JP7454729B2 - Pharmaceutical composition containing an amide derivative with antiviral activity - Google Patents

Description

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

Human respiratory syncytial virus (RSV) is a negative-strand, single-stranded RNA virus that is a member of the pneumovirus family of Paramyxoviridae and is the most common cause of bronchiolitis and pneumonia in children under 1 year of age. be. Most children become infected with RSV before their second birthday, and approximately 1-3% of those infected require hospitalization. The elderly and those with heart, lung, or immune system disorders are particularly susceptible and have a high risk of severe disease and complications (Non-Patent Document 1).

RSV exists in two antigenic subtypes, A and B. Generally, these two types are observed simultaneously in RSV epidemics, but their ratios vary geographically and seasonally, and this is thought to be one of the reasons why each epidemic has a different clinical impact. ing. 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).

Until now, there was no vaccine that could prevent RSV infection, but at the end of 2022, an application was filed for the RSV PreF vaccine to be administered to pregnant women to prevent lower respiratory tract diseases in newborns and infants. Palivizumab is a monoclonal antibody used prophylactically to prevent RSV infection in high-risk infants, such as preterm infants and infants with heart or lung disease, and the high cost of palivizumab treatment makes it an over-the-counter drug. Although there has been limited use of this drug, nilsevimab, a long-acting antibody with an extended half-life, was approved in late 2022 for the prophylaxis of lower respiratory tract disease caused by respiratory syncytial virus in neonates and infants. Meanwhile, as a treatment, the nucleic acid analog ribavirin has been approved in the United States as the only antiviral agent to treat RSV infections, but its efficacy is limited due to concerns about its side effect profile. Therefore, there is a need for the development of a safe and effective RSV treatment that can be widely used for all types of RSV and for age groups ranging from infants to the elderly (Non-Patent Document 1).

RSV therapeutics currently in clinical development include ziresovir and cisunatovir, which are inhibitors that act on the F protein involved in RSV membrane fusion, and inhibitors that act on the N protein, which is involved in genome stabilization. There is EDP-938 as an agent. EDP-323, which inhibits L protein polymerase, is also under development (Non-Patent Documents 2 and 3).
To date, no pharmaceutical compositions containing amide derivatives having RSV inhibitory activity as described in the present application are known.

Cellular and Molecular Life Sciences, 2020, Jun 16, 1-14 Expert Opinion on Investigational Drugs, 2020, Mar29, 3, 285-294 Enanta Pharmaceuticals ReceivesFDA Fast Track Design for EDP-323, its Oral, L-Protein Inhibitor in Development for the Treatment of Respiratory Syncytial Virus", [online], April 6, 2023, Enata Press Release, [April 24, 2023 Internet <URL: https://ir.enanta.com/news-releases/news-release-details/enanta-pharmaceuticals-receives-fda-fast-track-designation-edp-0>

An object of the present invention is to provide a pharmaceutical composition containing a compound having RSV inhibitory activity. More preferably, the present invention provides medicaments containing compounds useful for the treatment and/or prevention of RSV infection and related diseases caused by infection.

で示される基が、

（式中、各記号は上記項目（１）と同義）で示される基である、上記項目（１）～（７）のいずれかに記載の化合物またはその製薬上許容される塩、を含有する医薬組成物。
（９）式：

で示される基が、

（式中、Ｒ^４は上記項目（１）と同義であり、Ｒ^７は置換もしくは非置換のアルキル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニルまたは置換もしくは非置換の非芳香族炭素環スルホニル）で示される基である、上記項目（１）～（８）のいずれかに記載の化合物またはその製薬上許容される塩、を含有する医薬組成物。
（１０）式：

で示される基が、

（式中、Ｒ^４は上記項目（１）と同義であり、Ｒ^７およびＲ^８はそれぞれ独立して水素原子、または置換もしくは非置換のアルキル、または、Ｒ^７およびＲ^８は結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成する）で示される基である、上記項目（１）～（８）のいずれかに記載の化合物またはその製薬上許容される塩、を含有する医薬組成物。
（１１）Ｒ^４が置換もしくは非置換のアルキルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアミノ、ヒドロキシ、ハロゲン、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換もしくは非置換の非芳香族炭素環式基である、上記項目（１）～（１０）のいずれかに記載の化合物またはその製薬上許容される塩、を含有する医薬組成物。
（１２）Ｒ^４が置換もしくは非置換の非芳香族複素環オキシまたは置換もしくは非置換の非芳香族炭素環オキシである、上記項目（１）～（１１）のいずれかに記載の化合物またはその製薬上許容される塩、を含有する医薬組成物。
（１３）化合物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およびＩ－６１８からなる群から選択される、上記項目（１）記載の化合物またはその製薬上許容される塩、を含有する医薬組成物。
（１４）ＲＳウイルス増殖阻害剤である、上記項目（１）記載の医薬組成物。
（１５）ＲＳウイルス感染症の治療剤および／または予防剤である、上記項目（１）記載の医薬組成物。 The present invention relates to the following items (1) to (17).
(1) Formula (I):

(In the formula,
Dashed lines indicate the presence or absence of bonds;
R ¹ is 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;
L is substituted or unsubstituted non-aromatic carbocyclic diyl, substituted or unsubstituted non-aromatic heterocyclic diyl, or substituted or unsubstituted alkylene;
R ² is substituted or unsubstituted alkyl;
R ³ is 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, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-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 aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted non-aromatic carbocyclic group;
R ⁵ and R ⁶ each independently represent 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 represent oxo. may be formed;
R ⁷ and R ⁸ each independently represent 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 a substituted or unsubstituted non-aromatic heterocyclic group. Substituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Substituted non-aromatic carbocycle sulfonyl, substituted or unsubstituted alkylsulfonyl, or R ⁷ and R ⁸ taken together with the carbon atoms to which they are attached, substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted may form a non-aromatic heterocycle; or
R ⁵ and R ⁷ together with the carbon atoms to which they are bonded may form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted aromatic carbocycle;
R ⁴ is a hydrogen atom, 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 aromatic heterocycleoxy, 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 or ^a pharmaceutically acceptable compound ^thereof ; A pharmaceutical composition containing a salt.
(2) A pharmaceutical composition containing the compound described in item (1) above or a pharmaceutically acceptable salt thereof, wherein R ¹ is carboxy.
(3) A pharmaceutical composition containing the compound described in item (1) or (2) above, or a pharmaceutically acceptable salt thereof, wherein L is substituted or unsubstituted non-aromatic carbocyclic diyl.
(4) A pharmaceutical composition containing the compound according to any one of items (1) to (3) above, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom.
(5) A pharmaceutical composition containing the compound according to any one of items (1) to (4) above or a pharmaceutically acceptable salt thereof, wherein V is -N= and W is =N- .
(6) Formula:

The group represented by

(In the formula, each symbol has the same meaning as the above item (1)), which contains a compound according to any one of the above items (1) to (5) or a pharmaceutically acceptable salt thereof. Pharmaceutical composition.
(7) Formula:

The group represented by

(In the formula, each symbol has the same meaning as the above item (1)), which contains a compound according to any one of the above items (1) to (6) or a pharmaceutically acceptable salt thereof. Pharmaceutical composition.
(8) Formula:

The group represented by

(wherein each symbol has the same meaning as the above item (1)), the compound according to any one of the above items (1) to (7) or a pharmaceutically acceptable salt thereof. Pharmaceutical composition.
(9) Formula:

The group represented by

(In the formula, R ⁴ has the same meaning as the above item (1), R ⁷ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocycle) formula group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocycle oxycarbonyl or substituted or unsubstituted non-aromatic carbocyclic sulfonyl), the compound according to any one of items (1) to (8) above, or a pharmaceutically acceptable salt thereof. Pharmaceutical composition.
(10) Formula:

The group represented by

(In the formula, R ⁴ has the same meaning as the above item (1), R ⁷ and R ⁸ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, or R ⁷ and R ⁸ are bonded carbon atoms. Any of the above items (1) to (8), which together with , form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle or a pharmaceutically acceptable salt thereof.
(11) R ⁴ 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 an unsubstituted non-aromatic carbocyclic group, the compound according to any one of items (1) to (10) above, or a pharmaceutically acceptable salt thereof.
(12) The compound or its compound according to any of the above items (1) to (11), wherein R ⁴ is substituted or unsubstituted non-aromatic heterocyclic oxy or substituted or unsubstituted non-aromatic carbocyclic oxy A pharmaceutical composition containing a pharmaceutically acceptable salt.
(13) 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) The pharmaceutical composition according to item (1) above, which is an RS virus growth inhibitor.
(15) The pharmaceutical composition according to item (1) above, which is a therapeutic and/or preventive agent for RS virus infection.

The pharmaceutical composition according to the present invention contains a compound having RSV inhibitory activity, and is useful as a therapeutic and/or prophylactic agent for RSV infection and related diseases caused by infection.

Figure 2 is a graph of experimental results showing the therapeutic effect of compound I-82 administration on RSV A2 infection in mice. The vertical axis shows the intrapulmonary virus titer, and the horizontal axis shows each administration group. LLOQ indicates the lower limit of quantification. 1 is a graph of experimental results showing the therapeutic effect of administration of compound I-162 on RSV A2 infection in mice. The vertical axis shows the intrapulmonary virus titer, and the horizontal axis shows each administration group. LLOQ indicates the lower limit of quantification.

The meaning of each term used in this specification will be 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 features.
The term "comprising" is meant to be non-limiting and does not exclude elements not listed.
Hereinafter, the present invention will be described while showing embodiments. Throughout this specification, references to the singular should be understood to include the plural unless specifically stated otherwise. Therefore, singular articles (e.g., "a,""an,""the," etc. in English) should be understood to also include the plural concept, unless specifically stated otherwise.
Furthermore, it should be understood that the terms used herein have the meanings commonly used in the above-mentioned fields, unless otherwise specified. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will control.

"Halogen" includes fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms. Particularly preferred are fluorine atoms and chlorine atoms.

"Alkyl" includes a straight chain or branched 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. do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl. , isooctyl, n-nonyl, n-decyl and the like.
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.

"Alkenyl" has one or more double bonds at any position, and has 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. straight-chain or branched hydrocarbon groups. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl. etc.
Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include ethenyl, n-propenyl, and the like.

"Alkynyl" refers to a carbon number having one or more triple bonds at any position, having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms. Includes straight chain or branched hydrocarbon groups. Furthermore, it may have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like.
Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

"Alkylene" refers to a linear or branched divalent hydrocarbon 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. includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and the like.

"Aromatic carbocyclic group" means a monocyclic or two or more ring cyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl, and the like.
A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

"Aromatic carbocyclic ring" means a ring derived from the above-mentioned "aromatic carbocyclic group".

Examples of the "substituted or unsubstituted aromatic carbocycle formed by R ⁵ and R ⁷ together with the carbon atom to which they are bonded" include the following rings.

単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは炭素数３～１２、さらに好ましくは炭素数４～８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
２環以上の非芳香族炭素環式基としては、炭素数８～２０が好ましく、より好ましくは炭素数８～１６である。例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The term "non-aromatic carbocyclic group" means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having a single ring or two or more rings. The "non-aromatic carbocyclic group" having two or more rings also includes a ring in the above-mentioned "aromatic carbocyclic group" fused to a monocyclic or two-ring or more non-aromatic carbocyclic group.
Furthermore, the "non-aromatic carbocyclic group" also includes a group that is bridged as described below or a group that forms a spiro ring.

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, cyclohexadienyl, and the like.
The non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, and the like.

"Non-aromatic carbocyclic ring" means a ring derived from the above-mentioned "non-aromatic carbocyclic group".

Examples of the "substituted or unsubstituted non-aromatic carbon ring formed by R ⁵ and R ⁷ together with the carbon atom to which they are bonded" include the following rings.

Examples of the "substituted or unsubstituted non-aromatic carbon ring formed by R ⁷ and R ⁸ together with the carbon atom to which they are bonded" include the following rings.

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

"Aromatic heterocyclic group" means a monocyclic or bicyclic or more aromatic cyclic group having one or more same or different heteroatoms arbitrarily selected from O, S, and N in the ring. do.
The aromatic heterocyclic group having two or more rings includes those in which the ring in the above "aromatic carbocyclic group" is fused to a monocyclic or two or more ring aromatic heterocyclic group, and the bond is It may be present in either ring.
The monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like.
The two-ring aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazo Lyle, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. can be mentioned.
The aromatic heterocyclic group having 3 or more rings is preferably 13 to 15 members. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and the like.

"Aromatic heterocyclic ring" means a ring derived from the above-mentioned "aromatic heterocyclic group".

単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。
３員非芳香族複素環式基としては、例えば、チイラニル、オキシラニル、アジリジニル等が挙げられる。４員非芳香族複素環式基としては、例えば、オキセタニル、アゼチジニル等が挙げられる。５員非芳香族複素環式基としては、例えば、オキサチオラニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、テトラヒドロフリル、ジヒドロチアゾリル、テトラヒドロイソチアゾリル、ジオキソラニル、ジオキソリル、チオラニル等が挙げられる。６員非芳香族複素環式基としては、例えば、ジオキサニル、チアニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロピラニル、ジヒドロオキサジニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキサジニル、チイニル、チアジニル等が挙げられる。７員非芳香族複素環式基としては、例えば、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、オキセパニル等が挙げられる。
２環以上の非芳香族複素環式基としては、８～２０員が好ましく、より好ましくは８～１０員である。例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。 "Non-aromatic heterocyclic group" refers to a mono- or bi- or more-ring non-aromatic cyclic group having one or more same or different heteroatoms arbitrarily selected from O, S, and N in the ring. means. A non-aromatic heterocyclic group with two or more rings is a monocyclic or a non-aromatic heterocyclic group with two or more rings, and the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", and / or each ring in the "aromatic heterocyclic group" is condensed, and the ring in the above "aromatic heterocyclic group" is condensed to a non-aromatic carbocyclic group having a single ring or two or more rings. The bond may be present in any ring.
Furthermore, the "non-aromatic heterocyclic group" also includes a group that is crosslinked as described below or a group that forms a spiro ring.

The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
Examples of the 3-membered non-aromatic heterocyclic group include thiiranyl, oxiranyl, and aziridinyl. Examples of the 4-membered non-aromatic heterocyclic group include oxetanyl and azetidinyl. Examples of the 5-membered non-aromatic heterocyclic group include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, and the like. Can be mentioned. Examples of the 6-membered non-aromatic heterocyclic group include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydroxazinyl, and tetrahydropyridazinyl. Examples include hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl, and the like. Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl, and the like.
The non-aromatic heterocyclic group having two or more rings is preferably 8 to 20 members, more preferably 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl, and the like.

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

（式中、Ｒ’は水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のカルバモイル、置換もしくは非置換の非芳香族複素環式基、または、置換もしくは非置換のアルキルカルボニル） Examples of the "substituted or unsubstituted non-aromatic heterocycle formed by R ⁷ and R ⁸ together with the carbon atom to which they are bonded" include the following rings.

(In the formula, R' is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group , substituted or unsubstituted carbamoyl, substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted alkylcarbonyl)

Examples of the "substituted or unsubstituted non-aromatic heterocycle formed by R ⁴ and R ^U together with the carbon atom to which they are bonded" include the following rings.

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

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

As used herein, "may be substituted with substituent group α" means "may be substituted with one or more groups selected from substituent group α". The same applies to the substituent groups β, γ, γ', etc.

"Substituted alkyl", "Substituted alkenyl", "Substituted alkynyl", "Substituted alkyloxy", "Substituted alkenyloxy", "Substituted alkynyloxy", "Substituted alkylcarbonyloxy", "Substituted alkenylcarbonyloxy", "Substituted alkynyl""carbonyloxy","substitutedalkylcarbonyl","substitutedalkenylcarbonyl","substitutedalkynylcarbonyl","substitutedalkyloxycarbonyl","substitutedalkenyloxycarbonyl","substitutedalkynyloxycarbonyl","substitutedalkylsulfanyl"," Substituents such as "substituted alkenylsulfanyl", "substituted alkynylsulfanyl", "substituted alkylsulfinyl", "substituted alkenylsulfinyl", "substituted alkynylsulfinyl", "substituted alkylsulfonyl", "substituted alkenylsulfonyl", "substituted alkynylsulfonyl", etc. Examples 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, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl,
Alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, unsubstituted with substituent group α alkylcarbonyloxy which may be substituted with substituent group α, alkenylcarbonyloxy which may be substituted with substituent group α, alkynylcarbonyloxy which may be optionally substituted with substituent group α, alkylcarbonyl which may be 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, 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, alkenyl optionally substituted with substituent group α Sulfanyl, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, substituted with substituent group α Alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α,
Amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, and optionally substituted with substituent group β. sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic carbocyclic group optionally substituted with substituent group γ group heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy which may be substituted with substituent group γ, aromatic heterocyclic oxy which may be substituted with substituent group γ', non-aromatic heterocyclic oxy which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocycle optionally substituted with substituent group γ Ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, unsubstituted 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', substituent group γ Aromatic carbocyclic oxycarbonyl optionally substituted with , non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ Carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, substituted with substituent group γ' Non-aromatic carbocyclic alkyloxy, optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy, optionally substituted with substituent group γ', substituent Aromatic carbocyclic alkyloxycarbonyl optionally substituted with group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic alkyloxycarbonyl group, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituent group γ' Optionally substituted non-aromatic carbocyclic sulfanyl, 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 heterocycle optionally substituted with substituent group γ Ring sulfinyl, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, even if substituted with substituent group γ' Good non-aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

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

Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, optionally substituted with substituent group α Alkynyl, 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 Alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be 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 which may be 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 carbocyclic group optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyl which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyl optionally substituted with 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, optionally substituted with substituent group γ' Non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', substituent group γ Aromatic carbocyclic sulfanyl optionally substituted with , 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 group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' Carbocyclic sulfinyl, aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', even if substituted with substituent group γ Good aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and substituted with substituent group γ' Non-aromatic heterocyclic sulfonyl which may be

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

Substituent group γ': substituent group γ and oxo.

"substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocyclic oxy", "substituted aromatic heterocyclic oxy", "substituted aromatic carbocyclic carbonyloxy", "substituted "aromatic heterocycle carbonyloxy", "substituted aromatic carbocycle carbonyl", "substituted aromatic heterocycle carbonyl", "substituted aromatic carbocycle oxycarbonyl", "substituted aromatic heterocycle oxycarbonyl", "substituted aromatic "carbocyclic sulfanyl", "substituted aromatic heterocyclic sulfanyl", "substituted aromatic carbocyclic sulfinyl", "substituted aromatic heterocyclic sulfinyl", "substituted aromatic carbocyclic sulfonyl", "substituted aromatic heterocyclic sulfonyl", and Substituents on the rings of "aromatic carbocycles" and "aromatic heterocycles" such as "substituted aromatic carbocycles formed by R ⁵ and R ⁷ together with the carbon atoms to which they are bonded" include: The following substituent group B may be mentioned. 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, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl,
Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, optionally substituted with substituent group α Alkyloxy, optionally substituted alkenyloxy with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, substituent group α Alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, optionally substituted with substituent group α Good alkenylcarbonyl, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, substituent Alkynyloxycarbonyl optionally substituted with group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, substituted with substituent group α alkynylsulfanyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, substituent group Alkylsulfonyl optionally substituted with α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,
Amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, and optionally substituted with substituent group β. sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic carbocyclic group optionally substituted with substituent group γ group heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy which may be substituted with substituent group γ, aromatic heterocyclic oxy which may be substituted with substituent group γ', non-aromatic heterocyclic oxy which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocycle optionally substituted with substituent group γ Ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, unsubstituted 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', substituent group γ Aromatic carbocyclic oxycarbonyl optionally substituted with , non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ Carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, even if substituted with substituent group γ' Good non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituted with substituent group γ aromatic carbocyclic alkyloxy which may be substituted with the substituent group γ', non-aromatic carbocyclic alkyloxy which may be substituted with the substituent group γ', Non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, even substituted with substituent group γ' Good non-aromatic carbocyclic alkyloxycarbonyl, 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', even substituted with substituent group γ Good aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituent group Non-aromatic carbocyclic sulfanyl optionally substituted with γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic ring optionally substituted with substituent group γ' Sulfanyl, aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ group heterocyclic sulfinyl, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, substituent group γ' non-aromatic carbocyclic sulfonyl which may be optionally substituted, aromatic heterocyclic sulfonyl which may be optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

"Substituted non-aromatic carbocyclic group", "Substituted non-aromatic heterocyclic group", "Substituted non-aromatic carbocyclic oxy", "Substituted non-aromatic heterocyclic oxy", "Substituted non-aromatic carbocyclic carbonyl""oxy","substituted non-aromatic heterocyclic carbonyloxy", "substituted non-aromatic carbocyclic carbonyl", "substituted non-aromatic heterocyclic carbonyl", "substituted non-aromatic carbocyclic oxycarbonyl", "substituted non-aromatic "heterocyclic oxycarbonyl", "substituted non-aromatic carbocyclic sulfanyl", "substituted non-aromatic heterocyclic sulfanyl", "substituted non-aromatic carbocyclic sulfinyl", "substituted non-aromatic heterocyclic sulfinyl", "substituted non-aromatic "substituted non-aromatic carbocyclic sulfonyl", "substituted non-aromatic heterocyclic sulfonyl", "substituted non-aromatic carbocyclic diyl", "substituted non-aromatic heterocyclic diyl", "substituted non-aromatic carbocyclic oxyimino", "substituted non-aromatic "Substituted non-aromatic carbocyclic ring formed by R ⁵ and R ⁷ together with the carbon atom to which they are bonded", "A substituted non-aromatic carbocycle formed by R ⁷ and R ⁸ together with the carbon atom to which they are bonded""Substituted non-aromatic carbocycle formed by R ⁷ and R ⁸ together with the carbon atoms to which they are bonded" and "Substituted non-aromatic heterocycle formed by R 7 and R 8 together with the carbon atoms to which they bond" and "R ⁴ and R ^U bond Examples of substituents on the rings of the "non-aromatic carbocycle" and "non-aromatic heterocycle" of the "substituted non-aromatic heterocycle" that are formed together with carbon atoms include the following substituent group C. It will be done. 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.

When "non-aromatic carbocycle" and "non-aromatic heterocycle" are substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are substituted as shown below.

Examples of substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following substituent group D. It 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, optionally substituted with substituent group α Alkynyl, 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 Alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be 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 which may be substituted with substituent group α;
Amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, and optionally substituted with substituent group β. sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic carbocyclic group optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyl which may be substituted with substituent group γ', substituent Aromatic carbocyclic carbonyl optionally substituted with 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, optionally substituted with substituent group γ' Non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', substituent group γ Aromatic carbocyclic sulfanyl optionally substituted with , 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 group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' Carbocyclic sulfinyl, aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', even if substituted with substituent group γ Good aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and substituted with substituent group γ' Non-aromatic heterocyclic sulfonyl which may be

R ¹ , R ^1B , R ^1C , L, R ² , R ³ , X, Y, U, V, W, Z ^A , Z ^B , Z ^C , R ⁵ , R in the compound represented by formula (I) Preferred embodiments of ⁶ , R ⁷ , R ⁸ , R ^X , R ^Y , R ^V , R ^W , R ^U and R ⁴ are shown below. As the compound represented by formula (I), all combinations of the specific examples shown below are exemplified.

R ¹ is carboxy, cyano, 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, substituted or unsubstituted alkyl, substituted or unsubstituted aminosulfonyl, or substituted or unsubstituted non-aromatic heterocyclic sulfonyl (hereinafter referred to as a-1).
R ¹ is carboxy or -C(=O)-NR ^1B R ^1C ; R ^1B and R ^1C are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aminosulfonyl, or substituted or unsubstituted non-aromatic heterocyclic sulfonyl (hereinafter referred to as a-2).
R ¹ is carboxy (hereinafter referred to as a-3).

L is substituted or unsubstituted non-aromatic carbocyclic diyl, substituted or unsubstituted non-aromatic heterocyclic diyl, or substituted or unsubstituted alkylene (hereinafter referred to as b-1).
L is substituted or unsubstituted non-aromatic carbocyclic diyl or substituted or unsubstituted non-aromatic heterocyclic diyl (hereinafter referred to as b-2).
L is substituted or unsubstituted non-aromatic carbocyclic diyl (hereinafter referred to as b-3).
L is substituted or unsubstituted adamantanediyl or substituted or unsubstituted cyclohexanediyl (hereinafter referred to as b-4).
L is substituted or unsubstituted adamantane-2,2-diyl or substituted or unsubstituted cyclohexane-1,1-diyl (hereinafter referred to as b-5).
L is a non-aromatic carbocyclic diyl substituted with one or more substituents selected from substituent group a (substituent group a: cyano, alkyloxy, hydroxy and halogen) or unsubstituted non-aromatic carbocyclic diyl; (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 halogen-substituted cyclohexanediyl or unsubstituted cyclohexanediyl (hereinafter referred to as b-9).
L is cyclohexane-1,1-diyl substituted with 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 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, cyclohexane-1,1-diyl substituted with halogen; 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).
L is unsubstituted cyclohexane-1,1-diyl (hereinafter referred to as b-16).

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

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).
R ³ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino (hereinafter referred to as d-2).
R ³ is a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as d-3).
R ³ is a hydrogen atom, alkyl substituted with one or more substituents selected from substituent group b (substituent group b: dialkylamino, amino, and hydroxy), or unsubstituted alkyl (hereinafter referred to as d- 4).
R ³ is a hydrogen atom (hereinafter referred to as d-5).

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 is =CR ^x - or =N-, and R ^x is a hydrogen atom, halogen, or substituted or unsubstituted alkyl (hereinafter referred to as e-2).
X is =CR ^x - or =N-, and R ^x is 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).

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 is =CR ^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).

U is -CR ^U = or -N=, and R ^U is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbon Ring oxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, hydroxy, halogen, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group 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 is -CR ^U = or -N=, and R ^U is a hydrogen atom, halogen, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, or substituted or unsubstituted It is a substituted alkyloxy (hereinafter referred to as g-2).
U is -CR ^U = or -N=, and R ^U is a hydrogen atom, a halogen, a pyrazolyl-substituted non-aromatic carbocyclic oxy or an unsubstituted non-aromatic carbocyclic oxy, an oxetanyl-substituted non-aromatic It is aromatic heterocyclic oxy, unsubstituted non-aromatic heterocyclic oxy, or 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).

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 is -CR ^V = or -N=, and R ^V is a hydrogen atom, cyano, or substituted or unsubstituted carbamoyl (hereinafter referred to as h-2).
V is -CR ^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).

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).

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

Z ^B is -CR ⁵ R ⁶ -, -CR ⁵ =, -NR ⁵ - or -N=, and R ⁵ and R ⁶ are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic hetero The cyclic group, hydroxy or substituted or unsubstituted alkyl, or R ⁵ and R ⁶ together form oxo (hereinafter referred to as k-1).
Z ^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 substituted or unsubstituted alkyl, or R ⁵ and R ⁶ together form oxo (hereinafter referred to as k-2).
Z ^B is -CR ⁵ R ⁶ - or -CR ⁵ =, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, hydroxy, or a substituted or unsubstituted non-aromatic heterocyclic group. Substituted alkyl or R ⁵ and R ⁶ together form oxo (hereinafter referred to as k-3).
Z ^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 combined to form oxo (hereinafter referred to as k-4).
Z ^B is -CR ⁵ =, and 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 k-5) .
Z ^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 form oxo (hereinafter referred to as k-6).
Z ^B is -CR ⁵ R ⁶ -, 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 are to form oxo (hereinafter referred to as k-7).
Z ^B is -CR ⁵ =, and R ⁵ is a hydrogen atom or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as k-8).
Z ^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).
Z ^B is -CR ⁵ R ⁶ -, and R ⁵ and R ⁶ are each independently a hydrogen atom (hereinafter referred to as k-10).
Z ^B is -CR ⁵ =, and R ⁵ is a hydrogen atom (hereinafter referred to as k-11).
Z ^B is -CR ⁵ R ⁶ - or -CR ⁵ =, 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 form oxo (hereinafter referred to as k-12).
Z ^B is -CR ⁵ R ⁶ -, R ⁵ and R ⁶ are each independently a hydrogen atom, an unsubstituted non-aromatic heterocyclic group, or R ⁵ and R ⁶ together are Forms oxo (hereinafter referred to as k-13).
Z ^B is -CR ⁵ =, and R ⁵ is a hydrogen atom or an unsubstituted non-aromatic heterocyclic group (hereinafter referred to as k-14).
Z ^B is -CH ₂ - (hereinafter referred to as k-15).
Z ^B is -CH= (hereinafter referred to as k-16).

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, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or Unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted alkylsulfonyl, or R ⁷ and R ⁸ forms a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as 1-1) together with the carbon atom to which it is bonded.
Z ^C is -CR ⁷ R ⁸ -, -CR ⁷ = or -NR ⁷ -, and R ⁷ and R ⁸ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non- Aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted alkylsulfonyl, or R ⁷ and R ⁸ are bonded Together with carbon atoms, it may form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as 1-2).
Z ^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, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted alkylsulfonyl, or R ⁷ and R ⁸ together with the carbon atom to which they are attached Thus, a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle may be formed (hereinafter referred to as 1-3).
Z ^C is -CR ⁷ R ⁸ -, and R ⁷ and R ⁸ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted substituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic group substituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted alkylsulfonyl, or R ⁷ and R ⁸ taken together with the carbon atom to which they are attached are substituted or It may form an unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as 1-4).
Z ^C is -NR ⁷ -, and R ⁷ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group , substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl , substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or substituted or unsubstituted alkylsulfonyl (hereinafter referred to as 1-5).
Z ^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, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, or R ⁷ and R ⁸ taken together with the carbon atoms to which they are attached are substituted or unsubstituted Forms a non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as 1-6).
Z ^C is -CR ⁷ R ⁸ -, and R ⁷ and R ⁸ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted Substituted non-aromatic heterocyclic group, or R ⁷ and R ⁸ together with the carbon atoms to which they are attached represent a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as l-7).
Z ^C is -NR ⁷ -, and R ⁷ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group , substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl , or a substituted or unsubstituted non-aromatic carbocyclic sulfonyl (hereinafter referred to as 1-8).
Z ^C is -CR ⁷ R ⁸ - or -NR ⁷ -, and R ⁷ and R ⁸ each independently represent a hydrogen atom, substituent group c (substituent group c: halogen, hydroxy, alkyloxy, non- one or more substituents selected from aromatic carbocyclic groups, halogen-substituted non-aromatic carbocyclic groups, non-aromatic heterocyclic groups, non-aromatic heterocyclic carbonyls, and aromatic carbocyclic groups) one or more substituents selected from alkyl substituted with a group or unsubstituted alkyl, substituent group d (substituent group d: alkyloxy substituted with halogen, alkyloxy, cyano, hydroxy, haloalkyl, and phenyl) -substituted non-aromatic carbocyclic group or unsubstituted non-aromatic carbocyclic group, haloalkyl-substituted non-aromatic heterocyclic group or unsubstituted non-aromatic heterocyclic group, substituent group Aromatic carbocyclic group substituted with one or more substituents selected from e (substituent group e: halogen, alkyl, haloalkyl, alkyloxy, and cyano) or unsubstituted aromatic carbocyclic group, substituent An aromatic heterocyclic group substituted with one or more substituents selected from group f (substituent group f: alkyl, halogen, haloalkyl, alkyloxy, hydroxy, and cyano) or an unsubstituted aromatic heterocyclic group , unsubstituted non-aromatic carbocycle oxycarbonyl, unsubstituted non-aromatic heterocycle oxycarbonyl, unsubstituted non-aromatic carbocycle sulfonyl, or R ⁷ and R ⁸ taken together with the bonding carbon atom , halogen-substituted non-aromatic carbocycle or unsubstituted non-aromatic carbocycle, or substituent group g (substituent group g: alkyl, haloalkyl, alkylcarbonyl, phenyl-substituted alkyloxycarbonyl, alkyl one or more substituents selected from (oxycarbonyl, non-aromatic heterocyclic group, alkylcarbamoyl, non-aromatic carbocyclic group, aromatic heterocyclic group, and halogen-substituted aromatic heterocyclic group) form a non-aromatic heterocycle substituted with or an unsubstituted non-aromatic heterocycle. (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 hetero A cyclic group, or R ⁷ and R ⁸ together with the bonded carbon atoms are a halogen-substituted non-aromatic carbocycle or an unsubstituted non-aromatic carbocycle, or selected from substituent group g (hereinafter referred to as 1-10).
Z ^C is -NR ⁷ -, and R ⁷ is a hydrogen atom, alkyl substituted with one or more substituents selected from substituent group c, or unsubstituted alkyl, selected from substituent group d Non-aromatic carbocyclic group or unsubstituted non-aromatic carbocyclic group substituted with one or more substituents, non-aromatic heterocyclic group substituted with haloalkyl or unsubstituted non-aromatic heterocyclic group group, an aromatic carbocyclic group substituted with one or more substituents selected from substituent group e, or an unsubstituted aromatic carbocyclic group, one or more substituents selected from substituent group f. Substituted aromatic heterocyclic group or unsubstituted aromatic heterocyclic group, unsubstituted non-aromatic carbocycle oxycarbonyl, unsubstituted non-aromatic heterocycle oxycarbonyl or unsubstituted non-aromatic carbocycle It is sulfonyl (hereinafter referred to as l-11).
Z ^C is -CR ⁷ R ⁸ -, and R ⁷ and R ⁸ are each independently unsubstituted alkyl (hereinafter referred to as 1-12).
Z ^C is -NR ⁷ -, and R ⁷ is unsubstituted alkyl (hereinafter referred to as 1-13).

R ⁴ is a hydrogen atom, 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 aromatic heterocycleoxy, 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 Group heterocycle carbonyl, or R ⁴ and R ^U together with the carbon atoms to which they are bonded form a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as m-1).
^R4 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 Substituted or unsubstituted aromatic heterocyclicoxy, 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 heterocyclic group Carbonyl, or R ⁴ and R ^U together with the bonded carbon atom form a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as m-2).
^R4 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 Substituted 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 heterocycle formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic carbonyl, or R ⁴ and R ^U are bonded Together with carbon atoms, it forms a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as m-3).
R ⁴ is a substituent group h (substituent group h: halogen, hydroxy, alkyloxy, cyano, alkylcarbonyloxy, substituted aromatic heterocyclic group (substituent: alkyl or alkyloxy), non-aromatic heterocyclic group group, substituted non-aromatic heterocyclic group (substituent: aromatic heterocyclic group, alkyl or halogen), aromatic heterocyclic amino, aromatic carbocyclic group, and aromatic carbon substituted with alkyloxy alkyloxy substituted with one or more substituents selected from cyclic groups) or unsubstituted alkyloxy;
Substituent group j (substituent group j: alkyl, halogen, haloalkyl, cyanoalkyl, alkylcarbonyl, alkylcarbamoyl, alkyloxycarbonyl, alkyloxyalkyl, alkylsulfonylalkyl, non-aromatic heterocyclic group, substituted aromatic heterocycle Formula group (substituent: 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 (substituent: 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 heterocyclic oxy or unsubstituted non-aromatic heterocyclic oxy;
Substituent group k (substituent group k: alkyl, halogen, haloalkyl, alkyloxy, alkylsulfonyl, haloalkylamino, alkylamino, aromatic heterocyclic group, halogen-substituted non-aromatic heterocyclic group, non-aromatic group heterocyclic group, halogen-substituted aromatic heterocyclic group, halogen-substituted aromatic heterocyclic amino, halogen-substituted non-aromatic heterocyclic alkyl, non-aromatic carbocyclic oxy, and non-aromatic carbocyclic oxy or unsubstituted non-aromatic carbocyclic oxy substituted with one or more substituents selected from halogen-substituted non-aromatic carbocyclic iminooxy;
aromatic carbocyclic oxy;
Substituent group 1 (substituent group 1: halogen, aromatic carbocyclic group, aromatic carbocyclic group substituted with alkyloxy, non-aromatic heterocyclic group, and substituted non-aromatic heterocyclic group) (Substituent: aromatic heterocyclic group, non-aromatic heterocyclic group substituted with alkyl or halogen), and one or more substituents selected from halogen-substituted non-aromatic carbocyclic oximino) alkyl substituted with or unsubstituted alkyl;
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) alkenyl or unsubstituted alkenyl 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 substituted with aromatic heterocyclic group) group, aromatic heterocyclic group, aromatic carbocyclic sulfonyl, aromatic carbocyclic carbonyl, alkyl, and aromatic heterocyclic group substituted with haloalkyl). amino or unsubstituted amino;
Carbamoyl substituted with haloalkyl or unsubstituted carbamoyl;
Hydroxy;
halogen;
Aromatic carbocyclic group substituted with alkyloxyalkyl or unsubstituted aromatic carbocyclic group;
unsubstituted aromatic heterocyclic group;
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) cyclic group or unsubstituted non-aromatic heterocyclic group;
A non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group p (substituent group p: carbamoyl and dialkylcarbamoyl) or an unsubstituted non-aromatic carbocyclic group;
Substituent group q (substituent group q: aromatic heterocyclic group, haloalkyl, halogen-substituted non-aromatic heterocyclic group, halogen-substituted aromatic heterocyclic group, halogen, and alkyloxy ) or unsubstituted non-aromatic heterocyclic carbonyl substituted with one or more substituents selected from;
non-aromatic carbocyclic oximino substituted with halogen;
Alternatively, R ⁴ and R ^U together with the carbon atoms to which they are bonded form a halogen-substituted non-aromatic heterocycle or an unsubstituted non-aromatic heterocycle (hereinafter referred to as m-4).
R ⁴ is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted carbamoyl, or substituted or unsubstituted non-aromatic It is an aromatic heterocyclic carbonyl (hereinafter referred to as m-5).
^R4 is alkyloxy or unsubstituted alkyloxy substituted with one or more substituents selected from substituent group h, non-aromatic substituted with one or more substituents selected from substituent group j heterocyclic oxy or unsubstituted non-aromatic heterocyclic oxy, non-aromatic carbocyclic oxy substituted with one or more substituents selected from substituent group k, or unsubstituted non-aromatic carbocyclic oxy, haloalkyl; Substituted carbamoyl or unsubstituted carbamoyl, or non-aromatic heterocyclic carbonyl or unsubstituted non-aromatic heterocyclic carbonyl substituted with one or more substituents selected from substituent group q (hereinafter, m-6).
R ⁴ is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, or substituted or unsubstituted non-aromatic carbocyclic oxy (hereinafter referred to as m-7).
R ⁴ is alkyloxy or unsubstituted alkyloxy substituted with one or more substituents selected from substituent group h, non-aromatic substituted with one or more substituents selected from substituent group j Heterocyclic oxy or unsubstituted non-aromatic heterocyclic oxy, or non-aromatic carbocyclic oxy or unsubstituted non-aromatic carbocyclic oxy substituted with one or more substituents selected from substituent group k. Yes (hereinafter referred to as m-8).
R ⁴ is substituted or unsubstituted alkyloxy (hereinafter referred to as m-9).
R ⁴ is alkyloxy substituted with one or more substituents selected from substituent group h or unsubstituted alkyloxy (hereinafter referred to as m-10).
R ⁴ is substituted or unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as m-11).
R ⁴ is a non-aromatic heterocyclic oxy substituted with one or more substituents selected from substituent group j or an unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as m-12).
R ⁴ is substituted or unsubstituted non-aromatic carbocyclic oxy (hereinafter referred to as m-13).
R ⁴ is 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-14).
R ⁴ is a non-aromatic carbocyclic oxy substituted with one or more substituents selected from substituent group k (hereinafter referred to as m-15).
R ⁴ is substituted non-aromatic carbocyclic oxy (substituent: non-aromatic heterocyclic group substituted with halogen) (hereinafter referred to as m-16).
R ⁴ is substituted non-aromatic heterocyclic oxy (substituent: aromatic heterocyclic group) (hereinafter referred to as m-17).
R ⁴ is substituted non-aromatic heterocyclic oxy (substituent: aromatic heterocyclic group substituted with halogen) (hereinafter referred to as m-18).
R ⁴ is a substituted non-aromatic heterocyclic oxy (substituent: haloalkyl) (hereinafter referred to as m-19).
R ⁴ is substituted non-aromatic carbocyclic oxy (substituent: haloalkylamino) (hereinafter referred to as m-20).

で示される基、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およびＲ^４の好ましい態様を以下に示す。 Further, as the compound represented by formula (I), all combinations of the specific examples shown below are exemplified.
formula:

Groups 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 , Preferred embodiments of R ^U and R ⁴ are shown below.

で示される基は、以下の（Ｉ－ａ）、（Ｉ－ｂ）、（Ｉ－ｃ）、（Ｉ－ｄ）、（Ｉ－ｅ）、（Ｉ－ｆ）、（Ｉ－ｇ）、（Ｉ－ｈ）または（Ｉ－ｉ）である。

formula:

The groups represented by are the following (I-a), (I-b), (I-c), (I-d), (I-e), (If), (I-g), (Ih) or (Ii).

で示される基は、（Ｉ－ａ）、（Ｉ－ｂ）、（Ｉ－ｈ）または（Ｉ－ｉ）である。 formula:

The group represented by is (Ia), (Ib), (Ih) or (Ii).

で示される基は、（Ｉ－ａ）、（Ｉ－ｂ）または（Ｉ－ｉ）である。 formula:

The group represented by is (Ia), (Ib) or (Ii).

で示される基は、（Ｉ－ａ）または（Ｉ－ｂ）である。 formula:

The group represented by is (Ia) or (Ib).

で示される基は、（Ｉ－ａ）である。 formula:

The group represented by is (Ia).

で示される基は、（Ｉ－ｂ）である。 formula:

The group represented by is (Ib).

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

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

R ^U is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-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 aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as gg-1).
R ^U is a hydrogen atom, a halogen, 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). ).
R ^U is a hydrogen atom, halogen, pyrazolyl-substituted non-aromatic carbocyclic oxy or unsubstituted non-aromatic carbocyclic oxy, oxetanyl-substituted non-aromatic heterocyclic oxy or unsubstituted non-aromatic heterocyclic ring It is oxy or unsubstituted alkyloxy (hereinafter referred to as gg-3).
R ^U is a hydrogen atom (hereinafter referred to as gg-4).

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

R ⁷ and R ⁸ each independently represent 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 a substituted or unsubstituted non-aromatic heterocyclic group. Substituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Substituted non-aromatic carbocycle sulfonyl, substituted or unsubstituted alkylsulfonyl, or R ⁷ and R ⁸ taken together with the carbon atoms to which they are attached, substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted (hereinafter referred to as ll-1).
R ⁷ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocycle oxycarbonyl, substituted or unsubstituted non-aromatic heterocycle oxycarbonyl, substituted or unsubstituted non-aromatic carbocycle It is sulfonyl or substituted or unsubstituted alkylsulfonyl (hereinafter referred to as 11-5).
R ⁷ and R ⁸ each independently represent 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 a substituted or unsubstituted non-aromatic heterocyclic group. Substituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Substituted non-aromatic carbocycle sulfonyl, or R ⁷ and R ⁸ together with the bonding carbon atoms form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as ll-6).
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 R ⁷ and R ⁸ together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as ll-7).
R ⁷ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocycle oxycarbonyl, substituted or unsubstituted non-aromatic heterocycle oxycarbonyl, or substituted or unsubstituted non-aromatic carbon It is a ring sulfonyl (hereinafter referred to as ll-8).
R ⁷ and R ⁸ are each independently a hydrogen atom, an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group c, and one or more substituents selected from substituent group d. non-aromatic carbocyclic group substituted with group or unsubstituted non-aromatic carbocyclic group, non-aromatic heterocyclic group substituted with haloalkyl or unsubstituted non-aromatic heterocyclic group, substituent Aromatic carbocyclic group or unsubstituted aromatic carbocyclic group substituted with one or more substituents selected from group e, aromatic substituted with one or more substituents selected from substituent group f group heterocyclic group or unsubstituted aromatic heterocyclic group, unsubstituted non-aromatic carbocyclic oxycarbonyl, unsubstituted non-aromatic heterocyclic oxycarbonyl, unsubstituted non-aromatic carbocyclic sulfonyl, or R ⁷ and R ⁸ together with the bonded carbon atoms are a halogen-substituted non-aromatic carbocycle or an unsubstituted non-aromatic carbocycle, or one or more substituents selected from substituent group g. Forms a non-aromatic heterocycle substituted with a group or an unsubstituted non-aromatic heterocycle (hereinafter referred to as ll-9).
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 R ⁷ and R ⁸ are a bond a non-aromatic carbocycle substituted with a halogen or an unsubstituted non-aromatic carbocycle, or a non-aromatic substituted with one or more substituents selected from substituent group g form a group heterocycle or an unsubstituted non-aromatic heterocycle (hereinafter referred to as ll-10).
R ⁷ and R ⁸ are each independently unsubstituted alkyl (hereinafter referred to as ll-11).
^R7 is a hydrogen atom, an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group c, or a non-aromatic substituted with one or more substituents selected from substituent group d. 1 selected from group carbocyclic group or unsubstituted non-aromatic carbocyclic group, haloalkyl-substituted non-aromatic heterocyclic group or unsubstituted non-aromatic heterocyclic group, substituent group e An aromatic carbocyclic group substituted with the above substituents or an unsubstituted aromatic carbocyclic group; an aromatic heterocyclic group substituted with one or more substituents selected from substituent group f or a non-substituted aromatic carbocyclic group; Substituted aromatic heterocyclic group, unsubstituted non-aromatic carbocycle oxycarbonyl, unsubstituted non-aromatic heterocycle oxycarbonyl or unsubstituted non-aromatic carbocycle sulfonyl (hereinafter referred to as 11-12) ).
R ⁷ is unsubstituted alkyl (hereinafter referred to as ll-13).
R ⁷ and R ⁸ together with the carbon atoms to which they are bonded form an unsubstituted non-aromatic heterocycle (hereinafter referred to as ll-14).
R ⁷ and R ⁸ together with the carbon atoms to which they are bonded form a halogen-substituted non-aromatic carbocycle (hereinafter referred to as ll-15).
R ⁷ is a substituted non-aromatic carbocyclic group (substituent: halogen) (hereinafter referred to as 11-16).
R ⁷ is substituted alkyl (substituent: alkyloxy) (hereinafter referred to as 11-17).

R ¹ is (a-1), (a-2) or (a-3) above.

L is the above (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) be.

R ² is (c-1), (c-2) or (c-3) above.

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

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

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

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).

で示される基は、（Ｉ－ａ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^５およびＲ^６は、（ｋｋ－９）であり、
Ｒ^７およびＲ^８は、（ｌｌ－１４）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１７）である。 (1-A)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ia),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁵ and R ⁶ are (kk-9),
R ⁷ and R ⁸ are (ll-14),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-17).

で示される基は、（Ｉ－ｂ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^７は、（ｌｌ－１５）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－３）であり、
Ｒ^４は、（ｍ－１７）である。 (1-B)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ib),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁷ is (ll-15),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-3),
R ⁴ is (m-17).

で示される基は、（Ｉ－ｂ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^７は、（ｌｌ－１５）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１６）である。 (1-C)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ib),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁷ is (ll-15),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-16).

で示される基は、（Ｉ－ｂ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^７は、（ｌｌ－１３）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１６）である。 (1-D)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ib),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁷ is (ll-13),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-16).

で示される基は、（Ｉ－ｉ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^５およびＲ^６は、（ｋｋ－９）であり、
Ｒ^７およびＲ^８は、（ｌｌ－１４）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１８）である。 (1-E)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (I-i),
R ^x is (ee-4),
R ^Y is (ff-3),
R ⁵ and R ⁶ are (kk-9),
R ⁷ and R ⁸ are (ll-14),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-18).

で示される基は、（Ｉ－ａ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^５およびＲ^６は、（ｋｋ－９）であり、
Ｒ^７およびＲ^８は、（ｌｌ－１４）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１６）である。 (1-F)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ia),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁵ and R ⁶ are (kk-9),
R ⁷ and R ⁸ are (ll-14),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-16).

で示される基は、（Ｉ－ａ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^５およびＲ^６は、（ｋｋ－９）であり、
Ｒ^７およびＲ^８は、（ｌｌ－１４）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１９）である。
（１－Ｈ）
一つの実施態様として、式（Ｉ）で示される化合物は、式：

で示される基は、（Ｉ－ａ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^５およびＲ^６は、（ｋｋ－９）であり、
Ｒ^７およびＲ^８は、（ｌｌ－１４）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－２０）である。
（１－Ｉ）
一つの実施態様として、式（Ｉ）で示される化合物は、式：

で示される基は、（Ｉ－ｂ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^７は、（ｌｌ－１７）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１６）である。 (1-G)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ia),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁵ and R ⁶ are (kk-9),
R ⁷ and R ⁸ are (ll-14),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-19).
(1-H)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ia),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁵ and R ⁶ are (kk-9),
R ⁷ and R ⁸ are (ll-14),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-20).
(1-I)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ib),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁷ is (ll-17),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-16).

で示される基は、（Ｉ－ａ）であり、
Ｒ^ｘは、（ｅｅ－４）であり、
Ｒ^Ｙは、（ｆｆ－３）であり、
Ｒ^Ｕは、（ｇｇ－４）であり、
Ｒ^５およびＲ^６は、（ｋｋ－９）であり、
Ｒ^７およびＲ^８は、（ｌｌ－１１）であり、
Ｒ^１は、（ａ－３）であり、
Ｌは、（ｂ－１４）であり、
Ｒ^２は、（ｃ－３）であり、
Ｒ^３は、（ｄ－５）であり、
Ｖは、（ｈ－６）であり、
Ｗは、（ｉ－４）であり、
Ｒ^４は、（ｍ－１６）である。 (1-J)
In one embodiment, the compound of formula (I) has the formula:

The group represented by is (Ia),
R ^x is (ee-4),
R ^Y is (ff-3),
R ^U is (gg-4),
R ⁵ and R ⁶ are (kk-9),
R ⁷ and R ⁸ are (ll-11),
R ¹ is (a-3),
L is (b-14),
R ² is (c-3),
R ³ is (d-5),
V is (h-6),
W is (i-4),
R ⁴ is (m-16).

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

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

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

Examples of pharmaceutically acceptable salts of the compound represented by formula (I) include compounds represented by formula (I) and 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, picoline, quinoline, etc.) and amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid, etc.). , trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfone acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to the present invention may form a solvate (for example, a hydrate, etc.), a co-crystal, and/or a crystal polymorph; The invention also encompasses various such solvates, co-crystals and polymorphs. A "solvate" may be coordinated with an arbitrary number of solvent molecules (eg, water molecules, etc.) with respect to the compound represented by formula (I). When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water, adhere to adsorbed water, or form a hydrate. Furthermore, crystal polymorphs may be formed by recrystallizing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. "Co-crystal" means that the compound or salt represented by formula (I) and the counter molecule exist in the same crystal lattice, and may contain any number of counter molecules.

The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to the present invention may form a prodrug, and the present invention also includes such various prodrugs. Prodrugs are derivatives of the compounds according to the invention that have chemically or metabolically degradable groups, which become pharmaceutically active compounds according to the invention in vivo upon solvolysis or under physiological conditions. It is. Prodrugs are compounds that undergo enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo and are converted to the compound represented by formula (I), and compounds that are hydrolyzed by gastric acid etc. to form the compound represented by formula (I). It includes compounds that are converted into the indicated compounds. Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.

When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or by reacting 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 -, and p-CH ₃ PhSO ₃ -.

The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
The compounds according to the invention may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of an injection solution or suspension. It can be administered as a pharmaceutical composition topically, for example in the form of a lotion, gel, ointment or cream, or in nasal or suppository form. Pharmaceutical compositions containing a compound according to the 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 mixing in a conventional manner. , granulation or coating methods. For example, the oral composition may be a tablet, granule, or capsule containing an excipient, a disintegrant, a binder, a lubricant, etc., and an active ingredient. In addition, the composition for injection may be in the form of a solution or suspension, may be sterilized, and may contain a preservative, a stabilizing agent, a buffering agent, and the like.

The pharmaceutical composition of the present invention is 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. In other words, it is useful for cold symptoms such as cough, runny nose, and fever, as well as symptoms such as wheezing and depressed breathing that occur when the symptoms become more severe, and also for diseases such as bronchiolitis and pneumonia that occur when these symptoms worsen. It is useful for

(Method for producing the compound according to the present invention)
The compound represented by 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 in the same manner as in ordinary organic chemistry experiments.
The compound represented by formula (I) according to the present invention can be synthesized with reference to techniques known in the art.

（式中、各記号は上記と同義であり、Ｒ^Ａは－Ｂ（ＯＨ）_２、－Ｓｎ（Ｃ１－Ｃ６アルキル）_３等、Ｒ^ＢはＣ１－Ｃ６アルキル等である。）
第１工程
化合物（Ａ－１）と化合物（Ａ－２）は、テトラヒドロフラン、トルエン、ジメチルホルムアミド、１，４－ジオキサン、エタノール、水などの単独または混合溶媒中で、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウムなどの金属触媒と、炭酸カリウムや炭酸水素ナトリウム、リン酸ナトリウムやリン酸水素ナトリウム、リン酸カリウム、リン酸水素カリウム、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシドなどの塩基を加えて、２０℃～溶媒の還流温度にて０．１時間～４８時間、好ましくは０．５時間～１２時間反応させることにより、化合物（Ａ－３）を得ることができる。 (Method A)

(In the formula, each symbol has the same meaning as above, R ^A is -B(OH) ₂ , -Sn(C1-C6 alkyl) ₃ , etc., and R ^B is C1-C6 alkyl, etc.)
First step Compound (A-1) and compound (A-2) are prepared using tetrakis(triphenylphosphine)palladium in a single or mixed solvent such as tetrahydrofuran, toluene, dimethylformamide, 1,4-dioxane, ethanol, and water. , bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, and other metal catalysts, as well as potassium carbonate, sodium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, and potassium phosphate. , potassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, etc., and the mixture is heated for 0.1 to 48 hours, preferably at 20°C to the reflux temperature of the solvent. Compound (A-3) can be obtained by reacting for 5 to 12 hours.

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

Third step Compound (A-4) is added to the compound (A-4) in a single or mixed solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, acetonitrile, water, etc., in the presence or absence of a base such as triethylamine, pyridine, diisopropylamine, 1-methylimidazole, etc. Compound (IA) can be obtained by reacting compound (A-5) with a dehydration condensation agent such as , dicyclohexylcarbodiimide, carbonyldiimidazole, EDC·HCl, or HATU.
Further, compound (A-4) in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethylformamide, etc., in the presence or absence of a base such as pyridine, triethylamine, diisopropylamine, 1-methylimidazole, Acid chloride is generated by adding an acylating reagent such as thionyl chloride or oxalyl chloride, compound (A-5) is added, and the mixture is heated at -20°C to 60°C, preferably -10°C to 30°C for 0.1 hour. Compound (IA) can also be obtained by reacting for 24 hours, preferably 0.5 to 12 hours.

（式中、各記号は上記と同義である。）
第１工程
化合物（Ｂ－１）に、１，４－ジオキサン、トルエン、テトラヒドロフラン、ジメチルホルムアミド、Ｎ－メチルピロリドンなどの溶媒中、トリエチルアミン、ジイソプロピルアミン、炭酸セシウム、炭酸カリウム、水素化ナトリムなどの塩基の存在下または非存在下、もしくはトルエンスルホン酸、酢酸、塩化水素、硫酸などの酸の存在下または非存在下で、化合物（Ａ－２）を加えて、２０℃～溶媒の還流温度、好ましくは４０℃～１２０℃で、０．１時間～４８時間、好ましくは０．５時間～１２時間反応させることにより、化合物（Ｂ－２）を得ることができる。
また、化合物（Ｂ－１）に、１，４－ジオキサン、トルエン、テトラヒドロフラン、ジメチルホルムアミド、Ｎ－メチルピロリドン、ブタノール、水等の単独または混合溶媒中で、Ｘａｎｔｐｈｏｓやジフェニルホスフィノフェロセン、Ｘ－Ｐｈｏｓ等の配位子の存在下または非存在下で、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム(ＩＩ)二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）等の金属触媒と、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸ナトリウム、リン酸水素ナトリウム、水酸化リチウム，水酸化ナトリウム等の塩基を加えて、化合物（Ａ－２）と、２０℃～溶媒の還流温度、場合によってはマイクロウェーブ照射下の温度で、０．１時間～４８時間、好ましくは０．５時間～１２時間反応させることにより、化合物（Ｂ－２）を得ることができる。 (Method B)

(In the formula, each symbol has the same meaning as above.)
1st step Compound (B-1) is added to a base such as triethylamine, diisopropylamine, cesium carbonate, potassium carbonate, sodium hydride, etc. in a solvent such as 1,4-dioxane, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, etc. or in the presence or absence of an acid such as toluenesulfonic acid, acetic acid, hydrogen chloride, or sulfuric acid, compound (A-2) is added, and the mixture is heated at a temperature of 20°C to the reflux temperature of the solvent, preferably Compound (B-2) can be obtained by reacting at 40°C to 120°C for 0.1 to 48 hours, preferably 0.5 to 12 hours.
In addition, compound (B-1) may be treated with Xantphos, diphenylphosphinoferrocene, or In the presence or absence of ligands such as -tert-butylphosphine) and bases such as potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydrogen phosphate, lithium hydroxide, and sodium hydroxide. and react with compound (A-2) for 0.1 to 48 hours, preferably 0.5 to 12 hours at 20°C to the reflux temperature of the solvent, or in some cases at a temperature under microwave irradiation. Compound (B-2) can be obtained by this.

Second to Third Steps Compound (IB) can be obtained by carrying out the second to third steps of Method A using compound (B-2).

（式中、各記号は上記と同義である。）
第１工程
化合物（Ｃ－１）に、ジメチルホルムアミド、テトラヒドロフラン、ジクロロメタン、アセトニトリル、水等の単独または混合溶媒中、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール、ＥＤＣ・ＨＣｌ、ＨＡＴＵ等の脱水縮合剤を加えて、さらにＮＨＲ^１ＢＲ^１Ｃと、トリエチルアミン、ピリジン、ジイソプロピルアミン、１－メチルイミダゾール、水素化ナトリウム等の塩基を加えて反応させることにより、化合物（Ｉ－Ｃ）を得ることができる。 (Method C)

(In the formula, each symbol has the same meaning as above.)
Step 1 Compound (IC) can be obtained by adding a dehydration condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, EDC.HCl, HATU, etc. to compound (C-1) in a single or mixed solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, acetonitrile, water, etc., and further adding NHR ^1B R ^1C and a base such as triethylamine, pyridine, diisopropylamine, 1-methylimidazole, sodium hydride, etc.

（式中、各記号は上記と同義である。）
第１工程
化合物（Ｄ－１）に、１，４－ジオキサン、ジメチルホルムアミド、水などの単独または混合溶媒中、ジブチルスタナン、塩化亜鉛、塩化アンモニウムなどの添加剤の存在下で、アジドトリメチルシラン、アジ化ナトリウム、トリブチルスズアジド等のアジド化合物を、６０℃～溶媒の還流温度、場合によってはマイクロウェーブ照射下の温度で、０．５～４８時間、好ましくは１時間～４時間反応させることにより、化合物（Ｉ－Ｄ）を得ることができる。 (D method)

(In the formula, each symbol has the same meaning as above.)
First Step Add azidotrimethylsilane to compound (D-1) in the presence of additives such as dibutylstannane, zinc chloride, ammonium chloride, etc. alone or in a mixed solvent such as 1,4-dioxane, dimethylformamide, and water. , sodium azide, tributyltin azide, etc., at 60°C to the reflux temperature of the solvent, and in some cases at a temperature under microwave irradiation, for 0.5 to 48 hours, preferably for 1 hour to 4 hours. , compound (ID) can be obtained.

（式中、各記号は上記と同義である。）
第１工程
化合物（Ｄ－１）に、メタノール、エタノール、テトラヒドロフラン、水などの単独または混合溶媒中で、炭酸カリウムやトリエチルアミンなどの塩基の存在下または非存在下、ヒドロキシアミン等を加え、室温～溶媒の還流温度、場合によってはマイクロウェーブ照射下の温度で反応させることにより、化合物（Ｅ－２）を得ることができる。 (E method)

(In the formula, each symbol has the same meaning as above.)
1st step Hydroxyamine, etc. is added to compound (D-1) in a solvent such as methanol, ethanol, tetrahydrofuran, water, etc. alone or in a mixed solvent, in the presence or absence of a base such as potassium carbonate or triethylamine. Compound (E-2) can be obtained by reacting at the reflux temperature of the solvent, or in some cases at a temperature under microwave irradiation.

2nd step Compound (E-2) is mixed with a base such as triethylamine, DBU, potassium carbonate, etc., and 1,1'-carbonyldiimidazole or Compound (IE) can be obtained by adding ethyl chloroformate and reacting at room temperature to the reflux temperature of the solvent.

（式中、Ｒは置換基群ｎから独立して選択される基であり、その他の各記号は上記と同義である。）
第１工程
化合物（Ｆ－１）に、１，４－ジオキサン、トルエン、テトラヒドロフラン、ジメチルホルムアミド、Ｎ－メチルピロリドン、ブタノール、水等の単独または混合溶媒中で、Ｘａｎｔｐｈｏｓやジフェニルホスフィノフェロセン、Ｘ－Ｐｈｏｓ、ＢＩＮＡＰ等の配位子の存在下または非存在下で、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム(II)二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）等の金属触媒と、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸ナトリウム、リン酸水素ナトリウム、水酸化リチウム，水酸化ナトリウム等の塩基を加えて、アミンと２０℃～溶媒の還流温度、場合によってはマイクロウェーブ照射下の温度で、０．１時間～４８時間、好ましくは０．５時間～１２時間反応させることにより、化合物（Ｆ－２）を得ることができる。 (F method)

(In the formula, R is a group independently selected from substituent group n, and each other symbol has the same meaning as above.)
1st step Compound (F-1) is mixed with Xantphos, diphenylphosphinoferrocene, X- Palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, in the presence or absence of a ligand such as Phos, BINAP, etc. Metal catalysts such as bis(tri-tert-butylphosphine), potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydrogen phosphate, lithium hydroxide, sodium hydroxide By adding a base such as and reacting with the amine at a temperature of 20 ° C. to the reflux temperature of the solvent, in some cases at a temperature under microwave irradiation, for 0.1 to 48 hours, preferably 0.5 to 12 hours, Compound (F-2) can be obtained.

Second Step Compound (IF) can be obtained by carrying out the first step of Method A or the first step of Method B using Compound (F-2).

（式中、各記号は上記と同義であり、Ｌｅａは脱離基、Ｒ^ｚｚは水素原子、Ｃ１－Ｃ６アルキル等、Ｒ^ｘｘおよびＲ^ｙｙはそれぞれ独立して、水素原子、Ｃ１－Ｃ６アルキル等、または、Ｒ^ｘｘおよびＲ^ｙｙが隣接する窒素原子と一緒になって環を形成する。）
第１工程
化合物（Ｇ－１）に、Ａ法の第１工程を実施することで化合物（Ｇ－２）を得ることができる。 (G method)

(In the formula, each symbol has the same meaning as 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, C1-C6 alkyl, etc. , or R ^xx and R ^yy together with adjacent nitrogen atoms form a ring.)
First step Compound (G-2) can be obtained by subjecting compound (G-1) to the first step of method A.

2nd step Compound (G-2) is reacted with sodium periodate or oxone in a mixed solvent such as 1,4-dioxane, tetrahydrofuran, water, etc. by adding ruthenium chloride or potassium osmate. (G-3) can be obtained. Alternatively, ozonide is obtained by ozone oxidation, and compound (G-3) can be obtained by treatment with a reducing agent such as zinc, dimethyl sulfide, or triphenylphosphine.

3rd step Compound (G-3) is mixed with sodium dihydrogen phosphate and chlorine in the presence of 2-methyl-2-butene, sulfamic acid, etc., alone or in a mixed solvent such as tetrahydrofuran, tert-butanol, or water. Compound (G-4) can be obtained by adding sodium chloride or the like and reacting.

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

（式中、各記号は上記と同義であり、Ｒ^ｘｘおよびＲ^ｙｙは水素原子、Ｃ１－Ｃ６アルキル、Ｒ^ｘｘおよびＲ^ｙｙが隣接する窒素原子と一緒になって環を形成する等である。）
第１工程
化合物（Ｇ－３）に、クロロホルム、テトラヒドロフラン、アセトニトリル、酢酸などの単独または混合溶媒中で、ＮＨＲ^ｙｙＲ^ｘｘと、水素化トリアセトキシホウ素ナトリウムや２－ピコリンボラン等の還元剤を加えて、室温～溶媒の還流温度で、０．１時間～４８時間、好ましくは０．５時間～８時間反応させることにより、化合物（Ｉ－Ｈ）を得ることができる。 (H method)

(In the formula, each symbol has the same meaning as above, R ^xx and R ^yy are hydrogen atoms, C1-C6 alkyl, R ^xx and R ^yy together with adjacent nitrogen atoms form a ring, etc. )
1st step Add NHR ^yy R ^xx and a reducing agent such as sodium triacetoxyborohydride or 2-picoline borane to compound (G-3) in a single or mixed solvent such as chloroform, tetrahydrofuran, acetonitrile, or acetic acid. Compound (IH) can be obtained by reacting at room temperature to the reflux temperature of the solvent for 0.1 to 48 hours, preferably 0.5 to 8 hours.

（式中、各記号は上記と同義であり、Ｒ^ｚｚおよびＲ^ｙｙは水素原子、Ｃ１－Ｃ６アルキル、芳香族炭素環式基、芳香族複素環式基等である。）
第１工程
化合物（Ｊ－１）に、テトラヒドロフラン、メタノール、トルエン、クロロホルムなどの単独または混合溶媒中で、パラジウム炭素や水酸化パラジウム、ラネーニッケル、酸化白金等の不均一系触媒存在下、接触水素化を行うことにより、化合物（Ｉ－Ｊ）を得ることができる。 (J method)

(In the formula, each symbol has the same meaning as above, and R ^zz and R ^yy are a hydrogen atom, a C1-C6 alkyl, an aromatic carbocyclic group, an aromatic heterocyclic group, etc.)
First step Compound (J-1) is subjected to catalytic hydrogenation in a single or mixed solvent such as tetrahydrofuran, methanol, toluene, or chloroform in the presence of a heterogeneous catalyst such as palladium on carbon, palladium hydroxide, Raney nickel, or platinum oxide. Compound (IJ) can be obtained by performing the following steps.

Since the compound according to the present invention has an anti-RSV effect, that is, a CPE (Cytopathic Effect, cytopathic effect) suppressing effect, a pharmaceutical composition containing the present compound can be used as a therapeutic agent and/or preventive agent for diseases such as bronchiolitis and pneumonia. It is useful as a drug.
Furthermore, the compound according to the present invention has usefulness as a medicine, and preferably has one or more of the following excellent characteristics.
a) It has a weak inhibitory effect on CYP enzymes (eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.).
b) Shows good pharmacokinetics such as high bioavailability and appropriate clearance.
c) High metabolic stability.
d) Does not exhibit an irreversible inhibitory effect on CYP enzymes (eg, CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) exhibits high solubility;
h) It has a high RSV type A CPE inhibitory effect and a high RSV type B inhibitory effect.
i) Decrease the viral load in the lungs.

The pharmaceutical composition of the present invention can be administered either orally or parenterally. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drops, ear drops, and intravaginal administration.

For oral administration, solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.), liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, etc.) are prepared according to conventional methods. The drug may be administered in any commonly used dosage form, such as a limonade, an alcoholic beverage, an aromatic perfume, an extract, a decoction, a tincture, etc.). The tablets may be sugar-coated, film-coated, enteric-coated, extended-release, troches, sublingual, buccal, chewable or orally disintegrating tablets; powders and granules may be dry syrups; Alternatively, the capsules may be soft capsules, microcapsules or sustained release capsules.

For parenteral administration, injections, drops, external preparations (e.g. eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, gargles, enemas, It can be suitably administered in any commonly used dosage form such as ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.). The injection may be an emulsion of O/W, W/O, O/W/O, W/O/W type, or the like.

A pharmaceutical composition can be prepared by mixing an effective amount of the compound according to the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, as necessary. can. Furthermore, by appropriately changing the effective amount, dosage form, and/or various pharmaceutical additives of the compound according to the present invention, the pharmaceutical composition can be made into a pharmaceutical composition for children, the elderly, critically ill patients, or surgery. It can also be a thing. For example, pediatric pharmaceutical compositions may be used for neonates (less than 4 weeks after birth), infants (from 4 weeks after birth to less than 1 year), infants (from 1 year to 7 years), children (from 7 years old to less than 15 years), or children (from 7 years old to less than 15 years old). It can be administered to patients between the ages of 18 and 18. For example, geriatric pharmaceutical compositions may be administered to patients 65 years of age or older.

The dosage of the pharmaceutical composition of the present invention is desirably set in consideration of the patient's age, weight, type and severity of disease, administration route, etc., but when administered orally, it is usually 0.05 to 100 mg/day. kg/day, preferably within the range of 0.1 to 10 mg/kg/day. In the case of parenteral administration, the dose is usually 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day, although it varies greatly depending on the route of administration. This may be administered once to several times a day.

The compounds according to the present invention include L protein inhibitors, F protein inhibitors, N protein enzyme inhibitors, etc. (hereinafter referred to as concomitant drugs) for the purpose of enhancing the action of the compound or reducing the dosage of the compound. Can be used in combination with At this time, the timing of administering the compound according to the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times. Furthermore, the compound according to the present invention and the concomitant drug may be administered as two or more formulations containing the respective active ingredients, or as a single formulation containing these active ingredients.

The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. Further, the compounding ratio of the compound according to the present invention and the concomitant drug can be appropriately selected depending on the subject of administration, administration route, target disease, symptoms, combination, etc. For example, when the subject to be administered 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 according to the present invention.

EXAMPLES 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 thereto.

Furthermore, the abbreviations used in this specification represent the following meanings.
Boc ₂ O: di-tert-butyl dicarbonate DIAD: diisopropylazodicarboxylate 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)dipalladium 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 ]Palladium(II)
X-Phos: 2,4,6-triisopropyl-2'-(dicyclohexylphosphino)biphenyl

(Compound identification method)
NMR analysis obtained in each example was conducted at 400 MHz and measured using DMSO-d ₆ and CDCl ₃ . Furthermore, when NMR data is shown, there are cases where not all measured peaks are listed.
RT in the specification represents retention time in LC/MS: liquid chromatography/mass spectrometry, and was measured under the following conditions.
(Method 1)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (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: After performing a linear gradient of 5% to 100% solvent [B] in 3.5 minutes , 100% solvent [B] was maintained for 0.5 minutes.
(Method 2)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (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: After performing a linear gradient of 5% to 100% solvent [B] in 3.5 minutes , 100% solvent [B] was maintained for 0.5 minutes.
(Method 3)
Column: Shim-pack XR-ODS (2.2μm, i.d.50x3.0mm) (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% to 100% solvent [B] is performed in 3 minutes, and 0.5 100% solvent [B] was maintained for minutes.
(Method 4)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (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: After performing a linear gradient of 5% to 100% solvent [B] in 3.5 minutes , 100% solvent [B] was maintained for 0.5 minutes.
(Method 5)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (Waters)
Flow rate: 0.8 mL/min UV detection wavelength: 254nm (detection range 190-500nm)
Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: After performing a linear gradient of 5% to 100% solvent [B] in 3.5 minutes, 100% solvent for 0.5 minutes [B] was maintained.
(Method 6)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (Waters)
Flow rate: 0.8 mL/min UV detection wavelength: 254nm (detection range 190-400nm)
Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: After performing a linear gradient of 5% to 100% solvent [B] in 3.5 minutes, 100% solvent for 0.5 minutes [B] was maintained.
(Method 7)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (Waters)
Flow rate: 0.8 mL/min UV detection wavelength: 254nm (detection range 190-500nm)
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: After performing a linear gradient of 70% to 100% solvent [B] in 3.5 minutes , 100% solvent [B] was maintained for 0.5 minutes.
(Method 8)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (Waters)
Flow rate: 0.8 mL/min UV detection wavelength: 254nm (detection range 190-500nm)
Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: After performing a linear gradient of 50% to 100% solvent [B] in 3.5 minutes, 100% solvent for 0.5 minutes [B] was maintained.
(Method 9)
Column: ACQUITY UPLC® BEH C18 (1.7μm i.d. 2.1x50mm) (Waters)
Flow rate: 0.6 mL/min UV detection wavelength: 254nm (detection range 190-500nm)
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: After performing a linear gradient of 25% to 95% solvent [B] in 1.5 minutes , 95% solvent [B] was maintained for 1.5 minutes.
(Method 10)
Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm i.d. 2.1x50mm) (Waters)"
Flow rate: 0.6 mL/min UV detection wavelength: 254nm (detection range 190-500nm)
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: After performing a linear gradient of 25% to 95% solvent [B] in 1.5 minutes , 95% solvent [B] was maintained for 1.5 minutes.
(Method 11)
Column: ACQUITY UPLC® CSH C18 (1.7μm i.d. 2.1x50mm) (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: After performing a linear gradient of 25% to 95% solvent [B] in 1.5 minutes , 95% solvent [B] was maintained for 1.5 minutes.
In addition, in the specification, the description "MS (m/z)" indicates a value observed by mass spectrometry.

工程１ 化合物３の合成
化合物１（９１０ｍｇ、３．６２ｍｍｏｌ）にクロロホルム（２０ｍＬ）、ジイソプロピルエチルアミン（０．７６ｍＬ、４．３４ｍｍｏｌ）を加え、氷冷下で化合物２（８８７ｍｇ、３．６２ｍｍｏｌ）を加えた。室温に昇温して２時間攪拌した後に、水を加えた。クロロホルムで抽出して、二層を分離した。有機層を水洗して、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、得られた残渣に酢酸エチル－ヘキサンを加えて固体をろ取することにより、化合物３（１．３４ｇ、収率８１％）を得た。
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). 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. Ta. After the mixture was heated to room temperature and stirred for 2 hours, water was added. The two layers were separated by extraction with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate-hexane was added to the resulting residue, and the solid was collected by filtration to obtain Compound 3 (1.34 g, yield 81%).
¹ H-NMR (CDCl ₃ ) 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).

Step 2 Synthesis of Compound 5 Compound 4 (22.6 g, 76 mmol) was added to 1,4-dioxane (158 mL), bispinacolato diborane (25 g, 98 mmol), PdCl ₂ (dppf) (6.2 g, 7.6 mmol), Potassium acetate (11.1 g, 114 mmol) was added and stirred at 100°C. After 3 hours, the mixture was cooled to room temperature and filtered through Celite (registered trademark). 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 obtained concentrated residue was dissolved in tetrahydrofuran (226 mL), and 1 mol/L aqueous sodium hydroxide solution (114 mL, 114 mmol) and 30% hydrogen peroxide solution (11.6 mL, 114 mmol) were added under ice cooling. After stirring at room temperature for 1 hour, a sodium thiosulfate aqueous solution was added to stop the reaction. The two layers were separated by extraction with ethyl acetate, and the organic layer was washed with water. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off 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 (CDCl ₃ ) δ: 1.57 (s, 9H), 3.04 (t, J = 8.8Hz, 2H), 3.96 (m, 2H), 4.58 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 6.64 (s, 1H), 7.34 (brs, 0.4H), 7.73 (brs, 0.6H).

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 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 distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 7 (2.55 g, yield 69%).
¹ H-NMR (CDCl ₃ ) 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, 0.6 H).

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, an aqueous sodium hydrogen carbonate solution was added to neutralize. Two layers were separated by extraction with chloroform, and the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product, Compound 8 (1.95 g).
¹ H-NMR (CDCl ₃ ) 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).

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. The mixture was added and stirred at 50°C for 2 hours. Water was added and extracted with chloroform. After washing the organic layer with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Tetrahydrofuran (2 mL), ethanol (2 mL), and 4 mol/L lithium hydroxide aqueous solution (0.90 mL, 3.6 mmol) were added to the obtained residue. After stirring at 90° C. for 8 hours, a 10% aqueous citric acid solution was added. The two layers were separated by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-023) (90 mg, yield 41%).
¹ H-NMR (DMSO-d ₆ ) 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).

工程１ 化合物（Ｉ－０３３）の合成
化合物８（４１ｍｇ、０．１６ｍｍｏｌ）と化合物３と同様にして合成した化合物９（４０ｍｇ、０．１１ｍｍｏｌ）を１，４－ジオキサン（０．５ｍＬ）に溶解し、Ｘａｎｔｐｈｏｓ Ｐｄ Ｇ３（１０ｍｇ、０．０１ｍｍｏｌ）、炭酸カリウム（３８ｍｇ、０．２７ｍｍｏｌ）を加えた。１００℃で３時間攪拌した後に、水を加えた。クロロホルムで抽出して、有機層を水洗した。無水硫酸マグネシウムで乾燥して、溶媒を減圧留去した。
得られた残渣にエタノール（０．５ｍＬ）とテトラヒドロフラン（０．５ｍＬ）を加えて溶解し、４ｍｏｌ／Ｌ水酸化リチウム水溶液（０．２７ｍＬ）を加えて、５０℃で４時間攪拌した。クエン酸水溶液を加えてクロロホルムで抽出して、有機層を水洗した。無水硫酸マグネシウムで乾燥して、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物（Ｉ－０３３）（２０ｍｇ、収率３３％）を得た。
¹H-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). 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) synthesized in the same manner as compound 3 were dissolved in 1,4-dioxane (0.5 mL). Then, 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. It was extracted with chloroform and the organic layer was washed with water. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Ethanol (0.5 mL) and tetrahydrofuran (0.5 mL) were added to dissolve the resulting residue, and a 4 mol/L aqueous lithium hydroxide solution (0.27 mL) was added, followed by stirring at 50° C. for 4 hours. A citric acid aqueous solution was added and extracted with chloroform, and the organic layer was washed with water. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-033) (20 mg, yield 33%).
¹ H-NMR (DMSO-d ₆ ) 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, 3.5 Hz, 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).

工程１ 化合物１２の合成
化合物１０（３１ｇ、１２４ｍｍｏｌ）と化合物１１（１６．９ｇ、１４８ｍｍｏｌ）をジクロロメタン（６００ｍＬ）に懸濁して氷冷した。トリフルオロ酢酸（１９ｍＬ、２４７ｍｍｏｌ）を加え、３０分後に４５℃に昇温して３時間攪拌した。氷冷して炭酸ナトリウム水溶液を加えて中和し、セライト（登録商標）ろ過した。ろ液の二層を分離して有機層を水洗した後に、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣にジエチルエーテルを加えて固体をろ取することで化合物１２（９．０４ｇ、収率２５％）を得た。
¹H-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メソッド１ 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. The mixture was cooled with ice, neutralized by adding an aqueous sodium carbonate solution, and filtered through Celite (registered trademark). The filtrate was separated into two layers, and the organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 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 (CDCl ₃ ) 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

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 stirred for 2 hours. An ammonium chloride aqueous 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. Diisopropyl ether was added to the residue obtained by distilling off the solvent under reduced pressure, and the solid was collected by filtration to obtain Compound 13 (16.1 g, yield 89%).
¹ H-NMR (CDCl ₃ ) 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 (dd, 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

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. , and stirred at 50°C for 3 hours. The mixture was allowed to cool, water was added, and the mixture was extracted with chloroform. After washing the organic layer with water, it was dried over anhydrous magnesium sulfate. Ethyl acetate-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, and the solid was collected by filtration to obtain Compound 15 (25.3 g, yield 93%).
¹ H-NMR (DMSO-d ₆ ) 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

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 to the system. The inside of the reactor was replaced with hydrogen, and the mixture was stirred at room temperature and pressure for 2 hours. It was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue and the solid was collected by filtration to obtain Compound 16 (19.6 g, yield 95%).
¹ H-NMR (DMSO-d ₆ ) 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

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). The mixture was 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 stirred for 2 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, ethyl acetate-diisopropyl ether was added, and the solid was collected by filtration to obtain Compound 18 (20.3 g, yield 91%).
¹ H-NMR (DMSO-d ₆ ) 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

Step 6 Synthesis of Compound 19 Tetrahydrofuran (203 mL), ethanol (203 mL), and 4 mol/L lithium hydroxide aqueous solution (44.5 mL, 178 mmol) were added to Compound 18 (20.3 g, 35.6 mmol). After stirring at 50° C. for 4 hours, the mixture was allowed to cool to room temperature and a 10% aqueous citric acid solution was added. Compound 19 (19 g, yield 96%) was obtained by adding water and collecting the precipitated solid by filtration.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.8 Hz, 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

Step 7 Synthesis of Compound (I-082) Compound 19 (795 mg, 1.43 mmol) was added with dimethylformamide (8 mL), compound 20 (431 mg, 1.71 mmol), HATU (706 mg, 1.86 mmol), and triethylamine (0. 495 mL, 3.57 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration. Dichloromethane (5 mL) and trifluoroacetic acid (5 mL, 65 mmol) were added to the obtained solid, and the mixture was stirred at room temperature for 2 hours. After neutralizing by adding an aqueous sodium bicarbonate solution, the mixture was made acidic again by adding 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 distilled off 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-d ₆ ) 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).

工程１ 化合物２２の合成
化合物２１（１００ｍｇ、０．２０ｍｍｏｌ）（合成法は実施例６参照）のジメチルホルムアミド（１ｍＬ）溶液に、氷冷下６０ｗｔ％水素化ナトリウム（１１ｍｇ、０．２９ｍｍｏｌ）と２－（トリメチルシリル）エトキシメチルクロリド（４９ｍｇ、０．２９ｍｍｏｌ）を加え、室温で１．５時間攪拌した。飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出した。有機層を水洗後、無水硫酸ナトリウムで乾燥し溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２２（７４ｍｇ、収率５９％）を得た。
LC/MS(ESI):m/z= 642 [M+H]+, RT=1.182 min, ＬＣ／ＭＳメソッド７ 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) was added 60 wt% sodium hydride (11 mg, 0.29 mmol) and 2 -(trimethylsilyl)ethoxymethyl chloride (49 mg, 0.29 mmol) was added and stirred at room temperature for 1.5 hours. After adding a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 22 (74 mg, yield 59%).
LC/MS(ESI):m/z= 642 [M+H]+, RT=1.182 min, LC/MS method 7

Step 2 Synthesis of Compound 23 4 mol/L lithium hydroxide aqueous solution (0.28 mL, 1.16 mmol) was added to a solution of Compound 22 (74 mg, 0.12 mmol) in ethanol (0.7 mL), and the mixture was heated at 50°C for 1 hour and 40 minutes. Stirred. After adding a 10% aqueous citric acid solution, the mixture was extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off 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

Step 3 Synthesis of compound 24 Compound 23 (71 mg, 0.12 mmol) was dissolved in dimethylformamide (1.0 mL), compound 20 (30 mg, 0.12 mmol), HATU (52 mg, 0.14 mmol) and triethylamine (17 mg, 0.17 mmol) was 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, yield 96%).
LC/MS(ESI):m/z= 847[M+H]+, RT=2.80 min, LC/MS method 7

Step 4 Synthesis of compound 25 A solution of compound 24 (84 mg, 0.10 mmol) in tetrahydrofuran (0.3 mL) was added with a 1 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.50 mL, 0.50 mmol) and ethylenediamine (89 mg, 1 .50 mmol) was added thereto, and the mixture was stirred for 8 hours under heating and reflux. After adding a 10% aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 25 (70 mg, yield 99%).
LC/MS(ESI):m/z= 717[M+H]+, RT=1.42 min, LC/MS method 1

Step 5 Synthesis of Compound 26 Compound 25 (460 mg, 0.64 mmol) was added with 1,4-dioxane (6.9 mL), (1R,2R)-cyclohexane-1,2-diamine (22 mg, 0.19 mmol), and phosphoric acid. Tripotassium (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 heating under reflux for 8 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 26 (500 mg, yield 98%).
LC/MS(ESI):m/z= 793[M+H]+, RT=3.71 min, LC/MS method 1

Step 6 Synthesis of Compound (I-148) Synthesis was carried out in the same manner as in Step 8 of Example 10.
¹ H -NMR (DMSO-d ₆ ) 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).

工程１ 化合物２８の合成
化合物２７（２．０１ｇ、１５．００ｍｍｏｌ）のジメチルホルムアミド（２０．１ｍＬ）溶液に、イミダゾール（１．５３ｇ、２２．５０ｍｍｏｌ）とｔｅｒｔ－ブチルジメチルシリククロリド（２．７１ｇ、１８．００ｍｍｏｌ）を加え、室温で４０分間攪拌を行った。水を加えた後、酢酸エチルで抽出した。有機層を水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２８（３．７９ｇ、収率１００％）を得た。
LC/MS(ESI):m/z= 249 [M+H]+, RT=2.66 min, ＬＣ／ＭＳメソッド１ Example 5
Synthesis of compound (I-159) and compound (I-182)

Step 1 Synthesis of Compound 28 To a solution of Compound 27 (2.01 g, 15.00 mmol) in dimethylformamide (20.1 mL), imidazole (1.53 g, 22.50 mmol) and tert-butyldimethylsilicchloride (2.71 g) were added. , 18.00 mmol) and stirred at room temperature for 40 minutes. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 28 (3.79 g, yield 100%).
LC/MS(ESI):m/z= 249 [M+H]+, RT=2.66 min, LC/MS method 1

Step 2 Synthesis of Compound 29 To a solution of Compound 28 (3.73 g, 15.00 mmol) in tetrahydrofuran (74.5 mL) were added tert-butoxypotassium (3.87 g, 34.50 mmol) and iodine (8.0 mmol) under ice cooling. 76 g, 34.50 mmol) was added thereto, and the mixture was stirred for 1 hour under ice-cooling. After adding a 20% aqueous sodium thiosulfate solution, the mixture was extracted with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 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

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

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

Step 5 Synthesis of Compound 32 Synthesis was carried out 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

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 heated at 80°C. Stirred for 80 minutes. After distilling off the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 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

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-yl methanesulfonate (681 mg, 16.36 mmol) was added and stirred at 80° C. for 6 hours. After adding water, the mixture was extracted with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain an approximately 4:1 mixture of compound 34 and compound 35 ( 4.20 g, yield 100%) was obtained.
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

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,-hexamethyldister Nannan (2.00 g, 4.35 mmol) and Pd(PPh ₃ ) ₄ (0.75 g, 0.65 mmol) were added, and the mixture was stirred under heating under reflux for 1 hour. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 37 (1.74 g, yield 68%).
LC/MS(ESI):m/z= 590 [M+H]+, RT=3.34 min, LC/MS method 1

Step 9 Synthesis of Compound 40 and Compound 41 An approximately 4:1 mixture of Compound 38 and Compound 39 (1.01 g, 2.00 mmol) was dissolved in dimethylformamide (20 mL), and Compound 37 (1.74 g, 2.96 mmol) was dissolved in dimethylformamide (20 mL). , 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 heated at 95°C for 8. Stirred for 5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 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

Step 10 Synthesis of Compound (I-159) and Compound (I-182) Synthesis was carried out in the same manner as in Step 8 of Example 10.
Compound (I-159)
¹ H-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).

工程１ 化合物４４の合成
化合物４２（１０ｇ、２２．３ｍｍｏｌ）にテトラヒドロフラン（１００ｍＬ）とトリイソプロピルボレート（４．１９ｇ、２２．３ｍｍｏｌ）を加えて、ドライアイス－アセトンで－７８℃に冷却した。この溶液に１．５９ｍｏｌ／Ｌ ｎ－ブチルリチウム－ヘキサン溶液（１９．６ｍＬ、３１．２ｍｍｏｌ）を滴下し、－７８℃で２０分攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止し、室温に昇温して酢酸エチルで抽出した。有機層を水洗後、無水硫酸ナトリウムで乾燥して溶媒を減圧留去した。得られた残渣に１，４－ジオキサン（１０２ｍL）、化合物４３（６．２ｇ、２４．５ｍｍｏｌ）、ＰｄＣｌ_２（ｄｐｐｆ）（１．８２ｇ、２．２３ｍｍｏｌ）および２．２ｍｏｌ／Ｌ炭酸カリウム水溶液（２０．４ｍＬ、４４．５ｍｍｏｌ）を加え、１００℃で２時間攪拌した。放冷後、水を加えて酢酸エチルで抽出した。二層を分離して有機層を水洗した後に、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物４４（７．１ｇ、収率５９％）を得た。
¹H-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メソッド１ Example 6
Synthesis of compound (I-162)

Step 1 Synthesis of Compound 44 Tetrahydrofuran (100 mL) and triisopropyl borate (4.19 g, 22.3 mmol) were added to Compound 42 (10 g, 22.3 mmol), and the mixture was cooled to -78°C with dry ice-acetone. A 1.59 mol/L n-butyllithium-hexane solution (19.6 mL, 31.2 mmol) was added dropwise to this solution, and the mixture was stirred at -78°C for 20 minutes. The reaction was stopped by adding a saturated aqueous ammonium chloride solution, heated to room temperature, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 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 potassium carbonate aqueous solution ( 20.4 mL, 44.5 mmol) was added thereto, and the mixture was stirred at 100°C for 2 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. After separating the two layers and washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 44 (7.1 g, yield 59%).
¹ H-NMR (CDCl ₃ ) 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

Step 2 Synthesis of Compound 45 Tetrahydrofuran (307 mL) and 20 wt% palladium on carbon (6.34 g, 11.7 mmol) were added to Compound 44 (30.7 g, 56.8 mmol). The atmosphere in the system was replaced with hydrogen, and the mixture was stirred at room temperature and pressure for 2 hours. It was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue, and the solid was collected by filtration to obtain Compound 45 (22.0 g, yield 86%).
¹ H-NMR (CDCl ₃ ) 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

Step 3 Synthesis of compound 46 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), DMEAD (2.21 g, 9.44 mmol) was added. After stirring at 50° C. for 1 hour, water was added to stop the reaction. After extraction with ethyl acetate and washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 46 (4.07 g, yield 92%).
¹ H-NMR (CDCl ₃ ) 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 = 8.8Hz , 1H).
LC/MS(ESI):m/z= 612 [M+H]+, RT=3.59 min, LC/MS method 1

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 solution was concentrated under reduced pressure and neutralized by adding a saturated aqueous sodium hydrogen carbonate solution. It was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, chloroform was added to the resulting residue, and the solid was collected by filtration to obtain Compound 21 (800 mg, yield 22%). The filtrate was again concentrated under reduced pressure, toluene was added to the resulting residue, and the solid was collected by filtration to obtain Compound 21 (1.73 g, yield 48%). Furthermore, the filtrate was 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%).
¹ H-NMR (CDCl ₃ ) 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

Step 5 Synthesis of Compound 49 Add dimethylformamide (12 mL) to Compound 21 (800 mg, 1.56 mmol), cool on ice, and add 60 wt% sodium hydride (94 mg, 2.35 mmol) and Compound 48 (681 mg, 2.35 mmol). ) was added. After stirring at 90° C. for 30 minutes, the mixture was cooled on ice again, and 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 and 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 and 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, 60 wt% sodium hydride (94 mg, 2.35 mmol) and Compound 48 (681 mg, 2.35 mmol) were added, and the mixture was stirred at 90°C for 30 minutes. The reaction solution was poured into a 10% aqueous citric acid solution to stop the reaction, and the mixture was extracted with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 49 (900 mg, yield 96%).
¹ H-NMR (CDCl ₃ ) 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 method 1

Step 6 Synthesis of Compound (I-162) Synthesis was carried out in the same manner as in Step 7 of Example 3.
¹ H-NMR (DMSO-d ₆ ) 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 = 2.0 Hz, 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 method 1

工程１ 化合物５１の合成
化合物５０（４９．９ｇ、２９７ｍｍｏｌ）と２－メチル－２－プロパンスルフィンアミド（５３．９ｇ、４４５ｍｍｏｌ）をテトラヒドロフラン（２５０ｍＬ）に加えて、室温でオルトチタン酸テトラエチル（１３７ｍＬ、６５３ｍｍｏｌ）を加えた。８０℃で１時間攪拌した後、アセトニトリル（１Ｌ）に注いだ。水（５３．５ｇ）を加えて反応を停止した。１０分攪拌した後に、無水硫酸マグネシウムを加えて、固体を濾別した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製することで、化合物５１（５８．９ｇ、収率７０％）を得た。
LC/MS(ESI):m/z= 272 [M+H]+, RT=1.81 min, ＬＣ／ＭＳメソッド２ 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. After stirring at 80° C. for 1 hour, the mixture was poured into acetonitrile (1 L). The reaction was stopped by adding water (53.5 g). After stirring for 10 minutes, anhydrous magnesium sulfate was added and the solids were filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 51 (58.9 g, yield 70%).
LC/MS(ESI):m/z= 272 [M+H]+, RT=1.81 min, LC/MS method 2

Step 2 Synthesis of 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 an 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 obtained solid to suspend it, and the solid was collected by filtration 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

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 the mixture was stirred at room temperature for 1 hour. Extraction was performed by adding water and ethyl acetate. The aqueous layer was neutralized by adding an aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a mixture (55.2 g) of compound 54 and compound 55 as a crude product.
LC/MS(ESI):m/z= 196 [M+H]+, RT=1.01 min, LC/MS method 2

Step 4 Synthesis of 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. It was extracted with ethyl acetate, and the organic layer was washed with water. It was concentrated under reduced pressure, hexane was added to the obtained solid, and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a mixture of compound 56 and compound 57 (65.0 g, yield 86%).
¹ H-NMR (CDCl ₃ ) 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).

Step 5 Synthesis of 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), water (395 mL) and 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, additional sodium periodate (42.2 g, 197 mmol) was added. After 2 hours, the mixture was cooled on ice and an aqueous sodium thiosulfate solution was added to stop the reaction. After extraction with ethyl acetate, the organic layer was washed with a 10% aqueous citric acid solution and a 3% aqueous sodium hydrogen carbonate solution. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a mixture of compound 58 and compound 59 (32.5 g, yield 48%).
¹ H-NMR (CDCl ₃ ) 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).

Step 6 Synthesis of 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, a sodium thiosulfate aqueous solution was added to stop the reaction. It was extracted with ethyl acetate, and the organic layer was washed with water. By drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, a mixture (45 g) of compound 60 and compound 61 was obtained as a crude product.
LC/MS(ESI): m/z= 356 [MH]-, RT=2.32 min and 2.41 min, LC/MS method 2

Step 7 Synthesis of mixture of compound 62 and compound 63 A mixture (45 g) of crude product compound 60 and compound 61 was dissolved in tetrahydrofuran (227 mL) and methanol (227 mL), and diphenyldiazomethane (61.8 g, 318 mmol) was added. Ta. 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 an aqueous sodium carbonate solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The fractions were concentrated, hexane was added to the obtained residue to solidify it, and the solid was collected by filtration to obtain a mixture of Compound 62 and Compound 63 (21.5 g, yield 39%).
¹ H-NMR (CDCl ₃ ) 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).

Step 8 Synthesis of Compound 64 To a mixture of Compound 62 and Compound 63 (43.2 g, 82 mmol) were added 1 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (866 mL) and acetic acid (42.4 mL), and the mixture was heated under reflux for 15 hours. . The mixture was neutralized by adding an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed three times with an aqueous ammonium chloride solution, then with an aqueous sodium bicarbonate solution and brine. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to separate low polar compound 65 and high polar compound 64 to obtain compound 64 (19.5 g, yield 56%).
¹ H-NMR (DMSO-d ₆ ) 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).

Step 9 Synthesis of Compound 66 Synthesis was carried out 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

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 aqueous sodium carbonate solution. A citric acid aqueous 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 distilled off 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-d ₆ ) 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).

工程１ 化合物６８の合成
化合物６７（３００ｍｇ、１．５２ｍｍｏｌ）のＮ－メチルピロリドン（４．４２ｍＬ）溶液にアルゴン気流下攪拌しながら、６０ｗｔ％水素化ナトリウム（６１ｍｇ、１．５３ｍｍｏｌ）を室温で加え、室温で１０分間攪拌した。次いで、化合物４８（４４２ｍｇ、１．５２ｍｍｏｌ）を室温で加えた。１００℃で３時間攪拌した後に、化合物４８（４４２ｍｇ、１．５２ｍｍｏｌ）と６０ｗｔ％水素化ナトリウム（６１ｍｇ、１．５３ｍｍｏｌ）を追加して、８０℃で５時間攪拌した。反応終了後、反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物６８（２５２ｍｇ、収率５３％）を得た。
LC/MS(DUIS):m/z= 315 [M+H]+, RT=1.59min, ＬＣ／ＭＳメソッド９ 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 stirred at room temperature for 10 minutes. Compound 48 (442 mg, 1.52 mmol) was then 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 the reaction was completed, a 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 obtain Compound 68 (252 mg, yield 53%).
LC/MS(DUIS):m/z= 315 [M+H]+, RT=1.59min, LC/MS method 9

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 8 mol/L potassium hydroxide was added while stirring under an argon stream. Aqueous solution (0.06 mL, 0.48 mmol), Pd ₂ (dba) ₃ (15 mg, 0.02 mmol), 5-(Di-t-butylphosphino)-1',3',5'-triphenyl-1,4' -bi-1H-pyrazole (16 mg, 0.03 mmol) was added at room temperature and stirred at 75°C. After 2 hours, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a crude product, Compound 69 (51 mg).
LC/MS(DUIS):m/z= 253 [M+H]+, RT=1.04min, LC/MS method 9

Step 3 Synthesis of Compound 70 To a solution of crude product Compound 69 (49 mg, 0.19 mmol) in tetrahydrofuran (0.98 mL) was added Compound 17 (70 mg, 0.39 mmol), 1.9 mol/while stirring under an argon stream. L DIAD-toluene solution (145 μL, 0.28 mmol) and triphenylphosphine (74 mg, 0.28 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, an aqueous sodium hydrogen carbonate 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 distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 70 (47 mg, 58%).
LC/MS(DUIS):m/z= 414 [M+H]+, RT=1.77min, LC/MS method 9

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

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

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

Step 7 Synthesis of Compound (I-228) Synthesis was carried out in the same manner as in Step 8 of Example 10.
¹ H-NMR (DMSO-d ₆ ) 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=1.86min, LC/MS method 10

工程１ 化合物７５の合成
化合物１７（７６０ｍｇ、４．２４ｍｍｏｌ）のトルエン（１０ｍＬ）溶液に、アルゴン気流下攪拌しながら、６０ｗｔ％水素化ナトリウム（２８３ｍｇ、７．０８ｍｍｏｌ）を室温で加え、７０℃で１５分間攪拌した。次いで、化合物７４（９１０ｍｇ、３．５７ｍｍｏｌ）、Ｐｄ_２（ｄｂａ）_３（３２４ｍｇ、０．３５４ｍｍｏｌ）、（Ｒ）－（＋）－ＴｏｌＢＩＮＡＰ（２４０ｍｇ、０．３５４ｍｍｏｌ）を室温で加え、１００℃で攪拌した。３０分後に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物７５（８９９ｍｇ、収率６３％）を得た。
LC/MS(DUIS):m/z= 398 [M+H]+, RT=1.17 min, ＬＣ／ＭＳメソッド９ 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) was added 60 wt% sodium hydride (283 mg, 7.08 mmol) at room temperature while stirring under an argon atmosphere, and the mixture was heated at 70°C. Stir for 15 minutes. Then, compound 74 (910 mg, 3.57 mmol), Pd ₂ (dba) ₃ (324 mg, 0.354 mmol), (R)-(+)-TolBINAP (240 mg, 0.354 mmol) were added at room temperature, and the mixture was heated at 100 °C. Stirred. 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 distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 75 (899 mg, yield 63%).
LC/MS(DUIS):m/z= 398 [M+H]+, RT=1.17 min, LC/MS method 9

Step 2 Synthesis of Compound 76 To a solution of Compound 75 (899 mg, 2.26 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL, 26.1 mmol) at room temperature while stirring under an argon stream, and the mixture was stirred for 6 hours. After the reaction was completed, an aqueous sodium hydrogen carbonate 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. Compound 76 (695 mg, yield 100%) was obtained by distilling off the solvent under reduced pressure.
LC/MS(DUIS):m/z= 298 [M+H]+, RT=0.35 min, LC/MS method 9

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

Step 4 Synthesis of Compound 78 Cesium carbonate (1.22 g, 3.74 mmol) and Compound 48 ( 1.09 g, 3.75 mmol) was added at room temperature and stirred at 120°C for 3 hours. Then, 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 the reaction was completed, 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 distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 78 (520 mg, yield 100%).
LC/MS(DUIS):m/z= 414 [M+H]+, RT=0.91 min, LC/MS method 9

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. The mixture was stirred for 30 minutes. After the reaction was completed, an aqueous sodium hydrogen carbonate 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 distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 79 (180 mg, yield 29%).
LC/MS(ESI):m/z= 540 [M+H]+, RT=1.43 min, LC/MS method 10

Step 6 Synthesis of Compound 80 To a solution of Compound 79 (180 mg, 0.33 mmol) in 1,4-dioxane (3.6 mL), 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 stirred at 95°C for 1 hour. After the reaction was completed, 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 sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 80 (111 mg, yield 62%).
LC/MS(ESI):m/z= 540 [M+H]+, RT=1.29 min, LC/MS method 10

Step 7 Synthesis of Compound 81 Synthesis was carried out 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

Step 8 Synthesis of Compound (I-268) Synthesis was carried out in the same manner as Step 8 of Example 10.
¹ H-NMR (DMSO-d ₆ ) 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

工程１ 化合物８３の合成
２－（トリメチルシリル）エタン－１－オール（１．０８ｇ、９．１０ｍｍｏｌ）をテトラヒドロフラン（１０ｍＬ）に溶解し、氷冷下、６０ｗｔ％水素化ナトリウム（２１８ｍｇ、５．４６ｍｍｏｌ）を加えた。５分後に、化合物８２（１．００ｇ、４．５５ｍｍｏｌ）を加え、室温で３時間撹拌した。水を加えて反応を停止し、酢酸エチルで抽出した。有機層を水洗し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物８３（１．４５ｇ、収率１００％）を得た。
¹H-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). 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. added. After 5 minutes, compound 82 (1.00 g, 4.55 mmol) was added and stirred at room temperature for 3 hours. The reaction was stopped by adding water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 83 (1.45 g, yield 100%).
¹ H-NMR (CDCl ₃ ) 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, 2.8 Hz, 1H), 7.18 (d, J = 2.8Hz, 1H), 7.98 (d, J = 9.2Hz, 1H).

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

Step 3 Synthesis of Compound 85 Compound 84 (1.93 g, 6.70 mmol) was dissolved in dimethylformamide (10 mL), 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 and stirred 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 sodium bicarbonate solution and then with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 85 (816 mg, yield 32%).
LC/MS(ESI):m/z= 382 [M+H]+, RT=3.08 min, LC/MS method 1

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) and PdCl ₂ (dppf) (156 mg, 0.213 mmol) were added. , and stirred at 80°C for 2 hours. After the reaction solution was allowed to cool, water was added and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 86 (467 mg, yield 73%).
LC/MS(ESI):m/z= 302 [M+H]+, RT=2.50 min, LC/MS method 1

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), Xantphos Pd G2 (129 mg, 0.145 mmol) was added, and 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 materials were filtered off. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 87 (404 mg, yield 77%).
LC/MS(ESI):m/z= 725 [M+H]+, RT=3.54 min, LC/MS method 1

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

Step 7 Synthesis of Compound 89 Synthesis was carried out 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

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. After concentrating the reaction solution, it was dissolved in dichloromethane and neutralized with saturated aqueous sodium bicarbonate. A citric acid aqueous solution was added to the reaction mixture to make it acidic again, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-269) (30 mg, yield 65%).
¹ H-NMR (CDCl ₃ ) 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).

工程１ 化合物９１の合成
化合物９０（１．６４ｇ、５．６０ｍｍｏｌ）をジクロロメタン（１６．４ｍＬ）に溶解し、氷冷下ピリジン（１．３３ｇ、１６．８０ｍｍｏｌ）とパラトルエンスルホニルクロリド（２．１４ｇ、１１．２０ｍｍｏｌ）を加えた。室温で１．５時間攪拌した後、トリエチルアミン（１．７０ｇ、１６．８０ｍｍｏｌ）と１－メチルピペラジン（１．１２ｇ、１１．２０ｍｍｏｌ）を加え、３０分間攪拌した。氷冷下で濃塩酸を加えた後、酢酸エチルで抽出した。有機層を水洗後、無水硫酸ナトリウムで乾燥して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物９１（２．０８ｇ、収率８６％）を得た。
LC/MS(ESI):m/z= 432 [M+H]+, RT=2.76 min, ＬＣ／ＭＳメソッド１ 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 para-toluenesulfonyl chloride (2.14 g) were added under ice cooling. , 11.20 mmol) were added. 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 stirred for 30 minutes. After adding concentrated hydrochloric acid under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 91 (2.08 g, yield 86%).
LC/MS(ESI):m/z= 432 [M+H]+, RT=2.76 min, LC/MS method 1

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

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

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

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) was added thereto, and the mixture was stirred at room temperature for 15 minutes. A solution of Compound 94 (100 mg, 0.25 mmol) in dichloromethane (2 mL) was added to this solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After adding a 10% aqueous sodium thiosulfate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 95 (115 mg, yield 88%).
¹ H -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).

Step 6 Synthesis of Compound 96 Compound 95 (113 mg, 0.21 mmol) was dissolved in 1,4-dioxane (2.3 mL), and 2-isopropoxy-4,4,5,5-tetramethyl-1,3, Add 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) at 95 °C. Stirred for 2.5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 96 (110 mg, yield 97%).
¹ H-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 ).

Step 7 Synthesis of Compound 97 Compound 96 (108 mg, 0.20 mmol) was dissolved in 1,4-dioxane (1.4 mL), and compound 43 (57 mg, 0.22 mmol), 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 for 1 hour under heating under reflux. 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 distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 97 (92 mg, yield 73%).
LC/MS(ESI):m/z= 625[M+H]+, RT=3.45 min, LC/MS method 1

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

Step 9 Synthesis of Compound 99 Synthesis was carried out 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

Step 10 Synthesis of Compound 100 Synthesis was carried out 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

Step 11 Synthesis of Compound 101 To a solution of Compound 100 (34 mg, 0.06 mmol) in dimethylformamide (0.5 mL) was added 60 wt% sodium hydride (3.4 mg, 0.09 mmol) and methyl iodide (16 mg, 0.11 mmol) was added thereto, 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 distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 101 (26 mg, yield 75%).
LC/MS(ESI):m/z= 610[M+H]+, RT=3.04 min, LC/MS method 1

Step 12 Synthesis of Compound 102 Synthesis was carried out 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

Step 13 Synthesis of Compound (I-270) Synthesis was carried out in the same manner as in Step 6 of Example 6.
¹ H-NMR (CDCl ₃ )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).

工程１ 化合物１０４の合成
トリエチルシラン（１．７ｍＬ、１０．７５ｍｍｏｌ）とトリクロロ酢酸（１．１ｇ、６．７２ｍｍｏｌ）のトルエン（５ｍＬ）溶液を７０℃で攪拌し、この溶液に化合物１０３（１ｇ、４．４８ｍｍｏｌ）とシクロペンタノン（４１４ｍｇ、４．９３ｍｍｏｌ）のトルエン（１０ｍＬ）溶液を滴下した。滴下した後に７０℃で４０分間攪拌した。室温まで冷却して１０％炭酸ナトリウム水溶液を加えた。酢酸エチルで抽出し、有機層を水洗した。無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物１０４（６００ｍｇ、収率４６％）を得た。
LC/MS(ESI):m/z= 292 [M+H]+, RT=2.98 min, ＬＣ／ＭＳメソッド１ 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 compound 103 (1 g, A solution of 4.48 mmol) and cyclopentanone (414 mg, 4.93 mmol) in toluene (10 mL) was added dropwise. After the dropwise addition, the mixture was stirred at 70°C for 40 minutes. After cooling to room temperature, 10% aqueous sodium carbonate solution was added. It was extracted with ethyl acetate, and the organic layer was washed with water. It was dried over anhydrous sodium sulfate, and the solvent was distilled off 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

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, an aqueous potassium carbonate solution was added to neutralize. It was extracted with ethyl acetate, and the organic layer was washed with water. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 105 (340 mg, yield 59%).
LC/MS(ESI):m/z= 294 [M+H]+, RT=1.74 min, LC/MS method 1

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). The mixture was stirred at 90°C for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by amino column chromatography (hexane-ethyl acetate) to obtain Compound 106 (330 mg, yield 80%).
LC/MS(ESI):m/z= 717 [M+H]+, RT=2.96 min, LC/MS method 7

Step 4 Synthesis of Compound 107 Synthesis was carried out 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

Step 5 Synthesis of Compound 108 Synthesis was carried out 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

Step 6 Synthesis of Compound (I-486) Synthesis was carried out in the same manner as in Step 8 of Example 10.
¹ H-NMR (CDCl ₃ ) 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

工程１ 化合物１１０の合成
化合物１０（４２ｇ、１６６ｍｍｏｌ）と化合物１０９（１６．６ｇ、１６６ｍｍｏｌ）をジクロロメタン（２５０ｍＬ）に懸濁して氷冷した。トリフルオロ酢酸（２５．６ｍＬ、３３２ｍｍｏｌ）を加え、４５℃に昇温して５時間攪拌した。氷冷して炭酸ナトリウム水溶液を加えて中和し、クロロホルムで抽出した。有機層を水洗した後に、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）にて精製することで化合物１１０（８．９ｇ、収率１９％）を得た。
LC/MS(ESI):m/z= 280 [M+H]+, RT=2.59 min, ＬＣ／ＭＳメソッド１ 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, the temperature was raised to 45° C., and the mixture was stirred for 5 hours. The mixture was cooled with ice, neutralized by adding an aqueous sodium carbonate solution, and extracted with chloroform. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 110 (8.9 g, yield 19%).
LC/MS(ESI):m/z= 280 [M+H]+, RT=2.59 min, LC/MS method 1

Step 2 Synthesis of Compound 111 Synthesis was carried out 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

Step 3 Synthesis of Compound 113 Synthesis was carried out 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

Step 4 Synthesis of Compound 114 Synthesis was carried out 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

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 (0.2 mmol) were dissolved in dimethylformamide (8.6 mL). 39 mL, 2.8 mmol) was added. After stirring for 15 hours at room temperature, 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, yield 87%).
LC/MS(ESI):m/z= 701 [M+H]+, RT=3.88 min, LC/MS method 1

Step 6 Synthesis of Compound 116 Synthesis was carried out 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

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 stirred at 90° C. for 1 hour. The same amount of cesium carbonate and compound 117 were added 4 times every 30 minutes. After confirming that the raw materials had disappeared, water was added to stop the reaction. It was extracted with ethyl acetate, and the organic layer was washed with water. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by amino column chromatography (hexane-ethyl acetate) to obtain Compound 118 (63 mg, yield 70%).
LC/MS(ESI):m/z= 784 [M+H]+, RT=3.17 min, LC/MS method 1

Step 8 Synthesis of Compound (I-591) Synthesis was carried out under the same conditions as in Step 8 of Example 10.
¹ H -NMR (DMSO-d ₆ ) 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).

工程１ 化合物１２０の合成
化合物１１９（３ｇ、１８．９ｍｍｏｌ）をジクロロメタン（３０ｍＬ）に溶解させ、氷冷下でオキサリルクロリド（１．８ｍＬ、２０．８ｍｍｏｌ）とジメチルホルムアミド（０．１５ｍＬ、１．９ｍｍｏｌ）を加えた。室温で１時間攪拌した後に、反応液を減圧濃縮した。
得られた残渣をジクロロメタン（５ｍＬ）に溶解させ、化合物２０（４．７６ｇ、１８．９ｍｍｏｌ）とトリエチルアミン（５．３ｍＬ、３７．８ｍｍｏｌ）のジクロロメタン（３０ｍＬ）溶液に、氷冷下で滴下した。１時間後に水を加えて反応を停止し、クロロホルムで抽出した。有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣に酢酸エチルとジイソプロピルエーテルを加えて懸濁した。固体をろ取することで化合物１２０（７．０ｇ、収率９４％）を得た。
¹H-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). 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. ) was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure.
The obtained residue was dissolved in dichloromethane (5 mL), and added dropwise to a dichloromethane (30 mL) solution of Compound 20 (4.76 g, 18.9 mmol) and triethylamine (5.3 mL, 37.8 mmol) under ice cooling. After 1 hour, water was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and ethyl acetate and diisopropyl ether were added to the resulting residue to suspend it. Compound 120 (7.0 g, yield 94%) was obtained by filtering the solid.
¹ H-NMR (CDCl ₃ ) 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).

工程１ 化合物１２３の合成
化合物１２２（５１．５ｇ、３３７ｍｍｏｌ）をジメチルホルムアミド（３８６ｍＬ）に溶解し、炭酸セシウム（１６５ｇ、５０６ｍｍｏｌ）、４－メトキシベンジルクロリド（５３．４ｇ、３４１ｍｍｏｌ）を加えた。室温で４５分攪拌した後に、水を加えた。酢酸エチルで抽出し、有機層を水洗した。無水硫酸ナトリウムで乾燥して、溶媒を減圧留去した。得られた残渣にヘキサンと酢酸エチルを加えて固化し、ろ取することで化合物１２３（９０．９ｇ、収率９９％）を得た。
LC/MS(ESI):m/z= 273 [M+H]+, RT=2.21 min, ＬＣ／ＭＳメソッド１ 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 temperature was raised to 80°C and stirred for 1 hour. The reaction was stopped by cooling with ice and adding an aqueous sodium thiosulfate solution. It was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 121 (670 mg, yield 15%).
¹ H-NMR (DMSO-d ₆ ) 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. It was extracted with ethyl acetate, and the organic layer was washed with water. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane and ethyl acetate were added to the obtained residue to solidify it, and the mixture was filtered 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

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 for 45 minutes at room temperature, water was added. It was extracted with ethyl acetate, and the organic layer was washed with water. The crude product Compound 124 (154.6 g) was obtained by drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure.
LC/MS(ESI):m/z= 445 [M+H]+, RT=2.58 min, LC/MS method 1

Step 3 Synthesis of Compound 125 Crude 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. Ta. After stirring for 1 hour, the reaction solution was filtered using Celite (registered trademark) to remove insoluble materials. The filtrate was concentrated under reduced pressure, and water was added to the obtained solid. The suspension was stirred at room temperature, and the solid was collected by filtration to obtain Compound 125 (87 g, yield 100%).
LC/MS(ESI):m/z= 289 [M+H]+, RT=2.58 min, LC/MS method 1

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) was added. After stirring at room temperature for 3 hours, water was added. It was extracted with ethyl acetate, and the organic layer was washed with water. It was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 126 (245 mg, yield 90%).
LC/MS(ESI):m/z= 359 [M+H]+, RT=2.05 min, LC/MS method 1

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 solution was poured into an aqueous sodium carbonate solution to neutralize it, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained 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

Step 6 Synthesis of Compound 129 A 0.91 mol/L borane tetrahydrofuran complex-tetrahydrofuran solution (20 mL, 18.2 mmol) was added to Compound 127 (640 mg, 2.68 mmol), and the mixture was stirred at 70° C. for 30 minutes. After cooling on ice, methanol (10 mL) was added, and the mixture was stirred at 80°C for 30 minutes. After cooling, the reaction solution 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 solution was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 129 (550 mg, yield 63%).
LC/MS(ESI):m/z= 325 [M+H]+, RT=2.27 min, LC/MS method 1

Step 8 Synthesis of compound 130 Compound 129 (200 mg, 0.616 mmol) was dissolved in 1,4-dioxane (3 mL), Me4tBuXphos (30 mg, 0.062 mmol), Pd ₂ (dba) ₃ (28 mg, 0.031 mmol) , 6 mol/L potassium hydroxide aqueous solution (0.36 mL, 2.16 mmol) was added thereto, and the mixture was stirred at 100° C. for 1 hour. After cooling, the mixture was neutralized with a 2 mol/L aqueous hydrochloric acid solution. Extraction was performed with dichloromethane, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate-diisopropyl ether was added to the resulting residue, and 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

Step 9 Synthesis of Compound 133 Compound 130 (171 mg, 0.558 mmol) was dissolved in tetrahydrofuran (2 mL), triphenylphosphine (293 mg, 1.12 mmol), compound 131 (213 mg, 1.12 mmol), DIAD (226 mg, 1 .12 mmol) was added thereto, and the mixture was stirred 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 distilled off under reduced pressure.
Trifluoroacetic acid (4 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and dichloromethane was added to the residue to dissolve it. Aqueous sodium bicarbonate solution was added to neutralize and the two layers were separated. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 133 (212 mg, yield 100%).
LC/MS(ESI):m/z= 380 [M+H]+, RT=0.80 min, LC/MS method 1

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

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. After concentrating the reaction solution, it was dissolved in dichloromethane and neutralized by adding an aqueous sodium hydrogen carbonate solution. A citric acid aqueous 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 distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-594) (37 mg, yield 60%).
¹ H-NMR (DMSO-d ₆ ) 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).

工程１ 化合物１３６および化合物１３７の合成
化合物１３５（１．０ｇ、４．９０ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶解し、３，３-ジフルオロアゼチジン塩酸塩（１．２７ｇ、９．７９ｍｍｏｌ）、トリエチルアミン（１．２６ｍＬ、９．７９ｍｍｏｌ）、酢酸（０．２８ｍＬ、４．９０ｍｍｏｌ）、および水素化トリアセトキシホウ素ナトリウム（２．０８ｇ、９．７９ｍｍｏｌ）を加え、３時間攪拌した。水を加えてクロロホルムで抽出した。有機層を水洗した後に、無水硫酸ナトリウムで乾燥した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して、化合物１３６（８４６ｍｇ、収率６１％）と化合物１３７（４５４ｍｇ、収率３３％）を得た。
化合物１３６
¹H-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メソッド１
化合物１３７
¹H-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メソッド１ (Reference example)
Synthesis of compound 117 and compound 131

Step 1 Synthesis of Compound 136 and Compound 137 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 and stirred for 3 hours. Water was added and extracted with chloroform. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 136 (846 mg, yield 61%) and Compound 137 (454 mg, yield 33%).
Compound 136
¹ H-NMR (CDCl ₃ ) 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 (CDCl ₃ ) 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

Step 2 Synthesis of Compound 131 Compound 136 (0.72 g, 2.55 mmol) was dissolved in ethanol (10.7 mL), 10 wt% palladium on carbon (1.09 g, 0.51 mmol) was added, and the system was replaced with hydrogen. The mixture was stirred at 50°C for 3 hours. After filtering the reaction solution using Celite (registered trademark), the filtrate was concentrated under reduced pressure to obtain Compound 131 (0.42 g, yield 86%).
Compound 131
¹ H-NMR (CDCl ₃ ) 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).

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. ) was added. 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. Compound 117 (419 mg, yield 99%) was obtained by distilling off the solvent under reduced pressure.
¹ H-NMR (CDCl ₃ ) 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).

工程１ 化合物１３８の合成
実施例６の工程１と同様に合成した。
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メソッド９ Example 15
Synthesis of compound (I-570)

Step 1 Synthesis of Compound 138 Synthesis was carried out in the same manner as in Step 1 of Example 6.
¹ H-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

Step 2 Synthesis of Compound 139 Lithium hydroxide monohydrate (2 .92 g, 69.6 mmol) was added at room temperature and stirred at room temperature for 5 hours. After the reaction was completed, it was concentrated under reduced pressure, the residue was diluted with water, 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 obtain Compound 139 (4.81 g, yield 84%).
¹ H-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

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, 17.2 mmol) while stirring under an argon atmosphere. 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 the reaction was completed, water was added to the reaction solution, and the mixed solution 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, sonicated, and filtered. Further, the mixture was washed with a hexane-ethyl acetate mixed solution and dried to obtain Compound 140 (2.46 g, yield 41%).
¹ H-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

Step 4 Synthesis of Compound 141 Synthesis was carried out 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

Step 5 Synthesis of Compound 142 Synthesis was carried out under the same conditions as in Step 2 of Example 6.
¹ H-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

Step 6 Synthesis of Compound 143 Synthesis was carried out 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

Step 7 Synthesis of Compound 144 Synthesis was carried out under the same conditions as in Step 2.
¹ H-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

Step 8 Synthesis of Compound 146 Cesium carbonate (67 mg, 0.21 mmol) and Compound 145 (50 mg, 0 .21 mmol) was added at room temperature and stirred at 100°C for 2 hours. Then, 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. Further, 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 4 hours. After the reaction was completed, water was added to the reaction solution, and the mixed solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate). Further purification was performed by amino column chromatography (hexane-ethyl acetate) to obtain Compound 146 (42 mg, 77%).
¹ H-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 method 10

Step 9 Synthesis of Compound (I-570) Synthesis was carried out under the same conditions as in Step 8 of Example 10.
¹ H-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

The following compounds were synthesized according to the above general synthesis method and the method described in Examples.
In addition, in the structural formula, the "wedge shape" and the "dashed line" indicate the steric configuration. In particular, in compounds whose steric configuration is described, the term "steric structure" is defined as follows.
Blank: As described a: Racemic body b: Single compound, but stericity is unknown c: Diastereomer 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: The stereo of the substituent of Z ^c (R ⁷ ) is as described, and the stereo of the substituent of R ⁴ is unknown. e: The stereo of the substituent of Z ^c (R ⁷ ) is unknown, and the stereo of the substituent of R ⁴ is unknown. The steric structure of the substituent is f: racemic as described, and the relative configuration of cis/trans is single but unknown.

Below, biological test examples of compounds according to the present invention will be described.
The compound represented by formula (I) according to the present invention may be any compound as long as it has an inhibitory effect on cytopathic degeneration caused by RS virus and inhibits human cytopathic degeneration.
Specifically, in the evaluation method described below, the EC50 is preferably 5000 nM or less, more preferably 1000 nM or less, even more preferably 100 nM or less.

Test Example 1 In vitro CPE (Cytopathic Effect, Cytopathic Effect) Suppression Effect Confirmation Test The test sample was diluted in advance with DMSO to an appropriate concentration, and a 3-fold serial dilution series was prepared in a 384-well plate (0.32 μL/well). . Prepare HEp-2 cells (CCL-23; ATCC) to an appropriate number (2.4×10 ⁵ cells/mL) in 2% FBS E-MEM (Eagle's Minimum Essential Medium; prepared by adding kanamycin and FBS to Invitrogen). Then, 12.5 μL/well was added to a 384-well plate into which the test sample had been dispensed in advance. RSV A2 strain was diluted with culture medium to an appropriate concentration, and 12.5 μL/well was dispensed into a 384-well plate containing the test sample. Furthermore, the experiment was started by adding culture solution and finally adding 50 μL/well. For controls, wells were prepared in which only culture medium without virus was added. After statically culturing in a 5% CO ₂ incubator at 37°C for 4 days, remove the plate and leave it at room temperature for 30 minutes, then add CellTiter-Glo (registered trademark) 2.0 assay (Promega) at 15 μL/well. After mixing for 30 seconds, the mixture was left for approximately 1 hour. Luminescence was then quantified using EnVision (PerkinElmer). The inhibitory effect of the test reagent on RSV-induced CPE was calculated from the level of remaining viable cells by CellTiter-Glo® 2.0 for each test concentration at 0% and 100% inhibition rates. EC50 values were calculated by nonlinear regression as the concentration that inhibited RSV-induced cytopathic effects by 50%. When evaluating RSV type B, RSV B (Wash/18537 strain) was infected in the same manner as type A, cultured for 5 days, and then quantified in the same manner as for A2 strain.
(result)
Compounds according to the invention were tested essentially as described above.
The inhibitory effects of the compounds according to the present invention on RSV type A are shown below. Note that the EC50 value is "A" if it is less than 10 nM, "B" if it is 10 nM or more and less than 100 nM, and "C" if it is 100 nM or more and not more than 5000 nM.
Compound No. I-23: 0.96nM
Compound No. I-33: 7.5nM
Compound No. I-82: 0.27nM
Compound number I-148: 1.5nM
Compound No. I-159: 0.88nM
Compound number I-162: 0.88nM
Compound number I-165: 0.37nM
Compound No. I-182: 0.39nM
Compound number I-228: 1.3nM
Compound number I-268: 1.4nM
Compound number I-269: 1.3nM
Compound number I-270: 37nM
Compound No. I-486: 3nM
Compound number I-570: 0.70nM
Compound No. I-591: 0.61nM
Compound No. I-594: 0.38nM

Compounds according to the invention were tested essentially as described above.
The inhibitory effects of the compounds according to the present invention on RSV type B are shown below. Note that the EC50 value is "A" if it is less than 10 nM, "B" if it is 10 nM or more and less than 100 nM, and "C" if it is 100 nM or more and not more than 5000 nM.
Compound No. I-23: 16nM
Compound No. I-33: 110nM
Compound No. I-82: 0.34nM
Compound number I-148: 2.8nM
Compound No. I-159: 3nM
Compound number I-162: 3.3nM
Compound No. I-165: 0.62nM
Compound number I-182: 2.1 nM
Compound No. I-228: 36nM
Compound number I-268: 4.3nM
Compound No. I-486: 28nM
Compound number I-570: 2.1 nM
Compound No. I-591: 2.2nM
Compound No. I-594: 4.2nM

Test Example 2 In Vivo Mouse Efficacy Test Although mice are semi-permissive for human RSV replication, they are a model frequently used in non-clinical screening tests for RSV therapeutics. The in vivo drug efficacy was confirmed using Balb/c mice with RSV A2 strain, which has good proliferative properties.

<Materials and methods>
- Compound Compounds represented by formulas (I-82, I-162) were prepared using a medium (5% Tween 80/20% HP-β-CD in 7% Meiron solution). The administration volume was 10 mL/kg.
- Virus RSV A2 strain (VR-1540) purchased from ATCC was used.
- Mouse lung infection, medication, and lung collection Six-week-old female BALB/c mice (Charles River Japan Co., Ltd.) free of specific pathogens were used in this study. At the time of virus inoculation, mice were anesthetized by intramuscular administration of 100 μL of an anesthetic solution containing 0.03 mg/mL medetomidine hydrochloride, 0.4 mg/mL midazolam, and 0.5 mg/mL butorphanol tartrate in physiological saline. Mice were intranasally inoculated with RSV A2 at 5×10 ⁶ PFU/50 μL/mouse under anesthesia. Starting 3 days after virus infection, mice (n = 4/group) were administered the compound represented by formula (I-82, I-162) at 12.5 mg/kg, 25 mg/kg, 50 mg/kg, or 100 mg/kg. It was administered orally twice a day at a dose of kg. Control mice were orally administered with 5% Tween 80/20% HP-β-CD in 7% Meiron solution twice a day. Three days after the start of administration, mouse lungs were collected, 2 mL of PBS (containing penicillin-streptomycin) was added, homogenized, and the supernatant after centrifugation was collected.
・Measurement of intrapulmonary virus titer After preparing a 10-fold dilution series of the lung homogenate in a medium (MEM, 2% FBS, kanamycin), HEp-2 cells (ATCC:CCL- 23, 2×10 ⁴ cells/well) for 2 hours. After removing the virus solution, add new medium and culture in a CO ₂ incubator for 3 days. After fixing the cells with 4% paraformaldehyde phosphate buffer, immunostaining TCID using anti-RSV antibody (BIORAD 7950-0004). The virus titer contained in the lung homogenate was calculated using the method.
- Statistical analysis Group differences in virus titer in lung homogenate fluid were analyzed by Dunnett's test. Statistical analysis was performed using statistical analysis software SAS version 9.4 for Windows (SAS Institute (Cary, NC)). An adjusted two-sided P value of less than 0.05 was considered statistically significant.

Compounds according to the invention were tested essentially as described above. The results are shown below.
The compound I-82 administration group dose-dependently reduced the intrapulmonary virus titer 3 days after infection, with significantly lower virus titers than the vehicle administration group at all doses above 12.5 mg/kg. (Figure 1).
The compound I-162 administration group dose-dependently reduced the intrapulmonary virus titer 3 days after infection, with significantly lower virus titers than the vehicle administration group at all doses above 12.5 mg/kg. (Figure 2).

Test example 3: CYP inhibition test
Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin (CYP1A2), which is a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), and tolbutamide. Methyl-hydroxylation (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) are used as indicators to determine the amount of each metabolite produced. The degree of inhibition by the compounds according to the invention is evaluated.

Reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 30 or 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; Compound concentration according to the present invention, 1, 5, 10, 20 μmol/L (4 points).

Add each of the five substrates, human liver microsomes, and the compound according to the present invention in the above composition to a 96-well plate in 50 mmol/L Hepes buffer, add the coenzyme NADPH, and start the metabolic reaction as an index. do. After reacting at 37° C. for 15 minutes, the reaction is stopped by adding a methanol/acetonitrile=1/1 (V/V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifuged supernatant was quantified using a fluorescence multilabel counter or LC/MS/MS, and tolbutamide hydroxylated form (CYP2C9 metabolite) and mephenytoin 4' hydroxylated (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC/MS/MS. Note that the dilution concentration and dilution solvent are changed as necessary.

A control (100%) in which only DMSO, a solvent in which the compound was dissolved, was added to the reaction solution instead of the compound according to the present invention, the residual activity (%) was calculated, and using the concentration and inhibition rate, the logistic _IC50 is calculated by inverse estimation using the model.

Test Example 4: CYP3A4 (MDZ) MBI test Regarding CYP3A4 inhibition of the compound according to the present invention, this is a test to evaluate the mechanism based inhibition (MBI) ability from the enhancement of the inhibitory effect caused by the metabolic reaction of the compound according to the present invention. CYP3A4 inhibition is evaluated using pooled human liver microsomes using the 1-hydroxylation reaction of midazolam (MDZ) as an indicator.

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; 0.05 mg/mL (at 10-fold dilution) during reaction; concentration of compound according to the present invention during pre-reaction, 1, 5, 10, 20 μmol/L or 0.83, 5, 10, 20 μmol/L (4 points).

Pooled human liver microsomes and a compound solution according to the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the above pre-reaction composition, and K-Pi containing the substrate was added to another 96-well plate. -Transfer a portion of it to 1/10 dilution with Pi buffer, add the coenzyme NADPH to start the reaction as an indicator (Preincubation 0 min), and after reacting for a predetermined time, add methanol/acetonitrile. The reaction is stopped by adding =1/1 (V/V) solution. In addition, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (Preincubation 30 min), and after the pre-reaction for a predetermined period of time, the mixture was diluted to 1/10 with K-Pi buffer containing the substrate on another plate. The reaction begins as an indicator. After reacting for a predetermined time, the reaction is stopped by adding a methanol/acetonitrile=1/1 (V/V) solution. After centrifuging the plate on which each indicator reaction was performed at 3,000 rpm for 15 minutes, the amount of midazolam 1-hydroxide in the centrifuged supernatant is quantified by LC/MS/MS. Note that the dilution concentration and dilution solvent are changed as necessary.

A control (100%) in which only DMSO, a solvent in which the compound was dissolved, was added to the reaction solution instead of the compound according to the present invention, and residual activity (%) when each concentration of the compound according to the present invention was added. is calculated, and IC is calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The IC at Preincubation 0 min/IC at Preincubation 30 min is taken as the Shifted IC value, and if the Shifted IC is 1.5 or more, it is taken as Positive, and if the Shifted IC is 1.0 or less, it is taken as Negative.

Test Example 5: BA Test Examination of Oral Absorption Experimental Materials and Methods (1) Animals Used: Mice or rats are used.
(2) Breeding conditions: Mice or rats are allowed free access to solid food and tap water.
(3) Setting dosage and grouping: Administer orally and intravenously at prescribed dosages. Set up the group as follows. (Dosage may vary depending on compound)
Oral administration 2-60μmol/kg or 1-30mg/kg (n=2-3)
Intravenous administration 1-30μmol/kg or 0.5-10mg/kg (n=2-3)
(4) Preparation of administration solution: For oral administration, administer as a solution or suspension. For intravenous administration, solubilize and administer.
(5) Administration method: For oral administration, the drug is forcibly administered into the stomach using an oral probe. For intravenous administration, administer through the tail vein using a syringe with a needle attached.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound according to the present invention in plasma is measured using LC/MS/MS.
(7) Statistical analysis: The area under the plasma concentration-time curve (AUC) was calculated using the moment analysis method regarding the concentration change of the compound according to the present invention in plasma, and the dose ratio and AUC of the oral administration group and intravenous administration group were calculated. The bioavailability (BA) of the compound according to the present invention is calculated from the ratio.
Note that the dilution concentration and dilution solvent are changed as necessary.

Test Example 6 Clearance Evaluation Test Experimental Materials and Methods (1) Animals used: SD rats are used.
(2) Breeding conditions: SD rats are allowed free access to solid food and tap water.
(3) Setting dosage and grouping: Administer intravenously at a prescribed dosage. Set up the group as follows.
Intravenous administration 1 μmol/kg (n=2)
(4) Preparation of administration solution: Solubilize using dimethyl sulfoxide/propylene glycol = 1/1 solvent and administer.
(5) Administration method: Administer through the tail vein using a syringe with an injection needle attached.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound according to the present invention in plasma is measured using LC/MS/MS.
(7) Statistical analysis: Regarding the concentration change of the compound according to the present invention in plasma, the whole body clearance (CLtot) is calculated by the moment analysis method. Note that the dilution concentration and dilution solvent are changed as necessary.

Test Example 7: Metabolic stability test Pooled human liver microsomes or pooled rat liver microsomes were reacted with the compound according to the present invention for a certain period of time, and the residual rate was calculated by comparing the reacted sample and the unreacted sample. Evaluate the degree of metabolism in the liver.

Human or rat liver microsomes in 0.2 mL of buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL in the presence of 1 mmol/L NADPH. React at 37°C for 0 or 30 minutes (oxidation reaction). After the reaction, double the amount of methanol/acetonitrile = 1/1 (v/v) solution is added to a certain amount of the reaction solution, mixed, and centrifuged. The compound according to the present invention in the centrifuged supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and the amount of the compound according to the present invention at the time of 0 minute reaction was set as 100%. The ratio to the amount is shown as the residual rate. Note that the hydrolysis reaction is performed in the absence of NADPH, and the glucuronidation reaction is performed in the presence of 5 mmol/L UDP-glucuronic acid instead of NADPH, and the same operation is performed thereafter. The dilution concentration and dilution solvent are changed as necessary.

Test Example 8: Metabolic stability test (hepatocytes)
The compound according to the present invention is reacted with human, rat, dog, or monkey hepatocytes for a certain period of time, and the residual rate is calculated by comparing the reacted sample and the unreacted sample, and the extent to which the compound according to the present invention is metabolized in the liver is evaluated. do. In order to take into account the influence of serum protein binding on metabolism, up to 10% of the serum of the species corresponding to each hepatocyte may be added to the medium.

Human, rat, dog or monkey hepatocytes are suspended in William's medium E at 1×10 ⁶ cells/mL and reacted with the compound of the present invention at 37° C. for 0, 1 or 2 hours. When adding serum, add up to 10% serum to William's medium E in advance, and then suspend the hepatocytes. After the reaction, a 4-fold volume of methanol/acetonitrile = 1/1 (v/v) solution is mixed with a certain amount of the reaction solution, and the mixture is centrifuged. The compound according to the present invention in the centrifuged supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and the amount of the compound according to the present invention at the time of 0 minute reaction was set as 100%. The ratio to the amount is shown as the residual rate. The dilution concentration and dilution solvent are changed as necessary.

The pharmaceutical composition of the present invention contains a compound having an inhibitory effect on RSV, and is useful for the treatment and/or prevention of RSV infection and related diseases caused by infection.

Claims (21)

Formula (I):

(In the formula,
Dashed lines indicate the presence or absence of bonds;
R ¹ is carboxy, tetrazolyl or oxadiazolonyl ;
L is substituted or unsubstituted non-aromatic carbocyclic diyl, substituted or unsubstituted non-aromatic heterocyclic diyl, or substituted or unsubstituted alkylene;
R ² is substituted or unsubstituted alkyl;
R ³ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl ;
V is -CR ^V = or -N=;
W is =CR ^W - or =N- ;
R ^V and R ^W are each independently a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl ;
formula:

The group represented by

(wherein R ^X and R ^Y are each independently a hydrogen atom, cyano, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl;
R ^U is a hydrogen atom, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-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 aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted non-aromatic carbocyclic group;
R ⁵ and R ⁶ each independently represent 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 represent oxo. may be formed;
R ⁷ and R ⁸ each independently represent 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 a substituted or unsubstituted non-aromatic heterocyclic group. Substituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Substituted non-aromatic carbocycle sulfonyl, substituted or unsubstituted alkylsulfonyl, or R ⁷ and R ⁸ taken together with the carbon atoms to which they are attached, substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted may form a non-aromatic heterocycle; or
R ⁵ and R ⁷ together with the carbon atoms to which they are bonded may form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted aromatic carbocycle;
R ⁴ is a hydrogen atom, 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 aromatic heterocycleoxy, 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 group heterocycle carbonyl, or R ⁴ and R ^U may be taken together with the carbon atoms to which they are bonded to form a substituted or unsubstituted non-aromatic heterocycle)
)
A pharmaceutical composition containing the compound represented by or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is carboxy. 3. A pharmaceutical composition containing the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is substituted or unsubstituted non-aromatic carbocyclic diyl. A pharmaceutical composition containing the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom. A pharmaceutical composition containing the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein V is -N= and W is =N-. formula:

The group represented by

A pharmaceutical composition containing the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a group represented by the formula (wherein each symbol has the same meaning as in claim 1). formula:

The group represented by

A pharmaceutical composition containing the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a group represented by the formula (wherein each symbol has the same meaning as in claim 1). formula:

The group represented by

(In the formula, R ⁴ has the same meaning as in claim 1, R ⁷ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group) , substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl 3. A pharmaceutical composition comprising the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a group represented by (substituted or unsubstituted non-aromatic carbocyclic sulfonyl). formula:

The group represented by

(In the formula, R ⁴ has the same meaning as in claim 1, R ⁷ and R ⁸ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, or R ⁷ and R ⁸ are together with the carbon atom to which they are bonded. and forming a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle, or a pharmaceutically acceptable compound thereof, which is a group represented by A pharmaceutical composition containing a salt. R ⁴ 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 3. A pharmaceutical composition comprising the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group. A medicament containing the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is substituted or unsubstituted non-aromatic heterocyclic oxy or substituted or unsubstituted non-aromatic carbocyclic oxy. Composition. The following compounds:

A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of. The compound is:

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The compound is:

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The compound is:

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The compound is:

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The compound is:

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The compound is:

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The compound is:

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, which is an RS virus growth inhibitor. The pharmaceutical composition according to claim 1, which is a therapeutic and/or prophylactic agent for respiratory syncytial virus infection.

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