Amide derivatives with antiviral activity

Abstract

The present invention provides a compound having antiviral activity, formula (I): #imgabs0# (wherein the dotted line indicates the presence or absence of a bond; R 1 is a carboxyl group, etc.; L is a substituted or unsubstituted non-aromatic carbocyclic diyl group, etc.; R 2 is a substituted or unsubstituted alkyl group; R 3 is a hydrogen atom, etc.; X is =CR X ‑or=N‑;Y=CR Y ‑or=N‑;U is ‑CR U = or -N=; V is -CR V = or -N =; W = CR W ‑or=N‑;Z A is ‑C= or ‑N‑; Z B CR 5 R 6 ‑etc.; Z C CR 7 R 8 ‑et al.; R X 、R Y 、R V and R W are each independently a hydrogen atom, etc.; R U is a hydrogen atom, etc.; R 5 and R 6 are each independently a hydrogen atom, etc.; R 7 and R 8 are each independently a hydrogen atom, etc.; R 4 is a substituted or unsubstituted alkyloxy group, etc.) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.

Description

Technical Field

[0001] The present invention relates to compounds useful for treating and / or preventing respiratory syncytial virus (hereinafter referred to as RSV) infection and related diseases caused by the infection, and pharmaceutical compositions containing the same. In particular, the present invention relates to amide derivatives having RSV inhibitory activity. Background Art

[0002] Human respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus in the family Paramyxoviridae. It is the most common cause of bronchiolitis and pneumonia in children under one year old. Almost all children will be infected with RSV before their second birthday, and approximately 1 to 3% of those infected require hospitalization. The elderly and those with heart, lung, or immune system disorders are particularly susceptible, with a higher risk of severe illness and complications (Non-Patent Document 1).

[0003] RSV has two antigenic subtypes, A and B. Typically, these two subtypes are detected simultaneously during RSV epidemics, but their proportions vary geographically and seasonally, which is believed to be one of the reasons for the different clinical effects of each epidemic. Therefore, considering the treatment of RSV, it is desirable to have a drug that is effective against both subtypes A and B (Non-Patent Document 1).

[0004] At present, there is no vaccine that can prevent RSV infection. Palivizumab (Palivizumab) is a monoclonal antibody used prophylactically to prevent RSV infection in infants with high risk, for example, premature infants and infants with heart disease or lung disease. Due to the high cost of Palivizumab treatment, it is restricted in its use as a general medicine. With regard to therapeutic drugs, although ribavirin (Ribavirin), which belongs to nucleic acid analogs, is recognized as the only antiviral agent for the treatment of RSV infection in the U.S., except for concerns about the side effect profile, its effectiveness is also limited. Therefore, it is expected that development can be widely used in all types of RSV and the age group from infants to the elderly, and safe and effective RSV treatment (non-patent literature 1).

[0005] Among the RSV therapeutics currently in clinical development, inhibitors of the F protein involved in RSV membrane fusion include Ziresovir, JNJ-53718678, and RV-521, and inhibitors of the N protein involved in genome stabilization include EDP-938. Furthermore, agents such as PC786 are under development to inhibit the polymerase of the L protein (Non-Patent Document 2).

[0006] To date, there are no known amide derivatives having RSV inhibitory activity as described in this patent application.

[0007] Prior art literature

[0008] Non-patent literature

[0009] Non-patent literature 1: Cellular and Molecular Life Sciences, 2020, Jun 16, 1-14

[0010] Non-patent literature 2: Expert Opinion on Investigational Drugs, 2020, Mar 29, 3, 285-294 Summary of the Invention

[0011] Problems to be solved by the invention

[0012] The present invention aims to provide novel compounds having RSV inhibitory activity. More preferably, the present invention aims to provide compounds useful for the treatment and / or prevention of RSV infection and related diseases caused by the infection, and medicaments containing the same.

[0013] Means of solving problems

[0014] The present invention relates to the following items (1) to (17).

[0015] (1) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0016] [Chemistry 1]

[0017]

[0018] (Wherein, the dashed line indicates the presence or absence of a bond;

[0019] R 1 is a carboxyl group, a cyano group, a substituted or unsubstituted aromatic heterocyclic group, -C(=O)-NR 1B R 1C or -CH=CHC(=O)-OH;

[0020] R 1B and R 1C are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aminosulfonyl group, or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group;

[0021] L is a substituted or unsubstituted non-aromatic carbocyclic diyl, a substituted or unsubstituted non-aromatic heterocyclic diyl, or a substituted or unsubstituted alkylene group;

[0022] R 2 is a substituted or unsubstituted alkyl group;

[0023] R 3is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted carbamoyl group;

[0024] X = CR X - or = N-;

[0025] Y = CR Y - or = N-;

[0026] U for -CR U = or -N =;

[0027] V is -CR V = or -N =;

[0028] W = CR W - or = N-;

[0029] Z A is -C= or -N-;

[0030] Z B -CR 5 R 6 -、-CR 5 =、-NR 5 -or-N=;

[0031] Z C -CR 7 R 8 -、-CR 7 =、-NR 7 - or = N-;

[0032] R X 、R Y 、R V and R W are each independently a hydrogen atom, a cyano group, a halogen group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted carbamoyl group;

[0033] R U is a hydrogen atom, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a hydroxyl group, a halogen group, a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted aromatic heterocyclyl group, a substituted or unsubstituted non-aromatic heterocyclyl group, or a substituted or unsubstituted non-aromatic carbocyclyl group;

[0034] R 5 and R 6 are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group or a substituted or unsubstituted alkyl group, or R 5 and R6 Can form an oxo group together;

[0035] R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, a substituted or unsubstituted alkylsulfonyl group, or R 7 and R 8 may form, together with the carbon atom to which it is bonded, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; or

[0036] R 5 and R 7 Together with the carbon atom to which it is bonded, it may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted aromatic carbocyclic ring;

[0037] R 4 is a hydrogen atom, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclyloxy group, a substituted or unsubstituted non-aromatic carbocyclyloxy group, a substituted or unsubstituted aromatic carbocyclyloxy group, a substituted or unsubstituted aromatic heterocyclyloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a hydroxyl group, a halogen group, a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted aromatic heterocyclyl group, a substituted or unsubstituted non-aromatic heterocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, or a substituted or unsubstituted non-aromatic heterocyclic carbonyl group, or R 4 and R U Together with the carbon atom to which it is bonded, it may form a substituted or unsubstituted non-aromatic heterocyclic ring).

[0038] (2) The compound according to item (1) above or a pharmaceutically acceptable salt thereof, wherein R 1 It is a carboxyl group.

[0039] (3) The compound or pharmaceutically acceptable salt thereof according to item (1) or (2) above, wherein L is a substituted or unsubstituted non-aromatic carbocyclic diyl group.

[0040] (4) The compound according to any one of items (1) to (3) above, or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom.

[0041] (5) 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-.

[0042] (6) The compound or pharmaceutically acceptable salt thereof according to any one of items (1) to (5) above, wherein the formula

[0043] [Chemistry 2]

[0044]

[0045] The group represented by is a group represented by the following formula:

[0046] [Chemistry 3]

[0047]

[0048] (In the formula, each symbol has the same meaning as in the above item (1)).

[0049] (7) The compound or pharmaceutically acceptable salt thereof according to any one of items (1) to (6) above, wherein the formula

[0050] [Chemistry 4]

[0051]

[0052] The group represented by is a group represented by the following formula:

[0053] [Chemistry 5]

[0054]

[0055] (In the formula, each symbol has the same meaning as in the above item (1)).

[0056] (8) The compound according to any one of items (1) to (7) above, or a pharmaceutically acceptable salt thereof, wherein the formula:

[0057] [Chemistry 6]

[0058]

[0059] The group represented by is a group represented by the following formula:

[0060] [Chemistry 7]

[0061]

[0062] (In the formula, each symbol has the same meaning as in the above item (1)).

[0063] (9) The compound according to any one of items (1) to (8) above, or a pharmaceutically acceptable salt thereof, wherein the formula:

[0064] [Chemistry 8]

[0065]

[0066] The group represented by is a group represented by the following formula:

[0067] [Chemistry 9]

[0068]

[0069] (Where R 4 Same as above item (1), R 7 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group or a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group).

[0070] (10) The compound or pharmaceutically acceptable salt thereof according to any one of items (1) to (8) above, wherein the formula

[0071] [Chemistry 10]

[0072]

[0073] The group represented by is a group represented by the following formula:

[0074] [Chemistry 11]

[0075]

[0076] (Where R 4 Same as above item (1), R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring).

[0077] (11) The compound or pharmaceutically acceptable salt thereof according to any one of items (1) to (10), wherein R 4 is a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a hydroxyl group, a halogen group, a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted non-aromatic heterocyclyl group or a substituted or unsubstituted non-aromatic carbocyclyl group.

[0078] (12) The compound or pharmaceutically acceptable salt thereof according to any one of items (1) to (11), wherein R 4 is a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted non-aromatic carbocyclic group.

[0079] (13) The compound according to item (1) above, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds I-082, I-162, I-481, I-496, I-503, I-506, I-549, I-552, I-568, I-569, I-570, I-571, I-591, I-613, I-617, and I-618.

[0080] (14) A pharmaceutical composition comprising the compound according to any one of items (1) to (13) above or a pharmaceutically acceptable salt thereof.

[0081] (15) The pharmaceutical composition according to item (14) above, which has an anti-RS virus effect.

[0082] (16) A method for treating and / or preventing RSV infection, characterized by administering the compound according to any one of items (1) to (13) above or a pharmaceutically acceptable salt thereof.

[0083] (17) The compound according to any one of items (1) to (13) above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of RSV infection.

[0084] (18) Use of the compound according to any one of items (1) to (13) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or preventive drug for RSV infection.

[0085] Effects of the Invention

[0086] The compounds of the present invention are useful as therapeutic and / or preventive agents having RSV inhibitory activity for RSV infection and related diseases caused by the infection. Specific implementation plan

[0087] The following describes the meanings of the terms used in this specification. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms.

[0088] The term "consisting of..." means that it only has the constituent elements.

[0089] The term "comprising" does not limit the constituent elements and does not exclude undescribed elements.

[0090] The present invention will be described below while showing embodiments thereof. Throughout this specification, unless otherwise specified, expressions in the singular form are understood to include the concept of the plural form. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) are understood to include the concept of the plural form unless otherwise specified.

[0091] In addition, unless otherwise noted, the terms used in this specification are to be understood as having the meanings commonly used in the respective fields. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meanings as commonly understood by practitioners in the field to which this invention belongs. In the event of any conflict, this specification (including definitions) shall prevail.

[0092] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms, with fluorine and chlorine atoms being particularly preferred.

[0093] The "alkyl group" 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. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.

[0094] 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.

[0095] The “alkenyl group” includes a linear or branched hydrocarbon group having one or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms. Examples thereof include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.

[0096] Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl, n-propenyl, and the like.

[0097] "Alkynyl" includes straight-chain or branched hydrocarbon groups having one or more triple bonds at any position and having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. Alkynyl groups may also have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.

[0098] Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

[0099] The "alkylene group" includes a linear or branched divalent hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples thereof include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene.

[0100] "Aromatic carbocyclic group" refers to a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. Examples thereof include phenyl, naphthyl, anthracenyl, and phenanthrenyl.

[0101] Preferred embodiments of the "aromatic carbocyclic group" include phenyl.

[0102] The "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0103] “R 5 and R 7 Examples of the "substituted or unsubstituted aromatic carbon ring formed together with the carbon atom to which it is bonded" include the following rings.

[0104] [Chemistry 12]

[0105]

[0106] A "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or more cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. A "non-aromatic carbocyclic group" having two or more rings also includes a monocyclic or bicyclic or more non-aromatic carbocyclic group in which a ring of the aforementioned "aromatic carbocyclic group" is condensed.

[0107] Furthermore, the "non-aromatic carbocyclic group" also includes a bridged group or a spirocyclic group as described below.

[0108] [Chemistry 13]

[0109]

[0110] 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 thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.

[0111] 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 thereof include dihydroindenyl, indenyl, acenaphthenyl, tetrahydronaphthyl, and fluorenyl.

[0112] The "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0113] “R 5 and R 7 Examples of the “substituted or unsubstituted non-aromatic carbon ring formed together with the carbon atom to which it is bonded” include the following rings.

[0114] [Chemistry 14]

[0115]

[0116] “R 7 and R 8 Examples of the “substituted or unsubstituted non-aromatic carbon ring formed together with the carbon atom to which it is bonded” include the following rings.

[0117] [Chemistry 15]

[0118]

[0119] A "non-aromatic carbocyclic diyl group" refers to a divalent group derived from the above-mentioned "non-aromatic carbocyclic ring." Examples thereof include cyclopropyldiyl, cyclobutyldiyl, cyclopentyldiyl, cyclohexyldiyl, cycloheptyldiyl, cyclooctanediyl, bicyclo[2.2.2]octanediyl, bicyclo[2.2.1]heptyldiyl, and adamantanediyl. One carbon atom may have two connecting bonds. Examples thereof include cyclohexane-1,1-diyl and adamantane-2,2-diyl.

[0120] The "aromatic heterocyclic group" refers to a monocyclic or bicyclic aromatic ring group having one or more heteroatoms, the same or different, arbitrarily selected from O, S and N in the ring.

[0121] The aromatic heterocyclic group having two or more rings is also included in the monocyclic or bicyclic aromatic heterocyclic group in which the rings in the above-mentioned "aromatic carbocyclic group" are condensed, and the bonding bond may exist in any ring.

[0122] 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, and thiadiazolyl. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0123] The aromatic heterocyclic group of the two rings is preferably 8-10-membered, more preferably 9-membered or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, imidopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl.

[0124] The aromatic heterocyclic group having three or more rings is preferably 13 to 15-membered. Examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenothioxazinyl, phenoxazine, and dibenzofuranyl.

[0125] The "aromatic heterocyclic ring" refers to a ring derived from the above-mentioned "aromatic heterocyclic group".

[0126] The "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic non-aromatic group having one or more heteroatoms, the same or different, arbitrarily selected from O, S, and N, in the ring. A bicyclic or bicyclic non-aromatic heterocyclic group is a monocyclic or bicyclic non-aromatic heterocyclic group in which each ring of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group" is condensed. Furthermore, it also includes a monocyclic or bicyclic non-aromatic heterocyclic group in which a ring of the above-mentioned "aromatic carbocyclic group" is condensed, and the bonding bond may exist in one ring.

[0127] Furthermore, the "non-aromatic carbocyclic group" also includes a cross-linked group or a spirocyclic group as described below.

[0128] [Chemistry 16]

[0129]

[0130] The monocyclic non-aromatic heterocyclic group preferably has 3 to 8 members, more preferably 5 or 6 members.

[0131] Examples of the 3-membered non-aromatic heterocyclic group include thiopyranyl, oxiranyl, and aziridine. 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, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolanyl, and heterocyclopentyl. Examples of the 6-membered non-aromatic heterocyclic group include dioxanyl, thienyl, piperidinyl, hexahydropyrazinyl, morpholinyl, N-morpholinyl, thiomorpholinyl, N-thiomorpholinyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thienyl, and thiazinyl. Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazinyl, tetrahydrodiazinyl, and oxepanyl.

[0132] The non-aromatic heterocyclic group having two or more rings is preferably 8 to 20-membered, more preferably 8 to 10-membered. Examples thereof include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0133] The "non-aromatic heterocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0134] “R 7 and R 8 Examples of the “substituted or unsubstituted non-aromatic heterocyclic ring formed together with the carbon atom to which it is bonded” include the following rings.

[0135] [Chemistry 17]

[0136]

[0137] (wherein, R' is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxycarbonyl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkylcarbonyl group)

[0138] “R 4 and R U Examples of the “substituted or unsubstituted non-aromatic heterocyclic ring formed together with the carbon atom to which it is bonded” include the following rings.

[0139] [Chemistry 18]

[0140]

[0141] A "non-aromatic heterocyclic diyl group" refers to a divalent group derived from the above-mentioned "non-aromatic heterocycle." "Non-aromatic heterocyclic diyl groups" include non-aromatic ring diyl groups with 1 to 9 carbon atoms containing 1 to 4 nitrogen atoms, oxygen atoms, and / or sulfur atoms, and include, for example, pyrrolinediyl, pyrrolidinediyl, imidazolinediyl, imidazolidinediyl, pyrazolidinediyl, pyrazolidinediyl, piperidinediyl, piperazinediyl, morpholinediyl, and tetrahydropyrandiyl. A single carbon atom may have two connecting bonds. Examples include tetrahydropyran-4,4-diyl and piperidine-4,4-diyl.

[0142] A "trialkylsilyl group" refers to a group in which three of the aforementioned "alkyl groups" are bonded to a silicon atom. The three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0143] In this specification, “may be substituted by substituent group α” means “may be substituted by one or more groups selected from substituent group α.” The same applies to substituent groups β, γ, and γ′.

[0144] Substituents such as “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylcarbonyloxy”, “substituted alkenylcarbonyloxy”, “substituted alkynylcarbonyloxy”, “substituted alkylcarbonyl”, “substituted alkenylcarbonyl”, “substituted alkynylcarbonyl”, “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl”, “substituted alkynyloxycarbonyl”, “substituted alkylsulfanyl”, “substituted alkenylsulfanyl”, “substituted alkynylsulfanyl”, “substituted alkylsulfinyl”, “substituted alkenylsulfinyl”, “substituted alkynylsulfinyl”, “substituted alkylsulfonyl”, “substituted alkenylsulfonyl”, and “substituted alkynylsulfonyl” include the following Substituent Group A. A carbon atom at any position may be bonded to one or more groups selected from the following Substituent Group A.

[0145] Substituent Group A: halogen, hydroxy, carboxyl, formyl, formyloxy, sulfanyl, sulfinyl, sulfonic acid, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, urea, amidino, guanidino, pentafluorothio, trialkylsilyl,

[0146] an alkyloxy group which may be substituted by the α-substituent group, an alkenyloxy group which may be substituted by the α-substituent group, an alkynyloxy group which may be substituted by the α-substituent group, an alkylcarbonyloxy group which may be substituted by the α-substituent group, an alkenylcarbonyloxy group which may be substituted by the α-substituent group, an alkynylcarbonyloxy group which may be substituted by the α-substituent group, an alkylcarbonyl group which may be substituted by the α-substituent group, an alkenylcarbonyl group which may be substituted by the α-substituent group, an alkynylcarbonyl group which may be substituted by the α-substituent group, an alkyloxycarbonyl group which may be substituted by the α-substituent group, an alkenylcarbonyl group which may be substituted by the α-substituent group, alkyloxycarbonyl, alkynyloxycarbonyl which may be substituted by substituent group α, alkylsulfanyl which may be substituted by substituent group α, alkenylsulfanyl which may be substituted by substituent group α, alkynylsulfanyl which may be substituted by substituent group α, alkylsulfinyl which may be substituted by substituent group α, alkenylsulfinyl which may be substituted by substituent group α, alkynylsulfinyl which may be substituted by substituent group α, alkylsulfonyl which may be substituted by substituent group α, alkenylsulfonyl which may be substituted by substituent group α, alkynylsulfonyl which may be substituted by substituent group α,

[0147] an amino group which may be substituted by a substituent group β, an imino group which may be substituted by a substituent group β, a carbamoyl group which may be substituted by a substituent group β, a sulfamoyl group which may be substituted by a substituent group β,

[0148] Aromatic carbocyclic group which may be substituted by substituent group γ, non-aromatic carbocyclic group which may be substituted by substituent group γ', aromatic heterocyclic group which may be substituted by substituent group γ, non-aromatic heterocyclic group which may be substituted by substituent group γ', aromatic carbocyclic oxy group which may be substituted by substituent group γ, non-aromatic carbocyclic oxy group which may be substituted by substituent group γ', aromatic heterocyclic oxy group which may be substituted by substituent group γ, non-aromatic heterocyclic oxy group which may be substituted by substituent group γ', aromatic carbocyclic carbonyloxy group which may be substituted by substituent group γ, non-aromatic carbocyclic carbonyloxy group which may be substituted by substituent group γ', aromatic heterocyclic group which may be substituted by substituent group γ carbonyloxy, non-aromatic heterocyclic carbonyloxy which may be substituted by the γ' substituent group, aromatic carbocyclic carbonyl which may be substituted by the γ' substituent group, non-aromatic carbocyclic carbonyl which may be substituted by the γ' substituent group, aromatic heterocyclic carbonyl which may be substituted by the γ substituent group, non-aromatic heterocyclic carbonyl which may be substituted by the γ' substituent group, aromatic carbocyclic oxycarbonyl which may be substituted by the γ substituent group, non-aromatic carbocyclic oxycarbonyl which may be substituted by the γ' substituent group, aromatic heterocyclic oxycarbonyl which may be substituted by the γ substituent group, non-aromatic heterocyclic oxycarbonyl which may be substituted by the γ' substituent group, aromatic carbocyclic alkyloxy which may be substituted by the γ substituent group , a non-aromatic carbocyclic alkyloxy group which may be substituted with a γ' substituent group, an aromatic heterocyclic alkyloxy group which may be substituted with a γ' substituent group, a non-aromatic heterocyclic alkyloxy group which may be substituted with a γ' substituent group, an aromatic carbocyclic alkyloxycarbonyl group which may be substituted with a γ' substituent group, an aromatic heterocyclic alkyloxycarbonyl group which may be substituted with a γ' substituent group, a non-aromatic heterocyclic alkyloxycarbonyl group which may be substituted with a γ' substituent group, an aromatic carbocyclic sulfanyl group which may be substituted with a γ' substituent group, and a non-aromatic carbocyclic sulfanyl group which may be substituted with a γ' substituent group group, an aromatic heterocyclic sulfanyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic sulfanyl group which may be substituted by the substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic sulfinyl group which may be substituted by the substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic sulfinyl group which may be substituted by the substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic sulfonyl group which may be substituted by the substituent group γ', an aromatic heterocyclic sulfonyl group which may be substituted by the substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted by the substituent group γ'.

[0149] Substituent Group α: halogen, hydroxy, carboxyl, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0150] Substituent group β: halogen, hydroxyl, carboxyl, cyano, alkyl which may be substituted by substituent group α, alkenyl which may be substituted by substituent group α, alkynyl which may be substituted by substituent group α, alkylcarbonyl which may be substituted by substituent group α, alkenylcarbonyl which may be substituted by substituent group α, alkynylcarbonyl which may be substituted by substituent group α, alkylsulfanyl which may be substituted by substituent group α, alkenylsulfanyl which may be substituted by substituent group α, alkynylsulfanyl which may be substituted by substituent group α, alkylsulfinyl which may be substituted by substituent group α, alkenylsulfinyl which may be substituted by substituent group α, alkynylsulfinyl which may be substituted by substituent group α, alkylsulfonyl which may be substituted by substituent group α, alkenylsulfonyl which may be substituted by substituent group α, alkynylsulfonyl which may be substituted by substituent group α,

[0151] an aromatic carbocyclic group which may be substituted by the substituent group γ, a non-aromatic carbocyclic group which may be substituted by the substituent group γ', an aromatic heterocyclic group which may be substituted by the substituent group γ, a non-aromatic heterocyclic group which may be substituted by the substituent group γ', an aromatic carbocyclic alkyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic alkyl group which may be substituted by the substituent group γ', an aromatic heterocyclic alkyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic alkyl group which may be substituted by the substituent group γ', an aromatic carbocyclic carbonyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic carbonyl group which may be substituted by the substituent group γ', an aromatic heterocyclic carbonyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic carbonyl group which may be substituted by the substituent group γ', an aromatic carbocyclic oxycarbonyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic oxycarbonyl group which may be substituted by the substituent group γ', an aromatic heterocyclicoxycarbonyl group, a non-aromatic heterocyclicoxycarbonyl group which may be substituted with the substituent group γ', an aromatic carbocyclicsulfanyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclicsulfanyl group which may be substituted with the substituent group γ', an aromatic heterocyclicsulfanyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclicsulfanyl group which may be substituted with the substituent group γ', an aromatic carbocyclicsulfinyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclicsulfinyl group which may be substituted with the substituent group γ', an aromatic heterocyclicsulfinyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclicsulfinyl group which may be substituted with the substituent group γ', an aromatic carbocyclicsulfonyl group which may be substituted with the substituent group γ, a non-aromaticcarbocyclicsulfonyl group which may be substituted with the substituent group γ', an aromatic heterocyclicsulfonyl group which may be substituted with the substituent group γ, and a non-aromatic heterocyclicsulfonyl group which may be substituted with the substituent group γ'.

[0152] Substituent Group γ: Substituent Group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0153] Substituent group γ': substituent group γ and oxo group.

[0154] “substituted aromatic carbocyclic group”, “substituted aromatic heterocyclic group”, “substituted aromatic carbocyclic oxy group”, “substituted aromatic heterocyclic oxy group”, “substituted aromatic carbocyclic carbonyloxy group”, “substituted aromatic heterocyclic carbonyloxy group”, “substituted aromatic carbocyclic carbonyl group”, “substituted aromatic heterocyclic carbonyl group”, “substituted aromatic carbocyclic oxycarbonyl group”, “substituted aromatic heterocyclic oxycarbonyl group”, “substituted aromatic carbocyclic sulfanyl group”, “substituted aromatic heterocyclic sulfanyl group”, “substituted aromatic carbocyclic sulfinyl group”, “substituted aromatic heterocyclic sulfinyl group”, “substituted aromatic carbocyclic sulfonyl group”, “substituted aromatic heterocyclic sulfonyl group” and “R 5 and R 7 The substituents on the "aromatic carbocycle" and "aromatic heterocycle" such as "a substituted aromatic carbocycle" formed together with the carbon atoms to which it is bonded include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B.

[0155] Substituent Group B: halogen, hydroxy, carboxyl, formyl, formyloxy, sulfanyl, sulfinyl, sulfonic acid, thioformyl, thiocarboxyl, disulfide carboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, urea, amidino, guanidino, pentafluorothio, trialkylsilyl,

[0156] Alkyl which may be substituted by substituent group α, alkenyl which may be substituted by substituent group α, alkynyl which may be substituted by substituent group α, alkyloxy which may be substituted by substituent group α, alkenyloxy which may be substituted by substituent group α, alkynyloxy which may be substituted by substituent group α, alkylcarbonyloxy which may be substituted by substituent group α, alkenylcarbonyloxy which may be substituted by substituent group α, alkynylcarbonyloxy which may be substituted by substituent group α, alkylcarbonyl which may be substituted by substituent group α, alkenylcarbonyl which may be substituted by substituent group α, alkynylcarbonyl which may be substituted by substituent group α, an alkyloxycarbonyl group which may be substituted by the α substituent group, an alkenyloxycarbonyl group which may be substituted by the α substituent group, an alkynyloxycarbonyl group which may be substituted by the α substituent group, an alkylsulfanyl group which may be substituted by the α substituent group, an alkenylsulfanyl group which may be substituted by the α substituent group, an alkynylsulfanyl group which may be substituted by the α substituent group, an alkylsulfinyl group which may be substituted by the α substituent group, an alkynylsulfinyl group which may be substituted by the α substituent group, an alkylsulfonyl group which may be substituted by the α substituent group, an alkenylsulfonyl group which may be substituted by the α substituent group, and an alkynylsulfonyl group which may be substituted by the α substituent group,

[0157] an amino group which may be substituted by a substituent group β, an imino group which may be substituted by a substituent group β, a carbamoyl group which may be substituted by a substituent group β, a sulfamoyl group which may be substituted by a substituent group β,

[0158] an aromatic carbocyclic group which may be substituted by the substituent group γ, a non-aromatic carbocyclic group which may be substituted by the substituent group γ', an aromatic heterocyclic group which may be substituted by the substituent group γ, a non-aromatic heterocyclic group which may be substituted by the substituent group γ', an aromatic carbocyclic oxy group which may be substituted by the substituent group γ, a non-aromatic carbocyclic oxy group which may be substituted by the substituent group γ', an aromatic heterocyclic oxy group which may be substituted by the substituent group γ, a non-aromatic heterocyclic oxy group which may be substituted by the substituent group γ', an aromatic carbocyclic carbonyloxy group which may be substituted by the substituent group γ, a non-aromatic carbocyclic carbonyloxy group which may be substituted by the substituent group γ', an aromatic heterocyclic carbonyloxy group which may be substituted by the substituent group γ, a non-aromatic heterocyclic carbonyloxy group which may be substituted by the substituent group γ', an aromatic Carbocyclic carbonyl, non-aromatic carbocyclic carbonyl which may be substituted with the γ' substituent group, aromatic heterocyclic carbonyl which may be substituted with the γ' substituent group, non-aromatic heterocyclic carbonyl which may be substituted with the γ' substituent group, aromatic carbocyclic oxycarbonyl which may be substituted with the γ' substituent group, non-aromatic carbocyclic oxycarbonyl which may be substituted with the γ' substituent group, aromatic heterocyclic oxycarbonyl which may be substituted with the γ' substituent group, non-aromatic heterocyclic oxycarbonyl which may be substituted with the γ' substituent group, aromatic carbocyclic alkyl which may be substituted with the γ' substituent group, non-aromatic carbocyclic alkyl which may be substituted with the γ' substituent group, aromatic heterocyclic alkyl which may be substituted with the γ' substituent group, non-aromatic heterocyclic alkyl which may be substituted with the γ' substituent group, aromatic carbocyclic alkyloxy which may be substituted with the γ substituent group Non-aromatic carbocyclic alkyloxy group substituted by the substituent group γ', aromatic heterocyclic alkyloxy group which may be substituted by the substituent group γ, non-aromatic heterocyclic alkyloxy group which may be substituted by the substituent group γ', aromatic carbocyclic alkyloxycarbonyl group which may be substituted by the substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl group which may be substituted by the substituent group γ', aromatic heterocyclic alkyloxycarbonyl group which may be substituted by the substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl group which may be substituted by the substituent group γ', aromatic carbocyclic alkyloxyalkyl group which may be substituted by the substituent group γ, non-aromatic heterocyclic alkyloxyalkyl group which may be substituted by the substituent group γ , an aromatic carbocyclic sulfanyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclic sulfanyl group which may be substituted with the substituent group γ', an aromatic heterocyclic sulfanyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclic sulfanyl group which may be substituted with the substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclic sulfinyl group which may be substituted with the substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclic sulfinyl group which may be substituted with the substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclic sulfonyl group which may be substituted with the substituent group γ', an aromatic heterocyclic sulfonyl group which may be substituted with the substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted with the substituent group γ'.

[0159] “substituted non-aromatic carbocyclic group”, “substituted non-aromatic heterocyclic group”, “substituted non-aromatic carbocyclic oxy group”, “substituted non-aromatic heterocyclic oxy group”, “substituted non-aromatic carbocyclic carbonyloxy group”, “substituted non-aromatic heterocyclic carbonyloxy group”, “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 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 carbocyclic imidooxy”, “R 5 and R 7 together with the carbon atom to which it is bonded, to form a substituted non-aromatic carbocyclic ring, "R 7 and R 8 together with the carbon atom to which it is bonded, to form a substituted non-aromatic carbocyclic ring, "R 7 and R 8 together with the carbon atom to which it is bonded, to form a substituted non-aromatic heterocyclic ring" and "R 4 and R U The substituents on the "non-aromatic carbocycle" and "non-aromatic heterocycle" rings forming a "substituted non-aromatic heterocycle" together with the carbon atoms to which they are bonded include the following substituent group C. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group C.

[0160] Substituent Group C: Substituent Group B and oxo group.

[0161] When a "non-aromatic carbocycle" or "non-aromatic heterocycle" is substituted with an "oxo group", it refers to a ring in which two hydrogen atoms on a carbon atom are substituted as follows.

[0162] [Chemistry 19]

[0163]

[0164] The substituents of the "substituted amino group", "substituted imino group", "substituted carbamoyl group" and "substituted sulfamoyl group" include the following substituent group D. The substituent group may be substituted by one or two groups selected from the substituent group D.

[0165] Substituent Group D: halogen, hydroxyl, carboxyl, cyano, alkyl which may be substituted by Substituent Group α, alkenyl which may be substituted by Substituent Group α, alkynyl which may be substituted by Substituent Group α, alkylcarbonyl which may be substituted by Substituent Group α, alkenylcarbonyl which may be substituted by Substituent Group α, alkynylcarbonyl which may be substituted by Substituent Group α, alkylsulfanyl which may be substituted by Substituent Group α, alkenylsulfanyl which may be substituted by Substituent Group α, alkynylsulfanyl which may be substituted by Substituent Group α, alkylsulfinyl which may be substituted by Substituent Group α, alkenylsulfinyl which may be substituted by Substituent Group α, alkynylsulfinyl which may be substituted by Substituent Group α, alkylsulfonyl which may be substituted by Substituent Group α, alkenylsulfonyl which may be substituted by Substituent Group α, alkynylsulfonyl which may be substituted by Substituent Group α,

[0166] an amino group which may be substituted by a substituent group β, an imino group which may be substituted by a substituent group β, a carbamoyl group which may be substituted by a substituent group β, a sulfamoyl group which may be substituted by a substituent group β,

[0167] an aromatic carbocyclic group which may be substituted by the substituent group γ, a non-aromatic carbocyclic group which may be substituted by the substituent group γ', an aromatic heterocyclic group which may be substituted by the substituent group γ, a non-aromatic heterocyclic group which may be substituted by the substituent group γ', an aromatic carbocyclic alkyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic alkyl group which may be substituted by the substituent group γ', an aromatic heterocyclic alkyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic alkyl group which may be substituted by the substituent group γ', an aromatic carbocyclic carbonyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic carbonyl group which may be substituted by the substituent group γ', an aromatic heterocyclic carbonyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic carbonyl group which may be substituted by the substituent group γ', an aromatic carbocyclic oxycarbonyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic oxycarbonyl group which may be substituted by the substituent group γ', an aromatic heterocyclicoxycarbonyl group, a non-aromatic heterocyclicoxycarbonyl group which may be substituted with the substituent group γ', an aromatic carbocyclicsulfanyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclicsulfanyl group which may be substituted with the substituent group γ', an aromatic heterocyclicsulfanyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclicsulfanyl group which may be substituted with the substituent group γ', an aromatic carbocyclicsulfinyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclicsulfinyl group which may be substituted with the substituent group γ', an aromatic heterocyclicsulfinyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclicsulfinyl group which may be substituted with the substituent group γ', an aromatic carbocyclicsulfonyl group which may be substituted with the substituent group γ, a non-aromaticcarbocyclicsulfonyl group which may be substituted with the substituent group γ', an aromatic heterocyclicsulfonyl group which may be substituted with the substituent group γ, and a non-aromatic heterocyclicsulfonyl group which may be substituted with the substituent group γ'.

[0168] The following shows that R in the compound represented by formula (I) 1 、R 1B 、R 1C , L, R2 、R 3 , X, Y, U, V, W, Z A , Z B , Z C 、R 5 、R 6 、R 7 、R 8 、R X 、R Y 、R V 、R W 、R U and R 4 The compound represented by formula (I) is exemplified by all combinations of the specific examples shown below.

[0169] R 1 is a carboxyl group, a cyano group, a substituted or unsubstituted aromatic heterocyclic group, -C(=O)-NR 1B R 1C or -CH=CHC(=O)-OH; R 1B and R 1C Each is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aminosulfonyl group, or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group (hereinafter referred to as a-1).

[0170] R 1 is carboxyl or -C(=O)-NR 1B R 1C ; R 1B and R 1C Each is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aminosulfonyl group, or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group (hereinafter referred to as a-2).

[0171] R 1 It is a carboxyl group (hereinafter referred to as a-3).

[0172] L is a substituted or unsubstituted non-aromatic carbocyclic diyl group, a substituted or unsubstituted non-aromatic heterocyclic diyl group, or a substituted or unsubstituted alkylene group (hereinafter referred to as b-1).

[0173] L is a substituted or unsubstituted non-aromatic carbocyclic digroup or a substituted or unsubstituted non-aromatic heterocyclic digroup (hereinafter referred to as b-2).

[0174] L is a substituted or unsubstituted non-aromatic carbocyclic digroup (hereinafter referred to as b-3).

[0175] L is a substituted or unsubstituted adamantanediyl group or a substituted or unsubstituted cyclohexanediyl group (hereinafter referred to as b-4).

[0176] L is a substituted or unsubstituted adamantane-2,2-diyl group or a substituted or unsubstituted cyclohexane-1,1-diyl group (hereinafter referred to as b-5).

[0177] L is a non-aromatic carbocyclic diyl group substituted with one or more substituents selected from Substituent Group a (Substituent Group a: cyano, alkyloxy, hydroxyl, and halogen) or an unsubstituted non-aromatic carbocyclic diyl group (hereinafter referred to as b-6).

[0178] L is an adamantanediyl group substituted with one or more substituents selected from Substituent Group a or an unsubstituted adamantanediyl group (hereinafter referred to as b-7).

[0179] L is an adamantane-2,2-diyl group substituted with one or more substituents selected from Substituent Group a, or an unsubstituted adamantane-2,2-diyl group (hereinafter referred to as b-8).

[0180] L is a cyclohexanediyl group substituted with halogen or an unsubstituted cyclohexanediyl group (hereinafter referred to as b-9).

[0181] L is a cyclohexane-1,1-diyl group substituted with a halogen or an unsubstituted cyclohexane-1,1-diyl group (hereinafter referred to as b-10).

[0182] L is an adamantanediyl group substituted with one or more substituents selected from Substituent Group a, an unsubstituted adamantanediyl group, a cyclohexanediyl group substituted with a halogen, or an unsubstituted cyclohexanediyl group (hereinafter referred to as b-11).

[0183] L is adamantane-2,2-diyl group substituted with one or more substituents selected from Substituent Group a, unsubstituted adamantane-2,2-diyl group, cyclohexane-1,1-diyl group substituted with halogen, or unsubstituted cyclohexane-1,1-diyl group (hereinafter referred to as b-12).

[0184] L is adamantane-2,2-diyl group substituted with one or more substituents selected from Substituent Group a (hereinafter referred to as b-13).

[0185] L is an unsubstituted adamantane-2,2-diyl group (hereinafter referred to as b-14).

[0186] L is a cyclohexane-1,1-diyl group substituted with halogen (hereinafter referred to as b-15).

[0187] L is an unsubstituted cyclohexane-1,1-diyl group (hereinafter referred to as b-16).

[0188] R 2 It is a substituted or unsubstituted alkyl group (hereinafter referred to as c-1).

[0189] R 2 It is an alkyl group substituted with halogen or an unsubstituted alkyl group (hereinafter referred to as c-2).

[0190] R 2 It is an alkyl group substituted with halogen (hereinafter referred to as c-3).

[0191] R 3 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted amino group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as d-1).

[0192] R 3 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted amino group (hereinafter referred to as d-2).

[0193] R 3 is a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as d-3).

[0194] R 3 It is a hydrogen atom or an alkyl group substituted with one or more substituents selected from Substituent Group B (Substituent Group B: dialkylamino, amino, and hydroxyl), or an unsubstituted alkyl group (hereinafter referred to as d-4).

[0195] R 3 is a hydrogen atom (hereinafter referred to as d-5).

[0196] X = CR X - or =N-, R X It is a hydrogen atom, a cyano group, a halogen group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as e-1).

[0197] X = CR X - or =N-, R X is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (hereinafter referred to as e-2).

[0198] X = CR X - or =N-, R X is a hydrogen atom, a halogen or an unsubstituted alkyl group (hereinafter referred to as e-3).

[0199] X is ═CH— or ═N— (hereinafter referred to as e-4).

[0200] X is =CH- (hereinafter referred to as e-5).

[0201] X is =N- (hereinafter referred to as e-6).

[0202] Y = CR Y - or =N-, R Y It is a hydrogen atom, a cyano group, a halogen group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as f-1).

[0203] Y = CR Y - or =N-, R Y is a hydrogen atom or a halogen (hereinafter referred to as f-2).

[0204] Y is ═CH— or ═N— (hereinafter referred to as f-3).

[0205] Y is =CH- (hereinafter referred to as f-4).

[0206] Y is =N- (hereinafter referred to as f-5).

[0207] U for -CR U = or -N =, R U is a hydrogen atom, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a hydroxyl group, a halogen group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as g-1).

[0208] U for -CR U = or -N =, R U is a hydrogen atom, a halogen, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkyloxy group (hereinafter referred to as g-2).

[0209] U for -CR U = or -N =, R U It is a hydrogen atom, a halogen, a non-aromatic carbocyclic group substituted by a pyrazolyl group or an unsubstituted non-aromatic carbocyclic group, a non-aromatic heterocyclic group substituted by an oxetanyl group or an unsubstituted non-aromatic heterocyclic group, or an unsubstituted alkyloxy group (hereinafter referred to as g-3).

[0210] U is -CH= or -N= (hereinafter referred to as g-4).

[0211] U is -CH= (hereinafter referred to as g-5).

[0212] U is -N= (hereinafter referred to as g-6).

[0213] V is -CR V = or -N =, R V It is a hydrogen atom, a cyano group, a halogen group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as h-1).

[0214] V is -CR V = or -N =, RV It is a hydrogen atom, a cyano group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as h-2).

[0215] V is -CR V = or -N =, R V It is a hydrogen atom, a cyano group or an unsubstituted carbamoyl group (hereinafter referred to as h-3).

[0216] V is -CH= or -N= (hereinafter referred to as h-4).

[0217] V is -CH= (hereinafter referred to as h-5).

[0218] V is -N= (hereinafter referred to as h-6).

[0219] W = CR W - or =N-, R W It is a hydrogen atom, a cyano group, a halogen group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as i-1).

[0220] W is ═CH— or ═N— (hereinafter referred to as i-2).

[0221] W is =CH- (hereinafter referred to as i-3).

[0222] W is =N-(hereinafter referred to as i-4).

[0223] Z A It is -C= or -N- (hereinafter referred to as j-1).

[0224] Z A -C=(hereinafter referred to as j-2).

[0225] Z A -N- (hereinafter referred to as j-3).

[0226] Z B -CR 5 R 6 -、-CR 5 =、-NR 5 -or-N=,R 5 and R 6 Each independently represents a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group, a substituted or unsubstituted alkyl group, or R 5 and R 6 Together they form an oxo group (hereinafter referred to as k-1).

[0227] Z B -CR 5 R 6 -、-CR 5 = or -NR5 -, R 5 and R 6 are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group or a substituted or unsubstituted alkyl group, or R 5 and R 6 Together they form an oxo group (hereinafter referred to as k-2).

[0228] Z B -CR 5 R 6 -or-CR 5 =, R 5 and R 6 are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group or a substituted or unsubstituted alkyl group, or R 5 and R 6 Together they form an oxo group (hereinafter referred to as k-3).

[0229] Z B -CR 5 R 6 -, R 5 and R 6 are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group or a substituted or unsubstituted alkyl group, or R 5 and R 6 They may form an oxo group (hereinafter referred to as k-4) together.

[0230] Z B -CR 5 =, R 5 is a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group, or a substituted or unsubstituted alkyl group (hereinafter referred to as k-5).

[0231] Z B -CR 5 R 6 -or-CR 5 =, 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 they form an oxo group (hereinafter referred to as k-6).

[0232] Z B -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 6Together they form an oxo group (hereinafter referred to as k-7).

[0233] Z B -CR 5 =, R 5 is a hydrogen atom or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as k-8).

[0234] Z B -CR 5 R 6 -or-CR 5 =, R 5 and R 6 Each is independently a hydrogen atom (hereinafter referred to as k-9).

[0235] Z B -CR 5 R 6 -, R 5 and R 6 Each is independently a hydrogen atom (hereinafter referred to as k-10).

[0236] Z B -CR 5 =, R 5 is a hydrogen atom (hereinafter referred to as k-11).

[0237] Z B -CR 5 R 6 -or-CR 5 =, R 5 and R 6 are each independently a hydrogen atom, an unsubstituted non-aromatic heterocyclic group, or R 5 and R 6 Together they form an oxo group (hereinafter referred to as k-12).

[0238] Z B -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 they form an oxo group (hereinafter referred to as k-13).

[0239] Z B -CR 5 =, R 5 is a hydrogen atom or an unsubstituted non-aromatic heterocyclic group (hereinafter referred to as k-14).

[0240] Z B It is -CH2- (hereinafter referred to as k-15).

[0241] Z B It is -CH= (hereinafter referred to as k-16).

[0242] Z C -CR 7 R 8 -、-CR 7 =、-NR 7 - or =N-, R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, a substituted or unsubstituted alkylsulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 1-1).

[0243] Z C -CR 7 R 8 -、-CR 7 = or -NR 7 -, R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, a substituted or unsubstituted alkylsulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 1-2).

[0244] Z C -CR 7 R 8 -or-NR 7 -, R 7 and R 8are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, a substituted or unsubstituted alkylsulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 1-3).

[0245] Z C -CR 7 R 8 -, R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, a substituted or unsubstituted alkylsulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, they may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 1-4).

[0246] Z C -NR 7 -, R 7 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group or a substituted or unsubstituted alkylsulfonyl group (hereinafter referred to as 1-5).

[0247] Z C -CR 7 R 8 -or-NR 7 -, R 7 and R 8are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 1-6).

[0248] Z C -CR 7 R 8 -, R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, 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 it is bonded, it forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 1-7).

[0249] Z C -NR 7 -, R 7 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group or a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group (hereinafter referred to as 1-8).

[0250] Z C -CR 7 R 8 -or-NR 7 -, R 7 and R 8each independently represents a hydrogen atom, an alkyl group substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, hydroxyl, alkyloxy, non-aromatic carbocyclic group, non-aromatic carbocyclic group substituted with halogen, non-aromatic heterocyclic group, non-aromatic heterocyclic carbonyl and aromatic carbocyclic group), an unsubstituted non-aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen, alkyloxy, cyano, hydroxyl, haloalkyl and alkyloxy substituted with phenyl), a non-aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen, alkyloxy, cyano, hydroxyl, haloalkyl and alkyloxy substituted with phenyl), an unsubstituted non-aromatic carbocyclic group, a non-aromatic carbocyclic group substituted with a haloalkyl R is an aromatic heterocyclic group or an unsubstituted non-aromatic heterocyclic group, an aromatic carbocyclic group or an unsubstituted aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group e (Substituent Group e: halogen, alkyl, haloalkyl, alkyloxy and cyano), an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from Substituent Group f (Substituent Group f: alkyl, halogen, haloalkyl, alkyloxy, hydroxy and cyano), an unsubstituted non-aromatic carbocyclic oxycarbonyl group, an unsubstituted non-aromatic heterocyclic oxycarbonyl group, an unsubstituted non-aromatic carbocyclic sulfonyl group or R is an aromatic heterocyclic group or an unsubstituted non-aromatic heterocyclic group, 7 and R 8 Together with the carbon atom to which it is attached, it forms a halogen-substituted or unsubstituted non-aromatic carbocyclic ring, or a non-aromatic or unsubstituted non-aromatic heterocyclic ring substituted with one or more substituents selected from Substituent Group G (Substituent Group G: alkyl, haloalkyl, alkylcarbonyl, phenyl-substituted alkyloxycarbonyl, alkyloxycarbonyl, non-aromatic heterocyclic group, alkylcarbamoyl, non-aromatic carbocyclic group, aromatic heterocyclic group, and halogen-substituted aromatic heterocyclic group). (Hereinafter referred to as 1-9).

[0251] Z C -CR 7 R 8 -, R 7 and R 8 are each independently a hydrogen atom, an unsubstituted alkyl group, an unsubstituted non-aromatic carbocyclic group, an unsubstituted non-aromatic heterocyclic group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a non-aromatic carbocyclic ring substituted with halogen or an unsubstituted non-aromatic carbocyclic ring, or a non-aromatic heterocyclic ring substituted with one or more substituents selected from Substituent Group G or an unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 1-10).

[0252] Z C -NR 7 -, R 7is a hydrogen atom, an alkyl group substituted or unsubstituted alkyl group by one or more substituents selected from Substituent Group c, a non-aromatic carbocyclic group substituted or unsubstituted non-aromatic carbocyclic group by one or more substituents selected from Substituent Group d, a non-aromatic heterocyclic group substituted or unsubstituted non-aromatic heterocyclic group by a haloalkyl group, an aromatic carbocyclic group substituted or unsubstituted aromatic carbocyclic group by one or more substituents selected from Substituent Group e, an aromatic heterocyclic group substituted or unsubstituted aromatic heterocyclic group by one or more substituents selected from Substituent Group f, an unsubstituted non-aromatic carbocyclic oxycarbonyl group, an unsubstituted non-aromatic heterocyclic oxycarbonyl group, or an unsubstituted non-aromatic carbocyclic sulfonyl group (hereinafter referred to as 1-11).

[0253] Z C -CR 7 R 8 -, R 7 and R 8 Each is independently an unsubstituted alkyl group (hereinafter referred to as 1-12).

[0254] Z C -NR 7 -, R 7 is an unsubstituted alkyl group (hereinafter referred to as 1-13).

[0255] R 4 is a hydrogen atom, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclyloxy group, a substituted or unsubstituted non-aromatic carbocyclyloxy group, a substituted or unsubstituted aromatic carbocyclyloxy group, a substituted or unsubstituted aromatic heterocyclyloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a hydroxyl group, a halogen group, a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted aromatic heterocyclyl group, a substituted or unsubstituted non-aromatic heterocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, or a substituted or unsubstituted non-aromatic heterocyclic carbonyl group, or R 4 and R U Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as m-1).

[0256] R 4 is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, hydroxy, halogen, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyl or substituted or unsubstituted non-aromatic heterocyclic carbonyl, or R4 and R U Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as m-2).

[0257] R 4 is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, hydroxy, halogen, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyl or substituted or unsubstituted non-aromatic heterocyclic carbonyl, or R 4 and R U Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as m-3).

[0258] R 4 is an alkyloxy group substituted with one or more substituents selected from Substituent Group H (Substituent Group H: halogen, hydroxy, alkyloxy, cyano, alkylcarbonyloxy, substituted aromatic heterocyclic group (substituent: alkyl or alkyloxy), non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group (substituent: aromatic heterocyclic group, alkyl or halogen), aromatic heterocyclic amino group, aromatic carbocyclic group, and aromatic carbocyclic group substituted with alkyloxy); or an unsubstituted alkyloxy group;

[0259] a non-aromatic heterocyclyloxy group or an unsubstituted non-aromatic heterocyclyloxy group substituted with one or more substituents selected from Substituent Group J (Substituent Group J: alkyl, halogen, haloalkyl, cyanoalkyl, alkylcarbonyl, alkylcarbamoyl, alkyloxycarbonyl, alkyloxyalkyl, alkylsulfonylalkyl, non-aromatic heterocyclyl, substituted aromatic heterocyclyl (substituent: alkyl, alkyloxy, halogen, haloalkyl, or cyano), aromatic heterocyclyl, non-aromatic carbocyclyl, non-aromatic carbocyclyl substituted with halogen, substituted non-aromatic heterocyclyl (substituent: halogen or alkylcarbonyl), non-aromatic heterocyclylalkyl, non-aromatic carbocyclylalkyl, non-aromatic carbocyclylalkyl substituted with halogen, aromatic heterocyclylalkyl substituted with alkyl, non-aromatic heterocyclylcarbonyl, non-aromatic carbocyclylcarbonyl, aromatic heterocyclylcarbonyl, aromatic carbocyclylalkyloxycarbonyl, and non-aromatic carbocyclylsulfonyl);

[0260] a non-aromatic carbocyclic oxy group or an unsubstituted non-aromatic carbocyclic oxy group substituted with one or more substituents selected from Substituent Group K (Substituent Group K: alkyl, halogen, haloalkyl, alkyloxy, alkylsulfonyl, haloalkylamino, alkylamino, aromatic heterocyclic group, non-aromatic heterocyclic group substituted by halogen, non-aromatic heterocyclic group, aromatic heterocyclic group substituted by halogen, aromatic heterocyclicamino substituted by halogen, non-aromatic heterocyclic alkyl substituted by halogen, non-aromatic carbocyclic oxy group, and non-aromatic carbocyclic iminooxy group substituted by halogen);

[0261] aromatic carbocyclic groups;

[0262] an alkyl group or an unsubstituted alkyl group substituted with one or more substituents selected from Substituent Group 1 (Substituent Group 1: halogen, aromatic carbocyclic group, aromatic carbocyclic group substituted by alkyloxy, non-aromatic heterocyclic group, and substituted non-aromatic heterocyclic group (substituent: aromatic heterocyclic group, alkyl group, or non-aromatic heterocyclic group substituted by halogen), and non-aromatic carbocyclic imino group substituted by halogen);

[0263] an alkenyl group or an unsubstituted alkenyl group substituted with one or more substituents selected from Substituent Group M (Substituent Group M: aromatic carbocyclic groups substituted with alkyloxy groups, non-aromatic heterocyclic groups, and non-aromatic heterocyclic groups substituted with aromatic carbocyclic alkyloxycarbonyl groups);

[0264] an amino group or an unsubstituted amino group substituted with one or more substituents selected from Substituent Group n (Substituent Group n: aromatic carbocyclic alkyl groups substituted with alkyloxy groups, aromatic carbocyclic carbonyl groups substituted with alkyloxy groups, non-aromatic heterocyclic groups substituted with aromatic heterocyclic groups, aromatic heterocyclic groups, aromatic carbocyclic sulfonyl groups, aromatic carbocyclic carbonyl groups, alkyl groups, and aromatic heterocyclic groups substituted with haloalkyl groups);

[0265] a carbamoyl group substituted by a haloalkyl group or an unsubstituted carbamoyl group;

[0266] hydroxyl group;

[0267] halogen;

[0268] an aromatic carbocyclic group substituted by an alkyloxyalkyl group or an unsubstituted aromatic carbocyclic group;

[0269] unsubstituted aromatic heterocyclic group;

[0270] a non-aromatic heterocyclic group or an unsubstituted non-aromatic heterocyclic group substituted with one or more substituents selected from Substituent Group O (Substituent Group O: aromatic heterocyclic group, aromatic carbocyclic alkyl group, aromatic heterocyclic alkyl group, and haloalkyl group);

[0271] 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;

[0272] a non-aromatic heterocyclic carbonyl group or an unsubstituted non-aromatic heterocyclic carbonyl group substituted with one or more substituents selected from Substituent Group q (Substituent Group q: aromatic heterocyclic group, haloalkyl group, non-aromatic heterocyclic group substituted with halogen, aromatic heterocyclic group substituted with halogen, halogen, and alkyloxy);

[0273] Non-aromatic carbocyclic imino groups substituted by halogen;

[0274] or R 4 and R U Together with the carbon atom to which it is bonded, it forms a non-aromatic heterocyclic ring substituted with halogen or an unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as m-4).

[0275] R 4 is a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclicoxy group, a substituted or unsubstituted non-aromatic carbocyclicoxy group, a substituted or unsubstituted carbamoyl group or a substituted or unsubstituted non-aromatic heterocycliccarbonyl group (hereinafter referred to as m-5).

[0276] R 4 It is an alkyloxy group substituted or unsubstituted alkyloxy group by one or more substituents selected from Substituent Group H, a non-aromatic heterocyclicoxy group substituted or unsubstituted non-aromatic heterocyclicoxy group by one or more substituents selected from Substituent Group J, a non-aromatic carbocyclicoxy group substituted or unsubstituted non-aromatic carbocyclicoxy group by one or more substituents selected from Substituent Group K, a carbamoyl group substituted or unsubstituted carbamoyl group by a haloalkyl group, or a non-aromatic heterocycliccarbonyl group substituted or unsubstituted non-aromatic heterocycliccarbonyl group substituted or unsubstituted non-aromatic heterocycliccarbonyl group by one or more substituents selected from Substituent Group Q (hereinafter referred to as m-6).

[0277] R 4 It is a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclicoxy group or a substituted or unsubstituted non-aromatic carbocyclicoxy group (hereinafter referred to as m-7).

[0278] R 4 It is an alkyloxy group substituted with one or more substituents selected from Substituent Group H or an unsubstituted alkyloxy group, a non-aromatic heterocyclicoxy group substituted with one or more substituents selected from Substituent Group J or an unsubstituted non-aromatic carbocyclicoxy group substituted with one or more substituents selected from Substituent Group K or an unsubstituted non-aromatic carbocyclicoxy group (hereinafter referred to as m-8).

[0279] R 4 It is a substituted or unsubstituted alkyloxy group (hereinafter referred to as m-9).

[0280] R 4 It is an alkyloxy group substituted with one or more substituents selected from Substituent Group H or an unsubstituted alkyloxy group (hereinafter referred to as m-10).

[0281] R 4 is a substituted or unsubstituted non-aromatic heterocyclic oxy group (hereinafter referred to as m-11).

[0282] R 4 It is a non-aromatic heterocyclic oxy group substituted with one or more substituents selected from Substituent Group j or an unsubstituted non-aromatic heterocyclic oxy group (hereinafter referred to as m-12).

[0283] R 4 is a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as m-13).

[0284] R 4 It is a non-aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group K or an unsubstituted non-aromatic carbocyclic group (hereinafter referred to as m-14).

[0285] R 4 It is a non-aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group K (hereinafter referred to as m-15).

[0286] R 4 It is a substituted non-aromatic carbocyclic group (substituent: a non-aromatic heterocyclic group substituted with halogen) (hereinafter referred to as m-16).

[0287] R 4 It is a substituted non-aromatic heterocyclic oxy group (substituent: aromatic heterocyclic group) (hereinafter referred to as m-17).

[0288] R 4 It is a substituted non-aromatic heterocyclic oxy group (substituent: an aromatic heterocyclic group substituted with halogen) (hereinafter referred to as m-18).

[0289] R 4 It is a substituted non-aromatic heterocyclic oxy group (substituent: haloalkyl) (hereinafter referred to as m-19).

[0290] R 4 It is a substituted non-aromatic carbocyclic group (substituent: haloalkylamino group) (hereinafter referred to as m-20).

[0291] Furthermore, the compound represented by formula (I) includes all the combinations of the following specific examples:

[0292] Mode:

[0293] [Chemistry 20]

[0294]

[0295] The base, R 1 、R 1B 、R 1C , L, R 2 、R 3 , V, W, R 5 、R 6 、R 7 、R 8 、R X 、R Y 、R V 、R W 、R U and R 4 The preferred embodiment is shown below.

[0296] Mode:

[0297] [Chemistry 21]

[0298]

[0299] The group represented is (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) below.

[0300] [Chemistry 22]

[0301]

[0302] Mode:

[0303] [Chemistry 23]

[0304]

[0305] The group represented is (Ia), (Ib), (Ih) or (Ii). Formula:

[0306] [Chemistry 24]

[0307]

[0308] The group represented is (Ia), (Ib) or (Ii).

[0309] Mode:

[0310] [Chemistry 25]

[0311]

[0312] The group represented is (Ia) or (Ib).

[0313] Mode:

[0314] [Chemistry 26]

[0315]

[0316] The base represented is (Ia).

[0317] Mode:

[0318] [Chemistry 27]

[0319]

[0320] The base represented is (Ib).

[0321] R X is a hydrogen atom, a cyano group, a halogen group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as ee-1).

[0322] R X is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (hereinafter referred to as ee-2).

[0323] R X is a hydrogen atom, a halogen or an unsubstituted alkyl group (hereinafter referred to as ee-3).

[0324] R X is a hydrogen atom (hereinafter referred to as ee-4).

[0325] R Y is a hydrogen atom, a cyano group, a halogen group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted carbamoyl group (hereinafter referred to as ff-1).

[0326] R Y is a hydrogen atom or a halogen (hereinafter referred to as ff-2).

[0327] R Y is a hydrogen atom (hereinafter referred to as ff-3).

[0328] R U is a hydrogen atom, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a hydroxyl group, a halogen group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as gg-1).

[0329] R Uis a hydrogen atom, a halogen, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkyloxy group (hereinafter referred to as gg-2).

[0330] R U is a hydrogen atom, a halogen, a non-aromatic carbocyclic group substituted with a pyrazolyl group or an unsubstituted non-aromatic carbocyclic group, a non-aromatic heterocyclic group substituted with an oxetanyl group or an unsubstituted non-aromatic heterocyclic group, or an unsubstituted alkyloxy group (hereinafter referred to as gg-3).

[0331] R U is a hydrogen atom (hereinafter referred to as gg-4).

[0332] R 5 and R 6 are each independently a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group or a substituted or unsubstituted alkyl group, or R 5 and R 6 Together they form an oxo group (hereinafter referred to as kk-1).

[0333] R 5 is a hydrogen atom, a substituted or unsubstituted non-aromatic heterocyclic group, a hydroxyl group, or a substituted or unsubstituted alkyl group (hereinafter referred to as kk-5).

[0334] 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 they form an oxo group (hereinafter referred to as kk-6).

[0335] R 5 is a hydrogen atom or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as kk-8).

[0336] R 5 and R 6 are each independently a hydrogen atom (hereinafter referred to as kk-9).

[0337] R 5 is a hydrogen atom (hereinafter referred to as kk-10).

[0338] R 5 and R 6 are each independently a hydrogen atom, an unsubstituted non-aromatic heterocyclic group, or R 5 and R 6 Together they form an oxo group (hereinafter referred to as kk-12).

[0339] R 5is a hydrogen atom or an unsubstituted non-aromatic heterocyclic group (hereinafter referred to as kk-14).

[0340] R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, a substituted or unsubstituted alkylsulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-1).

[0341] R 7 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group or a substituted or unsubstituted alkylsulfonyl group (hereinafter referred to as 11-5).

[0342] R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-6).

[0343] R 7 and R 8 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, 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 it is bonded, it forms a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-7).

[0344] R 7is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl group, a substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl group or a substituted or unsubstituted non-aromatic carbocyclic sulfonyl group (hereinafter referred to as 11-8).

[0345] R 7 and R 8 R is independently a hydrogen atom, an alkyl group substituted or unsubstituted by one or more substituents selected from Substituent Group c, a non-aromatic carbocyclic group substituted or unsubstituted by one or more substituents selected from Substituent Group d, a non-aromatic heterocyclic group substituted or unsubstituted by a haloalkyl group, an aromatic carbocyclic group substituted or unsubstituted by one or more substituents selected from Substituent Group e, an aromatic heterocyclic group substituted or unsubstituted by one or more substituents selected from Substituent Group f, an unsubstituted non-aromatic carbocyclic oxycarbonyl group, an unsubstituted non-aromatic heterocyclic oxycarbonyl group, an unsubstituted non-aromatic carbocyclic sulfonyl group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a non-aromatic carbocyclic ring substituted with halogen or an unsubstituted non-aromatic carbocyclic ring, or a non-aromatic heterocyclic ring substituted with one or more substituents selected from Substituent Group G or an unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-9).

[0346] R 7 and R 8 are each independently a hydrogen atom, an unsubstituted alkyl group, an unsubstituted non-aromatic carbocyclic group, an unsubstituted non-aromatic heterocyclic group, or R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a non-aromatic carbocyclic ring substituted with halogen or an unsubstituted non-aromatic carbocyclic ring, or a non-aromatic heterocyclic ring substituted with one or more substituents selected from Substituent Group G or an unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-10).

[0347] R 7 and R 8 Each is independently an unsubstituted alkyl group (hereinafter referred to as 11-11).

[0348] R 7is a hydrogen atom, an alkyl group substituted or unsubstituted alkyl group by one or more substituents selected from Substituent Group c, a non-aromatic carbocyclic group substituted or unsubstituted non-aromatic carbocyclic group by one or more substituents selected from Substituent Group d, a non-aromatic heterocyclic group substituted or unsubstituted non-aromatic heterocyclic group by a haloalkyl group, an aromatic carbocyclic group substituted or unsubstituted aromatic carbocyclic group by one or more substituents selected from Substituent Group e, an aromatic heterocyclic group substituted or unsubstituted aromatic heterocyclic group by one or more substituents selected from Substituent Group f, an unsubstituted non-aromatic carbocyclic oxycarbonyl group, an unsubstituted non-aromatic heterocyclic oxycarbonyl group, or an unsubstituted non-aromatic carbocyclic sulfonyl group (hereinafter referred to as 11-12).

[0349] R 7 is an unsubstituted alkyl group (hereinafter referred to as 11-13).

[0350] R 7 and R 8 Together with the carbon atom to which it is bonded, it forms an unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as 11-14).

[0351] R 7 and R 8 Together with the carbon atom to which it is bonded, it forms a non-aromatic carbocyclic ring substituted with halogen (hereinafter referred to as 11-15).

[0352] R 7 is a substituted non-aromatic carbocyclic group (substituent: halogen) (hereinafter referred to as 11-16).

[0353] R 7 is a substituted alkyl group (substituent: alkyloxy group) (hereinafter referred to as 11-17).

[0354] R 1 It is the above-mentioned (a-1), (a-2) or (a-3).

[0355] L is (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (b-11), (b-12), (b-13), (b-14), (b-15) or (b-16) above.

[0356] R 2 It is (c-1), (c-2) or (c-3) above.

[0357] R 3 It is (d-1), (d-2), (d-3), (d-4) or (d-5) above.

[0358] V is (h-1), (h-2), (h-3), (h-4), (h-5) or (h-6) above.

[0359] W is (i-1), (i-2), (i-3) or (i-4) above.

[0360] R 4 The above-mentioned (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).

[0361] (1-A)

[0362] In one embodiment, the compound represented by formula (I) is

[0363] Mode:

[0364] [Chemistry 28]

[0365]

[0366] The base represented by is (Ia),

[0367] R X is (ee-4),

[0368] R Y is (ff-3),

[0369] R U is (gg-4),

[0370] R 5 and R 6 is (kk-9),

[0371] R 7 and R 8 is (ll-14),

[0372] R 1 is (a-3),

[0373] L is (b-14),

[0374] R 2 is (c-3),

[0375] R 3 is (d-5),

[0376] V is (h-6),

[0377] W is (i-4),

[0378] R 4 is (m-17).

[0379] (1-B)

[0380] In one embodiment, the compound represented by formula (I) is

[0381] Mode:

[0382] [Chemistry 29]

[0383]

[0384] The basis represented by is (Ib),

[0385] R X is (ee-4),

[0386] R Y is (ff-3),

[0387] R U is (gg-4),

[0388] R 7 is (ll-15),

[0389] R 1 is (a-3),

[0390] L is (b-14),

[0391] R 2 is (c-3),

[0392] R 3 is (d-5),

[0393] V is (h-6),

[0394] W is (i-3),

[0395] R 4 is (m-17).

[0396] (1-C)

[0397] In one embodiment, the compound represented by formula (I) is

[0398] Mode:

[0399] [Chemistry 30]

[0400]

[0401] The basis represented by is (Ib),

[0402] R Xis (ee-4),

[0403] R Y is (ff-3),

[0404] R U is (gg-4),

[0405] R 7 is (ll-15),

[0406] R 1 is (a-3),

[0407] L is (b-14),

[0408] R 2 is (c-3),

[0409] R 3 is (d-5),

[0410] V is (h-6),

[0411] W is (i-4),

[0412] R 4 is (m-16).

[0413] (1-D)

[0414] In one embodiment, the compound represented by formula (I) is

[0415] Mode:

[0416] [Chemistry 31]

[0417]

[0418] The basis represented by (Ib):

[0419] R X is (ee-4),

[0420] R Y is (ff-3),

[0421] R U is (gg-4),

[0422] R 7 is (ll-13),

[0423] R 1 is (a-3),

[0424] L is (b-14),

[0425] R 2 is (c-3),

[0426] R 3 is (d-5),

[0427] V is (h-6),

[0428] W is (i-4),

[0429] R 4 is (m-16).

[0430] (1-E)

[0431] In one embodiment, the compound represented by formula (I) is

[0432] Mode:

[0433] [Chemistry 32]

[0434]

[0435] The basis represented by is (Ii),

[0436] R X is (ee-4),

[0437] R Y is (ff-3),

[0438] R 5 and R 6 is (kk-9),

[0439] R 7 and R 8 is (ll-14),

[0440] R 1 is (a-3),

[0441] L is (b-14),

[0442] R 2 is (c-3),

[0443] R 3 is (d-5),

[0444] V is (h-6),

[0445] W is (i-4),

[0446] R 4 is (m-18).

[0447] (1-F)

[0448] In one embodiment, the compound represented by formula (I) is

[0449] Mode:

[0450] [Chemistry 33]

[0451]

[0452] The base represented by is (Ia),

[0453] R X is (ee-4),

[0454] R Y is (ff-3),

[0455] R U is (gg-4),

[0456] R 5 and R 6 is (kk-9),

[0457] R 7 and R 8 is (ll-14),

[0458] R 1 is (a-3),

[0459] L is (b-14),

[0460] R 2 is (c-3),

[0461] R 3 is (d-5),

[0462] V is (h-6),

[0463] W is (i-4),

[0464] R 4 is (m-16).

[0465] (1-G)

[0466] In one embodiment, the compound represented by formula (I) is

[0467] Mode:

[0468] [Chemistry 34]

[0469]

[0470] The base represented is (Ia):

[0471] R X is (ee-4),

[0472] R Y is (ff-3),

[0473] RU is (gg-4),

[0474] R 5 and R 6 is (kk-9),

[0475] R 7 and R 8 is (ll-14),

[0476] R 1 is (a-3),

[0477] L is (b-14),

[0478] R 2 is (c-3),

[0479] R 3 is (d-5),

[0480] V is (h-6),

[0481] W is (i-4),

[0482] R 4 is (m-19).

[0483] (1-H)

[0484] In one embodiment, the compound represented by formula (I) is

[0485] Mode:

[0486] [Chemistry 35]

[0487]

[0488] The base represented by is (Ia),

[0489] R X is (ee-4),

[0490] R Y is (ff-3),

[0491] R U is (gg-4),

[0492] R 5 and R 6 is (kk-9),

[0493] R 7 and R 8 is (ll-14),

[0494] R 1 is (a-3),

[0495] L is (b-14),

[0496] R 2 is (c-3),

[0497] R 3 is (d-5),

[0498] V is (h-6),

[0499] W is (i-4),

[0500] R 4 is (m-20).

[0501] (1-I)

[0502] In one embodiment, the compound represented by formula (I) is

[0503] Mode:

[0504] [Chemistry 36]

[0505]

[0506] The basis represented by is (Ib),

[0507] R X is (ee-4),

[0508] R Y is (ff-3),

[0509] R U is (gg-4),

[0510] R 7 is (ll-17),

[0511] R 1 is (a-3),

[0512] L is (b-14),

[0513] R 2 is (c-3),

[0514] R 3 is (d-5),

[0515] V is (h-6),

[0516] W is (i-4),

[0517] R 4 is (m-16).

[0518] (1-J)

[0519] In one embodiment, the compound represented by formula (I) is

[0520] Mode:

[0521] [Chemistry 37]

[0522]

[0523] The base represented by is (Ia),

[0524] R X is (ee-4),

[0525] R Y is (ff-3),

[0526] R U is (gg-4),

[0527] R 5 and R 6 is (kk-9),

[0528] R 7 and R 8 is (ll-11),

[0529] R 1 is (a-3),

[0530] L is (b-14),

[0531] R 2 is (c-3),

[0532] R 3 is (d-5),

[0533] V is (h-6),

[0534] W is (i-4),

[0535] R 4 is (m-16).

[0536] The compound represented by formula (I) is not limited to a specific isomer, and includes all possible isomers (eg, keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

[0537] One or more hydrogen, carbon and / or other atoms of the compound represented by formula (I) may be substituted by isotopes of hydrogen, carbon and / or other atoms. Examples of these isotopes are as follows: 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O.17 O. 31 P. 32 P. 35 S. 18 F. 123 I and 36 Cl, including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine. The compound represented by formula (I) also includes compounds substituted with such isotopes. Such isotope-substituted compounds can also be used as pharmaceuticals, including all radiolabeled forms of the compound represented by formula (I). In addition, the "radiolabeling method" for producing such "radiolabeled forms" is also included in the present invention, and such "radiolabeled forms" can be used as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays.

[0538] The radiolabeled form of the compound represented by formula (I) can be prepared by methods well known in the art. For example, the tritiated compound represented by formula (I) can be prepared by introducing tritium into the specific compound represented by formula (I) through a catalytic dehalogenation reaction using tritium. This method involves reacting the compound represented by formula (I) with a suitable halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing 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 14 C carbon raw material preparation.

[0539] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, salts of the compound represented by formula (I) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.), and amino acids; or salts of the compound represented by formula (I) with 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, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[0540] The compound represented by formula (I) of the present invention or its pharmaceutically acceptable salt may form a solvate (such as a hydrate, etc.), a cocrystal and / or a polymorph, and the present invention also includes various solvates, cocrystals and polymorphs of these. "Solvate" refers to the compound represented by formula (I) and can be coordinated with any number of solvent molecules (such as water molecules, etc.). By placing the compound represented by formula (I) or its pharmaceutically acceptable salt in the atmosphere, there is a situation where moisture is absorbed and adsorbed water is attached or a hydrate is formed. In addition, there is a situation where the compound represented by formula (I) or its pharmaceutically acceptable salt is recrystallized to form a polymorph. "Cocrystal" means that the compound or salt represented by formula (I) and the coordination molecule (countermolecular) are present in the same crystal lattice, and can contain any number of coordination molecules.

[0541] The compound represented by formula (I) of the present invention or its pharmaceutically acceptable salt may form a prodrug, and the present invention also includes various such prodrugs. A prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically decomposed, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to compounds represented by formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in the body, and compounds that are converted to compounds represented by formula (I) by hydrolysis such as gastric acid. Methods for selecting appropriate prodrug derivatives and methods for producing them are described in, for example, "Design of Prodrugs, Elsevier, Amsterdam, 1985". There are cases where the prodrug itself is active.

[0542] When the compound represented by formula (I) or its pharmaceutically acceptable salt has a hydroxyl group, examples thereof include acyloxy derivatives or prodrugs such as sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with a suitable acid halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride or a mixed acid anhydride, or by reacting with a condensing agent. Examples thereof include CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, p-CH3PhSO3-.

[0543] The formulation examples shown below are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0544] The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enteral administration, for example, orally in the form of tablets or capsules, parenterally in the form of injectable solutions or suspensions, topically in the form of lotions, gels, ointments, or creams, or nasally or as suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of pharmaceutically acceptable salts together with at least one pharmaceutically acceptable carrier or diluent can be manufactured by conventional methods such as mixing, granulation, or coating. For example, oral compositions can be prepared as tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, and the active ingredient. In addition, injectable compositions can be prepared as solutions or suspensions, can be sterilized, and can also contain preservatives, stabilizers, buffers, and the like.

[0545] The compounds of the present invention are useful for the following symptoms induced by RSV. However, RSV-induced symptoms range from mild cold-like symptoms to severe lower respiratory tract diseases such as bronchiolitis or pneumonia. Specifically, the compounds of the present invention are useful for treating cold symptoms such as cough, runny nose, and fever, as well as symptoms such as wheezing and respiratory distress that may develop from these symptoms. Furthermore, the compounds of the present invention are useful for treating diseases such as bronchiolitis and pneumonia that develop as these symptoms worsen.

[0546] (Method for producing the compound of the present invention)

[0547] The compound represented by formula (I) of the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. can be carried out by the same treatments as those generally performed in organic chemistry experiments.

[0548] The compounds of the present invention can be synthesized by referring to methods known in the art.

[0549] (Method A)

[0550] [Chemistry 38]

[0551]

[0552] (In the formula, each symbol has the same meaning as above, R A is -B(OH)2, -Sn(C1-C6 alkyl)3, etc., R B is C1-C6 alkyl, etc.)

[0553] Step 1

[0554] Compound (A-1) and compound (A-2) are reacted in a single or mixed solvent such as tetrahydrofuran, toluene, dimethylformamide, 1,4-dioxane, ethanol, or water, with the addition of a metal catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride (II), or bis(tri-tert-butylphosphine)palladium, and a base such as potassium carbonate or sodium bicarbonate, sodium phosphate or sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, or potassium tert-butoxide, and the reaction is carried out at a temperature from 20° C. to the reflux temperature of the solvent for 0.1 to 48 hours, preferably 0.5 to 12 hours, to thereby obtain compound (A-3).

[0555] Step 2

[0556] The deprotection reaction of the carboxylic acid protecting group of compound (A-3) can be carried out by a conventional method described in, for example, Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons).

[0557] Step 3

[0558] Compound (A-4) is reacted with compound (A-5) in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, acetonitrile, or water, either alone or in a mixed solvent, in the presence or absence of a base such as triethylamine, pyridine, diisopropylamine, or 1-methylimidazole, using a dehydration condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, EDC·HCl, or HATU, to obtain compound (IA).

[0559] Alternatively, an acylating agent such as thionyl chloride or oxalyl chloride can be added to compound (A-4) in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, or dimethylformamide, in the presence or absence of a base such as pyridine, triethylamine, diisopropylamine, or 1-methylimidazole to generate an acyl chloride, followed by addition of compound (A-5), and the reaction can be carried out at -20°C to 60°C, preferably at -10°C to 30°C, for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours, to obtain compound (IA).

[0560] (Method B)

[0561] [Chemistry 391]

[0562]

[0563] (In the formula, each symbol has the same meaning as above)

[0564] Step 1

[0565] Compound (B-1) is added to compound (A-2) in a solvent such as 1,4-dioxane, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, in the presence or absence of a base such as triethylamine, diisopropylamine, cesium carbonate, potassium carbonate, sodium hydride, or in the presence or absence of an acid such as toluenesulfonic acid, acetic acid, hydrogen chloride, sulfuric acid, and the reaction is carried out at 20°C to the reflux temperature of the solvent, preferably at 40°C to 120°C, for 0.1 hour to 48 hours, preferably 0.5 hour to 12 hours, thereby obtaining compound (B-2).

[0566] Alternatively, compound (B-1) is reacted with compound (A-2) in a single or mixed solvent such as 1,4-dioxane, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, butanol, or water in the presence or absence of a ligand such as Xantphos, diphenylphosphinoferrocene, or X-Phos, with the addition of a metal catalyst such as palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, or bis(tri-tert-butylphosphine), and a base such as potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydrogenphosphate, lithium hydroxide, or sodium hydroxide, at a temperature between 20° C. and the reflux temperature of the solvent, optionally under microwave irradiation, for 0.1 to 48 hours, preferably 0.5 to 12 hours, to obtain compound (B-2).

[0567] Steps 2 to 3

[0568] Compound (IB) can be obtained by carrying out steps 2 to 3 of method A using compound (B-2).

[0569] (C Method)

[0570] [Chemistry 40]

[0571]

[0572] (In the formula, each symbol has the same meaning as above)

[0573] Step 1

[0574] Compound (C-1) is added to a single or mixed solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, acetonitrile, water, etc., with a dehydration condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, EDC·HCl, HATU, etc., and then NHR 1B R 1C The compound (IC) can be obtained by reacting the obtained product with a base such as triethylamine, pyridine, diisopropylamine, 1-methylimidazole, or sodium hydride.

[0575] (D method)

[0576] [Chemistry 41]

[0577]

[0578] (In the formula, each symbol has the same meaning as above)

[0579] Step 1

[0580] Compound (D-1) is reacted with an azide compound such as trimethylsilylazide, sodium azide, or tributyltin azide in a single or mixed solvent such as 1,4-dioxane, dimethylformamide, or water in the presence of an additive such as dibutylstannane, zinc chloride, or ammonium chloride at a temperature ranging from 60°C to the reflux temperature of the solvent, depending on the situation, under microwave irradiation for 0.5 to 48 hours, preferably 1 to 4 hours, to obtain compound (ID).

[0581] (E Method)

[0582] [Chemistry 42]

[0583]

[0584] (In the formula, each symbol has the same meaning as above)

[0585] Step 1

[0586] Compound (D-1) is reacted in a single or mixed solvent such as methanol, ethanol, tetrahydrofuran, or water, in the presence or absence of a base such as potassium carbonate or triethylamine, with the addition of hydroxylamine or the like, and the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, and optionally under microwave irradiation, thereby obtaining compound (E-2).

[0587] Step 2

[0588] Compound (E-2) is reacted in a single or mixed solvent such as dimethylformamide, chloroform, dichloromethane, tetrahydrofuran, or toluene with the addition of a base such as triethylamine, DBU, or potassium carbonate, and 1,1'-carbonyldiimidazole or ethyl chloroformate, and the reaction is carried out at room temperature to the reflux temperature of the solvent to obtain compound (IE).

[0589] (F method)

[0590] [Chemistry 43]

[0591]

[0592] (wherein, R is a group independently selected from the substituent group n, and the other symbols have the same meanings as above)

[0593] Step 1

[0594] Compound (F-1) is reacted with an amine in a single or mixed solvent such as 1,4-dioxane, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, butanol, or water, in the presence or absence of a ligand such as Xantphos, diphenylphosphinoferrocene, X-Phos, or BINAP, with the addition of a metal catalyst such as palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, or bis(tri-tert-butylphosphine), and a base such as potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydrogen phosphate, lithium hydroxide, or sodium hydroxide, at a temperature from 20° C. to the reflux temperature of the solvent, optionally under microwave irradiation, for 0.1 to 48 hours, preferably 0.5 to 12 hours, to obtain compound (F-2).

[0595] Step 2

[0596] 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).

[0597] (G method)

[0598] [Chemistry 44]

[0599]

[0600] (In the formula, each symbol has the same meaning as above, Lea is a leaving group, R zz is a hydrogen atom, a C1-C6 alkyl group, etc., R xx and R yy are each independently a hydrogen atom, a C1-C6 alkyl group, or R xx and R yy Together with the adjacent nitrogen atom, it forms a ring)

[0601] Step 1

[0602] Compound (G-2) can be obtained by subjecting compound (G-1) to the first step of method A.

[0603] Step 2

[0604] Compound (G-2) can be reacted with sodium periodate or potassium permonosulfate (oxone) and ruthenium chloride or potassium osmate in a mixed solvent such as 1,4-dioxane, tetrahydrofuran, and water to obtain compound (G-3). Alternatively, compound (G-3) can be obtained by ozonation to obtain an ozonide, which is then treated with a reducing agent such as zinc, dimethyl sulfide, or triphenylphosphine.

[0605] Step 3

[0606] Compound (G-3) is reacted in tetrahydrofuran, tert-butanol, water, or a mixture thereof, in the presence of 2-methyl-2-butene or aminosulfonic acid, with the addition of sodium dihydrogen phosphate and sodium chlorite, to obtain compound (G-4).

[0607] Step 4

[0608] Compound (IG) can be obtained by subjecting compound (G-4) to step 1 of method C.

[0609] (H method)

[0610] [Chemistry 45]

[0611]

[0612] (In the formula, each symbol has the same meaning as above, R xx and R yy is a hydrogen atom, a C1-C6 alkyl group, R xx and R yy together with the adjacent nitrogen atom to form a ring, etc.)

[0613] Step 1

[0614] Compound (G-3) is added to chloroform, tetrahydrofuran, acetonitrile, acetic acid or other solvents alone or in a mixture thereof by adding NHR yy R xx and a reducing agent such as sodium triacetoxyborohydride or 2-methylpyridine borane, and reacting at room temperature to the reflux temperature of the solvent for 0.1 to 48 hours, preferably 0.5 to 8 hours, thereby obtaining compound (IH).

[0615] (J Method)

[0616] [Chemistry 46]

[0617]

[0618] (In the formula, each symbol has the same meaning as above, R zz and R yy is a hydrogen atom, a C1-C6 alkyl group, an aromatic carbocyclic group, an aromatic heterocyclic group, etc.)

[0619] Step 1

[0620] Compound (IJ) can be obtained by catalytic hydrogenation of compound (J-1) in tetrahydrofuran, methanol, toluene, chloroform, etc., alone or in a mixed solvent, in the presence of a heterogeneous catalyst such as palladium carbon, palladium hydroxide, Raney nickel, platinum oxide, etc.

[0621] The compounds of the present invention have an anti-RSV effect, that is, a cytopathic effect (CPE) inhibitory effect, and can be used as therapeutic and / or preventive agents for diseases such as bronchiolitis and pneumonia.

[0622] Furthermore, the compounds of the present invention have usefulness as pharmaceuticals and preferably have any one or more of the following excellent characteristics.

[0623] a) The inhibitory effect on CYP enzymes (such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.

[0624] b) It exhibits good pharmacokinetics such as high bioavailability and moderate clearance.

[0625] c) High metabolic stability.

[0626] d) No irreversible inhibitory effect on CYP enzymes (e.g., CYP3A4) was observed within the concentration range of the assay conditions described in this specification.

[0627] e) Not mutagenic.

[0628] f) Low risk to the cardiovascular system.

[0629] g) Shows high solubility.

[0630] h) has high RSV A type CPE inhibition and high RSV B type inhibition.

[0631] i) Reduce the amount of virus in the lungs.

[0632] The pharmaceutical composition of the present invention can be administered orally or parenterally. Examples of parenterally administered methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye, ear, and vaginal administration.

[0633] For oral administration, the drug can be prepared according to conventional methods into any dosage form commonly used by humans, such as 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, lemonades, alcoholic solutions, aromatic waters, extracts, decoctions, tinctures, etc.). Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets. Powders and granules may also be in the form of dry syrups. Capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0634] For parenteral administration, the drug can be preferably administered in any commonly used dosage form, such as injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, sprays, inhalants, lotions, infusions, coatings, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.). Injections may also be in the form of O / W, W / O, O / W / O, or W / O / W emulsions.

[0635] The effective amount of the compound of the present invention can be mixed with various pharmaceutical additives such as excipients, binders, disintegrants, lubricants suitable for its dosage form as needed to prepare a pharmaceutical composition. Furthermore, the pharmaceutical composition can be made into a pharmaceutical composition for children, the elderly, critically ill patients or surgery by appropriately changing the effective amount of the compound of the present invention, dosage form and / or various pharmaceutical additives. For example, a pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year old after birth), toddlers (over 1 year old but less than 7 years old), children (over 7 years old but less than 15 years old) or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to patients over 65 years old.

[0636] The dosage of the pharmaceutical composition of the present invention is preferably determined based on the patient's age, weight, type or severity of disease, and route of administration. For oral administration, the dosage is generally in the range of 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. For parenteral administration, the dosage varies greatly depending on the route of administration, but is generally in the range of 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage may be administered once daily or divided into several doses.

[0637] The compounds of the present invention can be used in combination with L protein inhibitors, F protein inhibitors, N protease inhibitors, etc. (hereinafter referred to as concomitant agents) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration period of the compounds of the present invention and the concomitant agents is not limited. For the subjects of administration, these can be administered simultaneously or with a time difference. Furthermore, the compounds of the present invention and the concomitant agents can be administered as two or more preparations containing each active ingredient, or as a single preparation containing these active ingredients.

[0638] The dosage of the combined drug can be appropriately selected based on the dosage used clinically. In addition, the ratio of the compound of the present invention to the combined drug can be appropriately selected according to the subject, route of administration, target disease, symptoms, combination, etc. For example, when the subject is human, 0.01 to 100 parts by weight of the combined drug can be used relative to 1 part by weight of the compound of the present invention.

[0639] [Example]

[0640] The present invention will be described in more detail below with reference to Examples, Reference Examples, and Test Examples; however, the present invention is not limited thereto.

[0641] In addition, the meanings of the abbreviations used in this specification are shown below.

[0642] Boc2O: di-tert-butyl dicarbonate

[0643] DIAD: diisopropyl azodicarboxylate

[0644] DMEAD: bis(2-methoxyethyl)azodicarboxylate

[0645] DMAP:4-dimethylaminopyridine

[0646] HATU:O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0647] Me4tBuXphos:2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl

[0648] TolBINAP:2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl

[0649] Ts: p-Toluenesulfonyl

[0650] Pd2(dba)3: Tris(dibenzylideneacetone)palladium

[0651] PdCl2(dppf):[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct

[0652] Pd(PPh3)4:Tetrakis(triphenylphosphine)palladium

[0653] Xantphos Pd G3:[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0654] Xantphos Pd G2: Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0655] X-Phos:2,4,6-Triisopropyl-2'-(dicyclohexylphosphino)biphenyl

[0656] (Method for Identification of Compounds)

[0657] The NMR analysis obtained in each example was performed at 400 MHz using DMSO-d6 and CDCl3. In addition, when NMR data are shown, not all measured peaks may be shown.

[0658] RT in the manual represents the retention time in LC / MS: liquid chromatography / mass spectrometry, and is measured under the following conditions.

[0659] (Method 1)

[0660] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0661] Flow rate: 0.8 mL / min

[0662] UV detection wavelength: 254nm (detection range 190-500nm)

[0663] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0664] Gradient: A linear gradient from 5% to 100% solvent [B] over 3.5 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B].

[0665] (Method 2)

[0666] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0667] Flow rate: 0.8 mL / min

[0668] UV detection wavelength: 254nm (detection range 190-400nm)

[0669] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0670] Gradient: A linear gradient from 5% to 100% solvent [B] over 3.5 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B].

[0671] (Method 3)

[0672] Column: Shim-pack XR-ODS (2.2 μm, ID 50 x 3.0 mm) (Shimadzu)

[0673] Flow rate: 1.6 mL / min

[0674] UV detection wavelength: 254nm (detection range 190-800nm)

[0675] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0676] Gradient: A linear gradient of 10% to 100% solvent [B] over 3 minutes, holding at 100% solvent [B] for 0.5 minutes was performed.

[0677] (Method 4)

[0678] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0679] Flow rate: 0.8 mL / min

[0680] UV detection wavelength: 254nm (detection range 210-500nm)

[0681] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0682] Gradient: A linear gradient from 5% to 100% solvent [B] over 3.5 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B].

[0683] (Method 5)

[0684] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0685] Flow rate: 0.8 mL / min

[0686] UV detection wavelength: 254nm (detection range 190-500nm)

[0687] Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile

[0688] Gradient: A linear gradient from 5% to 100% solvent [B] over 3.5 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B].

[0689] (Method 6)

[0690] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0691] Flow rate: 0.8 mL / min

[0692] UV detection wavelength: 254nm (detection range 190-400nm)

[0693] Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile

[0694] Gradient: A linear gradient from 5% to 100% solvent [B] over 3.5 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B].

[0695] (Method 7)

[0696] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0697] Flow rate: 0.8 mL / min

[0698] UV detection wavelength: 254nm (detection range 190-500nm)

[0699] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0700] Gradient: A linear gradient from 70% to 100% solvent [B] over 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B].

[0701] (Method 8)

[0702] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0703] Flow rate: 0.8 mL / min

[0704] UV detection wavelength: 254nm (detection range 190-500nm)

[0705] Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile

[0706] Gradient: A linear gradient of 50% to 100% solvent [B] over 3.5 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B].

[0707] (Method 9)

[0708] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0709] Flow rate: 0.6 mL / min

[0710] UV detection wavelength: 254nm (detection range 190-500nm)

[0711] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0712] Gradient: A linear gradient from 25% to 95% solvent [B] over 1.5 minutes was performed, followed by a 1.5 minute hold at 95% solvent [B].

[0713] (Method 10)

[0714] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0715] Flow rate: 0.6 mL / min

[0716] UV detection wavelength: 254nm (detection range 190-500nm)

[0717] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0718] Gradient: A linear gradient from 25% to 95% solvent [B] over 1.5 minutes was performed, followed by a 1.5 minute hold at 95% solvent [B].

[0719] (Method 11)

[0720] Column: ACQUITY UPLC (registered trademark) CSH C18 (1.7 μm id 2.1 x 50 mm) (Waters)

[0721] Flow rate: 0.6 mL / min

[0722] UV detection wavelength: 254nm (detection range 190-500nm)

[0723] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0724] Gradient: A linear gradient from 25% to 95% solvent [B] over 1.5 minutes was performed, followed by a 1.5 minute hold at 95% solvent [B].

[0725] In the specification, MS (m / z) indicates a value observed by mass spectrometry.

[0726] Example 1

[0727] Synthesis of compound (I-023)

[0728] [Chemistry 47]

[0729]

[0730] Step 1 Synthesis of compound 3

[0731] To compound 1 (910 mg, 3.62 mmol) were added chloroform (20 mL) and diisopropylethylamine (0.76 mL, 4.34 mmol), and compound 2 (887 mg, 3.62 mmol) was added under ice-cooling. After warming to room temperature and stirring for 2 hours, water was added. Extraction was performed with chloroform, and the two layers were separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and ethyl acetate-hexane was added to the obtained residue. The solid was filtered to obtain compound 3 (1.34 g, yield 81%).

[0732] 1 H-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).

[0733] Step 2 Synthesis of Compound 5

[0734] To compound 4 (22.6 g, 76 mmol) were added 1,4-dioxane (158 mL), bis(pinacolato)diboron (25 g, 98 mmol), PdCl2(dppf) (6.2 g, 7.6 mmol), and potassium acetate (11.1 g, 114 mmol), and the mixture was 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.

[0735] The obtained concentrated residue was dissolved in tetrahydrofuran (226 mL), and 1 mol / L sodium hydroxide aqueous 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, sodium thiosulfate aqueous solution was added to stop the reaction. The mixture was extracted with ethyl acetate, the two layers were separated, and the organic layer was washed with water. It was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 5 (7.7 g, yield 43%).

[0736] 1H-NMR (CDCl3) δ: 1.57 (s, 9H), 3.04 (t, J=8.8Hz, 2H), 3.96 (m, 2H), 4.58 (s, 1 H), 6.61 (d, J=8.8Hz, 1H), 6.64 (s, 1H), 7.34 (brs, 0.4H), 7.73 (brs, 0.6H).

[0737] Step 3 Synthesis of compound 7

[0738] To compound 5 (2.5 g, 10.6 mmol) were added dimethylformamide (25 mL), compound 6 (3.08 g, 15.9 mmol), and potassium carbonate (2.94 g, 21.3 mmol), and the mixture was stirred at 60°C for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The two layers were separated, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 7 (2.55 g, yield 69%).

[0739] 1 H-NMR (CDCl3) δ: 1.35 (m, 2H), 1.57 (s, 9H), 1.60-1.82 (m, 5H), 3.05 (t, J=8.8Hz, 2H), 3.40 (td, J=12.0, 1.6Hz, 2H), 3.90-4.00 (m, 6H), 6.68 (d, J=8.8Hz, 1H), 6.72 (s, 1H), 7.34 (brs, 0.4H), 7.73 (brs, 0.6H).

[0740] Step 4 Synthesis of Compound 8

[0741] To compound 7 (2.55 g, 7.34 mmol) were added dichloromethane (20 mL) and trifluoroacetic acid (10 mL, 130 mmol). After stirring at room temperature for 1 hour, aqueous sodium bicarbonate solution was added for neutralization. The mixture was extracted with chloroform, the two layers were separated, and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to obtain a crude product of compound 8 (1.95 g).

[0742] 1 H-NMR (CDCl3) δ: 1.35 (m, 2H), 1.61-1.84 (m, 5H), 2.78 (brs, 1H), 3.01 (t, J=8.4Hz, 2H), 3.40 (td , J=12.0, 1.6Hz, 2H), 3.54 (t, J=8.4Hz, 2H), 3.91-4.00 (m, 4H), 6.57-6.61 (m, 2H), 6.76 (s, 1H).

[0743] Step 5 Synthesis of Compound (I-023)

[0744] To compound 8 (107 mg, 0.43 mmol) were added 1,4-dioxane (3 mL), triethylamine (0.149 mL, 1.08 mmol), and compound 3 (150 mg, 0.36 mmol), and the mixture was stirred at 50°C for 2 hours. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

[0745] To the obtained residue, tetrahydrofuran (2 mL), ethanol (2 mL), and 4 mol / L lithium hydroxide aqueous solution (0.90 mL, 3.6 mmol) were added, and after stirring at 90°C for 8 hours, a 10% citric acid aqueous solution was added. The mixture was extracted with chloroform and the two layers were separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-023) (90 mg, 41% yield).

[0746] 1 H-NMR (DMSO-d6) δ: 1.22 (m, 2H), 1.53-1.72 (m, 11H), 1.80 (brs, 2H), 2.03-2.16 (m , 4H), 2.54 (s, 2H), 3.19 (t, J=8.4Hz, 2H), 3.28 (m, 2H), 3.83 (dd, J=11.2, 0.8Hz, 2 H), 4.00 (t, J=6.4Hz, 2H), 4.21 (t, J=8.4Hz, 2H), 6.82 (dd, J=8.8, 1.2Hz, 1H), 6.9 4 (d, J=1.2Hz, 1H), 8.16 (d, J=8.8Hz, 1H), 8.46 (s, 1H), 8.67 (s, 1H), 12.3 (s, 1H).

[0747] Example 2

[0748] Synthesis of compound (I-033)

[0749] [Chemistry 48]

[0750]

[0751] Step 1 Synthesis of Compound (I-033)

[0752] Compound 8 (41 mg, 0.16 mmol) and compound 9 (40 mg, 0.11 mmol), synthesized using the same procedure as compound 3, were dissolved in 1,4-dioxane (0.5 mL). 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. The mixture was extracted with chloroform, and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure.

[0753] To the obtained residue, ethanol (0.5 mL) and tetrahydrofuran (0.5 mL) were added to dissolve it, and a 4 mol / L lithium hydroxide aqueous solution (0.27 mL) was added, and the mixture was stirred at 50°C for 4 hours. A citric acid aqueous solution was added, and the mixture was extracted with chloroform. 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%).

[0754] 1 H-NMR(DMSO-d6)δ:1.15-1.30(m, 3H), 1.50-1.78(m, 12H), 2.03-2.10(m, 2H), 3 .22 (m, 2H), 3.29 (m, 2H), 3.83 (dd, J=10.8, 3.2Hz, 2H), 3.98 (t, J=6.4Hz, 2H), 4 .06 (t, J=8.0Hz, 2H), 6.77 (dd, J=8.8, 3.5Hz, 1H), 6.89 (s, 1H), 7.06 (d, J=8.8H z, 1H), 7.72 (d, J=8.8Hz, 1H), 8.24 (d, J=8.8Hz, 1H), 8.44 (s, 1H), 12.2 (s, 1H).

[0755] Example 3

[0756] Synthesis of compound (I-082)

[0757] [Chemistry 49]

[0758]

[0759] Step 1 Synthesis of compound 12

[0760] Compound 10 (31 g, 124 mmol) and compound 11 (16.9 g, 148 mmol) were suspended in dichloromethane (600 mL) and ice-cooled. Trifluoroacetic acid (19 mL, 247 mmol) was added, and the temperature was raised to 45°C after 30 minutes, and stirred for 3 hours. The mixture was ice-cooled, and an aqueous sodium carbonate solution was added to neutralize the mixture, and the mixture was filtered through diatomaceous earth (registered trademark). The two layers of the filtrate were separated, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and diethyl ether was added to the obtained residue. The solid was filtered to obtain compound 12 (9.04 g, yield 25%).

[0761] 1 H-NMR (CDCl3) δ: 1.63 (m, 2H), 1.93 (ddd, J=13.6, 10.0, 4.0Hz, 2H), 3.90 (m, 2H), 4.10 (m, 2H), 5.10 (s, 2H), 6.97 (dd, J=8.4, 2.4Hz, 1H), 7.06 (d, J=2.4Hz, 1H), 7.34 (m, 1H), 7.40 (m, 2H), 7.45 (m, 2H), 7.56 (d, J=8.4Hz, 1H), 8.32 (s, 1H).

[0762] LC / MS (ESI): m / z=294[M+H]+, RT=1.96 min, LC / MS method 1

[0763] Step 2 Synthesis of compound 13

[0764] Compound 12 (18 g, 61.4 mmol) was suspended in methanol (180 mL), ice-cooled, and sodium borohydride (2.55 g, 67.5 mmol) was added. After 10 minutes, the mixture was warmed to room temperature and stirred for 2 hours. An aqueous ammonium chloride solution was added under ice-cooling, 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, diisopropyl ether was added to the obtained residue, and the solid was filtered to obtain compound 13 (16.1 g, yield 89%).

[0765] 1 H-NMR (CDCl3) δ: 1.65 (d, J=13.6Hz, 2H), 1.94 (m, 2H), 3.52 (m, 2H), 3.55 (m, 2H), 3.96 (m, 2H), 4.99 (s, 2H), 6.59 (d, J =8.4Hz, 1H), 6.70 (d, J = 8.4, 2.4Hz, 1H), 6.79 (d, J = 2.4Hz, 1H), 7.26 (s, 1H), 7.31 (m, 1H), 7.38 (m, 2H), 7.43 (m, 2H).

[0766] LC / MS (ESI): m / z=296[M+H]+, RT=1.67 min, LC / MS method 1

[0767] Step 3 Synthesis of compound 15

[0768] Compound 13 (16.1 g, 54.5 mmol) was dissolved in 1,4-dioxane (242 mL), and triethylamine (17.4 mL, 125 mmol) and compound 14 (14.4 g, 60 mmol) were added, followed by stirring at 50°C for 3 hours. The mixture was allowed to cool, water was added, and extraction was performed with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate-hexane was added to the obtained residue. The solid was filtered to obtain compound 15 (25.3 g, 93% yield).

[0769] 1 H-NMR (DMSO-d6) δ: 1.58 (m, 2H), 1.98 (m, 2H), 3.52 (m, 2H), 3.86 (s, 3H), 3.90 (m, 2H), 4.27 (m, 2H), 5.12 (s, 2H), 6.98 (m, 1H), 7.13 (d, J=2.4Hz, 1H), 7.34 (m, 1H), 7.40 (m, 2H), 7.47 (m, 2H), 8.21 (m, 1H), 9.11 (s, 1H).

[0770] LC / MS (ESI): m / z=500[M+H]+, RT=3.10 min, LC / MS method 1

[0771] Step 4 Synthesis of compound 16

[0772] To compound 15 (25.3 g, 50.7 mmol) were added chloroform (253 mL) and tetrahydrofuran (127 mL) to dissolve it, and 5 wt% palladium hydroxide (5 g, 1.78 mmol) was added. The system was replaced with hydrogen and stirred at room temperature and pressure for 2 hours. The mixture was filtered through celite (registered trademark) and the filtrate was concentrated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue, and the solid was filtered to obtain compound 16 (19.6 g, 95% yield).

[0773] 1 H-NMR (DMSO-d6) δ: 1.58 (m, 2H), 1.88 (m, 2H), 3.52 (m, 2H), 3.86 (s, 3H), 3.89 (m, 2H), 4.24 (m, 2 H), 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).

[0774] LC / MS (ESI): m / z=410[M+H]+, RT=2.20 min, LC / MS method 1

[0775] Step 5 Synthesis of Compound 18

[0776] Compound 16 (16.1 g, 39.3 mmol) and compound 17 (10.6 g, 59.0 mmol) were dissolved in tetrahydrofuran (217 mL), cooled to ice, and DIAD (11.47 mL, 59.0 mmol) was added dropwise. After addition, the temperature was raised to 40°C and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature, and the reaction solution was concentrated under reduced pressure. Ethyl acetate-diisopropyl ether was added, and the solid was filtered to obtain compound 18 (20.3 g, 91% yield).

[0777] 1 H-NMR (DMSO-d6) δ: 1.52-1.63 (m, 4H), 1.97-2.05 (m, 4H), 3.46-3.58 (m, 4H), 3.87 (s, 3H), 3.90 (m, 2H), 4.20-4.28 (m, 4H) , 4.69 (m, 1H), 6.61 (t, J=4.8Hz, 1H), 6.96 (m, 1H), 7.11 (d, J=2.0Hz, 1H), 8.22 (m, 1H), 8.36 (d, J=4.8Hz, 2H), 9.12 (s, 1H).

[0778] LC / MS (ESI): m / z=571[M+H]+, RT=2.95 min, LC / MS method 1

[0779] Step 6 Synthesis of compound 19

[0780] To compound 18 (20.3 g, 35.6 mmol) were added tetrahydrofuran (203 mL), ethanol (203 mL), and a 4 mol / L aqueous lithium hydroxide solution (44.5 mL, 178 mmol). After stirring at 50°C for 4 hours, the mixture was cooled to room temperature and a 10% aqueous citric acid solution was added. Water was added, and the precipitated solid was filtered to obtain compound 19 (19 g, 96% yield).

[0781] 1H-NMR (DMSO-d6) δ: 1.52-1.61 (m, 4H), 1.97-2.05 (m, 4H), 3.46-3.57 (m, 4H), 3.90 (m, 2H), 4.24 (m, 2H), 4.26 (s, 2H), 4.69 (m, 1H), 6.61 (t, J=4.4Hz, 1H), 6.96 (dd, J=8.8, 2.8Hz, 1H), 7.10 (d, J=2.8Hz, 1H), 8.22 (d, J=8.8Hz, 1H), 8.36 (d, J=4.4Hz, 2H), 9.11 (S, 1H), 13.54 (s, 1H).

[0782] LC / MS (ESI): m / z=557[M+H]+, RT=2.44 min, LC / MS method 1

[0783] Step 7 Synthesis of Compound (I-082)

[0784] To compound 19 (795 mg, 1.43 mmol), dimethylformamide (8 mL), compound 20 (431 mg, 1.71 mmol), HATU (706 mg, 1.86 mmol) and triethylamine (0.495 mL, 3.57 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the precipitated solid was filtered out. 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 neutralization with sodium bicarbonate aqueous solution, a 10% citric acid aqueous solution was added, and the mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining compound (I-082) (820 mg, yield 78%).

[0785] 1 H-NMR(DMSO-d6)δ:1.52-1.60(m, 6H), 1.65-1.69(m, 4H), 1.80(m, 2H), 1.94-2.17(m , 8H), 2.54(brs, 2H), 3.46-3.58(m, 4H), 3.90(m, 2H), 4.22(s, 2H), 4.26(m, 2H), 4.67 (m, 1H), 6.61 (t, J=4.4Hz, 1H), 6.93 (dd, J=8.8, 2.0Hz, 1H), 7.08 (d, J=2.0Hz, 1H), 8 .17 (d, J=8.8Hz, 1H), 8.36 (d, J=4.4Hz, 2H), 8.46 (s, 1H), 8.68 (s, 1H), 12.34 (s, 1H).

[0786] Example 4

[0787] Synthesis of compound (I-148)

[0788] [Chemistry 50]

[0789]

[0790] Step 1 Synthesis of compound 22

[0791] To a solution of compound 21 (100 mg, 0.20 mmol) (synthesis method, see Example 6) in dimethylformamide (1 mL), 60 wt% sodium hydride (11 mg, 0.29 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (49 mg, 0.29 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. After adding saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 22 (74 mg, 59% yield).

[0792] LC / MS (ESI): m / z=642[M+H]+, RT=1.182 min, LC / MS method 7

[0793] Step 2 Synthesis of compound 23

[0794] To a solution of compound 22 (74 mg, 0.12 mmol) in ethanol (0.7 mL) was added a 4 mol / L aqueous lithium hydroxide solution (0.28 mL, 1.16 mmol), and the mixture was stirred at 50°C for 1 hour and 40 minutes. A 10% aqueous citric acid solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound 23 (73 mg) as a crude product.

[0795] LC / MS (ESI): m / z=614[M+H]+, RT=3.04 min, LC / MS method 1

[0796] Step 3 Synthesis of compound 24

[0797] Compound 23 (71 mg, 0.12 mmol) was dissolved in dimethylformamide (1.0 mL), and compound 20 (30 mg, 0.12 mmol), HATU (52 mg, 0.14 mmol), and triethylamine (17 mg, 0.17 mmol) were added. After stirring at room temperature for 17 hours, water was added and the precipitated solid was collected by filtration to obtain compound 24 (93 mg, 96% yield).

[0798] LC / MS (ESI): m / z=847[M+H]+, RT=2.80 min, LC / MS method 7

[0799] Step 4 Synthesis of compound 25

[0800] To a solution of compound 24 (84 mg, 0.10 mmol) in tetrahydrofuran (0.3 mL) were added a 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (0.50 mL, 0.50 mmol) and ethylenediamine (89 mg, 1.50 mmol), and the mixture was stirred under heating and reflux for 8 hours. A 10% aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 25 (70 mg, 99% yield).

[0801] LC / MS (ESI): m / z=717[M+H]+, RT=1.42 min, LC / MS method 1

[0802] Step 5 Synthesis of Compound 26

[0803] To compound 25 (460 mg, 0.64 mmol) were added 1,4-dioxane (6.9 mL), (1R, 2R)-cyclohexane-1,2-diamine (22 mg, 0.19 mmol), tripotassium phosphate (272 mg, 1.28 mmol), iodobenzene (236 mg, 1.16 mmol) and copper (I) iodide (12 mg, 0.06 mmol), and the mixture was stirred under heating and reflux for 8 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 26 (500 mg, yield 98%).

[0804] LC / MS (ESI): m / z=793[M+H]+, RT=3.71 min, LC / MS method 1

[0805] Step 6 Synthesis of Compound (I-148)

[0806] The synthesis was carried out in the same manner as in Step 8 of Example 10.

[0807] 1H-NMR (DMSO-d6) δ: 1.66-1.71 (m, 10H), 2.00-2.13 (m, 6H), 2.59 (s, 2H), 3.53-3.57 (m, 2 H), 4.16 (ddd, J=13.0, 6.4, 3.9Hz, 2H), 4.66-4.72 (m, 1H), 6.60 (t, J=4.8Hz, 1H), 7.07- 7.10 (m, 2H), 7.49 (t, J=7.3Hz, 1H), 7.64-7.66 (m, 2H), 7.70-7.72 (m, 2H), 7.80 (d, J=8. 3Hz, 1H), 8.25 (d, J=8.3Hz, 1H), 8.35 (d, J=4.8Hz, 2H), 8.53-8.54 (m, 3H), 12.32 (s, 1H).

[0808] Example 5

[0809] Synthesis of Compound (I-159) and Compound (I-182)

[0810] [Chemistry 51]

[0811]

[0812] Step 1 Synthesis of Compound 28

[0813] To a solution of compound 27 (2.01 g, 15.00 mmol) in dimethylformamide (20.1 mL) were added imidazole (1.53 g, 22.50 mmol) and tert-butyldimethylsilyl chloride (2.71 g, 18.00 mmol), and the mixture was stirred at room temperature for 40 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 28 (3.79 g, 100% yield).

[0814] LC / MS (ESI): m / z=249[M+H]+, RT=2.66 min, LC / MS method 1

[0815] Step 2 Synthesis of compound 29

[0816] To a solution of compound 28 (3.73 g, 15.00 mmol) in tetrahydrofuran (74.5 mL) were added potassium tert-butoxide (3.87 g, 34.50 mmol) and iodine (8.76 g, 34.50 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. A 20% aqueous sodium thiosulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound 29 (5.42 g) as a crude product.

[0817] LC / MS (ESI): m / z=375[M+H]+, RT=3.09 min, LC / MS method 1

[0818] Step 3 Synthesis of compound 30

[0819] To a solution of compound 29 (5.42 g, 14.48 mmol) in dichloromethane (54.2 mL) were added triethylamine (2.49 g, 24.61 mmol) and p-toluenesulfonyl chloride (2.49 g, 17.37 mmol) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. The insoluble matter was separated by filtration, and 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, 82% yield).

[0820] LC / MS (ESI): m / z=529[M+H]+, RT=3.67 min, LC / MS method 1

[0821] Step 4 Synthesis of compound 31

[0822] 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 the mixture was stirred at room temperature for 30 minutes. A 0.4 mol / L aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) and solidified with hexane-ethyl acetate to obtain compound 31 (2.87 g, 57% yield).

[0823] LC / MS (ESI): m / z=415[M+H]+, RT=2.30 min, LC / MS method 1

[0824] Step 5 Synthesis of compound 32

[0825] The synthesis was carried out in the same manner as in step 3 of Example 6.

[0826] LC / MS (ESI): m / z=576[M+H]+, RT=3.03 min, LC / MS method 1

[0827] Step 6 Synthesis of compound 33

[0828] To compound 32 (6.09 g, 10.58 mmol) were added ethanol (122 mL), water (146 mL), and 8 mol / L aqueous sodium hydroxide solution (6.61 mL, 52.90 mmol), and the mixture was stirred at 80°C for 80 minutes. The mixture was decompressed, the organic solvent was distilled off, and the mixture was 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 suspended in chloroform and filtered to obtain compound 33 (2.93 g, 66% yield).

[0829] LC / MS (ESI): m / z=422[M+H]+, RT=2.21 min, LC / MS method 1

[0830] Step 7 Synthesis of Compound 34 and Compound 35

[0831] Compound 33 (3.45 g, 8.19 mmol) was dissolved in dimethylformamide (34.5 mL). Cesium carbonate (5.33 g, 16.36 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (681 mg, 16.36 mmol) were added, and the mixture was stirred at 80°C for 6 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a mixture of compound 34 and compound 35 in a ratio of approximately 4:1 (4.20 g, 100% yield).

[0832] Compound 34

[0833] LC / MS (ESI): m / z=506[M+H]+, RT=2.65 min, LC / MS method 1

[0834] Compound 35

[0835] LC / MS (ESI): m / z=506[M+H]+, RT=2.39 min, LC / MS method 1

[0836] Step 8 Synthesis of compound 37

[0837] Compound 36 (2.00 g, 4.35 mmol), synthesized using the same procedure as compound 3, was suspended in toluene (40 mL). 1,1,1,2,2,2,-hexamethyldistanane (2.00 g, 4.35 mmol) and Pd(PPh3)4 (0.75 g, 0.65 mmol) were added, and the mixture was stirred under heating and reflux for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 37 (1.74 g, 68% yield).

[0838] LC / MS (ESI): m / z=590[M+H]+, RT=3.34 min, LC / MS method 1

[0839] Step 9 Synthesis of Compound 40 and Compound 41

[0840] A mixture of compound 38 and compound 39 in a ratio of approximately 4:1 (1.01 g, 2.00 mmol) was dissolved in dimethylformamide (20 mL), and compound 37 (1.74 g, 2.96 mmol), Pd(PPh3)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 stirred at 95°C for 8.5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation 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%).

[0841] Compound 40

[0842] LC / MS (ESI): m / z=803[M+H]+, RT=3.43 min, LC / MS method 1

[0843] Compound 41

[0844] LC / MS (ESI): m / z=803[M+H]+, RT=3.50 min, LC / MS method 1

[0845] Step 10 Synthesis of Compound (I-159) and Compound (I-182)

[0846] The synthesis was carried out in the same manner as in Step 8 of Example 10.

[0847] Compound (I-159)

[0848] 1H-NMR (CDCl3) δ: 1.78-1.83 (m, 6H), 1.92-1.95 (m, 4H), 2.03-2.12 (m, 6H), 2.23 (d, J=12.4Hz, 2H) , 2.56 (ddd, J=24.8, 12.4, 4.3Hz, 2H), 2.67 (s, 2H), 3.64 (t, J=12.4Hz, 2H), 3.79-3.85 (m, 2H), 4.1 4-4.21 (m, 4H), 4.70-4.76 (m, 2H), 6.38 (s, 1H), 6.51 (t, J=4.8Hz, 1H), 6.97 (d, J=1.8Hz, 1H), 7.0 6 (dd, J=9.0, 1.8Hz, 1H), 8.34 (d, J=4.8Hz, 2H), 8.49 (d, J=9.0Hz, 1H), 9.16 (s, 1H), 12.12 (s, 1H).

[0849] Compound (I-182)

[0850] 1 H-NMR (CDCl3) δ: 1.79-2.26 (m, 18H), 2.50 (ddd, J=24.2, 11.5, 4.2Hz, 2H), 2.68 (s, 2H), 3.60 (t, J=11.5Hz, 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, 4.0Hz, 1H), 6.30 (s, 1H), 6.49 (t, J=4.8Hz, 1H), 7.01 (dd, J=9. 2, 1.9Hz, 1H), 7.17 (d, J=1.9Hz, 1H), 8.32-8.33 (m, 3H), 9.15 (s, 1H), 12.12 (s, 1H).

[0851] Example 6

[0852] Synthesis of compound (I-162)

[0853] [Chemistry 52]

[0854]

[0855] Step 1 Synthesis of Compound 44

[0856] To compound 42 (10 g, 22.3 mmol) were added tetrahydrofuran (100 mL) and triisopropyl borate (4.19 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 the solution, and the mixture was stirred at -78°C for 20 minutes. The reaction was terminated by the addition of saturated aqueous ammonium chloride, the mixture was warmed to room temperature, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. To the resulting residue were added 1,4-dioxane (102 mL), compound 43 (6.2 g, 24.5 mmol), PdCl2(dppf) (1.82 g, 2.23 mmol), and a 2.2 mol / L aqueous potassium carbonate solution (20.4 mL, 44.5 mmol), and the mixture was stirred at 100°C for 2 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The two layers were separated, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 44 (7.1 g, yield 59%).

[0857] 1 H-NMR (CDCl3) δ: 1.42 (t, J=7.2Hz, 3H), 1.70 (s, 9H), 4.44 (q, J=7.2Hz, 2H), 5.17 (s, 2H), 7.10 (dd, J=8.8, 2.8 Hz, 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).

[0858] LC / MS (ESI): m / z=541[M+H]+, RT=3.21 min, LC / MS method 1

[0859] Step 2 Synthesis of compound 45

[0860] To compound 44 (30.7 g, 56.8 mmol) were added tetrahydrofuran (307 mL) and 20 wt% palladium on carbon (6.34 g, 11.7 mmol). The system was replaced with hydrogen and stirred at room temperature and pressure for 2 hours. The mixture was filtered through celite (registered trademark) and the filtrate was concentrated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue and the solid was filtered to obtain compound 45 (22.0 g, 86% yield).

[0861] 1H-NMR (CDCl3) δ: 1.42 (t, J=7.2Hz, 3H), 1.71 (s, 9H), 4.44 (q, J=7.2Hz, 2H), 4.94 (s, 1H), 6.93 (dd, J=8.8, 2 .4Hz, 1H), 7.71 (brs, 1H), 7.88 (d, J=8.4Hz, 1H), 8.11 (s, 1H), 8.14 (d, J=8.4Hz, 1H), 8.46 (d, J=8.8Hz, 1H).

[0862] LC / MS (ESI): m / z=451[M+H]+, RT=2.84 min, LC / MS method 1

[0863] Step 3 Synthesis of compound 46

[0864] To compound 45 (3.27 g, 7.26 mmol) were added tetrahydrofuran (39.2 mL), compound 17 (1.69 g, 9.44 mmol), triphenylphosphine (2.48 g, 9.44 mmol), and DMEAD (2.21 g, 9.44 mmol). After stirring at 50°C for 1 hour, water was added to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 46 (4.07 g, 92% yield).

[0865] 1 H-NMR (CDCl3) δ: 1.42 (t, J=7.2Hz, 3H), 1.72 (s, 9H), 1.90 (m, 2H), 2.06 (m , 2H), 3.76 (m, 2H), 4.19 (m, 2H), 4.44 (q, J=7.2Hz, 2H), 4.67 (m, 1H), 6.48 ( t, J=4.4Hz, 1H), 7.06 (dd, J=8.8, 2.0Hz, 1H), 7.83 (brs, 1H), 7.89 (d, J=8. 0Hz, 1H), 8.13-8.16 (m, 2H), 8.32 (d, J=4.8Hz, 2H), 8.49 (d, J=8.8Hz, 1H).

[0866] LC / MS (ESI): m / z=612[M+H]+, RT=3.59 min, LC / MS method 1

[0867] Step 4 Synthesis of Compound 21

[0868] To compound 46 (4.17 g, 6.82 mmol) was added dichloromethane (41.7 mL) and trifluoroacetic acid (41.7 mL, 541 mmol) and stirred at room temperature for 1 hour and 30 minutes. The reaction solution was concentrated under reduced pressure and neutralized by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, chloroform was added to the obtained residue, and the solid was filtered to obtain compound 21 (800 mg, 22% yield). The filtrate was then concentrated under reduced pressure, toluene was added to the obtained residue, and the solid was filtered to obtain compound 21 (1.73 g, 48% yield). Furthermore, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 21 (520 mg, 15% yield).

[0869] 1 H-NMR (CDCl3) δ: 1.42 (t, J=7.2Hz, 3H), 1.88 (m, 2H), 2.06 (m, 2H), 3.71 (m, 2H), 4.21 (m, 2H), 4.43 (q, J=7.2Hz, 2H), 4.61 (m, 1H), 6.48 (t, J=4.8 Hz, 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).

[0870] LC / MS (ESI): m / z=512[M+H]+, RT=2.80 min, LC / MS method 1

[0871] Step 5 Synthesis of Compound 49

[0872] To compound 21 (800 mg, 1.56 mmol) was added dimethylformamide (12 mL), the mixture was ice-cooled, 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 ice-cooled 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 ice-cooled 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 ice-cooled 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 ice-cooled again, and 60 wt% sodium hydride (94 mg, 2.35 mmol) and compound 48 (681 mg, 2.35 mmol) were added, followed by stirring at 90°C for 30 minutes. The reaction mixture was poured into a 10% aqueous citric acid solution to stop the reaction, and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 49 (900 mg, 96% yield).

[0873] 1 H-NMR (CDCl3) δ: 1.71-2.24 (m, 10H), 2.35 (m, 2H), 3.77 (m, 2H), 4.20 (m, 2H), 4.32 (m, 1H), 4.67 (m, 1H), 6.54 (t, J=4.8Hz, 1H), 6.96 (d, J=2.0 Hz, 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).

[0874] LC / MS (ESI): m / z=602[M+H]+, RT=2.71 min, LC / MS method 1

[0875] Step 6 Synthesis of Compound (I-162)

[0876] The synthesis was carried out in the same manner as in step 7 of Example 3.

[0877] 1H-NMR(DMSO-d6)δ:1.55-1.71(m, 8H), 1.81(brs, 2H), 1.98-2.25(m, 14H), 2.58( s, 2H), 3.62 (m, 2H), 4.19 (m, 2H), 4.68-4.78 (m, 2H), 6.62 (t, J=4.8Hz, 1H), 6.98 (dd, J=8.8, 2.0Hz, 1H), 7.31 (d, J=2.0Hz, 1H), 7.73 (d, J=8.4Hz, 1H), 8.17 (d, J= 8.4Hz, 1H), 8.37 (d, J=4.4Hz, 2H), 8.41-8.44 (m, 2H), 8.49 (s, 1H), 12.32 (s, 1H).

[0878] LC / MS (ESI): m / z=779[M+H]+, RT=3.06 min, LC / MS method 1

[0879] Example 7

[0880] Synthesis of compound (I-165)

[0881] [Chemistry 53]

[0882]

[0883] Step 1 Synthesis of Compound 51

[0884] Compound 50 (49.9 g, 297 mmol) and 2-methyl-2-propanesulfenamide (53.9 g, 445 mmol) were added to tetrahydrofuran (250 mL), and tetraethyl orthotitanate (137 mL, 653 mmol) was added at room temperature. After stirring at 80°C for 1 hour, the mixture was poured into acetonitrile (1 L). Water (53.5 g) was added to stop the reaction. After stirring for 10 minutes, anhydrous magnesium sulfate was added, and the solid was separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 51 (58.9 g, 70% yield).

[0885] LC / MS (ESI): m / z=272[M+H]+, RT=1.81 min, LC / MS method 2

[0886] Step 2 Synthesis of a mixture of compound 52 and compound 53

[0887] 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 extracted with ethyl acetate. The mixture was washed with water and the organic layer was concentrated under reduced pressure. Hexane was added to the obtained solid to suspend it, and the solid was filtered to obtain a mixture of compound 52 and compound 53 (46.1 g, yield 64%).

[0888] LC / MS (ESI): m / z=300[M+H]+, RT=2.01 min, LC / MS method 2

[0889] Step 3 Synthesis of a mixture of compound 54 and compound 55

[0890] To a mixture of Compound 52 and Compound 53 (70.7 g, 236 mmol) was added a 2 mol / L methanolic hydrogen chloride solution (354 mL, 708 mmol), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added for extraction. A sodium bicarbonate aqueous solution was added to the aqueous layer, neutralized, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a mixture of Compound 54 and Compound 55 (55.2 g) as a crude product.

[0891] LC / MS (ESI): m / z=196[M+H]+, RT=1.01 min, LC / MS method 2

[0892] Step 4 Synthesis of a mixture of compound 56 and compound 57

[0893] 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 solution of citric acid was added. The mixture was extracted with ethyl acetate and the organic layer was washed with water. The mixture was concentrated under reduced pressure, hexane was added to the obtained solid, and the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained 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%).

[0894] 1H-NMR (CDCl3) δ: 0.03 (s, 9H), 0.92-0.98 (m, 2H), 1.49-1.56 (m, 2H), 1.73-1.80 (m, 2H), 1.87-2.01 (m, 4H), 2 .13-2.28(m, 3H), 2.56(brs, 2H), 4.09(m, 2H), 4.62(s, 1H), 5.20-5.31(m, 2H), 6.10(dd, J=17.6, 2.8Hz, 1H).

[0895] Step 5 Synthesis of a mixture of compound 58 and compound 59

[0896] A mixture of compound 56 and compound 57 (67.0 g, 197 mmol) was dissolved in acetonitrile (1179 mL), and 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, sodium periodate (42.2 g, 197 mmol) was added. After 2 hours, the mixture was ice-cooled and an aqueous sodium thiosulfate solution was added to stop the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with a 10% aqueous citric acid solution and a 3% aqueous sodium bicarbonate solution. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a mixture of compound 58 and compound 59 (32.5 g, 48% yield).

[0897] 1 H-NMR (CDCl3) δ: 0.03 (s, 9H), 0.92-1.00 (m, 2H), 1.56-1.98 (m, 8H), 2.09-2.28 (m, 3H), 2.63-2.69 (m, 2H), 4.12 (m, 2H), 4.81-4.89 (m, 1H), 9.60-9.74 (m, 2H).

[0898] Step 6 Synthesis of a mixture of compound 60 and compound 61

[0899] A mixture of compound 58 and compound 59 (36.1 g, 106 mmol) was dissolved in tert-butanol (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-cold conditions. After stirring for 1 hour under ice-cold conditions, an aqueous sodium thiosulfate solution was added to stop the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to obtain a mixture of compound 60 and compound 61 (45 g) as a crude product.

[0900] LC / MS (ESI): m / z = 356 [MH]-, RT = 2.32 min and 2.41 min, LC / MS method 2

[0901] Step 7 Synthesis of a mixture of compound 62 and compound 63

[0902] A mixture of compound 60 and compound 61 (45 g) of the crude product was dissolved in tetrahydrofuran (227 mL) and methanol (227 mL), and diphenyldiazomethane (61.8 g, 318 mmol) was added. After stirring at room temperature for 2 hours, acetic acid (18.2 mL) was added. After stirring at room temperature for 1 hour, water was added and 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 obtained residue was refined by silica gel column chromatography (hexane-ethyl acetate). The fraction was concentrated, hexane was added to the obtained residue to solidify, and the solid was filtered to obtain a mixture of compound 62 and compound 63 (21.5 g, yield 39%).

[0903] 1 H-NMR (CDCl3) δ: 0.03 (s, 9H), 0.73-0.94 (m, 2H), 1.50-1.56 (m, 2H), 1.75-1.96 (m, 6H), 2.10-2 .20(m,3H),2.84(brs,2H),3.95(m,2H),4.83(brs,1H),6.90-6.93(m,1H),7.25-7.31(m,10H).

[0904] Step 8 Synthesis of compound 64

[0905] To a mixture of compound 62 and compound 63 (43.2 g, 82 mmol), 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (866 mL) and acetic acid (42.4 mL) were added and heated under reflux for 15 hours. Aqueous sodium bicarbonate solution was added for neutralization and extracted with ethyl acetate. The organic layer was washed three times with aqueous ammonium chloride solution, followed by washing with aqueous sodium bicarbonate solution and brine. Dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to separate the low-polarity compound 65 and the high-polarity compound 64, thereby obtaining compound 64 (19.5 g, yield 56%).

[0906] 1 H-NMR (DMSO-d6) δ: 1.30-1.35 (m, 2H), 1.65-1.77 (m, 6H), 1.99-2.11 (m, 3H), 2.19 -2.27(m, 2H), 2.35(brs, 2H), 6.82(s, 1H), 7.27(m, 2H), 7.35(m, 4H), 7.45(m, 4H).

[0907] Step 9 Synthesis of compound 66

[0908] The synthesis was carried out under the same conditions as in step 3 of Example 4.

[0909] LC / MS (ESI): m / z=918[M+H]+, RT=3.06 min, LCMS method 1

[0910] Step 10 Synthesis of Compound (I-165)

[0911] 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-cold conditions. After stirring for 30 minutes under ice-cold conditions, the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and neutralized with an aqueous sodium carbonate solution. An aqueous citric acid solution was added to the aqueous layer and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining compound (I-165) (33 mg, yield 61%).

[0912] 1H-NMR (DMSO-d6) δ: 1.45-1.48 (m, 2H), 1.53-1.60 (m, 4H), 1.78-1.84 (m, 4H), 1.97-2.05 (m, 6H), 2.16-2.24(m, 3H), 2.82(s, 2H), 3.48-3.56(m, 4H), 3.88-3.92(m, 2H), 4.22-4, 26(m, 4 H), 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).

[0913] Example 8

[0914] Synthesis of compound (I-228)

[0915] [Chemistry 54]

[0916]

[0917] Step 1 Synthesis of Compound 68

[0918] 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 under an argon stream while stirring, and the mixture was stirred at room temperature for 10 minutes. Subsequently, compound 48 (442 mg, 1.52 mmol) was added at room temperature. After stirring at 100°C for 3 hours, compound 48 (442 mg, 1.52 mmol) and 60 wt% sodium hydride (61 mg, 1.53 mmol) were added, and the mixture was stirred at 80°C for 5 hours. After 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 obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 68 (252 mg, 53% yield).

[0919] LC / MS (DUIS): m / z=315[M+H]+, RT=1.59 min, LC / MS method 9

[0920] Step 2 Synthesis of compound 69

[0921] Compound 68 (50 mg, 0.16 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.5 mL). 8 mol / L aqueous potassium hydroxide solution (0.06 mL, 0.48 mmol), Pd2(dba)3 (15 mg, 0.02 mmol), and 5-(di-t-butylphosphino)-1',3',5'-triphenyl-1,4'-bi-1H-pyrazole (16 mg, 0.03 mmol) were added at room temperature while stirring under an argon stream. The mixture was then stirred at 75°C. After 2 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 69 (51 mg) as a crude product.

[0922] LC / MS (DUIS): m / z=253[M+H]+, RT=1.04 min, LC / MS method 9

[0923] Step 3 Synthesis of compound 70

[0924] To a solution of the crude product compound 69 (49 mg, 0.19 mmol) in tetrahydrofuran (0.98 mL), compound 17 (70 mg, 0.39 mmol), 1.9 mol / L DIAD-toluene solution (145 μL, 0.28 mmol), and triphenylphosphine (74 mg, 0.28 mmol) were added at room temperature while stirring under an argon stream. Stirring was carried out at room temperature for 2 hours. After the reaction was completed, an aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 70 (47 mg, 58%).

[0925] LC / MS (DUIS): m / z=414[M+H]+, RT=1.77 min, LC / MS method 9

[0926] Step 4 Synthesis of Compound 71

[0927] The synthesis was carried out in the same manner as in Step 5 of Example 9.

[0928] LC / MS (DUIS): m / z=540[M+H]+, RT=1.98 min, LC / MS method 9

[0929] Step 5 Synthesis of Compound 72

[0930] The synthesis was carried out in the same manner as in Step 6 of Example 9.

[0931] LC / MS (DUIS): m / z=540[M+H]+, RT=2.00 min, LC / MS method 9

[0932] Step 6 Synthesis of Compound 73

[0933] The synthesis was carried out in the same manner as in Step 1 of Example 6.

[0934] LC / MS (DUIS): m / z=837[M+H]+, RT=2.29 min, LC / MS method 9

[0935] Step 7 Synthesis of Compound (I-228)

[0936] The synthesis was carried out in the same manner as in Step 8 of Example 10.

[0937] 1 H-NMR (DMSO-d6) δ: 1.55-1.84 (m, 10H), 2.02-2.28 (m, 14H), 2.55-2.58 (m, 2 H), 3.45-3.55(m, 2H), 4.30-4.42(m, 2H), 4.70-4.83(m, 1H), 5.23-5.33(m, 1 H), 6.63 (t, J=4.8Hz, 1H), 6.79 (d, J=8.5Hz, 1H), 8.31 (s, 1H), 8.37 (d, J=4.6 Hz, 2H), 8.61 (d, J=8.5Hz, 1H), 8.65 (brs, 1H), 8.87 (s, 1H), 12.51 (brs, 1H).

[0938] LC / MS (ESI): m / z=781[M+H]+, RT=1.86 min, LC / MS method 10

[0939] Example 9

[0940] Synthesis of compound (I-268)

[0941] [Chemistry 55]

[0942]

[0943] Step 1 Synthesis of Compound 75

[0944] To a toluene (10 mL) solution of compound 17 (760 mg, 4.24 mmol) was added 60 wt% sodium hydride (283 mg, 7.08 mmol) at room temperature under an argon stream while stirring, and the mixture was stirred at 70°C for 15 minutes. Subsequently, compound 74 (910 mg, 3.57 mmol), Pd2(dba)3 (324 mg, 0.354 mmol), and (R)-(+)-TolBINAP (240 mg, 0.354 mmol) were added at room temperature, and the mixture was stirred at 100°C. After 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 75 (899 mg, 63% yield).

[0945] LC / MS (DUIS): m / z=398[M+H]+, RT=1.17 min, LC / MS method 9

[0946] Step 2 Synthesis of Compound 76

[0947] 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 under an argon stream while stirring. The mixture was stirred for 6 hours. After completion of the reaction, an aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain compound 76 (695 mg, 100% yield).

[0948] LC / MS (DUIS): m / z = 298 [M+H] +, RT = 0.35 min, LC / MS method 9

[0949] Step 3 Synthesis of compound 77

[0950] To a toluene (15.9 mL) solution of compound 76 (530 mg, 1.78 mmol) was added manganese dioxide (775 mg, 8.91 mmol) at room temperature under an argon flow with stirring, and the mixture was stirred at 120°C for 6 hours. Subsequently, after stirring at room temperature for 18 hours, manganese dioxide (775 mg, 8.91 mmol) was added at room temperature under an argon flow with stirring, and the mixture was stirred at 120°C for 2 hours. After completion of the reaction, the reaction solution was filtered through Celite (registered trademark), washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain compound 77 (342 mg, 65% yield).

[0951] LC / MS (DUIS): m / z = 296 [M+H] +, RT = 0.36 min, LC / MS method 9

[0952] Step 4 Synthesis of Compound 78

[0953] To a solution of compound 77 (370 mg, 1.25 mmol) in N-methylpyrrolidone (7.4 mL) were added cesium carbonate (1.22 g, 3.74 mmol) and compound 48 (1.09 g, 3.75 mmol) at room temperature with stirring under an argon stream, and the mixture was stirred at 120°C for 3 hours. Subsequently, 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. Furthermore, 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 evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 78 (520 mg, yield 100%).

[0954] LC / MS (DUIS): m / z=414[M+H]+, RT=0.91 min, LC / MS method 9

[0955] Step 5 Synthesis of Compound 79

[0956] 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 under an argon stream while stirring, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, an aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 79 (180 mg, 29% yield).

[0957] LC / MS (ESI): m / z=540[M+H]+, RT=1.43 min, LC / MS method 10

[0958] Step 6 Synthesis of Compound 80

[0959] To a solution of compound 79 (180 mg, 0.33 mmol) in 1,4-dioxane (3.6 mL) were added triethylamine (185 μL, 1.33 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (195 μL, 1.34 mmol), X-Phos (32 mg, 0.07 mmol), and Pd2(dba)3 (31 mg, 0.03 mmol) at room temperature under an argon stream with stirring, and the mixture was stirred at 95°C for 1 hour. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 80 (111 mg, 62% yield).

[0960] LC / MS (ESI): m / z=540[M+H]+, RT=1.29 min, LC / MS method 10

[0961] Step 7 Synthesis of Compound 81

[0962] The synthesis was carried out in the same manner as in Step 1 of Example 6.

[0963] LC / MS (ESI): m / z=837[M+H]+, RT=1.99 min, LC / MS method 10

[0964] Step 8 Synthesis of Compound (I-268)

[0965] The synthesis was carried out in the same manner as in Step 8 of Example 10.

[0966] 1 H-NMR(DMSO-d6)δ:1.49-1.84(m, 10H), 2.01-2.22(m, 14H), 2.56-2.60( m, 2H), 3.54-3.63 (m, 2H), 4.21-4.31 (m, 2H), 4.60-4.73 (m, 1H), 5.33-5 .43 (m, 1H), 6.62 (t, J=4.8Hz, 1H), 7.15 (s, 1H), 8.37 (d, J=4.8Hz, 2H), 8 .41(brs, 1H), 8.51(brs, 1H), 8.89(s, 1H), 9.23(s, 1H), 12.51(brs, 1H).

[0967] LC / MS (DUIS): m / z=781[M+H]+, RT=1.56 min, LC / MS method 9

[0968] Example 10

[0969] Synthesis of compound (I-269)

[0970] [Chemistry 56]

[0971]

[0972] Step 1 Synthesis of Compound 83

[0973] 2-(Trimethylsilyl)ethane-1-ol (1.08 g, 9.10 mmol) was dissolved in tetrahydrofuran (10 mL), and 60 wt% sodium hydride (218 mg, 5.46 mmol) was added under ice-cooling. After 5 minutes, compound 82 (1.00 g, 4.55 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 83 (1.45 g, 100% yield).

[0974] 1 H-NMR (CDCl3) δ: 1.10 (s, 9H), 1.16 (t, J=8.0Hz, 2H), 4.14 (t, J=8.0Hz, 2H), 6.88 (dd, J=9.2, 2.8Hz, 1H), 7.18 (d, J=2.8Hz, 1H), 7.98 (d, J=9.2Hz, 1H).

[0975] Step 2 Synthesis of compound 84

[0976] Compound 83 (500 mg, 1.57 mmol) was dissolved in ethanol (5 mL), and water (1 mL), ammonium chloride (336 mg, 6.28 mmol), and iron (438 mg, 7.85 mmol) were added, and the mixture was stirred at 90°C for 3 hours. The reaction solution was cooled and diluted with ethyl acetate (30 mL), and the insoluble matter was filtered off using diatomaceous earth (registered trademark). Water was added to the filtrate, and the mixture was 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 obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 84 (303 mg, yield 67%).

[0977] LC / MS (ESI): m / z=288[M+H]+, RT=2.83 min, LC / MS method 1

[0978] Step 3 Synthesis of compound 85

[0979] Compound 84 (1.93 g, 6.70 mmol) was dissolved in dimethylformamide (10 mL), and cyclopent-1-ene-1-carboxylic acid (1.08 g, 1.44 mmol), triethylamine (3.39 g, 33.5 mmol), and HATU (3.80 g, 10.1 mmol) were added, and stirred at room temperature for 6 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and then washed with water. The organic layer was 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), thereby obtaining compound 85 (816 mg, yield 32%).

[0980] LC / MS (ESI): m / z=382[M+H]+, RT=3.08 min, LC / MS method 1

[0981] Step 4 Synthesis of Compound 86

[0982] Compound 85 (816 mg, 2.13 mmol) was dissolved in dimethylformamide (6 mL), and triethylamine (1.08 g, 10.6 mmol) and PdCl2(dppf) (156 mg, 0.213 mmol) were added. The mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 86 (467 mg, 73% yield).

[0983] LC / MS (ESI): m / z=302[M+H]+, RT=2.50 min, LC / MS method 1

[0984] Step 5 Synthesis of Compound 87

[0985] Compound 86 (218 mg, 0.723 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 36 (399 mg, 0.868 mmol), cesium carbonate (707 mg, 2.17 mmol), and Xantphos Pd G2 (129 mg, 0.145 mmol) were added. The mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. After cooling, the solution was diluted with ethyl acetate (10 mL) and the insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 87 (404 mg, 77% yield).

[0986] LC / MS (ESI): m / z=725[M+H]+, RT=3.54 min, LC / MS method 1

[0987] Step 6 Synthesis of Compound 88

[0988] To compound 87 (404 mg, 0.557 mmol) was added a 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (10 mL, 10 mmol) and stirred at 80°C for 1 hour. After cooling, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation 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. Methanol (20 mL) and potassium carbonate (231 mg, 1.67 mmol) were added, and water was added to the reaction mixture after stirring at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 88 (203 mg, 58% yield).

[0989] LC / MS (ESI): m / z=625[M+H]+, RT=2.77 min, LC / MS method 1

[0990] Step 7 Synthesis of Compound 89

[0991] The synthesis was carried out under the same conditions as in step 5 of Example 3.

[0992] LC / MS (ESI): m / z=786[M+H]+, RT=3.11 min, LC / MS method 1

[0993] Step 8 Synthesis of Compound (I-269)

[0994] Compound 89 (50 mg, 0.064 mmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated and dissolved in dichloromethane, and neutralized with saturated sodium bicarbonate water. Aqueous citric acid solution was added to the reaction solution, which was then acidified and 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%).

[0995] 1H-NMR (CDCl3) δ: 1.77-2.05 (m, 15H), 2.19-2.27 (m, 3H), 2.61-2.67 (m, 3H), 2.70-2.76 (m , 1H), 2.78-2.87(m, 1H), 3.69-3.75(m, 2H), 4.11-4.19(m, 2H), 4.51-4.57(m, 1H), 5.53-5 .56 (m, 1H), 6.24-6.27 (m, 1H), 6.49 (t, J = 5.2Hz, 1H), 6.55 (brs, 1H), 6.81 (d, J = 2.8Hz, 1H ), 6.90 (dd, J=8.8, 2.4Hz, 1H), 7.88 (d, J=9.2Hz, 1H), 8.32 (d, J=4.8Hz, 2H), 9.12 (s, 1H).

[0996] Example 11

[0997] Synthesis of compound (I-270)

[0998] [Chemistry 57]

[0999]

[1000] Step 1 Synthesis of Compound 91

[1001] Compound 90 (1.64 g, 5.60 mmol) was dissolved in dichloromethane (16.4 mL), and pyridine (1.33 g, 16.80 mmol) and p-toluenesulfonyl chloride (2.14 g, 11.20 mmol) were added under ice-cold conditions. After stirring at room temperature for 1.5 hours, triethylamine (1.70 g, 16.80 mmol) and 1-methylpiperazine (1.12 g, 11.20 mmol) were added, and the mixture was stirred for 30 minutes. Concentrated hydrochloric acid was added under ice-cold conditions, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 91 (2.08 g, 86% yield).

[1002] LC / MS (ESI): m / z=432[M+H]+, RT=2.76 min, LC / MS method 1

[1003] Step 2 Synthesis of compound 92

[1004] Compound 91 (0.45 g, 1.04 mmol) was dissolved in dimethylformamide (2.89 mL), and 4-ethynyltetrahydro-2H-pyran (0.17 g, 1.56 mmol), copper (I) iodide (39 mg, 0.21 mmol), triethylamine (2.11 g, 20.82 mmol), and PdCl2(dppf) (76 mg, 0.10 mmol) were added. The mixture was stirred at 100°C for 8 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 92 (0.35 g, 73% yield).

[1005] LC / MS (ESI): m / z=462[M+H]+, RT=2.99 min, LC / MS method 1

[1006] Step 3 Synthesis of compound 93

[1007] To a solution of compound 92 (200 mg, 0.43 mmol) in tetrahydrofuran (0.4 mL) was added a 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution (8.67 mL, 8.67 mmol), and the mixture was stirred under reflux for 17 hours. 1 mol / L hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 93 (130 mg, 98% yield).

[1008] LC / MS (ESI): m / z=308[M+H]+, RT=2.35 min, LC / MS method 1

[1009] Step 4 Synthesis of Compound 94

[1010] To a solution of compound 93 (130 mg, 0.42 mmol) in tetrahydrofuran (1.3 mL) were added Boc2O (220 mg, 1.01 mmol) and DMAP (5.2 mg, 0.04 mmol), and the mixture was stirred at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 94 (160 mg, 93% yield).

[1011] LC / MS (ESI): m / z=408[M+H]+, RT=3.18 min, LC / MS method 1

[1012] Step 5 Synthesis of Compound 95

[1013] Iodine (62 mg, 0.25 mmol) was dissolved in dichloromethane (0.5 mL), and pyridine (39 mg, 0.49 mmol) and iodobenzene bis(trifluoroacetate) (106 mg, 0.25 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. To this solution, a dichloromethane (2 mL) solution of compound 94 (100 mg, 0.25 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A 10% aqueous sodium thiosulfate solution 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 removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 95 (115 mg, yield 88%).

[1014] 1 H-NMR (CDCl3) δ: 1.63-1.65 (m, 2H), 1.67 (s, 9H), 2.70 (ddd, J=25.3, 11.8, 4.1Hz, 2H), 3.53 (td, J=11.8, 1.7Hz, 2H), 3.76-3.82 (m, 1H), 4.11 (dd, J= 11.8, 4.1Hz, 2H), 5.13 (s, 2H), 6.99 (dd, J=8.6, 2.2Hz, 1H), 7.29-7.33 (m , 2H), 7.38 (t, J=7.3Hz, 2H), 7.45 (d, J=7.3Hz, 2H), 7.60 (d, J=2.2Hz, 1H).

[1015] Step 6 Synthesis of Compound 96

[1016] Compound 95 (113 mg, 0.21 mmol) was dissolved in 1,4-dioxane (2.3 mL), and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (163 mg, 1.27 mmol), X-Phos (30 mg, 0.06 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), and triethylamine (129 mg, 1.27 mmol) were added, followed by stirring at 95°C for 2.5 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 96 (110 mg, 97% yield).

[1017] 1H-NMR (CDCl3) δ: 1.40 (s, 12H), 1.67 (s, 9H), 1.73 (d, J=12.0Hz, 2H), 2.42 (dd d, J=24.8, 12.0, 4.1Hz, 2H), 3.50 (t, J=10.9Hz, 2H), 3.72-3.77 (m, 1H), 4.07 (dd, J=10.9, 4.1Hz, 2H), 5.11 (s, 2H), 6.92 (dd, J=8.5, 2.3Hz, 1H), 7.29-7.3 9 (m, 3H), 7.45 (d, J = 7.2Hz, 2H), 7.59 (d, J = 2.3Hz, 1H), 7.77 (d, J = 8.5Hz, 1H).

[1018] Step 7 Synthesis of Compound 97

[1019] Compound 96 (108 mg, 0.20 mmol) was dissolved in 1,4-dioxane (1.4 mL), and compound 43 (57 mg, 0.22 mmol), PdCl2(dppf) (17 mg, 0.02 mmol), water (0.3 mL), and cesium carbonate (132 mg, 0.41 mmol) were added. The mixture was stirred under reflux for 1 hour. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 97 (92 mg, 73% yield).

[1020] LC / MS (ESI): m / z=625[M+H]+, RT=3.45 min, LC / MS method 1

[1021] Step 8 Synthesis of Compound 98

[1022] To compound 97 (90 mg, 0.14 mmol) were added tetrahydrofuran (0.63 mL), ethanol (0.63 mL), and 20 wt% palladium on carbon (18 mg, 0.17 mmol). The mixture was stirred at room temperature and pressure for 2.5 hours under a hydrogen atmosphere. After filtration through Celite (registered trademark), the filtrate was concentrated under reduced pressure to obtain compound 98 (100 mg) as a crude product.

[1023] LC / MS (ESI): m / z=535[M+H]+, RT=2.72 min, LC / MS method 1

[1024] Step 9 Synthesis of Compound 99

[1025] The synthesis was carried out in the same manner as in step 3 of Example 6.

[1026] LC / MS (ESI): m / z=696[M+H]+, RT=3.08 min, LC / MS method 1

[1027] Step 10 Synthesis of Compound 100

[1028] The synthesis was carried out in the same manner as in step 4 of Example 6.

[1029] LC / MS (ESI): m / z=596[M+H]+, RT=2.61 min, LC / MS method 1

[1030] Step 11 Synthesis of Compound 101

[1031] To a solution of compound 100 (34 mg, 0.06 mmol) in dimethylformamide (0.5 mL) were added 60 wt% sodium hydride (3.4 mg, 0.09 mmol) and iodomethane (16 mg, 0.11 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ice 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 removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 101 (26 mg, 75% yield).

[1032] LC / MS (ESI): m / z=610[M+H]+, RT=3.04 min, LC / MS method 1

[1033] Step 12 Synthesis of compound 102

[1034] The synthesis was carried out in the same manner as in step 2 of Example 4.

[1035] LC / MS (ESI): m / z=582[M+H]+, RT=2.25 min, LC / MS method 1

[1036] Step 13 Synthesis of Compound (I-270)

[1037] The synthesis was carried out in the same manner as in Step 6 of Example 6.

[1038] 1H-NMR (CDCl3) δ: 1.78-2.32 (m, 20H), 2.70 (s, 2H), 3.48 (t, J=11.0Hz, 2H), 3.73 (ddd, J=1 3.2, 8.3, 4.1Hz, 2H), 3.91-3.94 (m, 4H), 4.08-4.15 (m, 2H), 4.19 (dq, J=13.2, 4.1Hz, 2H), 4.59-4.65 (m, 1H), 6.14 (s, 1H), 6.49 (t, J=4.7Hz, 1H), 6.90-6.91 (m, 2H), 7.60 (d, J=8.2H z, 1H), 7.81 (d, J=8.2Hz, 1H), 7.98 (d, J=8.2Hz, 1H), 8.33 (d, J=4.7Hz, 2H), 12.12 (s, 1H).

[1039] Example 12

[1040] Synthesis of compound (I-486)

[1041] [Chemistry 58]

[1042]

[1043] Step 1 Synthesis of Compound 104

[1044] A toluene (5 mL) solution of triethylsilane (1.7 mL, 10.75 mmol) and trichloroacetic acid (1.1 g, 6.72 mmol) was stirred at 70°C, and a toluene (10 mL) solution of compound 103 (1 g, 4.48 mmol) and cyclopentanone (414 mg, 4.93 mmol) was added dropwise to the solution. After addition, the mixture was stirred at 70°C for 40 minutes. The mixture was cooled to room temperature and a 10% aqueous sodium carbonate solution was added. The mixture was extracted with ethyl acetate and the organic layer was washed with water. The mixture was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 104 (600 mg, 46% yield).

[1045] LC / MS (ESI): m / z=292[M+H]+, RT=2.98 min, LC / MS method 1

[1046] Step 2 Synthesis of compound 105

[1047] Compound 104 (570 mg, 1.96 mmol) was dissolved in acetic acid (2 mL), and sodium cyanoborohydride (246 mg, 3.91 mmol) was added under ice-cooling. After stirring at room temperature for 50 minutes, aqueous potassium carbonate solution was added for neutralization. The mixture was extracted with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 105 (340 mg, 59% yield).

[1048] LC / MS (ESI): m / z=294[M+H]+, RT=1.74 min, LC / MS method 1

[1049] Step 3 Synthesis of compound 106

[1050] Compound 36 (266 mg, 0.58 mmol), diisopropylamine (0.2 mL, 1.16 mmol), and compound 105 (170 mg, 0.58 mmol) were dissolved in 1,4-dioxane (2.55 mL) and stirred at 90°C for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by amino column chromatography (hexane-ethyl acetate) to obtain compound 106 (330 mg, 80% yield).

[1051] LC / MS (ESI): m / z=717[M+H]+, RT=2.96 min, LC / MS method 7

[1052] Step 4 Synthesis of Compound 107

[1053] The synthesis was carried out under the same conditions as in step 4 of Example 3.

[1054] LC / MS (ESI): m / z=627[M+H]+, RT=3.42 min, LC / MS method 1

[1055] Step 5 Synthesis of Compound 108

[1056] The synthesis was carried out under the same conditions as in step 5 of Example 3.

[1057] LC / MS (ESI): m / z=806[M+H]+, RT=3.12 min, LC / MS method 7

[1058] Step 6 Synthesis of Compound (I-486)

[1059] The synthesis was carried out in the same manner as in Step 8 of Example 10.

[1060] 1H-NMR (CDCl3) δ: 1.23-1.72 (m, 5H), 1.81 (dd, J=14.9, 7.5Hz, 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=10.5Hz, 1H), 4.50-4.53(m, 1H), 6.02(s, 1H), 6.8 6-6.92 (m, 2H), 8.20 (s, 2H), 8.28 (d, J=8.3Hz, 1H), 8.78 (s, 1H), 12.34 (s, 1H).

[1061] LC / MS (ESI): m / z=750[M+H]+, RT=3.56 min, LC / MS method 1

[1062] Example 13

[1063] Synthesis of compound (I-591)

[1064] [Chemistry 59]

[1065]

[1066] Step 1 Synthesis of Compound 110

[1067] Compound 10 (42 g, 166 mmol) and compound 109 (16.6 g, 166 mmol) were suspended in dichloromethane (250 mL) and ice-cooled. Trifluoroacetic acid (25.6 mL, 332 mmol) was added, the temperature was raised to 45°C, and stirred for 5 hours. After ice-cooling, an aqueous sodium carbonate solution was added to neutralize the mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 110 (8.9 g, yield 19%).

[1068] LC / MS (ESI): m / z=280[M+H]+, RT=2.59 min, LC / MS method 1

[1069] Step 2 Synthesis of compound 111

[1070] The synthesis was carried out under the same conditions as in step 2 of Example 3.

[1071] LC / MS (ESI): m / z=282[M+H]+, RT=1.57 min, LC / MS method 1

[1072] Step 3 Synthesis of compound 113

[1073] The synthesis was carried out under the same conditions as in step 3 of Example 3.

[1074] LC / MS (ESI): m / z=496[M+H]+, RT=3.60 min, LC / MS method 1

[1075] Step 4 Synthesis of compound 114

[1076] The product was synthesized under the same conditions as in step 6 of Example 3.

[1077] LC / MS (ESI): m / z=468[M+H]+, RT=3.14 min, LC / MS method 1

[1078] Step 5 Synthesis of Compound 115

[1079] Compound 114 (570 mg, 1.22 mmol) and compound 20 (429 mg, 1.71 mmol) were dissolved in dimethylformamide (8.6 mL), and HATU (788 mg, 2.07 mmol) and triethylamine (0.39 mL, 2.8 mmol) were added. After stirring at room temperature for 15 hours, water was added. The precipitated solid was filtered and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 115 (740 mg, 87% yield).

[1080] LC / MS (ESI): m / z=701[M+H]+, RT=3.88 min, LC / MS method 1

[1081] Step 6 Synthesis of compound 116

[1082] The synthesis was carried out under the same conditions as in step 4 of Example 3.

[1083] LC / MS (ESI): m / z=611[M+H]+, RT=1.42 min, LC / MS method 7

[1084] Step 7 Synthesis of Compound 118

[1085] 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 material disappeared, water was added to stop the reaction. The mixture 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 obtained residue was purified by amino column chromatography (hexane-ethyl acetate) to obtain compound 118 (63 mg, yield 70%).

[1086] LC / MS (ESI): m / z=784[M+H]+, RT=3, 17 min, LC / MS method 1

[1087] Step 8 Synthesis of Compound (I-591)

[1088] The product was synthesized under the same conditions as in Step 8 of Example 10.

[1089] 1 H-NMR (DMSO-d6) δ: 0.70 (t, J=7.3Hz, 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, 2 H), 3.54 (t, J = 12.4Hz, 4H), 3.95 (s, 2H), 4.26-4.29 (m, 1H), 6.81-6.83 (m, 2H), 8.16 (d, J = 8.8Hz, 1H), 8.29 (s, 1H), 8.47 (s, 1H), 12.27 (br s, 1H).

[1090] Example 14

[1091] Synthesis of compound (I-594)

[1092] [Chemistry 60]

[1093]

[1094] Step 1 Synthesis of Compound 120

[1095] Compound 119 (3 ​​g, 18.9 mmol) was dissolved in dichloromethane (30 mL), and oxalyl chloride (1.8 mL, 20.8 mmol) and dimethylformamide (0.15 mL, 1.9 mmol) were added under ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure.

[1096] 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 obtained residue to suspend it. The solid was filtered to obtain compound 120 (7.0 g, yield 94%).

[1097] 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).

[1098] Step 2 Synthesis of compound 121

[1099] To compound 120 (3.8 g, 9.7 mmol), acetonitrile (30 mL) and water (15 mL) were added to suspend the mixture, and 2,2-difluoropropionic acid (2.1 g, 19.4 mmol), silver nitrate (4.9 g, 29.1 mmol), and ammonium persulfate (8.8 g, 38.8 mmol) were added. The mixture was heated to 80°C and stirred for 1 hour. After cooling with ice, an aqueous sodium thiosulfate solution was added to stop the reaction. The mixture was filtered through diatomaceous earth (registered trademark), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 121 (670 mg, 15% yield).

[1100] 1 H-NMR (DMSO-d6) δ: 1.42 (s, 9H), 1.56 (m, 2H), 1.65-1.79 (m, 4H), 1.99 (t, J=19.2Hz, 3H), 2.05 (m, 4H), 2.53 (s, 2H), 8.54 (s, 1H), 8.74 (s, 1H).

[1101] [Chemistry 61]

[1102]

[1103] Step 1 Synthesis of compound 123

[1104] 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. The mixture was extracted with ethyl acetate, and the organic layer was washed with water. Drying was performed over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Hexane and ethyl acetate were added to the resulting residue to solidify, which was then collected by filtration to obtain compound 123 (90.9 g, 99% yield).

[1105] LC / MS (ESI): m / z=273[M+H]+, RT=2.21 min, LC / MS method 1

[1106] Step 2 Synthesis of compound 124

[1107] Compound 123 (81.2 g, 298 mmol) was dissolved in 1,4-dioxane (812 mL), and pyridinium tribromide (349 g, 1.09 mol) was added. After stirring at room temperature for 45 minutes, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product of Compound 124 (154.6 g).

[1108] LC / MS (ESI): m / z=445[M+H]+, RT=2.58 min, LC / MS method 1

[1109] Step 3 Synthesis of compound 125

[1110] The crude product of compound 124 (154.6 g) was dissolved in tetrahydrofuran (1065 mL), methanol (266 mL) and acetic acid (42.6 mL), and zinc (97 g, 1490 mmol) was added under ice-cooling. After stirring for 1 hour, the reaction solution was filtered using diatomaceous earth (registered trademark) to remove insoluble matter. 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 filtered to obtain compound 125 (87 g, yield 100%).

[1111] LC / MS (ESI): m / z=289[M+H]+, RT=2.58 min, LC / MS method 1

[1112] Step 4 Synthesis of Compound 126

[1113] Compound 125 (220 mg, 0.76 mmol) was dissolved in dimethylformamide (3.3 mL), and cesium carbonate (745 mg, 2.29 mmol) and 2-iodoethyl ether (497 mg, 1.52 mmol) were added under ice-cooling. After stirring at room temperature for 3 hours, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 126 (245 mg, 90% yield).

[1114] LC / MS (ESI): m / z=359[M+H]+, RT=2.05 min, LC / MS method 1

[1115] Step 5 Synthesis of Compound 127

[1116] To compound 126 (130 mg, 0.36 mmol) were added trifluoroacetic acid (0.52 mL) and trifluoromethanesulfonic acid (0.33 mL), and the mixture was stirred at 50°C for 1 hour. The reaction mixture was poured into an aqueous sodium carbonate solution, neutralized, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue to solidify, and the solid was filtered to obtain compound 127 (56 mg, 65% yield).

[1117] LC / MS (ESI): m / z=239[M+H]+, RT=1.22 min, LC / MS method 1

[1118] Step 6 Synthesis of compound 129

[1119] To compound 127 (640 mg, 2.68 mmol) was added 0.91 mol / L borane tetrahydrofuran complex-tetrahydrofuran solution (20 mL, 18.2 mmol) and stirred at 70 ° C for 30 minutes. It was ice-cooled, methanol (10 mL) was added and stirred at 80 ° C for 30 minutes. After cooling, the reaction solution was concentrated under reduced pressure and the obtained residue was dissolved in dichloromethane (10 mL). Triethylamine (1.36 g, 13.4 mmol), Boc2O (2.92 g, 13.4 mmol) and dimethylaminopyridine (327 mg, 2.68 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 129 (550 mg, 63% yield).

[1120] LC / MS (ESI): m / z=325[M+H]+, RT=2.27 min, LC / MS method 1

[1121] Step 8 Synthesis of Compound 130

[1122] Compound 129 (200 mg, 0.616 mmol) was dissolved in 1,4-dioxane (3 mL), and Me4tBuXphos (30 mg, 0.062 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), and a 6 mol / L aqueous potassium hydroxide solution (0.36 mL, 2.16 mmol) were added, followed by stirring at 100°C for 1 hour. After cooling, the mixture was neutralized with a 2 mol / L aqueous hydrochloric acid solution. The mixture was extracted with dichloromethane, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate-diisopropyl ether was added to the obtained residue. The precipitated solid was filtered to obtain compound 130 (171 mg, 91% yield).

[1123] LC / MS (ESI): m / z=307[M+H]+, RT=1.42 min, LC / MS method 1

[1124] Step 9 Synthesis of compound 133

[1125] Compound 130 (171 mg, 0.558 mmol) was dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (293 mg, 1.12 mmol), compound 131 (213 mg, 1.12 mmol), and DIAD (226 mg, 1.12 mmol) were added, followed by stirring at room temperature. After 30 minutes, triphenylphosphine (293 mg, 1.12 mmol), compound 131 (213 mg, 1.12 mmol), and DIAD (226 mg, 1.12 mmol) were added. After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure.

[1126] To the obtained residue was added trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated and dichloromethane was added to the residue to dissolve it. A sodium bicarbonate aqueous solution was added to neutralize it 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 obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 133 (212 mg, 100% yield).

[1127] LC / MS (ESI): m / z=380[M+H]+, RT=0.80 min, LC / MS method 1

[1128] Step 10 Synthesis of Compound 134

[1129] Compound 133 (70 mg, 0.184 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 121 (101 mg, 0.221 mmol), potassium carbonate (76 mg, 0.552 mmol), and Xantphos Pd G3 (26 mg, 0.028 mmol) were added. The mixture was stirred at 80°C for 90 minutes under a nitrogen atmosphere. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 134 (66 mg, 45% yield).

[1130] LC / MS (ESI): m / z=799[M+H]+, RT=2.49 min, LC / MS method 8

[1131] Step 11 Synthesis of Compound (I-594)

[1132] Compound 134 (66 mg, 0.083 mmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated and then neutralized by adding an aqueous sodium bicarbonate solution dissolved in dichloromethane. An aqueous citric acid solution was added to the reaction solution, which was then acidified and 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%).

[1133] 1 H-NMR(DMSO-d6)δ: 1.12-1.24(m, 2H), 1.35-1.43(m, 2H), 1.53-1.79(m, 12H), 1.90-2.14(m, 11H), 2.20-2.26(m, 1H), 2.56(s, 2H), 3.50- 3.58(m, 6H), 3.87-3.90(m, 2H), 4.21(s, 2H), 4.88-4.95(m, 1H), 6.85(s, 1H), 8.37(brs, 1H), 8.54(s, 1H), 8.91(s, 1H), 12.33(brs, 1H).

[1134] (Reference example)

[1135] Synthesis of Compound 117 and Compound 131

[1136] [Chemistry 62]

[1137]

[1138] Step 1 Synthesis of Compound 136 and Compound 137

[1139] 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. The organic layer was washed with water and dried over anhydrous sodium sulfate. The obtained 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%).

[1140] Compound 136

[1141] 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).

[1142] LC / MS (ESI): m / z=282[M+H]+, RT=1.24 min, LC / MS method 1

[1143] Compound 137

[1144] 1 H-NMR (CDCl3) δ: 1.08-1.18 (m, 2H), 1.26-1.39 (m, 2H), 1.77-1.81 (m, 2H), 2.05-2.15 (m, 3H), 3.33-3.40 (m, 1H), 3.54 (t, J=11.6Hz, 4H), 4.54 (s, 2H), 7.25-7.30 (m, 1H), 7.31-7.34 (m, 4H).

[1145] LC / MS (ESI): m / z=282[M+H]+, RT=1.20 min, LC / MS method 1

[1146] Step 2 Synthesis of compound 131

[1147] Compound 136 (0.72 g, 2.55 mmol) was dissolved in ethanol (10.7 mL), and 10 wt% palladium on carbon (1.09 g, 0.51 mmol) was added. The system was replaced with hydrogen, and the mixture was stirred at 50°C for 3 hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain Compound 131 (0.42 g, 86% yield).

[1148] Compound 131

[1149] 1 H-NMR (CDCl3) δ: 1.30 (brs, 1H), 1.44-1.61 (m, 6H), 1.69-1.79 (m, 2H), 2.20 (m, 1H), 3.53 (t, J=12.0Hz, 4H), 3.81 (m, 1H).

[1150] Step 3 Synthesis of compound 117

[1151] Compound 131 (300 mg, 1.57 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (0.44 mL, 3.14 mmol) and methanesulfonyl chloride (0.18 mL, 2.35 mmol) were added under ice-cooling. After 1 hour and 30 minutes, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain compound 117 (419 mg, 99% yield).

[1152] 1 H-NMR (CDCl3) δ: 1.53-1.59 (m, 4H), 1.62-1.72 (m, 2H), 2.03-2.13 (m, 2H), 2.23 (m, 1H), 3.00 (s, 3H), 3.54 (t, J=12.0Hz, 4H), 4.86 (m, 1H).

[1153] Example 15

[1154] Synthesis of compound (I-570)

[1155] [Chemistry 63]

[1156]

[1157] Step 1 Synthesis of Compound 138

[1158] The synthesis was carried out in the same manner as in Step 1 of Example 6.

[1159] 1 H-NMR(DMSO-d6)δ:ppm 1.33 (t, J=7.15Hz, 3H), 1.67 (s, 9H), 2.17 (t, J=19.32Hz, 3H), 4.38 (q, J=7.15Hz, 2H), 5.21 (s, 2H), 7.16 (dd, J=8.9, 2.3Hz, 1H), 7.32-7.38 (m, 1H), 7.39-7.44 (m, 2H), 7.48-7.52 (m, 2H), 7.82 (d, J=2.1Hz, 1H), 8.43 (s, 1H), 8.45 (d, J=8.9Hz, 1H), 9.19 (s, 1H).

[1160] LC / MS (DUIS): m / z=538[M+H]+, RT=2.08 min, LC / MS method 9

[1161] Step 2 Synthesis of compound 139

[1162] To a solution of compound 138 (7.48 g, 13.9 mmol) in tetrahydrofuran (59.8 mL), methanol (29.9 mL), and water (15.0 mL) was added lithium hydroxide monohydrate (2.92 g, 69.6 mmol) at room temperature, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with water, 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, 84% yield).

[1163] 1 H-NMR(DMSO-d6)δ:ppm 2.14 (t, J=19.1Hz, 3H), 5.16 (s, 2H), 6.96 (dd, J=8.8, 2.3Hz, 1H), 7.07 (d, J=2.3Hz, 1H), 7.29-7.37 (m, 1H), 7.38-7.45 (m, 2H), 7.47-7.52 (m, 2H), 8.23 ​​(d, J=2.9Hz, 1H), 8.34 (d, J=8.7Hz, 1H), 9.00 (s, 1H), 11.76 (d, J=2.4Hz, 1H), 13.45 (br s, 1H).

[1164] LC / MS (DUIS): m / z=410[M+H]+, RT=1.32 min, LC / MS method 9

[1165] Step 3 Synthesis of compound 140

[1166] To a solution of compound 139 (4.8 g, 11.72 mmol) in dichloromethane (48.0 mL) and dimethylformamide (2.0 mL) was added triethylamine (2.45 mL, 17.58 mmol), Boc2O (3.23 mL, 14.06 mmol), and DMAP (72 mg, 0.59 mmol) at room temperature under an argon stream while stirring. 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. Subsequently, a hexane-ethyl acetate mixed solution was added, ultrasonicated, and filtered. The mixture was further washed with a hexane-ethyl acetate mixed solution and dried to obtain compound 140 (2.46 g, 41% yield).

[1167] 1H-NMR(DMSO-d6)δ:ppm 1.67 (s, 9H), 2.16 (t, J=19.3Hz, 3H), 5.21 (s, 2H), 7.16 (dd, J=8.8, 2.4Hz, 1H), 7.32-7.37 (m, 1H), 7.39-7.44 (m, 2H), 7.48-7.52 (m, 2H), 7.83 (d, J=2.3Hz, 1H), 8.42 (s, 1H), 8.46 (d, J=8.8Hz, 1H), 9.17 (s, 1H), 13.81 (br s, 1H).

[1168] LC / MS (DUIS): m / z=510[M+H]+, RT=1.79 min, LC / MS method 9

[1169] Step 4 Synthesis of Compound 141

[1170] The synthesis was carried out under the same conditions as in step 3 of Example 4.

[1171] 1 H-NMR(DMSO-d6)δ:ppm 1.45(s, 9H), 1.54-1.60(m, 2H), 1.67(s, 9H), 1.68-1.73(m, 4H), 1.77-1.86(m , 2H), 2.10 (t, J=19.2Hz, 3H), 2.00-2.18 (m, 4H), 2.52-2.57 (m, 2H), 5.21 (s, 2 H), 7.16 (dd, J=8.9, 2.3Hz, 1H), 7.32-7.37 (m, 1H), 7.39-7.44 (m, 2H), 7.48-7 .52 (m, 2H), 7.82 (d, J = 2.4Hz, 1H) 8.40 (s, 1H), 8.48 (d, J = 8.8Hz, 1H), 8.56 (br s, 1H), 8.79 (s, 1H).

[1172] LC / MS (DUIS): m / z=743[M+H]+, RT=2.37 min, LC / MS method 9

[1173] Step 5 Synthesis of Compound 142

[1174] The synthesis was carried out under the same conditions as in step 2 of Example 6.

[1175] 1H-NMR(DMSO-d6)δ:ppm 1.45 (s, 9H), 1.57 (m, 2H), 1.62-1.73 (m, 4H), 1.67 (s, 9H), 1.78-1.84 (m, 2H), 2.10 (t, J=19.1Hz, 3H), 2.00-2.18 (m, 4 H), 2.51-2.55 (m, 2H), 6.89 (dd, J=8.7, 2.3Hz, 1H), 7.63 (d, J=2.1Hz, 1H), 8.32 (s, 1H), 8.36 (d, J=8.7Hz, 1H), 8.55 (br s, 1H), 8.77 (s, 1H), 9.68 (s, 1H).

[1176] LC / MS (DUIS): m / z=653[M+H]+, RT=1.92 min, LC / MS method 9

[1177] Step 6 Synthesis of compound 143

[1178] The synthesis was carried out in the same manner as in step 5 of Example 3.

[1179] 1 H-NMR(DMSO-d6)δ:ppm 1.12-1.25(m, 2H), 1.39-1.51(m, 2H), 1.45(s, 9H), 1.54-1.62(m, 2H), 1.68 (s, 9H), 1.69-1.73 (m, 4H), 1.75-1.85 (m, 4H), 2.10 (t, J=19.1Hz, 3H), 2.01 -2.18(m, 6H), 2.21-2.30(m, 1H), 2.52-2.55(m, 2H), 3.55(t, J=12.3Hz, 4H), 4.32-4.42(m, 1H), 7.06 (dd, J=8.8, 2.3Hz, 1H), 7.69 (d, J=2.1Hz, 1H), 8.40 (s, 1H), 8.45 (d, J=8.8Hz, 1H), 8.55 (br s, 1H), 8.78 (s, 1H).

[1180] LC / MS (DUIS): m / z=826[M+H]+, RT=1.88 min, LC / MS method 9

[1181] Step 7 Synthesis of Compound 144

[1182] The synthesis was carried out under the same conditions as step 2.

[1183] 1H-NMR(DMSO-d6)δppm 1.12-1.24(m, 2H), 1.37-1.42(m, 2H), 1.45(s, 9H), 1.53-1.61(m, 2H), 1.65-1.74(m, 4H), 1.75 -1.85(m, 4H), 2.08(t, J=19.0Hz, 3H), 2.00-2.19(m, 6H), 2.20-2.28(m, 1H), 2.52-2.55(m, 2H), 3.55 (t, J=12.4Hz, 4H), 4.25-4.37 (m, 1H), 6.86 (dd, J=8.8, 2.3Hz, 1H), 7.00 (d, J=2.3Hz, 1H), 8.19 (d, J=2.8Hz, 1H), 8.32 (d, J=8.8Hz, 1H), 8.46 (s, 1H), 8.64 (s, 1H), 11.62 (d, J=2.6Hz, 1H).

[1184] LC / MS (DUIS): m / z=726[M+H]+, RT=1.47 min, LC / MS method 9

[1185] Step 8 Synthesis of Compound 146

[1186] To a solution of compound 144 (50 mg, 0.07 mmol) in N-methylpyrrolidone (1.0 mL) were added cesium carbonate (67 mg, 0.21 mmol) and compound 145 (50 mg, 0.21 mmol) at room temperature with stirring under an argon stream, and the mixture was stirred at 100°C for 2 hours. Subsequently, 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. Furthermore, 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 mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The residue was then purified by amino column chromatography (hexane-ethyl acetate) to obtain Compound 146 (42 mg, 77%).

[1187] 1H-NMR(DMSO-d6)δ:ppm 0.72(t, J=7.3Hz, 6H), 1.19-1.28(m, 2H), 1.35-1.43(m, 2H), 1.45(s, 9H), 1.53-1.62(m, 2H), 1.65-1.72 (m, 4H), 1.74-1.83 (m, 4H), 1.91 (qd, J=7.2Hz, 4H), 2.09 (t, J=19.0Hz, 3H), 2.01-2. 18(m, 6H), 2.20-2.30(m, 1H), 2.52-2.56(m, 2H), 3.55(t, J=12.4Hz, 4H), 4.32-4.47(m, 2H), 6 .89 (dd, J=8.9, 2.1Hz, 1H), 7.21 (d, J=1.9Hz, 1H), 8.24 (s, 1H), 8.35 (d, J=8.8Hz, 1H), 8.45 (br s, 1H), 8.63 (s, 1H).

[1188] LC / MS (ESI): m / z=796[M+H]+, RT=1.82 min, LC / MS method 10

[1189] Step 9 Synthesis of Compound (I-570)

[1190] The product was synthesized under the same conditions as in Step 8 of Example 10.

[1191] 1 H-NMR(DMSO-d6)δ:ppm 0.71 (t, J=7.3Hz, 6H), 1.18-1.29 (m, 2H), 1.34-1.47 (m, 2H), 1.48-1.59 (m, 2H), 1.59-1. 73(m, 4H), 1.75-1.83(m, 4H), 1.86-1.94(m, 4H), 2.08(t, J=19.0Hz, 3H), 2.00-2.18(m, 6H ), 2.19-2.28(m, 1H), 2.55-2.61(m, 2H), 3.55(t, J=12.4Hz, 4H), 4.34-4.47(m, 2H), 6.88( dd, J=8.9, 2.1Hz, 1H), 7.20 (d, J=1.9Hz, 1H), 8.21 (s, 1H), 8.35 (d, J=8.8Hz, 1H), 8.46 (br s, 1H), 8.64 (s, 1H), 12.45 (br s, 1H).

[1192] LC / MS (DUIS): m / z=740[M+H]+, RT=1.36 min, LC / MS method 9

[1193] The following compounds were synthesized based on the above general synthesis method and the method described in the Examples.

[1194] In the structural formula, "wedges" and "dashed lines" represent steric configurations. In particular, in compounds where steric configurations are described, the term "steric structure" has the following definition.

[1195] Blank: As recorded

[1196] a: racemate

[1197] b: Single compound, with unknown stereochemistry

[1198] c: diastereomeric mixture

[1199] However, I-273, I-371, I-376, I-403, I-414, I-451, I-11, I-12, and I-13 include racemates thereof.

[1200] d:Z C (R 7 ) is as described, R 4 The stereochemistry of the substituents is unclear

[1201] e:Z C (R 7 ) is not known, R 4 The stereochemistry of the substituents is as described

[1202] f: racemate, the relative configuration of cis / trans is single but unknown

[1203] [Table 1]

[1204]

[1205] [Table 2]

[1206]

[1207] [Table 3]

[1208]

[1209] [Table 4]

[1210]

[1211] [Table 5]

[1212]

[1213] [Table 6]

[1214]

[1215] [Table 7]

[1216]

[1217] [Table 8]

[1218]

[1219] [Table 9]

[1220]

[1221] [Table 10]

[1222]

[1223] [Table 1 1]

[1224]

[1225] [Table 12]

[1226]

[1227] [Table 13]

[1228]

[1229] [Table 14]

[1230]

[1231] [Table 15]

[1232]

[1233] [Table 16]

[1234]

[1235] [Table 17]

[1236]

[1237] [Table 18]

[1238]

[1239] [Table 19]

[1240]

[1241] [Table 20]

[1242]

[1243] [Table 21]

[1244]

[1245] [Table 22]

[1246]

[1247] [Table 23]

[1248]

[1249] [Table 24]

[1250]

[1251] [Table 25]

[1252]

[1253] [Table 26]

[1254]

[1255] [Table 27]

[1256]

[1257] [Table 28]

[1258]

[1259] [Table 29]

[1260]

[1261] [Table 30]

[1262]

[1263] [Table 3 1]

[1264]

[1265] [Table 32]

[1266]

[1267] [Table 33]

[1268]

[1269] [Table 34]

[1270]

[1271] [Table 35]

[1272]

[1273] [Table 36]

[1274]

[1275] [Table 37]

[1276]

[1277] [Table 38]

[1278]

[1279] [Table 39]

[1280]

[1281] [Table 40]

[1282]

[1283] [Table 41]

[1284]

[1285] [Table 42]

[1286]

[1287] [Table 43]

[1288]

[1289] [Table 44]

[1290]

[1291] [Table 45]

[1292]

[1293] [Table 46]

[1294]

[1295] [Table 47]

[1296]

[1297] [Table 48]

[1298]

[1299] [Table 49]

[1300]

[1301] [Table 50]

[1302]

[1303] [Table 51]

[1304]

[1305] [Table 52]

[1306]

[1307] [Table 53]

[1308]

[1309] [Table 54]

[1310]

[1311] [Table 55]

[1312]

[1313] [Table 56]

[1314]

[1315] [Table 57]

[1316]

[1317] [Table 58]

[1318]

[1319] [Table 59]

[1320]

[1321] [Table 60]

[1322]

[1323] [Table 61]

[1324]

[1325] [Table 62]

[1326]

[1327] [Table 63]

[1328]

[1329] [Table 64]

[1330]

[1331] [Table 65]

[1332]

[1333] [Table 66]

[1334]

[1335] [Table 67]

[1336]

[1337] [Table 68]

[1338]

[1339] [Table 69]

[1340]

[1341] [Table 70]

[1342]

[1343] [Table 71]

[1344]

[1345] [Table 72]

[1346]

[1347] [Table 73]

[1348]

[1349] [Table 74]

[1350]

[1351] [Table 75]

[1352]

[1353] [Table 76]

[1354]

[1355] [Table 77]

[1356]

[1357] [Table 78]

[1358]

[1359] [Table 79]

[1360]

[1361] [Table 80]

[1362]

[1363] [Table 81]

[1364]

[1365] [Table 82]

[1366]

[1367] [Table 83]

[1368]

[1369] [Table 84]

[1370]

[1371] [Table 85]

[1372]

[1373] [Table 86]

[1374]

[1375] [Table 87]

[1376]

[1377] [Table 88]

[1378]

[1379] [Table 89]

[1380]

[1381] [Table 90]

[1382]

[1383] [Table 91]

[1384]

[1385] [Table 92]

[1386]

[1387] [Table 93]

[1388]

[1389] [Table 94]

[1390]

[1391] [Table 95]

[1392]

[1393] [Table 96]

[1394]

[1395] [Table 97]

[1396]

[1397] [Table 98]

[1398]

[1399] [Table 99]

[1400]

[1401] [Table 100]

[1402]

[1403] [Table 101]

[1404]

[1405] [Table 102]

[1406]

[1407] [Table 103]

[1408]

[1409] [Table 104]

[1410]

[1411] [Table 105]

[1412]

[1413] [Table 106]

[1414]

[1415] [Table 107]

[1416]

[1417] The following are biological test examples of the compounds of the present invention.

[1418] The compound represented by formula (I) of the present invention may be any compound as long as it has an inhibitory effect on the cytopathic effect caused by RS virus and inhibits the cytopathic effect on human cells.

[1419] Specifically, in the evaluation method described below, EC50 is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.

[1420] Test Example 1: Test to confirm the inhibitory effect of CPE (Cytopathic Effect) in vitro

[1421] The test sample was diluted in DMSO to an appropriate concentration in advance, and a three-fold serial dilution series (0.32 μL / well) was prepared in a 384-well plate. HEp-2 cells (CCL-23; TCC) were cultured in 2% FBS E-MEM (Eagle's Minimum Essential Medium; Invitrogen) supplemented with kanamycin and FBS to an appropriate number (2.4×10 5 cells / mL) and added to a 384-well plate pre-filled with test samples at 12.5 μL / well. The RSV A2 strain was diluted with culture medium to an appropriate concentration and dispensed into a 384-well plate containing test samples at 12.5 μL / well per well. Culture medium was then added, and the experiment was finally started at 50 μL / well. For the control group, wells were made in which only culture medium was added without virus. After static culture in a 37°C, 5% CO2 incubator for 4 days, the plate was taken out and placed at room temperature for 30 minutes before adding CellTiter-Glo (registered trademark) 2.0 assay (Promega) at 15 μL / well, mixing was performed for 30 seconds, and the plate was left for about 1 hour. Afterwards, luminescence was quantified using EnVision (PerkinElmer). The inhibitory effect of the test drug on RSV-induced CPE was calculated from the level of viable cells remaining according to CellTiter-Glo (registered trademark) 2.0, with the inhibition rate at each test concentration being 0% and 100%. The EC value of each compound was calculated. 50The value was calculated by nonlinear regression as the concentration that inhibited RSV-induced cytopathic effect by 50%. In addition, when evaluating RSV type B, RSV B (Wash / 18537 strain) was infected in the same manner as type A, cultured for 5 days, and quantified in the same manner as A2 strain.

[1422] (result)

[1423] The compounds of the invention were tested essentially as described above.

[1424] The following shows the inhibitory effects of the compounds of the present invention on RSV type A. EC50 values ​​less than 10 nM were designated as "A," 10 nM to less than 100 nM were designated as "B," and 100 nM to 5000 nM were designated as "C."

[1425] Compound No. I-23: 0.96nM Compound No. I-33: 7.5nM Compound No. I-82: 0.27nM Compound No. I-148: 1.5nM Compound No. I-159: 0.88nM Compound No. I-162: 0.88nM Compound No. I-165: 0.37nM Compound No. I-182: 0.39nM Compound No. I-228: 1.3nM Compound No. I-268: 1.4nM Compound No. I-269: 1.3nM Compound No. I-270: 37nM Compound No. I-486: 3nM Compound No. I-570: 0.70nM Compound No. I-591: 0.61nM Compound No. I-594: 0.38nM

[1426] [Table 108]

[1427]

[1428] [Table 109]

[1429]

[1430] [Table 110]

[1431]

[1432] The compounds of the invention were tested essentially as described above.

[1433] The following shows the inhibitory effects of the compounds of the present invention on RSV type B. EC50 values ​​less than 10 nM were designated as "A," 10 nM to less than 100 nM were designated as "B," and 100 nM to 5000 nM were designated as "C."

[1434] Compound No. I-23: 16 nM

[1435] Compound No. I-33: 110 nM

[1436] Compound No. I-82: 0.34 nM

[1437] Compound No. I-148: 2.8 nM

[1438] Compound No. I-159: 3nM

[1439] Compound No. I-162: 3.3 nM

[1440] Compound No. I-165: 0.62 nM

[1441] Compound No. I-182: 2.1 nM

[1442] Compound No. I-228: 36 nM

[1443] Compound No. I-268: 4.3 nM

[1444] Compound No. I-486: 28 nM

[1445] Compound No. I-570: 2.1 nM

[1446] Compound No. I-591: 2.2 nM

[1447] Compound No. I-594: 4.2 nM

[1448] [Table 111]

[1449]

[1450] Test Example 2 In vivo efficacy test in mice

[1451] Although mice are semi-permissive for human RSV replication, they are a frequently used model in non-clinical screening of RSV therapeutics. Balb / c mice, which have a high proliferative capacity for RSV A2 strain, were used to confirm the efficacy of the drug in vivo. RSV A2 strain was inoculated into 6-week-old female BALB / c mice at a rate of 5×10 6 PFU / mouse were inoculated intranasally. The test sample was administered at a fixed dose twice daily (8 / 16 hour intervals) starting after infection. Lungs were removed on the 4th or 5th day. Lungs were homogenized in PBS, flash-frozen, and stored at -80°C. Supernatants from lung homogenates were used for titer determination using the immuno-TCID50 assay to measure viral titer.

[1452] Test Example 3: CYP inhibition test

[1453] Commercially available pooled human liver microsomes were used to evaluate the extent to which the compounds of the present invention inhibited the production of each metabolite by using the O-deethylation of 7-ethoxyresorufin (CYP1A2), the methyl-hydroxylation of tolbutamide (CYP2C9), the 4'-hydroxylation of mephenytoin (CYP2C19), the O-demethylation of dextromethorphan (CYP2D6), and the hydroxylation of terfenadine (CYP3A4), which are typical substrate metabolism reactions of the major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, and 3A4).

[1454] The reaction conditions are as follows: substrate: 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-methylphenidate (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time: 15 minutes; reaction temperature: 37°C; enzyme: mixed human liver microsomes 0.2 mg protein / mL; concentrations of the compound of the present invention: 1, 5, 10, and 20 μmol / L (4 types).

[1455] In a 96-well plate, five substrates, human liver microsomes, and the compound of the present invention were added to 50 mmol / L Hepes buffer in the aforementioned composition. NADPH, a coenzyme, was added to initiate the metabolic reaction as an indicator. The reaction was allowed to proceed at 37°C for 15 minutes, followed by the addition of a 1 / 1 (v / v) methanol / acetonitrile solution to terminate the reaction. After centrifugation at 3000 rpm for 15 minutes, resorufin (a CYP1A2 metabolite) in the supernatant was quantified using a fluorescent multilabel counter or LC / MS / MS. Tolbutamide hydroxide (a CYP2C9 metabolite), methylphenidate 4' hydroxide (a CYP2C19 metabolite), dextrorphan (a CYP2D6 metabolite), and terfenadine ethanol (a CYP3A4 metabolite) were also quantified using LC / MS / MS. The dilution concentration and dilution solvent can be varied as needed.

[1456] A control group (100%) was prepared by adding only DMSO as a solvent for dissolving the compound to the reaction solution instead of the compound of the present invention. The residual activity (%) was calculated. The IC was calculated by reverse estimation based on the logistic model using the concentration and inhibition rate. 50 .

[1457] Test Example 4: CYP3A4 (MDZ) MBI Test

[1458] The CYP3A4 inhibition of the compounds of this invention is assessed by measuring the mechanism-based inhibition (MBI) potential of the compounds of this invention based on the enhanced inhibitory effect on metabolic reactions. CYP3A4 inhibition is assessed using pooled human liver microsomes and the 1-hydroxylation reaction of midazolam (MDZ) as an indicator.

[1459] The reaction conditions are as follows: substrate: 10 μmol / L MDZ; pre-reaction time: 0 or 30 minutes; substrate metabolism reaction time: 2 minutes; reaction temperature: 37°C; mixed human liver microsomes: 0.5 mg / mL in the pre-reaction, 0.05 mg / mL (when diluted 10-fold) in the reaction; the concentration of the compound of the present invention in the pre-reaction was 1, 5, 10, 20 μmol / L or 0.83, 5, 10, 20 μmol / L (4 types).

[1460] In a 96-well plate, a mixture of human liver microsomes and a solution of the compound of the present invention was added to a pre-reaction solution in K-Pi buffer (pH 7.4) as the pre-reaction solution. A portion of this solution was transferred to a separate 96-well plate with K-Pi buffer containing a substrate and diluted 1 / 10. NADPH was added as a coenzyme to initiate a target reaction (pre-incubation for 0 minutes). After the pre-reaction was allowed to proceed for a predetermined period of time, a 1 / 1 (v / v) methanol / acetonitrile solution was added to terminate the reaction. Separately, NADPH was added to the remaining pre-reaction solution to initiate a pre-reaction (pre-incubation for 30 minutes). After the reaction was allowed to proceed for a predetermined period of time, a portion of this solution was transferred to a separate plate with K-Pi buffer containing a substrate and diluted 1 / 10 to initiate a target reaction. After the reaction was allowed to proceed for a predetermined period of time, a 1 / 1 (v / v) methanol / acetonitrile solution was added to terminate the reaction. The plates carrying out each target reaction were centrifuged at 3000 rpm for 15 minutes, and the 1-midazolam hydroxide in the supernatant was quantified by LC / MS / MS. Furthermore, the dilution concentration or dilution solvent may be changed as needed.

[1461] A control (100%) was prepared by adding only DMSO (the solvent for dissolving the compound) to the reaction solution, replacing the compound of the present invention. The residual activity (%) of the compound of the present invention at various concentrations was calculated. Using the concentration and inhibition rate, the IC was calculated by back-estimation using a logistic model. The shifted IC value was calculated as the ratio of the IC after 0 minutes of preincubation / the IC after 30 minutes of preincubation. A shifted IC value of 1.5 or higher was considered positive, while a shifted IC value of 1.0 or lower was considered negative.

[1462] Test Example 5: BA test

[1463] Discussion on oral absorption Experimental materials and methods

[1464] (1) Animals used: Mice or rats were used.

[1465] (2) Feeding conditions: Mice or rats were allowed to freely consume solid feed and sterilized tap water.

[1466] (3) Dosage and group setting: Oral and intravenous administration at a prescribed dose. Groups were set as follows. (The dosage of each compound may vary.)

[1467] Oral administration: 2 to 60 μmol / kg or 1 to 30 mg / kg (n=2 to 3)

[1468] Intravenous administration: 1 to 30 μmol / kg or 0.5 to 10 mg / kg (n=2 to 3)

[1469] (4) Preparation of dosing solution: For oral administration, prepare a solution or suspension. For intravenous administration, prepare a soluble solution.

[1470] (5) Administration: Oral administration is forced administration into the stomach via an oral probe. Intravenous administration is administration via the tail vein via a syringe with an injection needle.

[1471] (6) Evaluation items: Blood was collected over time and the concentration of the compound of the present invention in plasma was determined using LC / MS / MS.

[1472] (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) was calculated by moment vector analysis for the concentration changes of the compound of the present invention in plasma. The bioavailability (BA) of the compound of the present invention was calculated from the dosage ratio and AUC ratio of the oral and intravenous administration groups.

[1473] Furthermore, the dilution concentration or dilution solvent may be changed as needed.

[1474] Test Example 6: Clearance Evaluation Test

[1475] Experimental materials and methods

[1476] (1) Animals used: SD rats were used.

[1477] (2) Feeding conditions: SD rats were allowed to freely consume solid feed and sterilized tap water.

[1478] (3) Dosage and group setting: The intravenous administration was performed at the prescribed dose. Groups were set as follows.

[1479] Intravenous administration of 1 μmol / kg (n=2)

[1480] (4) Preparation of drug solution: Use dimethyl sulfoxide / propylene glycol = 1 / 1 solvent to make a soluble drug solution.

[1481] (5) Administration method: Administer the drug through the tail vein via a syringe with an injection needle.

[1482] (6) Evaluation items: Blood was collected over time and the concentration of the compound of the present invention in plasma was determined using LC / MS / MS.

[1483] (7) Statistical Analysis: The total body clearance (CLtot) was calculated by moment vector analysis based on the concentration changes of the compound of the present invention in plasma. In addition, the dilution concentration or dilution solvent can be changed as needed.

[1484] Test Example 7: Metabolic stability test

[1485] Mixed human liver microsomes or mixed rat liver microsomes are reacted with the compound of the present invention for a certain period of time. The residual rate is calculated by comparing the reaction sample and the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver.

[1486] 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 of human or rat liver microsomes, the reaction was carried out at 37°C for 0 minutes or 30 minutes in the presence of 1 mmol / L NADPH (oxidation reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1 / 1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the amount of the compound of the present invention at 0 minutes of reaction was taken as 100%, and the ratio to the amount of the compound after the reaction was expressed as the residual rate. In addition, the hydrolysis reaction was carried out in the absence of NADPH, and the glucuronic acid conjugation reaction was carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation was performed thereafter. The dilution concentration or dilution solvent can be changed as needed.

[1487] Test Example 8: Metabolic Stability Test (Hepatocytes)

[1488] Human, rat, dog, or monkey hepatocytes were reacted with the compounds of the present invention for a specific period of time. The residual rate of the reacted and unreacted samples was compared to evaluate the extent of hepatic metabolism of the compounds of the present invention. To assess the effect of serum protein-bound metabolism, serum corresponding to a maximum of 10% of the respective hepatocyte type was also added to the culture medium.

[1489] Human, rat, dog or monkey hepatocytes were cultured in William's E Medium at a rate of 1×10 6 Cells / mL were suspended and reacted with the compound of the present invention at 37°C for 0, 1 or 2 hours. When serum was added, the hepatocytes were suspended after adding a maximum of 10% serum to William's medium E in advance. After the reaction, 30 μL of the reaction solution was mixed with 120 μL of a methanol / acetonitrile = 1 / 1 (v / v) solution and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the amount of the compound of the present invention at 0 minutes of reaction was taken as 100%, and the ratio to the amount of the compound after the reaction was expressed as the residual rate. The dilution concentration or dilution solvent can be changed as needed.

[1490] Industrial applicability

[1491] The compounds of the present invention have an inhibitory effect on RSV and are useful for the treatment and / or prevention of RSV infection and related diseases caused by the infection.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, Where, Dashed lines indicate the presence or absence of a bond; R 1 is a carboxyl group; L is adamantane-2,2-diyl group substituted with one or more substituents selected from Substituent Group a, an unsubstituted adamantane-2,2-diyl group, a cyclohexane-1,1-diyl group substituted with a halogen, or an unsubstituted cyclohexane-1,1-diyl group; Substituent group a is cyano, alkyloxy, hydroxyl and halogen; R 2 is an alkyl group substituted by halogen or an unsubstituted alkyl group; R 3 is a hydrogen atom; V is -N=; W is =CH- or =N-; Mode: [Chemistry 2] The group represented is a group represented by the following (Ia), (Ib) or (Ii): Where, R X is a hydrogen atom; R Y is a hydrogen atom; R U is a hydrogen atom; R 5 and R 6 are each independently a hydrogen atom; R 7 is a hydrogen atom, a substituted alkyl group, an unsubstituted alkyl group, an unsubstituted non-aromatic carbocyclic group, a substituted non-aromatic carbocyclic group, or an unsubstituted non-aromatic heterocyclic group; the substituent of a substituted alkyl group is an alkyloxy group; the substituent of a substituted non-aromatic carbocyclic group is a halogen; R 8 is a hydrogen atom, an unsubstituted alkyl group, an unsubstituted non-aromatic carbocyclic group or an unsubstituted non-aromatic heterocyclic group; or R 7 and R 8 Together with the carbon atom to which it is bonded, it may form a non-aromatic carbocyclic ring substituted with a halogen or an unsubstituted non-aromatic carbocyclic ring, or a non-aromatic heterocyclic ring substituted with one or more substituents selected from Substituent Group G or an unsubstituted non-aromatic heterocyclic ring; Substituent group g is an alkyl group, a haloalkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group substituted by a phenyl group, an alkyloxycarbonyl group, a non-aromatic heterocyclic group, an alkylcarbamoyl group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, and an aromatic heterocyclic group substituted by a halogen; R 4 is an alkyloxy group substituted with one or more substituents selected from Substituent Group H or an unsubstituted alkyloxy group, a non-aromatic heterocyclicoxy group substituted with one or more substituents selected from Substituent Group J or an unsubstituted non-aromatic carbocyclicoxy group substituted with one or more substituents selected from Substituent Group K or an unsubstituted non-aromatic carbocyclicoxy group, Substituent group h is halogen, hydroxy, alkyloxy, cyano, alkylcarbonyloxy, substituted aromatic heterocyclic group, non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group, aromatic heterocyclic amino group, aromatic carbocyclic group, and aromatic carbocyclic group substituted by alkyloxy; the substituent of the substituted aromatic heterocyclic group is alkyl or alkyloxy; the substituent of the substituted non-aromatic heterocyclic group is aromatic heterocyclic group, alkyl or halogen; Substituent Group j is alkyl, halogen, haloalkyl, cyanoalkyl, alkylcarbonyl, alkylcarbamoyl, alkyloxycarbonyl, alkyloxyalkyl, alkylsulfonylalkyl, non-aromatic heterocyclic group, substituted aromatic heterocyclic group, aromatic heterocyclic group, non-aromatic carbocyclic group, non-aromatic carbocyclic group substituted by halogen, substituted non-aromatic heterocyclic group, non-aromatic heterocyclic alkyl, non-aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl substituted by halogen, aromatic heterocyclic alkyl substituted by alkyl, non-aromatic heterocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, aromatic carbocyclic alkyloxycarbonyl and non-aromatic carbocyclic sulfonyl; the substituent of the substituted aromatic heterocyclic group is alkyl, alkyloxy, halogen, haloalkyl or cyano; the substituent of the substituted non-aromatic heterocyclic group is halogen or alkylcarbonyl; Substituent group k is alkyl, halogen, haloalkyl, alkyloxy, alkylsulfonyl, haloalkylamino, alkylamino, aromatic heterocyclic group, non-aromatic heterocyclic group substituted by halogen, non-aromatic heterocyclic group, aromatic heterocyclic group substituted by halogen, aromatic heterocyclicamino substituted by halogen, non-aromatic heterocyclic alkyl substituted by halogen, non-aromatic carbocyclicoxy group, and non-aromatic carbocyclic iminooxy group substituted by halogen; "Alkyl" is a straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms; "Aromatic carbocyclic group" is phenyl, naphthyl, anthracenyl or phenanthrenyl; "Non-aromatic carbocyclic group" is a monocyclic group having 3 to 16 carbon atoms or a cyclic saturated hydrocarbon group having 8 to 20 carbon atoms or a cyclic non-aromatic unsaturated hydrocarbon group; "Aromatic heterocyclic group" means a 5- to 8-membered monocyclic or 8- to 10-membered bicyclic or 13- to 15-membered tricyclic or higher aromatic ring group having one or more heteroatoms, the same or different, arbitrarily selected from O, S, and N in the ring; The "non-aromatic heterocyclic group" is a 3- to 8-membered monocyclic or 8- to 20-membered bicyclic or more non-aromatic ring group having one or more heteroatoms, the same or different, arbitrarily selected from O, S, and N in the ring.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a non-aromatic heterocyclic oxy group substituted with one or more substituents selected from Substituent Group j, an unsubstituted non-aromatic heterocyclic oxy group, or a non-aromatic carbocyclic oxy group substituted with one or more substituents selected from Substituent Group k.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a non-aromatic heterocyclic oxy group substituted by an aromatic heterocyclic group, a non-aromatic heterocyclic oxy group substituted by a halogen-substituted aromatic heterocyclic group, a non-aromatic heterocyclic oxy group substituted by a haloalkyl group, a non-aromatic carbocyclic oxy group substituted by a halogen-substituted non-aromatic heterocyclic group, or a non-aromatic carbocyclic oxy group substituted by a haloalkylamino group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is an alkyl group substituted by an alkyloxy group, an unsubstituted alkyl group, or a non-aromatic carbocyclic group substituted by a halogen; R 8 is an unsubstituted alkyl group; or R 7 and R 8 Together with the carbon atom to which it is bonded, it may form a non-aromatic carbocyclic ring substituted with halogen or an unsubstituted non-aromatic heterocyclic ring.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is an adamantane-2,2-diyl group substituted with one or more substituents selected from Substituent Group a, or an unsubstituted adamantane-2,2-diyl group.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is an alkyl group substituted by halogen.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Mode: [Chemistry 3] The group represented by is a group represented by the following formula: [Chemistry 4] In the formula, each symbol has the same meaning as in claim 1.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Mode: [Chemistry 5] The group represented by is a group represented by the following formula: [Chemistry 6] In the formula, each symbol has the same meaning as in claim 1.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Mode: [Chemistry 7] The group represented by is a group represented by the following formula: [Chemistry 8] In the formula, each symbol has the same meaning as in claim 1.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Mode: [Chemistry 9] The group represented by is a group represented by the following formula: [Chemistry 10] Where R 4 is a non-aromatic heterocyclic oxy group substituted by an aromatic heterocyclic group, a non-aromatic heterocyclic oxy group substituted by a halogen-substituted aromatic heterocyclic group, a non-aromatic heterocyclic oxy group substituted by a haloalkyl group, a non-aromatic carbocyclic oxy group substituted by a halogen-substituted non-aromatic heterocyclic group, or a non-aromatic carbocyclic oxy group substituted by a haloalkylamino group; R 7 is an alkyl group substituted by an alkyloxy group, an unsubstituted alkyl group, or a non-aromatic carbocyclic group substituted by a halogen; L is an adamantane-2,2-diyl group substituted with one or more substituents selected from Substituent Group a, or an unsubstituted adamantane-2,2-diyl group; R 2 It is an alkyl group substituted by halogen.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Mode: [Chemistry 11] The group represented by is a group represented by the following formula: [Chemistry 12] Where R 4 is a non-aromatic heterocyclic oxy group substituted by an aromatic heterocyclic group, a non-aromatic heterocyclic oxy group substituted by a halogen-substituted aromatic heterocyclic group, a non-aromatic heterocyclic oxy group substituted by a haloalkyl group, a non-aromatic carbocyclic oxy group substituted by a halogen-substituted non-aromatic heterocyclic group, or a non-aromatic carbocyclic oxy group substituted by a haloalkylamino group; R 7 is an alkyl group substituted by an alkyloxy group, an unsubstituted alkyl group, or a non-aromatic carbocyclic group substituted by a halogen; R 8 is an unsubstituted alkyl group; or R 7 and R 8 Together with the carbon atom to which it is bonded, it may form a non-aromatic carbocyclic ring substituted with halogen or an unsubstituted non-aromatic heterocyclic ring; L is an adamantane-2,2-diyl group substituted with one or more substituents selected from Substituent Group a, or an unsubstituted adamantane-2,2-diyl group; R 2 It is an alkyl group substituted by halogen.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or preventive drug for RSV infection.

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