Polycyclic carbamoylpyridone derivatives

Abstract

To provide a novel compound that is for use in treating and / or preventing HIV infection, offers a high resistance barrier and exhibits a long-acting integrase inhibitory activity.SOLUTION: The present invention provides a compound represented by the formula (I), wherein ring A is a substituted or unsubstituted heterocycle; ring C is a benzene ring or the like; R1 is halogen or the like; R2a and R2b are each independently hydrogen or the like; R3 is substituted or unsubstituted alkyl or the like; R4 is hydrogen or the like; and n is an integer of 1 to 3.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel compound having an antiviral action, and more particularly to a polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity and a medicament containing the same, especially an anti-HIV drug.

Background Art

[0002] Among viruses, the human immunodeficiency virus (HIV), which is a type of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). As a therapeutic agent for AIDS, currently, a combination of an integrase inhibitor (such as dolutegravir) and two nucleoside reverse transcriptase inhibitors (ABC + 3TC, FTC + TAF, etc.) with different resistance profiles is recommended for naive patients in various guidelines. Since the drug efficacy is strong and the safety is high, the satisfaction is higher than that of the initial therapeutic agents. On the other hand, because a safe drug has been developed and the prognosis is good, it has become recommended to start treatment as soon as HIV infection is detected, and since the average remaining life of HIV-infected patients is approaching that of healthy people, the duration of medication has been extended. Due to long-term medication, if side effects of nucleoside reverse transcriptase inhibitors or resistant viruses once appear, there will be no simple treatment method thereafter, so there is a movement to keep nucleoside reverse transcriptase inhibitors unused. Therefore, the establishment of dual therapy with two main drugs is desired, and the development of main drugs that can be combined with integrase inhibitors is desired. In addition, in order to improve the QOL (Quality of Life) of patients, such as improving medication fatigue due to long-term medication and enjoying daily life more, the development of a therapeutic agent with a longer dosing interval, that is, a sustained injection agent that can complete treatment by injecting once at an interval of one month or more, is desired.

[0003] To meet such demands, the integrase inhibitor cabotegravir is being developed in Phase 3 as a long-acting injectable. In addition, the non-nucleoside reverse transcriptase inhibitor rilpivirine is also being developed as a long-acting injectable, and the establishment of a treatment method using these two drugs is being aimed at. However, these drugs are injections once a month or once every two months, and 3 to 4 painful injections are required. Therefore, in order to further improve the QOL of patients, the development of drugs with lower doses, less pain, and treatment completed with an injection once every three months is desired. As integrase inhibitors, raltegravir and elvitegravir have already been marketed as the first-generation oral agents, and dolutegravir has been marketed as the second-generation. When treatment-naive patients use dolutegravir, resistance mutations do not occur. However, when dolutegravir is used for the treatment of patients infected with resistant viruses to the first-generation integrase inhibitors, additional resistance mutations may be added and dolutegravir may become ineffective. Therefore, the development of inhibitors with a higher resistance barrier than dolutegravir is also desired.

[0004] In addition, as one of the anti-HIV drugs having an integrase inhibitory action, bicyclic or higher carbamoylpyridone derivatives are known (Patent Documents 1 to 29). Among these, Patent Document 3 describes carbamoylpyridotriazine derivatives. However, the optically active tricyclic or higher carbamoylpyridotriazine derivatives, which are the compounds of the present application, are not described.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 22

Patent Document 23

Patent Document 24

Patent Document 25

Patent Document 26

Patent Document 27

Patent Document 28

Patent Document 29

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a novel compound having a persistent integrase inhibitory activity with a high resistance barrier.

Means for Solving the Problems

[0007] As a result of intensive studies, the present inventors have found that a novel carbamoylpyridone derivative has an integrase inhibitory action with a high resistance barrier. Furthermore, the present inventors have found that the compounds of the present invention and pharmaceuticals containing them are useful as antiviral agents (e.g., antiretroviral agents, anti-HIV agents, anti-HTLV-1 (Human T cell leukemia virus type 1) agents, anti-FIV (Feline immunodeficiency virus) agents, anti-SIV (Simian immunodeficiency virus) agents), particularly anti-HIV agents, anti-AIDS agents, or therapeutic agents for related diseases, etc., and have completed the present invention as shown below.

[0008] The present invention provides the inventions shown below. [1] A compound represented by the following formula or a pharmaceutically acceptable salt thereof. Formula (I): [Chemical formula] (In the formula, Ring A is a substituted or unsubstituted non-aromatic heterocyclic ring; Ring C is a benzene ring, a pyridine ring or a 5-membered aromatic heterocyclic ring; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl or haloalkyl; R 2a and R 2b may together with adjacent carbon atoms form a non-aromatic carbocyclic ring or a non-aromatic heterocyclic ring; R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R 4 is hydrogen, or a substituted or unsubstituted alkyl. R 3 and R 4 or R 3 and the substituent on the A ring may together with adjacent atoms form a substituted or unsubstituted non-aromatic heterocyclic ring; n is an integer from 1 to 3) [2] The compound according to [1] wherein the A ring is the following ring or a pharmaceutically acceptable salt thereof.

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

[10] R 2a is hydrogen and R 2b is hydrogen or alkyl, or or R 2a and R 2b together with the adjacent carbon atoms form a C3-C4 carbocyclic ring, the compound according to any one of [1] to [3], or [5] to [9], or a pharmaceutically acceptable salt thereof.

[11] R 2a is hydrogen, R 2b is hydrogen or alkyl, the compound according to any one of [1] to [9], or a pharmaceutically acceptable salt thereof.

[12] The C ring is a benzene ring or a pyridine ring, the compound according to any one of [1] to [3], or [5] to

[11] , or a pharmaceutically acceptable salt thereof.

[13] The compound according to [1], or a pharmaceutically acceptable salt thereof, selected from the group consisting of compound I-2, I-6, I-11 and I-15.

[14] The compound according to [1], or a pharmaceutically acceptable salt thereof, selected from the group consisting of compound II-4, II-8, II-9, II-15, II-18, II-20, II-21, II-22, II-23, II-24, II-26, II-28, II-31, II-37, II-40, II-41, II-42, II-44, II-46, II-49, II-51, II-53, II-57, II-60, II-66, II-70, II-71, II-87, II-90, II-99, II-106, II-112, II-133, II-136, II-153 and II-156.

[15] A pharmaceutical composition containing the compound according to any one of [1] to

[14] , or a pharmaceutically acceptable salt thereof.

[16] The pharmaceutical composition according to

[15] , which is an anti-HIV agent.

[17] An HIV integrase inhibitor containing the compound according to any one of [1] to

[14] , or a pharmaceutically acceptable salt thereof.

[18] A method for treating and / or preventing HIV infection, characterized by administering the compound according to any one of [1] to

[14] , or a pharmaceutically acceptable salt thereof.

[19] A compound according to any one of [1] to

[14] , or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of HIV infection.

[0009] [1’]A compound represented by the following formula or a pharmaceutically acceptable salt thereof. Formula (I’):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0010] The present invention further provides a method for preventing or treating HIV, characterized by administering an effective amount of the above compound to a human. The present invention further provides the above compound for use as an anti-HIV drug.

Advantages of the Invention

[0011] The compounds of the present invention have integrase inhibitory activity and / or cell growth inhibitory activity against viruses, particularly HIV and its resistant viruses. Therefore, they are useful for the prevention or treatment of various diseases and viral infections (e.g., AIDS) involving integrase. More preferably, the compounds of the present invention are useful as persistent integrase inhibitors. Furthermore, they are excellent in terms of resistance profiles such as being less likely to generate new HIV-resistant viruses. Even more preferably, the compounds of the present invention have a preventive or therapeutic effect against HIV drug-resistant viruses. Even more preferably, the compounds of the present invention are useful as pharmaceuticals with low clearance, long in vivo half-life, excellent solubility, metabolic stability, or bioavailability, and with few concerns about cytotoxicity and side effects (e.g., mutagenicity, prolongation of electrocardiogram QT interval, arrhythmia).

Mode for Carrying Out the Invention

[0012] The meanings of the terms used in this specification are explained below. Each term is used with the same meaning whether used alone or in combination with other terms, unless otherwise specified. The term "consisting of" means having only the constituent elements. The term "comprising" means not being limited to the constituent elements and not excluding elements not described.

[0013] "Halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Particularly, a fluorine atom and a chlorine atom are preferred.

[0014] "Alkyl" includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl, etc. 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.

[0015] "Alkenyl" means a linear or branched hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, with one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, and the like. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl.

[0016] "Aromatic carbocyclic group" means a monocyclic or polycyclic cyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl, and the like. A preferred embodiment of "aromatic carbocyclic group" is phenyl.

[0017] "Non-aromatic carbocyclic group" means a monocyclic or polycyclic cyclic saturated hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group. Polycyclic "non-aromatic carbocyclic groups" also include those in which the rings in the above "aromatic carbocyclic groups" are condensed to monocyclic or polycyclic non-aromatic carbocyclic groups. Furthermore, "non-aromatic carbocyclic groups" also include groups that are cross-linked as follows, or groups that form spiro rings.

Chemical formula

[0018] The "aromatic heterocyclic group" means a monocyclic or polycyclic aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S and N in the ring. The polycyclic aromatic heterocyclic group also includes those in which the ring in the above-mentioned "aromatic carbocyclic group" is condensed with a monocyclic or polycyclic aromatic heterocyclic group, and the bond may be in any of the rings. As the monocyclic aromatic heterocyclic group, 5 to 8 members are preferred, more preferably 5 or 6 members. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. As the bicyclic aromatic heterocyclic group, 8 to 10 members are preferred, more preferably 9 or 10 members. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned. As the aromatic heterocyclic group having 3 or more rings, 13 to 15 members are preferred. For example, carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like can be mentioned.

[0019] The "non-aromatic heterocyclic group" means a monocyclic or polycyclic non-aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S and N in the ring. The polycyclic non-aromatic heterocyclic group is a group in which each ring in the above "aromatic carbocyclic group", "non-aromatic carbocyclic group", and / or "aromatic heterocyclic group" is condensed with a monocyclic or polycyclic non-aromatic heterocyclic group, and further includes a group in which the ring in the above "aromatic heterocyclic group" is condensed with a monocyclic or polycyclic non-aromatic carbocyclic group, and the bond may be in any of the rings. Furthermore, the "non-aromatic heterocyclic group" also includes a group having a crosslink as described below or a group forming a spiro ring.

Chemical formula

[0020] The "aromatic carbocyclic ring", "non-aromatic carbocyclic ring", "aromatic heterocyclic ring" and "non-aromatic heterocyclic ring" each mean a ring derived from the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", "aromatic heterocyclic group" and "non-aromatic heterocyclic group", respectively.

[0021] The "carbocyclic ring" means the above-mentioned "aromatic carbocyclic ring" or "non-aromatic carbocyclic ring".

[0022] The "heterocyclic ring" means the above-mentioned "aromatic heterocyclic ring" or "non-aromatic heterocyclic ring".

[0023] The "spiro ring" means the above-mentioned "non-aromatic carbocyclic ring" or "non-aromatic heterocyclic ring".

[0024] In this specification, "optionally substituted with a substituent group α" means "optionally substituted with one or more groups selected from the substituent group α". The same applies to "optionally substituted with a substituent group β", "optionally substituted with a substituent group γ", and "optionally substituted with a substituent group γ'".

[0025] Examples of the substituents for "substituted alkyl", "substituted alkyloxy", "substituted alkylcarbonyl", "substituted alkyloxycarbonyl", and "substituted C1-C4 bridge", "substituted C2-C4 bridge" include the following substituent group A. The carbon atom at any position may be bonded to one or more groups selected from the following substituent group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino Alkyloxy optionally substituted with a substituent group α, alkenyloxy optionally substituted with a substituent group α, alkylcarbonyloxy optionally substituted with a substituent group α, alkenylcarbonyloxy optionally substituted with a substituent group α, alkylcarbonyl optionally substituted with a substituent group α, alkenylcarbonyl optionally substituted with a substituent group α, alkyloxycarbonyl optionally substituted with a substituent group α, alkenyloxycarbonyl optionally substituted with a substituent group α, alkylsulfanyl optionally substituted with a substituent group α, alkenylsulfanyl optionally substituted with a substituent group α, alkylsulfinyl optionally substituted with a substituent group α, alkenylsulfinyl optionally substituted with a substituent group α, alkylsulfonyl optionally substituted with a substituent group α, alkenylsulfonyl optionally substituted with a substituent group α Amino optionally substituted with a substituent group β, imino optionally substituted with a substituent group β, carbamoyl optionally substituted with a substituent group β, sulfamoyl optionally substituted with a substituent group β, ureido optionally substituted with a substituent group β An aromatic carbocyclic group which may be substituted with a substituent group γ, a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ, a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic oxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxy which may be substituted with a substituent group γ', an aromatic heterocyclic oxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxy which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyloxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyloxy which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyloxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyloxy which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, an aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyloxy which may be substituted with a substituent group γ', an aromatic heterocyclic alkyloxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyloxy which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyloxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyloxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl,Optionally substituted non-aromatic carbocyclic sulfinyl with substituent group γ', optionally substituted aromatic heterocyclic sulfinyl with substituent group γ, optionally substituted non-aromatic heterocyclic sulfinyl with substituent group γ', optionally substituted aromatic carbocyclic sulfonyl with substituent group γ, optionally substituted non-aromatic carbocyclic sulfonyl with substituent group γ', optionally substituted aromatic heterocyclic sulfonyl with substituent group γ, and optionally substituted non-aromatic heterocyclic sulfonyl with substituent group γ'.

[0026] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, sulfanyl, cyano, nitro, and guanidino.

[0027] Substituent group β: optionally substituted alkyl with substituent group α, optionally substituted alkenyl with substituent group α, optionally substituted alkylcarbonyl with substituent group α, optionally substituted alkenylcarbonyl with substituent group α, optionally substituted alkylsulfanyl with substituent group α, optionally substituted alkenylsulfanyl with substituent group α, optionally substituted alkylsulfinyl with substituent group α, optionally substituted alkenylsulfinyl with substituent group α, optionally substituted alkylsulfonyl with substituent group α, optionally substituted alkenylsulfonyl with substituent group α An aromatic carbocyclic group which may be substituted with a substituent group γ, a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ, a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyl which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ, an aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ, and a non-aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ'.

[0028] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkylcarbonyl, haloalkylcarbonyl, and alkenylcarbonyl.

[0029] Substituent group γ': Substituent group γ and oxo.

[0030] Examples of the substituents on the rings of the "substituted carbocyclic ring", "substituted heterocyclic ring", "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocyclic oxy", "substituted aromatic heterocyclic oxy", "substituted aromatic carbocyclic carbonyl", "substituted aromatic heterocyclic carbonyl", "substituted aromatic carbocyclic oxycarbonyl" and "substituted aromatic heterocyclic oxycarbonyl" for the "aromatic carbocyclic ring" and "aromatic heterocyclic ring" include the following substituent group B. The atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, and guanidino, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkyloxycarbonyloxy optionally substituted with substituent group α, alkenyloxycarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, ureido optionally substituted with substituent group β, An aromatic carbocyclic group which may be substituted with a substituent group γ, a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ, a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic oxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxy which may be substituted with a substituent group γ', an aromatic heterocyclic oxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxy which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyloxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyloxy which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyloxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyloxy which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, an aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyl which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyloxy which may be substituted with a substituent group γ', an aromatic heterocyclic alkyloxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyloxy which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyloxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyloxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxyalkyl,Optionally substituted non-aromatic carbocyclic alkyloxyalkyl, optionally substituted aromatic heterocyclic alkyloxyalkyl, optionally substituted non-aromatic heterocyclic alkyloxyalkyl, optionally substituted aromatic carbocyclic sulfanyl, optionally substituted non-aromatic carbocyclic sulfanyl, optionally substituted aromatic heterocyclic sulfanyl, optionally substituted non-aromatic heterocyclic sulfanyl, optionally substituted aromatic carbocyclic sulfinyl, optionally substituted non-aromatic carbocyclic sulfinyl, optionally substituted aromatic heterocyclic sulfinyl, optionally substituted non-aromatic heterocyclic sulfinyl, optionally substituted aromatic carbocyclic sulfonyl, optionally substituted non-aromatic carbocyclic sulfonyl, optionally substituted aromatic heterocyclic sulfonyl, and optionally substituted non-aromatic heterocyclic sulfonyl.

[0031] Examples of the substituents on the rings of "substituted carbocycle", "substituted heterocycle", "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocyclic oxy", "substituted non-aromatic heterocyclic oxy", "substituted non-aromatic carbocyclic carbonyl", "substituted non-aromatic heterocyclic carbonyl", "substituted non-aromatic carbocyclic oxycarbonyl" and "substituted non-aromatic heterocyclic oxycarbonyl" include the following substituent group C. Atoms at any position on the ring may be bonded to one or more groups selected from the following substituent group C. Substituent group C: Substituent group B and oxo.

[0032] Examples of the substituents of "substituted amino", "substituted carbamoyl" and "substituted ureido" include the following substituent group D. It may be substituted with one or two groups selected from substituent group D. Substituent group D: alkyl which may be substituted with substituent group α, alkenyl which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, An aromatic carbocyclic group which may be substituted with a substituent group γ, a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ, a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyl which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ, and a non-aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ'.

[0033] In the compound represented by formula (I) or (I'), preferred embodiments of each symbol are shown below. As the compound represented by formula (I) or (I'), embodiments of all combinations of the specific examples shown below are exemplified.

[0034] Examples of the A ring include substituted or unsubstituted non-aromatic heterocycles. The A ring is preferably a 5- to 7-membered ring containing 1 to 3, preferably 1 to 2, O, S and / or N atoms, more preferably selected from the above non-aromatic heterocycles. One preferred embodiment of the A ring is the ring of the following (a), (b) or (c), more preferably the ring of (a) or (b).

Chemical formula

[0035] Z 1 、Z 2 、Z 3 、Z 4 and Z 5 are each independently CR 5a R 5b 、CR 5a 、O、N、NR 5c or S, where Z 1 、Z 2 、Z 3 、Z 4 and Z 5 the number of heteroatoms constituting the ring structure of the A ring is 0 or 1. Z 1 One preferred embodiment of is CR 5a R 5b 、O、S or NR 5c and CR 5a R 5b is more preferred. Z 2 One preferred embodiment of is CR 5a R 5b 、O、S or NR 5c and CR 5a R 5b 、O or NR 5c is more preferred, and CR 5a R 5b or O is particularly preferred. Z 3 One preferred embodiment of is CR 5a R 5b 、O、S or NR 5c and CR 5a R5b or O is more preferred, CR 5a R 5b is particularly preferred. Z 4 One of the preferred embodiments of 5a R 5b is CR 5c R 5a R 5b is more preferred. Z 5 One of the preferred embodiments of 5a R 5b is CR 5c R 5a R 5b is more preferred. Or, Z 1 and Z 3 Z 1 and Z 4 Z 1 and Z 5 Z 2 and Z 4 Z 2 and Z 5 Z 3 and Z 5 R 4 and Z 2 R 4 and Z 3 R 4 and Z 4 or R 4 and Z 5 There may be a substituted or unsubstituted C1-C4 bridge formed between them. Preferably, Z 1 and Z 3 Z 1 and Z 4 Z 1 and Z 5 Z 2 and Z 4 Z 2 and Z 5 or Z 3 and Z 5 There may be a substituted or unsubstituted (C1-C4) bridge formed between them.

[0036] Ring A may further have Ring B as follows. In this case, Z constituting Ring B 1 Z2 , Z 3 , Z 4 and Z 5 are each independently CR 5a , C or N. [Chemical formula] Ring A is more preferably a ring of (a1), (b1), (1c) or (e1), and particularly preferably a ring of (a1) or (b1). Ring B is preferably a substituted or unsubstituted 3- to 7-membered carbocyclic ring (examples of substituents: alkyl, halogen, hydroxy, haloalkyl) or a substituted or unsubstituted 4- to 7-membered heterocyclic ring (examples of substituents: alkyl, halogen, hydroxy, haloalkyl), and more preferably a benzene ring, a 5- to 6-membered unsubstituted carbocyclic ring or a 5- to 6-membered unsubstituted heterocyclic ring.

[0037] One of another preferred embodiment of Ring A is the following ring: [Chemical formula] can be mentioned. One of a more preferred embodiment of Ring A is the following ring. [Chemical formula] A more preferred embodiment of Ring A is the above ring of (a2) or (b3).

[0038] As X1, CR A9a R A9b , O or NR A9c can be mentioned. One of a preferred embodiment of X1 is CR A9a R A9b or O.

[0039] As X2, CR A13a R A13b , O or NR A13c can be mentioned. One of the preferred embodiments of X2 is CR A13a R A13b or O. As X3, CR A14a R A9b , O or NR A14c is exemplified. One of the preferred embodiments of X3 is CR A14a R A14b or O. However, when either X2 or X3 is NR A13c , NR A14c or O, the other of X2 or X3 is CR A13a R A13b or CR A14a R A14b .

[0040] R A5a R A5b R A6a R A6b R A7a and R A7b are each independently hydrogen, alkyl, alkyloxy or alkyloxyalkyl. R A5a One of the preferred embodiments of is hydrogen or alkyl, preferably hydrogen. R A5b One of the preferred embodiments of is hydrogen or alkyl, preferably hydrogen. R A6a One of the preferred embodiments of is hydrogen, alkyl or alkyloxyalkyl, preferably hydrogen. R A6b One of the preferred embodiments of is hydrogen. R A7a One of the preferred embodiments of is hydrogen, alkyl or alkyloxyalkyl, preferably alkyloxyalkyl. R A7b One of the preferred embodiments of is hydrogen. R A5a and R A6a , or R A6a and R A7amay combine with an adjacent atom to form an optionally halogen - substituted aromatic carbocyclic ring, an optionally halogen - substituted 3 - to 6 - membered non - aromatic carbocyclic ring, or an optionally halogen - substituted 4 - to 6 - membered non - aromatic heterocyclic ring (however, when forming an aromatic carbocyclic ring, R A5b and R A6b or R A6b and R A7b combine to form a bond). R A5b and R A6b may combine to form a bond. R A6a and R A6b may combine with an adjacent atom to form a 3 - to 6 - membered non - aromatic carbocyclic ring or a 4 - to 6 - membered non - aromatic heterocyclic ring.

[0041] R A8a R A8b R A9a R A9b R A10a R A10b R A11a and R A11b are each independently hydrogen, alkyl, haloalkyl, alkyloxy, or alkyloxyalkyl. One preferred embodiment of R A8a is hydrogen or alkyl, preferably hydrogen. One preferred embodiment of R A8b is hydrogen or alkyl, preferably hydrogen. One preferred embodiment of R A9a is hydrogen, alkyl, or alkyloxyalkyl. One preferred embodiment of R A9b is hydrogen or alkyl, preferably hydrogen. One preferred embodiment of R A10a is hydrogen, alkyl, or alkyloxy, preferably hydrogen. One preferred embodiment of R A10b is hydrogen. R A11aOne of the preferred embodiments is hydrogen or alkyl, preferably hydrogen. R A11b One of the preferred embodiments is hydrogen. R A8a And R A10a Or R A8a And R A11a May together form a C1-C3 bridge. R A10a And R A11a May together with adjacent atoms form a 5-membered non-aromatic carbon ring. R A9a And R A9b May together with adjacent atoms form a 4-membered non-aromatic carbon ring or a 5-membered non-aromatic heterocyclic ring. R A8a And R A9a May together form a bond. R A9c Is hydrogen, alkyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbamoyl, aromatic carbocyclic group, aromatic heterocyclic group, aromatic carbocyclic alkyl, or aromatic heterocyclic alkyl.

[0042] R A12a 、R A12b 、R A13a 、R A13b 、R A14a 、R A14b 、R A15a 、R A15b 、R A16a And R A16b Are each independently hydrogen, alkyl, alkyloxy or alkyloxyalkyl. R A13c Or R A14c Are each independently alkyl, alkyloxyalkyl, alkyloxycarbonyl, alkylcarbamoyl, aromatic carbocyclic group, aromatic heterocyclic group, aromatic carbocyclic alkyl, or aromatic heterocyclic alkyl.

[0043] R 1Examples include, independently of each other, halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy. R 1 One preferred embodiment of 1 is halogen, alkyl or haloalkyl. R 1 is preferably halogen.

[0044] R 2a and R 2b Examples include, independently of each other, hydrogen, alkyl or haloalkyl. R 2a and R 2b One preferred embodiment of 2a and 2b is hydrogen. R 2a and R 2b Another preferred embodiment of 2a and 2b is a carbocyclic ring together with adjacent carbon atoms. R 2a is preferably hydrogen. R 2b is preferably hydrogen or methyl, more preferably hydrogen. R 2a and R 2b are preferably a C3-C4 non-aromatic carbocyclic ring together with adjacent carbon atoms.

[0045] R 3 Examples include substituted or unsubstituted alkyl (examples of substituents: halogen, alkyloxy, haloalkyloxy, non-aromatic cyclic group, non-aromatic heterocyclic group), substituted or unsubstituted non-aromatic carbocyclic group (examples of substituents: halogen), or substituted or unsubstituted non-aromatic heterocyclic group (examples of substituents: halogen). R 3 One preferred embodiment of 3 is alkyl or haloalkyl. R 3 is preferably alkyl.

[0046] R 4 Examples include hydrogen or alkyl. R 4One of the preferred embodiments is hydrogen or methyl, and a more preferred embodiment is hydrogen.

[0047] R 5a and R 5b are each independently hydrogen, halogen, substituted or unsubstituted alkyl (examples of substituents: halogen, alkyloxy) or substituted or unsubstituted alkyloxy (examples of substituents: halogen), and R 5a and R 5b may together form a substituted or unsubstituted non-aromatic carbocyclic ring (examples of substituents: halogen) or a substituted or unsubstituted non-aromatic heterocyclic ring (examples of substituents: halogen). R 5a and R 5b One of the preferred embodiments is each independently hydrogen, alkyl, or alkyloxyalkyl.

[0048] R 5c are each independently hydrogen, substituted or unsubstituted alkyl (examples of substituents: alkyloxy, aromatic carbocyclic group, aromatic heterocyclic group), substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl (examples of substituents: alkyl), substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted non-aromatic heterocyclic group. R 5c One of the preferred embodiments is each independently hydrogen, or substituted or unsubstituted alkyl (examples of substituents: alkyloxy).

[0049] n is an integer from 1 to 3. One of the preferred embodiments of n is an integer from 2 to 3. One of the more preferred embodiments of n is an integer from 1 to 2.

[0050] The C ring includes a benzene ring, a pyridine ring or a 5-membered aromatic heterocyclic ring. One preferred embodiment of the C ring is a benzene ring or a pyridine ring, preferably a benzene ring.

[0051] In addition, the compound represented by the formula (I') is preferably the compound represented by the following formula (I-2).

Chemical formula

[0052] The preferred embodiments of each symbol in the compound represented by the formula (I-2) are shown below. As the compound represented by the formula (I-2), all combinations of the specific examples shown below are exemplified. R 1 、R 2a 、R 2b 、R 3 、R 4 、and n are the same as the preferred embodiments of the compound represented by the above formula (I').

[0053] One preferred embodiment of X is CR 9a R 9b 、NR 10 、or O, and CR 9a R 9b or NR 10 is more preferred, and CR 9a R 9b is particularly preferred.

[0054] R 6a 、R 6b 、R 7a 、R 7b 、R 8a 、R 8b 、R 9a 、and R 9b One preferred embodiment of each is, independently of one another, hydrogen or substituted or unsubstituted alkyl. R 6a 、R 6b 、R 7a 、R 7b 、R 8a 、R 8b 、R 9a 、and R 9bis preferably, each independently, hydrogen, or substituted or unsubstituted alkyl (examples of substituents: halogen), and hydrogen or methyl is particularly preferred.

[0055] R 10 One of the preferred embodiments of 10 is substituted or unsubstituted alkyl.

[0056] One of the preferred embodiments of the compound represented by formula (I) is Ring A is the following ring;

Chemical formula

[0057] The characteristics of the compounds of the present invention are that, in formula (I), (I') or formula (I-2), by fixing the A ring at a specific steric position, the resistance profile, pharmacokinetics and safety are excellent. Further, the characteristics of the compounds of the present invention are that, in formula (I), (I') or formula (I-2), by using an optically active tricyclic or higher carbamoylpyridotriazine derivative, the resistance profile, pharmacokinetics and safety are excellent.

[0058] Unless otherwise specified, the compounds of the present invention are not limited to specific isomers, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.

[0059] Examples of the pharmaceutically acceptable salts of the compounds of the present invention include salts of the compounds of the present invention 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 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, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). These salts can be formed by the commonly used methods.

[0060] The compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.), co-crystal and / or crystal polymorph, and the present invention also encompasses such various solvates, co-crystals and crystal polymorphs. A "solvate" may coordinate with any number of solvent molecules (e.g., water molecules, etc.) with respect to the compound of the present invention. When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere, or a hydrate may be formed. Also, when the compound of the present invention or a pharmaceutically acceptable salt thereof is recrystallized, a crystal polymorph may be formed. A "co-crystal" means that the compound of the present invention or a salt and a counter molecule are present within the same crystal lattice, and may form with any number of counter molecules.

[0061] The compound of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically decomposed, and is a compound that becomes the pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo and are converted into the compounds represented by formula (I), (I') or formula (I-2), compounds that are hydrolyzed by gastric acid, etc. and are converted into the compounds represented by formula (I), (I') or formula (I-2), etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug may itself have activity.

[0062] When the compound represented by formula (I), (I') or formula (I-2) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting a compound having a hydroxyl group with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride and a mixed anhydride or by reacting with a condensing agent are exemplified. For example, CH 3 COO-, C 2 H 5 COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH(NH 2 )COO-, CH 2 N(CH 3 ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p-CH 3 O-PhSO 3 -, PhSO 3 -, p-CH 3 PhSO 3 - are mentioned.

[0063] (Method for producing the compound of the present invention) The compounds of the present invention can be produced, for example, by the general synthetic methods shown below. Extraction, purification, etc. may be carried out by the treatments performed in ordinary organic chemistry experiments. The compounds of the present invention can be synthesized with reference to the methods known in the art. (Production method 1)

Chemical formula

[0064] (Production Method 2)

Chemical Formula

[0065] (Preparation Method 3)

Chemical Formula

[0066] (Production Method 4)

Chemical formula

[0067] (Production Method 5)

Chemical formula

[0068] The compound of the present invention obtained above may be further chemically modified to synthesize another compound. Also, during the above reaction, if a reactive functional group (e.g., OH, COOH, NH 2 ) is present in the side chain portion or the like, it may be protected before the reaction and deprotected after the reaction if desired. Examples of protective groups (such as amino-protecting groups and hydroxy-protecting groups) include those described in Protective Groups in Organic Synthesis, by T.W. Green, John Wiley & Sons Inc. (1991), such as ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. The methods for introducing and removing protective groups can be obtained by the methods described in or according to the methods commonly used in organic synthetic chemistry [for example, see Protective Groups in Organic Synthesis, by T.W. Greene, John Wiley & Sons Inc. (1991)]. In addition, the conversion of functional groups contained in each substituent can also be carried out by known methods other than the above production methods [for example, Comprehensive Organic Transformations, by R.C. Larock (1989), etc.]. Among the compounds of the present invention, some can be further led to novel derivatives using these as synthetic intermediates. The intermediates and target compounds in the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. Also, in the case of intermediates, it is also possible to use them for the next reaction without particular purification.

[0069] The compounds of the present invention are useful as pharmaceuticals such as antiviral agents, for example. The compounds of the present invention have a remarkable inhibitory effect on viral integrase. Therefore, the compounds of the present invention can be expected to have a preventive or therapeutic effect against various diseases caused by viruses that produce at least integrase and proliferate during infection in animal cells. For example, they are useful as integrase inhibitors against retroviruses (e.g., HIV-1, HIV-2, HTLV-1, SIV, FIV, etc.) and are useful as anti-HIV drugs, etc. More preferable compounds have characteristics such as high blood concentration, long duration of effect, and / or remarkable tissue migration in terms of pharmacokinetics. Also, preferable compounds are safe in terms of side effects (e.g., inhibition of CYP enzymes, mutagenicity, prolongation of the electrocardiogram QT interval, arrhythmia).

[0070] In addition, the compound of the present invention can also be used in combination therapy in combination with anti-HIV drugs having different action mechanisms such as reverse transcriptase inhibitors, protease inhibitors, and / or entry inhibitors. Furthermore, the above uses include not only use as a combined agent for anti-HIV, but also use as a combined agent for increasing the anti-HIV activity of other anti-HIV drugs, such as in cocktail therapy. In addition, the compound of the present invention can be used in the field of gene therapy to prevent the spread of retroviral vector infection other than the target tissue when using a retroviral vector based on HIV or MLV. In particular, when the vector is infected into cells in vitro and then returned to the body, if the compound of the present invention is administered in advance, unnecessary infection in the body can be prevented.

[0071] The pharmaceutical composition of the present invention can be administered by any of oral and parenteral methods. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, intranasal, ophthalmic, otic, intravaginal administration, etc.

[0072] In the case of oral administration, it may be prepared into any of the commonly used dosage forms such as internal solid preparations (for example, tablets, powders, granules, capsules, pills, film agents, etc.), internal liquid preparations (for example, suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic waters, extracts, decoctions, tinctures, etc.) according to conventional methods and then administered. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, the powders and granules may be dry syrups, and the capsules may be soft capsules, microcapsules or sustained-release capsules.

[0073] In the case of parenteral administration, it can be preferably administered in any of the commonly used dosage forms such as injections, drip infusions, external preparations (e.g., eye drops, nasal drops, ear drops, aerosol preparations, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellies, creams, patches, cataplasms, external powders, suppositories, etc.). The injection can be an emulsion such as O / W, W / O, O / W / O, W / O / W type, etc.

[0074] An effective amount of the compound of the present invention can be mixed with various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form as needed to form a pharmaceutical composition. Furthermore, the pharmaceutical composition can be made into a pharmaceutical composition for pediatric use, elderly use, critically ill patients or surgical use 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 pediatric use can be administered to patients such as neonates (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (over 1 year to less than 7 years old), children (7 years to 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 aged 65 years or older.

[0075] The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, administration route, etc. When administered orally, it is usually 0.05 - 100 mg / kg / day, preferably in the range of 0.1 - 10 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the administration route, but is usually 0.005 - 10 mg / kg / day, preferably in the range of 0.01 - 1 mg / kg / day. It can be administered once a day to once a month or once every three months.

Examples

[0076] Examples are shown below. 〈Abbreviations〉 ADDP: 1,1'-(azodicarbonyl)dipiperidine Bn: benzyl DEAD: diethyl azodicarboxylate DIAD: diisopropyl azodicarboxylate DIEA: N,N-Diisopropylethylamine DMA: Dimethylacetamide DMEAD: Di-2-methoxyethyl azodicarboxylate DMF: Dimethylformamide DMSO: Dimethyl sulfoxide HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate NMP: N-Methylpyrrolidone PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TBAF: Tetrabutylammonium fluoride THF: Tetrahydrofuran WSC·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0077] The NMR analysis obtained in each example was performed at 300 MHz or 400 MHz and measured using DMSO-d 6 , CDCl 3 . Also, when showing NMR data, there are cases where not all measured peaks are described. In the examples, "No." represents the compound number, "Structure" represents the chemical structure, and "MS" represents the molecular weight in LC / MS (Liquid Chromatography / Mass Spectrometry).

[0078] (Measurement conditions) (A) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1x50 mm) (Waters) Flow rate: 0.8 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid [B] is an acetonitrile solution containing 0.1% formic acid A linear gradient of 5%-100% solvent [B] was performed for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (B) Column: Shim-pack XR-ODS (2.2 μm, i.d. 50 x 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10% - 100% solvent [B] was performed over 3 minutes, and 100% solvent [B] was maintained for 0.5 minutes. (C) Column: Shim-pack XR-ODS (2.2 μm, i.d. 50 x 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10% - 100% solvent [B] was performed over 8 minutes, and 100% solvent [B] was maintained for 0.5 minutes.

[0079] Example 1 [Chemical formula] Step 1 To compound 1 (1.50 g, 3.59 mmol), a methanol solution of 2 mol / L ethylamine (17.9 ml, 35.9 mmol) was added, and the mixture was stirred at 100 °C for 1 hour under microwave irradiation. After distilling off the solvent of the reaction solution under reduced pressure, dilute hydrochloric acid was added to make it acidic, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound 2 (1.15 g, yield 74%). 1H-NMR(CDCl 3 ) δ: 14.53(s, 1H), 8.64(brs, 1H), 8.46(s, 1H), 7.37(m, 5H), 6.57(brs, 1H), 5.38(s, 2H), 3.24(dt, J = 14.0, 6.6 Hz, 2H), 1.45(s, 9H), 1.02(t, J = 7.3 Hz, 4H). Project 2 Compound 2 (9.59 g, 22.2 mmol) was dissolved in dichloromethane (180 ml), and (2,4-difluorophenyl)methanamine (4.77 g, 33.3 mmol), PyBOP (13.9 g, 26.7 mmol) and DIEA (11.7 ml, 66.7 mmol) were added, followed by stirring at room temperature for 18 h. The reaction mixture was washed with water and saturated brine, and the organic layer was dried over sodium sulfate and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain Compound 3 (11.5 g, yield 93%). 1H-NMR(CDCl 3 ) δ: 10.20 (t, J = 5.8 Hz, 1H), 8.54 (brs, 1H), 8.49 (s, 1H), 7.38 (m, 5H), 6.87 - 6.79 (m, 2H), 6.61 (t, J = 5.5 Hz, 1H), 5.28 (s, 2H), 4.64 (d, J = 5.9 Hz, 2H), 3.18 (ddt, J = 18.8, 10.2, 3.8 Hz, 3H), 1.83 - 1.80 (m, 1H), 1.43 (s, 9H), 0.99 (t, J = 7.3 Hz, 3H). Project 3 Compound 3 (11.5 g, 9.54 mmol) was dissolved in dioxane (57.5 ml), and 4 mol / L hydrochloric acid / dioxane solution (300 ml) was added, followed by stirring at room temperature for 4 h. After distilling off the solvent of the reaction mixture under reduced pressure, saturated aqueous sodium carbonate solution was added, and extraction was performed with chloroform - methanol. After drying the organic layer over sodium sulfate, the solvent was distilled off, and the obtained crude product was solidified from diisopropyl ether to obtain Compound 4 (7.80 g, yield 83%). 1H-NMR(CDCl 3 ) δ: 10.33 (s, 1H), 8.60 (s, 1H), 7.39 (m, 5H), 6.83 (m, 3H), 5.82 (s, 2H), 5.26 (s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 3.28 - 3.21 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H). Project 4 Compound 4 (200 mg, 0.438 mmol) was dissolved in dichloromethane (4 ml), compound 5 (111 mg, 0.920 mmol) and acetic acid (catalytic amount) were added, and the mixture was stirred at room temperature for 19 hours. After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (chloroform - methanol) to obtain compound 6 (265 mg, yield 100%). MS: m / z = 559 [M+H]+ Step 5 Compound 6 (245 mg, 0.438 mmol) was dissolved in DMF (5 ml), cesium carbonate (428 mg, 1.31 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain a racemic mixture (139 mg, yield 60%). The obtained racemic mixture was optically resolved by SFC to obtain compound 7. Column: CHIRALPAK IA / SFC (5μm, i.d.250x20mm) Flow rate: 30 mL / min UV detection wavelength: 250 nm Fractionation condition: MeOH / CO 2 = Maintaining a composition ratio of 45 / 55, the solution was pumped for 21 minutes. 1H-NMR(CDCl 3 )δ: 10.46(s, 1H), 8.51(s, 1H), 7.58(m, 2H), 7.34(m, 4H), 6.81(m, 2H), 5.41(d, J = 10.4Hz, 1H), 5.26(d, J = 10.4Hz, 1H), 4.91(s, 1H), 4.64(m, 2H), 4.39(dd, J = 14.3, 7.2Hz, 1H), 3.18 - 2.88(m, 3H), 2.24(d, J = 14.7Hz, 1H), 2.00(m, 1H), 1.85(m, 2H), 1.72(d, J = 13.6Hz, 1H), 1.38(m, 1H), 1.16(t, J = 7.1Hz, 3H). Step 6 Compound 7 (44.0 mg, 0.0840 mmol) was dissolved in DMF (0.88 ml), lithium chloride (35.7 mg, 0.842 mmol) was added, and the mixture was stirred at 90 °C for 1.5 hours. Water was added to the reaction solution, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated. The obtained crude product was solidified from diethyl ether to obtain Compound I-2 (19 mg, yield 52%). 1H-NMR(CDCl 3 ) δ: 11.98 (s, 1H), 10.42 (s, 1H), 8.46 (s, 1H), 7.36 (dd, J = 15.2, 8.6 Hz, 1H), 6.83 - 6.77 (m, 2H), 5.06 (s, 1H), 4.64 (m, 2H), 4.35 (td, J = 14.2, 6.9 Hz, 1H), 3.20 - 3.09 (m, 2H), 3.00 (d, J = 10.8 Hz, 1H), 2.31 (d, J = 15.4 Hz, 1H), 2.06 (m, 1H), 1.89 (m, 2H), 1.76 (m, 1H), 1.42 - 1.36 (m, 1H), 1.24 (t, J = 7.1 Hz, 4H).

[0080] Example 2

Chemical Structure

[0081] Example 3

Chemical formula

[0082] Example 4 [Chemical formula] Step 1 To a solution of Compound 11 (326 mg, 0.59 mmol), Compound 19 (87 mg, 0.77 mmol) and triphenylphosphine (307 mg, 1.18 mmol) in THF (3.5 mL) was added di-2-methoxyethyl azodicarboxylate (274 mg, 1.18 mmol) at 0 °C, and the mixture was allowed to stand at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 20 (293 mg, yield 77%). MS: m / z = 653 [M+H]+ Step 2 Compound 20 (287 mg, 0.44 mmol) was suspended in dioxane (3.4 mL) and water (2.3 mL). At 0 °C, 2,6-lutidine (0.10 mL), sodium periodate (282 mg, 1.32 mmol), and potassium osmate(VI) dihydrate (8.0 mg, 0.02 mmol) were added, and the temperature was raised from 0 °C to room temperature over 5 hours. The reaction mixture was filtered through Celite®. A 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 21 (223 mg, 78% yield). MS: m / z = 655 [M+H]+ Step 3 Compound 21 (192 mg, 0.29 mmol) was dissolved in 4 mol / L hydrochloric acid / dioxane solution (1.47 ml) and stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting crude product was dissolved in toluene (2.0 ml). A catalytic amount of acetic acid was added, and the mixture was stirred at 90 °C for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography to obtain a mixture of diastereomers. The resulting mixture of diastereomers was optically resolved by SFC to obtain Compound 22 (69 mg, 44% yield). Column: Two CHIRALPAK IC / SFC (5 μm, i.d. 250x20 mm) columns were used in series Flow rate: 20 mL / min UV detection wavelength: 220 nm Fractionation conditions: MeOH / CO 2 The composition ratio of = 65 / 35 was maintained, and the solution was fed for 35 minutes. MS: m / z = 537 [M+H]+ Step 4 The same reaction as in Step 6 of Example 1 was carried out to obtain Compound II-40. MS: m / z = 447 [M+H]+

[0083] Example 5 [Chemical] Engineering 1 To a solution of compound 23 (1.59 g, 12.2 mmol) in DMF (16.0 mL) was added imidazole (0.998 g, 14.66 mmol) and t-butyldimethylsilyl chloride (1.84 g, 12.21 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to give compound 24 (1.39 g, yield 47%). 1H-NMR(CDCl 3 ) δ: 3.47 - 3.55 (m, 4H), 2.09 - 2.15 (m, 2H), 1.88 - 1.95 (s, 1H), 1.65 - 1.79 (m, 2H), 1.32 - 1.42 (m, 2H), 0.88 - 0.89 (m, 1H), 0.85 (s, 9H), 0.039 (s, 6H). Engineering 2 To a solution of compound 24 (400 mg, 0.164 mmol), compound 11 (700 mg, 1.26 mmol) and triphenylphosphine (660 mg, 2.52 mmol) in THF (7 mL) was added di-2-methoxyethyl azodicarboxylate (589 mg, 2.52 mmol) at 0 °C, and the mixture was allowed to stand at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was roughly purified by silica gel column chromatography (hexane - ethyl acetate). Engineering 3 To a solution of Compound 25 (1.06 g, 1.35 mmol) in THF (10.0 mL) was added 1 mol / L TBAF / THF solution (1.63 mL, 1.63 mmol), and the mixture was stirred at room temperature for 12 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to give Compound 26 (720 mg, yield 80%). MS: m / z = 669 [M+H]+ Step 4 To a solution of Compound 26 (720 mg, 1.08 mmol) in dichloromethane (8.0 mL) was added Dess - Martin periodinane at 0 °C, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution and an aqueous saturated sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to give Compound 27 (393 mg, yield 55%). MS: m / z = 667 [M+H]+ Step 5 A solution of Compound 27 (393 mg, 0.59 mmol) in acetonitrile (8.0 mL) was heated to 60 °C and stirred for 80 minutes. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude product was dissolved in DMF (4.0 mL), and cesium carbonate (576 mg, 1.77 mmol) and benzyl bromide (0.21 mL, 1.77 mmol) were added at 0 °C, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) and subjected to SFC optical resolution to give Compound 28 (89 mg, yield 28%). Column: Two CHIRALPAK IC / SFC (5 μm, i.d.250x20 mm) columns were used in series Flow rate: 20 mL / min UV detection wavelength: 220 nm Fractionation condition: MeOH / CO 2 The composition ratio of MeOH / CO = 75 / 25 was maintained and elution was carried out for 45 minutes. MS: m / z = 549 [M+H]+ Step 6 The same reaction as in Step 6 of Example 1 was carried out to obtain Compound II-4 (11 mg, yield 74%). MS: m / z = 459 [M+H]+

[0084] The following compounds were also synthesized in the same manner.

[0085] [Table 1] [Table 2] [Table 3]

[0086] [Table 4] [Table 5] [Table 6]

[0087] [Table 7] [Table 8] [Table 9]

[0088]

Table 10

Table 11

Table 12

[0089]

Table 13

[0090] The physical data of each compound are shown below.

Table 14

[0091] The biological test examples of the compounds of the present invention are described below. The compound of the present invention only needs to significantly inhibit the integrase of the virus. Specifically, in the evaluation method described below, the EC50 is preferably 100 nM or less, more preferably 10 nM or less, and even more preferably 5 nM.

[0092] Test Example 1: Anti-HIV Activity A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). 2.5 x 10 5 cells / mL of the MT-4 cell suspension were dispensed into the plate containing the test sample at 100 μL / well, and then 50 μL / well of the HIV virus solution was dispensed. The mixture was mixed with a plate mixer and cultured in a CO 2 incubator for 4 days. 30 μL of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution was dispensed into each well. CO 2It was reacted in an incubator for 1 hour. 150 μL of the supernatant was removed from each well without sucking the cells. 150 μL of cell lysate was added and mixed well with a plate mixer until all the cells were lysed. The absorbance of the mixed plate was measured at two wavelengths of 560 nm / 690 nm with a microplate reader. The 50% HIV inhibitory concentration (EC50) was determined from the concentration-dependent curve using the four-parameter logistic curve fitting model shown below. y = A + ((B - A) / (1 + (C / x) D )) A = Minimum value of inhibition rate (negative control, 0%) B = Maximum value of inhibition rate (positive control, 100%) C = Compound concentration at the inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%) (Results)

Table 15

[0093] Test Example 2: Resistance Evaluation Test A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). After dispensing 100 μL / well of a 2.5×10 5 cells / mL HeLa-CD4 cell suspension into the plate containing the test sample, 50 μL / well of the HIV virus solution (wild type and mutant strains) was dispensed. It was mixed with a plate mixer and CO 2It was cultured in an incubator for 3 days. The culture supernatant in each well was aspirated and removed, 100 μL of cell lysis buffer in the reporter measurement kit was dispensed, and it was frozen in a freezer (-80 °C). After thawing the plate frozen in the freezer at room temperature, it was mixed with a plate mixer and centrifuged at 1,200 rpm for 5 minutes. 20 μL of the supernatant from each well was aliquoted into a 96-well microplate (BLACK). 100 μL of the chemiluminescence reagent in the reporter assay kit was dispensed, reacted at room temperature for about 1 hour, and then the luminescence amount was measured with MicroBeta TRILUX. The 50% HIV inhibition concentration (EC50) was determined from the concentration-dependent curve using the following four-parameter logistic curve fitting model. y = A + ((B - A) / (1 + (C / x) D )) A = Minimum value of inhibition rate (negative control, 0%) B = Maximum value of inhibition rate (positive control, 100%) C = Compound concentration at the inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%) In addition, the resistance degree (Fold change (FC)) of each mutant strain was calculated based on the following calculation formula. FC = EC50 of mutant strain / EC50 of wild strain (Results) The FC for mutant strain 1 (E138K / G140S / Q148H / N155H) and the FC for mutant strain 2 (E92Q / E138T / G140S / Q148H) are shown in the table.

Table 16

[0094] Test Example 3: CYP Inhibition Test Using commercially available pooled human liver microsomes, the O - deethylation of 7 - ethoxyresorufin (CYP1A2), methyl - hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O - demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), which are typical substrate metabolic reactions of the major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), were used as indicators to evaluate the degree to which the metabolite production of each was inhibited by the compound of the present invention. The reaction conditions were as follows: Substrates, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S - mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37°C; enzyme, pooled human liver microsomes 0.2 mg protein / mL; concentration of the compound of the present invention, 1, 5, 10, 20 μmol / L (4 points). Into a 96 - well plate, each of the five substrates, human liver microsomes, and the compound of the present invention were added in the above composition in 50 mmol / L Hepes buffer, and NADPH, a coenzyme, was added to initiate the metabolic reaction used as an indicator. After reacting at 37°C for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifuged supernatant was quantified by a fluorescence multi - label counter or LC / MS / MS, and the tolbutamide hydroxylated form (CYP2C9 metabolite), mephenytoin 4'-hydroxylated form (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol form (CYP3A4 metabolite) were quantified by LC / MS / MS. A control (100%) was prepared by adding only DMSO, the solvent in which the compound was dissolved, instead of the compound of the present invention to the reaction solution. The residual activity (%) was calculated, and using the concentration and inhibition rate, the IC 50 was calculated by inverse estimation using a logistic model.

[0095] Test Example 4: CYP3A4 (MDZ) MBI Test Regarding the CYP3A4 inhibition of the compound of the present invention, this is a test for evaluating the Mechanism based inhibition (MBI) ability from the enhancement of the inhibitory effect caused by the metabolic reaction of the compound of the present invention. Using pooled human liver microsomes, CYP3A4 inhibition was evaluated using the 1-hydroxylation reaction of midazolam (MDZ) as an index. 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; pooled human liver microsomes, 0.5 mg / mL at pre-reaction, 0.05 mg / mL (10-fold dilution) during reaction; concentration of the compound of the present invention at pre-reaction, 1, 5, 10, 20 μmol / L (4 points) or 0.83, 5, 10, 20 μmol / L (4 points). In a 96-well plate, pooled human liver microsomes and the solution of the compound of the present invention were added to K-Pi buffer (pH 7.4) as a pre-reaction solution according to the composition of the above pre-reaction. A part of it was transferred to another 96-well plate so as to be diluted 1 / 10 with K-Pi buffer containing the substrate, and the reaction using NADPH as a coenzyme was started (Preincubation 0 min without pre-reaction). After reacting for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. Also, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (Preincubation 30 min with pre-reaction). After pre-reacting for a predetermined time, a part of it was transferred to another plate so as to be diluted 1 / 10 with K-Pi buffer containing the substrate to start the reaction as an index. After reacting for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. Each plate on which the index reaction was performed was centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the centrifuged supernatant was quantified by LC / MS / MS. Using only DMSO, which is the solvent in which the compound was dissolved instead of the compound of the present invention, added to the reaction solution as a control (100%), the residual activity (%) when the compound of the present invention was added at each concentration was calculated, and using the concentration and the inhibition rate, the IC was calculated by inverse estimation using a logistic model. The IC of Preincubation 0 min / the IC of Preincubation 30 min was defined as the Shifted IC value. If the Shifted IC is 1.5 or more, it is positive (+), and if the Shifted IC is 1.0 or less, it is negative (-). (Results) Compound I-15: (-) Compound II-066: (-)

[0096] Test Example 5: BA Test Experimental Materials and Methods for Examining Oral Absorbability (1) Animals Used: Rats were used. (2) Breeding Conditions: The rats were allowed free access to solid feed and sterilized tap water. (3) Dosage and Grouping Settings: Oral administration and intravenous administration were performed at a predetermined dosage. The groups were set as follows. (The dosage was changed for each compound) Oral Administration 2 - 60 μmol / kg or 1 - 30 mg / kg (n = 2 - 3) Intravenous Administration 1 - 30 μmol / kg or 0.5 - 10 mg / kg (n = 2 - 3) (4) Preparation of Dosage Solutions: Oral administration was performed as a solution or suspension. Intravenous administration was performed after solubilization. (5) Administration Methods: Oral administration was forcibly administered into the stomach using an oral sonde. Intravenous administration was administered from the tail vein using a syringe with a needle. (6) Evaluation Items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS. (7) Statistical Analysis: Regarding the change in the concentration of the compound of the present invention in plasma, the area under the plasma concentration-time curve (AUC) was calculated by the moment analysis method, and the bioavailability (BA) of the compound of the present invention was calculated from the dosage ratio and AUC ratio between the oral administration group and the intravenous administration group.

[0097] Test Example 6: Clearance Evaluation Test Experimental Materials and Methods (1) Test Animals: Rats were used. (2) Breeding Conditions: The rats were allowed free access to solid feed and sterilized tap water. (3) Dosage and Grouping: Intravenous administration was carried out at a predetermined dosage. The groups were set as follows. Intravenous administration 1 μmol / kg (n = 2) (4) Preparation of Administration Solution: It was solubilized using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent and administered. (5) Administration Method: It was administered via the tail vein using a syringe with a needle. (6) Evaluation Items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS. (7) Statistical Analysis: For the change in the concentration of the compound of the present invention in plasma, the total body clearance (CLtot) and elimination half-life (t1 / 2) were calculated by the moment analysis method. Compound I-15: 0.111 mL / min / kg, 12.3 hr Compound II-028: 0.102 mL / min / kg, 26.7 hr From the above results, it was found that the compound of the present invention has a low clearance and a long elimination half-life, and thus is useful as a sustained integrase inhibitor.

[0098] Test Example 7 (Metabolic Stability Test) A commercially available pooled human liver microsome was reacted with the compound of the present invention for a certain period of time, and the residual rate was calculated by comparing the reaction sample and the unreacted sample to evaluate the degree to which the compound of the present invention is metabolized in the liver. 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 liver microsomes, the reaction was carried out at 37 °C for 0 minutes or 30 minutes in the presence of 1 mmol / L NADPH (oxidative 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 centrifuged supernatant was quantified by LC / MS / MS or solid-phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention after the reaction was calculated with the amount of the compound at 0 minutes of reaction taken as 100%. (Result) The residual rates at a compound concentration of 0.5 μmol / L are shown in the following table.

Table 17

[0099] Test Example 8: Fluctuation Ames Test The mutagenicity of the compound of the present invention was evaluated. 20 μL of frozen Salmonella typhimurium TA98 strain and TA100 strain were inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-cultured with shaking at 37 °C for 10 hours. For the TA98 strain, 7.70 - 8.00 mL of the bacterial solution was centrifuged (2000×g, 10 minutes) to remove the culture solution. The same volume of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 ·7H 2The bacteria were suspended in O: 0.1 g / L and added to 120 mL of Exposure medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL). For TA100 strain, 3.10 - 3.42 mL of the bacterial solution was added to 120 - 130 mL of Exposure medium to prepare the test bacterial solution. The DMSO solution of the compound of the present invention (serially diluted from the highest dose of 50 mg / mL with a common ratio of 2 - 3), DMSO as the negative control, and under non - metabolic activation conditions, for TA98 strain, a 50 μg / mL DMSO solution of 4 - nitroquinoline - 1 - oxide, for TA100 strain, a 0.25 μg / mL DMSO solution of 2 - (2 - furyl)-3-(5 - nitro - 2 - furyl)acrylamide, under metabolic activation conditions, for TA98 strain, a 40 μg / mL DMSO solution of 2 - aminoanthracene, and for TA100 strain, a 20 μg / mL DMSO solution of 2 - aminoanthracene, 12 μL each were mixed with 588 μL of the test bacterial solution (under metabolic activation conditions, a mixture of 498 μL of the test bacterial solution and 90 μL of S9 mix), and cultured with shaking at 37 °C for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was mixed with 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL), and dispensed into 48 - well microplates at 50 μL per dose, and statically cultured at 37 °C for 3 days. Wells containing bacteria that acquired growth ability due to mutation of the amino acid (histidine) synthase gene change color from purple to yellow due to pH change. Therefore, the number of wells with yellow - colored bacterial growth in 48 wells per dose was counted and evaluated by comparison with the negative control group. Those with negative mutagenicity are indicated as (-), and those with positive mutagenicity are indicated as (+).

[0100] Test Example 9: hERG Test For the purpose of evaluating the risk of prolonging the QT interval of the electrocardiogram of the compound of the present invention, using CHO cells expressing the human ether - a - go - go related gene (hERG) channel, the effect of the compound of the present invention on the delayed rectifier K + current (I Kr ) was examined. Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), by the whole cell patch clamp method, the cells were held at a membrane potential of -80 mV, a leak potential of -50 mV was applied, and then a depolarizing stimulus of +20 mV was applied for 2 seconds, and then a repolarizing stimulus of -50 mV was applied for 2 seconds. The induced I Kr was recorded. The extracellular fluid adjusted to 0.1% with dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was used as the medium, and the extracellular fluid in which the medium and the compound of the present invention were dissolved at the target concentration was applied to the cells at room temperature for 7 minutes or more. The obtained I Kr From, using analysis software (QPatch Assay software; Sophion Bioscience A / S), the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention with respect to the maximum tail current after application of the medium was calculated as the inhibition rate, and the effect of the compound of the present invention on I Kr was evaluated.

[0101] Test Example 10: Solubility Test The solubility of the compound of the present invention was determined under the condition of adding 1% DMSO. A 10 mmol / L compound solution was prepared with DMSO. 2 μL of the compound solution of the present invention was added to 198 μL of JP-1 solution and JP-2 solution, respectively. After shaking at room temperature for 1 hour, the mixture was suction filtered. The filtrate was diluted 10 or 100 times with methanol / water = 1 / 1 (V / V) or acetonitrile / methanol / water = 1 / 1 / 2 (V / V / V), and the concentration in the filtrate was measured by LC / MS or solid phase extraction (SPE) / MS using the absolute calibration curve method. The composition of the JP-1 solution is as follows. Dissolve 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid in water and make up to 1000 mL with water. The composition of JP-2 solution is as follows. Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of disodium hydrogen phosphate anhydrous in water to make 1000 mL, and add 1 volume of water to 1 volume of this solution.

[0102] Test Example 11: Powder Solubility Test Put an appropriate amount of the compound of the present invention into a suitable container, and add 200 μL each of JP-1 solution (dissolve 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid in water and make up to 1000 mL), JP-2 solution (dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of disodium hydrogen phosphate anhydrous in water to make 1000 mL, and add 1 volume of water to 1 volume of this solution), and 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (add JP-2 solution to 1.08 g of TCA and make up to 100 mL) to each container. If the whole amount was dissolved after adding the test solution, the compound of the present invention was added appropriately. After sealing and shaking at 37°C for 1 hour, filter, and add 100 μL of methanol to 100 μL of each filtrate for 2-fold dilution. The dilution factor was changed as necessary. Check for the absence of bubbles and precipitates, seal, and shake. The compound of the present invention was quantified by HPLC using the absolute calibration curve method.

[0103] Test Example 12: Ames Test The mutagenicity of the compound of the present invention is evaluated by the Ames test using Salmonella typhimurium TA98 strain, TA100 strain, TA1535 strain, TA1537 strain and Escherichia coli WP2uvrA strain as test strains. To 0.1 mL of the DMSO solution of the compound of the present invention, 0.5 mL of S9 mix under metabolic activation conditions, 0.5 mL of phosphate buffer under non-metabolic activation conditions and 0.1 mL of the test bacterial solution are mixed, and overlaid on a minimal glucose agar plate together with 2 mL of the double-layer soft agar containing histidine and biotin, or tryptophan. At the same time, the same procedure is carried out for the negative control substance (DMSO) and the positive control substances (2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene). After culturing at 37 °C for 48 hours, the number of revertant colonies that appear is counted and evaluated by comparison with the negative control group. When the number of revertant colonies increases in a concentration-dependent manner and is more than twice the number of colonies in the negative control group, it is judged as positive (+).

[0104] Test Example 13: Nav test For the purpose of evaluating the risk of arrhythmia induction by the compound of the present invention, using HEK cells expressing Voltage gated sodium channel (Nav1.5 channel) encoded by the SCN5A gene, Na + current (I Na ) of the compound of the present invention was examined. Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), by the whole cell patch clamp method, the cells were held at a membrane potential of -100 mV, and I Na induced when a depolarizing stimulus of -10 mV was applied for 20 milliseconds was recorded. The extracellular fluid adjusted to 0.3% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2: 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, TEA (Tetraethylammonium Hydroxide): 10 mmol / L, pH = 7.4) was used as the medium. The extracellular fluid in which the medium and the compound of the present invention were dissolved at the target concentration was applied to the cells at room temperature for 5 minutes or more respectively. The obtained I Na From, using analysis software (QPatch Assay software; Sophion Bioscience A / S), the absolute value of the maximum peak current was measured based on the current value at the holding membrane potential. Furthermore, the ratio of the maximum peak current when the compound of the present invention was applied to the maximum peak current when the medium was applied was calculated, and the I Na of the compound of the present invention was evaluated. (Results) Compound I-2 101% Compound I-15 92.1% Compound II-31 79% From the above results, no obvious increase in current was observed, and it was found that the compound of the present invention has a low concern about arrhythmia caused by an increase in Na current.

[0105] Test Example 14: Anti-HIV activity evaluation test using peripheral blood mononuclear cells (PBMC) of healthy humans A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). PBMC stimulated with 1.0 x 10 5 cells / well of Phytohemagglutinin (PHA) and the virus solution of HIV were mixed for the required number of wells and reacted at 37°C for 1 hour. After the reaction, the cell suspension was centrifuged to discard the supernatant, and the infected cells were dispersed in the culture medium for the required number of wells at 150 μL / well and dispensed into the 96-well microplate containing the test sample at 150 μL / well each. Mixed with a plate mixer, CO 2It was cultured in an incubator for 4 days. The reverse transcriptase activity in the culture solution was measured. The 90% HIV inhibitory concentration (EC90) was determined from the concentration-dependent curve using the following four-parameter logistic curve fitting model. y = A + ((B - A) / (1 + (C / x) D )) A = Minimum value of inhibition rate (negative control, 0%) B = Maximum value of inhibition rate (positive control, 100%) C = Compound concentration at the inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%) (Results) Compound II-31 0.73 nM Compound II-51 3.3 nM

[0106] Test Example 15: Anti-HIV Activity Evaluation Test in the Presence of Human Serum Protein A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). A human serum protein solution (human serum protein concentration 50%) was dispensed into the 96-well microplate containing the test sample at 100 μL / well each and allowed to stand at room temperature for 1 hour. The culture solution was dispensed into the plate without serum at 100 μL / well each. 3.0 x 10 5 cells / well of MT-4 cells and 3 μL / well of the HIV virus solution were mixed for the required number of wells and reacted at 37°C for 1 hour. After the reaction, the cell suspension was centrifuged to discard the supernatant, and the infected cells were dispersed in the culture solution for the required number of wells at 50 μL / well and dispensed into the 96-well microplate containing the test sample and human serum protein at 50 μL / well each (final human serum protein concentration: 25%). It was mixed with a plate mixer and cultured in a CO 2 incubator for 4 days. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution was dispensed into each well at 30 μL each. CO 2It was reacted in an incubator for 1 hour. 150 μL of the supernatant was removed from each well without sucking up the cells. 150 μL of cell lysate was added and mixed well with a plate mixer until all the cells were lysed. The absorbance of the mixed plate was measured at two wavelengths of 560 nm / 690 nm with a microplate reader. The 50% HIV inhibition concentration (EC50) was determined from the concentration-dependent curve using the following four-parameter logistic curve fitting model. y = A + ((B - A) / (1 + (C / x) D )) A = Minimum value of inhibition rate (negative control, 0%) B = Maximum value of inhibition rate (positive control, 100%) C = Compound concentration at the inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%) Also, based on the following calculation formula, potency whift (PS) was calculated. Note that PS is the 100% extrapolated value of human serum protein concentration. PS = 4 x (EC50 in the presence of 25% human serum protein / EC50 in the absence of human serum protein) (Results) PS in the presence of human serum protein is shown in the table (100% extrapolated value). Compound II - 31 364 Compound II - 51 236

[0107] Formulation Example The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injection solutions or suspensions, topically, for example, in the form of lotions, gels, ointments or creams, or in nasal form or suppository form. A pharmaceutical composition containing the compound of the present invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be produced by conventional methods, by mixing, granulating or coating methods. For example, oral compositions can be made into tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and the active ingredient, etc. Also, injection compositions can be made into solutions or suspensions, may be sterilized, and may contain preservatives, stabilizers, buffering agents, etc.

Industrial Applicability

[0108] The compounds of the present invention have integrase inhibitory activity and / or cell growth inhibitory activity against viruses, particularly HIV. Therefore, they are useful for the prevention or treatment of various diseases and viral infections (e.g., AIDS) involving integrase.

Claims

1. A compound represented by the following formula: or a pharma- ceutically acceptable salt thereof. Formula (I): 【Chemistry 1】 (In the formula, Ring A is a substituted or unsubstituted non-aromatic heterocycle; Ring C is a benzene ring, a pyridine ring or a 5-membered aromatic heterocycle; R １ are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R ２ａ and R ２ｂ are each independently hydrogen, alkyl, or haloalkyl; R ２ａ and R ２ｂ may be taken together with adjacent carbon atoms to form a non-aromatic carbocyclic or heterocyclic ring; R ３ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ４ is hydrogen, or substituted or unsubstituted alkyl; R ３ and R ４ , or R ３ and the substituents on ring A, together with adjacent atoms, may form a substituted or unsubstituted non-aromatic heterocyclic ring; n is an integer from 1 to 3, However, the following compounds are excluded: 【Chemistry 2】

2. 2. The compound according to claim 1, wherein ring A is the following ring: or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】 (In the formula, R ４ is hydrogen or substituted or unsubstituted alkyl; The dashed line represents the presence or absence of a bond; Z １ , Z ２ , Z ３ , Z ４ and Z ５ are each independently CR ５ａ R ５ｂ , C.R. ５ａ , O, N, N.R. ５ｃ or S, where Z １ , Z ２ , Z ３ , Z ４ and Z ５ wherein the number of heteroatoms constituting the ring structure of ring A is 0 or 1; Z １ and Z ３ , Z １ and Z ４ , Z １ and Z ５ , Z ２ and Z ４ , Z ２ and Z ５ , Z ３ and Z ５ , R ４ and Z ２ , R ４ and Z ３ , R ４ and Z ４ Or R ４ and Z ５ Between them, N.R. ５ｃ a substituted or unsubstituted C1-C4 bridge optionally interrupted by one heteroatom selected from O and S; R ５ａ and R ５ｂ are each independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R on the same carbon atom ５ａ and R ５ｂ may be taken together to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle; R ５ｃ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, or substituted or unsubstituted non-aromatic heterocyclic groups; R ３ and R ４ may be joined together with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle.

3. 2. The compound according to claim 1, wherein ring A is any one of the following rings, or a pharma- ceutically acceptable salt thereof. 【Chemistry 4】 (In the formula, R ４ is hydrogen or substituted or unsubstituted alkyl; The dashed line represents the presence or absence of a bond; Ring B is a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, or a substituted or unsubstituted non-aromatic heterocycle; Z １ , Z ２ , Z ３ , Z ４ and Z ５ are each independently CR ５ａ R ５ｂ , C.R. ５ａ , C.O., N.R. ５ｃ or S (provided that when it is a constituent atom of ring B, it is not CR ５ａ , C or N; Z １ and Z ３ , Z １ and Z ４ , Z １ and Z ５ , Z ２ and Z ４ , Z ２ and Z ５ , Z ３ and Z ５ , R ４ and Z ２ , R ４ and Z ３ , R ４ and Z ４ Or R ４ and Z ５ Between them, N.R. ５ｃ a substituted or unsubstituted C2-C4 bridge optionally interrupted by one heteroatom selected from O and S; R ５ａ and R ５ｂ are each independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R on the same carbon atom ５ａ and R ５ｂ may be taken together to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle; R ５ｃ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted non-aromatic heterocyclic group; R ３ and R ４ may be joined together with adjacent atoms to form a substituted or unsubstituted non-aromatic heterocycle.

4. The compound according to any one of claims 1 to 3, represented by the following formula or a pharma- ceutically acceptable salt thereof: Formula (I): 【Chemistry 5】 (In the formula, The A ring is the following ring: 【Chemistry 6】 X1 is CR Ａ９ａ R Ａ９ｂ or O; R Ａ５ａ , R Ａ５ｂ , R Ａ６ａ , R Ａ６ｂ , R Ａ７ａ and R Ａ７ｂ are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R Ａ５ａ and R Ａ６ａ , or R Ａ６ａ and R Ａ７ａ may be joined together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R Ａ５ｂ and R Ａ６ｂ , or R Ａ６ｂ and R Ａ７ｂ together form a bond); R Ａ５ｂ and R Ａ６ｂ may be taken together to form a bond; R Ａ８ａ , R Ａ８ｂ , R Ａ９ａ , R Ａ９ｂ , R Ａ１０ａ , R Ａ１０ｂ , R Ａ１１ａ and R Ａ１１ｂ are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R Ａ８ａ and R Ａ１０ａ may together form a C1-C3 bridge; R Ａ１０ａ and R Ａ１１ａ may, together with adjacent atoms, form a 5-membered non-aromatic carbocyclic ring; R Ａ９ａ and R Ａ９ｂ may be joined together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R Ａ８ａ and R Ａ９ａ may together form a bond; Ring C is a benzene ring or a pyridine ring; R １ are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R ２ａ and R ２ｂ are each independently hydrogen, alkyl, or haloalkyl; R ３ is alkyl or haloalkyl; R ４ is hydrogen or alkyl; and n is an integer from 1 to 3.

5. R ３ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is alkyl or haloalkyl.

6. R ３ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is alkyl.

7. R ４ The compound according to any one of claims 1 to 3, 5 or 6, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or alkyl.

8. R １ The compound according to any one of claims 1 to 7, wherein each is independently halogen, alkyl or haloalkyl, or a pharma- ceutically acceptable salt thereof.

9. R １ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein each of is independently a halogen.

10. R ２ａ is hydrogen and R ２ｂ is hydrogen or alkyl, or R ２ａ and R ２ｂ The compound according to any one of claims 1 to 3, or 5 to 9, wherein, together with adjacent carbon atoms, forms a C3-C4 carbocyclic ring, or a pharma- ceutically acceptable salt thereof.

11. R ２ａ is hydrogen, R ２ｂ The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or alkyl.

12. The compound according to any one of claims 1 to 3, or 5 to 11, wherein Ring C is a benzene ring or a pyridine ring, or a pharma- ceutically acceptable salt thereof.

13. or a pharma- ceutically acceptable salt thereof.

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