s, 1H), 12.27 (br s, 1H).

[0216] Example 14 Synthesis of Compound (I-594) Step 1: Synthesis of Compound 120 Compound 119 (3 ​​g, 18.9 mmol) was dissolved in dichloromethane (30 mL), and oxalyl chloride (1.8 mL, 20.8 mmol) and dimethylformamide (0.15 mL, 1.9 mmol) were added under ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mL) and added dropwise to a solution of compound 20 (4.76 g, 18.9 mmol) and triethylamine (5.3 mL, 37.8 mmol) in dichloromethane (30 mL) under ice-cooling. After 1 hour, water was added to terminate the reaction, followed by extraction with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was suspended in ethyl acetate and diisopropyl ether. The solid was collected by filtration to obtain compound 120 (7.0 g, yield 94%). 1 H-NMR (CDCl3) δ: 1.46 (s, 9H), 1.73-1.82 (m, 6H), 1.86-1.99 (m, 4H), 2.17 (m, 2H), 2.59 (s, 2H), 6.14 (s, 1H), 8.95 (s, 2H).

[0217] Step 2: Synthesis of Compound 121 Compound 120 (3.8 g, 9.7 mmol) was suspended in acetonitrile (30 mL) and water (15 mL), and 2,2-difluoropropionic acid (2.1 g, 19.4 mmol), silver nitrate (4.9 g, 29.1 mmol), and ammonium persulfate (8.8 g, 38.8 mmol) were added. The mixture was heated to 80°C and stirred for 1 hour. After ice cooling, an aqueous sodium thiosulfate solution was added to terminate the reaction. The mixture was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 121 (670 mg, yield 15%). 1 H-NMR (DMSO-d6) δ: 1.42 (s, 9H), 1.56 (m, 2H), 1.65-1.79 (m, 4H), 1.99 (t, J = 19.2Hz, 3H), 2.05 (m, 4H), 2.53 (s, 2H), 8.54 (s, 1H), 8.74 (s, 1H). Step 1: Synthesis of Compound 123 Compound 122 (51.5 g, 337 mmol) was dissolved in dimethylformamide (386 mL), and cesium carbonate (165 g, 506 mmol) and 4-methoxybenzyl chloride (53.4 g, 341 mmol) were added. After stirring at room temperature for 45 minutes, water was added. Extraction was performed with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane and ethyl acetate were added to the resulting residue to solidify it, and the solid was collected by filtration to obtain compound 123 (90.9 g, yield 99%). LC / MS (ESI): m / z = 273 [M+H]+, RT = 2.21 min, LC / MS Method 1

[0218] Step 2 Synthesis of Compound 124 Compound 123 (81.2 g, 298 mmol) was dissolved in 1,4-dioxane (812 mL), and pyridinium tribromide (349 g, 1.09 mol) was added. After stirring at room temperature for 45 minutes, water was added. Extraction was performed with ethyl acetate, and the organic layer was washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain the crude product, Compound 124 (154.6 g). LC / MS (ESI): m / z = 445 [M+H]+, RT = 2.58 min, LC / MS Method 1

[0219] Step 3: Synthesis of Compound 125 The crude product, Compound 124 (154.6 g), was dissolved in tetrahydrofuran (1065 mL), methanol (266 mL), and acetic acid (42.6 mL), and zinc (97 g, 1490 mmol) was added under ice-cooling. After stirring for 1 hour, the reaction mixture was filtered through Celite (registered trademark) to remove insoluble materials. The filtrate was concentrated under reduced pressure, and water was added to the resulting solid. The suspension was stirred at room temperature, and the solid was collected by filtration to obtain Compound 125 (87 g, 100% yield). LC / MS (ESI): m / z = 289 [M+H]+, RT = 2.58 min, LC / MS Method 1

[0220] Step 4 Synthesis of Compound 126 Compound 125 (220 mg, 0.76 mmol) was dissolved in dimethylformamide (3.3 mL), and cesium carbonate (745 mg, 2.29 mmol) and 2-iodoethyl ether (497 mg, 1.52 mmol) were added under ice-cooling. After stirring at room temperature for 3 hours, water was added. Extraction was performed with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 126 (245 mg, yield 90%). LC / MS (ESI): m / z = 359 [M+H]+, RT = 2.05 min, LC / MS Method 1

[0221] Step 5: Synthesis of Compound 127 Trifluoroacetic acid (0.52 mL) and trifluoromethanesulfonic acid (0.33 mL) were added to compound 126 (130 mg, 0.36 mmol), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was poured into aqueous sodium carbonate solution to neutralize it, and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the resulting residue to solidify it, and the solid was collected by filtration to obtain compound 127 (56 mg, yield 65%). LC / MS (ESI): m / z = 239 [M+H]+, RT = 1.22 min, LC / MS Method 1

[0222] Step 6 Synthesis of Compound 129 Compound 127 (640 mg, 2.68 mmol) was added with 0.91 mol / L borane tetrahydrofuran complex-tetrahydrofuran solution (20 mL, 18.2 mmol) and stirred at 70°C for 30 minutes. After ice cooling, methanol (10 mL) was added and stirred at 80°C for 30 minutes. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (10 mL). Triethylamine (1.36 g, 13.4 mmol), Boc ２ O (2.92 g, 13.4 mmol) and dimethylaminopyridine (327 mg, 2.68 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 129 (550 mg, yield 63%). LC / MS (ESI): m / z = 325 [M+H] +, RT = 2.27 min, LC / MS Method 1

[0223] Step 8 Synthesis of Compound 130 Compound 129 (200 mg, 0.616 mmol) was dissolved in 1,4-dioxane (3 mL), and Me4tBuXphos (30 mg, 0.062 mmol), Pd ２ (dba) ３(28 mg, 0.031 mmol) and 6 mol / L aqueous potassium hydroxide solution (0.36 mL, 2.16 mmol) were added, and the mixture was stirred at 100°C for 1 hour. After cooling, the mixture was neutralized with 2 mol / L aqueous hydrochloric acid solution. The mixture was extracted with dichloromethane, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate-diisopropyl ether was added to the resulting residue. The precipitated solid was collected by filtration to obtain compound 130 (171 mg, yield 91%). LC / MS (ESI): m / z = 307 [M+H]+, RT = 1.42 min, LC / MS Method 1

[0224] Step 9 Synthesis of Compound 133 Compound 130 (171 mg, 0.558 mmol) was dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (293 mg, 1.12 mmol), compound 131 (213 mg, 1.12 mmol), and DIAD (226 mg, 1.12 mmol) were added, followed by stirring at room temperature. After 30 minutes, triphenylphosphine (293 mg, 1.12 mmol), compound 131 (213 mg, 1.12 mmol), and DIAD (226 mg, 1.12 mmol) were added. After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure. Trifluoroacetic acid (4 mL) was added to the resulting residue, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. Aqueous sodium bicarbonate solution was added to neutralize, and the two layers were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 133 (212 mg, yield 100%). LC / MS (ESI): m / z = 380 [M+H] +, RT = 0.80 min, LC / MS Method 1

[0225] Step 10: Synthesis of Compound 134 Compound 133 (70 mg, 0.184 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 121 (101 mg, 0.221 mmol), potassium carbonate (76 mg, 0.552 mmol), and Xantphos Pd G3 (26 mg, 0.028 mmol) were added. The mixture was stirred at 80°C under a nitrogen atmosphere for 90 minutes. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 134 (66 mg, 45% yield). LC / MS (ESI): m / z = 799 [M+H]+, RT = 2.49 min, LC / MS Method 8

[0226] Step 11 Synthesis of Compound (I-594) Compound 134 (66 mg, 0.083 mmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, then dissolved in dichloromethane, and neutralized by adding aqueous sodium bicarbonate solution. Aqueous citric acid solution was added to the reaction solution to make it acidic again, and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-594) (37 mg, yield 60%). 1 H-NMR (DMSO-d6) δ: 1.12-1.24 (m, 2H), 1.35-1.43 (m, 2H), 1.53-1.79 (m, 12H), 1.90-2.14 (m, 11H), 2.20-2.26 (m, 1H), 2.56 (s, 2H), 3.50-3.58 (m, 6H), 3.87-3.90 (m, 2H), 4.21 (s, 2H), 4.88-4.95 (m, 1H), 6.85 (s, 1H), 8.37 (brs, 1H), 8.54 (s, 1H), 8.91 (s, 1H), 12.33 (brs, 1H).

[0227] (Reference Example) Synthesis of Compound 117 and Compound 131 Step 1: Synthesis of Compound 131 and Compound 117 Compound 135 (1.0 g, 4.90 mmol) was dissolved in dichloromethane (10 mL), and 3,3-difluoroazetidine hydrochloride (1.27 g, 9.79 mmol), triethylamine (1.26 mL, 9.79 mmol), acetic acid (0.28 mL, 4.90 mmol), and sodium triacetoxyborohydride (2.08 g, 9.79 mmol) were added, followed by stirring for 3 hours. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 136 (846 mg, yield 61%) and Compound 137 (454 mg, yield 33%). Compound 136 1 H-NMR (CDCl3) δ: 1.44-1.60 (m, 6H), 1.90-1.96 (m, 2H), 2.14-2.19 (m, 1H), 3.53 (t, J = 12.4Hz, 4H), 3.55 (m, 1H), 4.50 (s, 2H), 7.23-7.28 (m, 1H), 7.30-7.36 (m, 4H). LC / MS(ESI):m / z= 282 [M+H]+, RT=1.24 min, LC / MS method 1 Compound 137 1 H-NMR (CDCl3) δ: 1.08-1.18 (m, 2H), 1.26-1.39 (m, 2H), 1.77-1.81 (m, 2H), 2.05-2.15 (m, 3H), 3.33-3.40 (m, 1H), 3.54 (t, J = 11.6Hz, 4H), 4.54 (s, 2H), 7.25-7.30 (m, 1H), 7.31-7.34 (m, 4H).LC / MS(ESI):m / z= 282 [M+H]+, RT=1.20 min, LC / MS method 1

[0228] Step 2: Synthesis of Compound 131 Compound 136 (0.72 g, 2.55 mmol) was dissolved in ethanol (10.7 mL), and 10 wt % palladium carbon (1.09 g, 0.51 mmol) was added. The system was purged with hydrogen and stirred at 50° C. for 3 hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain Compound 131 (0.42 g, 86% yield). Compound 131 1 H-NMR (CDCl3) δ: 1.30 (brs, 1H), 1.44-1.61 (m, 6H), 1.69-1.79 (m, 2H), 2.20 (m, 1H), 3.53 (t, J = 12.0Hz, 4H), 3.81 (m, 1H).

[0229] Step 3: Synthesis of Compound 117 Compound 131 (300 mg, 1.57 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (0.44 mL, 3.14 mmol) and methanesulfonyl chloride (0.18 mL, 2.35 mmol) were added under ice-cooling. After 1 hour and 30 minutes, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound 117 (419 mg, yield 99%). 1 H-NMR (CDCl3) δ: 1.53-1.59 (m, 4H), 1.62-1.72 (m, 2H), 2.03-2.13 (m, 2H), 2.23 (m, 1H), 3.00 (s, 3H), 3.54 (t, J = 12.0Hz, 4H), 4.86 (m, 1H).

[0230] Example 15 Synthesis of Compound (I-570) Step 1: Synthesis of Compound 138 The compound was synthesized in the same manner as in Step 1 of Example 6. 1H-NMR (DMSO-d6) δ: ppm 1.33 (t, J=7.15 Hz, 3 H), 1.67 (s, 9 H), 2.17 (t, J=19.32 Hz, 3 H), 4.38 (q, J=7.15 Hz, 2 H), 5.21 (s, 2 H), 7.16 (dd, J=8.9, 2.3 Hz, 1 H), 7.32 - 7.38 (m, 1 H), 7.39 - 7.44 (m, 2 H), 7.48 - 7.52 (m, 2 H), 7.82 (d, J=2.1 Hz, 1 H), 8.43 (s, 1 H), 8.45 (d, J=8.9 Hz, 1 H), 9.19 (s, 1 H). LC / MS (DUIS): m / z = 538 [M+H]+, RT = 2.08 min, LC / MS Method 9

[0231] Step 2: Synthesis of Compound 139 To a solution of compound 138 (7.48 g, 13.9 mmol) in tetrahydrofuran (59.8 mL), methanol (29.9 mL), and water (15.0 mL), lithium hydroxide monohydrate (2.92 g, 69.6 mmol) was added at room temperature and stirred at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with water and neutralized with 2 mol / L hydrochloric acid (35 mL, 70.0 mmol), and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 139 (4.81 g, 84% yield). 1H-NMR (DMSO-d6) δ : ppm 2.14 (t, J=19.1 Hz, 3 H), 5.16 (s, 2 H), 6.96 (dd, J=8.8, 2.3 Hz, 1 H), 7.07 (d, J=2.3 Hz, 1 H), 7.29 - 7.37 (m, 1 H), 7.38 - 7.45 (m, 2 H), 7.47 - 7.52 (m, 2 H), 8.23 ​​(d, J=2.9 Hz, 1 H), 8.34 (d, J=8.7 Hz, 1 H), 9.00 (s, 1 H), 11.76 (d, J=2.4 Hz, 1 H), 13.45 (br s, 1 H). LC / MS (DUIS): m / z = 410 [M+H]+, RT = 1.32 min, LC / MS Method 9

[0232] Step 3 Synthesis of Compound 140 To a solution of compound 139 (4.8 g, 11.72 mmol) in dichloromethane (48.0 mL) and dimethylformamide (2.0 mL) was added triethylamine (2.45 mL, 17.58 mmol), Boc ２ O (3.23 mL, 14.06 mmol) and DMAP (72 mg, 0.59 mmol) were added at room temperature, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol / L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Next, a hexane-ethyl acetate mixed solution was added, and the mixture was subjected to ultrasonic treatment and filtration. The mixture was further washed with a hexane-ethyl acetate mixed solution and dried to obtain compound 140 (2.46 g, yield 41%). 1H-NMR (DMSO-d6) δ: ppm 1.67 (s, 9 H), 2.16 (t, J=19.3 Hz, 3 H), 5.21 (s, 2 H), 7.16 (dd, J=8.8, 2.4 Hz, 1 H), 7.32 - 7.37 (m, 1 H), 7.39 - 7.44(m, 2 H), 7.48 - 7.52 (m, 2 H), 7.83 (d, J=2.3 Hz, 1 H), 8.42 (s, 1 H), 8.46 (d, J=8.8 Hz, 1 H), 9.17 (s, 1 H), 13.81 (br s, 1 H). LC / MS(DUIS):m / z= 510 [M+H]+, RT=1.79 min, LC / MS Method 9

[0233] Step 4: Synthesis of Compound 141 Compound 141 was synthesized under the same conditions as in Step 3 of Example 4. 1 H-NMR (DMSO-d6) δ: ppm 1.45 (s, 9 H), 1.54 - 1.60 (m, 2 H), 1.67 (s, 9 H), 1.68 - 1.73 (m, 4 H), 1.77 - 1.86 (m, 2 H), 2.10 (t, J=19.2 Hz, 3 H), 2.00-2.18(m, 4 H), 2.52 - 2.57 (m, 2 H), 5.21 (s, 2 H), 7.16 (dd, J=8.9, 2.3 Hz, 1 H), 7.32 - 7.37 (m, 1 H), 7.39 - 7.44 (m, 2 H), 7.48 - 7.52 (m, 2 H), 7.82 (d, J=2.4 Hz, 1 H) 8.40 (s, 1 H), 8.48 (d, J=8.8 Hz, 1 H), 8.56 (br s, 1 H), 8.79 (s, 1 H). LC / MS(DUIS): m / z= 743 [M+H]+, RT=2.37 min, LC / MS Method 9

[0234] Step 5: Synthesis of Compound 142 Compound 142 was synthesized under the same conditions as in Step 2 of Example 6. 1H-NMR (DMSO-d6) δ: ppm 1.45 (s, 9 H), 1.57 (m, 2 H), 1.62 - 1.73 (m, 4 H), 1.67(s, 9 H), 1.78 - 1.84 (m, 2 H), 2.10 (t, J=19.1 Hz, 3 H), 2.00 - 2.18 (m, 4 H), 2.51 - 2.55 (m, 2 H), 6.89 (dd, J=8.7, 2.3 Hz, 1 H), 7.63 (d, J=2.1 Hz, 1 H), 8.32 (s, 1 H), 8.36 (d, J=8.7 Hz, 1 H), 8.55 (br s, 1 H), 8.77 (s, 1 H), 9.68 (s, 1 H). LC / MS (DUIS): m / z = 653 [M+H]+, RT = 1.92 min, LC / MS Method 9

[0235] Step 6: Synthesis of Compound 143 The compound was synthesized in the same manner as in Step 5 of Example 3. 1 H-NMR (DMSO-d6) δ: ppm 1.12 - 1.25 (m, 2 H), 1.39 - 1.51 (m, 2 H), 1.45 (s, 9 H), 1.54 - 1.62 (m, 2 H), 1.68 (s, 9 H), 1.69 - 1.73 (m, 4 H), 1.75 - 1.85 (m, 4 H), 2.10 (t, J=19.1 Hz, 3 H), 2.01 -2.18 (m, 6 H), 2.21 - 2.30 (m, 1 H), 2.52 - 2.55 (m, 2 H), 3.55 (t, J=12.3 Hz, 4 H), 4.32 - 4.42 (m, 1 H), 7.06 (dd, J=8.8, 2.3 Hz, 1 H), 7.69 (d, J=2.1 Hz, 1 H), 8.40 (s, 1 H), 8.45 (d, J=8.8 Hz, 1 H), 8.55 (br s, 1 H), 8.78 (s, 1 H). LC / MS(DUIS): m / z= 826 [M+H]+, RT=1.88 min, LC / MS Method 9

[0236] Step 7: Synthesis of Compound 144 Synthesis was carried out under the same conditions as in Step 2. 1H-NMR (DMSO-d6) δ ppm 1.12 - 1.24 (m, 2 H), 1.37 - 1.42 (m, 2 H), 1.45 (s, 9 H), 1.53 - 1.61 (m, 2 H), 1.65 - 1.74 (m, 4 H), 1.75 - 1.85 (m, 4 H), 2.08 (t, J=19.0 Hz, 3 H), 2.00 - 2.19 (m, 6 H), 2.20 - 2.28 (m, 1 H), 2.52 - 2.55 (m, 2 H), 3.55 (t, J=12.4 Hz, 4 H), 4.25 - 4.37 (m, 1 H), 6.86 (dd, J=8.8, 2.3 Hz, 1 H), 7.00 (d, J=2.3Hz, 1 H), 8.19 (d, J=2.8 Hz, 1 H), 8.32 (d, J=8.8 Hz, 1 H), 8.46 (s, 1 H), 8.64 (s, 1 H), 11.62 (d, J=2.6 Hz, 1 H). LC / MS(DUIS):m / z= 726 [M+H]+, RT=1.47 min, LC / MS method 9

[0237] Step 8: Synthesis of Compound 146 To a solution of Compound 144 (50 mg, 0.07 mmol) in N-methylpyrrolidone (1.0 mL) was added cesium carbonate (67 mg, 0.21 mmol) and Compound 145 (50 mg, 0.21 mmol) at room temperature under argon atmosphere while stirring, and the mixture was stirred at 100°C for 2 hours. Next, cesium carbonate (67 mg, 0.21 mmol) and Compound 145 (50 mg, 0.21 mmol) were added, and the mixture was stirred at 100°C for 3 hours. Cesium carbonate (67 mg, 0.21 mmol) and Compound 145 (50 mg, 0.21 mmol) were further added, and the mixture was stirred at 100°C for 4 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). Further purification by amino column chromatography (hexane-ethyl acetate) gave Compound 146 (42 mg, 77%). 1H-NMR (DMSO-d6) δ: ppm 0.72 (t, J=7.3 Hz, 6 H), 1.19 - 1.28 (m, 2 H), 1.35 - 1.43 (m, 2 H), 1.45 (s, 9 H), 1.53 - 1.62 (m, 2 H), 1.65 - 1.72 (m, 4H), 1.74 - 1.83 (m, 4 H), 1.91 (qd, J=7.2 Hz, 4 H), 2.09 (t, J=19.0 Hz, 3 H), 2.01 - 2.18 (m, 6 H), 2.20 - 2.30 (m, 1 H), 2.52 - 2.56 (m, 2 H), 3.55 (t, J=12.4Hz, 4 H), 4.32 - 4.47 (m, 2H), 6.89 (dd, J=8.9, 2.1 Hz, 1 H), 7.21 (d, J=1.9Hz, 1 H), 8.24 (s, 1 H), 8.35 (d, J=8.8 Hz, 1 H), 8.45 (br s, 1 H), 8.63 (s, 1 H). LC / MS(ESI):m / z= 796 [M+H]+, RT=1.82 min, LC / MSメソッド10

[0238] Process 9: Synthesis of compound (I-570) in Example 10: Process 8 was synthesized under the same conditions. 1H-NMR (DMSO-d6) δ: ppm 0.71 (t, J=7.3 Hz, 6 H), 1.18 - 1.29 (m, 2 H), 1.34 - 1.47 (m, 2 H), 1.48 - 1.59 (m, 2 H), 1.59 - 1.73 (m, 4 H), 1.75 - 1.83(m, 4 H), 1.86 - 1.94 (m, 4 H), 2.08(t, J=19.0 Hz, 3H), 2.00 - 2.18 (m, 6 H), 2.19 - 2.28 (m, 1 H), 2.55 - 2.61 (m, 2 H), 3.55 (t, J=12.4 Hz, 4 H), 4.34 - 4.47 (m, 2 H), 6.88 (dd, J=8.9, 2.1 Hz, 1 H), 7.20 (d, J=1.9 Hz, 1 H), 8.21 (s, 1 H), 8.35 (d, J=8.8 Hz, 1 H), 8.46 (br s, 1 H), 8.64 (s, 1 H), 12.45 (br s, 1 H). LC / MS(DUIS):m / z= 740 [M+H]+, RT=1.36 min, LC / MS method 9

[0239] The following compounds were synthesized according to the general synthesis method and the method described in the Examples above. In the structural formulas, the "wedge shape" and "dashed line" indicate the configuration. In particular, for compounds in which the configuration is described, the "stereostructure" item is defined as follows: Blank: As described a: Racemic form b: Single compound, but the configuration is unknown c: Diastereomeric mixture However, I-273, I-371, I-376, I-403, I-414, I-451, I-11, I-12, and I-13 include their racemates. d: Z ｃ (R ７ The stereochemistry of the substituents of R ４ The stereochemistry of the substituents is unknown e:Z ｃ (R ７ The stereochemistry of the substituents of R ４ The stereochemistry of the substituents is as described. f: Racemic, cis / trans relative configuration is single but unknown

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[0346]

[0347] Biological test examples of the compound of the present invention are described below. The compound represented by formula (I) according to the present invention may have an inhibitory effect on cytopathic effects caused by respiratory syncytial virus and inhibits human cytopathic effects. Specifically, in the evaluation method described below, the EC50 is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.

[0348] Test Example 1: In vitro CPE (Cytopathic Effect) Inhibitory Effect Confirmation Test The test sample was diluted to an appropriate concentration with DMSO in advance, and a 3-fold serial dilution series was prepared on a 384-well plate (0.32 μL / well). HEp-2 cells (CCL-23; ATCC) were cultured at an appropriate number (2.4 × 10) in 2% FBS E-MEM (Eagle's Minimum Essential Medium; prepared by adding kanamycin and FBS to Invitrogen). 5The RSV A2 strain was diluted to an appropriate concentration with culture medium and dispensed at 12.5 μL / well into a 384-well plate containing the test sample. Culture medium was then added to the plate, with a final volume of 50 μL / well, before the experiment began. For control wells, culture medium alone without virus was added. After 4 days of static culture in a 37°C, 5% CO2 incubator, the plate was removed and left at room temperature for 30 minutes. CellTiter-Glo® 2.0 assay (Promega) was added at 15 μL / well, mixed for 30 seconds, and then left for approximately 1 hour. Luminescence was then quantified using EnVision (PerkinElmer). The inhibitory effect of test reagents on RSV-induced CPE was calculated for each test concentration using the remaining viable cell levels measured by CellTiter-Glo® 2.0, with 0% and 100% inhibition. The EC50 value for each compound was calculated by nonlinear regression as the concentration required for 50% inhibition of RSV-induced cytopathic effect. When evaluating against RSV type B, RSV B (Wash / 18537 strain) was infected in the same manner as for type A, cultured for 5 days, and then quantified in the same manner as for the A2 strain. (Results) The compounds of the present invention were tested essentially as described above. The inhibitory effect of the compounds of the present invention against RSV type A is shown below. EC50 values ​​are categorized as follows: "A" for less than 10 nM, "B" for 10 nM to 100 nM, and "C" for 100 nM to 5000 nM. Compound No. I-23: 0.96 nM Compound No. I-33: 7.5 nM Compound No. I-82: 0.27 nM Compound No. I-148: 1.5 nM Compound No. I-159: 0.88 nM Compound No. I-162: 0.88 nM Compound No. I-165: 0.37 nM Compound No. I-182: 0.39 nM Compound No. I-228: 1.3 nM Compound No. I-268: 1.4 nM Compound No. I-269: 1.3 nM Compound No. I-270: 37 nM Compound No. I-486: 3 nM Compound No. I-570: 0.70 nM Compound No. I-591: 0.61 nM Compound No. I-594: 0.38 nM

[0349]

[0350]

[0351]

[0352] The compounds of the present invention were tested essentially as described above. The inhibitory effects of the compounds of the present invention against RSV type B are shown below. EC50 values ​​are categorized as "A" for less than 10 nM, "B" for 10 nM or more but less than 100 nM, and "C" for 100 nM or more but less than 5000 nM. Compound No. I-23: 16nM Compound No. I-33: 110nM Compound No. I-82: 0.34nM Compound No. I-148: 2.8nM Compound No. I-159: 3nM Compound No. I-162: 3.3nM Compound No. I-165: 0.62nM Compound No. I-182: 2.1nM Compound No. I-228: 36nM Compound No. I-268: 4.3nM Compound No. I-486: 28nM Compound No. I-570: 2.1nM Compound No. I-591: 2.2nM Compound No. I-594: 4.2nM

[0353]

[0354] Test Example 2: In vivo drug efficacy test in mice Although mice are semi-permissive to human RSV replication, they are a model frequently used in non-clinical screening tests of RSV therapeutic agents. Balb / c mice, which have good growth potential for the RSV A2 strain, were used to confirm the in vivo drug efficacy. 6-week-old BALB / c mice (female) were inoculated with 5 x 10 6 The mice were inoculated intranasally at a PFU / mouse level, and the test sample was administered twice daily (at 8- and 16-hour intervals) at a fixed dose starting from post-infection. Lungs were removed on day 4 or 5. The lungs were homogenized in PBS, flash-frozen, and stored at -80°C. The supernatant from the lung homogenate was subjected to titer determination using the immune TCID50 assay to determine the virus titer.

[0355] Test Example 3: CYP inhibition test Using commercially available pooled human liver microsomes, the extent to which the production of each metabolite is inhibited by the compound of the present invention is evaluated using as indicators the typical substrate metabolic reactions of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), namely, O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4).

[0356] The reaction conditions were as follows: substrates, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37°C; enzyme, pooled human liver microsomes, 0.2 mg protein / mL; concentration of the compound of the present invention, 1, 5, 10, 20 μmol / L (4 points).

[0357] Five substrates, human liver microsomes, and the compound of the present invention were added to a 96-well plate in the above-mentioned composition in 50 mmol / L Hepes buffer, and the coenzyme NADPH was added to initiate the metabolic reaction. After 15 minutes of reaction at 37°C, the reaction was stopped by adding a 1:1 (V / V) methanol / acetonitrile solution. After 15 minutes of centrifugation at 3000 rpm, resorufin (a CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter or LC / MS / MS, and tolbutamide hydroxylate (a CYP2C9 metabolite), mephenytoin 4'-hydroxylate (a CYP2C19 metabolite), dextrorphan (a CYP2D6 metabolite), and terfenadine alcohol (a CYP3A4 metabolite) were quantified by LC / MS / MS. The dilution concentration and solvent were adjusted as needed.

[0358] The control (100%) was a reaction solution in which only DMSO, the solvent in which the compound was dissolved, was added instead of the compound of the present invention. The remaining activity (%) was calculated, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. ５０ Calculate.

[0359] Test Example 4: CYP3A4 (MDZ) MBI Test This test evaluates the mechanism-based inhibition (MBI) ability of the compounds of the present invention in terms of the CYP3A4 inhibition, based on the enhancement of the inhibitory effect caused by the metabolic reaction of the compounds of the present invention. CYP3A4 inhibition is evaluated using pooled human liver microsomes and the 1-hydroxylation reaction of midazolam (MDZ) as an index.

[0360] The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL during pre-reaction and 0.05 mg / mL (10-fold dilution) during reaction; concentration of the compound of the present invention during pre-reaction, 1, 5, 10, 20 μmol / L or 0.83, 5, 10, 20 μmol / L (4 points).

[0361] Pooled human liver microsomes and a solution of the compound of the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) at the pre-reaction composition described above. A portion of this solution was transferred to another 96-well plate so that it was diluted 1 / 10 with K-Pi buffer containing the substrate, and the coenzyme NADPH was added to initiate the reaction (pre-incubation 0 min). After the predetermined reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. NADPH was also added to the remaining pre-reaction solution to initiate the pre-reaction (pre-incubation 30 min). After the predetermined reaction time, a portion of this solution was transferred to another plate so that it was diluted 1 / 10 with K-Pi buffer containing the substrate, and the reaction was started. After the predetermined reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. After centrifuging the plates where the respective indicator reactions were carried out at 3000 rpm for 15 minutes, the amount of 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS. The dilution concentration and dilution solvent were changed as necessary.

[0362] A control (100%) was prepared by adding only DMSO, the solvent in which the compound was dissolved, to the reaction solution instead of the compound of the present invention. The residual activity (%) was calculated when the compound of the present invention was added at each concentration, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The Shifted IC value was calculated as the IC at 0 min preincubation / IC at 30 min preincubation. If the Shifted IC was 1.5 or higher, it was considered positive, and if the Shifted IC was 1.0 or lower, it was considered negative.

[0363] Test Example 5: BA Test Materials and Methods for Experiments to Examine Oral Absorbability (1) Animals Used: Mice or rats are used. (2) Breeding Conditions: Mice or rats are allowed free access to solid feed and sterilized tap water. (3) Dosage and Grouping: Predetermined dosages are administered orally and intravenously. Groups are set up as follows. (Dosages vary depending on the compound) Oral Administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous Administration: 1-30 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of Dosage Solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization. (5) Administration Method: Oral administration is administered by forced administration into the stomach using an oral probe. Intravenous administration is administered via the tail vein using a syringe with an injection needle attached. (6) Evaluation item: Blood samples are collected over time, and the plasma concentration of the compound of the present invention is measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound of the present invention over time is calculated using moment analysis, and the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio and AUC ratio between the oral and intravenous administration groups. The dilution concentration and dilution solvent are changed as necessary.

[0364] Test Example 6 Clearance Evaluation Test Experimental Materials and Methods (1) Animals: SD rats were used. (2) Breeding Conditions: SD rats were allowed free access to solid feed and sterilized tap water. (3) Dose and Grouping: Intravenous administration was performed at a predetermined dose. Groups were set up as follows: Intravenous administration: 1 μmol / kg (n=2) (4) Preparation of Dosage Solution: Solubilized and administered using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent. (5) Administration Method: Administered via the tail vein using a syringe with an injection needle. (6) Evaluation Items: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical Analysis: The total body clearance (CLtot) was calculated using moment analysis of the plasma concentration of the compound of the present invention. The dilution concentration and dilution solvent were changed as necessary.

[0365] Test Example 7: Metabolic stability test Pooled human liver microsomes or pooled rat liver microsomes are reacted with the compound of the present invention for a certain period of time, and the residual rate is calculated by comparing the reacted sample with the unreacted sample to evaluate the extent to which the compound of the present invention is metabolized in the liver.

[0366] Human or rat liver microsomes (0.5 mg protein / mL) were incubated in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) at 37°C for 0 or 30 minutes in the presence of 1 mmol / L NADPH (oxidation reaction). After the reaction, 50 μL of the reaction mixture was added to 100 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The amount of the compound of the present invention in the supernatant was quantified by LC / MS / MS or solid-phase extraction (SPE) / MS. The ratio of the amount of the compound of the present invention at 0 minutes of reaction to the amount of compound after the reaction was expressed as the residual percentage. Note that the hydrolysis reaction was performed in the absence of NADPH, and the glucuronidation reaction was performed in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same procedures were then repeated. The dilution concentration and dilution solvent may be changed as necessary.

[0367] Test Example 8: Metabolic stability test (hepatocytes) Human, rat, dog, or monkey hepatocytes are reacted with the compound of the present invention for a certain period of time, and the residual rate is calculated by comparing the reacted sample with the unreacted sample to evaluate the degree to which the compound of the present invention is metabolized in the liver. In order to take into account the effect of serum protein binding on metabolism, up to 10% of serum from the species corresponding to each hepatocyte may be added to the culture medium.

[0368] Human, rat, dog, or monkey hepatocytes were cultured in William's medium E at 1 x 10 ６The hepatocytes are suspended at 37°C for 0, 1, or 2 hours with the compound of the present invention. When serum is added, up to 10% serum is added to Williams' medium E before suspending the hepatocytes. After the reaction, 30 μL of the reaction mixture is mixed with 120 μL of a 1 / 1 (v / v) methanol / acetonitrile solution and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant is quantified by LC / MS / MS or solid-phase extraction (SPE) / MS, and the ratio of the amount of the compound of the present invention at 0 minutes of reaction to the amount of the compound after the reaction is expressed as the residual rate, with the amount of the compound of the present invention at 0 minutes of reaction being 100%. The dilution concentration and dilution solvent may be changed as necessary.

[0369] The compounds of the present invention have an inhibitory effect on RSV and are useful for the treatment and / or prevention of RSV infection and related diseases caused by infection.

Claims

DEPCT6603 / 07 / 25661. Compounds with the formula (I):(chemical formula)(I) where: a dashed line indicates the presence or absence of a bond; R1 is a substituted or unsubstituted carboxy, cyano, aromatic heterocyclyl, -C(=O)-NR1BR1C or -CH=CHC(=O)-OH; R1B and R1C independently are substituted or unsubstituted hydrogen, alkyl, aminosulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl atoms; L is a substituted or unsubstituted non-aromatic carboxyldiyl, or substituted or unsubstituted non-aromatic heterocyclyldiyl. R1 is a substituted or unsubstituted alkyl; R2 is a substituted or unsubstituted alkyl; R3 is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted amino, or a substituted or unsubstituted carbamoyl; X is =CRX- or =N-; Y is =CRY- or =N-; U is -CRU= or -N=; V is -CRV= or -N=; W is =CRW- or =N-; ZA is -C= or -N-; ZB is -CR5R6-, -CR5=, -NR5- or -N=; ZC is -CR7R8-, -CR7=, -NR7- or =N-; RX, RY, RV, and RW independently represent hydrogen, cyanobacteria, halogen, etc.Substituted or unsubstituted alkyls or substituted or unsubstituted carbamoyls; RU is a hydrogen atom; substituted or unsubstituted alkyloxys, substituted or unsubstituted non-aromatic heterocyclic alkyls, substituted or unsubstituted non-aromatic carbocyclic alkyls, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted amino acids, hydroxyls, halogens, substituted or unsubstituted aromatic carbocyclyls, substituted or unsubstituted aromatic heterocyclyls, non-aromatic heterocyclic Substituted or unsubstituted alkyl or non-aromatic carbocyclyl; R5 and R6 independently are hydrogen atoms, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted hydroxyl or alkyl, or R5 and R6 combined to form oxo; R7 and R8 independently are hydrogen atoms, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyl.Substituted or unsubstituted aromatic heterocyclyls, substituted or unsubstituted non-aromatic carbocyclyl oxycarbonyls, substituted or unsubstituted non-aromatic heterocyclyl oxycarbonyls, substituted or unsubstituted non-aromatic carbocyclyl sulfonyls, substituted or unsubstituted alkyl sulfonyls, or R7 and R8 are combined with the carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring; or R5 and R7. They are combined with the carbon atoms to which they are attached to form a substituted or unsubstituted non-aromatic carbon ring or a substituted or unsubstituted aromatic carbon ring; or R4 is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic heterocyclic atom, a substituted or unsubstituted non-aromatic carbocyclic atom, a substituted or unsubstituted aromatic carbocyclic atom, a substituted or unsubstituted aromatic heterocyclic atom, or a substituted or unsubstituted alkyl.Substituted or unsubstituted alkenyls, substituted or unsubstituted amino acids, substituted or unsubstituted carbamoyls, hydroxyls, halogens, substituted or unsubstituted aromatic carbocyclyls, substituted or unsubstituted aromatic heterocyclyls, substituted or unsubstituted non-aromatic heterocyclyls.

1. A substituted or unsubstituted non-aromatic carboxyl or a substituted or unsubstituted non-aromatic heterocyclic carbonyl or R4 and RU are combined with the carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic heterocyclic ring or its pharmaceutically acceptable salt.

2. A compound under claim 1 where R1 is a carboxyl or its pharmaceutically acceptable salt.

3. A compound under claim 1 or 2 where...

1. Any compound under claims 1 to 3 where R3 is a hydrogen atom or its pharmaceutically acceptable salt.

2. Any compound under claims 1 to 4 where V is -N= and W is =N- or its pharmaceutically acceptable salt.

3. Any compound under claims 1 to 5 where the group with the formula:(chemical formula) is (chemical formula).or (chemical formula) in which each symbol is as defined in Relief 1 or its pharmaceutically acceptable salt.

7. Any compound under Reliefs 1 through 6 in which the group with the formula: (chemical formula) is (chemical formula) or (chemical formula) in which each symbol is as defined in Relief 1 or its pharmaceutically acceptable salt.

8. Any compound under Reliefs 1 through 7 in which the group with the formula: (chemical formula) is (chemical formula) or (chemical formula) in which each symbol is as defined in Relief 1 or its pharmaceutically acceptable salt.

9. Any compound under any of the claims 1 through 8 in which the group with the formula:(chemical formula) is (chemical formula) in which R4 is as defined in claim 1; and R7 is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclyl, a substituted or unsubstituted non-aromatic heterocyclyl, an substituted or unsubstituted aromatic carbocyclyl, an substituted or unsubstituted aromatic heterocyclyl, a substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl.

10. Any compound under claims 1 through 8 in which the group with the formula:(chemical formula) is (chemical formula) in which R4 is as defined in claim 1; and R7 and R8 independently are either substituted or unsubstituted hydrogen or alkyl atoms, or R7 and R8 are combined with the carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbon ring.

11. Any compound under any of Claims 1 through 10 where R4 is a substituted or unsubstituted alkyloxy, a substituted or unsubstituted non-aromatic heterocyclic alkyl, a substituted or unsubstituted non-aromatic carbocyclic alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted amino, a substituted or unsubstituted hydroxy,12. Any compound under claims 1 through 11 where R4 is a substituted or unsubstituted non-aromatic heterocyclic or substituted or unsubstituted non-aromatic carbocyclic or its pharmaceutically acceptable salt.

13. A compound under claim 1 selected from a group comprising compounds I-082, I-162, I-481, I-496, I-503, I-506, I-549, I-552, I-568, I-569, I-570, I-571, I-591, I-613,I-617 and I-618 or their pharmaceutically acceptable salts; 14. Pharmaceutical compositions incorporating any of the compounds of claims 1 through 13 or their pharmaceutically acceptable salts; 15. Pharmaceutical compositions under claim 14 that have anti-RSV activity; 16. Methods for the treatment and / or prevention of RSV infection characterized by the provision of any of the compounds of claims 1 through 13 or their pharmaceutically acceptable salts; 17. Any of the compounds of claims 1 through 13 or their pharmaceutically acceptable salts for the treatment and / or prevention of RSV infection; 18. Use of any of the compounds of claims 1 through 13 or their pharmaceutically acceptable salts for the manufacture of medicines for the treatment and / or prevention of RSV infection;