JP2018090562A - Cyclic dinucleotide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound that has STING agonistic activity and is expected to be useful as an agent for the prevention or treatment of STING-related disease.SOLUTION: This invention relates to a compound represented by formula (I) [where each symbol is as described in the specifications] or a salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a cyclic dinucleotide that has STING (stimulator of interferon genes) agonist activity and is expected to be useful as a preventive or therapeutic agent for cancer and the like.

BACKGROUND OF THE INVENTION
STING is a receptor that recognizes a nucleic acid different from TLR (toll-like receptor). Examples of natural ligands that can be recognized include 2 ', 3'-cGAMP synthesized by bacterial or protozoan-derived cyclic nucleotides (CDN) or upstream cGAS (cyclic GMP-AMP synthase) (Non-patent Document 1). One natural ligand, 2 ', 3'-cGAMP, is reported to be degraded by ENPP1 (ecto-nucleotide pyrophosphatase / phosphodiesterase), a type of pyrophosphatase / phosphodiesterase, and that other CDNs are degraded by phosphodiesterase. (Non-Patent Documents 2, 3 and 4). STING is activated by these natural ligands and induces phosphorylation of TBK1 (TANK binding kinase 1) downstream, and by activating IRF3 (Interferon regulatory factor 3) signal and NFkB signal downstream of it It induces type I interferon (IFN) response (Non-patent Document 1). The importance of STING signal in cancer has been shown by tests with knockout mice. In allogeneic tumor transplanted mice using STING and downstream signal IRF3 knockout mice, it has been reported that cancer cells proliferate more than wild type mice due to suppression of the cancer immune system (Non-patent Document 5). In addition, radiation treatment in allogeneic tumor transplanted mice suppresses the growth of cancer cells, but knockout mice of receptor IFNAR1 (Interferon (alpha and beta) receptor 1) of type I IFN produced by STING and downstream signals When used, it is also reported that the radiation effect is diminished (Non-patent Document 6). From these facts, STING plays an important role in suppressing the growth of cancer cells, and it is thought that the activation of the immune signal induced by the activation of STING is linked to the anticancer effect. Thus, STING agonists may be used as anti-cancer agents aimed at cancer immunity. In addition, activation of STING is considered to play an important role in the immune effect of the vaccine since it activates innate immunity (Non-patent Document 7). Thus, STING agonists may be used as adjuvants for various vaccines.

The following compounds are known as cyclic dinucleotides.
Patent Document 1 has the following formula:

[Wherein each symbol is as defined in Patent Document 1]. ]
It is described that the compound represented by is a STING-dependent TBK1 activator, is useful for the treatment of cancer (particularly solid cancer) and the like, and is useful as an adjuvant.

  Patent Document 2 has the following formula:

[Wherein each symbol is as defined in Patent Document 2]. ]
It is described that the compound represented by is an immunity promoting agent via STING and is useful for the treatment of cancer and the like.

  Patent Document 3 and Non-Patent Document 8 have the following formulas:

[Wherein each symbol is as defined in Patent Document 3]. ]
It is described that the compound represented by is a STING agonist and is useful for the treatment of cancer and the like.

  In Patent Document 4 and Non-patent Document 9, c-di-AMP, c-di-GMP, c-di-IMP, c-AMP-GMP, c-AMP-IMP, and c-GMP-IMP are STING- It is described that it is a dependent TBK1 activator.

  Patent Document 5 has the following formula:

[Wherein each symbol is as defined in Patent Document 5]. ]
It is described that the compounds represented by the above inhibit STING-dependent signal transduction and are useful for the treatment of autoimmune diseases and the like.

  Patent Document 6 has the following formula:

[Wherein each symbol is as defined in Patent Document 6]. ]
It is described that the compound represented by is a STING modulator and is useful for the treatment of inflammation, allergic autoimmune disease, cancer and the like, and also useful as a vaccine adjuvant.

  Patent Document 7 has the following formula:

[Wherein each symbol is as defined in Patent Document 7]. ]
It is described that the compound represented by is a Type I interferon production enhancer, and is useful for treating cancer, autoimmune disease, allergic reaction and the like, and useful as an adjuvant.

  Patent Document 8 and Non-Patent Document 10 have the following formulas:

[Wherein each symbol is as defined in Patent Document 8]. ]
It is described that the compound represented by is a type I interferon production enhancer and is useful for the treatment of diseases characterized by inflammation, autoimmune diseases, Schönren's syndrome and the like.

  Patent Document 9 has the following formula:

It is described that the compound represented by is a STING modulator, and is useful for treating cancer, autoimmune disease and the like, and also useful as a vaccine.

  Patent Document 10 has the following formula:

It is described that the compound represented by is a STING agonist and is useful for the treatment of cancer (particularly, solid pancreatic cancer).

  Patent Document 11 has the following formula:

It is described that the compound represented by is a STING agonist.

  Patent Document 12 has the following formula:

It is described that the compound represented by is a STING agonist.

  Patent Document 13 has the following formula:

It is described that the compound represented by is a STING agonist.

  Patent Document 14 has the following formula:

[Wherein each symbol is as defined in Patent Document 14]. ]
It is described that the compound represented by is a STING agonist.

  Patent Document 15 has the following formula:

[Wherein each symbol is as defined in Patent Document 15]. ]
It is described that the compound represented by is a STING agonist.

  Patent Document 16 has the following formula:

[Wherein each symbol is as defined in Patent Document 16]. ]
It is described that the compound represented by is a STING agonist.

  Patent Document 17 has the following formula:

[Wherein each symbol is as defined in Patent Document 17]. ]
It is described that the compound represented by is a STING agonist.

International Publication No. 2014/093936 International Publication No. 2014/189805 International Publication No. 2015/077354 International Publication No. 2013/185052 WO 2014/189806 International Publication No. 2015/185565 International Publication No. 2014/179760 International Publication No. 2014/179335 International Publication No. 2015/017652 International Publication No. 2016/096577 International Publication No. 2011/030025 International Publication No. 2016/096174 International Publication No. 2016/120305 International Publication No. 2016/145102 International Publication No. 2017/027646 International Publication No. 2017/075477 International Publication No. 2017/027654

Trends in Immunology 35, 88-93 (2014). Nat Chem Biol 10, 1043-1048 (2014). Cell Res 25, 539-550 (2015). Biochemistry 55, 837-849 (2016). Immunity 41, 830-842 (2014). Immunity 41, 843-852 (2014). Ther Adv Vaccines 1, 131-143 (2013). Cell reports 11, 1010-1030 (2015). Sci. Transl. Med. 283, 283ra 52 (2015). Mol. Cell 154, 748-762 (2013).

  An object of the present invention is to provide a compound which has STING agonist activity and which is expected to be useful as a preventive or therapeutic agent for cancer and the like.

  As a result of intensive studies to solve the above problems, the present inventors have found that a compound represented by the following formula (I) has STING agonizing activity and therefore can be useful as a preventive or therapeutic agent for cancer and the like. And completed the present invention.

That is, the present invention is as follows.
[1] Formula (I):

[In the formula,
Partial structure:

The following formula (IIA):

A partial structure represented by or the following formula (IIB):

Indicates a partial structure represented by
R ¹ and R ² each independently represent a hydroxy group or a halogen atom;
B ¹ is

Indicates a group represented by
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ each independently represent a hydrogen atom or a substituent;
Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ each independently represent N or CR ^1a ;
Z < ¹¹ >, Z < ¹² >, Z < ¹³ >, Z < ¹⁴ >, Z < ¹⁵ > and Z < ¹⁶ > respectively independently show N or C;
R ^1a represents a hydrogen atom or a substituent;
B ² is

Indicates a group represented by
^{R 23, R 24, R 25} , R 26 and ^{R 27} each independently represents a hydrogen atom or a substituent;
Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ each independently represent N or CR ^2a ;
Z ²¹ , Z ²² , Z ²³ , Z ²⁴ , Z ²⁵ and Z ²⁶ each independently represent N or C;
R ^2a represents a hydrogen atom or a substituent;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
Each of X ¹ and X ² independently represents an oxygen atom or a sulfur atom;
Each of Q ¹ , Q ² , Q ³ and Q ⁴ independently represents an oxygen atom or a sulfur atom. ]
Or a salt thereof (hereinafter, also referred to as compound (I)).
[2] A medicament comprising the compound of the above-mentioned [1] or a salt thereof.
[3] The medicine according to the above-mentioned [2], which is a STING agonist.
[4] The medicine according to the above-mentioned [2], which is a preventive or therapeutic drug for cancer.

  According to the present invention, it is possible to provide a compound which can have excellent STING agonist activity and can be useful as a preventive or therapeutic agent for cancer and the like.

(Detailed Description of the Invention)
Hereinafter, the present invention will be described in detail.

Hereinafter, the definition of each substituent used in the present specification will be described in detail. Each substituent has the following definition, unless otherwise stated.
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, examples of the "C _1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
In the present specification, the "optionally halogenated C _1-6 alkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkyl group is mentioned. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl and 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri And fluoropentyl, hexyl and 6,6, 6-trifluorohexyl.
In the present specification, examples of the " _C2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, examples of the " _C2-6 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- And pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
In the present specification, examples of the "C _3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, adamantyl.
In the present specification, the "optionally halogenated C _3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{3- And 10} cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present specification, examples of the "C _3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
In the present specification, examples of the "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
In the present specification, examples of the "C _7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, the "optionally halogenated C _1-6 alkoxy group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkoxy group is mentioned. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl And oxy and hexyloxy.
In the present specification, examples of the "C _3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
In the present specification, examples of the "C _1-6 alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, the "optionally halogenated C _1-6 alkylthio group optionally", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkylthio group is mentioned. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
In the present specification, examples of the “C _1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2, 2- Dimethylpropanoyl, hexanoyl, heptanoyl can be mentioned.
In the present specification, examples of the “ _optionally halogenated C _1-6 alkyl-carbonyl group” include, for example, C ₁ optionally having 1 to 7, preferably 1 to 5 halogen atoms. _{And -6} alkyl-carbonyl group. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, as the "C _1-6 alkoxy-carbonyl group", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, And pentyloxycarbonyl and hexyloxycarbonyl.
In the present specification, examples of the "C _6-14 aryl-carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the "C _7-16 aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl.
In the present specification, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclic carbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C _1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
In the present specification, examples of the "mono- or di-C _7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.
In the present specification, examples of the "C _1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
In the present specification, the “optionally halogenated C _1-6 alkylsulfonyl group” is, for example, C _1-, which may have 1 to 7, preferably 1 to 5 halogen atoms. ₆ alkyl sulfonyl group is mentioned. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
In the present specification, examples of the "C _6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and the like. Amino group, carbamoyl group which may be substituted, thiocarbamoyl group which may be substituted, sulfamoyl group which may be substituted, hydroxy group which may be substituted, sulfanyl which may be substituted And SH) groups and silyl groups which may be substituted.
In the present specification, examples of the “hydrocarbon group” (including the “hydrocarbon group” in the “optionally substituted hydrocarbon group”) include, for example, a C _1-6 alkyl group, a C _2-6 alkenyl group, A _C2-6 alkynyl group, a _C3-10 cycloalkyl group, a _C3-10 cycloalkenyl group, a _C6-14 aryl group, a _C7-16 aralkyl group is mentioned.

In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following Substituent Group A.
[Substituent group A]
(1) halogen atom,
(2) nitro group,
(3) cyano group,
(4) oxo group,
(5) hydroxy group,
(6) C _1-6 alkoxy group which may be halogenated,
(7) C _6-14 aryloxy group (eg, phenoxy, naphthoxy),
(8) C _7-16 aralkyloxy group (eg, benzyloxy),
(9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy),
(10) 3- to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy),
(11) C _1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy),
(12) C _6-14 aryl-carbonyloxy group (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
(13) C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy)
(14) Mono- or di-C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
(15) C _6-14 aryl-carbamoyloxy group (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy),
(16) 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyl oxy),
(17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, morpholinyl carbonyloxy, piperidinyl carbonyloxy),
(18) C _1-6 alkylsulfonyloxy group which may be halogenated (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy),
(19) a C _6-14 arylsulfonyloxy group which may be substituted by a C _1-6 alkyl group (eg, phenylsulfonyloxy, toluenesulfonyloxy),
(20) C _1-6 alkylthio group which may be halogenated,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3- to 14-membered non-aromatic heterocyclic group,
(23) formyl group,
(24) carboxy group,
(25) C _1-6 alkyl-carbonyl group which may be halogenated,
(26) C _6-14 aryl-carbonyl group,
(27) 5- to 14-membered aromatic heterocyclic carbonyl group,
(28) 3- to 14-membered non-aromatic heterocyclic carbonyl group,
(29) C _1-6 alkoxy-carbonyl group,
(30) C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
(31) C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl),
(32) carbamoyl group,
(33) thiocarbamoyl group,
(34) mono- or di-C _1-6 alkyl-carbamoyl group,
(35) C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl),
(36) 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl, thienylcarbamoyl),
(37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (eg morpholinyl carbamoyl, piperidinyl carbamoyl),
(38) C _1-6 alkylsulfonyl group which may be halogenated,
(39) C _6-14 arylsulfonyl group,
(40) 5- to 14-membered aromatic heterocyclic sulfonyl group (eg, pyridylsulfonyl, thienylsulfonyl),
(41) optionally halogenated C _1-6 alkylsulfinyl group,
(42) C _6-14 arylsulfinyl group (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) 5- to 14-membered aromatic heterocyclic sulfinyl group (eg, pyridylsulfinyl, thienylsulfinyl),
(44) amino group,
(45) Mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N -Methylamino),
(46) mono- or di-C _6-14 arylamino group (eg, phenylamino),
(47) 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino),
(48) C _7-16 aralkylamino group (eg, benzylamino),
(49) formylamino group,
(50) C _1-6 alkyl-carbonylamino group (eg, acetylamino, propanoylamino, butanoylamino),
(51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino),
(52) C _6-14 aryl-carbonylamino group (eg, phenylcarbonylamino, naphthylcarbonylamino),
(53) C _1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
(54) C _7-16 aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino),
(55) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino),
(56) a C _6-14 arylsulfonylamino group which may be substituted by a C _1-6 alkyl group (eg, phenylsulfonylamino, toluenesulfonylamino),
(57) C _1-6 alkyl group which may be halogenated,
(58) C _2-6 alkenyl group,
(59) C _2-6 alkynyl group,
(60) C _3-10 cycloalkyl group,
(61) _C3-10 cycloalkenyl group, and (62) _C6-14 aryl group.

The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
In the present specification, examples of the “heterocyclic group” (including the “heterocyclic group” in the “optionally substituted heterocyclic group”) include, for example, a nitrogen atom, a sulfur atom and a carbon atom as a ring constituting atom (I) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered hetero bridged ring groups, each containing 1 to 4 heteroatoms selected from oxygen atoms .

In the present specification, examples of the "aromatic heterocyclic group" (including the "5- to 14-membered aromatic heterocyclic group") include, as ring-constituting atoms, selected from nitrogen atoms, sulfur atoms and oxygen atoms in addition to carbon atoms. And 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing 1 to 4 heteroatoms.
Preferable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, , 5 to 6-membered monocyclic aromatic heterocyclic groups such as 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolo pyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, flopirimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2,3 -B] thienyl, phenoxatyinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quina 8- to 14-membered fused polycyclic (preferably 2- or 3-ring) aromatic heterocyclic groups such as linyl, cinnolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like .

In the present specification, examples of the “non-aromatic heterocyclic group” (including “3- to 14-membered non-aromatic heterocyclic group”) include, as ring-constituting atoms, a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. And 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from
Preferred examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, and the like. Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl Tetrahydropyranyl tetrahydrothiopyranyl morpholinyl thiomorpholinyl azepanyl diaze Cycloalkenyl, azepinyl, oxepanyl, azocanyl, 3 to 8-membered monocyclic non-aromatic heterocyclic group such as Jiazokaniru;
Dihydrobenzofuranyl, dihydrobenzoimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho [2,3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, Indolinyl, Isoindolinyl, Tetrahydrothieno [2,3-c] pyridinyl, Tetrahydrobenzoazepinyl, Tetrahydroquinoxalinyl, Tetrahydrophenanthridinyl, Hexahydrophenothiazinyl, Hexahydrophenoxazinyl, Tetrahydrophthalazinyl, Tetrahydrol Naphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydric acid Rofenajiniru, tetrahydrothiophenyl key Sante alkenyl, 9 to 14 membered fused polycyclic, such as octahydro-isoquinolylmethyl (preferably 2 or tricyclic), and the non-aromatic heterocyclic group.

In the present specification, preferable examples of the “7 to 10-membered hetero bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
In the present specification, as the "nitrogen-containing heterocyclic group", among the "heterocyclic groups", those containing at least one or more nitrogen atoms as ring constituent atoms can be mentioned.
In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the above-mentioned substituent group A.
The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

In the present specification, as the “acyl group”, for example, “1 selected from“ halogen atom, optionally halogenated C _1-6 alkoxy group, hydroxy group, nitro group, cyano group, amino group and carbamoyl group ” to three of the substituents may be _{respectively, C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 3-10 cycloalkyl, C 3-10} cycloalkenyl _{group, C 6-14} aryl Formyl optionally having one or two substituents each selected from a group, a C _7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group Groups, carboxy group, carbamoyl group, thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group and phosphono group.
In addition, as the “acyl group”, a hydrocarbon-sulfonyl group, a heterocycle-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group can also be mentioned.
Here, the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic ring-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded, and the hydrocarbon-sulfinyl group is a hydrocarbon group And a heterocycle-sulfinyl group mean a sulfinyl group to which a heterocyclic group is linked.
Preferable examples of the “acyl group” include a formyl group, a carboxy group, a C _1-6 alkyl-carbonyl group, a C _2-6 alkenyl-carbonyl group (eg, crotonoyl), a C _3-10 cycloalkyl-carbonyl group ( Examples: cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C _3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexene carbonyl), C _6-14 aryl-carbonyl group, C _7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl) , _{naphthyloxycarbonyl), C 7- 6} aralkyloxy - carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl carbonyl), a carbamoyl group, mono- - or di _{-C 1-6} alkyl - carbamoyl group, mono- - or di _{-C 2-6} alkenyl - carbamoyl group (e.g. , Diallylcarbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg cyclopropylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di _{-C 2-6} alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di _{-C 3-10} cycloalkyl - thiocarbamoyl group (e.g., cyclopropyl thiocarbamoyl, cyclohexyl Thiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl group (eg, benzylthiocarbamoyl, phenethylthiocarbamoyl) ), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (eg, pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 alkylsulfonyl _{group, C 6- 4} arylsulfonyl group, a phosphono group, a mono - or di -C _1-6 alkyl phosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) and the like.

In the present specification, examples of the “optionally substituted amino group” include, for example, “a C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, _C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _1-6 alkylsulfonyl group and C _{6- The} amino group which may have 1 or 2 substituents "chosen from ₁₄ aryl sulfonyl groups is mentioned.
Preferred examples of the amino group which may be substituted include amino group, mono- or di- (optionally halogenated C _1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-6 alkenylamino group (eg, diallylamino), mono- or di-C _3-10 cycloalkylamino group (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C _6-14 arylamino (eg, phenylamino), mono- or di-C _7-16 aralkylamino (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C _1-6 alkyl) - carbonyl amino group (e.g., a Chiruamino, propionylamino), mono- - or di _{-C 6-14} aryl - carbonyl amino group (e.g., benzoylamino), mono - or di _{-C 7-16} aralkyl - carbonyl amino group (e.g., benzyl carbonyl amino), mono -Or di-5- to 14-membered aromatic heterocyclic carbonylamino group (eg, nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino group (eg, piperidine) N-carbonylcarbonylamino), mono- or di-C _1-6 alkoxy-carbonylamino (eg tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino (eg pyridylamino), carbamoylamino ( mono - or di _{-C 1-6} alkyl - carbamoyl) amino group (e.g., methylcarbamoyl Carbamoylamino), (mono - or di _{-C 7-16} aralkyl - carbamoyl) amino group (e.g., benzylcarbamoyl _{amino), C 1-6} alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), _{C 6 -14} arylsulfonylamino group (eg, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino), (C _1-6 And alkyl) (C _6-14 aryl-carbonyl) amino groups (eg, N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substituted carbamoyl group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, _C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group The have include a carbamoyl group which may.
Preferable examples of carbamoyl group which may be substituted include carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _2-6 alkenyl-carbamoyl group (eg, diallyl carbamoyl group ), Mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, mono- or di-C _1-6 alkyl-carbonyl-carbamoyl group (eg, acetylcarbamoyl, propionylcarbamoyl), mono- or di-C _6-14 aryl-carbonyl-carbamoyl Group (eg benzoylcarbamoyl) And 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

In the present specification, examples of the “optionally substituted thiocarbamoyl group” include, for example, “C _1-6 alkyl which may have 1 to 3 substituents selected from Substituent Group A. Group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - one or two location selected from a carbamoyl group Have a group "include good thiocarbamoyl group.
Preferred examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio Carbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg, diallyl thiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group ( Examples: cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl (eg phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl (eg , Benzylthioca Bamoiru, phenethyl thio carbamoyl), mono - or di _{-C 1-6} alkyl - carbonyl - thiocarbamoyl group (e.g., acetyl thiocarbamoyl, propionylthio carbamoyl), mono - or di _{-C 6-14} aryl - carbonyl - thiocarbamoyl And groups such as benzoylthiocarbamoyl, 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups such as pyridylthiocarbamoyl.

In the present specification, as the "optionally substituted sulfamoyl group", for example, a "C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent group A" , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, _C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group Have a "include sulfamoyl group.
Preferred examples of sulfamoyl group which may be substituted include sulfamoyl group and mono- or di-C _1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl Sulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _2-6 alkenyl-sulfamoyl group (eg, diallylsulfamoyl), mono- or di-C _3-10 cycloalkyl- Sulfamoyl group (eg, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14 aryl-sulfamoyl group (eg, phenylsulfamoyl), mono- or di-C _7-16 aralkyl- Sulfamoyl group (eg benzylsulfamoyl, phenethylsulfamoy ), Mono - or di _{-C 1-6} alkyl - carbonyl - sulfamoyl group (e.g., acetyl sulfamoyl, propionitrile acylsulfamoyl), mono - or di _{-C 6-14} aryl - carbonyl - sulfamoyl group (e.g., benzoyl And sulfamoyl), 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

In the present specification, examples of the “optionally substituted hydroxy group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, _C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _1-6 alkylsulfonyl group and C _The hydroxy group which may have "a substituent chosen from _6-14 arylsulfonyl groups" is mentioned.
Preferred examples of the hydroxy group which may be substituted include a hydroxy group, a C _1-6 alkoxy group, and a C _2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) ), C _3-10 cycloalkyloxy group (eg, cyclohexyloxy), C _6-14 aryloxy group (eg, phenoxy, naphthyloxy), C _7-16 aralkyloxy group (eg, benzyloxy, phenethyloxy), C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 aryl-carbonyloxy group (eg, benzoyloxy), C _7-16 aralkyl- A carbonyloxy group (eg benzyl carbonyl oxide ), 5 to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyl oxy), 3 to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., piperidinylcarbonyl oxy), C _1-6 alkoxy - carbonyl Oxy group (eg, tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), carbamoyloxy group, C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy), C _7-16 aralkyl-carbamoyloxy group (eg, benzylcarbamoyloxy), C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy), C _6-14 arylsulfonyloxy group (eg, phenylsulfonyl) Oxy).

In the present specification, examples of the “optionally substituted sulfanyl group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group and 5 to Examples thereof include sulfanyl group which may have a substituent selected from 14-membered aromatic heterocyclic groups, and halogenated sulfanyl group.
Preferable examples of the optionally substituted sulfanyl group, sulfanyl (-SH) _{group, C 1-6} alkylthio _{group, C 2-6} alkenylthio group (e.g., allyl, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C _3-10 cycloalkylthio group (eg, cyclohexylthio), C _6-14 arylthio group (eg, phenylthio, naphthylthio), C _7-16 aralkylthio group (eg, benzylthio, phenethylthio), C _1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C _6-14 aryl-carbonylthio group (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio group (Eg, pyridylthio), halogenated thio (eg, pentafluorothio) E) can be mentioned.

In the present specification, examples of the “optionally substituted silyl group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. And silyl groups optionally having 1 to 3 substituents selected from C _2-6 alkenyl groups, C _3-10 cycloalkyl groups, C _6-14 aryl groups and C _7-16 aralkyl groups It can be mentioned.
Preferred examples of the silyl group which may be substituted include tri-C _1-6 alkylsilyl groups (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).

  Below, the definition of each symbol in Formula (I) is explained in full detail.

  Partial structure:

The following formula (IIA):

A partial structure represented by or the following formula (IIB):

Shows a partial structure represented by

  Partial structure:

Is preferably of the formula (IIA):

It is a partial structure represented by

  Formula (IIA):

The partial structure represented by is preferably of the formula (IIAa):

Is a partial structure represented by formula (IIAb):

It is a partial structure represented by

  Formula (IIB):

The partial structure represented by is preferably of the formula (IIBa):

Is a partial structure represented by and more preferably a compound of formula (IIBb):

It is a partial structure represented by

  Partial structure:

Is preferably

And more preferably

It is.

R ¹ and R ² each independently represent a hydroxy group or a halogen atom.
R ¹ and R ² are preferably each independently a hydroxy group or a fluorine atom.
R ¹ is preferably a hydroxy group.
R ² is preferably a hydroxy group or a fluorine atom.

B ¹ is

Represents a group represented by
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ each independently represent a hydrogen atom or a substituent.
Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ each independently represent N or CR ^1a .
^{Z 11, Z 12, Z 13} , Z 14, Z 15 and ^{Z 16} each independently represents N or C.
R ^1a represents a hydrogen atom or a substituent.

R ¹³ is preferably a hydrogen atom.
R ¹⁴ is preferably a hydrogen atom or an amino group which may be substituted, more preferably a hydrogen atom or an amino group, and particularly preferably a hydrogen atom.
R ¹⁵ is preferably a hydrogen atom.
More preferably, R ¹³ and R ¹⁵ are both a hydrogen atom, and R ¹⁴ is a hydrogen atom or an amino group which may be substituted (in particular, a hydrogen atom or an amino group), particularly preferably R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen atoms.

R ¹⁶ is preferably a hydrogen atom.
R ¹⁷ is preferably a hydrogen atom.

Y ¹¹ is preferably N.
Y ¹² is preferably N or CH, particularly preferably N.
Y ¹³ is preferably N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom)), more preferably N or CF, particularly preferably CF It is.
More preferably, Y ¹¹ is N, Y ¹² is N or CH, and Y ¹³ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom)). is there.
More preferably, Y ¹¹ is N, Y ¹² is N or CH, and Y ¹³ is N or CF.
Even more preferably,
Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF,
Y ¹¹ is N, Y ¹² is N and Y ¹³ is N, or Y ¹¹ is N, Y ¹² is CH and Y ¹³ is N.
Particularly preferably, Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF.

Y ¹⁴ is preferably N.
Y ¹⁵ is preferably N.
Y ¹⁶ is preferably N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom)), more preferably N or CF, particularly preferably N It is.
More preferably, Y ¹⁴ is N, Y ¹⁵ is N, and Y ¹⁶ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom)).
More preferably, Y ¹⁴ is N, Y ¹⁵ is N, and Y ¹⁶ is N or CF.
Even more preferably,
Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is N, or Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is CF.
Particularly preferably, Y ¹⁴ is N, Y ¹⁵ is N, and Y ¹⁶ is N.

Z ¹¹ is preferably C.
Z ¹² is preferably C.
Z ¹³ is preferably N.
More preferably, Z ¹¹ is C, Z ¹² is C, and Z ¹³ is N.

Z ¹⁴ is preferably C.
Z ¹⁵ is preferably C.
Z ¹⁶ is preferably N.
More preferably, Z ¹⁴ is C, Z ¹⁵ is C, and Z ¹⁶ is N.

B ² is

Represents a group represented by
^{R 23, R 24, R 25} , R 26 and ^{R 27} each independently represent a hydrogen atom or a substituent.
Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ each independently represent N or CR ^2a .
Z ²¹ , Z ²² , Z ²³ , Z ²⁴ , Z ²⁵ and Z ²⁶ each independently represent N or C.
R ^2a represents a hydrogen atom or a substituent.

R ²³ is preferably a hydrogen atom.
R ²⁴ is preferably a hydrogen atom or an amino group which may be substituted, more preferably a hydrogen atom or an amino group, and particularly preferably a hydrogen atom.
R ²⁵ is preferably a hydrogen atom.

R ²⁶ is preferably a hydrogen atom.
R ²⁷ is preferably a hydrogen atom.

Y ²¹ is preferably N.
Y ²² is preferably N.
Y ²³ is preferably N or CR ^2a (wherein R ^2a is a halogen atom (preferably a fluorine atom)), more preferably N or CF, particularly preferably CF It is.
More preferably, Y ²¹ is N, Y ²² is N, and Y ²³ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom)).
More preferably, Y ²¹ is N, Y ²² is N, and Y ²³ is N or CF.
Even more preferably,
Y ²¹ is N, Y ²² is N, and Y ²³ is CF, or Y ²¹ is N, Y ²² is N, and Y ²³ is N.
Particularly preferably, Y ²¹ is N, Y ²² is N, and Y ²³ is CF.

Y ²⁴ is preferably N.
Y ²⁵ is preferably N or CH, more preferably N.
Y ²⁶ is preferably N or CR ^2a (wherein R ^2a is a halogen atom (preferably a fluorine atom)), more preferably N or CF, particularly preferably N It is.
More preferably, Y ²⁴ is N, Y ²⁵ is N or CH, and Y ²⁶ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom)). is there.
More preferably, Y ²⁴ is N, Y ²⁵ is N or CH, and Y ²⁶ is N or CF.
Even more preferably,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is CF, or Y ²⁴ is N, Y ²⁵ is CH, and Y ²⁶ is N.
Particularly preferably, Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N.

Z ²¹ is preferably N or C, particularly preferably C.
Z ²² is preferably C.
Z ²³ is preferably N or C, particularly preferably N.
More preferably, Z ²¹ is N or C, Z ²² is C, and Z ²³ is N or C.
More preferably,
Z ²¹ is is ^{C, Z 22} is is C, and either ^{Z 23} is N, or ^{Z 21} is ^{N, Z 22} is C, and ^{Z 23} is a C.
Particularly preferably, Z ²¹ is C, Z ²² is C, and Z ²³ is N.

Z ²⁴ is preferably N or C, more preferably C.
Z ²⁵ is preferably C.
Z ²⁶ is preferably N or C, more preferably N.
More preferably, Z ²⁴ is N or C, Z ²⁵ is C, and Z ²⁶ is N or C.
More preferably,
Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N, or Z ²⁴ is N, Z ²⁵ is C, and Z ²⁶ is C.
Particularly preferably, Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N.

B ¹ and B ² are preferably each independently

It is. Here, at least one of B ¹ and B ² is

Preferably, in this case the other is

It is more preferable that
Particularly preferably, B ¹ is

And B ² ,

It is.

However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C.

Each of X ¹ and X ² independently represents an oxygen atom or a sulfur atom.
X ¹ and X ² are preferably both oxygen atoms.

Each of Q ¹ , Q ² , Q ³ and Q ⁴ independently represents an oxygen atom or a sulfur atom.
Q ¹ is preferably an oxygen atom.
Q ³ is preferably an oxygen atom.
More preferably, Q ¹ and Q ³ are both oxygen atoms, and Q ² and Q ⁴ are each independently an oxygen atom or a sulfur atom.
In another embodiment, more preferably
Q ¹ is an oxygen atom,
Q ² is an oxygen atom or a sulfur atom,
Q ³ is an oxygen atom, and Q ⁴ is an oxygen atom or a sulfur atom.

  The compound (I) is preferably of the formula (Ia):

(In the formula, partial structure:

Is the formula (IIAa):

A partial structure represented by or a formula (IIBa):

It is a partial structure represented by )
Or a salt thereof (hereinafter also referred to as compound (Ia)), more preferably a compound of formula (Ib):

(In the formula, partial structure:

Is the formula (IIAb):

A partial structure represented by or formula (IIBb):

It is a partial structure represented by )
Or a salt thereof (hereinafter, also referred to as compound (Ib)).

  Preferred examples of the compound (I) include the following compounds.

[Compound A1]
Partial structure:

Is the formula (IIA):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a halogen atom (preferably a fluorine atom);
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group which may be substituted;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CR ^1a (wherein, R ^1a is a halogen atom (preferably a fluorine atom));
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom));
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are each independently an oxygen atom or a sulfur atom; and Q ¹ , Q ² , Q ³ and Q ⁴ are each independently an oxygen atom or a sulfur atom;
Compound (I).

[Compound B1]
Partial structure:

Is the formula (IIA):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CF;
(Preferably,
Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF,
Y ¹¹ is N, Y ¹² is N and Y ¹³ is N, or Y ¹¹ is N, Y ¹² is CH and Y ¹³ is N. )
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CF;
(Preferably,
Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is N, or Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is CF. )
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CF;
(Preferably,
Y ²¹ is N, Y ²² is N, and Y ²³ is CF, or Y ²¹ is N, Y ²² is N, and Y ²³ is N. )
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CF;
(Preferably,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is CF, or Y ²⁴ is N, Y ²⁵ is CH, and Y ²⁶ is N. )
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
(Preferably,
Z ²¹ is is ^{C, Z 22} is is C, and either ^{Z 23} is N, or ^{Z 21} is ^{N, Z 22} is C, and ^{Z 23} is a C. )
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
(Preferably,
Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N, or Z ²⁴ is N, Z ²⁵ is C, and Z ²⁶ is C. )
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (I).

[Compound A1-a]
Partial structure:

Is the formula (IIAa):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a halogen atom (preferably a fluorine atom);
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group which may be substituted;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CR ^1a (wherein, R ^1a is a halogen atom (preferably a fluorine atom));
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom));
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are each independently an oxygen atom or a sulfur atom; and Q ¹ , Q ² , Q ³ and Q ⁴ are each independently an oxygen atom or a sulfur atom;
Compound (Ia).

[Compound B1-a]
Partial structure:

Is the formula (IIAa):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CF;
(Preferably,
Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF,
Y ¹¹ is N, Y ¹² is N and Y ¹³ is N, or Y ¹¹ is N, Y ¹² is CH and Y ¹³ is N. )
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CF;
(Preferably,
Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is N, or Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is CF. )
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CF;
(Preferably,
Y ²¹ is N, Y ²² is N, and Y ²³ is CF, or Y ²¹ is N, Y ²² is N, and Y ²³ is N. )
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CF;
(Preferably,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is CF, or Y ²⁴ is N, Y ²⁵ is CH, and Y ²⁶ is N. )
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
(Preferably,
Z ²¹ is is ^{C, Z 22} is is C, and either ^{Z 23} is N, or ^{Z 21} is ^{N, Z 22} is C, and ^{Z 23} is a C. )
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
(Preferably,
Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N, or Z ²⁴ is N, Z ²⁵ is C, and Z ²⁶ is C. )
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ia).

[Compound A1-b]
Partial structure:

Is the formula (IIAb):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a halogen atom (preferably a fluorine atom);
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group which may be substituted;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CR ^1a (wherein, R ^1a is a halogen atom (preferably a fluorine atom));
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom));
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are each independently an oxygen atom or a sulfur atom; and Q ¹ , Q ² , Q ³ and Q ⁴ are each independently an oxygen atom or a sulfur atom;
Compound (Ib).

[Compound B1-b]
Partial structure:

Is the formula (IIAb):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CF;
(Preferably,
Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF,
Y ¹¹ is N, Y ¹² is N and Y ¹³ is N, or Y ¹¹ is N, Y ¹² is CH and Y ¹³ is N. )
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CF;
(Preferably,
Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is N, or Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is CF. )
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CF;
(Preferably,
Y ²¹ is N, Y ²² is N, and Y ²³ is CF, or Y ²¹ is N, Y ²² is N, and Y ²³ is N. )
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CF;
(Preferably,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is CF, or Y ²⁴ is N, Y ²⁵ is CH, and Y ²⁶ is N. )
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
(Preferably,
Z ²¹ is is ^{C, Z 22} is is C, and either ^{Z 23} is N, or ^{Z 21} is ^{N, Z 22} is C, and ^{Z 23} is a C. )
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
(Preferably,
Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N, or Z ²⁴ is N, Z ²⁵ is C, and Z ²⁶ is C. )
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ib).

[Compound A2]
Partial structure:

Is the formula (IIA):

A partial structure represented by or formula (IIB):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a halogen atom (preferably a fluorine atom);
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group which may be substituted;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CR ^1a (wherein, R ^1a is a halogen atom (preferably a fluorine atom));
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom));
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom or an amino group which may be substituted;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are each independently an oxygen atom or a sulfur atom; and Q ¹ , Q ² , Q ³ and Q ⁴ are each independently an oxygen atom or a sulfur atom;
Compound (I).

[Compound B2]
Partial structure:

Is the formula (IIA):

A partial structure represented by or formula (IIB):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CF;
(Preferably,
Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF,
Y ¹¹ is N, Y ¹² is N and Y ¹³ is N, or Y ¹¹ is N, Y ¹² is CH and Y ¹³ is N. )
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CF;
(Preferably,
Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is N, or Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is CF. )
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom or an amino group;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CF;
(Preferably,
Y ²¹ is N, Y ²² is N, and Y ²³ is CF, or Y ²¹ is N, Y ²² is N, and Y ²³ is N. )
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CF;
(Preferably,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is CF, or Y ²⁴ is N, Y ²⁵ is CH, and Y ²⁶ is N. )
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
(Preferably,
Z ²¹ is is ^{C, Z 22} is is C, and either ^{Z 23} is N, or ^{Z 21} is ^{N, Z 22} is C, and ^{Z 23} is a C. )
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
(Preferably,
Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N, or Z ²⁴ is N, Z ²⁵ is C, and Z ²⁶ is C. )
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (I).

[Compound A2-a]
Partial structure:

Is the formula (IIAa):

A partial structure represented by or a formula (IIBa):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a halogen atom (preferably a fluorine atom);
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group which may be substituted;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CR ^1a (wherein, R ^1a is a halogen atom (preferably a fluorine atom));
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom));
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom or an amino group which may be substituted;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are each independently an oxygen atom or a sulfur atom; and Q ¹ , Q ² , Q ³ and Q ⁴ are each independently an oxygen atom or a sulfur atom;
Compound (Ia).

[Compound B2-a]
Partial structure:

Is the formula (IIAa):

A partial structure represented by or a formula (IIBa):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CF;
(Preferably,
Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF,
Y ¹¹ is N, Y ¹² is N and Y ¹³ is N, or Y ¹¹ is N, Y ¹² is CH and Y ¹³ is N. )
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CF;
(Preferably,
Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is N, or Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is CF. )
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom or an amino group;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CF;
(Preferably,
Y ²¹ is N, Y ²² is N, and Y ²³ is CF, or Y ²¹ is N, Y ²² is N, and Y ²³ is N. )
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CF;
(Preferably,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is CF, or Y ²⁴ is N, Y ²⁵ is CH, and Y ²⁶ is N. )
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
(Preferably,
Z ²¹ is is ^{C, Z 22} is is C, and either ^{Z 23} is N, or ^{Z 21} is ^{N, Z 22} is C, and ^{Z 23} is a C. )
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
(Preferably,
Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N, or Z ²⁴ is N, Z ²⁵ is C, and Z ²⁶ is C. )
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ia).

[Compound A2-b]
Partial structure:

Is the formula (IIAb):

A partial structure represented by or formula (IIBb):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a halogen atom (preferably a fluorine atom);
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group which may be substituted;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CR ^1a (wherein, R ^1a is a halogen atom (preferably a fluorine atom));
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CR ^1a (wherein R ^1a is a halogen atom (preferably a fluorine atom));
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom or an amino group which may be substituted;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CR ^2a (wherein, R ^2a is a halogen atom (preferably a fluorine atom));
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are each independently an oxygen atom or a sulfur atom; and Q ¹ , Q ² , Q ³ and Q ⁴ are each independently an oxygen atom or a sulfur atom;
Compound (Ib).

[Compound B2-b]
Partial structure:

Is the formula (IIAb):

A partial structure represented by or formula (IIBb):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

A group represented by
R ¹³ is a hydrogen atom;
R ¹⁴ is a hydrogen atom or an amino group;
R ¹⁵ is a hydrogen atom;
R ¹⁶ is a hydrogen atom;
R ¹⁷ is a hydrogen atom;
Y ¹¹ is N;
Y ¹² is N or CH;
Y ¹³ is N or CF;
(Preferably,
Y ¹¹ is N, Y ¹² is N, and Y ¹³ is CF,
Y ¹¹ is N, Y ¹² is N and Y ¹³ is N, or Y ¹¹ is N, Y ¹² is CH and Y ¹³ is N. )
Y ¹⁴ is N;
Y ¹⁵ is N;
Y ¹⁶ is N or CF;
(Preferably,
Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is N, or Y ¹⁴ is N, Y ¹⁵ is N and Y ¹⁶ is CF. )
Z ¹¹ is C,
Z ¹² is C;
Z ¹³ is N;
Z ¹⁴ is C,
Z ¹⁵ is C;
Z ¹⁶ is N;
B ² is

A group represented by
R ²³ is a hydrogen atom;
R ²⁴ is a hydrogen atom or an amino group;
R ²⁵ is a hydrogen atom;
R ²⁶ is a hydrogen atom;
R ²⁷ is a hydrogen atom;
Y ²¹ is N;
Y ²² is N;
Y ²³ is N or CF;
(Preferably,
Y ²¹ is N, Y ²² is N, and Y ²³ is CF, or Y ²¹ is N, Y ²² is N, and Y ²³ is N. )
Y ²⁴ is N;
Y ²⁵ is N or CH;
Y ²⁶ is N or CF;
(Preferably,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is N,
Y ²⁴ is N, Y ²⁵ is N, and Y ²⁶ is CF, or Y ²⁴ is N, Y ²⁵ is CH, and Y ²⁶ is N. )
Z ²¹ is N or C;
Z ²² is C;
Z ²³ is N or C;
(Preferably,
Z ²¹ is is ^{C, Z 22} is is C, and either ^{Z 23} is N, or ^{Z 21} is ^{N, Z 22} is C, and ^{Z 23} is a C. )
Z ²⁴ is N or C;
Z ²⁵ is C;
Z ²⁶ is N or C;
(Preferably,
Z ²⁴ is C, Z ²⁵ is C, and Z ²⁶ is N, or Z ²⁴ is N, Z ²⁵ is C, and Z ²⁶ is C. )
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ib).

[Compound C2]
Partial structure:

Is the formula (IIA):

A partial structure represented by or formula (IIB):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ and B ² are each independently

And at least one of B ¹ and B ² is

[Preferably, the other is

It is. ];
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (I).

[Compound C2-a]
Partial structure:

Is the formula (IIAa):

A partial structure represented by or a formula (IIBa):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ and B ² are each independently

And at least one of B ¹ and B ² is

[Preferably, the other is

It is. ];
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ia).

[Compound C2-b]
Partial structure:

Is the formula (IIAb):

A partial structure represented by or formula (IIBb):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ and B ² are each independently

And at least one of B ¹ and B ² is

[Preferably, the other is

It is. ];
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ib).

[Compound D2]
Partial structure:

Is the formula (IIA):

A partial structure represented by or formula (IIB):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

And
B ² is

And
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (I).

[Compound D2-a]
Partial structure:

Is the formula (IIAa):

A partial structure represented by or a formula (IIBa):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

And
B ² is

And
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ia).

[Compound D2-b]
Partial structure:

Is the formula (IIAb):

A partial structure represented by or formula (IIBb):

A partial structure represented by
R ¹ is a hydroxy group;
R ² is a hydroxy group or a fluorine atom;
B ¹ is

And
B ² is

And
X ¹ and X ² are both oxygen atoms;
Q ¹ is an oxygen atom;
Q ² is an oxygen atom or a sulfur atom;
Q ³ is an oxygen atom; and Q ⁴ is an oxygen atom or a sulfur atom;
Compound (Ib).

  As a specific example of a compound (I), the compound of Examples 1-20 and 3a is mentioned, for example.

When the compound (I) is a salt, such salt is preferably a pharmacologically acceptable salt, such as a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, an organic acid And salts with basic or acidic amino acids.
Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts and ammonium salts.
Preferred examples of salts with organic bases are trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, Dicyclohexylamine and salts with N, N-dibenzylethylenediamine can be mentioned.
Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
Preferred examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid And salts with p-toluenesulfonic acid.
Preferred examples of salts with basic amino acids include salts with arginine, lysine and ornithine.
Preferred examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.
When the compound (I) is a salt, a salt with triethylamine or sodium is preferred, and a salt with triethylamine is more preferred.

  The process for producing the compound of the present invention is described below.

  The raw materials and reagents used in each step of the following production method, and the obtained compound may each form a salt. Such salts include, for example, those similar to the salts of the compound of the present invention described above.

  When the compound obtained in each step is a free compound, it can be converted to a target salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or another type of desired salt by a method known per se.

  The compound obtained in each step may be used as the reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step may be concentrated from the reaction mixture according to a conventional method It can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like.

  When the raw material of each process and the compound of a reagent are marketed, a commercial item can be used as it is.

  In the reaction of each step, the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

  In the reaction of each step, the reaction temperature may vary depending on the reagent and solvent used, but unless otherwise specified, it is generally -78 ° C to 300 ° C, preferably -78 ° C to 150 ° C.

  In the reaction of each step, the pressure may differ depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

  In the reaction of each step, for example, a microwave synthesizer such as Biotage's Initiator may be used. The reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually room temperature to 300 ° C, preferably 50 ° C to 250 ° C. The reaction time may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

  In the reaction of each step, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent also serves as the reaction solvent, the amount of the solvent is used.

In the reaction of each step, unless otherwise specified, these reactions are carried out without solvent, or dissolved or suspended in a suitable solvent. Specific examples of the solvent include the solvents described in the examples, or the following.
Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol etc .;
Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc .;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene etc .;
Saturated hydrocarbons: cyclohexane, hexane etc .;
Amides: N, N-dimethylformamide, N-methylpyrrolidone and the like;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride etc .;
Nitriles: acetonitrile, etc .;
Sulfoxides: dimethyl sulfoxide and the like;
Aromatic organic bases: pyridine and the like;
Acid anhydrides: acetic anhydride etc .;
Organic acids: Formic acid, acetic acid, trifluoroacetic acid etc .;
Inorganic acids: hydrochloric acid, sulfuric acid etc .;
Esters: Ethyl acetate etc .;
Ketones: acetone, methyl ethyl ketone etc .;
water.
The above solvents may be used as a mixture of two or more at an appropriate ratio.

When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the examples are used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate etc .;
Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-Undecene, imidazole, piperidine etc .;
Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc .;
Alkali metal hydrides: sodium hydride etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide etc .;
Organic lithiums: n-butyllithium and the like.

When an acid or acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in the examples is used.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid etc .;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .;
Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.

  Unless otherwise specified, the reaction of each step is a method known per se, for example, 5th Edition Experimental Chemistry Lecture, Volume 13 to Volume 19 (edited by The Chemical Society of Japan); New Experimental Chemistry Lecture, Volume 14 to 15 (Japan) Chemical Chemistry Ed .; Precision Organic Chemistry, Rev. 2 (L. F. Tietze, Th. Eicher, Nan-e-do); Revised Organic Personal Name Reactions Mechanisms and Points (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII ( John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures by Jie Jack Li, OXFORD UNIVERSITY ); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (Elsevier Japan Co., Ltd.); Organic synthesis strategy learned from personal name reaction (translated by Kiyoshi Tomioka, published by Chemical Doujinshi); Method described in Comprehensive Organic Transformations (VCH Publishers Inc.) 1989, etc. Alternatively, it is carried out according to the method described in the examples.

In each step, protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, Wiley-Interscience 2007, "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. M. Wuts E.) The method described in Thieme, Inc. 2004, "Protecting Groups 3rd Ed." (P. J. Kocienski), etc. or the method described in the examples is used.
Examples of protecting groups for hydroxyl group (for example, hydroxyl group such as alcohol and phenolic hydroxyl group) include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether; acetate ester, benzoic acid Examples include carboxylic acid ester type protective groups such as esters; sulfonic acid ester type protective groups such as methane sulfonic acid ester; carbonic acid ester type protective groups such as tert-butyl carbonate.
Examples of the protecting group for the carbonyl group of aldehyde include an acetal type protecting group such as dimethyl acetal; and a cyclic acetal type protecting group such as 1,3-dioxane.
Examples of the protecting group of carbonyl group of ketone include ketal protecting group such as dimethyl ketal; cyclic ketal protecting group such as 1,3-dioxane; oxime protecting group such as O-methyl oxime; N, N-dimethyl A hydrazone type protective group such as hydrazone may be mentioned.
Examples of protecting groups for carboxyl groups include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N, N-dimethylamide.
Examples of the thiol protecting group include ether-type protecting groups such as benzyl thioether; and ester-type protecting groups such as thioacetic acid ester, thiocarbonate and thiocarbamate.
Examples of protecting groups for amino heterocycles and aromatic heterocycles such as imidazole, pyrrole and indole include carbamate protecting groups such as benzyl carbamate; amide protecting groups such as acetamide, benzamide and isobutyramide; N-triphenylmethyl And alkylamine type protecting groups such as amines; and sulfonamide type protecting groups such as methane sulfonamide.
Removal of the protecting group is carried out by a method known per se (eg, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl) It can be carried out using a method using iodide, trimethylsilyl bromide) or a reduction method).

  When performing a reduction reaction in each step, the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride Metal hydrides such as triacetoxyborohydride and tetramethylammonium hydride; boranes such as borane-tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. In the case of reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as palladium-carbon or Lindlar catalyst.

  When an oxidation reaction is carried out in each step, examples of the oxidizing agent used include m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, peroxides such as tert-butyl hydroperoxide, etc .; tetrabutylammonium perchlorate etc. Perchlorates; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese dioxide Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), reagents having chromium such as Jones reagent; N-bromosuccinimide (NBS) Halogen compounds such as: oxygen; ozone; sulfur trioxide / pyridine complex; Sumiumu; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

  When performing radical cyclization reaction in each process, as a radical initiator used, azo compounds such as azobisisobutyronitrile (AIBN); 4-4'-azobis-4-cyanopentanoic acid (ACPA) Water soluble radical initiators; triethyl boron in the presence of air or oxygen; benzoyl peroxide and the like. Further, as a radical reaction agent to be used, tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like can be mentioned.

  When carrying out a Wittig reaction in each step, examples of the Wittig reagent used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared by methods known per se, for example, by reacting a phosphonium salt with a strong base.

  When performing the Horner-Emmons reaction in each step, as reagents used, phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organic lithiums It can be mentioned.

  When carrying out the Friedel-Crafts reaction in each step, a reagent used is a combination of a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (eg, halogenated alkyls, alcohols, olefins) A combination is mentioned. Alternatively, instead of the Lewis acid, an organic acid or inorganic acid can be used, and instead of the acid chloride, an acid anhydride such as acetic anhydride can be used.

  When performing an aromatic nucleophile substitution reaction in each step, a nucleophile (eg, amines, imidazole) and a base (eg, organic bases) are used as reagents.

  When performing nucleophilic addition reaction with carbanion, nucleophilic 1,4-addition reaction with carbanion (Michael addition reaction), or nucleophilic substitution reaction with carbanion in each step, a base used to generate carbanion And organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.

  When the Grignard reaction is carried out in each step, examples of the Grignard reagent include aryl magnesium halides such as phenyl magnesium bromide; and alkyl magnesium halides such as methyl magnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with magnesium metal with ether or tetrahydrofuran as a solvent.

  When performing Knoevenagel condensation reaction in each step, as reagents, active methylene compounds (eg, malonic acid, diethyl malonate, malononitrile etc.) and bases (eg, organic bases, etc.) sandwiched between two electron withdrawing groups Metal alkoxides, inorganic bases) are used.

  When Vilsmeier-Haack reaction is performed in each step, phosphoryl chloride and an amide derivative (eg, N, N-dimethylformamide etc.) are used as reagents.

  When carrying out the azidation reaction of alcohols, alkyl halides and sulfonic acid esters in each step, examples of the azidation agent to be used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide and the like. For example, in the case of azide alcohol, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, and the like.

  When the reductive amination reaction is carried out in each step, the reducing agent to be used includes sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen and formic acid. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde as well as aldehydes such as acetaldehyde and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines to be used include ammonia, primary amines such as methylamine; secondary amines such as dimethylamine, and the like.

  When the Mitsunobu reaction is performed in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

  When performing esterification reaction, amidation reaction, or urea conversion reaction in each step, as reagents used, acyl chloride such as acid chloride and acid bromide; acid anhydride, active ester, sulfuric acid ester And activated carboxylic acids. Carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD) as an activating agent for carboxylic acid; 4- (4,6-dimethoxy-1,3,5-) Triazine-based condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); Carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Phosphorus azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformic acid such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-te Tramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. When a carbodiimide type condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be further added to the reaction.

  When a coupling reaction is carried out in each step, the metal catalyst used is palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl) Phosphine compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenyl phosphino) ferrocene palladium (II) chloride; tetrakis (triphenyl phosphine) nickel (0) And nickel compounds such as tris (triphenylphosphine) rhodium (III); cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds and the like. Furthermore, a base may be added to the reaction, and such bases include inorganic bases.

  When thiocarbonylation is carried out in each step, typically, diphosphorus pentasulfide is used as a thiocarbonylating agent, but in addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) Reagents having a 1,3,2,4-dithiadiphosphetan-2,4-disulfide structure such as 1,3), 2,4-dithiadiphosphetan-2,4-disulfide (Lawesson's reagent) May be used.

  When performing Wohl-Ziegler reaction in each process, as a halogenating agent to be used, N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like Can be mentioned. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile or the like to the reaction.

  When performing a halogenation reaction of a hydroxy group in each step, as a halogenating agent to be used, an acid halide of a hydrohalic acid and an inorganic acid, specifically, in chlorination, hydrochloric acid, thionyl chloride, oxy For bromination, such as phosphorus chloride, 48% hydrobromic acid and the like can be mentioned. Alternatively, a method of obtaining a halogenated alkyl from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method may be used in which a halogenated alkyl is synthesized through a two-step reaction in which an alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride or sodium iodide.

  When the Arbuzov reaction is carried out in each step, examples of reagents used include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite and tri (isopropyl) phosphite.

  When a sulfonic acid esterification reaction is carried out in each step, examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.

  When performing a hydrolysis reaction in each step, an acid or a base is used as a reagent. Examples of the above acids include pyridine 2,2,2-trifluoroacetate. When the acid hydrolysis reaction of tert-butyl ester is carried out, formic acid, triethylsilane or the like may be added to reductively trap the by-produced tert-butyl cation.

  When dehydration reaction is carried out in each step, examples of the dehydrating agent used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

  In addition to those described above, in each step, for example, an ether-type protecting group such as bis (4-methoxyphenyl) (phenyl) methyl ether can also be used as the protecting group for hydroxyl group.

  In addition to those described above, imidoamide-type protecting groups such as N, N-dimethylformimidamide can also be used as the protecting group for the amino group used in each step.

  In each step, the deprotection reaction is carried out, for example, in addition to acetic acid, 1,1,1,3,3,3-hexafluoropropan-2-ol, triethylamine trihydrofluoride, methylamine, 2 It can also be carried out using -methylpropan-2-amine, hydrogen fluoride-pyridine, trifluoroacetic acid.

  When transfer reaction is carried out in each step, examples of the reagent used include bases such as triethylamine.

  When performing a phosphoroamidite reaction in each step, as a reagent, a phosphoroamidite agent (eg, phosphorodiamidites such as 3-((bis (diisopropylamino) phosphino) oxy) propanenitrile; 2-cyanoethyl diisopropylate Chlorophosphoroamidites such as chlorophosphoramidite and bases (eg, organic bases) are used.

  In each step, when performing thiophosphoramidite reaction, as a reagent, thiophosphoramidite agent (eg, 2-cyanoethyl dipropan-2-yl phosphoroamido chloride thioit) and a base (eg, organic bases) Is used.

  When H-phosphonate reaction is performed in each step, examples of the H-phosphonate agent used include diphenyl phosphite and the like.

  When H-thiophosphonate reaction is performed in each step, examples of the H-thiophosphonate agent used include a combination of an activator such as diphenyl phosphite and a sulfur atom source such as lithium sulfide.

  When condensation reaction is carried out in each step, examples of the activating agent used include pyridine 2,2,2-trifluoroacetate, 1H-tetrazole, 5- (ethylsulfanyl) -2H-tetrazole and the like.

  When an oxidation reaction is carried out in each step, as the oxidizing agent to be used, in addition to the above, a halogen simple substance such as iodine, which is usually used for nucleic acid synthesis, and the like can also be mentioned.

  In each step, when a sulfurizing reaction is carried out, as a sulfurizing agent to be used, 3H-benzo [c] [1,2] dithiole-3-one, 3H-benzo [c] [1,2] dithiole-3-one One example is 1,1-dioxide, ((dimethylaminomethylidene) amino) -3H-1,2,4-dithiazoline-3-thione and the like. Besides, for example, 2,6-lutidine suspension of sulfur, carbon disulfide solution of sulfur, tetraethylthiuram disulphide (TETD) (H. Vu et al., Tetrahedron Lett., 32, 3005-3008. (1991)), Beauge reagent (R.P. Lyer et al., J. Am. Chem. Soc., 112, 1253-1254 (1990)), Lawesson's reagent can also be used for the sulfurization reaction. In addition, as a method of constructing a phosphorodithioate structure, reference can be made to Marshall et al. (Science 259: 1564-1570, 1993) and Caruthers and Nielsen (WO 1989/011486).

  When performing a cyclization reaction in each step, as an activating agent to be used, 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide, pivaloyl chloride, 2 -(Benzoyltriazol-1-yloxy) -1,3-dimethyl-2-pyrrolidin-1-yl-1,3,2-diazaphosphoridinium hexafluorate (BOMP), N, N-bis (2-) And oxazolidinyl) phosphonic chloride (BopCl), pyrophosphoric acid and the like. When the activator is not used, it can be substituted by heating. Furthermore, a base may be added to the reaction, and such bases include organic bases.

  When performing the bond formation reaction of a nucleobase and ribose in each process, trimethylsilyl N- (trimethylsilyl) acetoimidate, trimethylsilyl trifluoromethanesulfonate etc. are mentioned as an activating agent used.

  Partial structure:

Is the formula (IIA):

Compound (IA) can be produced from compound (1a) or (1b) and compound (2a) or (2b) in the following method.

[Wherein, PG ^a represents a hydroxyl protecting group, and the other symbols are as defined above. ]

  Or partial structure:

Is a partial structure represented by formula (IIA), compound (IA) can also be produced from compound (8a) or (8b) and compound (9a) or (9b) by the following method.

[Wherein, PG ^b represents a hydroxyl protecting group, and the other symbols are as defined above. ]

  Partial structure:

Is the formula (IIB):

Compound (IB) can be produced from compound (15a) or (15b) and compound (2a) or (2b) in the following method.

[The symbols in the formula are as defined above. ]

  Or partial structure:

Is a partial structure represented by formula (IIB), compound (IB) can also be produced from compound (8a) or (8b) and compound (21a) or (21b) by the following method.

[Wherein, PG ^c represents a hydroxyl protecting group, and the other symbols are as defined above. ]

PG ^a, as the protective group for the hydroxyl group represented by PG ^b or PG ^c, bis (4-methoxyphenyl) (phenyl) methyl ether, 3-hydroxy-1,1,3,3-tetraisopropyl di Shiroki Sani ethers such as Ether type protecting groups are preferred.
When each of R ¹ and R ² is a hydroxyl group, the hydroxyl group may be protected. Suitable hydroxy protecting groups include ether-type protecting groups such as tert-butyldimethylsilyl ether, 3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl ether.
When R ¹ is a hydroxyl group, the hydroxyl group represented by the hydroxyl group and PG ^a is a 1,1,3,3-tetraisopropyldisiloxanyl group:

May be protected by In this case, the deprotection reaction for removing PG ^a, the hydroxyl group of ^{R 1} is 3-hydroxy-1,1,3,3-tetraisopropyl disiloxanyl group:

To form a protected compound.
When B ¹ has a functional group, the functional group may be protected. For example, B ¹ is

When R ¹⁴ is —NH ₂ group, the —NH ₂ group may be protected. Also, for example, B ¹ is

If in a group represented by the -NH ₂ group may be protected.

When B ² has a functional group, the functional group may be protected. For example, B ² is

When R ²⁴ is —NH ₂ group, the —NH ₂ group may be protected. Also, for example, B ² is

If in a group represented by the -NH ₂ group may be protected.

Suitable protecting groups for -NH ₂ group, benzamide, and amide type protecting groups, such as isobutyramide, N, include Imidoamido type protecting groups such as N- dimethylformamide imide amide.

  The aforementioned compounds (1a), (1b), (9a) and (9b) can be produced from compound (27) by the following method.

[The symbols in the formula are as defined above. ]

  The aforementioned compounds (2a), (2b), (8a) and (8b) can be produced from compound (29) by the following method.

[The symbols in the formula are as defined above. ]

  The aforementioned compounds (15a), (15b), (21a) and (21b) can be produced from compound (31) by the following method.

[The symbols in the formula are as defined above. ]

Another substituent contained in compound (I) is obtained by converting the substituent in compound (I) thus obtained by applying a means known per se (ie, introducing a substituent or converting a functional group). Compounds or salts thereof can also be produced.
As a method of introducing a substituent or converting a functional group, a known general method is used, and for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine) or C _1-6 alkyl which may be halogenated Methyl group, cyclopropyl group, vinyl group, cyano group, formyl group, carbonyl group, carboxyl group of sulfonyl-oxy group [eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (triflate)] , Conversion of formyl group to ethynyl group by the carbonization reaction of Ceyfers-Gilbert; conversion to carboxy group by hydrolysis of ester; to carbamoyl group by amidation of carboxy group Conversion; hydroxymethyl by reduction of the carboxy group Conversion to a group; reduction to the carbonyl group or conversion to an alcohol form by alkylation; reductive amination of a carbonyl group; oximation of a carbonyl group; acylation of an amino group; urealation of an amino group; sulfonylation of an amino group Alkylation of amino group; substitution or amination of active halogen with amine; alkylation of hydroxy group; substitution or amination of hydroxy group.
When introducing a substituent or converting a functional group, if there is a reactive site where a reaction other than the purpose occurs, a protective group is introduced in advance to the reactive site by a means known per se if necessary, After carrying out the desired reaction, the protective group may be removed by a means known per se to produce a compound within the scope of the present invention.
For example, when the starting compound or the intermediate has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups may be protected by a protecting group generally used in peptide chemistry and the like. In this case, after the reaction, the target compound can be obtained by removing the protecting group as necessary.

  When compound (I) has one or more isomers such as optical isomers, stereoisomers, regioisomers, rotational isomers and the like, either one isomer or a mixture is also encompassed in compound (I). For example, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I). These isomers can be obtained individually as synthetic products and separation techniques (eg, concentration, solvent extraction, column chromatography, recrystallization) known per se.

Compound (I) may be a crystal, and a single crystal or a mixture of crystal forms is encompassed in compound (I). The crystals can be produced by crystallization using a crystallization method known per se.
Compound (I) may also be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or co-crystal salt is composed of two or more unique solids at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, stability). Means crystalline material. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
Compound (I) may be a hydrate, non-hydrate, solvate or non-solvate, both of which are encompassed in compound (I). Ru.
Compounds labeled or substituted with isotopes (eg, ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I) and the like are also encompassed in compound (I). The isotope-labeled or substituted compound (I) can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET) and can be useful in the field such as medical diagnosis .

Compound (I) may be a prodrug.
The prodrug of compound (I) is a compound which is converted to compound (I) by reaction with an enzyme or gastric acid under physiological conditions in the living body, that is, enzymatic oxidation, reduction, hydrolysis etc. Or a compound which is converted to a compound (I) by hydrolysis or the like by gastric acid or the like.

As a prodrug of compound (I), for example,
(1) Compound (I) wherein the amino is acylated, alkylated or phosphorylated (for example, the amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-) Oxo-1,3-dioxolene-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropyl carbonylated compounds);
(2) Compound (I) hydroxy is acylated, alkylated, phosphorylated, borated (for example, compound (I) hydroxy is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated , Fumarylation, alanylation, dimethylaminomethylcarbonylated compounds);
(3) Compounds in which the carboxy of compound (I) is esterified and amidated (eg, the carboxy of compound (I) is ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethylesterified, pi Baroyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamide Compounds);
Can be mentioned. These compounds can be produced from compound (I) by a method known per se.

In addition, prodrugs of Compound (I) are those which change into Compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design, pages 163 to 198. It may be.
In the present specification, the prodrug may form a salt, and such salt includes those exemplified as the salt of the compound represented by the above-mentioned formula (I).

The compound (I) can also be used as a payload (above, a portion corresponding to a drug) in an antibody (or peptide antigen recognition sequence) -drug complex. When Compound (I) is used as a payload, Compound (I) can be linked to an antibody (or a peptidic antigen recognition sequence) via a linker.
As an example when compound (I) is used as the payload,
(1) B ¹ is

And a compound (I) which is a group represented by
(2) B ² is

Compound (I) which is a group represented by
Can be mentioned.

When Compound (I) is used as a payload, an antibody (or peptidic antigen recognition sequence) -drug complex obtained by converting Compound (I) as follows can be used.
(1) B ¹ in the formula (I),

In the group represented by or B ² in formula (I),

Convert to the group represented by
Here, R ^a and R ^b are each independently
(i) C _1-6 alkyl group,
(ii) an acyl group, or
(iii) Formula:

R in the formula is a bond between an antibody and a peptidic antigen recognition sequence (wherein the bond is shared between the linker and a functional group present in the side chain of the antibody or peptidic antigen recognition sequence) Each R ′ represents a hydrogen atom or a substituent.
(2) R ¹ and R ² in the formula (I) are each independently selected from the formula: —OR ³ (wherein R ³ is
(i) C _1-6 alkyl group,
(ii) an acyl group (preferably a C _1-6 alkoxy-carbonyl group),
(iii) Formula:

A group represented by
(iv) Formula:

A group represented by
(v) Formula:

A group represented by
(vi) Formula:

A group represented by
(vii) Formula:

A group represented by
(viii) Formula:

Or a group represented by
(ix) Formula:

Represents a group represented by Convert to the group represented by). In addition, each R and each R 'in a formula are synonymous with the above-mentioned.

(3) Q ² H and Q ⁴ H in formula (I) are each independently
(i) Formula: -SR ⁴ (wherein R ⁴ is
(a) C _1-6 alkyl group,
(b) an acyl group,
(c) a group represented by the formula: -SR,
(d) Formula:

A group represented by
(e) Formula:

A group represented by
(f) Formula:

A group represented by
(g) Formula:

A group represented by
(h) Formula:

Or a group represented by
(i) Formula:

Represents a group represented by A group represented by),
(ii) Formula: -OR ⁵ (wherein R ⁵ is
(a) C _1-6 alkyl group,
(b) an acyl group,
(c) Formula:

A group represented by
(d) Formula:

A group represented by
(e) Formula:

Or a group represented by
(f) Formula:

Represents a group represented by Or a group represented by
(iii) Formula: -NHR ⁶ wherein R ⁶ is
(a) C _1-6 alkyl group,
(b) an acyl group,
(c) Formula:

A group represented by
(d) Formula:

Or a group represented by
(e) Formula:

Represents a group represented by Convert to the group represented by). In addition, each R and each R 'in a formula are synonymous with the above-mentioned.
When Compound (I) is used as a payload, Chem. Rev., 114, 9154-9218 (2014), Pharma. Res. 32, 3526-3540 (2015), Bioconjugate Chem. 21, 5-13 (2010). And the AAPS journal, 17, 339-351 (2015), WO 2011/050761 and the like may be used.

Compound (I) or a prodrug thereof (which may be collectively abbreviated as “the compound of the present invention” in the present specification) have STING agonist activity, and a preventive or therapeutic agent for cancer, cancer growth inhibition The agent may be useful as a cancer metastasis inhibitor.
The compound of the present invention exhibits an agonistic activity on STING, and the compound of the present invention exhibits efficacy, pharmacokinetics (eg, absorption, distribution, metabolism, excretion), solubility (eg, water solubility), other pharmaceutical agents and the like Interaction (eg, drug metabolizing enzyme inhibitory action), safety (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity), stability (eg, chemical stability) It is also excellent in terms of stability to enzymes, and may be useful as a medicine.
Accordingly, the compounds of the present invention can be used to enhance the STING activity in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans).
The compound of the present invention is a disease that may be affected by STING (sometimes abbreviated as "STING-related disease" in the present specification), for example, cancer [eg, colon cancer (eg, colon cancer, rectal cancer) Anal cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, , Pancreatic ductal cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma), duodenal cancer, small intestine cancer, breast cancer (eg, invasive breast duct) Cancer, ductal ductal carcinoma, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low grade tumor), testicular tumor, prostate cancer (eg , Hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (eg, hepatocellular carcinoma) Primary liver cancer, extrahepatic cholangiocarcinoma), thyroid cancer (eg, medullary thyroid carcinoma), kidney cancer (eg, renal cell carcinoma (eg, clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter) Uterine cancer (eg, cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumor (eg, medulloblastoma, glioma, pineal stellate cell tumor, ciliated stellate cell) Tumor, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (eg, basal cell carcinoma, malignant melanoma), sarcoma (eg, rhabdomyosarcoma, smooth muscle) Tumor, soft tissue sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, hematologic cancer (eg, multiple myeloma, leukemia (eg, acute myeloid leukemia), malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disease), [Preventive agent or therapeutic agent of unknown cancer], growth inhibitor of cancer, metastasis inhibitor of cancer, apoptosis promoter, precancerous lesion (eg myelodystrophy) It can be used as medicaments, such as therapeutic agents of the group).
In particular, the compound of the present invention can be used as a medicine for colon cancer, breast cancer, skin cancer, malignant lymphoma, lung cancer.

The compounds of the present invention can be orally or parenterally administered to mammals (preferably humans) as medicaments, as they are or in combination with pharmacologically acceptable carriers.
Hereinafter, the medicament comprising the compound of the present invention (sometimes abbreviated as "the medicament of the present invention") will be described in detail. The dosage form of the medicament of the present invention includes, for example, tablets (eg, sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, intraoral rapid disintegrating tablets), pills, granules, powders, capsules (eg, soft capsules) Agents, microcapsules), syrups, emulsions, suspensions, films (eg, orally disintegrating films, buccal film for oral mucous membranes) and the like. Moreover, as a dosage form of the medicine of the present invention, for example, injections, drips, transdermal agents (eg, iontophoretic transdermal agents), suppositories, ointments, transnasal agents, transpulmonary agents, eye drops And the like. In addition, the medicament of the present invention may be a controlled release preparation such as an immediate release preparation, a sustained release preparation (eg, sustained release microcapsules) and the like.
As a dosage form of the medicament of the present invention, a preparation using a nanoparticle preparation or a bacteria-derived membrane can be used.

The medicament of the present invention can be manufactured by known manufacturing methods (eg, methods described in Japanese Pharmacopoeia) generally used in the pharmaceutical technology field. In the pharmaceutical of the present invention, if necessary, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants which are usually used in the pharmaceutical field. Additives such as preservatives, fragrances, flavors, stabilizers, thickeners and the like can be suitably contained in appropriate amounts.
The above-mentioned pharmacologically acceptable carrier includes these additives.

  For example, tablets can be manufactured using excipients, binders, disintegrants, lubricants and the like, and pills and granules can be manufactured using excipients, binders, disintegrants. In addition, powders and capsules can be manufactured using excipients and the like, syrups and the like as sweeteners and the like, emulsions and suspensions can be manufactured using the suspending agent, surfactant, emulsifier and the like.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate and calcium sulfate.
Examples of binders include 5 to 10 wt% starch paste solution, 10 to 20 wt% gum arabic solution or gelatin solution, 1 to 5 wt% tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin.
Examples of disintegrants include starch and calcium carbonate.
Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.
Examples of sweetening agents include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin and simple syrup.
Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan mono fatty acid ester, polyoxyl 40 stearate.
Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite.
Examples of emulsifying agents include gum arabic, tragacanth, gelatin, polysorbate 80.

  For example, when the medicament of the present invention is a tablet, the tablet is added to the compound of the present invention according to a method known per se, for example, excipients (eg, lactose, sucrose, starch), disintegrants (eg, starch, carbonated Calcium), binders (eg starch, gum arabic, carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose) or lubricants (eg talc, magnesium stearate, polyethylene glycol 6000) and compression molded, then necessary It can be prepared by coating in a manner known per se for taste masking, enteric or sustained purposes. As a coating agent used for coating, for example, hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F 68, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, bengala, titanium dioxide) can be used.

  The injections include, in addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections and the like.

  Such injections are prepared in a manner known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid. Examples of the aqueous liquid include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride) and the like. The aqueous liquid contains a suitable solubilizer such as alcohol (eg ethanol), polyalcohol (eg propylene glycol, polyethylene glycol), nonionic surfactant (eg polysorbate 80, HCO-50). It may be Examples of the oily liquid include sesame oil, soybean oil and the like. The oily liquid may contain suitable solubilizers. Examples of the solubilizer include benzyl benzoate, benzyl alcohol and the like. In addition, the injections include buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride), stabilizers (eg, human serum albumin, polyethylene glycol) And preservatives (eg, benzyl alcohol, phenol) may be blended. The prepared injection can usually be filled into ampoules.

  Although the content of the compound of the present invention in the medicament of the present invention varies depending on the form of the preparation, it is usually about 0.01 to about 100% by weight, preferably about 2 to about 85% by weight based on the whole preparation. More preferably, it is about 5 to about 70% by weight.

  The content of the additive in the medicament of the present invention varies depending on the form of the preparation, but it is usually about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight based on the whole preparation. is there.

  The compounds of the present invention can be used stably, with low toxicity and safely. The daily dose of the compound of the present invention varies depending on the patient's condition, body weight, type of compound, administration route, etc. For example, when orally administered to a patient for the purpose of treating cancer, adults (body weight about 60 kg) 1 The daily dose of the compound of the present invention is about 1 to about 1000 mg, preferably about 3 to about 300 mg, more preferably about 10 to about 200 mg, which can be administered once or in 2 to 3 times. .

  When the compound of the present invention is administered parenterally, it is usually administered in the form of a solution (eg, injection). Although the single dose of the compound of the present invention varies depending on the administration subject, target organ, condition, administration method, etc., it is usually about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg per kg body weight. More preferably, about 0.01 to about 20 mg of the compound of the present invention is administered by intravenous injection.

  The compounds of the present invention can be used in combination with other drugs. Specifically, the compounds of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and agents that inhibit the action of their receptors. Hereinafter, drugs that can be used in combination with the compound of the present invention are abbreviated as concomitant drugs.

  Examples of “hormone therapeutic agents” include phosphestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepaltricin, Raloxifene, olmeloxifene, levormeloxifene, anti-estrogen (eg, tamoxifen citrate, toremifene citrate), pill formulation, mepithiostan, testolactone, aminoglutethiimide, LH-RH agonist (eg, goserelin acetate, buserelin (Leuprorelin acetate), droloxifene, epithiostanol, ethynyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, leto Zole, exemestane, vorozole, formestane), antiandrogen (eg, flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductase inhibitors (eg, finasteride, epristeride, dutasteride), corticosteroids (eg, dexamethasone, prednisolone) , Betamethasone, triamcinolone), inhibitors of androgen synthesis (eg, abiraterone), retinoids and agents that retard the metabolism of retinoids (eg, liarozole), thyroid hormones, and their DDS (Drug Delivery System) formulations may be used.

  As the "chemotherapeutic agent", for example, alkylating agents, anti-metabolites, anti-cancer antibiotics, plant-derived anti-cancer agents can be used.

  Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, inprosulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, mel Phalaen, dacarbazine, lanimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etolequiside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, alretamine, ambamustin, dibrospidium hydrochloride, fotemustine, Prednismustine, pumithepa, ribomustine, temozolomide, treosulphan, trofosfamide, Roh statins scan chima Lamar, adozelesin, cystemustine, Bizereshin and DDS preparations thereof may be used.

  Examples of the "metabolite" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, pecitrexide, enocitabine, cytarabine, cytarabine ocfosphato, ancitabine hydrochloride, 5-FU drug (eg, fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nelzalavin, leucovorin calcium, tabloid, butosin, folinate calcium, levoforinate calcium, cladolibine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, hydroxy carbamide Idoxyuridine, Mitoguazone, Thiazofrine, Ambamustine, Bendamustine and their D S formulations may be used.

  Examples of the "anticancer antibiotic" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride Neocarzinostatin, misuramycin, sarkomycin, carcininophilin, mitotane, zolubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations (eg, doxorubicin-encapsulated PEG liposomes) can be used.

  As the “plant-derived anticancer agent”, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, kabazitaxel, vinorelbine and their DDS preparations can be used.

  Examples of the “immunotherapeutic agent” include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum Levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody (eg, ipilimumab, tremelimumab), anti-PD-1 antibody (eg, nivolumab, pembrolizumab), anti-PD-L1 antibody may be used.

  The "cell growth factor" in the "cell growth factor and a drug that inhibits the action of its receptor" may be any substance that promotes cell growth, and generally has a molecular weight of 20,000 or less. The peptide includes an agent that exerts an action at a low concentration by binding to a receptor, and specifically, (1) a substance having an EGF (epidermal growth factor) or an activity substantially identical thereto [eg, TGFα], (2) insulin or a substance having substantially the same activity as it (eg, insulin, IGF (insulin-like growth factor) -1, IGF-2), (3) FGF (fibroblast growth factor) or it Substances having substantially the same activity [eg, acidic FGF, basicity GF, KGF (keratinocyte growth factor), FGF-10], (4) other cell growth factors [eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth) PDGF- (platelet-derived growth factor), TGF- (transforming growth factor beta), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiopoietin] may be used.

  The “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, and specifically, an EGF receptor, heregulin receptor (eg, HER3) Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (eg, Tie2), PDGF receptor, etc. obtain.

  Examples of “a drug that inhibits the action of a cell growth factor and its receptor” include an EGF inhibitor, a TGFα inhibitor, a haregulin inhibitor, an insulin inhibitor, an IGF inhibitor, an FGF inhibitor, a KGF inhibitor, a CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Body inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibition Agent, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor, PKC inhibitor, Smo inhibitor, ALK inhibitor, ROR1 inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, MET Inhibitors, CDK inhibitors, Akt inhibitors, ERK inhibitors, PI3K inhibitors and the like can be used. More specifically, anti-VEGF antibody (eg, Bevacizumab, Ramucurumab), anti-HER2 antibody (eg, Trastuzumab, Pertuzumab), anti-EGFR antibody (eg, Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-HGF antibody, Imatinib, Erlotinib , Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib, 6- [4- (4-ethylpiperazin-1-yl] (Tyl) phenyl] -N- [1 (R) -phenylethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, Tozasertib, phosphoric acid 2- [N- [3- [4- [5- [N- (3-fluorophenyl) carbamoylmethyl] -1H-pyrazol-3-ylamino] quinazoline-7-yloxy] propyl] -N-ethylamino] ethyl Ester (AZD-1152), 4- [9-chloro-7- (2,6-difluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ylamino] benzoic acid, N- [5 2-methoxy-5-[(E) -2- (2,4,6-trimethoxyphenyl) vinyls Phonylmethyl] phenyl] glycine sodium salt (ON-1910 Na), Volasertib, Selumetinib, Trametinib, N- [2 (R), 3-dihydroxypropoxy] -3,4-difluoro-2- (2-fluoro-4-iodophenyl Amino) benzamide (PD-0325901), Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib, Dabrafenib etc. may be used.

  In addition to the above-mentioned drugs, L-asparaginase, L-arginase, arginine deiminase, acegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin sodium, topoisomerase I inhibitors (eg, irinotecan, topotecan, indotecan, Indimitecan ), Topoisomerase II inhibitors (eg, sobzoxan), differentiation inducers (eg, retinoids, vitamin Ds), other angiogenesis inhibitors (eg, fumagillin, shark extract, COX-2 inhibitor), α-blockers (Eg, tamsulosin hydrochloride), bisphosphonic acid (eg, pamidronate, zoledronate), thalidomide, lenalidomide, pomalidomide, azacitidine, decitabine, proteasome inhibitors (eg, bortezomib, carfizomi , Ixazomib), NEDD8 inhibitor (eg, Pevonedistat), UAE inhibitor, PARP inhibitor (eg, Olaparib, Niraparib, Veliparib), anti-CD20 antibody (eg, Rituximab, Obinutuzumab), anti-CCR4 antibody (eg, Mogamulizumab), etc. Anti-tumor antibodies, antibody drug complexes (eg, trastuzumab emtansine, brentuximab bedotin) and the like can also be used as concomitant drugs.

  By combining the compound of the present invention and the concomitant drug, (1) the dose can be reduced as compared with the case where the compound of the present invention or the concomitant drug is administered alone; (3) the treatment period can be set long, (4) the therapeutic effect can be sustained, (5) the compound of the present invention and the concomitant drug By combining and using, it is possible to obtain excellent effects such as obtaining a synergistic effect.

Hereinafter, the case where the compound of the present invention and the concomitant drug are used in combination is referred to as "the concomitant drug of the present invention".
When using the concomitant drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be simultaneously administered to the subject of administration. It may be administered. When administering with a time lag, the time lag varies depending on the active ingredient, dosage form, and administration method to be administered, but for example, when the concomitant drug is administered first, within 1 minute to 3 days after administering the concomitant drug, preferably The compound of the present invention may be administered within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after administering the compound of the present invention . The dose of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

Examples of administration forms in which the compound of the present invention and the concomitant drug are used in combination include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) combined use with the compound of the present invention Simultaneous administration by the same route of administration of two preparations obtained by separately formulating the drug and (3) by the same route of administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration with time lag, (4) coadministration of two formulations obtained by separately formulating the compound of the present invention and the concomitant drug in different administration routes, and (5) the compound of the present invention and the concomitant drug Administration with different administration routes by two administrations obtained by separately formulating with different administration routes (for example, administration in the order of the compound of the present invention → combination drug, or administration in the reverse order) can be mentioned.
The dose of the concomitant drug can be appropriately selected based on the dose clinically used. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, condition, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used based on 1 part by weight of the compound of the present invention.

  Furthermore, the compound of the present invention or the combination drug of the present invention may be used in combination with non-drug therapy. Specifically, the compound of the present invention or the combination drug of the present invention includes, for example, (1) surgery, (2) hypertensive chemotherapy using angiotensin II or the like, (3) gene therapy, (4) thermotherapy, (5) May be combined with cryotherapy, (6) laser ablation, (7) nondrug therapy of radiation therapy.

  For example, use of the compound of the present invention or the combination drug of the present invention before or after the aforementioned surgery or the like, or before or after the treatment combining these two or three types, inhibition of development of tolerance, disease free (Disease-Free Survival) Effects such as prolongation), suppressing cancer metastasis or recurrence, prolonging life, etc. can be obtained.

  In addition, therapy with the compound of the present invention or the concomitant drug of the present invention, and supportive therapy [(i) an antibiotic against co-occurrence of various infectious diseases (eg, β-lactams such as pansporin, macrolides such as clarithromycin)] Administration, (ii) hypercaloric infusion to improve malnutrition, amino acid preparation, administration of multivitamins, (iii) morphine administration for pain relief, (iv) nausea, vomiting, anorexia, diarrhea, leukopenia, Administration of a drug that improves side effects such as thrombocytopenia, hemoglobin concentration reduction, alopecia, liver disorder, renal disorder, DIC, fever, etc., and (v) administration of a drug for suppressing multidrug resistance of cancer etc. It can also be done.

The present invention is further described in detail by the following examples, test examples and formulation examples, which are not intended to limit the present invention and may be varied within the scope of the present invention.
"Room temperature" in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates weight% unless otherwise specified.
In the silica gel column chromatography, when it was described as Diol, 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used. When it was described as C18 in silica gel column chromatography and HPLC (high performance liquid chromatography), octadecyl-bonded silica gel was used. The ratio of elution solvents indicates the volume ratio unless otherwise specified.
The LC / MS measurement was performed under the following conditions [column: L-Column 2 ODS, 3.0 mm ID × 50 mm, mobile phase: acetonitrile / 5 mM ammonium acetate buffer = 900/100)].

The following abbreviations are used in the following examples.
mp: melting point
MS: Mass spectrum
[M + H] ⁺ , [MH] ^- : Molecular ion peak
M: molar concentration
N: regulation
CDCl ₃ : Heavy chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
D ₂ O: Heavy water
¹ H NMR: proton nuclear magnetic resonance
³¹ P NMR: phosphorus nuclear magnetic resonance
LC / MS: Liquid chromatograph mass spectrometer
ESI: ElectroSpray Ionization, Electrospray Ionization
APCI: Atmospheric Pressure Chemical Ionization, Atmospheric Pressure Chemical Ionization
THF: tetrahydrofuran
DMF: N, N-dimethylformamide
¹ H NMR and ³¹ P NMR were measured by Fourier transform NMR. For analysis, ACD / SpecManager (trade name) etc. were used. There is no description about a very mild peak such as a hydroxyl group or an amino group.
MS was measured by LC / MS. As the ionization method, ESI method or APCI method was used. Data described actual value (found). Usually, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group, a peak from which a tert-butoxycarbonyl group or a tert-butyl group has been eliminated may be observed as a fragment ion. Further, in the case of a compound having a hydroxyl group, a peak from which H ₂ O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or fragment ion peak is usually observed.

Example 1
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-2,10,16-trihydroxy- 2,10-Dioxide Octahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt

A) 7-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) -5-fluoro- 3H-Pyrrolo [2,3-d] pyrimidin-4 (7H) -one
7-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -5-fluoro-3H-pyrrolo [2,3-d] pyrimidine-4 ( To a solution of 7H) -one (6.26 g) in pyridine (100 mL) was added 4,4'-dimethoxytrityl chloride (8.92 g) at room temperature and stirred overnight at room temperature under an argon atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (8.65 g).
MS: [MH] ^- 586.0.

B) 7- (5-O- (Bis (4-methoxyphenyl) (phenyl) methyl) -3-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -5-fluoro-3, 7-Dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
7-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) -5-fluoro-3H- To a solution of pyrrolo [2,3-d] pyrimidin-4 (7H) -one (2.65 g) in DMF (20 mL) was added imidazole (0.614 g) and tert-butyldimethylchlorosilane (0.816 g) and stirred overnight at room temperature did. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.1 g).
MS: [MH] ^- 700.2.

C) 7- (5-O- (Bis (4-methoxyphenyl) (phenyl) methyl) -3-O- (tert-butyl (dimethyl) silyl) -2-O-((2-cyanoethoxy) (diisopropyl) Amino) phosphino) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
7- (5-O- (Bis (4-methoxyphenyl) (phenyl) methyl) -3-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -5-fluoro-3,7 Dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (5.43 g) was azeotropically dehydrated three times with anhydrous toluene and dissolved in anhydrous N, N-dimethylformamide (15 mL). To this solution were added 3-((bis (diisopropylamino) phosphino) oxy) propanenitrile (3.19 mL), 1H-tetrazole (0.542 g) and 1-methyl-1H-imidazole (0.306 mL), and the mixture was argon at room temperature. After stirring overnight, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DIOL, ethyl acetate / hexane). The obtained crude product was purified again by silica gel column chromatography (ethyl acetate / hexane, containing 0.5% triethylamine) to give the title compound (4.22 g) as a mixture of two diastereomers.
MS: [MH] ^- 901.2.

D) (2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -2-((((((2R, 3R, 4R, 5R) -4-((tert) -Butyldimethylsilyl) oxy) -2- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -5- (hydroxymethyl) tetrahydrofuran-3-yl ) Oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) 4- fluorotetrahydrofuran-3-yl hydrogen phosphonate
N-Benzoyl-2'-deoxy-2'-fluoro-3'-O- (hydroxy (oxide) phosphoranyl) adenosine (1.2 g) and 7- (5-O- [bis (4-methoxyphenyl) (phenyl) Methyl] -3-O- [tert-butyl (dimethyl) silyl] -2-O-{(2-cyanoethoxy) [diisopropylamino] phosphino} -beta-D-ribofuranosyl) -5-fluoro-3,7- After dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (3.4 g) was azeotropically dehydrated with anhydrous acetonitrile, anhydrous acetonitrile (15 mL) and anhydrous tetrahydrofuran (5 mL) were added. To the mixture was added a mixture of anhydrous acetonitrile and azeotropically dehydrated 5- (ethylsulfanyl) -2H-tetrazole (1.07 g) and anhydrous acetonitrile (10 mL), and stirred at 55 ° C. under argon atmosphere for 2 hours, and then 70% tert. -Butyl hydroperoxide (1.12 mL) was added and stirred at room temperature for 20 minutes. A mixture of sodium thiosulfate (5920 mg) and water (3 mL) was added to the reaction mixture, and concentrated under reduced pressure. The residue was added with 80% acetic acid (30 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1.1 g).
MS: [M + H] ⁺ 952.2

E) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -16-((tert-butyl (dimethyl) silyl) oxy) -15-fluoro-7- (5- Fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2,10-dihydroxy-2,10-dioxideoctahydro-12H-5,8- Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -2-((((((2R, 3R, 4R, 5R) -4-((tert-butyl) Dimethylsilyl) oxy) -2- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy ) (2-Cyanoethoxy) phosphoryl) oxy) methyl) -4-fluorotetrahydrofuran-3-yl hydrogen phosphonate (350 mg) was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, and then anhydrous pyridine (15 mL) was added . To the mixture was added 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (238 mg), stirred at room temperature under argon atmosphere for 1 hour, water (232 μL) and iodine (121 mg) was added and stirred for another 20 minutes at room temperature. A mixture of sodium thiosulfate pentahydrate (91 mg) and water (1 mL) was added to the reaction mixture and stirred at room temperature for 5 minutes, then toluene was added and the mixture was concentrated under reduced pressure. To the residue were added anhydrous acetonitrile (15 mL) and 2-methylpropan-2-amine (5.26 mL), and the mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (332 mg).
MS: [M + H] ⁺ 897.1

F) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -16-((tert-butyl (dimethyl) silyl) ) Oxy) -15-fluoro-2,10-dihydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,2 10] Pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -16-((tert-butyl (dimethyl) silyl) oxy) -15-fluoro-7- (5-fluoro- 4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2,10-dihydroxy-2,10-dioxideoctahydro-12H-5,8-methanofuro [ 3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide (332 mg) to 40% After adding methylamine ethanol solution (7.6 mL) and stirring at room temperature under argon atmosphere for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography (methanol / ethyl acetate), and the obtained residue is purified by HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile), The title compound (106.4 mg) was obtained.
MS: [M + H] ⁺ 793.1

G) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-2,10,16-tri Hydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7- ) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -16-((tert-butyl (dimethyl) silyl) oxy ) -15-Fluoro-2,10-dihydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] Triethylamine trihydrofluoride to pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (106.4 mg) (1094 μL) was added. The reaction mixture was stirred at 50 ° C. for 1 hour, cooled to room temperature, and then ethoxy (trimethyl) silane (6266 μL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the residue were added ethoxy (trimethyl) silane (6266 μL) and methanol (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile / 10 mM triethylammonium acetate buffer) to give the title compound (82 mg).
¹ H NMR (400 MHz, D ₂ O) δ 1.18 (18 H, t, J = 7.3 Hz), 3.1 1 (12 H, q, J = 7.4 Hz), 4.01-4.14 (2 H, m), 4.17-4.26 (1 H , m), 4.34 (2H, d, J = 3.4 Hz), 4.42-4.50 (1H, m), 4.54 (1 H, d, J = 4.2 Hz), 4.86-4.99 (2H, m), 5.38-5.60 ( 1H, m), 6.30-6.45 (2H, m), 7.24 (1H, d, J = 2.0 Hz), 7.91 (1 H, s), 8.05 (1 H, s), 8.17 (1 H, s).
³¹ P NMR (162 MHz, D ₂ O) δ -2.16, -1.66.

Example 2
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-10,16-dihydroxy-2,10 -Dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)

A) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -16-((tert-butyl (dimethyl) silyl) ) Oxy) -15-fluoro-10-hydroxy-2,10-dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2 , 10] Pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer)
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -2-((((((2R, 3R, 4R, 5R) -4-((tert-butyl) Dimethylsilyl) oxy) -2- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy ) (2-Cyanoethoxy) phosphoryl) oxy) methyl) -4-fluorotetrahydrofuran-3-yl hydrogen phosphonate (700 mg) was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, and then anhydrous pyridine (50 mL) was added . To the mixture was added 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (475 mg) at room temperature and stirred at room temperature under argon atmosphere for 1 hour, then water (464 μL) And 3H-benzo [c] [1,2] dithiole-3-one (186 mg) were added, and the mixture was further stirred at room temperature for 30 minutes. A mixture of sodium thiosulfate (913 mg) and water (3 mL) was added to the reaction mixture, and concentrated under reduced pressure. To the residue were added anhydrous acetonitrile (30 mL) and 2-methylpropan-2-amine (10 mL), and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (methanol / ethyl acetate), 40% methylamine ethanol solution (7.3 mL) is added to the obtained residue, and after stirring for 30 minutes under argon atmosphere at room temperature, the reaction mixture is depressurized. Concentrated under. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The resulting residue is purified by HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile), and the two diastereomers (LC / MS with smaller retention time) The title compound (70 mg, tR1) and the title compound (150 mg, tR2) were obtained in the order of tR1 and tR2).
MS (tR1): [M + H] ⁺ 809.1
MS (tR2): [M + H] ⁺ 809.1

B) 7-[(5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-10,16-dihydroxy-2 10-Dioxide-2-sulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7- [I]]-5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -16-((tert-butyl (dimethyl) silyl) oxy ) -15-Fluoro-10-hydroxy-2,10-dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,10 ] Pentaoxadiphosphacyclotetradecin-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer) (70 mg, derived from tR1 Methanol (3.0 mL) and triethylamine trihydrofluoride (1.41 mL) were added to). The reaction mixture was concentrated and methanol was distilled off, and then stirred at 55 ° C. for 1 hour. After cooling to room temperature, ethoxy (trimethyl) silane (7.8 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile / 10 mM triethylammonium acetate buffer) to give the title compound (56 mg).
¹ H NMR (400 MHz, D ₂ O) δ 1.23 (18 H, t, J = 7.3 Hz), 3. 15 (12 H, q, J = 7.3 Hz), 4.15-4.23 (3 H, m), 4.37-4. 50 (2 H , m), 4.54 (1 H, d, J = 10.3 Hz), 4.61 (1 H, d, J = 3.9 Hz), 4.96 (2 H, dt, J = 7.9, 3.9 Hz), 5.77-5.95 (1 H, m) , 6.36 (1 H, d, J = 8.1 Hz), 6.40 (1 H, d, J = 15.4 Hz), 7.51 (1 H, d, J = 1.7 Hz), 7.99 (2 H, d, J = 13.7 Hz), 8.23. (1H, s).
³¹ P NMR (162 MHz, D ₂ O) δ-2.43, 54.03.

Example 3
7-[(5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-10,16-dihydroxy-2,10 -Dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl] -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 1.7 triethylammonium salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -16-((tert-butyl (dimethyl) silyl) oxy ) -15-Fluoro-10-hydroxy-2,10-dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,10 ] Pentaoxadiphosphacyclotetradecin-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer) (150 mg, derived from tR2 Methanol (3.0 mL) and triethylamine trihydrofluoride (3.02 mL) were added to). The reaction mixture was concentrated and methanol was distilled off, and then stirred at 55 ° C. for 1 hour. After cooling to room temperature, ethoxy (trimethyl) silane (16.4 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile / 10 mM triethylammonium acetate buffer) to give the title compound (155 mg).
¹ H NMR (400 MHz, D ₂ O) δ 1.23 (15 H, t, J = 7.3 Hz), _3. 15 (10 H, q, J = 7.3 Hz), 4.06 (1 H, dd, J = 11.7, 4.9 Hz), 4.18 (1 H, dd, J = 11.6, 2.8 Hz), 4.29-4.47 (3 H, m), 4.51 (1 H, d, J = 8.8 Hz), 4.58 (1 H, d, J = 3.9 Hz), 4.93-5.14 (2H, m), 5.44-5.64 (1H, m), 6.33-6. 45 (2H, m), 7.32 (1H, d, J = 1.5 Hz), 7.95 (1H, s), 8.06 (1H, s), 8.24 (1 H, s).
³¹ P NMR (162 MHz, D ₂ O) δ-2.41, 55.33.

Example 3a
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-10,16-dihydroxy-2,10 -Dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one disodium salt (optical isomer)
Deionized water (400 mL) was permeated through a column in which an empty column was packed with AG 50W-X8 cation exchange resin (100-200 mesh, 25.3 g). Furthermore, 1 M aqueous sodium hydroxide solution (240 mL) and deionized water (450 mL) were permeated. 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro- was added to the resin subjected to the above pretreatment. 10,16-Dihydroxy-2,10-dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadifo It is composed of sphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one ditriethylamine salt (optical isomer) (1.30 g) After passing ionized water (45 mL), deionized water (60 mL) was passed to obtain an aqueous solution containing the title compound.
Deionized water (400 mL) was allowed to pass through a column in which an empty column was packed with AG 50W-X8 cation exchange resin (100-200 mesh, 26.3 g). Furthermore, 1 M aqueous sodium hydroxide solution (270 mL) and deionized water (540 mL) were permeated. 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro- was added to the resin subjected to the above pretreatment. 10,16-Dihydroxy-2,10-dioxide-2-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadifo It is composed of sfacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2triethylamine salt (optical isomer) (1.18 g) After passing ionized water (54 mL), deionized water (63 mL) was passed to obtain an aqueous solution containing the title compound. The two aqueous solutions containing the title compound were combined and lyophilized to give the title compound (2.0 g).
¹ H NMR (300 MHz, D ₂ O) δ 3.97-4.07 (1 H, m), 4.11-4.20 (1 H, m), 4.27-4. 42 (3 H, m), 4.43-4.51 (1 H, m), 4.55 (4 1H, d, J = 3.8 Hz), 4.88-5.12 (2H, m), 5.34-5.59 (1H, m), 6.30-6.40 (2H, m), 7.28 (1 H, d, J = 1.9 Hz), 7.91 (1H, s), 8.01 (1H, s), 8.18 (1H, s).
³¹ P NMR (121 MHz, D ₂ O) δ-2.38, 55.3.

Example 4
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -2,10,15,16-tetrahydroxy-2, 10-Dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5 -Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt

A) (2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyldimethylsilyl) oxy) -2-((( , 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -2- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidine-7 (4H) -yl ) -5- (Hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate
N-Benzoyl-2'-O- (tert-butyl (dimethyl) silyl) -3'-O- (hydroxy (oxide) phosphoranyl) adenosine (369 mg) and 7- (5-O- (bis (4-methoxy) Phenyl) (phenyl) methyl) -3-O- (tert-butyl (dimethyl) silyl) -2-O-((2-cyanoethoxy) (diisopropylamino) phosphino) -beta-D-ribofuranosyl) -5-fluoro Azeotropic dehydration of -3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (817 mg) with anhydrous acetonitrile (3 times), anhydrous acetonitrile (3.6 mL) and anhydrous tetrahydrofuran (1.2 It suspended in mL). To the mixture was added a mixture of anhydrous acetonitrile and azeotropically dehydrated 5- (ethylsulfanyl) -2H-tetrazole (262 mg) and anhydrous acetonitrile (2.4 mL), and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. To the reaction mixture was added 70% tert-butyl hydroperoxide (0.276 mL), and the mixture was further stirred at room temperature for 40 minutes. The reaction mixture was quenched with sodium thiosulfate (636 mg) and water (2 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in 80% acetic acid (5 mL) and stirred at room temperature for 2 and a half hours. The reaction mixture was concentrated under reduced pressure and azeotropically dehydrated with anhydrous acetonitrile and toluene. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (538 mg).
MS: [M + H] ⁺ 1064.3.

B) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyano Ethoxy) -7- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-2,10-dioxide octahydro- 12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) Benzamide
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyldimethylsilyl) oxy) -2-((( , 4R, 5R) -4-((tert-Butyldimethylsilyl) oxy) -2- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl)- 5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate (538 mg) was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, and anhydrous It was suspended in pyridine (12 mL). Add 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (327 mg) and stir at room temperature for 1 hour, then add water (0.319 mL) and iodine (167 mg) In addition, it was further stirred at room temperature for 30 minutes. The reaction mixture was quenched with sodium thiosulfate (208 mg) and water (2 mL), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (509 mg).
MS: [M + H] ^< +> 1062.3.

C) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl ( Dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,10 ] Pentaoxadiphosphacyclotetradecin-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy) -7- (5-Fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-2,10-dioxideoctahydro-12H- 5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide ( 509 mg) was dissolved in 33% methylamine ethanol solution (10 mL) and stirred at room temperature under argon atmosphere for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained residue was purified by HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile) to give the title compound (227 mg).
MS: [M + H] ⁺ 905.2.

D) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -2,10,15,16-tetrahydroxy- 2,10-Dioxide Octahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl (dimethyl)) Silyl) oxy) -2,10-dihydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] penta Oxyphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (227 mg) to triethylamine trihydrofluoride ( 0.818 mL) was added and stirred at 50 ° C. for 5 hours. The solvent was evaporated under reduced pressure, 1 M aqueous triethylammonium bicarbonate solution was added for neutralization, and the solvent was evaporated again under reduced pressure. The residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile), and the obtained solid was lyophilized to give the title compound (103 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.26 (18 H, t, J = 7.4 Hz), 3. 18 (12 H, q, J = 7.4 Hz), 4.06-4.29 (3 H, m), 4.34-4.52 ( 3H, m), 4.62 (1 H, d, J = 3.8 Hz), 4.69-4.83 (1 H, m), 4.84-4.95 (1 H, m), 4.98-5.09 (1 H, m), 6.14 (1 H, d, J = 1.5 Hz), 6.41 (1 H, dd, J = 8.3, 1.5 Hz), 7.33 (1 H, d, J = 1.9 Hz), 7.99 (1 H, s), 8.16 (1 H, s), 8.25 (1 H, s).
³¹ P NMR (121 MHz, D ₂ O) δ −1.96, −1.21.

Example 5
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide-2 10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl)- 5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)

A) 7- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -3-O- (tert-butyl (dimethyl) silyl) -2-O- (hydroxy (oxide) phosphoranyl) -beta -D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
7- (5-O- (Bis (4-methoxyphenyl) (phenyl) methyl) -3-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -5-fluoro-3,7 Dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (835 mg) was dissolved in pyridine (4 mL) and diphenyl phosphite (0.456 mL) was added. After stirring at room temperature for 2 hours, water (1 mL) and ammonium hydroxide (2 mL) were added. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (611 mg).
MS: [MH] ^- 764.1.

B) 7- (3-O- (tert-Butyl (dimethyl) silyl) -2-O- (hydroxy (oxide) phosphoranyl) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H- Pyrrolo [2,3-d] pyrimidin-4-one
7- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -3-O- (tert-butyl (dimethyl) silyl) -2-O- (hydroxy (oxide) phosphoranyl) -beta-D A mixture of (ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (611 mg) and 80% acetic acid (4 mL) was stirred at room temperature for 2 hours . The reaction mixture was diluted with methanol and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (358 mg).
MS: [M + H] ⁺ 464.1.

C) (2R, 3R, 4R, 5R) -5-(((((((2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert) -Butyldimethylsilyl) oxy) -2- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy)- 2- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate
7- (3-O- (tert-Butyl (dimethyl) silyl) -2-O- (hydroxy (oxide) phosphoranyl) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [ 2,3-d] pyrimidin-4-one (358 mg) and N-benzoyl-5'-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2'-O- (tert-butyl (dimethyl) A mixture of (silyl) -3'-O-((2-cyanoethoxy) (diisopropylamino) phosphino) adenosine (1.02 g) was azeotropically dehydrated with anhydrous acetonitrile and suspended in anhydrous acetonitrile (10 mL). Pyridine 2,2,2-trifluoroacetate (386 mg) was added, and the mixture was stirred at room temperature under an argon atmosphere for 1 hour, and then ((dimethylamino-methylidene) amino) -3H-1,2,4-dithiazoline- 3-thione (199 mg) was added and stirred for another 30 minutes at room temperature. The reaction mixture was quenched with an aqueous solution (2.5 mL) of sodium thiosulfate (250 mg), and the solvent was evaporated under reduced pressure. The residue was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (10 mL) and stirred at room temperature for 30 minutes, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (328 mg).
MS: [M + H] ⁺ 1080.3.

D) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -2- (2-cyano) Ethoxy) -7- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -10-oxide-10-sulfanyl-2-sulfide octahydro -12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl ) Benzamide (optical isomer)
((2R, 3R, 4R, 5R) -5-((((((2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyl) Dimethylsilyl) oxy) -2- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -2- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate (328 mg) and a mixture of anhydrous pyridine (10 mL), 2-Chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (196 mg) was added. After stirring for 30 minutes at room temperature under an argon atmosphere, water (0.5 mL) and 3H-benzo [c] [1,2] dithiole-3-one (61 mg) were added and stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and further purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile) to give the title compound (optical isomer) (92 mg, tR4) I got
MS: [M + H] ^< +> 1094.3.

E) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl ( Dimethyl) silyl) oxy) -2,10-dioxide-2,10-disulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,10 ] Pentaoxadiphosphacyclotetradecin-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -2- (2-cyanoethoxy) -7- (5-Fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -10-oxide-10-sulfanyl-2-sulfide octahydro-12H -5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide (Optical isomer) (90 mg) was dissolved in 40% methylamine-methanol solution (3.0 mL) and stirred at room temperature under argon atmosphere for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (32 mg).
MS: [M + H] ⁺ 937.1.

F) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide -2,10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl ) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl (dimethyl)) Silyl) oxy) -2,10-dioxide-2,10-disulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] penta Oxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer) (32 mg) and triethylamine trifluoride The mixture of hydrobromide (0.12 mL) was stirred at 50 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was neutralized with 1 M aqueous triethylammonium bicarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile). The obtained solid was lyophilized to give the title compound (21 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.23 (18 H, t, J = 7.3 Hz), 3. 15 (12 H, q, J = 7.4 Hz), 3.99-4.09 (1 H, m), 4.23-4.30 ( 2H, m), 4.30-4.41 (2H, m), 4.41-4.45 (1H, m), 4.47-4.54 (1H, m), 4.83-4.88 (2H, m), 4.96-5.13 (3H, m), 6.11 (1 H, d, J = 1.1 Hz), 6.36 (1 H, d, J = 7.4 Hz), 7.31 (1 H, d, J = 1.9 Hz), 7.95 (1 H, s), 8.11 (1 H, s), 8.22 (1 H, s).
^{31 P NMR (121 MHz, D} 2 O) δ52.25, 54.88.

Example 6
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide-2 10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl)- 5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)

A) 7- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -5-fluoro-3, 7-Dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
7-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) -5-fluoro-3H- To a solution of pyrrolo [2,3-d] pyrimidin-4 (7H) -one (2.65 g) in DMF (20 mL) was added imidazole (0.614 g) and tert-butyldimethylchlorosilane (0.816 g) and stirred overnight at room temperature did. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.2 g).
MS: [MH] ^- 700.3.

B) 7- (5-O- (Bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -3-O-((2-cyanoethoxy) (diisopropyl) Amino) phosphino) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
7- (5-O- (Bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -5-fluoro-3,7 Dissolve dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (2.37 g) in dimethylformamide (6.75 mL) and add 3-((bis (diisopropylamino) phosphino) oxy) propanenitrile to this solution (2.15 mL), 1H-tetrazole (0.237 g) and 1-methyl-1H-imidazole (0.134 mL) were added, and the mixture was stirred at room temperature for 20 minutes under an argon atmosphere. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, containing 0.5% triethylamine) to give the title compound (2.67 g).
MS: [MH] ^- 900.2.

C) 7- (2-O- (tert-Butyl (dimethyl) silyl) -3-O- (hydroxy (oxide) phosphoranyl) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H- Pyrrolo [2,3-d] pyrimidin-4-one
7- (5-O- (Bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -3-O-((2-cyanoethoxy) (diisopropylamino) Dissolve phosphino) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (1.54 g) in acetonitrile (15 mL), pyridine 2,2,2-Trifluoroacetate (0.396 g) and water (0.062 mL) were added at room temperature and stirred at room temperature for 50 minutes. To the reaction solution was added 2-methylpropan-2-amine (8.07 mL) at room temperature and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, 80% acetic acid (8.54 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour.
Similarly, 7- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -3-O-((2-cyanoethoxy) (diisopropyl) Amino) phosphino) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (1.13 g) dissolved in acetonitrile (10 mL) , Pyridine 2,2,2-trifluoroacetate (0.290 g) and water (0.045 mL) were added at room temperature and stirred at room temperature for 50 minutes. To the reaction solution was added 2-methylpropan-2-amine (5.92 mL) at room temperature, and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, 80% acetic acid (6.27 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (961 mg).
MS: [M + H] ^< +> 464.0.

D) (2R, 3R, 4R, 5R) -2-((((((2R, 3R, 4R, 5R) -2- (6-benzamido-9H-purin-9-yl) -4-((tert) -Butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy)- 5- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate
7- (2-O- (tert-Butyl (dimethyl) silyl) -3-O- (hydroxy (oxide) phosphoranyl) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [ 2,3-d] pyrimidin-4-one (400 mg) and N-benzoyl-5'-O- (bis (4-methoxyphenyl) (phenyl) methyl) -3'-O- (tert-butyl (dimethyl) )) Silyl) -2'-O-((2-cyanoethoxy) (diisopropylamino) phosphino) adenosine (1.02 g) was azeotropically dehydrated with anhydrous acetonitrile (3 times) and suspended in anhydrous acetonitrile (6 mL) . Pyridine 2,2,2-trifluoroacetate (333 mg) was added, and the mixture was stirred at room temperature under an argon atmosphere for 1 hour, and then (dimethylamino-methylidene) amino) -3H-1,2,4-dithiazoline-3 -Thione (195 mg) was added and stirred for another 30 minutes at room temperature. The reaction mixture was quenched with sodium thiosulfate (316 mg) and water (0.5 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and azeotropically dehydrated with anhydrous acetonitrile and toluene. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (556 mg).
MS: [M + H] ⁺ 1080.3.

E) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyano Ethoxy) -14- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-2,10-disulfide octahydro-12H -5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -9H-purin-6-yl) benzamide (Optical isomer)
((2R, 3R, 4R, 5R) -2-((((((2R, 3R, 4R, 5R) -2- (6-benzamido-9H-purin-9-yl) -4-((tert- Butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -5 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate (556 mg) azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine The mixture was dissolved in anhydrous pyridine (15 mL), and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (332 mg) was added to the mixture at room temperature under an argon atmosphere. After stirring for 30 minutes at room temperature, water (1 mL) and 3H-1,2-benzodithiole-3-one (108 mg) were added, and the mixture was further stirred for 1 hour at room temperature Saturated aqueous sodium bicarbonate was added to the reaction mixture, Extracted with ethyl acetate Saturated extract The extract was washed with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate / methanol) .The obtained residue was HPLC (L-column 2 ODS, 50) Purified by × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile), divided into four diastereomers (in order of increasing retention time by LC / MS, tR1, tR2, tR3, tR4) The title compound (120 mg, tR2) and the title compound (183 mg, tR4) were obtained.
tR2 MS: [M + H] ⁺ 1094.3.
tR4 MS: [M + H] ⁺ 1094.3.

F) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl ( Dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-disulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] Pentaoxadiphosphacyclotetradecyne-14-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy) -14- (5-Fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-2,10-disulfide octahydro-12H-5 , 8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecin-7-yl) -9H-purin-6-yl) benzamide (optical The isomer (derived from tR2) (120 mg) was dissolved in 33% methylamine ethanol solution (5.0 mL) and stirred at room temperature for 1.5 hours under an argon atmosphere, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (84.4 mg).
MS: [M + H] ⁺ 9372.

G) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide -2,10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl ) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl (dimethyl)) Silyl) oxy) -2,10-dihydroxy-2,10-disulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxa Diphosphacyclotetradecyne-14-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer, derived from tR2) (84.4 mg) in triethylamine Trihydrofluoride (0.294 mL) was added and stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature, neutralized with 1 M aqueous triethylammonium bicarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile), and the obtained solid was lyophilized to give the title compound (58.4 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.26 (18 H, t, J = 7.4 Hz), _3. 18 (12 H, q, J = 7.3 Hz), 3. 94-4. 05 (1 H, m), 4. 10-4. 20 (1 H , m), 4.28-4.45 (2H, m), 4.50 (2H, brs), 4.59 (1H, d, J = 4.2 Hz), 4.71-4.81 (1H, m), 5.32 (2H, d, J = 10.6 Hz), 6.23-6.32 (2H, m), 7.17 (1 H, d, J = 2.3 Hz), 8.05 (1 H, s), 8.20 (1 H, s), 8. 66 (1 H, s).
³¹ P NMR (121 MHz, D ₂ O) δ 55.8, 59.2.

Example 7
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide-2 10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl)- 5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)

A) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl ( Dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-disulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] Pentaoxadiphosphacyclotetradecyne-14-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy) -14- (5-Fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-2,10-disulfide octahydro-12H-5 , 8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecin-7-yl) -9H-purin-6-yl) benzamide (optical The isomer (derived from tR4) (183 mg) was dissolved in 33% methylamine ethanol solution (5.0 mL) and stirred at room temperature under argon atmosphere for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (107 mg).
MS: [M + H] ⁺ 937.1.

B) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide -2,10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl ) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl (dimethyl)) Silyl) oxy) -2,10-dihydroxy-2,10-disulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxa Diphosphacyclotetradecyne-14-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer, derived from tR4) (107 mg) in triethylamine Trihydrofluoride (0.372 mL) was added, and the mixture was stirred at 50 ° C. for two and a half hours. The reaction mixture was cooled to room temperature, neutralized with 1 M aqueous triethylammonium bicarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile), and the obtained solid was lyophilized to give the title compound (78 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.26 (18 H, t, J = 7.4 Hz), _3. 18 (12 H, q, J = 7.2 Hz), 4.09-4.18 (1 H, m), 4.21-4.29 (2 H , m), 4.33-4.43 (1H, m), 4.51 (2H, brs), 4.65-4.71 (1H, m), 4.89 (1H, d, J = 4.2 Hz), 4.99-5.11 (1H, m), 5.29-5.42 (1 H, m), 6.23-6. 31 (2 H, m), 7.00 (1 H, d, J = 1.9 Hz), 8.03 (1 H, s), 8.17 (1 H, s), 8.56 (1 H, s) .
³¹ P NMR (121 MHz, D ₂ O) δ 52.8, 55.1.

Example 8
2-amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (4-amino-5-fluoro-7H-pyrrolo [2,3-d] pyrimidine-7- Yl) -2,10,15,16-tetrahydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,2 10] Pentaoxadiphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt

A) N- (7-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) -5 -Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzamide
(2R, 3R, 4R, 5R) -2-((Benzoyloxy) methyl) -5- (4-chloro-5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) tetrahydrofuran-3 The 4-diyl dibenzoate (14.09 g) was divided into 17 sealed vessels, and 2 M ammonia isopropanol solution (20 mL) was added to each. Each mixture was stirred at 130 ° C. for 5 hours under microwave irradiation. The resulting mixtures were combined and concentrated in vacuo. The obtained residue was azeotroped twice using toluene, then pyridine (100 mL) was added and the mixture was cooled to 0 ° C. Benzoyl chloride (26.6 mL) was added at 0 ° C. and stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane). Pyridine (350 mL) and ethanol (100 mL) were added to the obtained compound, the mixture was cooled to 0 ° C., 1 M aqueous sodium hydroxide solution (103 mL) was added, and the mixture was stirred at 0 ° C. for 1 hour. Furthermore, 1 M aqueous sodium hydroxide solution (45.7 mL) was added, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was strongly acidic cation-exchange resin Dowex ^TM 50Wx4 100-200 in a (95 g) was added at room temperature, the solid was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). Pyridine (60 mL) and 4,4'-dimethoxytrityl chloride (5.98 g) were added to the obtained product (5.71 g) and stirred at room temperature for 4 hours. More 4,4'-dimethoxytrityl chloride (5.98 g) was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.50 g).
MS: [M + H] ^< +> 691.2.

B) N- (7-((2R, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3-((tert-butyldimethylsilyl) oxy)- 4-hydroxytetrahydrofuran-2-yl) -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzamide
N- (7-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) -5-fluoro To a mixture of -7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzamide (7.51 g) and DMF (30 mL) was added imidazole (1.924 g) and tert-butyldimethylchlorosilane (2.13 g), and the mixture was allowed to stand at room temperature. Stir overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.94 g).
MS, found: 501.2.

C) N-Benzoyl-7- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -3-O-((2-cyano) Ethoxy) (diisopropylamino) phosphino) -beta-D-ribofuranosyl) -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-amine
N- (7-((2R, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3-((tert-butyldimethylsilyl) oxy) -4-) Hydroxytetrahydrofuran-2-yl) -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzamide (1.03 g) was azeotropically dehydrated with anhydrous toluene, and dried under an argon atmosphere with anhydrous DMF (5 mL) was added. 3-((Bis (diisopropylamino) phosphino) oxy) propanenitrile (0.771 g), 1H-tetrazole (0.090 g) and 1-methyl-1H-imidazole (0.051 mL) were added and stirred for 6 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (0.5% triethylamine in ethyl acetate / hexane) to give the title compound (1.12 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ -0.17 (3 H, d, J = 2.6 Hz), -0.04-0.00 (3 H, m), 0.78 (9 H, s), 1.04 (3 H, d, J = 6.8) Hz), 1.13-1.23 (9 H, m), 2. 32 (1 H, t, J = 6.6 Hz), 2. 68 (1 H, td, J = 6.4, 1.9 Hz), 3.21-3. 36 (1 H, m), 3.42-3. 71 (4H, m), 3.79 (6H, d, J = 1.1 Hz), 3.85-4.05 (1H, m), 4.25-4.45 (2H, m), 4.64-4.82 (1H, m), 6.39 (1H, dd , J = 14.2, 5.9 Hz), 6.74-6.89 (4H, m), 7.19-7.41 (8H, m), 7.43-7.67 (5H, m), 7.98 (2H, d, J = 7.6 Hz), 8.50 (8 1H, s), 8.64 (1H, d, J = 5.3 Hz).

D) (2R, 3R, 4R, 5R) -5- (4-benzamido-5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -4-((tert-butyldimethylsilyl) Oxy) -2- (hydroxymethyl) tetrahydrofuran-3-yl hydrogen phosphonate
N-Benzoyl-7- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -3-O-((2-cyanoethoxy) (Diisopropylamino) phosphino) -beta-D-ribofuranosyl) -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-amine (1.12 g) in acetonitrile (5 mL), water (40 μL) and Pyridine 2,2,2-trifluoroacetate (258 mg) was added. After stirring at room temperature for 10 minutes, tert-butylamine (5.43 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 80% acetic acid (5.5 mL) was added, and the mixture was further stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (527 mg).
MS: [M + H] ⁺ 5672.

E) (2R, 3R, 4R, 5R) -5- (4-benzamido-5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -4-((tert-butyldimethylsilyl) Oxy) -2-((((((2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (2-isobutylamide-6-) Oxo-1H-purin-9 (6H) -yl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -5- (4-benzamido-5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -4-((tert-butyldimethylsilyl) oxy) -2- (Hydroxymethyl) tetrahydrofuran-3-yl hydrogen phosphonate (527 mg) and 3'-O- (tert-butyl (dimethyl) silyl) -2'-O-((2-cyanoethoxy) (diisopropylamino) Phosphino) -N-isobutyryl guanosine (1.083 g) was azeotropically dehydrated three times with anhydrous acetonitrile, and anhydrous acetonitrile (10 mL) was added. Pyridine 2,2,2-trifluoroacetate (359 mg) was added and stirred at room temperature for 30 minutes, 70% tert-butyl hydroperoxide (382 μL) was added, and stirred at room temperature for another 20 minutes. Sodium thiosulfate (693 mg) and water (1 mL) were added to the reaction mixture, and concentrated under reduced pressure. To the residue was added 80% acetic acid (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and azeotropically dehydrated with toluene three times. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (175 mg).
MS: [M + H] ^< +> 1149.4.

F) N- (7-[(5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyano Ethoxy) -2-hydroxy-7- (2-((2-methylpropanoyl) amino) -6-oxo-1,6-dihydro-9H-purin-9-yl) -2,10-dioxide octahydro -12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl] -5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) benzamide
(2R, 3R, 4R, 5R) -5- (4-benzamido-5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -4-((tert-butyldimethylsilyl) oxy) -2-((((((2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (2-isobutylamido-6-oxo- 1H-Purine-9 (6H) -yl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate (175 mg) was azeotroped three times with anhydrous acetonitrile After dehydration, anhydrous pyridine (3 mL) and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (98 mg) were added and stirred at room temperature under argon atmosphere for 10 minutes. Water (96 μL) and iodine (50 mg) were added, and the mixture was further stirred at room temperature for 20 minutes. The reaction mixture was added with a mixture of sodium thiosulfate (98 mg) and water (0.4 mL), stirred for 5 minutes, and concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (48 mg).
MS: [M + H] ^< +> 1147.6.

G) 2-Amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (4-amino-5-fluoro-7H-pyrrolo [2,3-d] pyrimidine- 7-yl) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-dioxideoctahydro-12H-5,8-methanofuro [3,2- l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one
N- (7-[(5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy) -2-Hydroxy-7- (2-((2-methylpropanoyl) amino) -6-oxo-1,6-dihydro-9H-purin-9-yl) -2,10-dioxideoctahydro-12H -5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl] -5-fluoro-7H-pyrrolo [2 3,3-d] pyrimidin-4-yl) benzamide (48 mg) was azeotropically dehydrated twice with anhydrous acetonitrile, 33% methylamine ethanol solution (2 mL) was added, and the mixture was stirred overnight at room temperature under an argon atmosphere. The resulting mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (methanol / ethyl acetate), and the resulting residue is HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM acetic acid The reaction mixture was purified with aqueous ammonium solution / acetonitrile), and the obtained fraction was concentrated under reduced pressure and lyophilized to give the title compound (5 mg).
MS: [M + H] ⁺ 920.3.

H) 2-Amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (4-amino-5-fluoro-7H-pyrrolo [2,3-d] pyrimidine- 7-yl) -2,10,15,16-tetrahydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11, 2, 10] Pentaoxadiphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt
2-amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (4-amino-5-fluoro-7H-pyrrolo [2,3-d] pyrimidine-7- Yl) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] Pentaoxadiphosphacyclotetradecin-7-yl) -1,9-dihydro-6H-purin-6-one (5 mg) and triethylamine trifluoride The mixture of hydrogen salt (200 μL) was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature and then neutralized with 1 M aqueous triethylammonium hydrogen carbonate solution. The reaction mixture was purified by C18 column chromatography (acetonitrile / 10 mM triethylammonium buffer solution), and the target fraction was concentrated under reduced pressure and lyophilized to give the title compound (3.2 mg).
¹ H NMR (600 MHz, D ₂ O) δ 1.23 (18 H, t, J = 7.3 Hz), 3. 15 (12 H, q, J = 7.3 Hz), 4.06-4.11 (1 H, m), 4.14-4. 19 (1 H , m), 4.21-4.26 (1H, m), 4.31-4.37 (2H, m), 4.40 (1H, d, J = 1.5 Hz), 4.56 (1 H, dd, J = 15.2, 4.3 Hz), 4.61- 4.68 (1H, m), 5.00 (1H, ddd, J = 8.5, 6.6, 4.5 Hz), 5.60 (1H, td, J = 7.9, 4.1 Hz), 5.93 (1 H, d, J = 8.5 Hz), 6.26 (1 H, s), 7.14 (1 H, d, J = 1.6 Hz), 7.87 (1 H, s), 8. 10 (1 H, s).

Example 10
1-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -2,10,15,16-tetrahydroxy-2, 10-Dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -1 , 5-Dihydro-4H-imidazo [4,5-c] pyridin-4-one

A) (2R, 3R, 4R, 5R) -2-((benzoyloxy) methyl) -5- (4-oxo-4,5-dihydro-1H-imidazo [4,5-c] pyridin-1-yl ) Tetrahydrofuran-3,4-diyl dibenzoate
Formic acid (123 mL) and water (30 mL) were added to 4-chloro-1H-imidazo [4,5-c] pyridine (20 g) at room temperature and stirred at 100 ° C. for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Concentrated hydrochloric acid (100 mL) was added to the residue, and the mixture was stirred at 100 ° C. for 1 hour. The mixture was concentrated under reduced pressure, and the residue was suspended in MeOH (100 mL) and diisopropyl ether (100 mL), and triethylamine (50 mL) was added. The resulting solid was collected by filtration and dissolved in acetonitrile (600 mL), then trimethylsilyl N- (trimethylsilyl) acetimidate (38.2 mL) was added at room temperature and stirred for 10 minutes. After adding (2S, 3R, 4R, 5R) -2-acetoxy-5-((benzoyloxy) methyl) tetrahydrofuran-3,4-diyl dibenzoate (79.0 g) to the reaction mixture at room temperature, the mixture is heated to 80.degree. Heated. Trimethylsilyl trifluoromethanesulfonate (28.2 mL) was added to the reaction liquid, and it stirred at 80 degreeC overnight under argon atmosphere. After cooling to room temperature, water (500 mL) was added and the resulting solid was collected by filtration. The solid was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (25.9 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 4.65-4.96 (3H, m), 5. 91 (2H, brs), 6.23-6.42 (1H, m), 6.64 (1H, brs), 7.15 (1H, brs), 7.32-7.56 (9H, m), 7.92-8.15 (7H, m), 12.11-12.50 (1H, m).
MS: [M + H] ⁺ 580.1

B) 1-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1H-imidazo [4,5-c] pyridine-4 (5H) -on
(2R, 3R, 4R, 5R) -2-((benzoyloxy) methyl) -5- (4-oxo-4,5-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) tetrahydrofuran A 40% methylamine methanol solution (200 mL) was added to -3,4-diyl dibenzoate (30.0 g), and the mixture was stirred at room temperature under argon for 1 hour, and then the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (11.2 g).
MS: [M + H] ⁺ 268.1

C) 1-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) -1H-imidazo [ 4,5-c] pyridin-4 (5H) -one
1-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1H-imidazo [4,5-c] pyridin-4 (5H) -one To a solution of (18.0 g) in pyridine (140 mL), 4,4′-dimethoxytrityl chloride (18.46 g) was added at room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (18.2 g).
MS: [M + H] ⁺ 570.2

D) 1-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -3-hydroxy Tetrahydrofuran-2-yl) -1H-imidazo [4,5-c] pyridin-4 (5H) -one
1-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) -1H-imidazo [4, After adding imidazole (4.30 g) and tert-butyldimethylchlorosilane (5.72 g) to a solution of 5-c] pyridin-4 (5H) -one (18.02 g) in DMF (158 mL), the mixture was stirred at room temperature for 3 hours . After further adding tert-butyldimethylchlorosilane (2.38 g), the mixture was stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The isolated regioisomer of the title compound was dissolved in MeOH and triethylamine and stirred overnight at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (11.5 g).
MS: [M + H] + 684.2

E) (2R, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -2- (4-oxo -4,5-Dihydro-1H-imidazo [4,5-c] pyridin-1-yl) tetrahydrofuran-3-yl hydrogen phosphonate
1-((2R, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -3-hydroxytetrahydrofuran- To a mixture of 2-yl) -1H-imidazo [4,5-c] pyridin-4 (5H) -one (8.0 g) and pyridine (117 mL) was added diphenyl phosphite (4.5 mL). After stirring at room temperature for 1 h, water (20 mL) was added to the reaction mixture. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (8.5 g).
MS: [M + H] + 748.3

F) (2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (4-oxo-4,5-dihydro-1H-imidazo [4] , 5-c] Pyridin-1-yl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -2- (4-oxo-4 , 5-Dihydro-1H-imidazo [4,5-c] pyridin-1-yl) tetrahydrofuran-3-yl hydrogen phosphonate (8.2 g) and 1,1,1,3,3,3-hexafluoropropane-2 -The mixture of ol (30 mL) was stirred at room temperature for 2 hours. After adding methanol (10 mL) and stirring at 60 ° C. for 1 hour, the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate and diisopropyl ether to give the title compound (4.3 g).
MS: [M + H] ⁺ 446.1

G) (2R, 3R, 4R, 5R) -5-((((((2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert) -Butyldimethylsilyl) oxy) -2- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -2- (4-Oxo-4,5-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (4-oxo-4,5-dihydro-1H-imidazo [4,5] -c] Pyridin-1-yl) tetrahydrofuran-3-yl hydrogen phosphonate (250 mg) and N-benzoyl-5′-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2′-O- ( After tert-butyl (dimethyl) silyl) -3'-O-((2-cyanoethoxy) (diisopropylamino) phosphino) adenosine (776 mg) was azeotropically dehydrated with anhydrous acetonitrile, anhydrous acetonitrile (5.61 mL) was added. The Pyridine 2,2,2-trifluoroacetate (271 mg) was added to the mixture and stirred at room temperature for 40 minutes, 70% tert-butyl hydroperoxide (231 μL) was added, and stirred at room temperature for 20 minutes. A mixture of sodium thiosulfate (1.3 g) and water (3 mL) was added to the reaction mixture, and concentrated under reduced pressure. To the residue was added 1,1,1,3,3,3-hexafluoropropan-2-ol (15 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane and methanol / ethyl acetate) to give the title compound (170 mg).
MS: [M + H] ⁺ 1046.3

H) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -2- (2-cyano) Ethoxy) -10-hydroxy-2,10-dioxide-7- (4-oxo-4,5-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) octahydro-12H-5,8- Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide
((2R, 3R, 4R, 5R) -5-((((((2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyl) Dimethylsilyl) oxy) -2- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -2- (4 -Oxo-4,5-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) tetrahydrofuran-3-yl hydrogen phosphonate (160 mg) was azeotropically dehydrated with anhydrous pyridine and then anhydrous pyridine (3.0 mL) was added. After adding 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (99 mg) to the mixture at room temperature and stirring at room temperature for 1 hour, water (96 μL) and iodine ( 50.5 mg) was added and stirred for another 20 minutes at room temperature. After a mixture of sodium thiosulfate (190 mg) and water (0.4 mL) was added to the reaction mixture, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (10.6 mg).
MS: [M + H] ⁺ 1044.3

I) 1-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl ( Dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,10 ] Pentaoxadiphosphacyclotetradecin-7-yl) -1,5-dihydro-4H-imidazo [4,5-c] pyridin-4-one
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -2- (2-cyanoethoxy) -10-hydroxy-2,10-dioxide-7- (4-oxo-4,5-dihydro-1H-imidazo [4,5-c] pyridin-1-yl) octahydro-12H-5,8-methanofuro [ 40% to 3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide (10.6 mg) After adding methylamine ethanol solution (5.0 mL) and stirring at room temperature under argon atmosphere for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (9.0 mg).
MS: [M + H] ⁺ 887.2

J) 1-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -2,10,15,16-tetrahydroxy- 2,10-Dioxide Octahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -1,5-Dihydro-4H-imidazo [4,5-c] pyridin-4-one
1-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl (dimethyl)) Silyl) oxy) -2,10-dihydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] penta Oxadiphosphacyclotetradecyne-7-yl) -1,5-dihydro-4H-imidazo [4,5-c] pyridin-4-one (9.0 mg) in methanol (1.0 mL) and triethylamine trihydrofluoride Salt (165 μL) was added. The reaction mixture was concentrated and methanol was distilled off, and then stirred at 55 ° C. for 1 hour. After cooling to room temperature, ethoxy (trimethyl) silane (0.90 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile / 10 mM triethylammonium acetate buffer) to give the title compound (0.3 mg).
¹ H NMR (400 MHz, D ₂ O) a 4.15 (2 H, d, J = 11.5 Hz), 4.46 (4 H, brs), 4.56-4.62 (1 H, m), 4.98-4.99 (2 H, m), 6.05 -6.20 (2H, m), 6.79-6.87 (1H, m), 7.06-7.12 (1H, m), 8.00 (1 H, s), 7.96-8.10 (1 H, m), 8.23 (2 H, s).
³¹ P NMR (162 MHz, D ₂ O) δ -2.36, -1.94.

Example 11
2-amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (4-amino-1H-imidazo [4,5-c] pyridin-1-yl) -2 10,15,16-Tetrahydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxa Diphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt

A) N-Benzoyl-1- (2-O- (tert-butyl (dimethyl) silyl) -3,5-O- (di-tert-butylsilylene) -beta-D-ribofuranosyl) -1H-imidazo [4 , 5-c] Pyridine-4-amine
Dissolve N-benzoyl-1- (beta-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridin-4-amine (2.41 g) in DMF (25 mL), di-tert-butylsilanediyl Bis (trifluoromethanesulfonate) (2.32 mL) was added at 0 ° C. and stirred at 0 ° C. for 75 minutes. Di-tert-butylsilanediyl bis (trifluoromethanesulfonate) (0.63 mL) was added at 0 ° C. and stirred for another 30 minutes at 0 ° C. Di-tert-butylsilanediyl bis (trifluoromethanesulfonate) (0.63 mL) was added at 0 ° C. and stirred for another 35 minutes at 0 ° C. To the reaction mixture was added 1H-imidazole (2.22 g) and stirred at room temperature for 10 minutes. Tert-butyldimethylchlorosilane (1.18 g) was added and stirred at 60 ° C. for one and a half hours. Tert-butyldimethylchlorosilane (0.294 g) was added and stirred at 60 ° C. for 14 and a half hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.28 g).
MS: [M + H] ⁺ 625.2.

B) N-Benzoyl-1- (2-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridin-4-amine
Pyridinium poly (hydrogen fluoride) (1.86 mL) is dissolved in pyridine (10 mL) at 0 ° C. and N-benzoyl-1- (2-O- (tert-butyl (dimethyl) silyl) -3,5- O- (di-tert-butylsilylene) -beta-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridin-4-amine (1.64 g) in tetrahydrofuran (13 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 8 minutes. This reaction was repeated twice. The reaction solutions were combined, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane and methanol / ethyl acetate) to give the title compound (2.24 g).
MS: [M + H] ⁺ 485.1.

C) N-Benzoyl-1- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -1H- Imidazo [4,5-c] pyridin-4-amine
N-benzoyl-1- (2-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridin-4-amine (2.24 g) with pyridine ( The mixture was dissolved in 25 mL), 4,4'-dimethoxytrityl chloride (2.04 g) was added at room temperature, and stirred at room temperature for 4 and a half hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.29 g).
MS: [M + H] ⁺ 787.3.

D) N-Benzoyl-1- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -3-O-((2-cyano) Ethoxy) (diisopropylamino) phosphino) -beta-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridin-4-amine
N-Benzoyl-1- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -beta-D-ribofuranosyl) -1H-imidazo [ Dissolve 4,5-c] pyridin-4-amine (3.29 g) in anhydrous N, N-dimethylformamide (9.5 mL) and add 3-((bis (diisopropylamino) phosphino) oxy) propanenitrile 2.98 mL), 1H-tetrazole (0.328 g) and 1-methyl-1H-imidazole (0.185 mL) were added, and the mixture was stirred at room temperature for 2.5 hours under an argon atmosphere. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, containing 0.5% triethylamine) to give the title compound (3.85 g).
MS: [M + H] ^< +> 987.4.

E) N-Benzoyl-1- (2-O- (tert-butyl (dimethyl) silyl) -3-O- (hydroxy (oxide) phosphoranyl) -beta-D-ribofuranosyl) -1H-imidazo [4,5- c] Pyridine-4-amine
N-Benzoyl-1- (5-O- (bis (4-methoxyphenyl) (phenyl) methyl) -2-O- (tert-butyl (dimethyl) silyl) -3-O-((2-cyanoethoxy) (Diisopropylamino) phosphino) -beta-D-ribofuranosyl) -1H-imidazo [4,5-c] pyridin-4-amine (3.85 g) is dissolved in acetonitrile (30 mL), pyridine 2,2,2- Trifluoroacetate (0.904 g) and water (0.141 mL) were added at room temperature and stirred at room temperature for 30 minutes. To the reaction solution was added 2-methylpropan-2-amine (9 mL) at room temperature and stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and 1,1,1,3,3,3-hexafluoropropan-2-ol (25 mL) was added to the residue, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, acetic acid (20 mL) and water (5 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1.85 g).
MS: [M + H] ⁺ 549.1.

F) (2R, 3R, 4R, 5R) -5- (4-benzamido-1H-imidazo [4,5-c] pyridin-1-yl) -4-((tert-butyldimethylsilyl) oxy) -2 -((((((2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (2-isobutylamido-6-oxo-1H- Purine-9 (6H) -yl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate
N-Benzoyl-1- (2-O- (tert-butyl (dimethyl) silyl) -3-O- (hydroxy (oxide) phosphoranyl) -beta-D-ribofuranosyl) -1H-imidazo [4,5-c] Pyridin-4-amine (300 mg) and 5'-O- (bis (4-methoxyphenyl) (phenyl) methyl) -3'-O- (tert-butyl (dimethyl) silyl) -2'-O- ( (2-Cyanoethoxy) (diisopropylamino) phosphino) -N-isobutyrylguanosine (637 mg) was azeotropically dehydrated with anhydrous acetonitrile (three times) and suspended in anhydrous acetonitrile (6 mL). Pyridine 2,2,2-trifluoroacetate (264 mg) was added and stirred at room temperature under argon atmosphere for 1 hour, then 70% tert-butyl hydroperoxide (0.225 mL) was added and stirred at room temperature for another hour did. The reaction mixture was quenched with sodium thiosulfate (400 mg) and water (1.5 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in 80% acetic acid (5 mL) and stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure and azeotropically dehydrated with anhydrous acetonitrile and toluene. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (469 mg).
MS: [M + H] ^< +> 1131.4.

G) N- (1-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyano Ethoxy) -2-hydroxy-7- (2- (isobutyrylamino) -6-oxo-1,6-dihydro-9H-purin-9-yl) -2,10-dioxide octahydro-12H-5 , 8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -1H-imidazo [4,5-c] pyridine -4-yl) benzamide
(2R, 3R, 4R, 5R) -5- (4-benzamido-1H-imidazo [4,5-c] pyridin-1-yl) -4-((tert-butyldimethylsilyl) oxy) -2- ( (((((2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (2-isobutyramido-6-oxo-1H-purine- 9 (6H) -yl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate (469 mg) was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, Suspended in anhydrous pyridine (10 mL). Add 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (268 mg) and stir at room temperature for 15 minutes under argon atmosphere, then add water (1 mL) and iodine ( 158 mg) was added and stirred at room temperature for a further 13 minutes. The reaction mixture was quenched with sodium thiosulfate (170 mg) and water (0.5 mL), the solvent was evaporated under reduced pressure, and azeotropic dehydration was performed with toluene. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (419 mg).
MS: [M + H] ⁺ 1129.3.

H) 2-Amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (4-amino-1H-imidazo [4,5-c] pyridin-1-yl) -15,16-Bis ((tert-butyl (dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-dioxideoctahydro-12H-5,8-methanofuro [3,2-l] [1 , 3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one
N- (1-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy) -2-Hydroxy-7- (2- (isobutyrylamino) -6-oxo-1,6-dihydro-9H-purin-9-yl) -2,10-dioxideoctahydro-12H-5,8 -Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -1H-imidazo [4,5-c] pyridine-4 -Yl) benzamide (419 mg) was dissolved in 33% methylamine ethanol solution (10.0 mL) and stirred at room temperature for 18.5 hours under argon atmosphere. After adding 33% methylamine ethanol solution (5 mL) and further stirring for 3 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in 33% methylamine ethanol solution (10.0 mL) and stirred at room temperature for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (173 mg).
MS: [M + H] ⁺ 902.3.

I) 2-Amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (4-amino-1H-imidazo [4,5-c] pyridin-1-yl) -2,10,15,16-Tetrahydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] Pentaoxadiphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt
2-amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (4-amino-1H-imidazo [4,5-c] pyridin-1-yl) -15 , 16-Bis ((tert-butyl (dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-dioxideoctahydro-12H-5,8-methanofuro [3,2-l] [1,3 , 6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one (173 mg) to triethylamine trihydrofluoride ( 0.625 mL) was added and stirred at 50 ° C. for 3 hours. After cooling to room temperature, 1 M aqueous triethylammonium bicarbonate solution was added for neutralization, and then the solvent was evaporated under reduced pressure. The residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile), and the obtained solid was lyophilized to give the title compound (123 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.25 (18 H, t, J = 7.4 Hz), 3. 17 (12 H, q, J = 7.2 Hz), 3.87-4. 10 (1 H, m), 4.1 1-4. 30 (3 H , m), 4.32-4.45 (2H, m), 4.52 (1 H, d, J = 3.8 Hz), 4.65 (1 H, d, J = 4.2 Hz), 4.97-5.10 (1 H, m), 5.79 (1 H, brs), 5.94 (2H, d, J = 8.3 Hz), 7.10 (1 H, d, J = 6.8 Hz), 7.68-7.78 (1 H, m), 7.83 (1 H, s), 7.94-8.26 (1 H, m) ).
^{31 P NMR (121 MHz, D} 2 O) δ-1.36.

Example 12
8-((5R, 7R, 8R, 12aR, 14S, 15S, 15aS, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide-2 10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) pyrazolo [1,5-a] [1,3,5] Triazin-4 (3H) -one 2-triethylamine (optical isomer)

A) 8-((2S, 3S, 4R, 5R) -3,4-bis (benzyloxy) -5-((benzyloxy) methyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] [1 , 3,5] Triazine-4 (3H) -one
4-((2S, 3S, 4R, 5R) -3,4-bis (benzyloxy) -5-((benzyloxy) methyl) tetrahydrofuran-2-yl) -1H-pyrazol-5-amine (17.3 g) Ethyl formimidate hydrochloride (19.5 g) was added to a solution of potassium carbonate (24.6 g) in DMF (200 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added diethyl carbonate (126 g) at room temperature, and the reaction mixture was stirred at 100 ° C. for 1 hour. To the reaction mixture was added 20% sodium ethoxide ethanol solution (60.6 g) at room temperature. The reaction mixture was stirred at 100 ° C. for 30 minutes. The reaction mixture was neutralized at room temperature with acetic acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (5.79 g).
MS: [M + H] ⁺ 539.1.

B) 8-((2S, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5] triazine- 4 (3H)-on
8-((2S, 3S, 4R, 5R) -3,4-bis (benzyloxy) -5-((benzyloxy) methyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3 , 5] A solution of triazine-4 (3H) -one (3.49 g) and 20% palladium hydroxide in palladium hydroxide (1.37 g) in methanol (30 mL) was stirred at room temperature overnight under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (1.72 g).
MS: [M + H] ^< +> 269.0.

C) 8-((2S, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) pyrazolo [1,5 -a] [1,3,5] triazine-4 (3H) -one
8-((2S, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5] triazine-4 ( To a solution of 3H) -one (1.72 g) in dehydrated pyridine (30 mL) was added 4,4'-dimethoxytrityl chloride (2.39 g) under ice-cooling. The reaction mixture was stirred at room temperature under argon for 2 hours. To the reaction mixture, 4,4'-dimethoxytrityl chloride (0.217 g) was added under ice-cooling. The reaction mixture was stirred at room temperature under argon for 3 hours. To the reaction mixture was added 4,4'-dimethoxytrityl chloride (0.217 g) at room temperature. The reaction mixture was stirred at room temperature under argon for 30 minutes. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1.62 g).
MS: [MH] ^- 569.1.

D) 8-((2S, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3-((tert-butyldimethylsilyl) oxy) -4-hydroxy Tetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5] triazine-4 (3H) -one
tert-Butyldimethylchlorosilane (536 mg) and silver (I) nitrate (604 mg) in 8-((2S, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-Dihydroxytetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5] triazine-4 (3H) -one (1.69 g) and dehydrated pyridine (1.20 mL) in anhydrous THF 20 mL) was added to the solution at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 8 hours, and then tert-butyldimethylchlorosilane (89 mg) and silver (I) nitrate (101 mg) were added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature overnight. The insolubles were filtered off and washed with ethyl acetate. To the filtrate was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (740 mg).
MS: [MH] ^- 683.1.

E) (2R, 3R, 4S, 5S) -2-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -5- (4-oxo -3,4-Dihydropyrazolo [1,5-a] [1,3,5] triazin-8-yl) tetrahydrofuran-3-yl hydrogen phosphonate diphenyl phosphite (0.41 mL) with 8-((2S, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3-((tert-butyldimethylsilyl) oxy) -4-hydroxytetrahydrofuran-2-yl) pyrazolo [ To a solution of 1,5-a] [1,3,5] triazine-4 (3H) -one (740 mg) in pyridine (10 mL) was added at room temperature. The reaction mixture was stirred at room temperature under an argon atmosphere for 1 hour. Water (20 mL) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was added to water at room temperature and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (300 mg).
MS: [MH] ^- 747.1.

F) (2R, 3R, 4S, 5S) -4-((tert-butyldimethylsilyl) oxy) -2- (hydroxymethyl) -5- (4-oxo-3,4-dihydropyrazolo [1,5] -a] [1,3,5] Triazin-8-yl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4S, 5S) -2-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -5- (4-oxo-3 80% aqueous acetic acid (10 mL) is added to 3,4-dihydropyrazolo [1,5-a] [1,3,5] triazin-8-yl) tetrahydrofuran-3-yl hydrogen phosphonate (300 mg), and the mixture is allowed to stand at room temperature. The mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (170 mg).
MS: [M + H] ^< +> 447.0.

G) (2R, 3R, 4S, 5S) -2-((((((2R, 3R, 4R, 5R) -2- (6-benzamido-9H-purin-9-yl) -4-((tert) -Butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy)- 5- (4-Oxo-3,4-dihydropyrazolo [1,5-a] [1,3,5] triazin-8-yl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4S, 5S) -4-((tert-butyldimethylsilyl) oxy) -2- (hydroxymethyl) -5- (4-oxo-3,4-dihydropyrazolo [1,5-a ] [1,3,5] Triazin-8-yl) tetrahydrofuran-3-yl hydrogen phosphonate (190 mg) and N-benzoyl-5'-O- (bis (4-methoxyphenyl) (phenyl) methyl) -3 Dehydrated acetonitrile was added to '-O- (tert-butyl (dimethyl) silyl) -2'-O-((2-cyanoethyl) (diisopropylamino) phosphino) adenosine (505 mg), and azeotropic operation was performed three times . To the residue were added dehydrated acetonitrile (5 mL) and pyridine 2,2,2-trifluoroacetate (164 mg). The reaction mixture is stirred at room temperature under argon atmosphere for 10 minutes, and ((dimethylamino-methylidene) amino) -3H-1,2,4-dithiazoline-3-thione (96 mg) is added to the reaction mixture, and the reaction is allowed to proceed at room temperature 20. Stirred for a minute. To the reaction mixture was added an aqueous solution (0.2 mL) of sodium thiosulfate (0.2 g), and concentrated under reduced pressure. After adding 80% aqueous acetic acid solution (5 mL) to the residue and stirring at room temperature for 1 hour, acetonitrile was added to the reaction mixture to carry out azeotropic operation twice. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (260 mg).
MS: [M + H] ^< +> 1063.2.

H) 8-((5R, 7R, 8R, 12aR, 14S, 15S, 15aR, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl ( Dimethyl) silyl) oxy) -2,10-dihydroxy-2,10-disulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] Pentaoxadiphosphacyclotetradecyne-14-yl) pyrazolo [1,5-a] [1,3,5] triazine-4 (3H) -one (optical isomer)
((2R, 3R, 4S, 5S) -2-((((((2R, 3R, 4R, 5R) -2- (6-benzamido-9H-purin-9-yl) -4-((tert-butyl) Dimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -5- (4-Oxo-3,4-dihydropyrazolo [1,5-a] [1,3,5] triazin-8-yl) tetrahydrofuran-3-yl hydrogen phosphonate (260 mg) was added with dehydrated acetonitrile, The boiling operation was carried out twice. To the residue was added dehydrated pyridine, and an azeotropic operation was performed once. To a solution of the residue in dehydrated pyridine (5 mL) was added 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (158 mg), and the mixture was stirred at room temperature for 20 minutes under an argon atmosphere. . To the reaction mixture were added water (0.15 mL) and 3H-benzo [c] [1,2] dithiole-3-one (49.4 mg) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (methanol / ethyl acetate) and then separated by HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile) to obtain retention time The largest fraction was concentrated in vacuo. To the residue was added 33% methylamine ethanol solution (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (25 mg).
MS: [M + H] ⁺ 90.2.

I) 8-((5R, 7R, 8R, 12aR, 14S, 15S, 15aS, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-dihydroxy-2,10-dioxide -2,10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl ) Pyrazolo [1,5-a] [1,3,5] triazine-4 (3H) -one 2-triethylamine (optical isomer)
8-((5R, 7R, 8R, 12aR, 14S, 15S, 15aR, 16R) -7- (6-amino-9H-purin-9-yl) -15,16-bis ((tert-butyl (dimethyl)) Silyl) oxy) -2,10-dihydroxy-2,10-disulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxa Diphosphacyclotetradecyne-14-yl) pyrazolo [1,5-a] [1,3,5] triazine-4 (3H) -one (optical isomer) (25 mg) in methanol (2 mL) Triethylamine trihydrofluoride (0.177 mL) was added at room temperature and stirred at 50 ° C. for 2 hours. To the reaction mixture was added ethoxytrimethylsilane (5 mL) at room temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile) and lyophilized to give the title compound (13 mg).
¹ H NMR (300 MHz, D ₂ O) δ 4.02-4.19 (3H, m), 4.32-4.42 (2H, m), 4.44-4.49 (1H, m), 4.59-4.64 (1H, m), 4.76- 4.80 (1H, m), 4.95-5.04 (1H, m), 5.16 (1H, d, J = 4.9 Hz), 5.31 (1 H, ddd, J = 9.8, 8.7, 4.2 Hz), 6.22 (1 H, d, J = 8.3 Hz), 7.99 (1 H, s), 8.00 (1 H, s), 8. 14 (1 H, s), 8. 49 (1 H, s).

Example 13
2-amino-9-((5R, 7R, 8R, 12aR, 14S, 15S, 15aS, 16R) -14- (4-aminopyrazolo [1,5-a] [1,3,5] triazin-8-yl ) -2,10,15,16-tetrahydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2,10 ] Pentaoxadiphosphacyclotetradecin-7-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt

A) (2S, 3S, 4R, 5R) -2- (4- (N-benzoylbenzamido) pyrazolo [1,5-a] [1,3,5] triazin-8-yl) -5-((benzoyl) Oxy) methyl) tetrahydrofuran-3,4-diyl dibenzoate
(2S, 3R, 4S, 5R) -2- (4-aminopyrazolo [1,5-a] [1,3,5] triazin-8-yl) -5- (hydroxymethyl) tetrahydrofuran-3,4-diol To a solution of (2.98 g) and N, N-dimethyl-4-aminopyridine (1.36 g) in dehydrated pyridine (50 mL) was added benzoyl chloride (12.5 g) under ice-cooling. The reaction mixture was stirred for 1 hour under argon atmosphere. To the reaction mixture was added benzoyl chloride (3.13 g) under ice-cooling. The reaction mixture was stirred at room temperature under argon for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.51 g).
MS: [M + H] ⁺ 788.2.

B) N- (8-((2S, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5 ] Triazin-4-yl) benzamide
(2S, 3S, 4R, 5R) -2- (4- (N-benzoylbenzamido) pyrazolo [1,5-a] [1,3,5] triazin-8-yl) -5-((benzoyloxy) 1 M aqueous solution of sodium hydroxide (49.6 mL) is added to a mixed solution of pyridine (50 mL) and ethanol (25 mL) of methyl) tetrahydrofuran-3,4-diyl dibenzoate (6.51 g) under ice-cooling, and 2 Stir for hours. The reaction mixture was strongly acidic cation-exchange resin Dowex ^TM 50Wx4 100-200 in a (40 g) was added at room temperature and stirred for 15 minutes at room temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added methanol, and the obtained solid was collected by filtration to give the title compound (1.82 g).
MS: [M + H] ⁺ 372.1.

C) N- (8-((2S, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) pyrazolo [ 1,5-a] [1,3,5] triazin-4-yl) benzamide
N- (8-((2S, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5] triazine To a solution of 4-yl) benzamide (1.89 g) in dehydrated pyridine (30 mL) was added 4,4'-dimethoxytrityl chloride (517 mg) under ice-cooling. The reaction mixture was stirred at room temperature under argon for 3 hours. To the reaction mixture, 4,4′-dimethoxytrityl chloride (517 mg) was added at room temperature, and stirred overnight at room temperature under an argon atmosphere. To the reaction mixture, 4,4′-dimethoxytrityl chloride (1035 mg) was added at room temperature and stirred at room temperature for 1 hour under an argon atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (2160 mg).
MS: [MH] ^- 672.1.

D) N- (8-((2S, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3-((tert-butyldimethylsilyl) oxy)- 4-hydroxytetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl) benzamide
N- (8-((2S, 3R, 4S, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3,4-dihydroxytetrahydrofuran-2-yl) pyrazolo [1,1 Silver (I) nitrate (708 mg) and dehydrated pyridine (1.22 g) were added to a solution of 5-a] [1,3,5] triazin-4-yl) benzamide (2.16 g) in dehydrated THF (30 mL). The reaction mixture was stirred for 15 minutes under an argon atmosphere, and then tert-butyldimethylchlorosilane (628 mg) was added. The reaction mixture was stirred at room temperature under argon for 2 hours. Silver (I) nitrate (163 mg), tert-butyldimethylchlorosilane (145 mg) and dehydrated pyridine (507 mg) were added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature overnight under an argon atmosphere. Silver (I) nitrate (436 mg), tert-butyldimethylchlorosilane (387 mg) and dehydrated pyridine (761 mg) were added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature under argon for 2 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (980 mg).
MS: [MH] ^- 786.2.

E) (2R, 3R, 4S, 5S) -5- (4-benzamidopyrazolo [1,5-a] [1,3,5] triazin-8-yl) -4-((tert-butyldimethylsilyl) ) Oxy) -2- (hydroxymethyl) tetrahydrofuran-3-yl hydrogen phosphonate
N- (8-((2S, 3R, 4R, 5R) -5-((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3-((tert-butyldimethylsilyl) oxy) -4-) Dehydrated toluene is added to hydroxytetrahydrofuran-2-yl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl) benzamide (980 mg), and after performing azeotropic operation twice, dehydrated DMF Dissolve in (10 mL). To the reaction mixture was added 3-((bis (diisopropylamino) phosphino) oxy) propanenitrile (487 mg), 1H-tetrazole (87 mg) and 1-methyl-1H-imidazole (51 mg). The reaction mixture was stirred at room temperature for 5 hours under an argon atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.5% triethylamine in ethyl acetate / hexane). To a solution of the resulting mixture in acetonitrile (10 mL) were added water (0.04 mL) and pyridine 2,2,2-trifluoroacetate (256 mg) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, tert-butylamine (5.38 mL) was added, and the mixture was stirred at room temperature for 45 minutes. The solvent was distilled off under reduced pressure. To the residue was added 80% aqueous acetic acid (5.4 mL), the mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (530 mg).
MS: [M + H] ⁺ 550.2.

F) (2R, 3R, 4S, 5S) -5- (4-benzamidopyrazolo [1,5-a] [1,3,5] triazin-8-yl) -4-((tert-butyldimethylsilyl) )) Oxy) -2-((((((2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (2-isobutylamide-6 -Oxo-1H-purin-9 (6H) -yl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4S, 5S) -5- (4-benzamidopyrazolo [1,5-a] [1,3,5] triazin-8-yl) -4-((tert-butyldimethylsilyl) oxy ) -2- (Hydroxymethyl) tetrahydrofuran-3-yl hydrogen phosphonate (240 mg) and 5'-O- (bis (4-methoxyphenyl) (phenyl) methyl) -3'-O- (tert-butyl (dimethyl) Dehydrated acetonitrile was added to a mixture of (silyl) -2'-O-((2-cyanoethyl) (diisopropylamino) phosphino) -N-isobutyrylguanosine (635 mg), and azeotropic operation was carried out three times. To the residue was added a solution of dehydrated acetonitrile (5 mL), dehydrated THF (2.5 mL), and a solution of 5- (ethylthio) -2H-tetrazole (171 mg) which had been subjected to azeotrope operation beforehand with dehydrated acetonitrile (2.5 mL) The The reaction mixture was stirred at room temperature under argon atmosphere for 2 hours, and then 70% aqueous tert-butyl hydroperoxide solution (0.179 mL) was added and stirred at room temperature for 20 minutes. To the reaction mixture was added an aqueous solution (0.12 mL) of sodium thiosulfate pentahydrate (0.12 g), and the reaction mixture was concentrated under reduced pressure. To the residue was added 80% aqueous acetic acid (3 mL) and stirred at room temperature for 1 hour. Acetonitrile was added to the residue and an azeotropic operation was performed twice. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give a crude product (420 mg) containing the title compound.
MS: [M + H] ⁺ 1132.3.

G) N- (8-((5R, 7R, 8R, 12aR, 14S, 15S, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyano) Ethoxy) -2-hydroxy-7- (2-((2-methylpropanoyl) amino) -6-oxo-1,6-dihydro-9H-purin-9-yl) -2,10-dioxide octahydro -12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) pyrazolo [1,5-a] [1,3,5] Triazin-4-yl) benzamide
(2R, 3R, 4S, 5S) -5- (4-benzamidopyrazolo [1,5-a] [1,3,5] triazin-8-yl) -4-((tert-butyldimethylsilyl) oxy ) -2-((((((2R, 3R, 4R, 5R) -4-((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) -2- (2-isobutylamido-6-oxo) -1H-Purine-9 (6H) -yl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphoryl) oxy) methyl) tetrahydrofuran-3-yl Dehydrated to crude product containing hydrogen phosphonate (430 mg) Acetonitrile was added and the azeotropic operation was carried out twice. To the resulting residue was added dehydrated pyridine, and an azeotropic operation was performed once. To a solution of the obtained residue in dehydrated pyridine (3 mL) was added 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (245 mg), and the mixture was allowed to stand at room temperature under an argon atmosphere for 10 minutes. It stirred. Water (0.239 mL) and iodine (125 mg) were added to the reaction mixture, and stirred at room temperature for 20 minutes. To the reaction mixture was added an aqueous solution (0.4 mL) of sodium thiosulfate pentahydrate (245 mg), and the mixture was stirred at room temperature for 5 minutes, then toluene was added, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give a crude product (553 mg) containing the title compound.
MS: [M + H] ^< +> 1130.4.

H) 2-Amino-9-((5R, 7R, 8R, 12aR, 14S, 15S, 15aS, 16R) -14- (4-aminopyrazolo [1,5-a] [1,3,5] triazine-8 Yl) -2,10,15,16-tetrahydroxy-2,10-dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2 , 10] Pentaoxadiphosphacyclotetradecyne-7-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt
N- (8-((5R, 7R, 8R, 12aR, 14S, 15S, 15aR, 16R) -15,16-bis ((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy) -2-Hydroxy-7- (2-((2-methylpropanoyl) amino) -6-oxo-1,6-dihydro-9H-purin-9-yl) -2,10-dioxideoctahydro-12H -5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) pyrazolo [1,5-a] [1 A mixture of (3,5] triazin-4-yl) benzamide (553 mg) and 33% methylamine in ethanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate), and further separated by HPLC (ODS, mobile phase: water / acetonitrile (containing 5 mM ammonium acetate)) The obtained fraction was concentrated under reduced pressure. Triethylamine trihydrofluoride (0.072 mL) was added to a solution of the obtained residue in methanol (3 mL) at room temperature, and the mixture was stirred at 50 ° C. for 4 hours. Triethylamine trihydrofluoride (0.181 mL) was added to the reaction mixture at room temperature and stirred at 50 ° C. overnight. Triethylamine trihydrofluoride (0.181 mL) was added to the reaction mixture at room temperature and stirred at 50 ° C. for 5 hours. To the reaction mixture was added ethoxytrimethylsilane (1.034 mL) at room temperature and stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile) and lyophilized to give the title compound (10 mg).
¹ H NMR (300 MHz, D ₂ O) δ 3.99-4.08 (1H, m), 4.11-4.31 (4H, m), 4.34-4.42 (1H, m), 4.52-4.60 (2H, m), 4.94- 5.05 (1H, m), 5.27-5.35 (1H, m), 5.51-5.62 (1H, m), 5.94 (1H, d, J = 8.3 Hz), 7.89 (1H, s), 8.07 (1H, s) , 8.08 (1 H, s).

Example 14
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-16-hydroxy-2,10-dioxide -2,10-Disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl ) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one disodium salt (optical isomer)

A) (2R, 3R, 4R, 5R) -5-((((((2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-fluoro-2 -(Hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -2- (5-fluoro-4-) Oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate
7- (3-O- (tert-Butyl (dimethyl) silyl) -2-O- (hydroxy (oxide) phosphoranyl) -beta-D-ribofuranosyl) -5-fluoro-3,7-dihydro-4H-pyrrolo [ 2,3-d] pyrimidin-4-one (8.89 g) and N-benzoyl-5'-O- (bis (4-methoxyphenyl) (phenyl) methyl) -3'-O-((2-cyanoethoxy) Dehydrated acetonitrile was added to (diisopropylamino] phosphino) -2'-deoxy-2'-fluoroadenosine (18.5 g), and azeotropic operation was carried out three times: anhydrous acetonitrile (40 mL), anhydrous THF (20 g) mL) and a solution of 5- (ethylsulfanyl) -2H-tetrazole (7.49 g) in anhydrous acetonitrile (40 mL) were added The reaction mixture was stirred at room temperature under argon for 30 minutes, ((dimethylaminomethylidene) Amino) -3H-1,2,4-dithiazolin-3-thione (4.33 g) was added to the reaction mixture and stirred at room temperature for 30 minutes Sodium thiosulfate (5.24 g) in the reaction mixture Aqueous solution (5 mL) was added and concentrated under reduced pressure.80% aqueous acetic acid solution (100 mL) was added to the residue and stirred at room temperature for 1 hour, then toluene was added to the reaction mixture to carry out azeotropic operation The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (14.3 g).
MS: [M + H] ⁺ 968.3.

B) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -16-((tert-butyl (dimethyl) silyl) oxy) -2- (2-cyanoethoxy)- 15-Fluoro-7- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -10-oxide-10-sulfanyl-2-sulfide octa Hydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purine-6- I) benzamide (optical isomer)
((2R, 3R, 4R, 5R) -5-((((((2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-fluoro-2- ( Hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorothioyl) oxy) methyl) -4-((tert-butyldimethylsilyl) oxy) -2- (5-fluoro-4-oxo- Dehydrated pyridine was added to 3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate (1.07 g), and azeotropic operation was performed three times. To a solution of the residue in anhydrous pyridine (150 mL) was added 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (4.66 g), and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. . To the reaction mixture was added 3H-benzo [c] [1,2] dithiole-3-one (1.46 g) and water (4.55 mL) at room temperature, and the reaction mixture was stirred for 30 minutes. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (methanol / ethyl acetate), and then subjected to HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile) The fractions with the largest retention time were concentrated under reduced pressure to give the title compound (379 mg).
MS: [M + H] ^< +> 982.1.

C) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -16-((tert-butyl (dimethyl) silyl) ) Oxy) -15-fluoro-2,10-dioxide-2,10-disulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,2, 10] Pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -16-((tert-butyl (dimethyl) silyl) oxy) -2- (2-cyanoethoxy) -15- Fluoro-7- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -10-oxide-10-sulfanyl-2-sulfide octahydro- 12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) A solution of benzamide (optical isomer) (379 mg) in 40% methylamine methanol (10 mL) was stirred at room temperature for 3 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (319 mg).
MS: [M + H] ⁺ 825.1.

D) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-16-hydroxy-2,10 -Dioxide-2,10-disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 -Yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -16-((tert-butyl (dimethyl) silyl) oxy ) -15-Fluoro-2,10-dioxide-2,10-disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] Pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer) (319 mg) in methanol ( 1 mL) Triethylamine trihydrofluoride (2.52 mL) was added to the solution at room temperature, stirred at 50 ° C. for 3 hours, and then diluted with methanol (10 mL). To the reaction mixture was added ethoxytrimethylsilane (12 mL) at room temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure and the residue was diluted with methanol and then concentrated again. To the residue was added triethylammonium acetate buffer, the solid was filtered off, and the solid was washed with acetonitrile to give a white solid. The resulting white solid was purified by silica gel column chromatography (ODS, 10 mM triethylammonium acetate buffer / acetonitrile). Meanwhile, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) and silica gel column chromatography (ODS, 10 mM triethylammonium acetate buffer / acetonitrile). The fraction containing the title compound obtained by silica gel column chromatography (ODS, 10 mM triethylammonium buffer / acetonitrile) was concentrated under reduced pressure and lyophilized to give the title compound (195 mg).
MS: [M + H] ^< +> 711.0.

E) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-16-hydroxy-2,10 -Dioxide-2,10-disulfanyloctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 -Yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one disodium salt (optical isomer)
Deionized water (60 mL) was permeated through a column in which an empty column was packed with AG (trade name) 50W-X8 cation exchange resin (100-200 mesh, 3.9 g). Furthermore, 1 M aqueous sodium hydroxide solution (36 mL) and deionized water (68 mL) were permeated. 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro- was added to the resin subjected to the above pretreatment. 16-hydroxy-2,10-dioxide-2,10-disulfanyl octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxa Diphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2triethylamine salt (optical isomer) (195 mg) After deionized water (15 mL) was permeated, deionized water (19 mL) was permeated, and the obtained aqueous solution was lyophilized to give the title compound (165 mg).
¹ H NMR (300 MHz, D ₂ O) δ 4.00-4.08 (1 H, m), 4.22-4. 45 (4 H, m), 4.50-4. 57 (1 H, m), 4.81-4. 84 (1 H, m), 4. 98- 5.14 (2H, m), 5.40-5.61 (1H, m), 6.33-6.43 (2H, m), 7.28 (1H, d, J = 1.9 Hz), 7.94 (1H, s), 8.05 (1H, s) , 8.21 (1 H, s).
³¹ P NMR (121 MHz, D ₂ O) δ 52.1, 55.3.

Example 15
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-2,16-dihydroxy-2,10 -Dioxide-10-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)

A) 5-fluoro-7-((6aR, 8R, 9R, 9aS) -9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3, 5,2,4] Trioxadisilosin-8-yl) -3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
7-((2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -5-fluoro-3H-pyrrolo [2,3-d] pyrimidine-4 ( To a solution of 7H) -one (37.9 g) in pyridine (760 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (44.4 mL), and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. did. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with IPE and stirred at room temperature overnight. The solid was collected by filtration to give the title compound (32.3 g). The mother liquor was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (13.3 g).
MS: [M + H] ⁺ 528.2.

B) 2-Cyanoethyl (6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidine-7 (4H) -yl) -2,2,6 4,4-Tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl diisopropyl phosphoramidite
5-fluoro-7-((6aR, 8R, 9R, 9aS) -9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5, 2,4] trioxadisilosin-8-yl) -3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (20 g) is azeotropically dehydrated three times with anhydrous acetonitrile, It was dissolved in anhydrous N, N-dimethylformamide (100 mL). To this solution were added 3-((bis (diisopropylamino) phosphino) oxy) propanenitrile (24.1 mL), 1H-tetrazole (2.79 g) and 1-methyl-1H-imidazole (1.65 mL), and the mixture was argon at room temperature. After stirring overnight, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, containing 0.5% triethylamine) to give the title compound (20.8 g) as a mixture of two diastereomers.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.91-1.19 (40H, m), 2.69-2.82 (2H, m), 3.46-3.73 (2H, m), 3.78-4.12 (5H, m), 4.47 -4.61 (2H, m), 6.02-6.12 (1 H, m), 7.14-7.23 (1 H, m), 7.84-7.91 (1 H, m), 12.00-12.40 (1 H, br).

C) (2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -2-((((2-cyanoethoxy) ((((6aR, 8R, 9R, 9aR)) -8- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3, 2-f] [1,3,5,2,4] trioxadisilosin-9-yl) oxy) phosphorothioyl) oxy) methyl) -4-fluorotetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl hydrogen phosphonate (3.48 g) and 2- Cyanoethyl (6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4- A mixture of tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl diisopropyl phosphoramidite (7.82 g) is azeotroped with anhydrous acetonitrile It was dried and suspended in anhydrous acetonitrile (25 mL) and anhydrous THF (15 mL). A solution of 5- (ethylsulfanyl) -2H-tetrazole (3.11 g) which had been previously azeotropically dehydrated with anhydrous acetonitrile dissolved in anhydrous acetonitrile (6 mL) was added to the above suspension, and stirred at room temperature for 1 hour under an argon atmosphere. After that, ((dimethylaminomethylidene) amino) -3H-1,2,4-dithiazoline-3-thione (3.27 g) was added, and the mixture was further stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (6.73 g).
MS: [M + H] ^< +> 1096.2.

D) (2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -2-(((((2R, 3R, 4R, 5R)) -2- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyl) Disiloxanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphorothioyl) oxy) methyl) -4-fluorotetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -2-((((2-cyanoethoxy) ((((6aR, 8R, 9R, 9aR) -8 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2- f) [1, 3, 5, 2, 4] trioxadisilosin-9-yl) oxy) phosphorothioyl) oxy) methyl) 4- fluorotetrahydrofuran-3-yl hydrogen phosphonate (6.73 g) with tetrahydrofuran ( The mixture was dissolved in a mixture of 74.8 mL) and water (16.6 mL) and ice-cooled, trifluoroacetic acid (16.6 mL) was added, and the mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was quenched by adding an aqueous solution of sodium bicarbonate (25.8 g), and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (6.43 g).
MS: [M + H] ⁺ 11142.

E) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -10- (2-cyanoethoxy) -15-fluoro-7- (5-fluoro-4-oxo- 3,4-Dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-16-((3-hydroxy-1,1,3,3-tetra (propan-2-yl) ) Disiloxanyl) oxy) -2- oxide-10-sulfide octahydro-12 H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclo Tetradecyne-14-yl) -9H-purin-6-yl) benzamide
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -2-(((((2R, 3R, 4R, 5R) -2 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyl disiloxane) Sanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphorothioyl) oxy) methyl) -4-fluorotetrahydrofuran-3-yl hydrogen phosphonate (6.43 g) with anhydrous acetonitrile and anhydrous pyridine It was azeotropically dehydrated and suspended in anhydrous pyridine (130 mL). Add 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (3.73 g) and stir at room temperature under argon atmosphere for 1 hour, then add water (5.17 mL) and iodine ( Add 1.90 g) and stir at room temperature for an additional hour. The reaction mixture was quenched with sodium thiosulfate (7.16 g) and water (3.6 mL) and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (4.60 g).
MS: [M + H] ⁺ 11122.

F) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-2-hydroxy-16- ( (3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -2,10-dioxide-10-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [ 1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidine-4 -On (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -10- (2-cyanoethoxy) -15-fluoro-7- (5-fluoro-4-oxo-3, 4-Dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-16-((3-hydroxy-1,1,3,3-tetra (propan-2-yl) disiloxanyl) ) Oxy) -2-oxide-10-sulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne A 40% methylamine methanol solution (30 mL) was added to -14-yl) -9H-purin-6-yl) benzamide (6.42 g), and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. The resulting mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (methanol / ethyl acetate), and the resulting residue is HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM acetic acid The reaction mixture was purified with aqueous ammonium solution / acetonitrile), and the obtained fraction was concentrated under reduced pressure and lyophilized to give the title compound (420 mg).
MS: [M + H] ⁺ 955.2.

G) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-2,16-dihydroxy-2 10-Dioxide-10-sulfanyloctahydro-12H-5 8,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7- ) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-fluoro-2-hydroxy-16-((3 -Hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -2,10-dioxide-10-sulfanyloctahydro-12H-5,8-methanofuro [3,2-l] [1,1 3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (Optical isomer, derived from tR2) (420 mg) was added triethylamine trihydrofluoride (9.68 mL), and the mixture was stirred at 50 ° C. for 7 and a half hours. To the reaction mixture was added ethoxytrimethylsilane (36.3 mL) at room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile) and lyophilized to give the title compound (298 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.13-1.29 (16 H, m), 3. 12 (11 H, q, J = 7.2 Hz), 3.99-4.29 (4 H, m), 4.3 1-4. 43 (2 H, m) ), 4.50 (1H, d, J = 9.1 Hz), 4.81-5.08 (3H, m), 5.39-5.61 (1H, m), 6.30-6.42 (2H, m), 7.24 (1H, d, J = 1.9) Hz), 7.92 (1 H, s), 8.09 (1 H, s), 8. 19 (1 H, s).
³¹ P NMR (121 MHz, D ₂ O) δ 52.2, 1.63.

Example 16
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,10,18-trihydroxy-2,10- Dioxide hexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecine -7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2triethylamine salt (optical isomer)

A) (1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-((((2-cyanoethoxy) ((((6aR, 8R, 9R, 9aR)) -8- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3, 2-f] [1,3,5,2,4] trioxadisilosin-9-yl) oxy) phosphoryl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl Hydrogen phosphonate
(1S, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1- (hydroxymethyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl Hydrogen phosphonate (2.00 g) and 2-cyanoethyl (6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidine-7 (4H) -yl) -2,2,4,4-Tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl diisopropyl phosphoramidite (4.23 g) Was azeotropically dehydrated with anhydrous acetonitrile (about 50 mL, 3 times) and suspended in anhydrous THF (16 mL). Dissolve 5- (ethylsulfanyl) -2H-tetrazole (1.75 g) azeotropically dehydrated beforehand with anhydrous acetonitrile (about 30 mL, 3 times) in anhydrous acetonitrile (16 mL), add to the above suspension, and flow argon After stirring at room temperature for 15 hours, 70% tert-butyl hydroperoxide (1.86 mL) was added, and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was quenched with 10% aqueous sodium thiosulfate solution (13 mL) and concentrated under reduced pressure. After azeotropic dehydration with acetonitril (about 80 mL) and toluene (about 80 mL), the residue is subjected to silica gel column chromatography (methanol / ethyl acetate), and the target fraction is concentrated under reduced pressure to give the title compound. (5.36 g) was obtained as a white amorphous (mixture of 2 diastereomers).
MS: [M + H] ^< +> 1090.2.

B) (1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-(((((2R, 3R, 4R, 5R)) -2- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyl) Disiloxanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphoryl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl hydrogen phosphonate
(1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-((((2-cyanoethoxy) ((((6aR, 8R, 9R, 9aR) -8 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2- f] [1,3,5,2,4] trioxadisilosin-9-yl) oxy) phosphoryl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl hydrogen phosphonate (5.36 g) was dissolved in a mixture of THF (60 mL) and water (13 mL) and ice cooled, trifluoroacetic acid (13.18 mL) was added, and the mixture was stirred at 0 ° C. for 4 hours. The reaction mixture was quenched portionwise with a solution of sodium bicarbonate (20.65 g) in water (250 mL), then saturated with brine and extracted with ethyl acetate-THF (3: 1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / ethyl acetate), and the target fraction was concentrated under reduced pressure to give the title compound (3.06 g) as a white amorphous (a mixture of two diastereomers).
MS: [M + H] ⁺ 11083.

C) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -10- (2-cyanoethoxy) -7- (5-fluoro-4-oxo-3,4-) Dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-18-((3-hydroxy-1,1,3,3-tetra (propan-2-yl) disiloxanyl) oxy ) -2,10-Dioxidehexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] penta) Oxadiphosphacyclotetradecyne-14 (12H) -yl) -9H-purin-6-yl) benzamide
(1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-(((((2R, 3R, 4R, 5R) -2 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyl disiloxane) Sanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphoryl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl hydrogen phosphonate (3.06 g) Was sequentially azeotropically dehydrated with anhydrous acetonitrile (about 100 mL) and anhydrous pyridine (about 100 mL), and dissolved in anhydrous pyridine (75 mL). Add 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (1.78 g) and stir at room temperature for 1 hour under argon flow, then add water (1.74 mL) and iodine ( 911 mg) was added and stirred for another 15 minutes at room temperature. The reaction mixture was quenched with 10% aqueous sodium thiosulfate solution (7.5 mL) and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate-THF (3: 1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Toluene (about 100 mL) is added and the mixture is concentrated again under reduced pressure, and the residue is subjected to silica gel column chromatography (methanol / ethyl acetate), and the target fraction is concentrated under reduced pressure to give the title compound (2.38 g) as a white It was obtained as amorphous (a mixture of two diastereomers).
MS: [M + H] ⁺ 11063.

D) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,10-dihydroxy-18-((3 -Hydroxy-1,1,3,3-tetra (propan-2-yl) disiloxanyl) oxy) -2,10-dioxidehexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [ 3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -10- (2-cyanoethoxy) -7- (5-fluoro-4-oxo-3,4-dihydro- 7H-Pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-18-((3-hydroxy-1,1,3,3-tetra (propan-2-yl) disiloxanyl) oxy)- 2,10-Dioxidehexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadipho Dissolve sfacyclotetradecin-14 (12H) -yl) -9H-purin-6-yl) benzamide (2.38 g) in 40% methylamine methanol solution (40 mL), stir at room temperature for 1 hour, and mix the reaction mixture It concentrated under reduced pressure. Toluene (about 80 mL) is added and the mixture is concentrated again under reduced pressure, and the residue is subjected to silica gel column chromatography (methanol / ethyl acetate), and the target fraction is concentrated under reduced pressure to give the title compound (756 mg) as a white Obtained as a solid.
MS: [M + H] ⁺ 949.2.

E) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,10,18-trihydroxy-2, 10-Dioxide hexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclo Tetradecin-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,10-dihydroxy-18-((3-hydroxy) -1,1,3,3-Tetra (propan-2-yl) disiloxanyl) oxy) -2,10-dioxidehexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3 ,, 2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2 Dissolve [3-d] pyrimidin-4-one (756 mg) in methanol (2 mL) and triethylamine (0.8 mL), add triethylamine trihydrofluoride (3.90 mL), and stir at 50 ° C for 2 hours The The reaction mixture was cooled to room temperature, neutralized with 1 M aqueous triethylammonium hydrogen carbonate solution (110 mL), and stirred at room temperature for 15 minutes. The reaction mixture is concentrated under reduced pressure, and the residue is subjected to ODS column chromatography (acetonitrile / 10 mM triethylammonium acetate buffer), and the target fraction is concentrated under reduced pressure and lyophilized to give the title compound (504 mg) Obtained as a white solid.
¹ H NMR (300 MHz, D ₂ O) δ 1.20 (18 H, t, J = 7.4 Hz), 3. 12 (12 H, q, J = 7.2 Hz), 4.02-4.16 (4 H, m), 4.23-4. 37 (3 H , m), 4.55 (1 H, d, J = 4.5 Hz), 4.82-4.93 (3 H, m), 6.12 (1 H, s), 6. 39 (1 H, dd, J = 8.3, 1.5 Hz), 7.19 (1 H, 1 d, J = 1.9 Hz), 7.96 (1 H, s), 8.11 (1 H, s), 8. 17 (1 H, s).
^{31 P NMR (121 MHz, D} 2 O) δ -1.91, -1.80.

Example 17
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -10,18-dihydroxy-2,10-dioxide-2 -Sulfanylhexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecine -7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2triethylamine salt (optical isomer)

A) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -10- (2-cyanoethoxy) -7- (5-fluoro-4-oxo-3,4-) Dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -18-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -2,10-dioxide -2-sulfanylhexahydro-14H-15, 12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclo Tetradecin-14 (12H) -yl) -9H-purin-6-yl) benzamide
(1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-(((((2R, 3R, 4R, 5R) -2 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyl disiloxane) Sanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphoryl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl hydrogen phosphonate (3.71 g) Was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, and suspended in anhydrous pyridine (70 mL). After adding 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (2.15 g) and stirring at room temperature under an argon atmosphere for 1 hour, 3H-benzo [c] [1 , 2] Dithiol-3-one (674 mg) was added and stirred at room temperature for another hour. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, 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 residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (2.78 g).
MS: [M + H] ⁺ 1122.2

B) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -10-hydroxy-18-((3-hydroxy) -1,1,3,3-Tetraisopropyldisiloxanyl) oxy) -2,10-dioxide-2-sulfanylhexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3 ,, 2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2 , 3-d] Pyrimidin-4-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -10- (2-cyanoethoxy) -7- (5-fluoro-4-oxo-3,4-dihydro- 7H-Pyrrolo [2,3-d] pyrimidin-7-yl) -18-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -2,10-dioxide-2 -Sulfanylhexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecine -14 (12H) -yl) -9H-purin-6-yl) benzamide (2.78 g) is dissolved in 40% methylamine methanol solution (50 mL) and stirred at room temperature under argon atmosphere for 1 hour, Was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained residue was purified by HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile) to give the title compound (30 mg).
MS: [M + H] ⁺ 965.3.

C) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -10,18-dihydroxy-2,10-dioxide -2-sulfanylhexahydro-14H-15, 12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclo Tetradecin-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -10-hydroxy-18-((3-hydroxy-1 1,1,3,3-Tetraisopropyldisiloxanyl) oxy) -2,10-dioxide-2-sulfanylhexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2- l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3 -d] Pyrimidin-4-one (optical isomer) (30 mg) was added with triethylamine trihydrofluoride (0.70 mL) and methanol (1 mL), and the mixture was stirred at 50 ° C for 3 hours. To the reaction solution was added ethoxy (trimethyl) silane (2.5 mL), and the mixture was stirred at room temperature for 30 minutes, and then the solvent was evaporated under reduced pressure. The residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile), and the obtained solid was lyophilized to give the title compound (25 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.19 (18 H, t, J = 7.4 Hz), 3.11 (12 H, q, J = 7.2 Hz), 3.99-4.09 (3 H, m), 4.09-4.17 ( 2H, m), 4.22-4.29 (1H, m), 4.34-4.38 (1H, m), 4.50-4.54 (2H, m), 4.90-4.96 (1H, m), 5.06 (1H, s), 6.11 ( 1H, s), 6.35 (1H, dd, J = 8.3, 1.1 Hz), 7.19 (1H, d, J = 2.3 Hz), 7.94 (1H, s), 8.08 (1H, s), 8.16 (1H, s) ).
³¹ P NMR (121 MHz, D ₂ O) δ 55.76, -1.56.

Example 18
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,18-dihydroxy-2,10-dioxide-10 -Sulfanylhexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecine -7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2triethylamine salt (optical isomer)

A) (1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-((((2-cyanoethoxy) ((((6aR, 8R, 9R, 9aR)) -8- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3, 2-f] [1,3,5,2,4] trioxadisilosin-9-yl) oxy) phosphorothioyl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7 -Yl hydrogen phosphonate
(1S, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1- (hydroxymethyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl Hydrogen phosphonate (3.0 g) and 2-cyanoethyl (6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-Tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl diisopropyl phosphoramidite (5.86 g) The reaction mixture was azeotropically dehydrated with anhydrous acetonitrile and suspended in anhydrous THF (25 mL). Dissolve 5- (ethylsulfanyl) -2H-tetrazole (2.62 g) previously azeotropically dehydrated with anhydrous acetonitrile in anhydrous acetonitrile (25 mL) and add to the above suspension, and stir at room temperature overnight under an argon atmosphere Then, ((dimethylaminomethylidene) amino) -3H-1,2,4-dithiazoline-3-thione (2.75 g) was added, and the mixture was further stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (4.96 g).
MS: [M + H] ⁺ 11063.

B) (1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-(((((2R, 3R, 4R, 5R)) -2- (5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyl) Disiloxanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphorothioyl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl hydrogen phosphonate
(1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-((((2-cyanoethoxy) ((((6aR, 8R, 9R, 9aR) -8 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2- f] [1,3,5,2,4] trioxadisilosin-9-yl) oxy) phosphorothioyl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl Hydrogen phosphonate (4.96 g) was dissolved in a mixture of THF (60 mL) and water (12 mL) and ice cooled, trifluoroacetic acid (12.1 mL) was added, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was quenched by adding a solution of sodium bicarbonate (18.8 g) in water (100 mL), and then extracted with ethyl acetate-THF (3: 1). After drying over sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (3.77 g).
MS: [M + H] ⁺ 1124.2.

C) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -10- (2-cyanoethoxy) -7- (5-fluoro-4-oxo-3,4-) Dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-18-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -10 -Oxide-2-sulfide hexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadipho Sphacyclotetradecyne-14 (12H) -yl) -9H-purin-6-yl) benzamide
(1R, 3R, 4R, 7S) -3- (6-benzamido-9H-purin-9-yl) -1-(((((2R, 3R, 4R, 5R) -2 -(5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyl disiloxane) Sanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphorothioyl) oxy) methyl) -2,5-dioxabicyclo [2.2.1] heptane-7-yl hydrogen phosphonate (3.77 g) was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, and suspended in anhydrous pyridine (70 mL). Add 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (2.17 g) and stir at room temperature under argon atmosphere for 1 hour, then add water (2.12 mL) and iodine ( Add 1.11 g) and stir at room temperature for another hour. The reaction mixture was quenched with 10% aqueous sodium thiosulfate solution (15 mL), and the solvent was evaporated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate-THF (3: 1). The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (2.21 g).
MS: [M + H] ⁺ 1122.2.

D) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,10-dihydroxy-18-((3 -Hydroxy-1,1,3,3-tetra (propan-2-yl) disiloxanyl) oxy) -2,10-dioxidehexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [ 3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -10- (2-cyanoethoxy) -7- (5-fluoro-4-oxo-3,4-dihydro- 7H-Pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-18-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -10-oxide -2-Sulphide hexahydro-14H-15, 12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclo A 40% methylamine methanol solution (40 mL) was added to tetradecin-14 (12H) -yl) -9H-purin-6-yl) benzamide (2.38 g), and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. The resulting mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (methanol / ethyl acetate), and the resulting residue is HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM acetic acid The reaction mixture was purified with aqueous ammonium solution / acetonitrile), and the obtained fraction was concentrated under reduced pressure and lyophilized to give the title compound (710 mg).
MS: [M + H] ⁺ 965.2.

E) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,18-dihydroxy-2,10-dioxide -10-sulfanylhexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclo Tetradecin-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 18R) -14- (6-amino-9H-purin-9-yl) -2,10-dihydroxy-18-((3-hydroxy) -1,1,3,3-Tetra (propan-2-yl) disiloxanyl) oxy) -2,10-dioxidehexahydro-14H-15,12a- (epoxymethano) -5,8-methanofuro [3 ,, 2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7 (12H) -yl) -5-fluoro-3,7-dihydro-4H-pyrrolo [2 Triethylamine trihydrofluoride (4.80 mL) is added to a solution of (3-d) pyrimidin-4-one (optical isomer, derived from tR2) (710 mg) in methanol (20 mL), and the reaction is continued for 3 hours at 50 ° C. It stirred. To the reaction mixture was added ethoxytrimethylsilane (2.29 mL) at room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile) and lyophilized to give the title compound (530 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.22 (18 H, t, J = 7.2 Hz), 3. 14 (12 H, q, J = 7.6 Hz), 4.03-4.19 (4 H, m), 4.25-4. 41 (4 3H, m), 4.65 (1 H, d, J = 4.5 Hz), 4. 84 (1 H, d, J = 4.5 Hz), 4.91 (1 H, s), 4.99 (1 H, ddd, J = 10.1, 8.2, 4.3 Hz ), 6.14 (1H, s), 6.39 (1H, d, J = 7.9 Hz), 7.17 (1H, d, J = 2.3 Hz), 7.97 (1H, s), 8.11 (1H, s), 8.19 (1H) , s).
³¹ P NMR (121 MHz, D ₂ O) δ 52.5, 1.74.

Example 19
2-amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15-fluoro-7- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [ 2,3-d] pyrimidin-7-yl) -2,10,16-trihydroxy-2,10-dioxideoctahydro-12H-5,8-methanofuro [3,2-l] [1,3,3 6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt (optical isomer)

A) (2R, 3R, 4R, 5R) -2-((((2-cyanoethoxy) (((6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [ 2,3-d] Pyrimidine-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trio Xadisicillin-9-yl) oxy) phosphoryl) oxy) methyl) -4-fluoro-5- (2-isobutyramido-6-oxo-1H-purin-9 (6H) -yl) tetrahydrofuran-3-yl hydrogen Phosphonate
2'-Deoxy-2'-fluoro-3'-O- (hydroxy (oxide) phosphoranyl) -N-isobutyrylguanosine (680 mg) and 2-cyanoethyl (6aR, 8R, 9R, 9aR) -8- ( 5-Fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] Trioxadisilosin-9-yl diisopropyl phosphoramidite (1535 mg) was azeotropically dehydrated with anhydrous acetonitrile (3 times) and suspended in anhydrous THF (10.00 ml) . To the mixture was added a mixture of anhydrous acetonitrile and azeotropically dehydrated 5- (ethylsulfanyl) -2H-tetrazole (633 mg) and anhydrous acetonitrile (10 ml), and the mixture was stirred at room temperature for 7 hours under an argon atmosphere. 2-Cyanoethyl (6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidine-7 (4H)-, azeotropically dehydrated with anhydrous acetonitrile into a mixture Yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl diisopropyl phosphoramidite (1181 Add a mixture of mg, 1.62 mmol) and anhydrous acetonitrile (3 ml) and a mixture of anhydrous acetonitrile and azeotropically dehydrated 5- (ethylsulfanyl) -2H-tetrazole (633 mg) and anhydrous acetonitrile (3 ml) under argon atmosphere The mixture was stirred at room temperature overnight. To the reaction mixture, 70% tert-butyl hydroperoxide (0.674 mL) was added and stirred at room temperature for another 30 minutes. After a mixture of sodium thiosulfate pentahydrate (2817 mg) and water (4 mL) was added to the reaction mixture, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1260 mg).
MS: [M + H] ^< +> 1062.3.

B) (2R, 3R, 4R, 5R) -2-((((2-cyanoethoxy) (((2R, 3R, 4R, 5R) -2- (5-fluoro-4-oxo-3H-pyrrolo [ 2,3-d] Pyrimidine-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran- 3-yl) oxy) phosphoryl) oxy) methyl) -4-fluoro-5- (2-isobutylamido-6-oxo-1H-purin-9 (6H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -2-((((2-cyanoethoxy) (((6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2, 3-d] Pyrimidine-7 (4H) -yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadi (Silocin-9-yl) oxy) phosphoryl) oxy) methyl) -4-fluoro-5- (2-isobutyramido-6-oxo-1H-purin-9 (6H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate ( Trifluoroacetic acid (3.18 ml) was added to a mixture of 1.26 g), THF (16 ml) and water (4 ml) at 0 ° C. and stirred for 4 hours. To the mixture was added an aqueous solution of sodium hydrogen carbonate (4.98 g) and then saturated with sodium chloride. The mixture was extracted with ethyl acetate / THF, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (1000 mg).
MS: [M + H] ⁺ 1080.3.

C) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -10- (2-cyanoethoxy) -15-fluoro-7- (5-fluoro-4-oxo- 3,4-Dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-16-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) Oxy) -2,10-dioxideoctahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14 -Yl) -6-oxo-6,9-dihydro-1H-purin-2-yl) -2-methylpropanamide
(2R, 3R, 4R, 5R) -2-((((2-cyanoethoxy) (((2R, 3R, 4R, 5R) -2- (5-fluoro-4-oxo-3H-pyrrolo [2, 3-d] Pyrimidine-7 (4H) -yl) -4-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3- (I) oxy) phosphoryl) oxy) methyl) -4-fluoro-5- (2-isobutyramido-6-oxo-1H-purine-9 (6H) -yl) tetrahydrofuran-3-yl hydrogen phosphonate (1 g) It was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, and suspended in anhydrous pyridine (24 mL). After adding 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (598 mg) and stirring at room temperature under argon atmosphere for 15 minutes, water (0.584 mL) and iodine ( 305 mg) was added and stirred for another 25 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (800 mg).
MS: [M + H] ⁺ 1078.2

D) 2-Amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15-fluoro-7- (5-fluoro-4-oxo-3,4-dihydro-7H- Pyrrolo [2,3-d] pyrimidin-7-yl) -2,10-dihydroxy-16-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -2,10 -Dioxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -1, 9-dihydro-6H-purin-6-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -10- (2-cyanoethoxy) -15-fluoro-7- (5-fluoro-4-oxo-3, 4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-16-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -2,10-Dioxideoctahydro-12H-5,8-Methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl 33% methylamine ethanol solution (30 mL) was added to) -6-oxo-6,9-dihydro-1H-purin-2-yl) -2-methylpropanamide (800 mg, 0.74 mmol), and then under argon atmosphere After stirring overnight at room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained residue was purified by HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM aqueous ammonium acetate solution / acetonitrile) to give the title compound (163.4 mg).
MS: [M + H] ⁺ 955.3.

E) 2-Amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15-fluoro-7- (5-fluoro-4-oxo-3,4-dihydro-7H- Pyrrolo [2,3-d] pyrimidin-7-yl) -2,10,16-trihydroxy-2,10-dioxideoctahydro-12H-5,8-methanofuro [3,2-l] [1,1 3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -1,9-dihydro-6H-purin-6-one 2-triethylamine salt (optical isomer)
2-amino-9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15-fluoro-7- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [ 2,3-d] pyrimidin-7-yl) -2,10-dihydroxy-16-((3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -2,10-di Oxide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -1,9- A mixture of dihydro-6H-purin-6-one (optical isomer) (21.4 mg), triethylamine trihydrofluoride (0.183 mL) and methanol (0.07 mL) was stirred at 50 ° C. for 1 hour under an argon atmosphere. To the reaction mixture was added ethoxy (trimethyl) silane (1.046 mL), and the mixture was further stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile) and lyophilized to give the title compound (4.6 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.20 (18 H, t, J = 7.3 Hz), _3. ¹³ (12 H, q, J = 7.3 Hz), 4.07 (2 H, d, J = 11.1 Hz), 4.25 (4 2H, d, J = 7.6 Hz), 4.33-4.99 (4 H, m), 5.04-5.25 (1 H, m), 5.41-5. 70 (1 H, m), 6.17 (1 H, d, J = 19.0 Hz), 6.38 (1H, d, J = 9.2 Hz), 7.32 (1 H, s), 7.79 (1 H, brs), 7.95 (1 H, s).
³¹ P NMR (121 MHz, D ₂ O) δ -1.61, -1.52.

Example 20
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -2,10,15,16-tetrahydroxy-2- Oxide-10-sulfide octahydro-12H-5, 8-methanofuro [3, 2-1] [1, 3, 6, 9, 11, 2, 10] pentaoxadiphosphacyclotetradecyne-7-yl)- 5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)

A) (2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyldimethylsilyl) oxy) -2-((((2-cyano) Ethoxy) (((6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4 2,4-Tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl) oxy) phosphorothioyl) oxy) methyl) tetrahydrofuran-3 -Yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyldimethylsilyl) oxy) -2- (hydroxymethyl) tetrahydrofuran-3-yl Hydrogen phosphonate (3.0 g) and 2-cyanoethyl (6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4-Tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl diisopropyl phosphoramidite (5.36 g) The mixture was azeotropically dehydrated with anhydrous acetonitrile and suspended in anhydrous acetonitrile (25 mL) and anhydrous THF (15 mL). Dissolve 5- (ethylsulfanyl) -2H-tetrazole (2.13 g) previously azeotropically dehydrated with anhydrous acetonitrile in anhydrous acetonitrile (15 mL) and add to the above suspension, and stir at room temperature overnight under an argon atmosphere Then, ((dimethylaminomethylidene) amino) -3H-1,2,4-dithiazoline-3-thione (2.24 g) was added, and the mixture was further stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (5.15 g).
MS: [M + H] ^< +> 1208.3.

B) (2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyldimethylsilyl) oxy) -2-((((2-cyano) Ethoxy) ((((2R, 3R, 4R, 5R) -2- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3 -Hydroxy-1,1,3,3-tetraisopropyldisiloxanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) phosphorothioyl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyldimethylsilyl) oxy) -2-((((2-cyanoethoxy) (((6aR, 8R, 9R, 9aR) -8- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -2,2,4,4 -Tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilosin-9-yl) oxy) phosphorothioyl) oxy) methyl) tetrahydrofuran-3-yl Hydrogen phosphonate (5.15 g) was dissolved in a mixture of THF (48 mL) and water (10 mL) and ice cooled, trifluoroacetic acid (11.5 mL) was added, and the mixture was stirred at 0 ° C. for 3 hours. The reaction mixture was quenched by adding a solution of sodium bicarbonate (12.5 g) in water (100 mL), and then extracted with ethyl acetate-THF. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (5.13 g).
MS: [M + H] ^< +> 1226.4.

C) N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15-((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy)- 7- (5-Fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-16-((3-hydroxy-1,1 ,, 3,3-Tetra (propan-2-yl) disiloxanyl) oxy) -2-oxide-10-sulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9, 11,2,10] pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide
(2R, 3R, 4R, 5R) -5- (6-benzamido-9H-purin-9-yl) -4-((tert-butyldimethylsilyl) oxy) -2-((((2-cyanoethoxy) (((2R, 3R, 4R, 5R) -2- (5-fluoro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-7 (4H) -yl) -4-((3-hydroxy) -1,1,3,3-Tetraisopropyldisiloxanyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) phosphorothioyl) oxy) methyl) tetrahydrofuran-3-yl hydrogen phosphonate (5.13 g) was azeotropically dehydrated with anhydrous acetonitrile and anhydrous pyridine, and suspended in anhydrous pyridine (100 mL). Add 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinan 2-oxide (2.70 g) and stir at room temperature under argon atmosphere for 1 hour, then add water (2.64 g) and iodine ( Add 1.38 g) and stir at room temperature for another hour. The reaction mixture was quenched with sodium thiosulfate (5.19 g) and water (2.64 g) and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (3.53 g).
MS: [M + H] ^< +> 1224.4.

D) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-(((1,1-dimethylethyl) )) Dimethylsilyl) oxy) octahydro-2, 10-dihydroxy-16-((3-hydroxy-1,1,3,3-tetrakis (1-methylethyl) disiloxanyl) oxy) -2-oxide-10-sulfide- 5,8-Methano-12H-furo [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3, 7-Dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer)
N- (9-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -15-((tert-butyl (dimethyl) silyl) oxy) -10- (2-cyanoethoxy) -7- (5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-hydroxy-16-(((3-hydroxy-1,1,3,) 3-Tetra (propan-2-yl) disiloxanyl) oxy) -2-oxide-10-sulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11, 2, 10] Pentaoxadiphosphacyclotetradecyne-14-yl) -9H-purin-6-yl) benzamide (3.5 g) was added with 40% methylamine methanol solution (50 mL), and 1 at room temperature under argon atmosphere. Stir for hours. The resulting mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (methanol / ethyl acetate), and the resulting residue is HPLC (L-column 2 ODS, 50 × 150 mm, mobile phase: 5 mM acetic acid The reaction mixture was purified with aqueous ammonium solution / acetonitrile), and the obtained fraction was concentrated under reduced pressure and lyophilized to give the title compound (210 mg).
MS: [M + H] ^< +> 1067.4.

E) 7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aS, 16R) -14- (6-amino-9H-purin-9-yl) -2,10,15,16-tetrahydroxy- 2-Oxide-10-sulfide octahydro-12H-5,8-methanofuro [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl ) -5-Fluoro-3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one 2-triethylamine salt (optical isomer)
7-((5R, 7R, 8R, 12aR, 14R, 15R, 15aR, 16R) -14- (6-amino-9H-purin-9-yl) -15-(((1,1-dimethylethyl) dimethyl) Silyl) oxy) octahydro-2,10-dihydroxy-16-((3-hydroxy-1,1,3,3-tetrakis (1-methylethyl) disiloxanyl) oxy) -2-oxide-10-sulfide-5, 8-Methano-12H-furo [3,2-l] [1,3,6,9,11,2,10] pentaoxadiphosphacyclotetradecyne-7-yl) -5-fluoro-3,7- Trihydrofluoric acid in a solution of dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one (optical isomer, derived from tR2) (210 mg) in methanol (1.0 mL) -triethylamine (0.4 mL) The salt (0.962 mL) was added and stirred at 50 ° C. for 2 and a half hours. To the reaction mixture was added ethoxytrimethylsilane (4.59 mL) at room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 silica gel column chromatography (10 mM triethylammonium acetate buffer / acetonitrile) and lyophilized to give the title compound (125 mg).
¹ H NMR (300 MHz, D ₂ O) δ 1.13-1.28 (18 H, m), 3. 12 (12 H, q, J = 7.2 Hz), 4.02-4.11 (1 H, m), 4.13-4.25 (2 H, m) ), 4.27-4.40 (2H, m), 4.46 (1H, d, J = 6.4 Hz), 4.73-4.79 (2H, m), 4.80-4.91 (1H, m), 5.02 (1H, td, J = 8.8) , 4.2 Hz), 6.08 (1 H, d, J = 1.7 Hz), 6. 35 (1 H, d, J = 8.1 Hz), 7. 27 (1 H, d, J = 1.7 Hz), 7. 93 (1 H, s), 8. 14 ( 1H, s), 8.18 (1H, s).
³¹ P NMR (121 MHz, D ₂ O) δ 52.4, 1.21.

  Example compounds are shown in the following table. MS in the table indicates the measured value. The compound of Example 9 was synthesized in the same manner as in Example 8.

Test Example 1
STING binding test assay buffer (Dulbecco's Phosphate-Buffered Saline (Wako Pure Chemical Industries) containing 0.01% fatty acid-free bovine serum albumin (Wako Pure Chemical Industries)), 2 μL of test compound, 4 μL of Streptavidin- Terbium ( Cisbio) and Fluorescein-labeled 2 ', 3'-cGAMP (c [G (2', 5 ') p-2'-Fluo-AHC-A (3', 5 ') p]) (Biolog, Germany), 2 μL of biotinylated STING protein (wild-type, WT) was mixed and left at room temperature for 3 hours (final concentration is Streptavidin-Terbium 1/1000 dilution, FITC-cGAMP 1 μM, biotinylated STING protein 100 nM) . Time-resolved fluorescence resonance energy transfer (TR-FRET) was measured at wavelengths of 520 nm and 486 nm by EnVision (PerkinElmer, Waltham, Mass., US). The ratio of the count at 520 nm divided by the count at 486 nm was used to calculate the inhibition rate of binding of wild-type STING protein to 2 ', 3'-cGAMP by the test compound. The results are shown in Table 2.
The biotinylated STING protein (wild-type (WT)) was prepared by the following method.

<Preparation of Biotinylated Wild-type STING Protein>
ECOS (trade name) Competent E. coli BL21 (DE3) was purchased from Nippon Gene. Ampicillin, kanamycin, NaCl, Glycerol, isopropylthiogalactoside, (+)-Biotin, Imidazole, SEM Nuclease recombinant, and BCA protein assay kit were purchased from Wako Pure Chemical Industries, Ltd. Tryptone, Bacto, Yeast Extract, Bacto from Difco Laboratories, Tris Buffered Saline (TBS) Tablets, pH 7.6 from Takara Bio, Lysozyme (Egg White), 6x Cryst from Seikagaku Corporation, cOmplet (trade name) , EDTA-free Protease Inhibitor Cocktail was purchased from Roche. The Ni-NTA Superflow Cartridge was manufactured by QIAGEN, and the HiLoad 26/60 Superdex 200 pg was manufactured by GE Healthcare.
E. coli BirA was inserted into pRSF1b (Novagen) modified with Multiple Cloning Site, and introduced into ECOS JM109 to construct pRH8 / FLAG-BirA. PET21HH / His-Avi-SUMO-FLAG-hTMEM173 (139-379) (H232R) and pRH8 / FLAG-BirA for Avi tag biotinylation prepared by the method described later in Test Example 2 were used as ECO (trade name) Competent E. At the same time, E. coli BL21 (DE3) was transformed to produce an expression strain of His-Avi-SUMO-FLAG-hSTING (139-379, H232R). This expression strain is added to LB medium (10 g / L Tryptone, 5 g / L Yeast Extract, 5 g / L NaCl) containing 100 μg / L ampicillin and 50 μg / L kanamycin and precultured at 30 ° C. Then, it is extended to TB medium (12 g / L Tryptone, 24 g / L Yeast Extract, 4 mL / L Glycerol, 2.3 g / L KH ₂ PO ₄ , 12.5 g / LK ₂ HPO ₄ ) containing similar antibiotics. And cultured at 37.degree. When the turbidity of the culture reached 500 KU, the culture temperature was lowered to 16 ° C., 0.1 mM isopropylthiogalactoside and 50 μM (+)-Biotin were added, and the culture was further continued for 16 hours.
The culture solution was centrifuged, and the obtained cells were lysed with Lysis Buffer (50 mM TrisHCl, 150 mM NaCl, 20 mM Imidazole, 1 mg / mL Lysozyme, 5 U / mL SEM Nuclease, recombinant, Complete EDTA-free, pH 7.6 After suspension in a), proteins were extracted by sonication. The reagent was added so that the salt concentration of the extract became 300 mM NaCl, and the supernatant was recovered through centrifugation. The supernatant obtained is passed through NiNTA superflow Cartridge equilibrated with Wash Buffer (50 mM TrisHCl, 300 mM NaCl, 20 mM Imidazole, pH 7.6), and after washing the Cartridge with Wash Buffer, Elution Buffer (50 mM TrisHCl, 300) Elution was performed with mM NaCl, 250 mM Imidazole, pH 7.6). This eluate is passed through a HiLoad 26/60 Superdex 200 pg column equilibrated with Storage Buffer (50 mM TrisHCl, 150 mM NaCl, pH 7.6), and the eluted fraction is biotinylated His-Avi-SUMO-FLAG-hSTING ( 139-379, H232R). The protein concentration was measured using a BCA protein assay kit and stored frozen at -80 ° C until use.

  As a result, it became clear that the present compound inhibits the binding of the wild-type STING protein and its natural ligand 2 ', 3'-cGAMP, that is, the wild-type STING protein and the present compound are bound. .

Test example 2
Reporter Gene Assay <Preparation of various plasmids>
(i) Construction of expression plasmid such as human TMEM173 Expression of human STING (also referred to as human TMEM173 in this specification) in E. coli Plasmid For mutagenesis using the human TMEM173 cDNA Clone (GeneCopoeia) as a template Acquired by performing Overlap Extension PCR. First, two types of primers (5'-CCTGGCCCCCAGCTGAGATCTCTG-3 '(C-hTMEM (139 aa) -F) and 5'-GTAAACCCGATCCTTGATGCCAGCACGGTCACCGGTC-3' (hTMEM 173 (H232R) -R)) and two types of primers (5'-CTGCCCCCAGCAGACCAGTGTGGTCGTGCATCAG PCR was performed using -3 '(hTMEM173 (H232R) -F) and 5'-ATAATAGCGGCCGCTCCAAGAAATCGCTGGTGGAGAGG-3' (hTMEM173-st-Not-R). PCR was repeated using PrimeStar MAX DNA Polymerase (Takara Bio) (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds and 72 ° C, 10 seconds 25 times, (3) 72 ° C It reacted for 1 minute. Furthermore, PCR was performed using the obtained fragment as a template and two types of primers (C-hTMEM (139 aa) -F and hTMEM 173-st-Not-R). PCR was performed using PrimeStar GXL DNA Polymerase (Takara Bio) (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds and 72 ° C, 1.5 minutes repeated 35 times, (3) 72 ° C, It reacted for 1 minute. This is digested with Not I (Takara Bio), inserted into the Stu I / Not I site of the vector in which His-Avi-SUMO Tag is added to pET21a (Novagen) using Ligation High (Toyobo), and ECOS JM109 (Nippon Gene) Was introduced to construct pET21HH / His-Avi-SUMO-hTMEM 173 (139-379) (H232R).
Furthermore, PCR was performed using this type of plasmid as a template and two types of primers (5'-CGACTACAAGGACGACGATGACAAGGGATCCCTGGCCCCAGCTGAGATCTCTG-3 '(C-FLAG-Bam-hTMEM173 (139 aa) -F) and hTMEM173-st-Not-R). PCR was performed using PrimeStar MAX DNA Polymerase, (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds and 72 ° C, 10 seconds repeated 25 times, and (3) 72 ° C, 1 minute. . This was digested with Not I, inserted into the Stu I / Not I site of pET21a to which His-Avi-SUMO Tag was added in the same manner as above, using Ligation High, and introduced into ECOS JM109 to obtain pET21HH / His-Avi- SUMO-FLAG-hTMEM 173 (139-379) (H232R) was constructed.
The expression plasmid for Reporter Assay was obtained by performing Overlap Extension PCR to introduce a mutation using human TMEM173 cDNA Clone as a template as described above. First, 2 types of Primer (5'-GTACCCATACGATGTTCCAGATTACGCTGGATCCCGCCCACTCCAGCCTGCATC-3 '(HA-Bam-ko-hTMEM173-F) and hTMEM173 (H232R) -R) and 2 types of Primer (hTMEM173 (H232R) -F and hTMEM173-st-Nott) PCR was performed using -R). PCR was performed using PrimeStar MAX DNA Polymerase (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds and 72 ° C, 10 seconds repeated 25 times, (3) 72 ° C, 1 minute reaction did. Furthermore, PCR was performed using the obtained fragment as a template and two types of primers (5'-ATAATATCTAGAATTCGCCACCATGTACCCATACGATGTTCCAGATTACGC-3 '(Xba-Eco-ko-HA-F) and hTMEM173-st-Not-R). PCR was performed using PrimeStar GXL DNA Polymerase (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds and 65 ° C, 5 seconds and 72 ° C, 1.5 minutes repeated 35 times, (3) 72 It reacted for 1 minute. This was digested with Xba I (Takara Bio) and Not I, then inserted into Multiple cDNA Cloning Site in pcDNA3.3 (Invitrogen) and drug resistance was inserted into the Nhe I / Not I site of the vector using Zeocin using Ligation High. Then, it was introduced into ECOS JM109 to construct pcDNA3.3zeo / HA-hTMEM173 (H232R).
Two types of Primer (5'-TTCCAGATTACGCTGGATCCCGCACTCGCCCCCACTCCAGCCTGCATC-3 '(Bam-ko-hTEME173v1-F) and 5'-GTGTCTGCAGTGEGCAGTGEGGGATGCAGGATGCGTGCGEGGATGCGATGCAGGATGCGTGCGATGCGATGCAGGATGCAGCGTGCGGGATGC) It was constructed by PCR using 3 '(hTMEM173-st-Not-R2). PCR was performed using PrimeStar MAX DNA Polymerase (Takara Bio) (1) 98 ° C after 1 minute, (2) 98 ° C, 10 seconds and 68 ° C, 10 seconds repeated 30 times, (3) 72 ° C, It reacted for 1 minute. The obtained fragment was inserted into Bam HI / Not I site of vector obtained by adding HA-Tag to pcDNA3.1 (+) (ThermoFischer) using Gibson Assembly (NEB), and introduced into ECOS JM109 (Nippon gene). PcDNA3.1HA / HA-hTMEM173v1 was constructed.
Plasmid expressing human wild-type TMEM173 (H232R) has two types of primers (5'-GGAGACCCAAGCTGGCTAGCGCCACCATGTACCCATACGATG-3 '(Nhe-ko-HA-F) and 5' using pcDNA3.3zeo / HA-hTMEM173 (H232R) plasmid as a template It was constructed by carrying out PCR using '-CCTC TAG ACT CG AGC CG G CC GT C CTAAGAAATC GTG CGGA GAGG-3' (hTMEM 173-st-Not-R2). PCR was performed using PrimeStar MAX DNA Polymerase (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds and 72 ° C, 35 seconds repeated 30 times, and (3) 72 ° C, 1 minute. . The obtained fragment was inserted into the Nhe I / Not I site of pcDNA3.1zeo (ThermoFischer) using Gibson Assembly, and introduced into ECOS JM109 to construct pcDNA3.1zeo / HA-hTMEM173 (H232R).

(ii) Expression of firefly Luciferase Construction of plasmid Expression of firefly Luciferase Plasmid was constructed by inserting CMV Promoter into the Reporter vector. The pcDNA3.1 (+) vector (Invitrogen) is used as a template for two types of primers (5'-ATAATAGATCTGTTGACATTGATTATTGACTAGTTATTAATAG-3 '(CMVPro-BglII-F) and 5'-ATAATAAAGCTTGAGCTCTGCTTATATAGACCTCCC-3' (CMVPro-HindIII-R)) The PCR was done. PCR was performed using PrimeStar MAX DNA Polymerase, (1) 98 ° C, 1 minute, (2) 98 ° C, 10 seconds and 68 ° C, 3 seconds repeated 25 times, (3) 72 ° C, 1 minute reacted . This is digested with Bgl II and Hind III (Takara Bio), inserted into the Bgl II / Hind III site of pGL4.17 (Promega) using Ligation High (Toyobo), and introduced into ECOS JM109 to obtain pGL4.17 / CMV Pro was constructed.

<Reporter Gene Assay (1)>
A 293T stable expression cell line into which pNL [NLucP / ISRE / Hygro] vector (Promega, Fitchburg, WI, US) was introduced was constructed. The cells were transfected with pcDNA3.3zeo / HA-hTMEM173 (H232R) using Fugene HD (Promega, Fitchburg, WI, US). The cells were cultured for 1 day using Dulbecco's Modified Eagle's Medium (DMEM) (Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum. The cells were recovered and cryopreserved with Servanker 1 (Nippon Zunaku Kogyo Co., Ltd.).
On the day of the assay, test compounds diluted in assay buffer (DMEM containing 0.1% fatty acid-free bovine serum albumin) were dispensed at 10 μL / well in white 384-well plates (Corning, NY, US). Frozen cells were thawed and cells suspended in assay buffer were seeded at 10 μL / well (10000 cells / well). After culturing for 20 hours at 37 ° C. in a 5% CO ₂ environment, 20 μL of NanoGlo reagent (Promega, Fitchburg, Wis., US) solution was added. After a 5 minute incubation, luminescence was measured using EnVision (PerkinElmer, Waltham, Mass., US). The activity value of the test compound was calculated by setting the count in cells treated with 30 μM of 2 ′, 3′-cGAMP to 100% and the count in cells treated with solvent to 0%. The results are shown in Table 3.

  As a result, it became clear that the present compound has an agonist activity against wild type STING.

<Reporter Gene Assay (2)>
A 293T stable expression cell line into which pNL [NLucP / ISRE / Hygro] vector (Promega, Fitchburg, WI, US) was introduced was constructed. Suspensions of the cells transfected with pcDNA3.1zeo / HA-hTMEM173 (H232R) or pcDNA3.1HA / HA-hTMEM173v1 and FugeneHD (Promega, Fitchburg, WI, US) together with an expression plasmid for firefly Luciferase The cells were seeded on a 384 well plate (Corning, NY, US) and cultured for 2 days. After removing the culture broth, assay buffer (50 mM HEPES pH 7.0, 100 mM KCl, 3 mM MgCl ₂ , 85 mM Sucrose, 0.1 mM DTT, 0.2% BSA, 1 mM ATP, 0.1 mM GTP, 10 μg / ml Digitonin The test compound diluted in 2) was dispensed at 15 μL / well. After incubation for 30 minutes at 37 ° C. in a 5% CO ₂ environment, the assay buffer was removed. 20 μL / well of Dulbecco's Modified Eagle's Medium (DMEM) (Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum was added, and the cells were cultured at 37 ° C. in a 5% CO ₂ environment for 4 hours. Based on the protocol of the Nano-Glo Dual-Luciferase Reporter Assay System (Promega, Fitchburg, WI, US), luminescence signals from firefly Luciferase and NanoLuc Luciferase were measured using EnVision (PerkinElmer, Waltham, MA, US), respectively. . The ratio of NanoLuc Luciferase count divided by Firefly Luciferase count was used for calculation. The activity value of the test compound was calculated by setting the ratio in cells treated with 30 μM of 2 ′, 3′-cGAMP to 100% and the ratio in cells treated with solvent to 0%. The results are shown in Table 4.

  As a result, it was revealed that the present compound has agonist activity for wild type STING and mutant STING (R232H).

Test Example 3
Detection of phosphorylated IRF3 protein in FaDu cells The human pharyngeal carcinoma cell line FaDu cells (ATCC) were seeded, and 1 day after seeding, the medium was replaced with serum-free medium. After 1 day of culture after the above substitution, the natural ligand 2 ′, 3′-cGAMP (final concentration 30 μM) and the test compound (final concentration 15 μM or 30 μM) were added to the cells. Six hours after the addition, the cells were washed with PBS, and then the cell extract was prepared, and phosphorylated IRF3 protein was detected by ELISA or Western blotting. The IRF3 protein phosphorylation activity of the test compound was calculated based on a value of 100% of a sample to which a natural ligand 2 ′, 3′-cGAMP was added at a final concentration of 30 μM. The results are shown in Table 5.

  As a result, similarly to 2 ', 3'-cGAMP which is a natural type ligand, the present compound enhances the phosphorylation of IRF3 which is a downstream signal of STING, that is, the present compound acts as a STING agonist as a downstream signal of STING. It became clear to activate.

Formulation Example A medicine containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
1. Capsule (1) 10 mg of the compound obtained in Example 1
(2) Lactose 90 mg
(3) microcrystalline cellulose 70 mg
(4) Magnesium stearate 10 mg
1 capsule 180 mg
After mixing all of the above (1), (2) and (3) with 5 mg of (4), it is granulated, 5 mg of the remaining (4) is added to this, and the whole is sealed in a gelatin capsule.

2. Tablet (1) 10 mg of the compound obtained in Example 1
(2) Lactose 35 mg
(3) Corn starch 150 mg
(4) microcrystalline cellulose 30 mg
(5) Magnesium stearate 5 mg
1 tablet 230 mg
After mixing 20 mg of (4) and 2.5 mg of (5) with the total amount of the above (1), (2) and (3), it is granulated, and 10 mg of the remaining (4) and (5) Add 2.5 mg of the solution and press mold it to make a tablet.

  The compounds of the present invention may have STING agonist activity. Therefore, the compound of the present invention can be used as a STING agonist and can be useful as a preventive or therapeutic agent for STING-related diseases including cancer and the like.

Claims (4)

Formula (I):

[In the formula,
Partial structure:

The following formula (IIA):

A partial structure represented by or the following formula (IIB):

Indicates a partial structure represented by
R ¹ and R ² each independently represent a hydroxy group or a halogen atom;
B ¹ is

Indicates a group represented by
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ each independently represent a hydrogen atom or a substituent;
Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ each independently represent N or CR ^1a ;
Z < ¹¹ >, Z < ¹² >, Z < ¹³ >, Z < ¹⁴ >, Z < ¹⁵ > and Z < ¹⁶ > respectively independently show N or C;
R ^1a represents a hydrogen atom or a substituent;
B ² is

Indicates a group represented by
^{R 23, R 24, R 25} , R 26 and ^{R 27} each independently represents a hydrogen atom or a substituent;
Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ each independently represent N or CR ^2a ;
Z ²¹ , Z ²² , Z ²³ , Z ²⁴ , Z ²⁵ and Z ²⁶ each independently represent N or C;
R ^2a represents a hydrogen atom or a substituent;
However,
i) at least one of Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ is CR ^1a ,
ii) at least one of Y ²¹ , Y ²² , Y ²³ , Y ²⁴ , Y ²⁵ and Y ²⁶ is CR ^2a , or iii) at least one of Z ¹³ , Z ¹⁶ , Z ²³ and Z ²⁶ Is C;
Each of X ¹ and X ² independently represents an oxygen atom or a sulfur atom;
Each of Q ¹ , Q ² , Q ³ and Q ⁴ independently represents an oxygen atom or a sulfur atom. ]
Or a salt thereof.   A medicament comprising the compound according to claim 1 or a salt thereof.   The medicine according to claim 2, which is a STING agonist.   The medicine according to claim 2, which is a preventive or therapeutic drug for cancer.