Heterocyclic derivative

Abstract

Provided is a novel compound that is useful as an antiviral drug, exhibits strong drug efficacy in low dosages, can be used safely, and has reverse transcriptase inhibitory activity. This compound is expressed by formula (I) (wherein ring A is (i-a) or (i-b) (where R1 represents a halogen or the like, R2 represents a halogen or the like, R3 represents hydrogen or the like, L represents –O– or the like, R4 represents hydrogen or the like, ring B represents an optionally substituted five-membered or six-membered aromatic heterocycle ring or the like, and n represents an integer of 1-3), and Z is (Z) (where each R6 independently represents a halogen or the like, and m represents an integer of 0-2)).

Description

Heterocyclic Derivatives

[0001] The present invention relates to novel compounds having antiviral activity, more particularly to heterocyclic derivatives having reverse transcriptase inhibitory activity, and to pharmaceuticals, particularly anti-HIV drugs, containing the same.

[0002] Human immunodeficiency virus (HIV) is known to cause acquired immunodeficiency syndrome (AIDS). Currently, various guidelines recommend combination drugs for naive patients for the treatment of AIDS, primarily consisting of an integrase inhibitor (e.g., dolutegravir and bictegravir) and two nucleoside reverse transcriptase inhibitors with different resistance profiles (e.g., ABC+3TC, FTC+TAF). These drugs are highly effective and safe, resulting in higher patient satisfaction compared with earlier treatments. Meanwhile, the availability of safe drugs and favorable prognosis mean that treatment should be initiated as soon as HIV infection is identified. Furthermore, the average life expectancy of HIV-infected individuals is approaching that of healthy individuals, leading to longer drug use periods. Long-term use of nucleoside reverse transcriptase inhibitors can cause side effects, and once resistant viruses emerge, there is no easy treatment option, leading to a trend toward leaving nucleoside reverse transcriptase inhibitors unused. Therefore, the establishment of a dual-drug treatment using two major drugs with different mechanisms of action is desirable. JALKA® (DTG + RPV) was approved as a maintenance therapy in November 2017, and Dovate® (DTG + 3TC) was approved by the FDA in April 2019 as a treatment for naive patients. Furthermore, to improve patients' quality of life (QOL), such as reducing medication fatigue caused by long-term medication and enabling them to enjoy daily life more, the development of a long-acting injectable drug with a longer dosing interval, i.e., a single injection at intervals of one month or more, is desirable.

[0003] To meet this need, Cabenuva (Vocabria + Recamvis (CAB+RPV)), a two-drug treatment consisting of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine, was developed and approved by the FDA in January 2021 as a monthly long-acting injection and in February 2022 as a bimonthly long-acting injection. However, these drugs require frequent visits to the hospital for injections, are painful, and require two injections per treatment. Therefore, to further improve patients' quality of life, the development of a drug that can be administered at a lower dose with less pain and completes treatment with a single injection over three months or more is desirable. Recamvis, a long-acting rilpivirine injection, requires storage in a cool, dark place and requires a high dose of 900 mg / 3 mL for bimonthly injections. Furthermore, in a QT / QTc evaluation study in healthy adults, repeated administration of high-dose oral RPV (75 mg and 300 mg) has been reported to cause QTc prolongation as a side effect. Therefore, there is a need for a safer reverse transcriptase inhibitor that is effective at a low dose and can be administered with a single injection for treatment over three months or more (Non-Patent Document 1).

[0004] Known reverse transcriptase inhibitors include doravirine, rilpivirine, VM-1500A, etc. (Non-Patent Document 1). In addition, derivatives described in Patent Documents 1 to 14 and Non-Patent Documents 2 and 3 are known to be useful as reverse transcriptase inhibitors.

[0005] International Publication No. WO 2004 / 085406, International Publication No. WO 2005 / 090317, International Publication No. WO 2005 / 102989, International Publication No. WO 2006 / 010545, International Publication No. WO 2006 / 099978, International Publication No. WO 2007 / 039463, International Publication No. WO 2007 / 045573, International Publication No. WO 2008 / 019968, International Publication No. WO 2009 / 080534, International Publication No. WO 2009 / 067166, International Publication No. WO 2011 / 120133, International Publication No. WO 2011 / 126969, International Publication No. WO 2014 / 058747, International Publication No. WO 2015 / 153304

[0006] Journal of Medicinal Chemistry (2019), Volume 62, Issue 10, p.4783-5248Journal of Medicinal Chemistry (2012), Volume 55, Issue 23, p.10601-10609Bioorganic & Medicinal Chemistry Letters (2014), 24(3), p.917-922

[0007] An object of the present invention is to provide a novel compound having reverse transcriptase inhibitory activity that exhibits strong efficacy at low doses and can be used safely. A further object of the present invention is to provide a compound having a high resistance barrier and long-lasting activity in addition to the above characteristics.

[0008] As a result of extensive research, the present inventors have found that novel heterocyclic derivatives having a pyrazole ring or a benzene-fused ring on ring A of formula (I) have a significant reverse transcriptase inhibitory effect, are highly safe, have a high resistance barrier, and are long-lasting. Furthermore, the present inventors have found that the compounds of the present invention and pharmaceuticals containing them are useful as antiviral drugs (e.g., antiretroviral drugs, anti-HIV drugs, anti-HTLV-1 (human T cell leukemia virus type 1) drugs, anti-FIV (feline immunodeficiency virus: feline AIDS virus) drugs, anti-SIV (simian immunodeficiency virus: simian AIDS virus) drugs), particularly anti-HIV drugs, anti-AIDS drugs, or drugs for treating diseases related thereto, and have completed the present invention as described below.

[0009] The present invention provides the following inventions [1'], [1] to

[30] . [1] Formula (I): (Wherein, ring A is (wherein the asterisk (*) represents the attachment point of ring A to the methylene; R １ are each independently a halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, or non-aromatic carbocyclic group; (i) R ２represents halogen, alkyl optionally substituted with substituent group a, alkyloxy, alkylthio, —C(═O)N(R Ａ ) R Ｂ , -C(=O)R Ａ , -S(=O) ２ R Ａ or a non-aromatic carbocyclic group, the substituent group a is one or more groups selected from the group consisting of halogen, hydroxy and alkyloxy, and R ３ is hydrogen, halogen, alkyl, haloalkyl or —N(R Ａ ) R Ｂ or (ii) R ２ and R ３ together with the adjacent carbon atom, R Ｃ a benzene ring optionally substituted with R Ｃ forming a pyridine ring optionally substituted with R Ｃ is one or more groups selected from the group consisting of halogen, cyano, alkyl, and alkyloxy; L is —O— or —CH ２ -O-; R ４ is hydrogen or halogen; Ring B is R Ｄ or R Ｅ a 5- or 6-membered non-aromatic heterocycle optionally substituted with R Ｄ is one or more groups selected from the group consisting of halogen, amino, alkyl, haloalkyl, and hydroxyalkyl; R Ｅ is one or more groups selected from the group consisting of oxo, halogen, amino, alkyl, haloalkyl, and hydroxyalkyl, and n is an integer from 1 to 3; Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ are each independently a halogen atom, a hydroxyl group, a cyano group, an alkyl group which may be substituted by a substituent group b, an alkyloxy group, a haloalkyloxy group, or —N(R Ａ ) R Ｂ , -N(R Ａ ) S(=O) ２ R Ｂ, -N(R Ａ ) S(=O) ２ N (R Ａ ) R Ｂ , -N(R Ａ ) C(=O)R Ｂ , -N(R Ａ )C(=O)N(R Ａ ) R Ｂ , -SR Ａ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R Ａ are each independently hydrogen or alkyl; R Ｂ are each independently hydrogen or alkyl; and the substituent group b is a halogen, —N(R Ａ ) R Ｂ , -S(=O) ２ R Ａ and -S(=O) ２ N (R Ａ ) R Ｂ m is an integer of 0 to 2; R ８ is hydrogen or alkyl; R ９ is hydrogen, halogen or alkyl; R １０ is -S(=O) ２ R Ａ , or -S(=O) ２ N (R Ａ ) R Ｂ and R １１ is hydrogen, halogen, alkyl or haloalkyl; R １２ is hydrogen, halogen, alkyl or haloalkyl) The compounds in which the moiety represented by is as follows are excluded. ), or a pharmaceutically acceptable salt thereof. [1'] Formula (I): (Wherein, ring A is (wherein the asterisk (*) represents the attachment point of ring A to the methylene; R １ are each independently halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, or a non-aromatic carbocyclic group; R ２ represents halogen, alkyl optionally substituted with substituent group a, alkyloxy, alkylthio, —C(═O)N(R Ａ ) R Ｂ , -C(=O)R Ａ , -S(=O) ２ R Ａ or a non-aromatic carbocyclic group, the substituent group a is one or more groups selected from the group consisting of halogen, hydroxy and alkyloxy, R ３ is hydrogen, halogen, alkyl, haloalkyl or —N(R Ａ ) R Ｂ or R ２ and R ３ together with the adjacent carbon atom, R Ｃ a benzene ring optionally substituted with R Ｃ may form a pyridine ring optionally substituted with R Ｃ is one or more groups selected from the group consisting of halogen, cyano, alkyl, and alkyloxy; L is —O— or —CH ２ -O-; R ４ is hydrogen or halogen; Ring B is R Ｄ or R Ｅ a 5- or 6-membered non-aromatic heterocycle optionally substituted with R Ｄ is one or more groups selected from the group consisting of halogen, amino, alkyl, haloalkyl, and hydroxyalkyl; R Ｅ is one or more groups selected from the group consisting of oxo, halogen, amino, alkyl, haloalkyl, and hydroxyalkyl, and n is an integer from 1 to 3; Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６are each independently a halogen atom, a hydroxyl group, a cyano group, an alkyl group which may be substituted by a substituent group b, an alkyloxy group, a haloalkyloxy group, or —N(R Ａ ) R Ｂ , -N(R Ａ ) S(=O) ２ R Ｂ , -N(R Ａ ) S(=O) ２ N (R Ａ ) R Ｂ , -N(R Ａ ) C(=O)R Ｂ , -N(R Ａ )C(=O)N(R Ａ ) R Ｂ , -SR Ａ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R Ａ are each independently hydrogen or alkyl; R Ｂ are each independently hydrogen or alkyl; and the substituent group b is a halogen, —N(R Ａ ) R Ｂ , -S(=O) ２ R Ａ and -S(=O) ２ N (R Ａ ) R Ｂ m is an integer of 0 to 2; R ８ is hydrogen or alkyl; R ９ is hydrogen, halogen or alkyl; R １０ is -S(=O) ２ R Ａ , or -S(=O) ２ N (R Ａ ) R Ｂ and R １１ is hydrogen, halogen, alkyl or haloalkyl; R １２[2] A compound represented by the formula (wherein R is hydrogen, halogen, alkyl, or haloalkyl) (excluding compounds in which ring B is a furan ring), or a pharmaceutically acceptable salt thereof. １ [3] The compound according to [1'] or [1], or a pharmaceutically acceptable salt thereof, wherein R ２ is halogen, alkyl, haloalkyl, or —S(═O) ２ R Ａ (In the formula, R Ａ [4] The compound according to any one of [1'], [1], or [2], wherein R is alkyl, or a pharmaceutically acceptable salt thereof. ３ [5] The compound according to any one of [1'] and [1] to [3], or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or alkyl. ２ and R ３ together with adjacent carbon atoms to form one of the following rings: (In the formula, R Ｃ１ [6] The compound according to any one of [1'], [1] or [2], wherein L is —O—, or a pharmaceutically acceptable salt thereof. [7] R ４ [8] The compound according to any one of [1'] and [1] to [6], or a pharmaceutically acceptable salt thereof, wherein ring B is R Ｄ any of the following rings optionally substituted with: (In the formula, R ４ [9] The compound according to any one of [1'] and [1] to [7], wherein R is a halogen atom, or a pharmaceutically acceptable salt thereof. Ｄ

[10] The compound according to any one of [1'] and [1] to [9], wherein n is an integer of 2 to 3, or a pharmaceutically acceptable salt thereof.

[11] Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６is halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, —N(R Ａ ) R Ｂ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R ８ is hydrogen or alkyl; R ９ is a halogen; １０ is -S(=O) ２ -NH ２

[12] The compound according to any one of [1'] and [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, —N(R Ａ ) R Ｂ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R ８ is hydrogen or alkyl; R ９ is a halogen; １０ is -S(=O) ２ -NH ２

[13] The compound according to any one of [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is -S(=O) ２ NH ２ and R ８ is alkyl; R ９ is a halogen;１０ is -S(=O) ２ -NH ２

[14] The compound according to any one of [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is -S(=O) ２ NH ２ and R ８

[15] The compound according to any one of [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is -S(=O) ２ NH ２

[16] The compound according to any one of [1'] and [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein R ６ are each independently -S(=O) ２ NH ２

[17] The compound according to any one of [1'] and [1] to

[15] , or a pharmaceutically acceptable salt thereof, wherein R ８

[18] The compound according to any one of [1'] and [1] to

[16] , or a pharmaceutically acceptable salt thereof, wherein R ９

[19] The compound according to any one of [1'] and [1] to

[17] , or a pharmaceutically acceptable salt thereof, wherein R １０ But -S(=O) ２ NH ２

[20] The compound according to any one of [1'] and [1] to

[18] , or a pharmaceutically acceptable salt thereof, wherein R ９ is a halogen, and R １０ But -S(=O) ２ NH ２

[21] The compound according to any one of [1'] and [1] to

[19] , or a pharmaceutically acceptable salt thereof, wherein R １１

[22] The compound according to any one of [1'] and [1] to

[20] , wherein R is hydrogen, or a pharmaceutically acceptable salt thereof. １２

[23] The compound according to any one of [1'] and [1] to

[21] , or a pharmaceutically acceptable salt thereof, wherein R is halogen or haloalkyl. １１ is hydrogen, and R １２

[24] A compound selected from the group consisting of compounds I-001, I-002, I-004, I-006, I-096, I-137, I-138, I-139, I-140, I-141, I-142, I-144, I-145, I-147, I-148, I-149, I-150, I-151, I-152, I-153, I-154, I-155, I-157, I-158, I-159, I-160, I-161, I-162, I-163, I-165 and I-167, or a pharmaceutically acceptable salt thereof.

[25] A pharmaceutical composition comprising the compound according to any one of [1'] and [1] to

[24] or a pharmaceutically acceptable salt thereof.

[26] The pharmaceutical composition according to

[25] , which has an antiviral effect.

[27] The pharmaceutical composition according to

[25] or

[26] , which has an anti-HIV effect.

[28] A method for treating and / or preventing HIV infection, comprising administering the compound according to any one of [1'] and [1] to

[24] or a pharmaceutically acceptable salt thereof.

[29] The compound according to any one of [1'] and [1] to

[24] or a pharmaceutically acceptable salt thereof for treating and / or preventing HIV infection.

[30] Use of the compound according to any one of [1'] and [1] to

[24] or a pharmaceutically acceptable salt thereof for producing a medicament for treating and / or preventing HIV infection.

[0010] Furthermore, the present invention provides the following inventions [1A] to [11A]. [1A] Formula (II): (In the formula, R １ａ is hydrogen or halogen; R １ｂ is halogen, cyano, methyl or difluoromethyl; R １ｃ is halogen, cyano, methyl or difluoromethyl; (i) R ２is halogen, alkyl or haloalkyl, and R ３ is hydrogen or alkyl, or (ii) R ２ and R ３ together with the adjacent carbon atom, R Ｃ a benzene ring optionally substituted with R Ｃ forming a pyridine ring optionally substituted with R Ｃ is one or more groups selected from the group consisting of halogen and cyano; Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is -S(=O) ２ NH ２ and R ８ is hydrogen or alkyl; R ９ is a halogen; １０ is -S(=O) ２ -NH ２ [2A]R ８ [3A] The compound according to [1A], or a pharmaceutically acceptable salt thereof, wherein Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is -S(=O) ２ NH ２ [4A] The compound according to [1A] or [2A], or a pharmaceutically acceptable salt thereof, wherein R ２ is halogen, alkyl or haloalkyl, and R ３is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof. [5A] A compound selected from the group consisting of compounds I-001, I-004, I-096, I-137, I-139, I-140, I-142, I-144, I-145, I-147, I-148, I-149, I-150, I-151, I-152, I-153, I-154, I-155, I-157, I-158 and I-160, or a pharmaceutically acceptable salt thereof. [5A'] A compound selected from the group consisting of the following compounds, a deuterated version thereof, or a pharmaceutically acceptable salt thereof: [6A] A pharmaceutical composition comprising the compound according to any one of [1A] to [5A] or [5A'], a deuterated form thereof, or a pharmaceutically acceptable salt thereof. [7A] The pharmaceutical composition according to [6A], which has an antiviral activity. [8A] The pharmaceutical composition according to [6A] or [7A], which has an anti-HIV activity. [9A] A method for treating and / or preventing HIV infection, comprising administering the compound according to any one of [1A] to [5A] or [5A'], a deuterated form thereof, or a pharmaceutically acceptable salt thereof. [10A] The compound according to any one of [1A] to [5A] or [5A'], a deuterated form thereof, or a pharmaceutically acceptable salt thereof for treating and / or preventing HIV infection. [11A] Use of the compound according to any one of [1A] to [5A] or [5A'], a deuterated form thereof, or a pharmaceutically acceptable salt thereof for producing a medicament for treating and / or preventing HIV infection.

[0011] The compounds of the present invention have significant reverse transcriptase inhibitory activity and / or cell proliferation inhibitory activity against viruses, particularly HIV and HIV-resistant viruses. Therefore, they can be used at low doses for the prevention or treatment of various diseases and viral infections (e.g., AIDS) involving reverse transcriptase. More preferably, the compounds of the present invention are useful as persistent reverse transcriptase inhibitors. Furthermore, they are also excellent in terms of resistance profile, such as the resistance to the emergence of new HIV-resistant viruses. Even more preferably, the compounds of the present invention have preventive or therapeutic effects against drug-resistant HIV viruses. Even more preferably, the compounds of the present invention have low clearance, long in vivo half-life, and excellent solubility, metabolic stability, bioavailability, and the like. Furthermore, the compounds of the present invention are also preferably safe for use as pharmaceuticals, since they have few drug interactions (particularly, no contraindications for concomitant use) and little concern about cytotoxicity or side effects (e.g., mutagenicity, electrocardiogram QT interval prolongation, arrhythmia, and irritation risk).

[0012] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprises" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0013] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms, with fluorine and chlorine atoms being particularly preferred.

[0014] The term "alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0015] The term "alkenyl" encompasses straight-chain or branched hydrocarbon groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include ethenyl and n-propenyl.

[0016] "Alkynyl" includes a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more triple bonds at any position. It may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, etc.

[0017] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0018] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

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

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

[0021] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or multicyclic aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or multicyclic aromatic heterocyclic groups also include those in which the rings in the "aromatic carbocyclic group" are fused to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group, and the bond may be on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5- to 8-membered, and more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, and more preferably 9- or 10-membered. Examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. The tricyclic or more aromatic heterocyclic group is preferably 13- to 15-membered. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and the like.

[0022] The term "aromatic heterocycle" refers to a ring derived from the above-mentioned "aromatic heterocyclic group".

[0023] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include monocyclic or bicyclic or more non-aromatic heterocyclic groups fused with the respective rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as monocyclic or bicyclic or more non-aromatic carbocyclic groups fused with the rings of the above-mentioned "aromatic heterocyclic group," and the bond may be on any of the rings. Furthermore, the term "non-aromatic heterocyclic group" also includes bridged groups or groups forming spiro rings as described below. The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Non-aromatic heterocyclic groups having two or more rings preferably have 8 to 20 members, and more preferably have 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0024] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0025] In the present specification, the phrase "optionally substituted with substituent group a" means "optionally substituted with one or more groups selected from substituent group a". The same applies to substituent group b.

[0026] When a "non-aromatic carbocycle" or a "non-aromatic heterocycle" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows:

[0027] In formula (I) or (II), ring A, R １ , R １ａ , R １ｂ , R １ｃ , R ２ , substituent group a, R ３ , R Ｃ , L, R ４ , ring B, R Ｄ , R Ｅ , n, Z, substituent group b, m, R ６ , R Ａ , R Ｂ , R ８ , R ９ , R １０ , R １１ and R １２ Preferred embodiments of the compounds represented by formula (I) or (II) include all combinations of the specific examples shown below.

[0028] Ring A is the following ring (ia) or (ib): Ring A is the ring (ia) above. Ring A is the ring (ib) above.

[0029] R １ are each independently halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, or a non-aromatic carbocyclic group. １ are each independently halogen, cyano, alkyl, or haloalkyl.

[0030] R １ａ is hydrogen or halogen. １ａ is hydrogen.

[0031] R １ｂis halogen, cyano, methyl or difluoromethyl. １ｂ is cyano.

[0032] R １ｃ is halogen, cyano, methyl or difluoromethyl. １ｃ is halogen, methyl or difluoromethyl.

[0033] R ２ represents halogen, alkyl optionally substituted with substituent group a, alkyloxy, alkylthio, —C(═O)N(R Ａ ) R Ｂ , -C(=O)R Ａ , -S(=O) ２ R Ａ or a non-aromatic carbocyclic group. ２ is halogen, alkyl, haloalkyl, or —S(═O) ２ R Ａ (In the formula, R Ａ is alkyl). ２ is halogen, alkyl or haloalkyl.

[0034] Substituent group a is one or more groups selected from the group consisting of halogen, hydroxy, and alkyloxy. Substituent group a is one or more groups selected from the group consisting of halogen.

[0035] R Ａ are each independently hydrogen or alkyl. Ａ are each independently hydrogen. Ａ are each independently alkyl.

[0036] R Ｂ are each independently hydrogen or alkyl. Ｂ are each independently hydrogen. Ｂ are each independently alkyl.

[0037] R ３ is hydrogen, halogen, alkyl, haloalkyl or —N(R Ａ ) R Ｂ It is. ３is hydrogen or alkyl.

[0038] R ２ and R ３ together with the adjacent carbon atom, R Ｃ a benzene ring optionally substituted with R Ｃ R ２ and R ３ together with adjacent carbon atoms form the following ring: (In the formula, R Ｃ１ is hydrogen, halogen or cyano)

[0039] R Ｃ is one or more groups selected from the group consisting of halogen, cyano, alkyl, and alkyloxy. Ｃ is one or more groups selected from the group consisting of halogen and cyano.

[0040] L is —O— or —CH ２ L is —O—.

[0041] R ４ is hydrogen or halogen. ４ is a halogen.

[0042] Ring B is R Ｄ a 5- or 6-membered aromatic heterocycle optionally substituted with R Ｅ is a 5- or 6-membered non-aromatic heterocycle optionally substituted with The part indicated by is Ring B is R Ｄ any of the following rings optionally substituted with: (In the formula, R ４ and R is a halogen atom. Ring B is an unsubstituted ring selected from the following: (In the formula, R ４ is a halogen).

[0043] R Ｄ is one or more groups selected from the group consisting of halogen, hydroxy, amino, alkyl, haloalkyl, and hydroxyalkyl.Ｄ is one or more groups selected from the group consisting of alkyl. Ｅ is one or more groups selected from the group consisting of oxo, halogen, amino, alkyl, haloalkyl, and hydroxyalkyl.

[0044] n is an integer from 1 to 3. n is an integer from 2 to 3.

[0045] Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ are each independently a halogen atom, a hydroxyl group, a cyano group, an alkyl group which may be substituted by a substituent group b, an alkyloxy group, a haloalkyloxy group, or —N(R Ａ ) R Ｂ , -N(R Ａ ) S(=O) ２ R Ｂ , -N(R Ａ ) S(=O) ２ N (R Ａ ) R Ｂ , -N(R Ａ ) C(=O)R Ｂ , -N(R Ａ )C(=O)N(R Ａ ) R Ｂ , -SR Ａ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R Ａ are each independently hydrogen or alkyl; R Ｂ are each independently hydrogen or alkyl; and the substituent group b is a halogen, —N(R Ａ ) R Ｂ , -S(=O) ２ R Ａ and -S(=O) ２ N (R Ａ ) R Ｂ m is an integer of 0 to 2; R８ is hydrogen or alkyl; R ９ is hydrogen, halogen or alkyl; R １０ is -S(=O) ２ R Ａ , or -S(=O) ２ N (R Ａ ) R Ｂ and R １１ is hydrogen, halogen, alkyl or haloalkyl; R １２ is hydrogen, halogen, alkyl or haloalkyl. (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, —N(R Ａ ) R Ｂ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R ８ is hydrogen or alkyl; R ９ is a halogen; １０ is -S(=O) ２ -NH ２ Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is -S(=O) ２ NH ２ and R ８ is hydrogen or alkyl; R ９ is a halogen; １０ is -S(=O) ２ -NH ２ Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is -S(=O) ２ NH ２ ) is.

[0046] R ６ are each independently a halogen atom, a hydroxyl group, a cyano group, an alkyl group which may be substituted by a substituent group b, an alkyloxy group, a haloalkyloxy group, or —N(R Ａ ) R Ｂ , -N(R Ａ ) S(=O) ２ R Ｂ , -N(R Ａ ) S(=O) ２ N (R Ａ ) R Ｂ , -N(R Ａ ) C(=O)R Ｂ , -N(R Ａ )C(=O)N(R Ａ ) R Ｂ , -SR Ａ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl. ６ is halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, —N(R Ａ ) R Ｂ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl. ６ is -S(=O) ２ NH ２ is.

[0047] The substituent group b is a halogen atom, —N(R Ａ ) R Ｂ , -S(=O) ２ R Ａ and -S(=O) ２ N (R Ａ ) R Ｂand n is one or more groups selected from the group consisting of:

[0048] m is an integer of 0 to 2. m is an integer of 1.

[0049] R ８ is hydrogen or alkyl. ８ is alkyl.

[0050] R ９ is hydrogen, halogen or alkyl. ９ is a halogen.

[0051] R １０ is -S(=O) ２ R Ａ , or -S(=O) ２ N (R Ａ ) R Ｂ It is. １０ is -S(=O) ２ NH ２ is.

[0052] R １１ is hydrogen, halogen, alkyl or haloalkyl. １１ is hydrogen.

[0053] R １２ is hydrogen, halogen, alkyl or haloalkyl. １２ is halogen, or haloalkyl.

[0054] Unless otherwise specified, the compound of the present invention is not limited to a specific isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof. For example, the following compound of formula (I) includes the following tautomers:

[0055] One or more hydrogen, carbon and / or other atoms in the compound represented by formula (I) or (II) (hereinafter collectively referred to as "formula (I)" unless otherwise specified) may be substituted with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include: ２ H. ３H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. １２３ I and ３６ The isotopes of the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of formula (I) also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals. The compounds of formula (I) include all radiolabeled compounds substituted with radioactive isotopes contained in the isotopes. Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compound," and the "radiolabeled compound" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0056] The deuterated form of the compound of formula (I) is a compound in which one or more hydrogen atoms bonded to a carbon atom are deuterium ( ２ H), where the number of hydrogens replaced by deuterium is, at most, equal to the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of formula (I) when administered to a mammal, such as a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0057] The deuterated forms of the present invention may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. The deuterated forms of the present invention and their prodrugs can generally be prepared by the general synthetic methods described below or methods described in the Examples by substituting readily available isotopically labeled reagents with non-isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent in the compounds of formula (I).

[0058] Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) via catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of formula (I) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0059] Pharmaceutically acceptable salts of the compound of the present invention include salts of the compound 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 salts of the compound of the present invention with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, 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.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, etc. These salts can be formed by conventional methods.

[0060] The present invention includes the following forms. (i) The compound represented by formula (I) of the present invention may form a salt or a co-crystal. (ii) The compound represented by formula (I) of the present invention also includes solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (iii) The pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention also includes solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (iv) The co-crystal of the compound represented by formula (I) of the present invention also includes solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (v) A "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) relative to the compound represented by formula (I). (vi) When the compound represented by formula (I) of the present invention, a pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention, or a co-crystal of the compound represented by formula (I) of the present invention is left in the air, it may absorb moisture, resulting in the formation of adsorbed water or the formation of a hydrate. (vii) The compound represented by formula (I) of the present invention, a pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention, or a cocrystal of the compound represented by formula (I) of the present invention may be mutually converted by recrystallization. (viii) A pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention refers to a compound composed of the compound represented by formula (I) and a counter molecule or counter ion, with the two being bonded via an ionic bond. (ix) A cocrystal of the compound represented by formula (I) of the present invention means that the compound represented by formula (I) and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules. (x) A cocrystal is distinguished from a salt in that the compound represented by formula (I) remains essentially uncharged or neutral. (xi) A cocrystal is distinguished from a solvate (e.g., a hydrate, etc.) in that the counter molecule is not water or a solvent. Generally, a salt is considered to undergo proton transfer between the compound and the counter molecule, but it is also known that in some cases, the proton transfer may not be complete. This state is sometimes called a cocrystal because it is not a true salt. It is also known that proton transfer can vary continuously with temperature.Therefore, as used herein, "a pharmaceutically acceptable salt of a compound of formula (I)" includes co-crystals and refers to a pharmaceutically acceptable salt or co-crystal of a compound of formula (I).

[0061] (xii) The compound of the present invention represented by formula (I) may be amorphous. (xiii) The pharmaceutically acceptable salt of the compound of the present invention represented by formula (I) may be amorphous.

[0062] The compound of the present invention represented by formula (I), a deuterated product, or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of the compound of the present invention having a chemically or metabolically decomposable group, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." A prodrug may itself have activity.

[0063] When the compound represented by formula (I) of the present invention, a deuterated product or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting a compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride or a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH ３ COO-, C ２ H ５ COO-, tert-BuCOO-, C １５ H ３１ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ２ CH２ COO-, CH ３ CH(NH ２ ) COO-, CH ２ N (CH ３ ) ２ COO-, CH ３ SO ３ -, CH ３ CH ２ SO ３ -, CF ３ SO ３ -, CH ２ FSO ３ -, CF ３ CH ２ SO ３ -, p-CH ３ O-PhSO ３ -, PhSO ３ -, p-CH ３ PhSO ３ - are listed.

[0064] (Method for producing the compound of the present invention) The compound of the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments performed in ordinary organic chemistry experiments. The compound of the present invention can be synthesized by referring to methods known in the art.

[0065] (Method A) (wherein each symbol is as defined above, Lea is a leaving group such as halogen, -OTf or -OMs, and P １ is an amino protecting group; １ is any group that can be protected and / or deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), etc., and for example, P １(SEM, THP, etc.) (Step 1) Compound (A3) can be obtained by reacting compound (A1) with compound (A2) in the presence of a base. Compound (A1) is commercially available or can be synthesized by a known method. Compound (A2) is commercially available or can be synthesized by a known method. 1 to 1.5 molar equivalents, preferably 1 molar equivalent, can be used relative to compound (A1). Examples of bases include potassium carbonate, cesium carbonate, sodium hydride, potassium tert-butoxide, etc., and can be used in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (A1). The reaction temperature is room temperature to the reflux temperature of the solvent, preferably 40°C to the reflux temperature of the solvent. The reaction time is 0.1 to 72 hours, preferably 0.5 to 24 hours. Examples of reaction solvents include DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile, etc., and these can be used alone or in combination. (Step 2) Compound (A4) can be obtained by subjecting compound (A3) to a general deprotection reaction of an amino-protecting group. (Step 3) Compound (A6) can be obtained by reacting compound (A4) with compound (A5) in the presence of a base. Compound (A5) is commercially available or can be synthesized by a known method. It can be used in an amount of 1 to 1.5 molar equivalents, preferably 1 molar equivalent, relative to compound (A4). Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and potassium tert-butoxide. These bases can be used in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (A4). The reaction temperature is −20° C. to the reflux temperature of the solvent, preferably room temperature to the reflux temperature of the solvent. The reaction time is 0.1 to 72 hours, preferably 0.5 to 24 hours. Examples of reaction solvents include DMF, DMA, NMP, THF, 1,4-dioxane, and acetonitrile, and these can be used alone or in combination.

[0066] (Method B) (wherein each symbol is as defined above, A is C or N, R' is a carboxy-protecting group; R' may be any group that can be protected and / or deprotected by a method described in, for example, Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), and R' may be, for example, Et or BH.) (Step 1) Compound (B3) can be obtained by reacting compound (B2) with CDI, compound (B1), and a base. Compound (B1) is commercially available or can be synthesized by a known method. Compound (B2) is commercially available or can be synthesized by a known method. Compound (B2) can be used in an amount of 1 to 1.5 molar equivalents, preferably 1.1 molar equivalents, relative to compound (B1). Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and potassium tert-butoxide. These bases can be used in an amount of 1 to 5 molar equivalents, preferably 1.1 molar equivalents, relative to compound (B1). The reaction temperature is −20°C to the reflux temperature of the solvent, 0°C to 50°C. The reaction time is 0.1 to 72 hours, preferably 0.5 to 24 hours. Examples of reaction solvents include DMF, DMA, NMP, and THF, which can be used alone or in combination. (Step 2) Compound (B4) can be obtained by reacting compound (B3) with saturated saline. Alternatively, compound (B4) can be obtained by reacting with an acid. Examples of acids include acetic acid, TFA, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. The reaction temperature is −20°C to the reflux temperature of the solvent, 0°C to 150°C. The reaction time is 0.1 to 72 hours, preferably 0.5 to 24 hours. Examples of reaction solvents include DMSO, DMF, DMA, NMP, dichloromethane, and the like, which can be used alone or in combination. (Step 3) Compound (B5) can be obtained by reacting compound (B4) with hydrazine monohydrate. Hydrazine monohydrate can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (B4). The reaction temperature is 0°C to the reflux temperature of the solvent, or 0°C to 150°C.The reaction time is 0.1 to 72 hours, preferably 0.5 to 24 hours. The reaction solvent may be DMF, DMA, NMP, THF, 1,4-dioxane, or the like, and these may be used alone or in combination.

[0067] (C method) (wherein each symbol has the same meaning as above) Compound (C3) can be obtained by reacting Compound (C1) with Compound (C2) in the presence of a condensing agent. Compound (C1) is commercially available, can be synthesized by a known method, or can be synthesized by the method described above. Compound (C2) is commercially available, can be synthesized by a known method, or can be synthesized by the method described above. Compound (C2) can be used in an amount of 1 to 2 molar equivalents relative to Compound (C1). Examples of condensing agents include HATU, COMU, EDC, and propylphosphonic anhydride, and can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound (C2). Examples of bases include pyridine, triethylamine, DIEA, and methylmorpholine, and can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound (C1). The reaction temperature is 0°C to the reflux temperature of the solvent, preferably 0°C to room temperature. The reaction time is 0.1 to 24 hours, preferably 0.5 to 2 hours. Examples of reaction solvents include DMF, THF, etc., which can be used alone or in combination.

[0068] The compound of the present invention obtained above may be further chemically modified to synthesize another compound. In addition, during the above reaction, reactive functional groups (e.g., OH, COOH, NH) may be added to the side chain portion, etc. ２When a protecting group (amino protecting group, hydroxy protecting group, etc.) is present, it may be protected before the reaction and deprotected after the reaction, if desired. Examples of the protecting group (amino protecting group, hydroxy protecting group, etc.) include ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc., as described in Protective Groups in Organic Synthesis, by T. W. Green, John Wiley & Sons Inc. (1991). The protecting group can be introduced and removed by a method commonly used in organic synthetic chemistry [see, for example, Protective Groups in Organic Synthesis, by T. W. Greene, John Wiley & Sons Inc. (1991)] or a method similar thereto. In addition, the conversion of the functional groups contained in each substituent can also be carried out by known methods other than the above production methods [e.g., Comprehensive Organic Transformations, R. C. Larock (1989)], and some of the compounds of the present invention can be used as synthetic intermediates to further lead to novel derivatives. The intermediates and target compounds in each of 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 types of chromatography, etc. In addition, intermediates can also be subjected to the next reaction without any particular purification.

[0069] The compounds of the present invention are useful as pharmaceuticals, such as antiviral drugs. The compounds of the present invention have a strong inhibitory effect on reverse transcriptase. Therefore, the compounds of the present invention are expected to be effective in preventing or treating various diseases caused by viruses that produce at least reverse transcriptase and replicate in animal cells upon infection, even at low doses. For example, the compounds of the present invention are useful as reverse transcriptase inhibitors against retroviruses (e.g., HIV-1, HIV-2, HTLV-1, SIV, FIV, etc.), and are useful as anti-HIV drugs, etc. More preferred compounds also have characteristics in terms of pharmacokinetics, such as high blood concentration, long duration of effect, a high resistance barrier (less likely to develop resistance), few drug interactions (no contraindications for concomitant use), and / or significant tissue penetration. Furthermore, preferred compounds are safe in terms of side effects (e.g., mutagenicity, electrocardiogram QT interval prolongation, arrhythmia, and risk of irritation).

[0070] Furthermore, the compound of the present invention preferably has pharmaceutical utility, which can be evaluated by one or more of the following indices: a) weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.); b) good pharmacokinetics such as high bioavailability and moderate clearance; c) high metabolic stability; d) no irreversible inhibitory effect on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein; e) no mutagenicity; f) low cardiovascular risk; g) low risk of irritation.

[0071] The compounds of the present invention can also be used in combination therapy in combination with anti-HIV drugs having different mechanisms of action, such as integrase inhibitors, protease inhibitors, and / or entry blockers. Furthermore, the above-mentioned uses include not only anti-HIV combination drugs but also use as combination drugs that enhance the anti-HIV activity of other anti-HIV drugs, such as in cocktail therapy. Furthermore, the compounds of the present invention can be used in the field of gene therapy to prevent the spread of retroviral vector infection to tissues other than the target tissue when using retroviral vectors based on HIV or MLV. In particular, when cells, etc., are infected with a vector in a test tube and then infused back into the body, prior administration of the compounds of the present invention can prevent unnecessary infection in the body.

[0072] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0073] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0074] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0075] A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. Pediatric pharmaceutical compositions are preferably administered to patients under 12 or 15 years of age. Pediatric pharmaceutical compositions can also be administered to patients under 27 days of age, 28 days to 23 months of age, 2 to 11 years of age, or 12 to 17 or 18 years of age. Elderly pharmaceutical compositions are preferably administered to patients 65 years of age or older.

[0076] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of disease, route of administration, etc., but when administered orally, it is typically 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. When administered parenterally, the dosage varies greatly depending on the route of administration, but is typically 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage may be administered once a day to once a month, once every two months, or once every three or more months. For example, 100 mg to 1600 mg may be administered in a single treatment in an amount of 1 to 5 mL per site, once at intervals of three months or more. Preferably, 100 mg to 500 mg may be administered in a single treatment in an amount of 1 to 5 mL per site, once at intervals of three months or more. For example, it may be administered by subcutaneous injection, intramuscular injection, or implant.

[0077] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these.

[0078] The abbreviations used in this specification have the following meanings: BH: benzhydryl, Bn: benzyl, CDI: carbonyldiimidazole, DIBAL: diisobutylaluminum hydride, DIEA: N,N-diisopropylethylamine, DMA: dimethylacetamide, DMF: N,N-dimethylformamide, DMSO: dimethylsulfoxide, Et: ethyl, NBS: N-bromosuccinimide, NMP: N-methyl-2-pyrrolidone, PdCl ２ (dppf): [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc) ２ : Palladium (II) acetate PMB: p-methoxybenzyl SEM: 2-(trimethylsilyl)ethoxymethyl TFA: Trifluoroacetic acid THF: Tetrahydrofuran THP: 2-tetrahydropyranyl

[0079] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ , CDCl ３ The measurement was performed using the method described above. When NMR data is presented, not all measured peaks may be listed. In the specification, "MS (ESI): m / z" refers to the mass of the molecule observed by LC / MS (liquid chromatography / mass spectrometry). The measurement conditions for LC / MS include, but are not limited to, the conditions shown below. Unless otherwise specified, MS (ESI): m / z refers to [M+H] ＋(Measurement Condition 1) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Measurement Condition 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] was an aqueous solution containing 10 mM ammonium carbonate, [B] was acetonitrile Gradient: a linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes.

[0080] Example 1 Step 1: Under a nitrogen atmosphere, a mixture of compound 1 (36.0 g, 186 mmol), DIEA (38.9 mL, 223 mmol), and THF (540 mL) was ice-cooled, and 2-(chloromethoxy)ethyltrimethylsilane (36.0 mL, 204 mmol) was added. The mixture was stirred at room temperature for 1 hour and then allowed to stand for 2 days. Methanol (40.0 mL) was added and the mixture was ice-cooled. 2 mmol / L aqueous sodium hydroxide solution (186 mL, 371 mmol) and 30% aqueous hydrogen peroxide (20.9 mL, 204 mmol) were added, followed by stirring for 1 hour. Sodium thiosulfate pentahydrate (69.1 g, 278 mmol) dissolved in water (180 mL) was added, and the solvent was evaporated under reduced pressure. The resulting residue was extracted with diethyl ether, and the organic layer was then extracted with 1 mol / L aqueous sodium hydroxide solution and water. Citric acid monohydrate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 2 (19.2 g, yield 48%, 3:1 mixture of regioisomers). MS: m / z = 215 [M+H] ＋Step 2: Under a nitrogen atmosphere, compound 2 (19.2 g, 90.0 mmol), compound 3 (15.3 g, 90.0 mmol), cesium carbonate (43.8 g, 134 mmol), and DMA (192 mL) were mixed and stirred at 100°C for 30 minutes. After cooling, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give compound 4 (21.9 g, 57.8 mmol, yield 65%). MS: m / z = 366 [M+H] ＋ Step 3: Compound 4 (21.8 g, 57.8 mmol) was dissolved in 1,2-dichloroethane (218 mL), and TFA (107 mL, 1.39 mol) was added, followed by stirring at room temperature for 2 hours. The solvent was removed under reduced pressure, followed by adding toluene, and the solvent was removed under reduced pressure again. THF (218 mL) and 28% aqueous ammonia (107 mL, 1.39 mol) were added to the resulting residue, followed by stirring at room temperature for 2 hours. The solvent was removed under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 5 (12.9 g).

[0081] Step 4: Under a nitrogen atmosphere, compound 5 (12.8 g, 52.8 mmol) was dissolved in acetonitrile (128 mL) and cooled on ice. NBS (9.40 g, 52.8 mmol) was added, and the mixture was stirred under ice-cooling for 30 minutes. 10% aqueous sodium thiosulfate solution was added, and the solution was evaporated under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with hexane and diisopropyl ether to give compound 6 (13.6 g, 43.4 mmol, 82% yield). MS: m / z = 314 [M+H]+ Step 5: Compound 7 (134 mg, 0.496 mmol) was dissolved in DMA (2.0 mL), and potassium carbonate (411 mg, 2.97 mmol) and p-methoxybenzyl chloride (0.270 mL, 1.98 mmol) were added. The mixture was stirred at 60°C for 45 minutes and at 75°C for 60 minutes. Ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 8 (403 mg, yield 100%). 1H-NMR (CDCl3) δ: 1.52(t, J=7.0Hz, 3H), 3.72(s, 3H), 3.74(s, 6H), 4.37(s, 4H), 4.53(q, J=7.2Hz, 2H), 6.04(s, 2H), 6.62(d, J=8.7Hz, 4H), 6.69(d, J=8.8Hz, 2H), 6.80(d, J=8.7Hz, 4H), 7.23(d, J=8.7Hz, 2H), 7.33(t, J=8.3Hz, 1H), 8.03(d, J=6.4Hz, 1H), 8.26(d, J=7.7Hz, 1H). Process 6 Compound 8 (403 mg, 0.495 mmol) was dissolved in THF (4.0 mL), and under ice-cooling, a 1 mol / L DIBAL hexane solution (2.48 mL, 2.48 mmol) was added, followed by stirring at room temperature for 1.5 hours. A 1 mol / L DIBAL hexane solution (0.743 mL, 0.743 mmol) was added again, followed by stirring at room temperature for 30 minutes. The solution was added to an aqueous solution of potassium sodium tartrate tetrahydrate, followed by stirring at room temperature for 30 minutes, followed by addition of ethyl acetate, followed by stirring at room temperature for 30 minutes. Extraction with ethyl acetate was performed, and the organic layer was washed with water, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 9 (257 mg, yield 88%). 1 H-NMR (CDCl3) δ: 1.99(t, J=6.0Hz, 1H), 3.74(s, 6H), 3.75(s, 3H), 4.37(s, 4H), 5.02(d, J=5.6Hz, 2H), 5.64(s, 2H), 6.62(d, J=8.5Hz, 4H), 6.73(d, J=8.7Hz, 2H), 6.80(d, J=8.5Hz, 4H), 7.11(d, J=8.4Hz, 2H), 7.13(t, J=7.3Hz, 1H), 7.84(d, J=8.4Hz, 1H), 7.97(d, J=7.0Hz, 1H).

[0082] Step 7: Compound 9 (256 mg, 0.436 mmol) was dissolved in dichloromethane (2.56 mL), thionyl chloride (0.159 mL, 2.18 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Toluene was added, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 10 (240 mg, yield 91%). 1 H-NMR (CDCl3) δ: 3.74(s, 6H), 3.75(s, 3H), 4.34(s, 4H), 4.94(s, 2H), 5.63(s, 2H), 6.64(d, J=8.7Hz, 4H), 6.73(d, J=8.7Hz, 2H), 6.77(d, J=8.5Hz, 4H), 7.07(d, J=8.7Hz, 2H), 7.23(dd, J=8.3, 7.1Hz, 1H), 7.87(d, J=7.8Hz, 1H), 8.02(d, J=6.5Hz, 1H). Process 8 Compound 6 (57.0 mg, 0.181 mmol), compound 10 (110 mg, 0.181 mmol), and cesium carbonate (89.0 mg, 0.272 mmol) were suspended in DMF (0.570 mL) and stirred at 40°C for 30 minutes. Ethyl acetate-water-saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 11 (131 mg, yield 82%). 1H-NMR (CDCl3) δ: 3.74(s, 6H), 3.76(s, 3H), 4.42(s, 4H), 5.55(s, 2H), 5.64(s, 2H), 6.62(t, J=55.9Hz, 1H), 6.64(d, J=8.7Hz, 4H), 6.71(d, J=8.5Hz, 2H), 6.83(d, J=8.5Hz, 4H), 6.85(s, 1H), 6.90(d, J=8.7Hz, 2H), 7.24-7.33(m, 1H), 7.51-7.58(m, 3H), 7.82(d, J=8.3Hz, 1H), 8.05(d, J=6.9 Hz, 1H). Step 9: Compound 11 (260 mg, 0.294 mmol) and p-anisole (0.643 mL, 5.88 mmol) were dissolved in TFA (2.6 mL) and stirred at 80°C for 40 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in isopropanol-water at 70°C and stirred at room temperature for 15 minutes. The precipitated solid was collected by filtration, washed with isopropanol-water, and dried under reduced pressure to obtain compound I-004 (90.0 mg, yield 59%). 1 H-NMR (DMSO-d6) δ: 5.70(s, 2H), 7.05(t, J=55.3Hz, 1H), 7.28(t, J=7.8Hz, 1H), 7.52(s, 1H), 7.76(s, 1H), 7.80(d, J=7.3Hz, 1H), 7.85(s, 1H), 7.93(d, J=8.0Hz, 1H), 8.28(s, 1H), 13.04(brs, 1H).

[0083] Example 2 Step 1: Compound 12 (4.46 g, 19.2 mmol) was dissolved in DMF (31 mL), and potassium carbonate (5.30 g, 38.4 mmol) and benzyl mercaptan (5.62 mL, 48.0 mmol) were added. The mixture was stirred at 90°C for 3 hours and at 105°C for 2 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 13 (4.63 g, yield 75%). 1H-NMR (CDCl) δ: 4.66 (s, 2H), 7.24-7.36 (m, 4H), 7.41 (d, J = 7.0 Hz, 2H), 8.28 (d, J = 5.7 Hz, 1H), 10.15 (brs, 1H). Step 2: Under a nitrogen atmosphere, compound 13 (2.67 g, 8.34 mmol) was dissolved in THF (27 mL), and 3,4-dihydro-2H-pyran (3.8 mL, 42 mmol) and p-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) were added, followed by stirring at 60 °C for 24 hours. After cooling, triethylamine (0.58 mL, 4.2 mmol) was added, and the solvent was evaporated under reduced pressure. Methanol (50 mL) was added to the resulting residue, and the solvent was evaporated under reduced pressure. Methanol was further added, and the mixture was stirred at 0° C. for 20 minutes, and then the solid was collected by filtration to obtain Compound 14 (2.87 g, yield 85%). 1 H-NMR (CDCl3) δ: 1.56-1.66(m, 1H), 1.66-1.80(m, 2H), 2.05-2.18(m, 2H), 2.52-2.62(m, 1H), 3.80(td, J=11.5, 2.6Hz, 1H), 4.02(dt, J=11.7, 1.8Hz, 1H), 4.55(d, J=13.2Hz, 1H), 4.78(d, J=13.2Hz, 1H), 6.22(dd, J=9.7, 2.5Hz, 1H), 7.23(d, J=5.6Hz, 1H), 7.28-7.34(m, 3H), 7.46(d, J=7.4Hz, 2H), 8.23 ​​(d, J=5.4 Hz, 1H). Step 3: Under a nitrogen atmosphere, compound 14 (2.87 g, 7.10 mmol) was dissolved in 1,4-dioxane (43 mL), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (1.20 g, 1.42 mmol) and tributylstannylmethanol (6.2 mL, 21.3 mmol) were added, followed by stirring at 100°C for 80 minutes. After cooling, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 15 (1.34 g, 53% yield). 1H-NMR (CDCl3) δ: 1.56-1.61(m, 1H), 1.67-1.81(m, 2H), 1.95(t, J=6.1Hz, 1H), 2.03-2.15(m, 2H), 2.58(m, 1H), 3.79-3.88(m, 1H), 4.01-4.08(m, 1H), 4.56(d, J=13.2Hz, 1H), 4.78(d, J=13.2Hz, 1H), 5.01(d, J=6.0Hz, 2H), 6.27(dd, J=10.1, 2.3Hz, 1H), 7.27-7.35(m, 3H), 7.41-7.49(m, 3H), 8.20(d, J=5.7Hz, 1H).

[0084] Step 4: Compound 15 (292 mg, 0.821 mmol) was dissolved in THF (4 mL), and triethylamine (228 μL, 1.64 mmol), methanesulfonyl chloride (228 μL, 1.64 mmol), and lithium chloride (348 mg, 8.21 mmol) were added under ice-cooling, followed by stirring at room temperature for 90 minutes. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 16 (284 mg, yield 93%). 1H-NMR (CDCl3) δ: 1.56-1.65(m, 1H), 1.65-1.81(m, 2H), 2.03-2.15(m, 2H), 2.50-2.62(m, 1H), 3.78-3.87(m, 1H), 4.04(dt, J=11.7, 1.7Hz, 1H), 4.55(d, J=13.2Hz, 1H), 4.78(d, J=13.2Hz, 1H), 4.91(s, 2H), 6.26(dd, J=10.0, 2.2Hz, 1H), 7.27-7.35(m, 3H), 7.43-7.49(m, 3H), 8.23(d, J=5.4 Hz, 1H). Step 5: Under a nitrogen atmosphere, compound 16 (275 mg, 0.735 mmol) was dissolved in DMA (2 mL), and compound 6 (210 mg, 0.669 mmol), sodium iodide (10 mg, 0.067 mmol), and cesium carbonate (327 mg, 1.00 mmol) were added, followed by stirring at 50°C for 90 minutes. After cooling, aqueous citric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate) to give compound 17 (305 mg, 70% yield). 1H-NMR (CDCl3) δ: 1.56-1.65(m, 1H), 1.68-1.83(m, 2H), 2.03-2.17(m, 2H), 2.58(m, 1H), 3.80-3.88(m, 1H), 4.05-4.14(m, 1H), 4.55(d, J=13.2Hz, 1H), 4.78(d, J=13.2Hz, 1H), 5.52(s, 2H), 6.28(dd, J=10.0, 2.2Hz, 1H), 6.60(t, J=56Hz, 1H), 7.22-7.24(m, 1H), 7.27-7.34(m, 3H), 7.42-7.54 (m, 6H), 8.19 (d, J=5.7 Hz, 1H). Step 6: Compound 17 (305 mg, 0.468 mmol) was dissolved in dichloromethane (4 mL). Under ice-cooling, water (1.2 mL), acetic acid (0.61 mL), and 2 mol / L hydrochloric acid (0.23 mL) were added. A dichloromethane solution (2 mL) of 1,3-dichloro-5,5-dimethylhydantoin (277 mg, 1.40 mmol) was added dropwise, and the mixture was stirred under ice-cooling for 25 minutes. 28% aqueous ammonia (2.7 mL) was added, and the mixture was stirred under ice-cooling for 20 minutes. Aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate) to give compound 18 (221 mg, 78% yield). 1H-NMR (CDCl3) δ: 1.63-1.70(m, 1H), 1.69-1.93(m, 2H), 2.12-2.22(m, 2H), 2.51-2.66(m, 1H), 3.83-3.98(m, 1H), 3.98-4.09(m, 1H), 5.44-5.55(m, 2H), 5.60(s, 2H), 6.55(dd, J=9.7, 1.9Hz, 1H), 6.62(t, J=56Hz, 1H), 7.35(s, 1H), 7.49(s, 1H), 7.52(s, 1H), 7.54(s, 1H), 7.83(d, J=5.2Hz, 1H), 8.33 (d, J=5.2 Hz, 1H). Step 7: Compound 18 (206 mg, 0.339 mmol) was dissolved in 1,4-dioxane (1 mL), and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (2 mL) was added under ice-cooling, followed by stirring at room temperature for 1 hour. Under ice-cooling, 5% aqueous sodium bicarbonate and methanol were added, and the solid was collected by filtration. The resulting crude product was dissolved in THF, and methanol and water were added. The resulting solid was collected by filtration to obtain compound I-001 (141 mg, yield 79%). 1 H-NMR (DMSO-d6) δ: 5.74(s, 2H), 7.04(t, J=56Hz, 1H), 7.51(s, 1H), 7.74-7.82(m, 2H), 7.85(s, 1H), 7.92(d, J=5.4Hz, 1H), 8.30(s, 1H), 8.33(d, J=5.4Hz, 1H), 13.70(brs,1H).

[0085] Example 3 Step 1: Under a nitrogen atmosphere, compound 19 (7.00 g, 20.1 mmol) was dissolved in TFA (20 mL) and cooled to 0°C. Potassium nitrate (3.04 g, 30.1 mmol) was added, and the mixture was stirred at 60°C for 5 hours. After cooling, the mixture was added to an aqueous solution of sodium bicarbonate (25.3 g, 301 mmol) cooled to 0°C, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, and the mixture was extracted. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude compound 20 (7.89 g). Step 2: Under a nitrogen atmosphere, crude compound 20 (6.50 g, 16.5 mmol) was dissolved in acetonitrile (160 mL), and copper(II) bromide (7.37 g, 33.0 mmol) and tert-butyl nitrite (3.96 mL, 33.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added, and the mixture was extracted. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude compound 21 (7.41 g). Step 3: Crude compound 21 (7.41 g, 16.2 mmol) was dissolved in ethanol (74 mL), iron (4.52 g, 81.0 mmol) and concentrated hydrochloric acid (6.74 mL, 81.0 mmol) were added, and the mixture was stirred at 80°C for 2 hours. After cooling, the mixture was added to an aqueous solution of sodium bicarbonate (13.58 g, 162 mmol) cooled to 0°C and stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration using Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give compound 22 (3.82 g, yield 55%). 1H-NMR (CDCl3) δ: 1.26(t, J=7.2Hz, 3H), 3.60(d, J=0.8Hz, 2H), 4.18(q, J=7.2Hz, 2H), 6.67(d, J=6.0Hz, 1H), 7.03(m, 1H), 7.16(t, J=2.0Hz, 1H), 7.33(t, J=1.6Hz, 1H).

[0086] Step 4: Compound 22 (3.82 g, 8.89 mmol) was dissolved in 1,4-dioxane (38 mL) and water (3.8 mL), and the solution was added with 2,4,6-trimethylboroxine (1.49 mL, 10.7 mmol), potassium carbonate (3.68 g, 26.7 mmol), and PdCl ２(dppf) (0.73 g, 0.89 mmol) was added, and the mixture was stirred at 100°C under a nitrogen atmosphere for 1.5 hours. After cooling, water and ethyl acetate were added, insoluble matter was removed by filtration using Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give compound 23 (2.1 g, yield 65%). H-NMR (CDCl) δ: 1.25 (t, J = 7.2 Hz, 3H), 1.98 (s, 3H), 3.58 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 6.54 (d, J = 5.6 Hz, 1H), 7.00 (brs, 1H), 7.21 (t, J = 2.0 Hz, 1H), 7.29 (t, J = 1.6 Hz, 1H). Step 5: Compound 23 (2.1 g, 5.79 mmol) was dissolved in TFA (21 mL) and cooled to 0 °C. A solution of sodium nitrite (399 mg, 5.79 mmol) in water (4.2 mL) was added, and the mixture was stirred at 0 °C for 30 minutes. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate were added to the resulting residue. The mixture was stirred at 0°C for 30 minutes and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give compound 24 (680 mg, yield 31%). H-NMR (CDCl) δ: 1.27 (t, J = 7.2 Hz, 3H), 3.83 (d, J = 1.2 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 7.11 (brs, 1H), 7.24 (t, J = 2.0 Hz, 1H), 7.36-7.37 (m, 2H), 7.87 (s, 1H). Step 6: Compound 24 (400 mg, 1.07 mmol) was dissolved in ethyl acetate (3.2 mL) and cooled to 0 °C. Trimethyloxonium tetrafluoroborate (158 mg, 1.07 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over sodium sulfate.The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give compound 25 (290 mg, 70% yield). H-NMR (CDCl) δ: 1.25 (t, J = 7.2 Hz, 3H), 3.80 (d, J = 1.2 Hz, 2H), 4.16-4.22 (m, 5H), 7.10 (brs, 1H), 7.20 (t, J = 2.0 Hz, 1H), 7.33 (t, J = 1.6 Hz, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.71 (s, 1H).

[0087] Step 7: 2-Chloro-3-pyridinecarboxylic acid (44.7 mg, 0.284 mmol) was dissolved in DMF (0.8 mL), CDI (50.2 mg, 0.309 mmol) was added, and the mixture was stirred at 50°C for 1 hour. The mixture was cooled to 0°C, and compound 25 (100 mg, 0.258 mmol) and sodium hydride (30.9 mg, 0.258 mmol) were added, followed by stirring at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude compound 26 (123 mg). Step 8: Crude compound 26 (120 mg, 0.228 mmol) was dissolved in DMSO (1.2 mL), saturated aqueous sodium chloride (0.06 mL) was added, and the mixture was stirred at 150°C for 30 minutes. After cooling, water and ethyl acetate were added, followed by extraction. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give Compound 27 (45 mg, yield 43%). H-NMR (DMSO-d) δ: 4.12 (s, 3H), 4.57 (s, 2H), 7.38 (t, J = 2.0 Hz, 1H), 7.46 (q, J = 1.2 Hz, 1H), 7.57-7.62 (m, 2H), 7.81 (t, J = 1.2 Hz, 1H), 8.26-8.29 (m, 2H), 8.55 (dd, J = 4.8, 2.0 Hz, 1H). Step 9: Compound 27 (45 mg, 0.099 mmol) was dissolved in 1,4-dioxane (0.32 mL) and ethanol (0.045 mL), and hydrazine monohydrate (0.057 mL, 1.185 mmol) was added, followed by stirring at 50°C to 120°C for 26.5 hours. After cooling, water and ethyl acetate were added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform-methanol) to obtain compound I-003 (11 mg, yield 25%).1H-NMR (DMSO-d6) δ: 4.10(s, 3H), 4.45(s, 2H), 7.12(dd, J=8.0, 4.4Hz, 1H), 7.38(t, J=2.0Hz, 1H), 7.49(dd, J=4.8, 1.6Hz, 1H), 7.54(d, J=5.2Hz, 1H), 7.78(t, J=1.6Hz, 1H), 8.04(dd, J=8.0, 1.2Hz, 1H), 8.22(s, 1H), 8.48(dd, J=4.8, 1.6Hz, 1H).

[0088] Example 4 Step 1: Compound 29 (5.00 g, 32.6 mmol) was dissolved in THF (50 ml) and cooled to 0°C. Potassium tert-butoxide (3.44 g, 35.8 mmol) and compound 28 (6.35 g, 32.6 mmol) were added, and the mixture was stirred at room temperature. A suspension of potassium tert-butoxide (6.88 g, 71.6 mmol), THF (50 mL), and tert-butylethyl malonate (6.74 g, 35.8 mmol), separately prepared at 0°C, was added, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0°C, 2 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to obtain crude compound 30. Step 2: The crude compound 30 was dissolved in dichloromethane (10 ml), TFA (30 ml) was added, and the mixture was stirred at room temperature for 1 hour. After the solvent was removed under reduced pressure, ethyl acetate was added, washed with saturated aqueous sodium bicarbonate, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain compound 31 (4.79 g, yield 37%). MS: m / z = 395 [M-H]. Step 3: Compound 31 (4.79 g, 12.1 mmol) was dissolved in DMF (50 ml) and cooled to 0°C. A separately prepared suspension of 4-methoxybenzenemethanethiol (1.86 g, 12.0 mmol), DMF (20 ml), and potassium carbonate (2.50 g, 18.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 32.

[0089] Step 4: The crude product of compound 32 was dissolved in ethanol (100 ml) and water (10 ml), and ammonium chloride (3.23 g, 60.9 mmol) and iron (3.37 g, 60.2 g) were added, followed by stirring at 80°C for 2 hours. Ethyl acetate was added, and the insoluble matter was filtered off using Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water. After drying over sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give compound 33 (4.03 g, yield 67%). MS: m / z = 501 [M+H] ＋ Step 5: Compound 33 (3.00 g, 6.00 mmol) was dissolved in TFA (30 ml), trifluoromethanesulfonic acid (1.35 g, 9.00 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Toluene was added, and the solvent was evaporated under reduced pressure to obtain crude compound 34. Step 6: The crude compound 34 obtained was dissolved in ethyl orthoformate (30 ml), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate and saturated aqueous sodium bicarbonate were added, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain compound 35 (1.61 g, yield 69%). MS: m / z = 391 [M+H] ＋

[0090] Step 7: Compound 36 (194 mg, 0.77 mmol) was dissolved in DMF (1.6 mL), CDI (133 mg, 0.82 mmol) was added, and the mixture was stirred at 50°C for 40 minutes. The mixture was cooled to -20°C, and compound 35 (200 mg, 0.51 mmol) and 60% sodium hydride (82 mg, 2.05 mmol) were added. The mixture was stirred at -20°C for 5 minutes and at room temperature for 1.2 hours. Aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to obtain crude compound 37. Step 8: The crude compound 37 was dissolved in DMSO (3.64 mL), saturated saline (0.182 ml) was added, and the mixture was stirred at 150°C for 1 hour. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give compound 38 (0.141 g, 44% yield). H-NMR (DMSO-d) δ: 9.42 (1H, s), 9.29 (1H, d, J = 4.9 Hz), 8.15 (1H, d, J = 6.2 Hz), 8.10 (1H, d, J = 4.9 Hz), 7.77 (1H, t, J = 1.4 Hz), 7.62-7.52 (2H, m), 7.50 (2H, t, J = 1.2 Hz), 7.43 (1H, t, J = 2.2 Hz), 7.23 (1H, t, J = 8.7 Hz), 4.80 (2H, s). Compound 38 (139 mg, 0.25 mmol) was dissolved in 1,4-dioxane (0.973 ml) and ethanol (0.139 mL), and hydrazine monohydrate (0.122 mL, 2.51 mmol) was added, followed by stirring overnight at 120° C. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound I-005 (32 mg, yield 29%).1H-NMR(DMSO-d6)δ: 4.60(2H, s), 7.45(1H, t, J=2.1Hz), 7.52(1H, dd, J=2.3, 1.3Hz) 7.76(1H, t, J=1.6Hz), 8.06(1H, d, J=5.7Hz), 8.11(1H, d, J=6.2Hz), 9.08(1H, d, J=5.4Hz), 9.37(1H, s).

[0091] Example 5 Step 1: Under a nitrogen atmosphere, compound 20 (10.0 g, 25.4 mmol) was dissolved in ethanol (100 mL), and iron (14.2 g, 254 mmol) and ammonium chloride (13.6 g, 254 mmol) were added. The mixture was stirred at 80°C for 2 hours. After cooling, insoluble matter was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give crude compound 39 (9.59 g). Step 2: Under a nitrogen atmosphere, crude compound 39 (2.00 g) was dissolved in ethanol (40 mL), and 40% aqueous glyoxal solution (0.817 ml, 7.15 mmol) was added. The mixture was stirred at room temperature for 6 hours and then allowed to stand overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give compound 40 (2.06 g, yield 97%). MS: m / z = 389 [M+H] ＋ Step 3: Under a nitrogen atmosphere, compound 40 (2.06 g, 5.34 mmol) was dissolved in THF (40 mL), and 4 mol / L aqueous lithium hydroxide solution (4.00 mL, 16.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. 2 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give crude compound 41 (1.82 g).

[0092] Step 4: Under a nitrogen atmosphere, the crude product of compound 41 (1.82 g) was dissolved in THF (20 mL), and compound 42 (1.09 g, 5.60 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was washed with hexane to obtain crude product of compound 43 (2.30 g). Step 5: 3-Bromo-2-fluorobenzoic acid (0.39 g, 1.79 mmol) was dissolved in DMF (6.2 mL), and CDI (0.31 g, 1.91 mmol) was added. The mixture was stirred at 50°C for 20 minutes. The mixture was cooled to 0°C, and crude product of compound 43 (0.62 g) and sodium hydride (0.19 g, 4.76 mmol) were added, followed by stirring for 35 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain crude product of compound 44 (0.97 g). Step 6: Under a nitrogen atmosphere, the crude product of compound 44 (0.86 g, 1.19 mmol) was dissolved in anisole (1.30 mL), and TFA (3.45 mL, 44.8 mmol) was added. The mixture was stirred at room temperature for 40 minutes. Aqueous potassium carbonate solution was added under ice-cooling, and ethyl acetate was added for extraction. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform-methanol) to give compound 45 (0.48 g, yield 78%). 1 H-NMR(CDCl3)δ: 4.64(s, 2H), 7.10(s, 1H), 7.19(t, J=7.8Hz, 1H), 7.28-7.26(m, 1H), 7.34(s, 1H), 7.82(dd, J=7.8, 6.9Hz, 1H), 7.89(t, J=7.8Hz, 1H), 8.01(d, J=6.9Hz, 1H), 8.83(d, J=1.6 Hz, 1H), 8.91(d, J=1.6Hz, 1H).

[0093] Step 7: Compound 45 (0.53 g, 1.03 mmol) was dissolved in 1,4-dioxane (5.3 mL), hydrazine monohydrate (0.20 mL, 4.12 mmol) was added, and the mixture was stirred at 130°C for 80 minutes. After cooling, water and ethyl acetate were added and extracted. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was washed with ethyl acetate to give compound 46 (0.38 g, yield 73%). 1 H-NMR(DMSO-d6)δ: 4.66(2H, s), 7.05(1H, t, J=7.3Hz), 7.52(2H, s), 7.60(1H, d, J=7.3Hz), 7.73(1H, s), 7.77(1H, d, J=7.3Hz), 8.02(1H, d, J=7.3Hz), 8.86(1H, s), 8.96(1H, s), 13.33(1H, s). Process 8 Compound 46 (0.37 g, 0.73 mmol) was suspended in THF (7.4 mL), and 3,4-dihydro-2H-pyran (0.80 mL, 8.73 mmol) and p-toluenesulfonic acid monohydrate (13.8 mg, 0.07 mmol) were added, followed by stirring at 65°C for 11 hours. After cooling, triethylamine (0.10 mL, 0.73 mmol) was added, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give compound 47 (0.32 g, yield 74%). 1H-NMR(CDCl3)δ: 1.62-1.59(1H, m), 1.79-1.72(2H, m), 2.15-2.11(2H, m), 2.67-2.62(1H, m), 3.86-3.80(1H, m), 4.08-4.05(1H, m), 4.61(2H, s), 6.53(1H, dd, J=10.0, 1.9Hz), 7.00(1H, t, J=7.9Hz), 7.05(1H, s), 7.20(1H, t, J=1.9Hz), 7.34(1H, s), 7.55(1H, d, J=7.9Hz), 7.60(1H, d, J=7.4Hz), 7.88 (1H, d, J = 7.4 Hz), 8.76 (1H, d, J = 1.4 Hz), 8.83 (1H, d, J = 1.4 Hz). Step 9: Compound 47 (0.30 g, 0.51 mmol) was dissolved in 1,4-dioxane (3.0 mL), and 4-tert-butylbenzyl mercaptan (0.14 mL, 0.76 mmol), DIEA (0.18 mL, 1.01 mmol), and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-2'-amino-1,1'-biphenyl]palladium(II) methanesulfonate (48 mg, 0.05 mmol) were added, followed by stirring at 120°C for 1 hour. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to give Compound 48 (0.31 g, yield 89%). 1H-NMR(CDCl3)δ: 1.27(9H, s) 1.78-1.66(2H, m), 1.87-1.84(1H, m), 2.10-2.07(1H, m), 2.60-2.54(1H, m), 3.81-3.79(1H, m), 4.16-4.04(4H, m), 4.62(2H, s), 6.70(1H, dd, J=10.2, 1.9Hz), 7.07-7.03(4H, m), 7.19(1H, s), 7.32-7.29(2H, m), 7.34(1H, s), 7.42(1H, d, J=7.2Hz), 7.51(1H, d, J=8.0Hz), 7.86(1H, d, J=7.2Hz), 8.76(1H, d, J=1.3Hz), 8.82(1H, d, J=1.3Hz).

[0094] Step 10: Compound 48 (0.30 g, 0.43 mmol) was mixed with acetic acid (0.6 mL), THF (3.0 mL), water (0.3 mL), and NCS (0.17 g, 1.30 mmol) and stirred at room temperature for 23 minutes. A solution of 28% aqueous ammonia (1.0 mL) in THF (2.0 mL) was added, diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude compound 49 (0.36 g). Step 11: TFA (2.6 mL) and water (0.26 mL) were added to crude compound 49 (0.26 g) and stirred at room temperature for 50 minutes. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a residue. The insoluble matter from the extraction and the residue were combined and washed with methanol, and then purified by SFC. The solvent was evaporated under reduced pressure, and the resulting solid was washed with isopropyl ether-hexane to obtain compound I-006 (62 mg, yield 28%). SFC preparative conditions: preparative column (IA-IA, manufactured by Daicel), flow rate: 30 mL / min, mobile phase: 60% aqueous ethanol solution 1H-NMR(DMSO-d6)δ: 4.72(2H, s), 7.26(1H, t, J=7.3 Hz), 7.53(2H, s), 7.73(1H, s), 7.80(1H, d, J=7.3Hz), 8.01(1H, d, J=7.3Hz), 8.05(1H, d, J=8.0Hz), 8.86(1H, s), 8.95(1H, s).

[0095] Example 6 Step 1: Compound 22 (6.13 g, 13.4 mmol) was dissolved in THF (61 mL) and cooled to 0°C. Formic acetic anhydride (1.58 mL, 20.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, toluene was added, and the solvent was evaporated under reduced pressure again to obtain crude compound 50. Step 2: The crude compound 50 was dissolved in pyridine (122 mL), diphosphorus pentasulfide (1.49 g, 6.68 mmol) was added, and the mixture was stirred at 80°C for 1 hour. After cooling, aqueous citric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 51 (3.34 g, yield 53%). 1 H-NMR(CDCl3)δ: 1.28(t, J=5.4Hz, 3H), 3.72(s, 2H), 4.21(q, J=5.4Hz, 2H), 7.04(s, 1H), 7.17(t, J=1.5Hz, 1H), 7.28(d, J=4.5Hz, 1H), 7.39(d, J=1.5Hz, 1H), 9.25(d, J=10.5Hz, 1H), 9.83(d, J=10.5Hz, 1H). Process 3 Compound 51 (3.34 g, 7.08 mmol) was dissolved in 1,2-dimethoxyethane (134 mL), and copper iodide (0.135 g, 0.708 mmol), 1,10-phenanthroline (0.255 g, 1.416 mmol), and cesium carbonate (3.46 g, 10.62 mmol) were added, followed by refluxing for 20 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 52 (1.96 g, yield 71%). 1H-NMR(CDCl3)δ: 1.28(t, J=5.4Hz, 3H), 3.87(s, 2H), 4.21(q, J=5.4Hz, 2H), 7.10(s, 1H), 7.20(s, 1H), 7.39(s, 1H), 8.00(d, J=4.2Hz, 1H), 8.97(s, 1H).

[0096] Step 4: Compound 52 (301 mg, 0.789 mmol) was dissolved in THF (18 mL), water (2.25 mL) and a 4 mol / L aqueous lithium hydroxide solution (0.577 mL, 2.307 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 2 mol / L hydrochloric acid (1.346 mL, 2.69 mmol) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude compound 53. Step 5: The crude compound 53 was dissolved in THF (4 mL), diphenyldiazomethane (164 mg, 0.846 mmol) was added, and the mixture was stirred for 64 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 54 (344 mg, 0.65 mmol, 85% yield). 1 H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 6.85 (s, 1H), 7.25-7.36 (m, 10H), 7.54 (s, 1H), 7.59 (s, 1H), 7.86 (s, 1H), 8.14 (d, J = 4.2 Hz, 1H), 9.4 (s, 1H). Step 6: 2-Chloro-3-fluoroisonicotinic acid (148 mg, 0.845 mmol) was dissolved in DMF (2.5 mL), CDI (148 mg, 0.91 mmol) was added, and the mixture was stirred at 50 °C for 1 hour. The mixture was cooled to -20°C, and a solution of compound 54 (344 mg, 0.65 mmol) in DMF (1 mL) and sodium hydride (104 mg, 2.60 mmol) were added, followed by stirring at -20°C for 1 hour. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude compound 55.

[0097] Step 7: To the crude product of compound 55, a solution of anisole (0.71 mL, 6.5 mmol) and TFA (2.5 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 56 (42 mg, 0.089 mmol, yield 14%). 1 H-NMR (DMSO-d6) δ: 4.74 (s, 2H), 7.58 (s, 1H), 7.62 (s, 1H), 7.86 (s, 1H), 7.90 (t, J = 3.6 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 8.48 (d, J = 3.6 Hz, 1H), 9.4 (s, 1H). Step 8: Compound 56 (42 mg, 0.089 mmol) was dissolved in 1,4-dioxane (0.5 mL), and hydrazine monohydrate (0.066 mL, 0.133 mmol) was added. The mixture was stirred at 130 °C for 2 hours. Water was added, and the resulting solid was collected by filtration and washed with water to give crude compound 57. Step 9: The crude product of compound 57 was dissolved in 1,4-dioxane (1 mL), and 4-tert-butylphenylmethanethiol (0.011 mL, 0.061 mmol), [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (5.8 mg, 0.0061 mmol), and DIEA (0.021 mL, 0.122 mmol) were added, followed by stirring at 120°C for 30 minutes. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 58 (7.7 mg, 0.013 mmol, 21% yield). MS: m / z = 614 [M+H] ＋Step 10: Compound 58 (7.7 mg, 0.013 mmol) was added to dichloromethane (0.25 mL) and water (0.060 mL). Under ice-cooling, acetic acid (0.016 mL, 0.288 mmol), 4 mol / L hydrochloric acid (0.006 mL, 0.013 mmol), and a dichloromethane (0.5 mL) solution of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (7.4 mg, 0.038 mmol) were added, and the mixture was stirred under ice-cooling for 1 hour. Aqueous ammonia (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Chloroform was added to the resulting residue, filtered, and dried under reduced pressure to obtain compound I-002 (2.8 mg, 0.0054 mmol, yield 43%). 1 H-NMR(DMSO-d6)δ: 4.64(s, 2H), 7.56(s, 1H), 7.63(s, 1H), 7.75(bs, 2H), 7.85(s, 1H), 8.00(d, J=3.6Hz, 1H), 8.06(d, J=3.6Hz, 1H), 8.30-8.33(m, 1H), 9.37(s, 1H).

[0098] Example 7 Step 1: Under a nitrogen atmosphere, compound 19 (33.2 g, 95.0 mmol) was dissolved in methanol (66 mL) and chloroform (260 mL) and cooled to 0°C. Sodium bicarbonate (16.0 g, 190 mmol) and a 1 mmol / L solution of iodine monochloride in dichloromethane (105 mL, 1.90 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After removing insoluble matter by filtration, the solvent was evaporated under reduced pressure to obtain a crude product of compound 59. Step 2: Under a nitrogen atmosphere, allyl alcohol (215 μl, 3.16 mmol), N,N-dicyclohexylmethylamine (668 μl, 3.16 mmol), and tetrabutylammonium bromide (679 mg, 2.11 mmol) were dissolved in DMA (40 mL) and water (10 mL). The crude product of compound 59 (1.00 g, 2.11 mmol) and Pd(OAc) ２(47.3 mg, 0.211 mmol) was added and the mixture was stirred at 80°C for 30 minutes. After cooling, water and ethyl acetate were added, insoluble materials were removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give compound 60 (495 mg, yield 61%). MS: m / z = 385 [M+H] ＋ Step 3: Compound 60 was dissolved in THF (9.9 ml) and cooled to 0°C. 2 mmol / L aqueous lithium hydroxide solution (3.22 ml, 6.44 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After cooling to 0°C, 2 mmol / L hydrochloric acid was added, and the solvent was evaporated. Water was added, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated. The resulting residue was suspended in dichloromethane and isopropyl ether, and then filtered to give Compound 61 (282 mg, 62%). MS: m / z = 357 [M+H] ＋ Step 4 Compound 61 (282 mg, 0.791 mmol) and compound 62 (147 mg, 0.712 mmol) were dissolved in DMF (11 mL), and DIEA (533 μL, 3.16 mmol) and a 50% DMF solution of propylphosphonic anhydride (553 μL, 3.16 mmol) were added, followed by stirring at room temperature for 30 minutes. Ethyl acetate, hexane, and water were added, and the precipitated solid was collected by filtration. The resulting solid was purified by silica gel column chromatography (chloroform-methanol) and then purified by SFC. Methanol and water were added to the resulting solid, and the suspension was collected by filtration to give compound I-086 (7.9 mg, 1.8%). MS: m / z=545 [M+H] ＋

[0099] The following compounds were synthesized according to the above general synthesis methods and the methods described in the Examples.

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] The physical data for each compound is shown below. In the table, "MS" represents "MS (ESI): m / z", and "Charge" represents the molecular state observed by LC / MS (liquid chromatography / mass spectrometry).

[0116]

[0117] The following are examples of biological tests on the compounds of the present invention.

[0118] Test Example 1: Anti-HIV activity A serial dilution series of the test sample was prepared in a 384-well microplate (20 μL / well). ４ After dispensing 20 μL / well of the MT-4 cell suspension containing 100 cells / mL into the plate containing the test sample, 20 μL / well of the HIV virus solution was dispensed. ２ The cells were cultured in an incubator for 4 days. 10 μL of CellTiter-Glo 2.0 solution was added to each well, and the reaction was carried out while stirring well with a plate mixer. After the reaction, the luminescence intensity of the 384-well plate was measured using a microplate reader. The 50% HIV inhibitory concentration (EC ５０) was determined from the concentration-response curve using the four-parameter logistic curve fitting model shown below: y = A + ((B - A) / (1 + (C / x) Ｄ )) A = Minimum inhibition rate (negative control, 0%) B = Maximum inhibition rate (positive control, 100%) C = Compound concentration at inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%) (Results)

[0119]

[0120] Comparative Example: Compound I-3 described in Patent Document 8 was measured according to the method described in Test Example 1, and the results are as follows.

[0121] Test Example 2: Resistance Evaluation Test A serial dilution series of the test sample was prepared in a 384-well microplate, and 1.0 × 10 ５ A HeLa-CD4 cell suspension containing 200 cells / mL was dispensed at 20 μL / well into the plate containing the test sample. ２ The plate was incubated in an incubator for 1 hour. Appropriately diluted HIV virus solutions (wild-type and mutant strains) were dispensed at 20 μL per well. After mixing with a plate mixer, the plate was incubated in a CO ２ The plates were cultured in an incubator for 3 days. 20 μL of Beta-Glo solution was dispensed into each well, and then the plates were stirred for approximately 1 hour using a plate mixer. After the reaction, the luminescence intensity of the 384-well plate was measured using a microplate reader. The 50% HIV inhibitory concentration (EC ５０ ) was determined from the concentration-response curve using the four-parameter logistic curve fitting model shown below: y = A + ((B - A) / (1 + (C / x) Ｄ)) A = minimum inhibition rate (negative control, 0%) B = maximum inhibition rate (positive control, 100%) C = compound concentration at inflection point D = slope coefficient x = compound concentration y = inhibition rate (%) Examples of mutant strains that can be used include, but are not limited to, the following: K101E, K101P, K103N, V106A, V106I, V108I, E138A, E138K, V179D, Y181C, Y188L, G190A, F227C, M230L Furthermore, the resistance level (fold change (FC)) of each mutant strain was calculated based on the following formula: FC = EC of mutant strain ５０ / Wild strain EC ５０ (Results) Resistance of mutant strain V106A to compound I-159 FC = 1.05

[0122] Test Example 3: CYP inhibition test Using commercially available pooled human liver microsomes, the extent to which the production of each metabolite was inhibited by the compound of the present invention was evaluated using as indicators the typical substrate metabolic reactions of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), namely, O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4). The reaction conditions were as follows: substrates, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 30 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). Five types of substrates, human liver microsomes, and the compound of the present invention were added to a 96-well plate in 50 mmol / L Hepes buffer solution in the above-mentioned compositions, and the coenzyme NADPH was added to initiate the metabolic reaction used as an indicator. After 15 minutes of reaction at 37°C, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. After 15 minutes of centrifugation at 3000 rpm, resorufin (a CYP1A2 metabolite) in the supernatant was quantified using a fluorescence multilabel counter or LC / MS / MS. Hydroxylated tolbutamide (a CYP2C9 metabolite), 4'-hydroxylated mephenytoin (a CYP2C19 metabolite), dextrorphan (a CYP2D6 metabolite), and alcoholic terfenadine (a CYP3A4 metabolite) were quantified using LC / MS / MS. A control (100%) was prepared by adding only DMSO, the solvent in which the compound was dissolved, to the reaction solution instead of the compound of the present invention. The residual activity (%) was calculated, and the IC was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. ５０ was calculated.

[0123] Test Example 4: CYP3A4 (MDZ) MBI Test This test evaluated the mechanism-based inhibition (MBI) ability of the compounds of the present invention in terms of the CYP3A4 inhibition, based on the enhanced inhibitory effect due to the metabolic reaction of the compounds of the present invention. CYP3A4 inhibition was evaluated using pooled human liver microsomes, using the 1-hydroxylation of midazolam (MDZ) as an indicator. The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL pre-reaction, 0.05 mg / mL (10-fold dilution) pre-reaction; and compound of the present invention pre-reaction concentration, 0.83, 5, 10, 20 μmol / L (4 points) or 0.83, 5, 10, 20 μmol / L (4 points). A 96-well plate was prepared as a pre-reaction solution by adding pooled human liver microsomes and a solution of the compound of the present invention to K-Pi buffer (pH 7.4) in the above pre-reaction composition. A portion of this solution was transferred to another 96-well plate so that it was diluted 1 / 10 with K-Pi buffer containing the substrate. The coenzyme NADPH was added to initiate the reaction (no pre-reaction: pre-incubation 0 min). After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. NADPH was also added to the remaining pre-reaction solution to initiate the pre-reaction (pre-reaction: pre-incubation 30 min). After the specified reaction time, a portion of this solution was transferred to another plate so that it was diluted 1 / 10 with K-Pi buffer containing the substrate, and the reaction was started. After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. The plates in which each indicator reaction was performed were centrifuged at 3,000 rpm for 15 minutes, and 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS. A control (100%) was prepared by adding only DMSO, the solvent in which the compound was dissolved, to the reaction mixture instead of the compound of the present invention. The residual activity (%) was calculated when the compound of the present invention was added at each concentration, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate.The IC at 0 min of preincubation / IC at 30 min of preincubation was defined as the Shifted IC value, and if the Shifted IC was 1.5 or more, it was considered positive (+), and if the Shifted IC was less than 1.1, it was considered negative (-).

[0124] Test Example 5: BA Test: Experimental Materials and Methods for Examining Oral Absorbability (1) Animals Used: Rats were used. (2) Breeding Conditions: Rats were allowed free access to solid feed and sterilized tap water. (3) Dosage and Grouping: Predetermined doses were administered orally and intravenously. Groups were set up as follows. (Dosages varied 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 Solution: Oral administration was administered as a solution or suspension. Intravenous administration was administered after solubilization. (5) Administration Method: Oral administration was performed by forced intragastric administration using an oral probe. Intravenous administration was performed via the tail vein using a syringe with an injection needle. (6) Evaluation Items: Blood samples were collected over time, and plasma concentrations of the compound of the present invention were measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound of the present invention was calculated by moment analysis, and the bioavailability (BA) of the compound of the present invention was calculated from the dose ratio and AUC ratio between the oral and intravenous administration groups. The dilution concentration and dilution solvent were changed as necessary.

[0125] Test Example 6: Clearance Evaluation Test Experimental Materials and Methods (1) Animals Used: Rats were used. (2) Breeding Conditions: Rats were allowed to freely consume solid feed and sterilized tap water. (3) Dose and Grouping: Intravenous administration was performed at a predetermined dose. Groups were set up as follows: Intravenous administration: 1 μmol / kg (n=2) (4) Preparation of Dosage Solution: The compound was solubilized using a dimethyl sulfoxide / propylene glycol (1 / 1) solvent and administered. (5) Administration Method: The compound was administered via the tail vein using a syringe with an injection needle. (6) Evaluation Items: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical Analysis: The total body clearance (CLtot) and elimination half-life (t1 / 2) of the plasma concentration of the compound of the present invention were calculated using moment analysis. The dilution concentration and dilution solvent were changed as necessary.

[0126] Test Example 7: Metabolic Stability Test: Human liver microsomes (0.5 mg protein / mL) were incubated in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidative reaction). After the reaction, a fixed amount of the reaction solution was mixed with twice the amount of methanol / acetonitrile (1 / 1 (v / v) solution) and centrifuged to obtain a supernatant. The compound of the present invention in the centrifuged supernatant was measured by LC / MS / MS or solid phase extraction (SPE) / MS, and the amount of the compound remaining after the reaction was calculated, assuming the amount of compound at 0 minutes of reaction as 100%.

[0127] Test Example 8: Fluctuation Ames Test The mutagenicity of the compound of the present invention was evaluated. 20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was 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 to 8.00 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture medium. The same volume of Micro F buffer (K ２ HPO ４:3.5g / L, KH ２ P.O. ４ : 1 g / L, (NH ４ ) ２ SO ４ : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO ４ ・7H ２ The bacteria are suspended in 0.1 g / L of Exposure medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) and added to 120 mL of Exposure medium. For the TA100 strain, 3.10 to 3.42 mL of the bacterial solution is added to 120 to 130 mL of Exposure medium to prepare the test bacterial solution. DMSO solution of the compound of the present invention (diluted in several steps at 2- to 3-fold common ratios from the maximum dose of 50 mg / mL), DMSO as a negative control, 50 μg / mL 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain as a positive control under non-metabolic activation conditions, 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain as a positive control, 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain under metabolic activation conditions, 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain as a positive control, 12 μL each of which was mixed with 588 μL of test bacterial solution (a mixture of 498 μL of test bacterial solution and 90 μL of S9 mix under metabolic activation conditions), 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, and bromocresol purple: 37.5 μg / mL), and 50 μL of the mixture was dispensed into 48 wells of a microplate per dose and incubated statically at 37°C for 3 days. Wells containing bacteria that have acquired the ability to grow due to a mutation in the amino acid (histidine) synthase gene change color from purple to yellow due to a pH change, so the number of wells with bacterial growth that turned yellow out of 48 wells per dose was counted and evaluated by comparison with the negative control group. Negative mutagenicity was indicated as (-), and positive mutagenicity was indicated as (+).

[0128] Test Example 9: hERG Test For the purpose of evaluating the risk of electrocardiogram QT interval prolongation caused by the compounds of the present invention, the delayed rectifier K β, which plays an important role in the ventricular repolarization process, was assayed using CHO cells expressing the human ether-a-go-go related gene (hERG) channel. ＋ Current (I Ｋｒ The effect of the compound of the present invention on the I-cell response was investigated using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S). The cells were held at a membrane potential of −80 mV by the whole-cell patch clamp method, and a leak potential of −50 mV was applied. After that, a depolarizing stimulus of +20 mV was applied for 2 seconds, followed by a repolarizing stimulus of −50 mV for 2 seconds. Ｋｒ The extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl) was adjusted to 0.1% with dimethyl sulfoxide. ２ :2 mmol / L, MgCl ２ The vehicle used was a mixture of 1 mmol / L of ATP, 10 mmol / L of glucose, and 10 mmol / L of HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), pH 7.4. The vehicle and the compound of the present invention were dissolved in an extracellular solution at a desired concentration and applied to the cells for 7 minutes or more at room temperature. Ｋｒ The absolute value of the maximum tail current was measured using analysis software (QPatch Assay software; Sophion Bioscience A / S) based on the current value at the resting membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the vehicle was calculated as an inhibition rate, and the I of the compound of the present invention was calculated. Ｋｒ The impact on

[0129] Test Example 10: Solubility Test The solubility of the compound of the present invention was determined under conditions containing 1% DMSO. A 10 mmol / L compound solution was prepared in 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 at least 1 hour, the mixture was filtered. The filtrate was diluted 10- or 100-fold 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 using LC / MS or solid-phase extraction (SPE) / MS by the absolute calibration curve method. The composition of JP-1 solution is as follows: 2.0 g of sodium chloride, 7.0 mL of hydrochloric acid, and water were added to make 1000 mL. The composition of JP-2 solution is as follows. 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate are dissolved in water to make 1000 mL, and one volume of water is added to one volume of the solution.

[0130] Test Example 11: Powder Solubility Test An appropriate amount of the compound of the present invention was placed in an appropriate container, and 200 μL of JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid, and water added to 1000 mL), JP-2 solution (3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate were dissolved in water to make 1000 mL, and 1 volume of water was added), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g of TCA was added to JP-2 solution to make 100 mL), or pH 7.4 phosphate-buffered saline was added. If the entire amount was dissolved after adding the test solution, additional compound of the present invention was added as appropriate. The containers were sealed and shaken at 37°C for at least 1 hour, then filtered. 100 μL of each filtrate was diluted 2-fold by adding 100 μL of methanol. The dilution ratio was changed as necessary. The containers were checked for the presence of air bubbles and precipitates, sealed, and shaken. The compounds of the present invention were quantified using HPLC by the absolute calibration method.

[0131] Test Example 12: Ames Test The mutagenicity of the compound of the present invention was evaluated by the Ames test using Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli WP2uvrA strain as test strains. 0.5 mL of S9mix was added to a test tube under metabolic activation conditions, and 0.5 mL of phosphate buffer and 0.1 mL of test bacterial solution were added under non-metabolic activation conditions. This mixture was then mixed with 0.1 mL of a DMSO solution of the compound of the present invention and shaken at 37°C for 20 minutes. 2 mL of soft agar containing histidine, biotin, and tryptophan was added and layered on a minimal glucose agar plate. At the same time, the same experiments were performed on a negative control substance (DMSO) and a positive control substance (4-nitroquinoline 1-oxide, sodium azide, 9-aminoacridine, or 2-aminoanthracene). After 48 hours of culture at 37°C, the number of revertant colonies that appeared was counted and evaluated by comparison with the negative control group. A positive result was determined when the number of revertant colonies increased in a concentration-dependent manner and was at least twice the number of colonies in the negative control group.

[0132] Test Example 13: Anti-HIV activity evaluation test using peripheral blood mononuclear cells (PBMCs) from healthy individuals. A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). 5.0 x 10 ４ PBMCs stimulated with phytohemagglutinin (PHA) at 1 / well were mixed with the required number of wells containing the HIV virus solution and infected at 37°C for 1 hour. After infection, the cell suspension was centrifuged and the supernatant was discarded. The infected cells were dispersed in culture medium at 150 μL / well for the required number of wells, and dispensed at 150 μL / well into a 96-well microplate containing the test sample. The mixture was mixed using a plate mixer and incubated for 1 hour at 37°C. ２ The cells were cultured in an incubator for 7 days. The reverse transcriptase activity in the culture medium was measured. The 90% HIV inhibitory concentration (EC ９０ ) was determined from the concentration-response curve using the four-parameter logistic curve fitting model shown below: y = A + ((B - A) / (1 + (C / x) Ｄ)) A = Minimum inhibition rate (negative control, 0%) B = Maximum inhibition rate (positive control, 100%) C = Compound concentration at inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%)

[0133] Test Example 14: Evaluation test of anti-HIV activity in the presence of human serum proteins A serial dilution series of the test sample was prepared in a 384-well microplate, and 20 μL of human serum protein solution (human serum protein concentration 50%) was dispensed into the 384-well microplate containing the test sample at 20 μL / well, and allowed to stand at room temperature for 1 hour. 20 μL of culture medium was dispensed into the serum-free plate at 20 μL / well. ４ MT-4 cells (cells / well) and 3 μL / well of HIV virus solution were mixed for the required number of wells, and the cells were infected at 37°C for 1 hour. After infection, the cell suspension was centrifuged and the supernatant was discarded. The infected cells were dispersed in culture medium at 20 μL / well for the required number of wells, and dispensed at 20 μL / well into a 384-well microplate containing the test sample and human serum protein (final concentration of human serum protein: 25%). The mixture was mixed using a plate mixer, and then incubated for 1 hour at 37°C. ２ The cells were cultured in an incubator for 4 days. 10 μL of CellTiter-Glo 2.0 solution was added to each well, and the reaction was carried out while stirring well with a plate mixer. After the reaction, the luminescence intensity of the 384-well plate was measured using a microplate reader. The 50% HIV inhibitory concentration (EC ５０ ) was determined from the concentration-response curve using the four-parameter logistic curve fitting model shown below: y = A + ((B - A) / (1 + (C / x) Ｄ )) A = Minimum inhibition rate (negative control, 0%) B = Maximum inhibition rate (positive control, 100%) C = Compound concentration at inflection point D = Slope coefficient x = Compound concentration y = Inhibition rate (%) Furthermore, potency shift (PS) was calculated based on the following formula. PS is an extrapolated value based on a human serum protein concentration of 100%. PS = 4 x (EC ５０ / EC in the absence of human serum proteins ５０ )-3

[0134] The following formulation examples are illustrative only and are not intended to limit the scope of the invention. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments, or creams, or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0135] The compound of the present invention has reverse transcriptase inhibitory activity and / or cell proliferation inhibitory activity against viruses, particularly HIV, and is therefore useful for the prevention or treatment of various diseases involving reverse transcriptase and viral infections (e.g., AIDS).

Claims

1. Formula (I): (Wherein, ring A is (wherein the asterisk (*) represents the attachment point of ring A to the methylene; R １ are each independently a halogen, cyano, alkyl, haloalkyl, alkenyl, alkynyl, or non-aromatic carbocyclic group; (i) R ２ represents halogen, alkyl optionally substituted with substituent group a, alkyloxy, alkylthio, —C(═O)N(R Ａ ) R Ｂ , -C(=O)R Ａ , -S(=O) ２ R Ａ or a non-aromatic carbocyclic group, the substituent group a is one or more groups selected from the group consisting of halogen, hydroxy and alkyloxy, and R ３ is hydrogen, halogen, alkyl, haloalkyl or —N(R Ａ ) R Ｂ or (ii) R ２ and R ３ together with the adjacent carbon atom, R Ｃ a benzene ring optionally substituted with R Ｃ forming a pyridine ring optionally substituted with R Ｃ is one or more groups selected from the group consisting of halogen, cyano, alkyl, and alkyloxy; L is —O— or —CH ２ -O-; R ４ is hydrogen or halogen; Ring B is R Ｄ or R Ｄ a 5- or 6-membered non-aromatic heterocycle optionally substituted with R Ｄ is one or more groups selected from the group consisting of halogen, hydroxy, amino, alkyl, haloalkyl, and hydroxyalkyl, and n is an integer from 1 to 3; Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ are each independently a halogen atom, a hydroxyl group, a cyano group, an alkyl group which may be substituted by a substituent group b, an alkyloxy group, a haloalkyloxy group, or —N(R Ａ ) R Ｂ , -N(R Ａ ) S(=O) ２ R Ｂ , -N(R Ａ ) S(=O) ２ N (R Ａ ) R Ｂ , -N(R Ａ ) C(=O)R Ｂ , -N(R Ａ )C(=O)N(R Ａ ) R Ｂ , -SR Ａ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R Ａ are each independently hydrogen or alkyl; R Ｂ are each independently hydrogen or alkyl; and the substituent group b is a halogen, —N(R Ａ ) R Ｂ , -S(=O) ２ R Ａ and -S(=O) ２ N (R Ａ ) R Ｂ m is an integer of 0 to 2; R ８ is hydrogen or alkyl; R ９ is hydrogen, halogen or alkyl; R １０ is -S(=O) ２ R Ａ or -S(=O) ２ N (R Ａ ) R Ｂ and R １１ is hydrogen, halogen, alkyl or haloalkyl; R １２ is hydrogen, halogen, alkyl or haloalkyl) The compounds in which the moiety represented by is as follows are excluded. ), or a pharmaceutically acceptable salt thereof.

2. R １ 2. The compound of claim 1, wherein each is independently halogen, cyano, alkyl, or haloalkyl, or a pharmaceutically acceptable salt thereof.

3. R ２ is halogen, alkyl, haloalkyl or -S(=O) ２ R Ａ (In the formula, R Ａ is hydrogen or alkyl), or a pharmaceutically acceptable salt thereof.

4. R ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or alkyl.

5. R ２ and R ３ together with adjacent carbon atoms to form one of the following rings: (In the formula, R Ｃ１ is hydrogen, halogen or cyano), or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, wherein L is -O-, or a pharmaceutically acceptable salt thereof.

7. R ４ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is halogen.

8. Ring B is R Ｄ any of the following rings optionally substituted with: (In the formula, R ４ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

9. R Ｄ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein n is an integer of 2 or 3.

11. Z is (wherein the asterisk (*) represents the attachment point of Z to the methylene; R ６ is halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, —N(R Ａ ) R Ｂ , -S(=O)R Ａ , -S(=O) ２ R Ａ , -S(=O) ２ N (R Ａ ) R Ｂ , -C(=O)N(R Ａ ) R Ｂ or triazolyl; R ８ is hydrogen or alkyl; R ９ is a halogen; １０ is -S(=O) ２ -NH ２ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein 12. R ６ are each independently -S(=O) ２ NH ２ 12. The compound according to any one of claims 1 to 11, wherein:

13. R ８ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

14. R ９ is a halogen, and R １０ But -S(=O) ２ NH ２ 14. The compound according to any one of claims 1 to 13, wherein:

15. R １１ is hydrogen, and R １２ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is halogen or haloalkyl.

16. Any compound selected from the group consisting of compounds I-001, I-002, I-004, I-006, I-096, I-137, I-138, I-139, I-140, I-141, I-142, I-144, I-145, I-147, I-148, I-149, I-150, I-151, I-152, I-153, I-154, I-155, I-157, I-158, I-159, I-160, I-161, I-162, I-163, I-165, and I-167, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 17, which has an anti-HIV effect.

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