compound

Abstract

To provide novel analogs of cytisine, and their use in medicine, for example in the treatment of addiction, as well as improved synthetic methods for the preparation of analogs of cytisine.SOLUTION: Disclosed are novel analogs of cytisine, a process for their preparation, pharmaceutical compositions containing them, and their use in the prevention of or treatment of CNS disorders including addictive disorders. The chemical structure of the novel cytisine analogs of the present invention is illustrated in the following chemical formula.SELECTED DRAWING: None

Description

[Technical Field] 【0001】 This invention relates to a novel analogue of cyticine, and to a drug for use in, for example, the treatment of poisoning. This invention relates to the use of these. The present invention also provides a cytidine analogue. Made Improved synthesis method for We also provide legal information. [Background technology] 【0002】 Nicotinic acetylcholine receptor (nACh R) This is the various parts of the human brain and the central nervous system. nACh is an ion channel-embedded receptor expressed in other parts of the ion system. R is example For example, cognitive function, learning and memory, sleep, anxiety, arousal, reward, motor control and other neurological functions. It is involved in various physiological functions. nACh R is Also, for example, Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism It has been involved in numerous medical conditions, including schizophrenia and other illnesses. R is Also, for example, nicotine addiction (Non-patent document 1), alcoholism (Non-patent document 2), drug addiction (Non-patent document 3), etc. He has been involved in the addiction and dependence of various drugs. 【0003】 nACh R Numerous subtypes are known to exist. Muscle-type nicotinic receptors (neurosinus) (located at the transmuscular junction) consists of α, β, γ, δ and a recently discovered additional subunit ε It is known to be formed from five different substructures. 【0004】 Neuronal nACh R( Homomers (located in the central nervous system, surrounding ganglia, and adrenal medulla) or heteromer typeTwo classes named α2-α9 and β2-β9 can be combined. Only the subunits of the S will be displayed. Many neural subtypes have been discovered, but heteromer Type combination (α4)3( β2)2, α3β4 and homomer type α7 in the brain remarkable It is expected to play a role. Among them, heteromer Type combination α4β2 is a major subtype in the central nervous system. It accounts for approximately 90% of receptors and binds to ACh with high affinity. α7 homomer mold combination height This is another major subtype that binds to ACh with low affinity. 【0005】 heteromer Type combination α4β2 is two different stoichiometric models (α4)2(β2)3 And can be combined with (α4)3(β2)2, which are usually A2B3 and A3B, respectively. It is called 2. The main α4β2 subtype consists of two α4 and three β2 subunits. It has been presented that the resulting structure A2B3 is the main subtype involved in poisoning. 【0006】 Nicotine is thought to activate this α4β2 receptor subtype, and therefore drug-dependent Dopamine is released into the nucleus accumbens and prefrontal cortex, specific parts of the human brain that have been associated with survival. Increases the release of [something]. 【0007】 Furthermore, the α4β2 receptor subtype is associated with alcoholism (Non-Patent Literature 4) and drug addiction. (Non-patent document 5) has been involved in this project. 【0008】 nACh R Compounds that have the ability to regulate these receptors can treat symptoms related to those receptors. It has been found to be effective in reducing aging. For example, studies have shown that transdermal nicotine is effective in reducing aging. This suggests that cognitive function may be improved in people suffering from associated memory impairment (see, for example, Non-Patent Document 6). (See reference). However, even when administered transdermally, there are some drawbacks to nicotine use. For example... For example, nicotine use is known to be addictive, and the 2014 U.S. Surgeon General's report... In that study, it was mentioned that nicotine has adverse effects on pregnancy outcomes and fetal brain development. 【0009】 In the field of smoking cessation treatment, nicotine is used to help smokers quit smoking. Nicotine is administered orally (e.g., through tablets or chewing gum) or transdermally. sending reach Products that do this have also been developed and are publicly known. 【0010】 nACh R Other compounds used to adjust the composition were also found to be used in the treatment of poisoning. In the United States, Champix is ​​a registered trademark, and in Europe, Champix is ​​a registered trademark. It is commercialized by Pfizer under the brand name (registered trademark) and is approved for use in smoking cessation treatment. It was approved. Furthermore, drugs have lagged behind in the treatment of alcohol and drug addiction (non-specific (Authorized document 4, and non-patent document 5). 【0011】 Mihalak et al. (Non-Patent Document 7) found that varenicline is a partial agonist at the α4β2 receptor. It is a weak agonist at the α3β4 receptor, and partially at the α3β2 and α6 receptors. It was discovered to be an agonist, specifically an agonist that is effective on the α7 receptor. 【0012】 Another drug used in smoking cessation treatment is cyticine. Cyticine is naturally occurring, pyri It is an alkaloid containing don, nACh R It is known as a partial agonist. Pharmacologically, cyticine shows a high degree of similarity to nicotine and has been used as a smoking cessation aid for many years. It has been successfully used. The chemical structure of cytidine (or more specifically, the (-) of cytidine) The enantiomers are shown below. [ka] 【0013】 While cyticine is safe and effective in smoking cessation treatment, it also gives rise to functionalized derivatives of the compound. Attempts have been made to do so. 【0014】 Traditionally, various different numbering systems have been used for cytishine. This discussion, For the purpose of disclosing the present invention, the following numbering system is used. [ka] 【0015】 In two papers (Non-Patent Document 8 and Non-Patent Document 9), Kozikowski et al. stated that A summary of previous research on the introduction of substituents in thisine structures (mainly at the 3- and 5- positions). Furthermore, the synthesis of a racemic analogue reported to be novel, containing substituents at positions 3, 4, and 7, is disclosed. did. 【0016】 In Kozikowski et al.'s 2006 paper (Non-Patent Literature 8), they placed it in 4th place in the race. Despite the high selectivity of the substituted compound for this subtype, the α4β2 receptor subtype Operates via pip Drug activity It was reported that this was not demonstrated. The results presented in this 2006 paper suggested that a cyticine analog with the 4th position substituted is a weak antagonist of the α4β2 receptor subtype. 【0017】 Therefore, the study conducted by Kozikowski et al. found that cyticine substituted at position 4 The analogues were shown to be significantly different from the known addiction treatments cyticine and varenicline. Ta. 【0018】 More recently, research by other teams has focused on substitutions at other positions in the cytishine structure. For example, in Patent Document 1, an analogue of cyticine having the following overall structure is synthesized. Ta. [ka] Furthermore, in Patent Document 2, a similar substance to cytishine is , on the piperidine ring Placement at position 5 Replacement and / or is nitrogen Contains elementary atoms. 【0019】 Rouden et al. (Non-Patent Document 10) presented a comprehensive study of different functionalized derivatives of cyticine. We created a comprehensive review. [Prior art documents] [Patent Documents] 【0020】 [Patent Document 1] International Publication No. 2014 / 001318 [Patent Document 2] China Patent Publication No. 103509021 Specification [Patent Document 3] U.S. Patent No. 6,099,562 [Patent Document 4] U.S. Patent No. 5,886,026 [Patent Document 5] U.S. Patent No. 5,304,121 [Non-patent literature] 【0021】 [Non-Patent Document 1] Schalling and Waller, Acta Physiologica Scandinavica. Supplementum, 1980, volume 479, pages 53-56. 【Non-licensed Document 2】 Holgate et al., Brain Science, 2015, September 5(3), pages 258-274. [Non-licensed document 3] Rahman et al., Frontiers in Neuroscience, 2014, volume 8, article 426. 【Non-licensed Document 4】 Mitchell et al., Pyschopharmacology, October 2012, 223 3, pages 299 to 306. 【Non-licensed Document 5】 Crunelle et al., European Neuropsychopharmacology,February 2010,20,2,pages 69 to 79. 【Non-licensed Document 6】 White et al., Psychopharmacology, February 2004, 171, 4, pages 465 to 471. 【Non-licensed Document 7】 Mihalak et al. (Molecular Pharmacology, 2006, September, 70(3), pages 801 to 805. 【Non-licensed Document 8】 Kozikowski et al., Journal of Medical Chemistry, 2006, 49, pages 2673 to 2676. 【Non-licensed literature 9】 Kozikowski et al., ChemMedChem, 2007, 2, pages 1157 to 1161. 【Non-licensed literature 10】 Rouden et al., Chemical Reviews, 2014, 114, pages 712 to 778. [Non-Patent Document 11] Gross and Mienhoffer, eds., The Peptides,Vol.3, Academic Press, New York, 1981, pp.3-88. [Non-Patent Document 12] Green and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley and Sons, Inc., New York, 1999. [Non-Patent Document 13] Gallagher et al., Synlett, 2010, pages 2798 to 2791. [Non-Patent Document 14] SMBerge,et al., J..Pharmaceutical Sciences, 1977, 66, 1-19 [Non-Patent Document 15] Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin, Mark Publishing Co., Easton, Pa., 1980. [Non-Patent Document 16] Hartwig et al.,Chemical Reviews,2010,110,pages 890-931. [Non-Patent Document 17] Moroni et al., 2006. [Non-Patent Document 18] Carbone et al., 2009. [Non-Patent Document 19] Abin-Carriquiry et al., 2006 [Overview of the Initiative] [Problems that the invention aims to solve] 【0022】 Essential investigation of cyticine analogues, and cyticine and / or other nAChR-binding agents Regardless of their potential to provide pharmaceuticals with improved properties compared to, the inventor To the best of our knowledge, such compounds have never been put into clinical trials, much less into pharmaceuticals. It was never approved as a product. Therefore, for example as a medicine for treating poisoning, etc. Improved safety and / or Yes Efficacy and Therefore, there remains a need for pharmaceuticals with improved properties compared to cyticine. [Means for solving the problem] 【0023】 (First aspect) According to a first aspect of the present invention, a compound of chemical formula (I), or ,the Pharmaceutically acceptable salts, solvates 、 and / Or E Steal is provided. [ka] Here, R 1 From R 4 This will be specified later. 【0024】 The present invention also provides a pharmaceutical composition containing such a compound. as a drug Those compounds and composition Use Use and We will provide it together. 【0025】 (Further aspects) Further aspects of the present invention, described in more detail below, relate to a 4-substituted cyticene analogue. Conveniently Made This is a preparation method for that purpose. 【0026】 The compounds and compositions of the present invention are useful in medicine. For example, they are nicotine, and Prevention, treatment, or improvement of symptoms of central nervous system disorders, including addiction disorders such as alcohol and drug addiction. It is fine if it is used for good. stomach. 【0027】 Compounds in this embodiment of the present invention are, in particular, drugs, alcohols and / or tobaccos, as determined by the inventors. Therapeutic efficacy in the treatment of addiction and / or dependence for It has been identified as useful re . A limited number of 4-substituted cyticine analogues have been disclosed to date, but they are not available. The limited binding data on these compounds indicated their applicability to use in pharmaceuticals. The authors of those disclosures do not claim that these compounds cause neurotoxicity, including addiction and intoxication. It was concluded that it showed a weak effect as a modulator of receptors associated with medical diseases. For example, Rouden et al. concluded the following in Non-Patent Document 10 (Non-Patent Document) (Reference 10, p. 732). The 4-position cyticine analogs tested were "activating agonists." sex This shows Furthermore, the suppression of nicotine activation channel function in both α4β2 and α3β4 receptors is also present. It showed very little effect." However, surprisingly and unexpectedly, the inventors of this invention have further explained below. Based on the newly emerging data discussed, these compounds demonstrate previously unnoticed advantages. I discovered that. 【0028】 Compounds having a wide range of substituents at the 4-position of cyticine were developed by the inventors of the present invention. It was identified as therapeutically beneficial. 【0029】 As described herein, the compounds of the present invention are as described herein. , or Honmyo As exemplified by the specific compounds disclosed in the document, One or more substituents in Replaced Good . 【0030】 The term "aliphatic" is used in this specification. of The term "(alliphatech)" refers to alkyl, a The terms lukenil and alkinil are included, and each may be optionally substituted as described below. 【0031】 As used in this document Na The "alkyl" group has 1 to 12 (e.g., 1 to 8, 1 to 6) Alternatively, it refers to an aliphatic saturated hydrocarbon group containing carbon atoms as described in 1 to 4). The alkyl group may be a linear alkyl group or a branched alkyl group. Examples of alkyl groups are not limited to these, but include methyl, ethyl, propyl, isopropyl, and b Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl It is 2-ethylhexyl. Alkyl groups can be substituted with one or more substituents as follows (i.e., optionally substituted). ). Halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl] ], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloal Kenil, Ali - Ru, Hetero Ari - Alkyl, Alkoxy, Alloyl, Heteroaloyl, A C Ru [For example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, and [Heterocycloaliphatic]carbonyl, nitro, cyano, amide, for example (Cycloalkylalkyl)carbonylamino, Ali - L-carbonylamino, Aral Kill Carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl (alkyl)carbonylamino, heteroalkyl - L-carbonylamino, heteroalachilucal Bonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterosyl Chloalkylaminocarbonyl, ali - Luaminocarbonyl, or heteroal - Luamino Carbonyl, amino [e.g., aliphatic amino acids, cycloaliphatic amino acids] , or heterocycloaliphatic amino acids], sulfonyl [e.g., aliphatic- SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfa Moyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphatic Xy, heterocycloaliphatic oxy, ali - Luoxy, heteroant - Luoxy, Aralkyloxy, heteroant - Alalkoxy, alkoxycarbonyl, alkylcarbon Nyloxy, or hydroxy. 【0032】 As used in this document Na The "alkenyl" group has 2 to 12 (for example, 2 to 8, 2 to It is an aliphatic carbon group containing 6 or 2 to 4) carbon atoms and at least one double bond. Similar to alkyl groups, alkenyl groups can be straight-chain alkenyl groups or branched-chain alkenyl groups. It can be the basis. Examples of alkenyl groups are not limited to these, but include allyl, vinyl, isoprenyl, and 1-propene. Nyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 5-pentenyl, 1-hexenyl, 2-Hexenyl, 3-Hexenyl, 4-Hexenyl, 5-Hexenyl, and 6-Hexenyl That is the case. The alkenyl group has one or more substituents as follows: in It can be replaced arbitrarily. Halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl] ], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloal Kenil, Ali - Ru, Hetero Ari - Alkyl, Alkoxy, Alloyl, Heteroaloyl, A C Ru [For example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, and [heterocycloaliphatic)carbonyl, nitro, cyano, amine Do[ for example( Cycloalkylalkyl)carbonylamino, ali - Lukarbonylamino, Aralkylca Carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl Alkyl)carbonylamino, heteroal - L-carbonylamino, heteroaral kylcal Bonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterosyl Chloalkylaminocarbonyl, ali - Luaminocarbonyl, or heteroal - Luamino Carbonyl, amino [e.g., aliphatic amino acids, cycloaliphatic amino acids] [heterocycloaliphatic amino acids, or aliphatic sulfonyl amino acids], s Rufonyl [e.g., alkyl-SO2-, cycloaliphatic-SO2-, or ali] - Ru -SO2-], sulfinyl, sulfoxy, urea, thiourea, sulf Amoyl sulfamide oxo carboxy, carbamoyl, cycloaliphatic Oxy, heterocycloaliphatic oxy, ali - Luoxy, heteroant - Luoxy , aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyl Oxy, or hydroxy. 【0033】 As used in this document Na The "alkynyl" group has 2 to 12 (for example, 2 to 8, 2 to It is an aliphatic carbon group containing 6 or 2 to 4) carbon atoms and at least one triple bond. The alkynyl group may be a straight-chain alkynyl group or a branched-chain alkynyl group. Examples of alkynyl groups are not limited to these, but include propargyl, butynyl, acetylenyl, 1 -Propynnyl, 2-Propynnyl, 1-Butynyl, 2-Butynyl, 3-Butynyl, 1-Pen Zynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 1-hex Synyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 6-hexynyl It is xynyl. The alkynyl group has one or more substituents as follows: in It can be replaced arbitrarily. Aroyl, heteroaloyl, alkoxy, cycloalkyloxy, heterocycloalkyl Luoxy, Ali - Luoxy, heteroant - Luoxy, Aralkyloxy, Nitro, Carbo Xy, cyanide, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., alipha] Tix sulfanil or cycloaliphatic sulfanil], sulfinyl [for example] [if aliphatic sulfinyl or cycloaliphatic sulfinyl], sulfon Lu [e.g., aliphate-SO2-, aliphate-amino-SO2- or cycloal [Refa-SO2-], amide [e.g., aminocarbonyl, alkylaminocarbon] Nyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloal Killaminocarbonyl, cycloalkylcarbonylamino, ali - Luaminocarbonyl, Ant - Carbonylamino, Aralkylcarbonylamino, (heterocycloalkyl) Carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarboxy Bonylamino, heteroal - L-carbonylamino or heteroali - [Luaminocarbonyl] Urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkyl Lucarbonyloxy, cycloaliphatic, heterocycloaliphatic, ali - Ru, Hetero Ari - Lu, A C Lu [for example, (cycloaliphatic) carbonyl or (hetero) [Rocycloaliphatic)carbonyl], amino (e.g., aliphatic amino), Sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (Heterocycloaliphatic)oxy, or (heteroali - Alkoxy. 【0034】 As used in this document Na , used alone, or "Aralkill", "Aralcoki "shi", or "ari" - In the context of "oxyalkyl," etc., it is used as part of a larger portion. "Ant" - The "ru" group can be monocyclic (e.g., phenyl) or bicyclic (e.g., indenyl, naphtha). Renyl, tetrahydronaphthyl, tetrahydroindenyl) and tricyclic (e.g., fluorescein) (Nyl, tetrahydrofluorenyl, tetrahydroanthracenyl, anthracenyl) ring C It refers to the stem, single ring type ring The system is aromatic, or bicyclic or tricyclic ring System At least one of the ring It is aromatic. The bicyclic and tricyclic groups contain benzo-condensed 2- to 3-membered carbon rings. For example, a benzo-condensed group is 、2 More than C 4-8 The carbon ring portion Phenyl condensed with It holds. Ant - The l includes one or more substituents, including the following: in It can be replaced as desired. Aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic Tick, (cycloaliphatic)aliphatic, heterocycloaliphatic K, (heterocycloaliphatic)aliphatic, ali - Ru, Hetero Ari - Ru, Alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy Kishi, Ari - Luoxy, heteroant - Luoxy, (alariphatic) oxy, (hete (Roalariphatic) oxy, aroyl, heteroaloyl, amino, oxo (benzo contraction) Combined two-ring or three-ring ant - Non-aromatic carbon Ring (Above), nitro, carboxy amide, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic] )carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (alari (phatic)carbonyl, (heterocycloaliphatic)carbonyl, ((hetero Cycloaliphatic)aliphatic)carbonyl, or (heteroaliphatic) Carbonyl, sulfonyl [e.g., aliphatetic-SO2- or amino-S] O2-], sulfinyl [e.g., aliphate-S(O)- or cycloaliphatic] [S(O)], sulfanyl [e.g., aliphatic-S], cyano, ha Ro, hydroxy, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sul Famido or carbamoyl. Or, Ant - The letter "ル" may remain unsubstituted. 【0035】 Ali may have substituents (optionally substituted, the same applies below). - Restrict the Examples include the following: Halophila - Ru [for example mono-, ji (for example p, m- dihaloari] - (Lu) and (Trihalo) Ant - (ru) (carboxy) ari - Lu [for example (alkoxycarbonyl) ali - Ru, ( (Aralkyl)carbonyloxy)ant - Lu and (alkoxycarbonyl) ali - [Ru], (Amid) Ant - Lu [For example, (aminocarbonyl) ali - Lu, (((alkylamino Alkyl)aminocarbonyl)ali - (alkylcarbonyl)aminoal - Ru, (A Ri - (Luaminocarbonyl) Ali - Ru and (((heteroali - (Lu)amino)carbonyl)a Ri - [Ru], AminoAri -Group [e.g., ((alkylsulfonyl)amino)aryl - or ([dialkyl)amino)aryl (dialkyl)amino)aryl - Group, (cyanoalkyl)aryl - Group, (alkoxy)aryl - Group, (sulfamoyl)aryl - Group [e.g., (aminosulfonyl)aryl - Group], (alkyl sulfonyl)aryl - Group, (cyano)aryl - Group, (hydroxyalkyl)aryl - Group, (( alkoxy)alkyl)aryl - Group, (hydroxy)aryl - Group, ((carboxy)alkyl )aryl - Group, (((dialkyl)amino)alkyl)aryl - Group, (nitroalkyl)aryl - Group, ((((alkylsulfonyl)amino)alkyl)aryl - Group, ((heterocycloaryl fatty)carbonyl)aryl - Group, ((alkylsulfonyl)alkyl)aryl - Group, (cyanoalkyl)aryl - Group, (hydroxyalkyl)aryl - Group, (alkylcarbonyl )aryl - Group, alkylaryl - Group, (trihaloalkyl)aryl - Group, p-amino-m-alk oxycarbonylaryl - Group, p-amino-m-cyanoaryl - Group, p-halo-m-aminoa ry - Group or (m-(heterocycloarylfatty)-o-(alkyl)aryl - Group. 【0036】 As used herein Na"Aralifatic" is an "alal" form of "aralkil". - Ru Aliphatic groups substituted with a group (e.g., C 1-4 This refers to an alkyl group. "Aliphatic", "Alkyl", and "Ali" - "Ru" is defined herein. An example of an araryl group is benzyl. 【0037】 As used in this document Na The "Aralkil" base is Ali - Alkyl groups substituted with a group For example, C 1-4 This refers to an alkyl group. "Alkyl" and "Al" - Both "ru" and "ru" are defined above. An example of an aralkyl group is benzyl. An aralkyl can optionally have one or more substituents as follows: in It will be replaced. Aliphatic [for example, alkyl, alkenyl or alkynyl, carboxy] Alkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl ], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cyclo (Hydralkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, A Ri - Ru, Hetero Ari - Alkoxy, cycloalkyloxy, heterocycloalkyloxy Kishi, Ari - Luoxy, heteroant - Luoxy, Aralkyloxy, Heteroaralkylo Xy, alloyl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkyl Carbonyl oxy, amide [e.g., aminocarbonyl, alkylcarbonylamino, cy Chloalkylcarbonylamino, (cycloalkylalkylcarbonylamino, ali - Leu carbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonyl amino, (heterocycloalkylalkyl)carbonylamino, heteroaryl - carbonyl amino or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl , mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl , sulfamide, oxo or carbamoyl. 【0038】 As used herein Na "bicyclic ring system" means two ring rings that form an 8- to 1 2( membered ring (e.g., 9, 10 or 11) member and contain two ring rings that share at least one atom share such that (e.g., two atoms are share shared). The bicyclic ring system may be Bi cycloaliphatic (e.g., Bi cycloalkyl or Bi cycloalkenyl), cycloheteroaliphatic, Bi aryl and bicyclic hetero - aryl. bicyclic hetero aryl - groups. 【0039】 As used herein Na "carbocyclic formula" or "cycloaliphatic" group includes "cycloalkyl" and "cycloalkenyl" groups, each of which is optionally substituted as described above. substituted. 【0040】 As used herein NaThe "cycloalkyl" group has 3 to 10 (for example, 5 to 10) ) Monoring of a saturated carbon ring of carbon atoms formula or biring (fused or bridged) ring It refers to. Examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopropyl thyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, o Decahydro-indenyl, Decahydro-naphthyl, Bi Cyclo[3.2.1]octyl, Bi Cyclo[2.2.2]octyl, Bi Cyclo[3.3.1]nonyl, Bi Cyclo[3.3.2 Decil, Bi Cyclo[2.2.2]octyl, adamantyl or ((aminocarbonyl) Cycloalkyl) Cycloalkyl. 【0041】 The "cycloalkenyl" group, as used herein, has one or more double bonds. 3 to 10 (for example, 4 to 8) non-aromatic carbon atoms Ring To point. Examples of cycloalkenyl groups are as follows: Cyclopentenyl, 1,4-cyclohexa-dienyl, cycloheptenyl, cycloo Ctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cy Clopentenyl, Bi Cyclo[2.2.2]octenyl or Bi Cyclo[3.3.1]noneni Ru. 【0042】 A cycloalkyl or cycloalkenyl group has one or more substituents as follows: in Replace as you see fit It is possible. Phosphors, aliphatic [e.g., alkyl, alkenyl or alkynyl], cyclo Liphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic Tick, (heterocycloaliphatic)aliphatic, ali - Ru, Hetero Ari - alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic) (K) Oxy, Ari - Luoxy, heteroant - Luoxy, (alariphatic) oxy, (heteroalariphatic) oxy, aroyl, heteroaloyl, amino, amide [examples] For example, (aliphatic)carbonylamino, (cycloaliphatic)carbonyl Amino, ((cycloaliphatic)aliphatic)carbonylamino, (ali - (Lu) Carbonylamino, (Alariphatic) Carbonylamino, (Heterocycloaliphatic) (phatic)carbonylamino, ((heterocycloaliphatic)aliphatic (C) Carbonylamino, (hetero-alkaline) - (Lu) Carbonylamino, or (heteroalarifa [tic)carbonylamino], nitro, carboxy[e.g., HOOC-, alkoxy] Carbonyl or alkylcarbonyloxy, acyl [e.g., (cycloaliphatic (C) carbonyl, ((cycloaliphatic)aliphatic) carbonyl, (A (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)carbonyl, ((hetero) (Terocycloaliphatic)aliphatic)carbonyl, or (heteroaliphatic) [Tick] Carbonyl, Cyano, Halo, Hydroxy, Mercapto, Sulfonyl [e.g.] ,alkyl-SO2- and ali - [SO2-], sulfinyl [e.g., alkyl-S(O )-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, Sulfamoyl, sulfamide, oxo, or carbamoyl. 【0043】 As used in this document Na The term "heterocycloaliphatic" It includes heterocycloalkyl groups and heterocycloalkenyl groups, each of which is as described above. It can be replaced as you like. 【0044】 As used in this document Na The "heterocycloalkyl" group is a monocyclic ring with 3 to 10 members. formula also This refers to a biring (fused or bridged) (for example, a monoring with 5 to 10 members). formula (or bi-ring) saturated ring structure It refers to one or more ring Atoms are heteroatoms (for example, nitrogen, oxygen, sulfur, or combinations thereof). ) Examples of heterocycloalkyl groups include the following: Aziridinil, piperidil, piperadil, tetrahydropyranil, tetrahydrofuryl Titanyl, oxolanil, dioxanil, dioxolanil, thienyl, dithianil, to Lithianil, Thiomorpholinil, 1 , 3-Dioxolanil, Imidazolidinil, Oxazo Lidinil, Oxiranil, Oxetanil, Isoxazolidinil, Morpholinil, Helicobacter pylori Donyl, pyrazolidinyl, tetrahydrothiophenyl, oxathionlanyl, pyranyl, Thiomorpholyl, octahydrobenzofuryl, octahydroclomenyl, octahydro Thioclomenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinone Linyl, octahydrobenzo[b]thiophene hmm Il, 2-oxa- BiCyclo[2.2.2 Octill, 1-Aza- Bi Cyclo[2.2.2]octyl, 3-aza- Bi Cyclo[3.2 .1] Octyl and 2,6-dioxa-tricyclo[3.3.1.0 3,7 ] Nonil. Monocyclic heterocycloalkyl groups can be fused with the phenyl moiety to form tetrahydroisoquinol It forms structures such as , and it is heterozygous - It would likely be classified as a "ru" (a type of lizard). 【0045】 The "heterocycloalkenyl" group is defined as one or more double bonds, as used herein. Non-aromatic monocyclic or bicyclic (e.g., 5 to 10-membered monocyclic or bicyclic) having ring Structure It refers to construction, one or more ring The atoms are heteroatoms (for example, nitrogen, oxygen, or sulfur). Monocyclic and bicyclic heterocycloaliphatic Ku is Numbered according to standard chemical nomenclature. It will be done. 【0046】 The heterocycloalkyl or heterocycloalkenyl group may be one or more of the following: substituent in It can be replaced. Phosphors, aliphatic [e.g., alkyl, alkenyl or alkynyl], cyclo Liphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic Tick, (heterocycloaliphatic)aliphatic, ali - Ru, Hetero Ari - alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic) (K) Oxy, Ari - Luoxy, heteroant - Luoxy, (alariphatic) oxy, (heteroalariphatic) oxy, aroyl, heteroaloyl, amino, amide [examples] For example, (aliphatic)carbonylamino, (cycloaliphatic)carbonyl Amino, ((cycloaliphatic)aliphatic)carbonylamino, (ali - (Lu) Carbonylamino, (Alariphatic) Carbonylamino, (Heterocycloaliphatic) (phatic)carbonylamino, ((heterocycloaliphatic)aliphatic (C) Carbonylamino, (hetero-alkaline) - (Lu) Carbonylamino, or (heteroalarifa [tic)carbonylamino], nitro, carboxy[e.g., HOOC-, alkoxy] Carbonyl or alkylcarbonyloxy, acyl [e.g., (cycloaliphatic (C) carbonyl, ((cycloaliphatic)aliphatic) carbonyl, (A (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)carbonyl, ((hetero) (Terocycloaliphatic)aliphatic)carbonyl, or (heteroaliphatic) [Tick] Carbonyl, Nitro, Cyano, Halo, Hydroxy, Mercapto, Sulfonyl [For example, alkylsulfonyl or ali - [Sulfonyl], sulfinyl [e.g., alkyl Sulfinyl, Sulfanyl [e.g., alkylsulfanyl], Sulfoxy, Urea , thiourea, sulfamoyl, sulfamide, oxo or carbamoyl. 【0047】 "Heterocary ants" - The "L" group is used herein in 4 to 15 ring Having an atom Single ring, double ring, or triple ring ring Refers to a system, one or more ring Atoms are heteroatoms (for example) (Nitrogen, oxygen, sulfur, or a combination thereof), monocyclic ring Is the system aromatic, or is a two-ring or three-ring type ring at least one of the systems ring It is aromatic. Heterozygous ants - The group has two to three ring Benzo condensation The ring Includes the system. For example, the benzo-condensing group is one or two 4- to 8-membered heterocycloaliphatic compounds. Parts (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolyl) Nyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl It contains benzos that have been condensed with ) Heterozygous ants - Some examples of ants include azetidinil, pyridyl (e.g., 2-pyridyl, 3-pyridyl). -Pyridyl, 4-pyridyl), pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl , 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, thiophenyl, oxy Sazolyl, iso O Xazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiadi Azolyl, Imidazolyl, Diazolyl, Triazolyl, Tetrazolyl, Benzofuryl, I Soquinolinyl, benzothiazolyl, xanthine, thioxanthine, phenothiazine, dihydrotestosterone Doroindole, benzo[1,3]dioxol, benzo[b]furyl, benzo[b]ci Offenyl, Indazolyl, Benzimidazolyl, Benzothiazolyl, Puryl, Chinoli Lu, quinoryl, quinazolyl, thinolyl, phthalazyl, quinozolyl, quinolyl tree Salil, Isoki Noryl, 4H-Quinolidyl, Benzo-1,2,5-Thiasiazolyl or 1,8-Naphthyl Jill. 【0048】 Without restriction, monocyclic heterozygous - The following are included: Furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, im Dazolyl, pyrazolyl, iso O Xazolyl, isothiazolyl, 1,3,4-thiazolyl Pyrazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, pyridadyl, pyrimidyl, pyrazolyl , pyrazyl or 1,3,5-triazyl. Monocyclic heterozygous ant - The letters are numbered according to standard chemical nomenclature. 【0049】 Without restriction, biring heteroant - The following are included: Indolyzyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, ben Zo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indridge Nyl, isoindolyl, indolyl, benzo[b]furyl, benzo[b]thiophenyl, Indazolyl, benzimidadyl, benzothiazolyl, purinyl, 4H-quinolidyl, Quinoryl, Isoquinolyl, Synnoryl, Phthalazyl, Quinazolyl, Quino tree Salil, 1,8 - Naphthyridyl or Pteridyl. Bi-ring heterozygous ant - The letters are numbered according to standard chemical nomenclature. 【0050】 Heterozygous ants - Lu can optionally contain one or more substituents as follows: in It will be replaced. Aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic ick, (cycloaliphatic)aliphatic, heterocycloaliphatic (Heterocycloaliphatic)aliphatic, ali - Ru, Hetero Ari - Lu, A Lucoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy C, Ari - Luoxy, heteroant - Luoxy, (alariphatic)oxy, (hetero) Alariphatic) oxy, aroyl, heteroaloyl, amino, oxo (bicyclic or Tri-ring heterozygous ant - non-aromatic carbocyclic or heterocyclic ring (Above), carboxy, amine do, acyl [for example, (aliphatic) carbonyl, (cycloaliphatic) cal Bonyl, ((cycloaliphatic)aliphatic)carbonyl, (alaliphatic) (Ick) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocyclo Aliphatic) Aliphatic) Carbonyl, or (heteroalaliphatic) Carbonyl, sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl] ], sulfinyl [e.g., aliphatic sulfinyl], sulfanyl [e.g., Aliphatic sulfanil, nitro, cyano, halo, hydroxy, mercapto, s Ruhoxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl. Or, heterozygous ants - The letter "ル" may remain unsubstituted. 【0051】 Having substituents ru Heterozygous ants - Examples of cases where the restrictions are not applied include the following: (Hello) Heteroant - Lu [for example, mono-, di-(halo) hetero-ali - [Ru], (Carbohydrate C) Heteroant - For example, (alkoxycarbonyl) heterozygous - [Lu], cyanohetero Ant - Ru, amino heteroali - For example, ((alkylsulfonyl)amino) hetero Ri - Lu and ((dialkyl)amino) heteroalkyl - [Lu], (amide) heteroali - Lu [Example] For example, aminocarbonyl heteroali - ((alkylcarbonyl)amino) heteroal - Ru, ( (((alkyl)amino)alkyl)aminocarbonyl)heteroal - Ru, (( (heteroant - (Lu)amino)carbonyl)hetero) - Ru, ((heterocycloaliphatic (Ick) Carbonyl) Hetero - L and ((alkylcarbonyl)amino) heteroal - [Lu], (cyanoalkyl) heteroalkyl - Ru, (alkoxy) heteroali - Ru, (Sulf (Amoil) Heteroant - Lu [For example, (aminosulfonyl) heteroali - [Lu], (Sulfo) Nil) Heteroant - For example, (alkylsulfonyl) hetero-al - [Ru], (HydroKi (Cialkyl)heteroant - (alkoxyalkyl) heteroal - Lu, (hydroxy) Heterozygous ants - Ru, ((carboxy)alkyl) heteroali - Lu, ((((dialkyl)ami (N)Alkyl]hetero-Alkyl - (heterocycloaliphatic) heteroali - Ru, ( Cycloaliphatic (heteroaliphatic) -(nitroalkyl) heteroal - Lu, ((( Alkylsulfonyl)amino)alkyl)heteroalkyl - Lu, ((alkylsulfonyl) a Lukil) Hetero-Ari - (cyanoalkyl) heteroalkyl - Ru, (Acyl) Heteroali - For example, (alkylcarbonyl) heteroalkyl - [Lu], (alkyl) heteroal - Lu (Haloalkyl)heteroant - For example, trihaloalkyl hetero - [Ru]. 【0052】 "Heteroararylphatic" (heteroaralkyl group, etc.) as used herein is heterozygous ant - Lu group in Replaced Ta Aliphatic group (e.g., C 1-4 (Alkyl group) vinegar. "Alphatic", "Alkyl", and "Heteroal - "Ru" is defined above. 【0053】 The "heteroaralkyl" group is, as used herein, heteroaralkyl - Lu group in Substitution re Ta Alkyl (e.g., C 1-4 This refers to an alkyl group. "Alkyl" and "Heteroal" - Both "ru" and "ru" are defined above. A heteroaralkyl can optionally have one or more substituents as follows: in It will be replaced. Alkyl (carboxyalkyl, hydroxyalkyl, and trifluoromethyl) (containing haloalkyls), alkenyls, alkynyls, cycloalkyls, (cycloal (Kil)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, ali - Ru heterozygous ants - Alkoxy, cycloalkyloxy, heterocycloalkyloxy, Ant - Luoxy, heteroant - Luoxy, Aralkyloxy, Heteroaralkyloxy, Aroyl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyl Bonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl Luamino, (cycloalkylalkyl)carbonylamino, Ali - Carbonylamino, Aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)carbonylamino (Cloalkylalkyl)carbonylamino, heteroalkyl - Carbonylamino, heteroa Lalkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkyl Sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxy So or Carbamoil. 【0054】 As used in this document Na The "cyclic portion" and "cyclic group" are cycloaliphatic. Heterocycloaliphatic, ant - Ru or Heteroali - Single ring, double ring or It is a three-ring type ring This refers to the systems, each of which is defined above. 【0055】 As used in this document Na “Bridged Bicyclic ring The system is ring A biring complex bridged Ring Aliphatic ringSystem or bicyclic cycloaliphatic ring refers to the system. Bridged bicyclic ring Examples of the system include, but are not limited to, the following. Adamantanyl, norbornanyl, Bi cyclo[3.2.1]octyl, Bi cyclo[2. 2.2]octyl, Bi cyclo[3.3.1]nonyl, Bi cyclo[3.2.3]nonyl, 2 -oxa Bi cyclo[2.2.2]octyl, 1-aza Bi cyclo[2.2.2]octyl, 3-aza Bi cyclo[3.2.1]octyl and 2,6-dioxa-tricyclo[3.3. 1.0 3,7 nonyl. Bridged bicyclic ring The system is optionally substituted with one or more substituents as follows in substituted. Alkyl (including haloalkyl such as carboxyalkyl, hydroxyalkyl and trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl alkyl), heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl - oxy, heteroaryl oxy, aralkyl oxy, heteroaralkyl oxy, aryl - oyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl amino, (cycloalkylalkyl)carbonylamino, aryl - carbonylamino, aryl - carbonylamino, aralkylcarbonylamino, heteroaralkylcarbonylamino, aryl carbonyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl amino, (cycloalkylalkyl)carbonylamino, aryl carbonylamino, aryl - carbonylamino, aryl Lalkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl (Roalkylalkyl)carbonylamino, heteroalkyl - L-carbonylamino, heteroal Lukylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkyls Ruphanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo Or carbamoyl. 【0056】 As used in this document Na "Amide" is a combination of "aminoalbonyl" and "carbonylamino It encompasses both of the above. These terms, whether used alone or in combination with other groups, are used at the end of a group. -N(R x )-C(O)-R Y or -C(O)-N(R X ) refers to an amide group like 2, inside When used in -C(O)-N(R X )- or -N(R X )-C(O)- refers to, here R X and R Y This is defined below. Examples of amide groups include alkylamides (alkylcarbonylamides or amides) (such as hydroxylaminocarbonyl), (heterocycloaliphatic) amide, (heteroa Larkylamide, (hetero-alkaline) - (Lu)amide, (heterocycloalkyl)alkylamide D, Ari - Luamide, Aralkylamide, (cycloalkyl)alkylamide or cyclo Alkylamide. 【0057】 As used in this document Na The "amino" group is -NR X R Y This refers to R Xand R Y Each These are independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic (Aliphatek, Ali) - Ru, alariphatic, heterocycloaliphatic K, (heterocycloaliphatic)aliphatic, heteroali - Lu, Carboxy , sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycline (Cycloaliphatic) carbonyl, ((cycloaliphatic)aliphatic) ca Lubonil, Ali - rucarbonyl, (alariphatic)carbonyl, (heterocycloa (riphatic)carbonyl, ((heterocycloaliphatic)aliphatic) Carbonyl, (heterozygous) - (Lu) Carbonyl or (heteroalariphatic) carbonyl These are terms, each of which is defined herein and may be optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or ali. - Contains ruamino. If the term "amino" is not a terminal group (for example, alkylcarbonylamino), -NR X -represented by , R X This has the same meaning as above. 【0058】 As used in this document Na The "acyl" group is a formyl group or R X -C(O)-(for example) Alkyl-C(O)- (also called "alkylcarbonyl") refers to this, where R X and "Alkyl" was defined previously. Acetyl and pivaloyl are examples of acyl groups. 【0059】 As used in this document Na "Aroyl" or "heteroaloyl" are acceptable. - Ru-C(O )- or heterozygous ants - This refers to the "ru" (C(O))-. Aroyl or heteroaloyl ants - Ru and Heteroli - The position of the letter is as specified above. Uni can be substituted as desired. 【0060】 As used in this document Na The "alkoxy" group refers to an alkyl-O- group, and here "A "Lukil" was defined previously. 【0061】 As used in this document Na The "carbamoyl" group is -O-CO-NR X R Y or -NR X -CO-OR Z This refers to a group having the structure R X and R Y This is defined above, R Z is A Rephatic, Ali - Lu, alariphatic, heterocycloaliphatic, hetero Termites - It may be heteroalliptic or heteroalliptic. 【0062】 As used in this document Na The "carboxyl" group is -C when used as a terminal group. OOH, -COOR X -OC(O)H, -OC(O)R X This refers to, and when used internally. -OC(O)- or -C(O)O- 【0063】 As used in this document Na A "haloaliphatic" group consists of 1 to 3 halogen atoms. in Replaced Ta This refers to the aliphatic group. For example, the term haloalkyl refers to a group containing a -CF3 group. 【0064】 As used in this document Na The "mercapto" group refers to the -SH group. 【0065】 As used in this document Na The "sulfo" group, when used as a terminal group, is -SO3 H or -SO3R X It refers to -S(O)3- when used internally. 【0066】 As used in this document Na The "sulfamide" group, when used as a terminal group, NR X -S(O)2-NR Y R Z It refers to the structure, and when used internally, it is called -NR X -S(O)2 -NR Y - refers to, and here R X , R Y and R Z This is stipulated above. 【0067】 As used in this document Na The "sulfonamide" group is used as a terminal group. -S(O)2-NR X R Y or -NR X -S(O)2-R Z This refers to, and when used internally, - S(O)2-NR X - or -NR X -S(O)2- is pointed to, and here R X , R Y and R Z The above It was defined. 【0068】 As used in this document Na The "sulfanyl" group, when used as a terminal group, SR X It refers to -S- when used internally, and here R X This is stipulated above. Examples of sulfanils include aliphatic-S-, cycloaliphatic-S-, and ali - Includes Ru-S- etc. 【0069】 As used in this document Na The "sulfinyl" group, when used as a terminal group, - S(O)-R X It refers to -S(O)- when used internally, and here R X The above It was defined. For example, the sulfinyl group is aliphatic -S(O)-, ali - Ru-S(O)-, (cycloaliphatic (aliphatic))-S(O)-, cycloalkyl-S( O)-, heterocycloaliphatic-S(O)-, heteroaliphatic - Lu-S(O)- etc. include. 【0070】 As used in this document Na The "sulfonyl" group is -S when used as a terminal group. (O)2-R X It refers to -S(O)2- when used internally, and here R X The above It was defined. An example of a sulfonyl group is the aliphatic -S(O)2-, ali - Lu-S(O)2-, (cycloaliphatic (aliphatic))-S(O)2-, cycloaliphatic ck-S(O)2-, heterocycloaliphatic-S(O)2-, heteroali - Lu-S (O)2-, (cycloaliphatic(amide(aliphatic)))-S(O)2- Includes, etc. 【0071】 As used in this document Na The "sulfoxy" group is -O when used as a terminal group. -SO-R X or -SO-OR X This refers to -OS(O)- or when used internally. -S(O)-O- refers to R X This is stipulated above. 【0072】 As used in this document Na The "halogen" or "halo" group is fluorine, chlorine, bromine, or yo It refers to the element U. 【0073】 As used in this document Na , encompassed by the term carboxyl, "alkoxycarb "Nyl" can be used alone or in combination with other groups, such as alkyl-OC(O)- It refers to the base. 【0074】 As used in this document Na "Alkoxyalkyl" is an alkyl-O-alkyl- This refers to an alkyl group, where alkyl is defined above. 【0075】 As used in this document Na "Carbonyl" refers to -C(O)-. 【0076】 As used in this document Na "Oxo" refers to O. 【0077】 As used in this document Na The term "phosphorus" is phosph Naat and phospho Naat It refers to. Hosfi Naat and phospho Naat An example is -P(O)(R P )2, where R P Yes Phatic, Alkoxy, Ali - Luoxy, heteroant - Luoxy, (cycloalipha) (tic)oxy, (heterocycloaliphatic)oxy, ali - Ru, Hetero Ari - It is chloroalyphatic or amino. 【0078】 As used in this document Na "Aminoalkyl" is (R X ) Refers to the 2N-alkyl- structure vinegar. 【0079】 As used in this document Na "Cyanoalkyl" refers to the (NC)-alkyl- structure. . 【0080】 As used in this document Na The "urea" group is -NR X -CO-NR Y R Z It refers to the structure, "thiourea" group teeth When used as a terminal base, -NR X -CS-NR Y R Z Structure This refers to -NR when used internally. X -CO-NR Y - or -NR X -CS-NR Y - This refers to R X , R Y and R Z This is stipulated above. 【0081】 As used in this document Na "Aliphatic chain" refers to a branched or straight chain of aliphatic groups (for example, a This refers to a lukyl group, alkenyl group, or alkynyl group. A linear aliphatic chain is -[CH2] V- has the structure, where v is from 1 to 12. The aliphatic chain is substituted with one or more aliphatic groups. Ta It is a linear aliphatic chain. Branched aliphatic chains are -[CQQ] V - has the structure, where each Q is 、 Independent hand hydrogen or an aliphatic group, but Q must be an aliphatic group in at least one example. Aliphatic chains include alkyl chains, alkenyl chains, and alkynyl chains, where alkyl and alkynyl are included. Kenil and Alkinil are defined above. 【0082】 The phrase "arbitrarily substituted" is the same as the phrase "substituted or not substituted". It is used in this sense. As described herein, the compounds of the present invention are generally those described above or the present invention One or more substituents, as exemplified in the specific classes, subclasses, and types of the ABC model. in Place as you like It can be exchanged. Book statement As described above, The chemical formulas described herein contain R 1 , R 2 , R 3 and R 4 of Possible strange element Reach Other possible strange element is alkyl and ali - Includes specific bases such as . Unless otherwise specified, This specification includes R 1 , R 2 , R 3 and R 4 of Possible strange element Reach other of Possible strange element Each of the specific groups to which is one or more substituents described herein. in Replace as you see fit It is possible. 【0083】 Each substituent on a particular group may further consist of one to three of the following: in It's okay if it's replaced. Halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, ali - Ru, Cyclo Aliphatic, hetero Cyclo Aliphatic, heteroali - Lu, haloalkyl and Alkyl. For example, alkyl groups are alkylsulfanyl in Alkyl sulfanyl can be substituted, Halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, ali - Ru, Haroari - 1 to 3 units of alkyl in It may be replaced as desired. In further examples, the cycloalkyl portion of (cycloalkyl)carbonylamino is 1 to 3 of the following: 1, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl in It may be replaced as desired. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups The xy group, along with the atom to which they are bonded ring It can form. 【0084】 The compound of the present invention is useful nACh R Yes, for the treatment of central nervous system disorders such as poisoning disorders. to Contains Mare It is useful in pharmaceuticals. 【0085】 (compound) (First aspect (1)) According to the present invention, a compound of chemical formula (I), or ,the Pharmacologically acceptable salts and solvates 、 and / or An ester is provided. [Chemical formula] R 1 is hydroxy, halogen, an aliphatic group which may have a substituent, a cycloaliphatic group which may have a substituent, a heterocycloaliphatic group which may have a substituent, an aryl which may have a substituent - group, a heteroaryl which may have a substituent - group, -(CH2) m -NR 6 R 7 R 8 , -(CH2) m -O-(CH2) n -R 10 , -CN, -COOR 12 , -(CH2) O -CO-(CH2) P -R 13 , an amino acid or its ester, an acyl chloride, a protecting group, or cytosine. Here, R 6 and R 7 are each independently selected from groups consisting of the following. Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul foxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto , carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, having a substituent It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl, or R 6 and R 7 One of them is -CO-R 9 And R 6 and R 7 The other is as defined above. R 8 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl is either present or absent. R 9 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. m is 0, 1, 2, 3, 4, or 5. R 10 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. m and n are independently 0, 1, 2, 3, 4, or 5. R 12 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. R 13 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. o and p are independently 0, 1, 2, 3, 4, or 5. R 2 , R 3 and R 4 Each of these is independently selected from a base consisting of the following: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted Possible heterocycloalkenyls, amino acids, or cyticine, or R 4 Is a protecting group also acceptable? Or, -(CH2) V -It may also be a group having the structure of FORMULA 1, where v is 0, 1 , 2, 3, 4, 5 or 6, and FORMULA 1 is the chemical formula (I) described herein. It is a compound of ). R of chemical formula I 2 , R 3 and R 4 At least one of them is not hydrogen. 【0086】 As mentioned above, R 1 The substituent at the position is 、 Aliphatic which may have substituents, cycloaliphatic, which may have substituents, heterosymmetric, which may have substituents Cloaliphatic, may have substituents. 、 Ant - Lu or, optionally, heterozygous - Ru But that's fine. 【0087】 In embodiments of the present invention, R 1 The substituent at the position may have a substituent or Unsubstituted C 1-8 , C 1-4 or C 3-8 Alkyl alkyl groups, for example, propyl, isopropyl, butyl or It may also be tert-butyl. In one embodiment of the present invention, R 1 The substituent at the position is 、 C may have substituents 1-2 a C may have a luquill group or a substituent. 3-6 It may also be an alkyl group. In such embodiments, C 1-2 Alkyl groups are hydroxymethyl or fluoromethyl. External substituents may also be used. 【0088】 R in the compound of the present invention 1 It has substituents that are assumed to be used in conjunction at the position Examples of alkyl groups that may be included include the following: A methyl group which may have substituents, for example, aminomethyl, methyl halogen, for example chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, trifluoro Methyl, bromomethyl, dibromomethyl, or tribromomethyl; may have substituents. Ethyl groups, for example, 1- or 2-aminoethyl, hydroxyethyl, ethyl halogen, Examples include 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, or 2,2,2 -Trifluoroethyl, or , placed A propyl group which may have a substitution group, for example, 1-,2- Alternatively, 3-aminomethyl, hydroxypropyl, or halogenated propyl. 【0089】 In embodiments of the present invention, R 1 The substituent at the position is 、 Unsubstituted or substituted Good ants - It can be a ru. For example, the substituent may be a phenyl group, or a phenyl group which may have a substituent. It may also be a group, for example a halogenated phenyl group, such as chlorophenyl or bromophenyl. lin, fluorophenyl, perchlorophenyl, perbromophenyl, perfluorophen Nil, or, Tolyl, aniline, phenol, styrene, benzonitrile, anisole, acetophen It may be non-benzaldehyde or benzoic acid group. 【0090】 (First aspect (2)) In another embodiment, R 1 The substituent at the position may have a substituent or be heterozygous. - Ru It may also be benzyloxypyridine, pyridone (for example, 2-pyridone), Pyridine (e.g., 2-pyridine, 3-pyridine, or 4-pyridine), phenyltriaz triazoles, triazoles which may have substituents, and triazolemethylpivalic acid groups. You can. 【0091】 R 1 The substituents may alternatively be substituted with cyclic alkyl or heterocyclo Alkyl compounds are also acceptable, for example, cyclopentyl, cyclohexyl, morpholinyl, pipe Lysyl, piperadyl, tetrahydrofuryl, oxolanil, or dioxanil are also acceptable. stomach. 【0092】 R 1 An example of an alkenyl group which may have substituents that may be included at the position C 2-8 Alkeni For example, vinyl, acrylate, or a -C=C-C6H5 group. 【0093】 R 1 The alkynyl group which may have substituents that can be located at the position C 2-8 Alkinyl, It contains a -C≡C-C6H5 or -C≡C-trimethylsilyl group. 【0094】 Furthermore, the R of the compound of the present invention 1 Other groups that can be used as substituents include the following: 【0095】 (-(CH2) m -NR 6 R 7 R 8 ) Here, R 6 、 R 7 、 and R 8 This is stipulated above. In such embodiments, the compounds of the present invention include amines, N-alkylamines, and N,N-diamines. Alkylamine and amide groups R 1 It may also be included as a substituent at a specific position. Examples of groups that are expected to be present at that position include the following: amines, methylamines, etc. Tylamine, propylamine, isopropylamine, benzylamine, dimethylamine, Trimethylammonium methyl, dimethylaminomethyl, ben Z Amides and acetamides Base. In embodiments of the present invention, m is zero and R 8 If R does not exist, 6 and R 7 Both Not hydrogen, and / or R 6 and R 7 Neither of them is oxo. 【0096】 (-(CH2) n -O-(CH2) o -R 10 ) Here, R 10 This is stipulated above. In such embodiments, the compound of the present invention is R 1 Contains a group that includes an ether bond at position But that's fine. Examples of groups that are expected to be present at that position include the following: Methoxy, ethoxy, propoxy, benzyloxy or trifluoromethylbenzyloxy xyl group. In embodiments of the present invention, the following conditions apply. R 1 The substituent is a propoxymethyl group (i.e., -CH2-O-CH2-CH2CH3), lucoxymethyl group, or -CH2-O-CH2-C6H4-R 12 or -CH2-O-CH2-C 6H 10 -R 12 It is not a group having the structure of R 12 is hydrogen, trifluoromethyl, substitution It is a phenyl, halo, or fluorine group which may have a group. 【0097】 (-CN) (-COOR 12 ) Here, R 12 This is stipulated above. In such embodiments, the compound of the present invention has a carboxylic acid group or R 1 Esters at position, for example For example, ethyl esters, propyl esters, isopropyl esters, butyl esters or f It may also contain phenyl esters. In embodiments of the present invention, R 1 The substituents in C 1-3 Alkyl ester group or methyl group Other substituents besides the ester group may also be used. 【0098】 (-(CH2) p -CO-(CH2) q -R 13 ) Here, R 13 This is stipulated above. In such embodiments, the compound of the present invention 、R 1 at location Ketones is A Rudehyde group, e.g. For example, it may contain acetophenone. In one embodiment, R 1 The substituents in this compound are substituents other than -CO-NH2. 【0099】 (-amino acid) For example, naturally occurring amino acids or their esters, such as alanine, arginine, and a Sparagin, Aspa Lutart cysteine, glutamine, gluta mart , glycine, his Thidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, Serine, threonine, tryptophan, tyrosine, valine, or their methyl, ethyl, Propyl or isopropyl ester. 【0100】 The compound of the present invention is R 1 Embodiments of the present invention comprising an amino acid or its ester at the position. In this process, amino acids (or esters) can be introduced via any atom (e.g., oxygen, carbon, sulfur). (via yellow or nitrogen atoms), for example, via oxygen atoms in acid units, aminocyticin By forming mid, or via the nitrogen atom in the amine unit, pyridine forms the basic structure of cyticine. ring It may be combined with it. 【0101】 (-acyl chloride) (-protecting group) For example, tert-butyloxycarbonyl (Boc), formyl, acetyl (Ac), succinyl (Suc), methoxysucinyl (MeOSuc), benzyloxycarbon (Cbz), or fluorenyl methoxycarbonyl (Fmoc), or protected boryl Protecting group, optionally (pinacorato)borane (BPin) and (catecorato)borane (BCat It has a (RO)2B-structure like this. Embodiments of the present invention include any protecting group commonly used in organic synthesis, for example, non-patent documents. References 11 and 12 contain summaries of the available materials, and the contents of these documents are as specified herein. It is used in conjunction with [the text]. 【0102】 (-cytishinyl) In embodiments, the compound of the present invention may be a cyticine-cyticine dimer. Cyticine compounds are introduced, for example, via the carbon atoms at positions 3, 4, or 5 of each compound. They may be directly connected to each other. Alternatively, the two cyticine structures can be linked via a linker such as a carbon, oxygen, or nitrogen atom. They can be combined. When a linker is used, it itself is, for example, C 1-6 It may also have functional groups such as alkyl groups. stomach. 【0103】 position R 2 From R 4 The substituents are as defined above. In embodiments of the present invention, R of chemical formula I 2 and R 3 It could be hydrogen. In that case R 2 , R 3 and R 4 At least one of them is not hydrogen. Alternatively, R 2 R may be a halogen, while R 3 and R 4 It is hydrogen. In some embodiments of the present invention, R 4 The substituent is C 2-6 Even if substituents other than alkyl good. 【0104】 In embodiments of the present invention, position R 4 The substituents may be protecting groups such as the following: . tert-butyloxycarbonyl (Boc) 、 Formyl, acetyl (Ac), succin Suc (Suc), Methoxysucinyl (MeOSuc), Benzyloxycarbonyl (C bz) or fluorenyl methoxycarbonyl (Fmoc), or borated protecting group, In intention, B( ) borane (BPin) and (catecorato) borane (BCat) etc. OR)2 structures Embodiments of the present invention include any protecting group commonly used in organic synthesis, for example, non-patent documents. References 11 and 12 contain summaries of the available materials, and the contents of these documents are as specified herein. It is used in conjunction with [the text]. 【0105】 Unless otherwise specified, the structures described herein also apply, for example, to each chiral center. R and S configurations, double bond isomers of (Z) and (E), and conformational isomers of (Z) and (E) All isomers of structures such as (for example, enantiomers, diastereoisomers, geometric (and This means that it includes isomers (of three-dimensional structures). Therefore, the single stereochemistry of the compound of this application transformation Scientific isomers, enantiomers, and diastereoisomers Body and geometric (or three-dimensional) mixtures are within the scope of this application. Unless otherwise specified, all tautomers of the compounds of this application fall within the scope of the present invention. Furthermore, unless otherwise specified, the structures described herein also contain enriched isotopes of one or more isotopes. This means that the compound is different only in the presence of the atom that was added. For example, substitution of hydrogen with deuterium or tritium, or 13C- or 14C-enrichment of carbon. Carbon substitution Except Compounds having the structure of the present invention 、 This falls within the scope of the present invention. 【0106】 (First aspect (3)) The compounds used as examples in this application include, but are not limited to, the following compounds. 4-Bpin cyticine, 4-Hydroxycyticine, (+)4-hydroxycyticine, (-)4-methoxycyticine, 4-methoxycyticine, 4-(N-benzylamino)cyticine, (+)4-(N-benzylamino)cyticine, (-)4-(2,2,2-trifluoroethyl)cyticine, 4-(2,2,2-trifluoroethyl)cyticine 、 (-)4-(perfluorophenyl)cyticine, 4-(perfluorophenyl)cyticine, (-)4-(2-pyridinyl)cyticine, 4-(2-pyridinyl)cyticine, (-)4-(3-pyridinyl)cyticine 、 4-(3-pyridinyl)cyticine, (-)4-(4-pyridinyl)cyticine, 4-(4-pyridinyl)cyticine, 4-(4-(2-benzyloxy)pyridine)cyticine, 4-(4-(2-pyridone) ) Shichishin, (+)4-(4-(2-pyridone))cytidine 、 (-)4-iodoxycinne, (+)4-iodocyticine, (-)4-trifluoromethylcyticine, 4-trifluoromethylcyticine, 4-(N-methylamino)cyticine 、 (+)4-(N-methylamino)cyticine, 4-(N,N'-dimethylamino)cyticine, (+)4-(N,N'-dimethylamino)cyticine, 4-(N-benzoylamino)cyticine, (+)4-(N-benzoylamino)cyticine, 4-(N-morpholine)cyticine, (+)4-(N-morpholine)cyticine, 4-(N-(L-proline methyl ester)cyticine, (+)4-(N-(L-proline methyl ester)cyticine, (-)4-(N-(L-proline)cyticine, 4-(N-(L-proline)cyticine, (-)4-Cyticine carboxylic acid, 4-Cyticine carboxylate, (-)4-((trifluoromethyl)benzyl)oxycyticine, (-)4-Vinyl cythin, (+)4-vinyl cyticine, (-)4-ethylcyticine, (+)4-p-trilcyticine, (-)4-(N-2-pyridone)cytidine, 4-(N-2-pyridone)cytidine, 4-(trimethylsilylacetylene)cyticine, (-)4-(acetylenyl)cyticine, 4-(acetylenyl)cyticine, 4-(phenylacetylene)cyticine, (+)4-(phenylacetylene)cyticine, 4-(E-2-Methyl propenoate)cyticine 、 (+)4-(E-2-Methyl propenoate)cyticine, 4-(E-(2-phenylethenyl)cyticine, (+)4-(E-(2-phenylethenyl)cyticine, 4-(1-(4-phenyl)-NH-1,2,3,triazolyl)cyticine, (+)4-(1-(4-phenyl)-NH-1,2,3,triazolyl)cyticine 、 (-)4-(1,2,3-triazol-1-yl)methylpiva rate ) Shichishin 、 (+)4-(1,2,3-triazol-1-yl)methylpiva rate ) Shichishin, 4-(NH-1,2,3-triazolyl)cyticine, (+)4-(NH-1,2,3-triazolyl)cyticine, 4-(N-ethylamino)cyticine 、 (+)4-(N-ethylamino)cyticine, 4-(N-isopropylamino)cyticine, (+)4-(N-isopropylamino)cyticine, (-)4-cyanocyticine, 4-Cyanocyticine, (-)4-aminomethylcyticine, 4-aminomethylcyticine, (-)4-(N-methylaminomethyl)cyticine, 4-(N-methyl-aminomethyl)cyticine, (1R,5S,10S,11aR)-10-(aminomethyl)decahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazosin-8-one 、 Ami Nobi Cyticine derivatives 、 Methylamide Nobi Cyticine derivatives 、 (-)4-tetrazoylcyticine 、 4-Tetrazoylcyticine, (-)4-(trimethylammonium)methylcyticine, 4-(trimethylammonium)methylcyticine, (-)4-(N-acetyl)aminomethylcyticine, 4-(N-acetyl)aminomethylcyticine, 4-(N-piperazine)cyticine, (+)4-(N-piperazine)cyticine, (-)3-(trifluoromethyl)-4-bromocyticin 、 3-(trifluoromethyl)-4-bromocyticine, 3-bromo-4-iodocyticine, (+)3-bromo-4-iodocyticine, 3-bromo-4-N-methylaminocyticine, (+)3-Bromo-4- N- Methylaminocyticine. 【0107】 (synthesis) Conventional techniques for 4-position substituted cyticine compounds Limited disclosure was available. However, such transformation No convenient synthesis method for the compound has been proposed to date. To the best of the inventors' knowledge, it starts with cyticine. No synthetic pathway has been proposed to obtain a 4-position substitution analogue of cyticine. Moreover, such compounds had to be produced through total synthesis starting from monocyclic materials. See, for example, Scheme 1 in Non-Patent Document 9 and Non-Patent Document 13. 【0108】 (Further aspects) A further aspect of the present invention provides a method for preparing a 4-position cyticine analogue. This includes the following steps: 【0109】 (Step i: Step to produce a compound of chemical formula IIa) [ka] Here, R 2 , R 3 and R 4 Each of these is independently selected from a base consisting of the following: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted Possible heterocycloalkenyls, amino acids, or cyticine, or R 4 Is a protecting group also acceptable? Or, -(CH2) V -It may also be a group having the structure of FORMULA 1, where v is 0, 1 , 2, 3, 4, 5 or 6, and FORMULA 1 is the chemical formula (I) described herein. It is a compound of ). 【0110】 (Step II: Chemical formula IIb) : [ka] (In the formula, R 2 , R 3 and R 4 The above Identify And so, CompB is It is a boron complex. (A step of producing the compound by contacting the compound of chemical formula IIa with a boronating reagent.) 【0111】 (Step iii: BComp to R 1 Steps to produce a compound of chemical formula I by substitution (P) [ka] Here, R 1 teeth Hydroxy, halogen, Aliphatic which may have substituents, Cycloaliphatic, which may have substituents, Heterocycloaliphatic, which may have substituents Alis that may have substituents - Ru, Heteroalis may have substituents. - Ru, -(CH2) m -NR 6 R 7 R 8 , -(CH2) m -O-(CH2) n -R 10 , -CN, -COOR 12 , -(CH2) O -CO-(CH2) P -R 13 、 a Mino acids or their esters 、 salt Acyl chemistry 、 Protection Mamoru, also teeth C It is tisinyl. Here, R 6 and R 7 Each of these is independently selected from a base consisting of the following: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl, or R 6 and R 7 One of them is -CO-R 9 And R 6 and R 7 The other is as defined above. R 8 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl is either present or absent. R 9 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. m is 0, 1, 2, 3, 4, or 5. R 10 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. m and n are independently 0, 1, 2, 3, 4, or 5. R 12 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. R 13 The following elements are selected from the base: Hydrogen, halo, hydroxy, oxo, amino, amide, nitro, cyano, alkoxy, N -alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sul Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto Carbamoyl, methylpivalic acid, trimethylsilyl, urea, thiourea, substituted It's okay to do it. - The heterozygous may have substituents. - Lu, having substituents A alkyl group which may have substituents, a cycloaliphatic which may have substituents Possible heterocycloaliphatic, possibly heteroaliphatic having substituents - Ru, optionally substituted haloalkyl, optionally substituted alloyl, substituted A heteroaloyl which may have a substituent, an acyl which may have a substituent A potentially substituted alkenyl, a potentially substituted alkynyl, a potentially substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl Roalkenyl, possibly substituted heterocycloalkyl or substituted A good heterocycloalkenyl. o and p are independently 0, 1, 2, 3, 4, or 5. Also, the R of chemical formula I 2 , R 3 and R 4 At least one of them is not hydrogen. 【0112】 The starting material can be any compound contained within the chemical formula IIa outlined above. However, one advantage of the present invention is that this preparation method uses cyticine as a starting material. It is done for profit. Therefore, in the embodiment, R 2 , R 3 and R 4 All of it can be hydrogen. Alternatively, position R 4 The substituent may be a protecting group, or -(CH2) V -FORMUL A may be a group having the structure of 1, where v is 0, 1, 2, 3, 4, 5 or 6, and F ORMULA 1 is a compound of chemical formula (I) as described herein. 【0113】 Therefore, in the embodiment, the compound of chemical formula IIa is R 4 It may also contain a protecting group, The preparation method of the present invention involves adding a protecting group to a compound of chemical formula IIa (including cyticine). It is acceptable to include the top. Those skilled in the art are likely familiar with the technique of adding protecting groups to secondary amines, and to do so Any step of the preparation method is included within the scope of the present invention. For example, R 4 The protecting group added at position is Boc(tert-butoxylcarbonyl). In one embodiment, the preparation method provides a reagent containing Boc (e.g., (Boc)2O), It contains a suitable solvent (for example, tetrahydrofuran and sodium tricarbonate). thing) Medium This includes the step of bringing it into contact with cytisine. 【0114】 Therefore, in the embodiment of the present invention, R 4 The protecting group present at that position may be Boc. i. Other available protective groups may include the following: Formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOS) uc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (F moc), or a borated protecting group, optionally bis(pinacorato)diborane (B2Pin2) and (RO)2B- such as bis(catecorato)diborane (B2Cat2) B-(OR)2 structure Things that one possesses. Embodiments of the present invention include any protecting group commonly used in organic synthesis, for example, non-patent documents. The summaries provided in Reference 11 and Non-Patent Document 12 are available for use, and the contents of these documents This is incorporated herein by reference. 【0115】 The boronating reagent used in step ii of the preparation method of the present invention is from the field of boronating chemistry. It may be a boronation reagent known to engineers. For example, the boronating reagent may be a dialkyloxyborane or an alkylborane. Examples of dialkyloxyboranes include bis(pinacorato)diborane (B2Pin2) and bis( Catecoratoide diborane (B2Cat2) and general Formula (RO)2-BB-(OR)2 or H Any other boronation test having B(OR)2 medicine, For example, the information disclosed in Non-Patent Document 16 This document includes the following, and the contents of this document are incorporated herein by reference. An example of a boration reagent for alkylboranes is 9-borane Bi Cyclo(3.3.1) Nonan(9-B BN), B-alkyl-9-oxa-10-bora Bi Cyclo[3.3.2] Decane (OBB) D) Contains dicyamilborane, texilborane and HB(cHex)2. 【0116】 In embodiments of the present invention, the molar ratio of the boronating reagent to the starting material of chemical formula IIa is approximately 1 The range may be approximately 1 for values ​​less than or equal to 0, approximately 1 for values ​​less than or equal to 7, or approximately 1 for values ​​less than or equal to 5. Additionally or alternatively, the molar ratio of the boronating reagent to the starting material of chemical formula IIa is approximately 0.1. Top: Approximately 1, Approximately 0.2 or higher: Approximately 1, Approximately 0.3 or higher: Approximately 1, Approximately 0.4 or higher: Approximately 1 or approximately 0.5 The above: It may be within the range of approximately 1. 【0117】 In one embodiment of the present invention, the boronating reagent is more effective than the starting material of chemical formula IIa. It is acceptable if the ratio exceeds the limit. This is preferable in a given embodiment in which cyticine is used as a starting material of chemical formula IIa. It could be suitable. 【0118】 In another embodiment of the present invention, the starting material of chemical formula IIa is compared to the boronating reagent. It is acceptable if the ratio exceeds the limit. This is because a certain analogue of cytidine (e.g., N-boccytidine) is the starting point of chemical formula IIa. It may be suitable in a predetermined embodiment in which it is used as a substance. 【0119】 The reaction in step ii of the preparation method of the present invention uses a catalyst known to those skilled in the art to provide catalytic action. I'm willing to accept. In embodiments of the present invention, step ii is a catalytic action using, for example, a transition metal catalyst. To receive. In preferred embodiments, the catalyst used is iridium, palladium, zinc, nickel, and It contains / or rhodium atoms, which are part of the organic coordination complex shape It may be provided. A specific example of a catalyst that can be used in the preparation method of the present invention is Ir[(COD)(OMe)]2 Palladium(II) chloride, Pd / P(t-bu)3, Pd(dba)2, nickel chloride ( II) Contains [RhCl(cod)]2 or Et2Zn. Iodine may also be used as an additional or substitute catalyst. 【0120】 Step II of the preparation method of the present invention may be carried out in a solvent. Any solvent capable of accepting the boronation preparation method to be performed can be used in the preparation method of the present invention. ru. Examples of solvents that can be used include esters (e.g., ethyl acetate) and ethers (e.g., dio). Xanes, tetrahydrofurans), ketones (e.g., 2-butanone), sulfoxides (e.g., and Dimethyl sulfoxide, aromatic compounds (such as toluene), fluorinated aromatic compounds (such as Trifluorotoluene) and alkanes (e.g., cyclohexane, n-pentane, n-hexane) Contains xane. 【0121】 In the preparation method of the present invention, a ligand may be used in step ii. 【0122】 Examples of ligands that can be used are: ,single Aromatic or heteroaromatic compounds that may be cyclic or polycyclic thing phenanthroline compounds, etc. It may include this. Phenanthroline compounds include, but are not limited to, the following: Phenanthroline (phen), Dimethylphenanthroline (me2phen), Teto Lamethyl-1,10-phenanthroline (me4phen) and / or batphenanthroline Phosphorus (bathophen), bipyridyl compounds, for example bipyridyl (bby), di- tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bp y), dimethoxy-2,2'-bipyridyl (MeO-bpy), and / or other compounds, Examples include 1,1'-bis(diphenylphosphin)ferrocene (dppf), bis(2- Di-tert-butylphosphinofenyl) ether, 1,3-bis(diphenylphosphinofenyl) (dppp)propane, 1,2-bis(diphenylphosphin)ethane (dppe ), hexamethylbenzene (C6Me6), neocuproine, and xanthophos. Other examples include 1,2-bis(dimethylphosphin)ethane (DMPE) and Non-Patent Document 1. Including what is disclosed in 6, the contents of this document are incorporated herein by reference and illustrated below. Contains compounds. [ka] Alternatively, examples of ligands that can be used include polycyclic aromatic or heteroaromatic compounds. Includes. For example, tetramethyl-1,10-phenanthroline (Me4phen), di-te rt-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bpy) , 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-t ert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphino) Propane (dppp), 1,2-bis(diphenylphosphin)ethane (dppe), he Examples include xamethylbenzene (C6Me6) and xanthophos. Other examples include 1,2-bis(dimethylphosphin)ethane (DMPE) and Non-Patent Document 1. The contents of this document, including those disclosed in Section 6, are incorporated herein by reference. 【0123】 The inventors of the preparation method of the present invention used a ligand for a starting material of chemical formula IIa ( The molar ratio in this case is the conversion to the boronated compound of chemical formula IIb. conversion rate It was discovered that this could have an impact. did. In embodiments of the present invention, the molar ratio of ligand to starting material of chemical formula IIa is approximately 2 less than :1、 Approximately 1.5 Less than: 1, Approximately 1 Less than: 1, Approximately 0.75 Less than: 1, Approximately 0.5 Less than: 1, Approximately 0 .1 Less than: 1, Approximately 0.05 Less than: 1 The ratio is at least approximately 0.001:1. 【0124】 Boration reaction step ii is appropriate rateIf it proceeds in this manner, what kind of warmth It can be executed at any time. In embodiments of the present invention, the reaction occurs at approximately 0°C, approximately 10°C, approximately 20°C, approximately 30°C, approximately 40°C or From approximately 50℃ 、 The process may be carried out at temperatures of approximately 100°C, 120°C, or 150°C. 【0125】 The inventors of the preparation method of the present invention 、 Moles of boronating agent relative to the starting material of chemical formula IIa The ratio of the boration of chemical formula IIb did transformation into compounds conversion rate We discovered that this could have an impact. In embodiments of the present invention, the molar ratio of the boronating reagent to the starting material of chemical formula IIa is small. At least approximately 0.5:1, at least approximately 0.75:1, at least approximately 1:1, at least approximately 1 0.5:1, at least about 2:1, at least 2.5:1 or at least 3:1, A ratio of approximately 5:1 or 10:1 is also acceptable. 【0126】 The selective and effective synthesis of 4-substituted analogs of cyticine is based on the starting materials, solvents, catalysts, and ligatures. This was achieved regardless of the order in which the brand and / or boronating reagents were added. 【0127】 In one embodiment of the present invention, the boronating reagent and the starting material of chemical formula IIa are in the same reaction region. It is added at the same time or almost simultaneously. In such embodiments, even if a solvent, catalyst, and / or ligand are pre-added to the reaction region, It didn't have to happen. 【0128】 In another embodiment of the present invention, the boronating reagent is added before the starting material of chemical formula IIa is added. It may be added to the reaction region (which may optionally have a solvent, catalyst, and / or ligand pre-added). . In such embodiments, the boronating reagent is added before the starting material of chemical formula IIa is added. For example, a predetermined time such as approximately 1 minute or more, approximately 2 minutes or more, or approximately 5 minutes or more, in the reaction area (arbitrarily, solvent, It may be present (together with the catalyst and / or ligand). 【0129】 One advantage of the preparation method of the present invention is that the crude product obtained in step ii is The key is that no purification is required before i begins. Therefore, in the embodiment of the present invention, a purification step is performed between step ii and step iii. The program will not be executed. 【0130】 The advantages of the preparation method of the present invention are 、 The start of step ii) and at least step iii) The goal is to make it possible to perform the procedure within the same reaction region, that is, as a "one-pot synthesis." Therefore, in such embodiments, step iii) is chemical formula II b The borated compounds tone Made It may be initiated in the same reaction region. 【0131】 In step iii, BComp is cytosis ring Removed from the 4-position substitution, and specified above Defined substituent R 1 This is replaced by R in BComp. To avoid misunderstanding, 1 Replace with a single While it's not necessary to do this in the substitution step, it is desirable and can be seen in the following example. It is achievable. 【0132】 In embodiments of the present invention, in step iii, the final R 1 The substituent is cyticine ring The above Before being placed in 4th place, BComp was the first to have one or more intermediate R 1 Even when substituted with substituents good. In an embodiment of the present invention, the intermediate R 1 The substituents are halos, (for example, bromos, chloro) young Shiku (Iodine), benzyloxypyridine, alkyl esters (for example, methyl esters) ), alkenyl (e.g., vinyl), alkynyl (acetylene), trimethylsilyl acetyl Tylene, 1,2,3-triazole-1-yl)methylpivalate, cyano, aminomethyl , N-Boc-aminomethyl or (benzyloxy)carbonyl)piperazine-1-yl That's fine too. 【0133】 For simplicity, a borated compound of chemical formula IIb may have one or more intermediate R 1 The complete details of how each of the compounds of chemical formula I is formed via substituents are described herein. It will not be included. The reason is that a person skilled in the art would recognize and understand how such substitutions can be carried out. Because it seems so. The following examples are reactions that can be used in this regard. conditions Further details will be provided. 【0134】 In one embodiment, the preparation method of the present invention is cytidine ring The upper R 2 , R 3 and / or R 4 location It may include an additional step of performing a substitution. For example, shichishin ring If a substitution is required at the 3rd or 5th position above, this can be done. Such steps can be achieved using any techniques and reagents known to those skilled in the art. If you need advice on how such substitutions can be made, please contact us. The following examples illustrating the concept of "p" are available for reference. Additional Additional or alternative advice in this regard may include articles referenced herein. Non-patent document 16 provided is available for reference. 【0135】 Additional Additively or alternatively, the protecting group is R 4 In an embodiment where the present invention is positioned, preparation of the present invention The method is cytin ring Position 13- of The process includes a step of deprotecting the nitrogen atom. This deprotection step is performed after the completion of step ii and before the start of step iii. This may be done during step i or after the completion of step iii. Those skilled in the art will be familiar with deprotection techniques. However, Reni Ren death And some kind of advice If needed, the following examples can be referenced. 【0136】 As can be seen from the above, the preparation method of the present invention is the length of the above compound stomach Without requiring total synthesis , advantageously and for the first time, convenient preparation of cytishine analogs with 4-position substitution from cytishine itself Made allow ru. 【0137】 A further advantage of the present invention is that steps ii and iii do not involve molecular chiral rearrangement. Therefore, the preparation method is stereoselective. This offers further advantages to the industry and leads to the formation of cyticene racemic analogs. 。 【0138】 (Manufacturing method, administration, and use) Accordingly, in other embodiments of the present invention, pharmaceutically acceptable compositions are provided, and those The composition comprises any of the compounds described herein, and optionally a pharmaceutically acceptable carrier. Includes adjuvant drugs or delivery media. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents. 【0139】 Some of the compounds of the present invention are for therapeutic purposes Free In form, or, where appropriate, pharmacochemically It will be understood that these can exist as acceptable derivatives or prodrugs. According to the present invention, pharmaceutically acceptable derivatives or prodrugs are, but are not limited to, Pharmacologically acceptable salts, esters, salts of such esters, or to the therapeutic target in which they are needed. When administering, the compounds described elsewhere in this specification, or the metabolites or is remaining fastening Can be provided indirectly or directly. 、 This includes any other adducts or derivatives. 【0140】 As used in this document Na The term "pharmaceutically acceptable salt" is a valid medical judgment. Within the specified range, without excessive toxicity, irritation, allergic reactions, etc., and without contact with human or lower animal tissue. Suitable for use in this way, with a reasonable effect / risk ratio. Suitable It refers to salt. "Pharmacologically acceptable salt" is any salt of the compound of the present invention, or a salt of its ester. That is, When administering to a patient 、 The compound of the present invention or Inhibitory activity the metabolite or Residue Can provide fasteners directly or indirectly. thing, It means... 【0141】 Pharmaceutically acceptable salts are known in the industry. For example, SMBerge et al., in Non-Patent Document 14, describe a pharmaceutically acceptable salt in detail. This is described in [reference], and this reference is incorporated herein. A pharmaceutically acceptable salt of the compound of the present invention can be obtained from a suitable inorganic or organic acid or base. Origin vinegar This includes things that... 【0142】 Examples of pharmaceutically acceptable, non-toxic acid-added salts include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, Inorganic acids such as sulfuric acid and perchloric acid, or, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, and citric acid. , organic acids such as succinic acid or malonic acid in Formed, or used in industries such as ion exchange. Using other methods formed It is a salt of an amino group. 【0143】 Other pharmaceutically acceptable salts include the following: Adipine salt, alginate, ascorbate, aspartate, benzenesulfonate Nat, benzoic acid salt bisulfates, borates, butyrates, camphor Salt salts camphor sulfonate , citric acid salt Cyclopentanepropionate, digluconate, dodecyl sulfate salt , Eta Sulfonates, formates, fumarates, glucoheptonic acid salt , glycerophosphate salt , group Con Salt salts hemisulfate, heptanoic acid salt hexanoate, hydroiodide, 2-hydroxy - Ethanesulfonates, lactobionic acid salt lactic acid salt , lauric acid salt , Lauri Lu Sulfur acid salt , Ngo salts, maleates, malonic acid salt methanesulfonic acid salt , 2-naphthalene sulfonic acid salt nicotinic acid salt nitrates, oleates, oxalates, palmites bloodAcid salt pamoic acid salt , Pe Cutinate, persulfate, 3-phenylpropionate, phosphoric acid salt picrate, pival acid salt , propionate, stearate, succinic acid salt , sulfuric acid salt , tartrate, thio C An acid Salt, p-toluenesulfonic acid salt , undecanoate, valerate, etc. 【0144】 From the appropriate base Origin The salts produced are alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl ) Contains 4 salts. 【0145】 The present invention also envisions the quaternization of basic nitrogen-containing groups in the compounds disclosed herein. Products that are soluble or dispersible in water or oil are obtained through such quaternary classification. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, and calcium. Contains elements such as calcium and magnesium. Furthermore, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium and quaternary ammonium. , and containing amine cations, For example, halogen ion , hydroxy acid ion carboxylic acid ion , sulfuric acid ion ,phosphoric acid ion ,nitric acid ion , lower alkyl sulfonic acid ion , and ants - Ru sulfonic acid ion Formed using counterions such as ru . 【0146】 As described above, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, This includes auxiliary agents or delivery media, which include the following as used herein: 1 and all 、 Solvent, diluent, or other liquid solvent, dispersion or suspension Takuho Auxiliaries, surfactants These include isotonic agents, thickening agents or emulsifiers, preservatives, solid binders, lubricants, etc., and the desired special Suitable for a specific dosage form. 【0147】 Non-patent document 15 describes pharmaceutically acceptable compositions and their preparations. Made Known technologies for Formulation Various carriers used in formation are disclosed. For example, compositions that produce undesirable biological effects or are pharmaceutically acceptable. of Other transformations Any conventional transport medium may mix with the compound of the present invention by interacting with the compound in a harmful manner, etc. Unless otherwise possible, its use is considered to be within the scope of the present invention. 【0148】 Some examples of materials that can serve as pharmaceutically acceptable carriers are, but are not limited to, This includes the following: Ion exchanger, alumina, aluminum stearate, lecithin, serum protein, example For example, human serum albumin, buffering agents, such as phosphates, glycine, sorbic acid or sorbate. Potassium rubate, a mixture of partially glycerides of saturated vegetable fatty acids, water, salt or electrolyte, e.g. Protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride Zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylic acid rate , wax, polyethylene-polyoxypropylene-block polymer, wool tallow, Sugars, such as lactose, glucose, and saccharose; starch, such as corn starch. Stretch and potato starch, cellulose and its derivatives, such as carboxymethylcellulose. Sodium cellulose, ethylcellulose and cellulose acetate, tragacanth powder, malt, ze Latin, talc, excipients, such as cocoa. butter suppository wax, oil, for example, peanut Glutinous oil, cottonseed oil, vinaigrette oil, sesame oil, olive oil, corn oil and soybean oil, glycerin Coal, for example propylene glycol or polyethylene glycol, ester, for example Ethyl oleate and ethyl laurate, agar, buffer, for example, magnesium hydroxide and aluminum hydroxide, alginate, pyrogen-free water, isotonic saline, Ringer The solution, ethyl alcohol and phosphate buffer, and other non-toxic compatible lubricants, for example, Sodium uryl sulfate and magnesium stearate, and colorants, release agents, coatings The composition of ingredients, including flavoring agents, sweeteners, fragrances, preservatives, and antioxidants, may vary depending on the discretion of the manufacturer. It can exist in objects. 【0149】 The pharmaceutically acceptable compositions of the present invention are used in humans and depending on the severity of the infection being treated. In other animals, orally, rectally, parenterally, intravesically, vaginally, intraperitoneally, locally (powder, soft). It can be administered by means of an ointment or drops, buccally, orally, or as a nasal spray, etc. ru. In some examples, the compound of the present invention was found to produce a desired therapeutic effect in one day. The daily dose is approximately 0.01 mg / kg to approximately 50 mg / kg of the subject's body weight, preferably approximately 1 mg / kg The dosage level is approximately 25 mg / kg from kg, administered orally or parenterally at least once a day. You can. 【0150】 Oral liquid administration methods are not limited to this, but include pharmaceutically acceptable emulsions, micro-enzymes, etc. This includes emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosing form may contain inert diluents commonly used in the industry. Examples include water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, Sulfuric alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoin Benzyl acid, propylene glycol, 1,3-butylene glycol, dimethylformamine Oil (especially cottonseed oil, peanut oil) oil ,cone oil ,germ oil ,olive oil Castor oil and sesame oil ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and so Rubitan fatty acid ester, and A mixture thereof is an example. In addition to inert diluents, oral compounds also serve as adjuvants, such as wetting agents, emulsifiers, and suspending agents. It may contain sweetening agents, flavoring agents, and fragrance agents. 【0151】 An injectable preparation, such as a sterile injectable aqueous or oily suspension, is appropriately dispersed. Agent Alternatively, it may be formed by known techniques using wetting agents and suspending agents. Sterilized, injectable preparations, as well as non-toxic, parenterally acceptable diluents or solvents. at Extinction This may be a sterilized injectable solution, suspension, or emulsion, for example, 1,3-butanediol It can also be used as a solution of ru. Among the acceptable transfer media and solvents, do The ingredients are water, Ringer's solution, and the United States Pharmacopeia. And physiological saline solution. Furthermore, sterilized fixing oil has conventionally been used as a solvent or suspension medium. Therefore, any sterile fixative oil can be used, containing synthetic monoglycerides or diglycerides. ru. Furthermore, fatty acids such as oleic acid adjust the composition of the injected substance. Made It is used in [location / situation]. 【0152】 Injectable preparations are, for example, passed through a bacterial-retaining filter. vinegar By filtration, or before use, sterilize with water or other The sterilization of a sterile solid composition that can be dissolved or dispersed in a sterile injectable medium. It can be sterilized by incorporating a microbial agent. 【0153】 To prolong the effects of the compound of the present invention, the absorption of the compound from subcutaneous or intramuscular injection is slowed. It is often desirable to do so. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with low water solubility. ru. Furthermore, the absorption rate of a compound depends on its dissolution rate, that is, on its crystal size and crystal form. It is possible. Alternatively, the delayed absorption of the parenterally administered compound form may be due to the dissolution of the compound within the oily delivery medium. This is achieved by dissolving or suspending. Injectable depot forms include, for example, polylactide-polyglyco Ri Biodegradable polymers such as It is produced by forming a substrate in which the compound is microencapsulated. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound The release rate can be controlled. other biodegradable Examples of polymers include poly(orthoesters) and poly(anhydrides). nothing. Depot-type injectable formulations can also be transformed into liposomes or microemulsions that are miscible with biological tissues. It is formulated by incorporating a mixture of ingredients. 【0154】 For administration via rectal or vaginal composition The substance is the compound of the present invention It is a solid at ambient temperature, It becomes liquid at body temperature and therefore melts in the rectal or vaginal cavity, releasing active compounds, for example. Cocoa butter, polyethylene glycol, or suppository wax, etc., are appropriate non-irritating ingredients. Forming agent or carrier and Suppositories that can be compounded by mixing are preferred. stomach . 【0155】 Solid dosage forms for oral administration include capsules, tablets, granules, powders, and granules. In such a solid dosage form, the active compound is at least one inert compound, such as It is mixed with pharmaceutically acceptable excipients or carriers. Sodium citrate or dicalcium phosphate, and / or a) Fillers or bulking agents, such as starch, lactose, saccharose, glucose, ma Nitol and silicic acid, b) Binders, for example, carboxymethylcellulose, alginate, gelatin Chin, polyvinylpyrrolidone, saccharose and acacia, c) Moisturizers, e.g., glycerol, d) Disintegrants, e.g., agar, calcium carbonate, potato starch, or tapioca starch. Hmm, alginic acid, certain silicates, sodium carbonate, e) Dissolution retarders, e.g., paraffin, f) Absorption enhancers, for example, quaternary ammonium compounds, g) Wetting agents, for example, cetyl alcohol and glycerol monostearate, h) Absorbents, such as kaolin and bentonite clay, and i) Lubricants, e.g., talc, calcium stearate, magnesium stearate, Solid polyethylene glycol, sodium lauryl sulfate 、 and mixtures thereof. In the case of capsules, tablets, and cereal tablets, the dosage form may also include a buffering agent. 【0156】 Similar types of solid compositions also include lactose or milk sugar and high molecular weight polyethylene. Ricoh Ru Used as a filler for soft or hard gelatin capsules with the use of excipients such as the above. It's okay if that happens. Solid dosage forms such as tablets, dragees, capsules, granules, and granules are, for example, enteric coated. Using coatings and shells such as other coatings known in the coating and pharmaceutical formulation industries It can be formulated as follows. They may optionally contain an opacifying agent, and they may contain only the active ingredient, or preferably the intestinal tract The composition may be released at a predetermined location in a manner that is arbitrarily delayed. Can be used Embedded type Examples of treatment methods include polymerization. body Includes substances and waxes. Similar types of solid compositions also include lactose or milk sugar and high molecular weight polyethylene. Used as a filler for soft or hard gelatin capsules with excipients such as recourse. It's okay if that happens. 【0157】 The active compound is also in the form of a microcapsule using one or more of the above excipients. That's good too. Solid dosage forms such as tablets, dragees, capsules, granules, and granules are, for example, enteric coated. Coatings, release control coatings, and other coatings known in the pharmaceutical formulation industry. It can be formulated using ginger and shell. In such fixative formulations, the active compound is, for example, saccharose, lactose, or starch. It may be mixed with at least one inert diluent. Such dosage forms are also common practice. Other than inert diluents, For example, tablet lubricants, Furthermore, tableting aids containing magnesium stearate and microcrystalline cellulose, etc. The pursuit Canada It may contain substances. In the case of capsules, tablets, and cereal tablets, the dosage form may also include a buffering agent. They may optionally contain an opacifying agent, and they may contain only the active ingredient, or preferably the intestinal tract The composition may be released at a predetermined location in a manner that is arbitrarily delayed. Can be used Embedded type Examples of treatment methods include polymerization. body Includes substances and waxes. 【0158】 The dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, and lotions. Gel, powder, solution, spray, inhalation Agent Or includes a patch. The active ingredient may, if necessary, be a pharmaceutically acceptable carrier and any required preservatives or It is mixed in a sterile state with a buffering agent. Ophthalmic preparations, ear drops, and eye drops are also considered to be within the scope of this invention. Furthermore, the present invention takes into consideration the use of transdermal patches, and it body Controlling the transport of compounds into the body It has the additional advantage of being able to do so. Such dosage forms can be prepared by dissolving and dispersing the compound in a suitable medium. Absorption enhancers also affect the flow of compounds through the skin. re It can be used to increase [something]. The speed is controlled by providing a speed control membrane or by dispersing the compound within a polymer matrix or gel. It can be controlled by doing so. 【0159】 The compounds and pharmaceutically acceptable compositions of the present invention are used in combination for therapeutic purposes, i.e., the compounds and drugs A scientifically acceptable composition may be used simultaneously with or before one or more other desired therapeutic or medical procedures. It will also be understood that it may be used in a way that it can be administered at or after the drug. A combination of specific treatments (therapy or procedure) that uses a combined medication plan is a desirable treatment. Medical treatment and / or treatment Place and , the desired therapeutic effect to be achieved and Suitability They will take that into consideration. The treatment used achieves the desired effect on the same disease (e.g., creative compound It is possible to achieve the ability to administer the substance simultaneously with other drugs used to treat the same disease, It will also be understood that different effects can be achieved (for example, controlling adverse effects). As used in this document Further treatments to treat or prevent a specific disease or symptom However, it is usually administered , Known as "appropriate for the disease or condition being treated". It is . 【0160】 The amount of further therapeutic agents present in the composition of the present invention includes the therapeutic agent as the sole active agent. This will be about the same amount as the amount normally administered in the composition. Preferably, In this specification The amount of further therapeutic agents in the disclosed composition is such that the agent is only A range of approximately 50% to 100% of the amount typically present in a composition containing one therapeutic active agent. That will likely be the case. 【0161】 The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be used, for example, in artificial organs, artificial valves, etc. Composition for coating implantable medical devices such as blood vessels, stents, or catheters. I don't mind being absorbed. Accordingly, in other embodiments, the present invention relates to the classes and subclasses described herein. The compound of the present invention is outlined in the description below. , and suitable for coating the aforementioned portable devices. ta carrier Composition for coating portable devices, including things include. 【0162】 In yet another embodiment, the present invention relates to the classes and subclasses described herein, as described above. The compound of the present invention is outlined below. , and suitable for coating the aforementioned portable devices Carrier A portable machine coated with a composition containing The vessel include. Suitable coatings and overall adjustment of coated portable devices Made This is a patent document. 3. As described in Patent Documents 4 and 5. The coating is usually a hydrogel polymer. - Polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid These are biocompatible polymer materials such as ethylene vinyl acetate and its mixtures. 【0163】 The coating is composition To give controlled release characteristics within the material, optionally fluorosilicone Ko - Appropriate topcoats of polysaccharides, polyethylene glycol, phospholipids and combinations thereof. It's fine if it's covered even more. [Modes for carrying out the invention] [Examples] 【0164】 (key Made (and examples) (Extraction of (-)-cyticine from Laburnum seeds) As described above, the preparation method of the present invention is advantageous in that it uses the Laburnum tree called *Citrium*. We start with naturally occurring compounds that can be isolated. Cyticene is commercially available, Those skilled in the art are likely well familiar with the preparation methods for extracting cyticine from natural sources. However, Therefore The following preparation method of offer vinegar ru. 【0165】 Powdered laburnum seeds (332g), dichloromethane (465ml), methanol ( MeOH and ammonium hydroxide (59 ml, 35% aqueous solution) were mechanically stirred at room temperature for 3 days. The mixture was vigorously stirred with a mixer (400 rpm). The mixture was filtered until the solid matter was removed and the filtrate was colorless. Washed with dichloromethane (4 x 200 mL) until the end. The filtrate was 3 M salt acid (330 mL) The mixture was acidified to pH 1 and stirred for 2 hours (350 rpm). Separate the two layers , water layer Ammonium hydroxide (70 mL, 35% aqueous solution) pH 9 ~ It slowly becomes basic up to 10. The mixture was stirred for 2 hours and extracted with dichloromethane (10 × 70 mL). together did The organic layer is dried with sodium sulfate, filtered, and concentrated in a vacuum to obtain a yellowish-brown solid. Cyticeine (4.76g) was produced. Recrystallization from toluene (5mL) yielded a solid ( -)- It produced cyticine (4.27g, 1.3%). 【0166】 (Addition of protecting group - N-Boc cyticine (56)) [ka] (-)-cyticine (6.4) in tetrahydrofuran (135 mL) and water (70 mL) (1 g, 33.7 mmol) and di-tert-butyl dicarbonate (9.3 mL, 40.4 ml) A solution of sodium carbonate (4.28 g, 40.4 mmol, 1 ol) is added to the solution. M ) add The mixture was stirred for 3 days, and then diluted with ethyl acetate (200 mL) and brine (70 mL). The solution was found. The aqueous layer was extracted with ethyl acetate (3 x 150 mL). Together The organic layer is salted (15 Washed with 0 mL, dried with sodium sulfate, filtered, and concentrated under vacuum. Crude reaction mixture. The object is silica gel Ru Flash column chromatography [Dichloromethane / methanol ( (3% methanol) It is purified by and produces a colorless solid 56 (9.10g, 93%). I took it out. [ka] The spectroscopic properties of this compound were consistent with data available in the literature. 【0167】 (Removal of protecting group) As illustrated below, a wide range of 4-substituted cyticine derivatives can be used in the preparation method of the present invention. To further Made This is possible. In such compounds, tert-butoxycarbonyl (Boc) protection is used. It is desirable to remove the group. In the following examples, B is present in the 4-substituted cyticine analog. The OC protecting group was removed by one of the following two preparation methods. 【0168】 (General Procedure A) Cyticine derivative in methanol (0.1 M 0.5 (substrate concentration) M Dissolve in hydrogen chloride solution The reaction mixture was stirred at room temperature for 72 hours. The solvent was then removed under vacuum. residue The most It was dissolved in a small amount of methanol, and then acetone ten times the volume of methanol was slowly added. The liquid was stirred for 2 hours. The precipitate was then collected by filtration and washed with cold acetone. 【0169】 (General Procedure B) A derivative of cyticine is dioxane (0.1 M Substrate concentration) 4.0 M Dissolve in hydrogen chloride solution The reaction mixture was stirred at room temperature for 72 hours. The solvent was then removed under vacuum. residue of It was dissolved in the smallest possible amount of methanol, and then acetone ten times the volume of methanol was slowly added. The solution was stirred for 2 hours. The precipitate was then collected by filtration and washed with cold acetone. 【0170】 (Example 1 - N-Boc-4-Bpin cyticine (58)) [ka] Schlenk tubes filled with N-Boc-cyticine, 56 (290 mg, 1.00 mmol), bis -(Iridium-cyclooctadienyl-methoxide) (6.6 mg, 0.01 equivalents), 4,4'-2,2'-di-tert-butylbispyridine (5.4 mg, 0.02 equivalents) And filled with bis(pinacolato)-diborane (177 mg, 0.7 equivalents). Schlenk The tube was placed under vacuum and treated with nitrogen three times. Backfill Then, tetrahydrofuran (1.4 mL) In addition, the mixture was heated at 80°C for 24 hours. The mixture was cooled to room temperature and concentrated in a vacuum. Purification (see below) was possible but not required. The crude reaction mixture required further purification. It was not used in many subsequent conversions. 【0171】 Flash column chromatography of crude reaction mixture with silica gel [dichloromethane / Purified with methanol (5% methanol), it is a pale orange foam 58(1 80mg, 43%, silica Above It is an unstable compound, and only the pure fraction is collected. 1 H- We obtained a complete conversion (by NMR). [ka] 【0172】 (Example 2a-N-Boc-4-hydroxycyticine(66)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 1.0 mmol scale in The above discussion in Example 1 General procedure for the borylation reaction of cyticine Prepared according to did. 【0173】 The boration reaction mixture was cooled to 0°C and dissolved in tetrahydrofuran (8.6 mL). 3 M Add sodium hydroxide (1.0 mL, 3.0 mmol), and then add 30% Slowly add aqueous hydrogen peroxide (1.0 mL) over a period of 5 minutes or more. Stir the mixture at 0°C for 30 minutes. Then, the mixture was stirred overnight at room temperature under air. The mixture was diluted with water (3 mL), and the aqueous layer was separated. Washed with lolomethane (3 x 5 mL). The aqueous layer was divided into 3 M salt acid pH4 ~ Acidify up to 5, Extraction was performed using chloromethane (5 x 5 mL). Together The organic layer was dried with sodium sulfate. The mixture was filtered and concentrated under vacuum. The crude reaction mixture was then subjected to flash column chromatography using silica gel. Purified with Raffy [dichloromethane / methanol (5% methanol)], it has a grayish tint. It produced 66 (240 mg, 79%), a white solid. [ka] 【0174】 (Example 2b-(+)4-hydroxycyticine hydrochloride (67)) [ka] General procedure A Therefore A grayish-white solid formed from 66 (0.79 mmol) alcohol. It is the body alcohol It produced 67 (184 mg, 96%). [ka] 【0175】 (Example 3a-N-Boc-4-methoxycyticine (68)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cyticine 58, 0.50 mmol in The Shichishi discussed above in Example 1 General procedure for the boration reaction of 2 Prepared according to did. 【0176】 Newly Made The copper(II) sulfate pentahydrate (37 mg, 0) was found in methanol (5 mL). (0.15 mmol), potassium hydroxide (84 mg, 1.50 mmol) and molecular syrup -4 Å (300 mg) solution was stirred under a nitrogen atmosphere for 5 hours. Syringe Use Ho The reaction mixture was transferred to the crude product of the chemical reaction. The reaction mixture was stirred under reflux in an oxygen atmosphere for 18 hours. Dilute the solution with 10 mL of methanol, filter it through a Celite pad, and remove the solvent under vacuum. Removed. The crude product was treated with ammonia solution (15 mL, 15% aqueous solution) and dichloromethane (15 The solution was partitioned into (mL) and the aqueous phase was extracted with dichloromethane (4 × 15 mL). The organic phase was then extracted. together death The mixture was dried over magnesium sulfate, filtered, and concentrated. The crude reaction mixture was then flash-columned. Purified by chromatography [dichloromethane / methanol (2% methanol)], It produced 69 (130 mg, 81%), a colorless solid. [ka] 【0177】 (Example 3b-(-)4-methoxycyticine (69)) [ka] Dichloromethane (4 mL, 0.1 M ) Solution of ether 68 (130 mg, 0.42 Add trifluoroacetic acid (0.3 mL, 10 equivalents) to mmol all at once, and the reaction mixture is heated in a room. The mixture was stirred at warm temperature for 18 hours. Water (10 mL) was added, and the aqueous phase was converted to dichloromethane (3 × 10 mL). Washed with . The aqueous phase was basicized with ammonia (10 mL, 15% aqueous solution) and dichlorometh Extraction was performed using a 3 x 10 mL solution. The organic phase was extracted. together Then, dry with magnesium sulfate and filter. It was then concentrated to produce a colorless solid of 69 (76 mg, 85%). [ka] 【0178】 (Example 4a-N-Boc-4-(N-benzylamino)cyticine(70)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 5.00 mmol scale in The details are shown in Example 1 above. General procedure for the borylation reaction of cyticine Prepared according to did. 【0179】 In a separate container, copper(I) acetate water in acetonitrile (20 mL) (300mg, 1. Potassium fluoride (320 mg, 5.5 mmol) and molecular sieves 4 Å (4g) 15 ~ The mixture was stirred for 20 minutes. The crude product of the boration reaction was mixed with acetonitrile (5 ml). At L Dissolution And, the copper solution Syringe The crude reaction mixture was added and stirred for 10 minutes. Then, distillation was performed again. Add the prepared benzylamine (1.1 mL, 10.0 mmol) and the reaction mixture under an oxygen atmosphere. The mixture was heated under reflux for 18 hours. The reaction mixture was cooled and filtered through Celite®. The reaction was concentrated. The crude product of the reaction was mixed with ammonia (25 mL, 15% aqueous solution) and dichloromethane. The solution was divided into (25 mL) and the aqueous phase was extracted with dichloromethane (4 × 15 mL). together Ta The organic phase was dried with magnesium sulfate, filtered, and concentrated. The crude reaction mixture was flashed. Purification by ram chromatography [dichloromethane / methanol (2% methanol)] Therefore, 70 (1.70g, 72%) of the colorless solid was used. inseparable It was produced along with impurities. [ka] 【0180】 (Example 4b-(+)4-(N-benzylamino)cyticine(71)) [ka] Dichloromethane (43 mL, 0.1 M Solution of secondary amine 70 (1.70g, 4 Add trifluoroacetic acid (0.4 mL, 10 equivalents) to 0.30 mmol of the solution and cook at room temperature until 1 The mixture was stirred for 6 hours. Water (20 mL) was added, and the aqueous phase was washed with dichloromethane (3 × 30 mL). Then, the aqueous phase was basicized with ammonia (10 mL, 15% aqueous solution), and dichloromethyl Extraction was performed using a tungsten tube (4 x 10 mL). Together The organic layer was dried with magnesium sulfate and filtered. When it is concentrated, it is a colorless solid. 71 (970 mg, 76%) was produced. [ka] 【0181】 (Example 5-(-)4-(2,2,2-trifluoroethyl)cyticine hydrochloride (79 )) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Cytisine 58, 1.00 mmol scale in Details are shown in Example 1 above. General procedure for the borylation reaction of cyticine Prepared according to did. Add tris(dibenzylideneacetone)dipalladium(0)(2) to the crude borylation reaction mixture. 3 mg, 1 mmol), 2-dicyclohexylphosphino-2',4',6'-Tori Sopropylbiphenyl (Xphos) (47 mg, 2.5 mmol%), Cesium fluoride (4 Add 50 mg (3.0 equivalents) and cuprous chloride (99 mg, 1.0 equivalent) and shu The Lenck tube is placed under vacuum and subjected to three passes with nitrogen. Backfill The reaction mixture was N,N-dimethyl Sulfurformamide (4.0 mL, 0.25 M ) and 2,2,2-trifluoroethyl iodine Dissolve in Zide (0.19 mL, 2.0 equivalents), then add water (0.14 mL, 8.0 equivalents). The reaction mixture was stirred at 65°C for 18 hours. The solvent was removed under vacuum, and the crude reaction mixture was converted into acetate. The solution was divided into 15 mL of chill and 15 mL of water. The aqueous phase was extracted with ethyl acetate (3 × 15 mL). I released the organic phase. together The mixture was then dried with magnesium sulfate, filtered, and concentrated. Flash column chromatography of the compound [dichloromethane / methanol (2% methanol)] Purification by () yields a colorless solid N-Boc-4-(2,2,2-triflu Oroethyl)cyticine (190 mg, 50%) was produced. The obtained trifluorocyticine Syn derivatives Follow General Procedure A Deprotect hand Converted to a hydrochloride salt, it becomes a colorless solid ligand 79 (93 mg, 34%) was produced. [ka] 【0182】 (Example 6-(-)4-(perfluorophenyl)cyticine hydrochloride (75)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Cytisine 58, 1.00 mmol scale in Details are shown in Example 1 above. General procedure for the borylation reaction of cyticine Prepared according to did. 【0183】 Bromopentafluorobenzene (0.15 mL, 1.2 equivalents), dichlorobis(trif) Phenylphosphine) palladium (35 mg, 0.05 equivalent) and cesium carbonate (410 mg) Add tetrahydrofuran (5 g, 2.5 equivalents) to the crude product of the boration reaction, and the reaction mixture is converted to tetrahydrofuran (5 mL, 0.2 M The reaction mixture was dissolved in ammonia (25%) and stirred at 80°C for 18 hours. The solution was diluted (15% aqueous solution) and the aqueous phase was extracted with ethyl acetate (4 × 25 mL). together death The organic phase was dried with magnesium sulfate, the solid was filtered, and the solvent was evaporated under vacuum. Flash column chromatography of crude reaction mixture [dichloromethane / methanol (1 Purification with 0.5% methanol yields a colorless solid of 74 (509 mg, 99%). (Dichlorobis(triphenylphosphine)palladium) Contains contamination ) produced. [ka] General procedure A Therefore , N-Boc-protected cyticine derivative 74 (1.1 mmol) from, It produced 4-(perfluorophenyl)-cyticine hydrochloride 75, a colorless solid. . [ka] 【0184】 (Example 7a-N-Boc4-(2-pyridinyl)cyticine (100)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Cytisine 58, 1.00 mmol scale in In Example 1, the above details The general procedure for the borylation reaction of cyticine described above. Prepared according to did. 【0185】 Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenyl Phosphine palladium (35 mg, 5 mol%) was added to the crude mixture of the borylation reaction. Add dried tetrahydrofuran (10 mL), then 2-bromopyridine (115 μL) (L, 1.2 mmol) was added. The mixture was stirred at 80°C for 48 hours. Allow the reaction to cool to room temperature. It was cooled, diluted with ethyl acetate (50 mL), and filtered through Celite®. Wash the chamber with water (10 mL) and salt water (10 mL), dry with sodium sulfate, and filter. The crude product was concentrated in a vacuum. The crude product was subjected to flash column chromatography using silica gel. [Lolomethane / methanol (4% methanol) + 0.1% ammonia (15% aqueous solution)] The oil was refined to produce 100 (205 mg, 56%), a yellow oil. The product is further refined. It was used in the next step without being used. [ka] 【0186】 (Example 7b-(-)4-(2-pyridinyl)cyticine dihydrochloride (101)) [ka] General procedure A for deprotection of cyticine in accordance with N-Boc-4-(2-pyridinyl) -Citrine 100 (0.55 mmol) from 10¹ (99.2 mg, 6) is a colorless solid. It produced 3%. [ka] 【0187】 (Example 8-(-)4-(3-pyridinyl)cyticine dihydrochloride (104)) [ka] Schlenk tube N-Boc-4-bromocyticine 61 (370 mg, 1.0 mmol) ), Tris(dibenzylideneacetone)dipalladium(0)(9.0mg, 1 mmol%) ), tricyclohexylphosphine (7.0 mg, 2.4 mmol%) and 3-pyridyl Ni Fill with ruboronic acid (140 mg, 1.1 equivalents), place under vacuum, and fill with nitrogen three times. Backf ill The mixture was mixed with dioxane (2.6 mL, 0.4 M ) dissolve , Tricalcium phosphate water Solution (360g, 1.7 equivalents, 1.3 M )of Syringe The mixture was added dropwise for more than 10 minutes. The substance was heated at 100°C for 18 hours. The solution was filtered through Celite, and the solvent was removed under vacuum. Removed. Ammonia solution (5 mL, 15% aqueous solution) was added, and the aqueous phase was converted to dichloromethane (4 × Extracted using 25 mL. together The resulting organic phase was dried with magnesium sulfate, filtered, and concentrated. The obtained N-Boc-4-(3-pyridinyl)-cyticine derivative was used. General procedure A Therefore Deprotect hand It was converted to hydrochloride, yielding a colorless solid of 104 (210 mg, 78%). . [ka] 【0188】 (Example 9a-(-)N-Boc-4-(4-pyridinyl)cyticine (102)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 1.00 mmol scale in The details are described in Example 1 above. General procedure for the borylation reaction of cyticine Prepared according to It was done. 【0189】 Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenyl Phosphine palladium (35 mg, 5 mol%) was added to the crude mixture of the borylation reaction. Add dried tetrahydrofuran (10 mL), then 4-iodopyridine (246 mL) (g, 1.2 mmol) was added. The mixture was stirred at 80°C for 48 hours. Allow the mixture to cool to room temperature. It was cooled, diluted with ethyl acetate (50 mL), and filtered through Celite®. The chamber was washed with salt water (10 mL), dried with sodium sulfate, filtered, and concentrated under vacuum. The crude mixture was subjected to flash column chromatography using silica gel [dichloromethane / methane]. Purified with [Tanol (5% methanol) + 0.1% ammonia (15% aqueous solution)], and then olen It produced a dark-colored oil called 102 (312 mg, 85%). The product was then processed without further refining. It was used in the following step. [ka] 【0190】 (Example 9b-(-)4-(4-pyridinyl)cyticine dihydrochloride (103)) [ka] General Procedure A in accordance with , N-Boc-4-(4-pyridinyl)cyticine 102 (0.85 mmol) from It yielded a pale orange solid, 103 (122 mg, 48%). [ka] 【0191】 (Example 10a-N-Boc-4-(4-(2-benzyloxy)pyridine)ci (105) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 1.00 mmol scale in The above details are described in Example 1. General procedure for the borylation reaction of cyticine Prepared according to It was done. 【0192】 Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenyl Phosphine palladium (35 mg, 5 mol%) was added to the crude mixture of the borylation reaction. Add dried tetrahydrofuran (5.0 mL), and then add dried tetrahydrofuran. (5.0mL )of 4-Bromo-2-benzyloxypyridine (316 mg, 1.2 mmol) l ) melt The liquid was added. The mixture was stirred at 80°C for 48 hours. The solution was cooled to room temperature and acetic acid was added. Diluted with Chill (50 mL) and filtered through Celite (registered trademark). The organic layer was then separated into water (10 Wash with (mL) brine (10mL), dry with sodium sulfate, filter, and concentrate under vacuum. The crude reaction mixture was subjected to flash column chromatography of silica gel [dichlorometh Purify with [methanol (4% methanol) + 0.1% ammonia (15% aqueous solution)] It was a pale yellow oil, yielding 105 (485 mg, 99%) with almost no impurities. The product was used in the next step without further refinement. [ka] 【0193】 (Example 10b-(+)4-(4-(2-pyridone))cyticine hydrochloride (106)) [ka] N-Boc4-(4-(2-benzyloxy)pyridine in methanol (5.7 mL) ) In a solution of cyticine 105 (448 mg, 0.95 mmol), dark salt acid (2.9m L) of The mixture was heated under reflux for 24 hours. After cooling to room temperature, the solvent was removed under vacuum. The crude product was diluted with methanol (55 mL). Dissolution Then, acetone (550 mL) was added. Mixing The mixture was stirred for 2 hours. The solid was filtered, washed with acetone, and dried, resulting in a pale yellow solid. It produced 06 (254 mg, 84%). [ka] 【0194】 (Example 11-(-)N-Boc-4-chlorocyticin (59)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 1.00 mmol scale in The above example 1 illustrates the general outline. General procedure for the borylation reaction of cyticine Prepared according to It was done. 【0195】 Boronation reaction crude mixture in methanol (2.5 mL) Dissolve I did. Water (2.5mL) )of salt Copper chloride (470 mg, 3.5 mmol ) melt Add the liquid and leave the mixture at room temperature under air for 4 days. The mixture was stirred. The mixture was diluted with ammonium hydroxide (10 mL, 15% aqueous solution), and the aqueous phase was mixed. Extraction was performed using chloromethane (3 x 10 mL). Together The other layer was dried with sodium sulfate. The solution was filtered and concentrated in a vacuum. The crude product was then subjected to flash column chromatography using silica gel. Purified with ethyl acetate, it is a grayish-white solid (59 (247 mg, 76%) ) produced. [ka] 【0196】 (Example 12-(-)4-chlorocyticin(60)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 1.00 mmol scale in Example 1 outlines the above. General procedure for the borylation reaction of cyticine Prepared according to It was done. 【0197】 In a sealed tube, the crude boronation mixture was dissolved in methanol (2.5 mL). Dissolution copper chloride Aqueous solution of (470 mg, 3.5 mmol, 1.4 M ) was added. The reaction mixture was heated at 90°C for 18 hours. The reaction products were stirred. cooling Then, dilute with ammonium hydroxide (5 mL, 15% aqueous solution), The aqueous phase was extracted with dichloromethane (5 x 5 mL). Together The organic layer was concentrated in a vacuum. . Residue residue 3 M salt acid The aqueous layer was divided into (5 mL) and dichloromethane (5 mL). Wash with methane (2 x 5 mL), concentrated water Ammonium oxide solution pH 10 to It becomes basicized, Extraction was performed using chloromethane (5 x 5 mL). Together The organic layer was dried with sodium sulfate. The crude reaction mixture was filtered and concentrated under vacuum. Purified with Raffy [dichloromethane / methanol / ammonia (89:10:1)], then ash A colored white solid, 60 (179 mg, 80%), was produced. High purity sample The substance was obtained by recrystallization in toluene. [ka] 【0198】 (Example 13a-(-)N-Boc-4-iodocyticine(64)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 5.00 mmol scale in Details are shown in Example 1 above. General procedure for the borylation reaction of cyticine Prepared according to It was done. Copper(II) nitrate trihydrate (2.4 2g (10.0 mmol), Yo Ammonium (1 (0.45g, 10.0 mmol) and Molecular Sieve 4 Å (500 mg) is crudely boronized. In addition to the reaction mixture, the Schlenk tube was placed under nitrogen and subjected to three cycles with oxygen. Backfill Yes. Reaction Mixture with N,N-dimethylformamide (25 mL) )in Dissolve and heat at 80°C for 24 hours. The solvent was removed in a vacuum, and the remaining residue Dichlorometh n It dissolved. The mixture was dissolved in ammonia (3 The aqueous phase was poured over (0 mL, 15% aqueous solution) and extracted with dichloromethane (4 × 25 mL). . Together The organic layer is dried with magnesium sulfate, filtered and concentrated, and the crude product is flashed. Purified by column chromatography [dichloromethane / methanol (2% methanol)]. It produced iodide-64 (1.99g, 95%), a yellowish solid. [ka] 【0199】 (Example 13b-(+)4-iodocyticine hydrochloride (65)) [ka] General Procedure A in accordance with N-Boc-4-iodocyticine 64 (0.68 mmol) from A colorless solid of 65 (0.18g, 86%) was obtained. [ka] 【0200】 (Example 14a-(-)N-Boc-4-trifluoromethylcyticine (76)) [ka] A Schlenk tube is filled with N-Boc-4-iodocyticine 64 (2.08g, 5mmol), Copper uride (4.52g, 23.7mmol), anhydrous Potassium fluoride Mu ( 1.38g, 23.7 mmol) and trimethyl(trifluoromethyl)silane (3.5 mL, 23.7 mmol) The container was filled with l) and the reaction mixture was placed under nitrogen. N,N-dimethylformamide (24m L, 0.2 MThe reaction mixture was stirred at 50°C for 16 hours after adding the solvent. , remainder residue The solution was divided into dichloromethane (20 mL) and ammonia (20 mL, 15% aqueous solution). The aqueous phase was extracted with dichloromethane (3 x 20 mL). together The organic phase is converted to magnesium sulfate The mixture was dried with um, the solid was filtered, and the solvent was evaporated under vacuum. A flash color of the crude reaction mixture was obtained. Purification by chromatography [ethyl acetate / n-hexane (4:1)] yielded a colorless result. A solid sample of 76 (1.52g, 85%) was obtained. [ka] 【0201】 (Example 14b-(-)4-trifluoromethylcyticine hydrochloride (77)) [ka] General Procedure A in accordance with N-Boc-4-trifluoromethylcyticine 76 (0.28m mol) from It produced a colorless solid of 77 (55 mg, 77%). [ka] 【0202】 (Example 15a-N-Boc-4-bromocyticine (61)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 5.00 mmol scale in Details are shown in Example 1 above. General procedure for the borylation reaction of cyticine Prepared according to It was done. 【0203】 The crude mixture for the boration reaction was subjected to methanol (12.5 mL) Dissolution It was then cooled to 0°C. Water (12.5mL )of Copper(II) bromide (3.35g, 15.0mmol ) melt Leave the liquid in the refrigerator for 5 minutes or more. I added the ice bath. After 30 minutes, I removed it and left the reaction mixture in a flask with open air at room temperature for 2 days. The mixture was stirred. The mixture was diluted with ammonium hydroxide (25 mL, 15% aqueous solution), and the aqueous phase was prepared. Extraction was performed using dichloromethane (3 x 50 mL). Together Dry the other layer with sodium sulfate. The mixture was filtered and concentrated in a vacuum. The crude product was then subjected to flash column chromatography using silica gel. Purified with ethyl acetate, 61 (1.54g, 83) is a grayish-white solid. It produced %). [ka] 【0204】 (Example 15b-(-)4-bromocyticine(62)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il-Citridine 58, 1.00 mmol scale in The above details are shown in Example 1. General procedure for the borylation reaction of cyticine Prepared according to It was done. 【0205】 In a sealed tube, add methanol (2.5 mL) to the crude mixture of the boronation reaction. ) dissolve and water (2 0.5mL )of Copper(II) bromide (670mg, 3.0mmol ) melt The liquid was added. Mixture 8 The mixture was heated overnight at 0°C. The mixture was cooled and then treated with ammonium hydroxide (5 mL, 15% aqueous solution). The solution was diluted and extracted with dichloromethane (5 x 5 mL). Together The organic layer is concentrated in a vacuum. . Crude products 3 M salt acid The aqueous layer was divided into (5 mL) and dichloromethane (5 mL). Wash with lolomethane (2 x 5 mL), concentrated water Ammonium oxide aqueous solution Basic up to pH 10 The sample was then converted and extracted with dichloromethane (5 x 5 mL). Together In another layer, use sodium sulfate. The crude product was dried, filtered, and concentrated under vacuum. The crude product was then subjected to flash column chromatography using silica gel. Graphy [Dichloromethane / Methanol / Ammonium Hydroxide (89:10:1)] The purified bromide 62(228) is a grayish-white solid. m It produced g, 85%). A high-purity sample was obtained by recrystallization in toluene. [ka] 【0206】 (Example 16a-N-Boc-4-aminocyticin(80)) [ka] 【0207】 (Method A) In a Schlenk tube, N-Boc-4-B in ethanol / water (7:3) (5 mL) Romocythicine 61 (184 mg, 0.5 mmol), sodium azide (65 mg, 1 0.0 mmol), copper(I) iodide (9 mg, 10 mol%), L-proline (17 mg, A mixture of 30 mol% sodium hydroxide (6 mg, 30 mol%) is incubated overnight at 95°C. It was heated. The mixture was cooled and partitioned into water and dichloromethane. The aqueous layer was divided into dichloromethane (2× Extracted using 10 mL. Together Wash the organic layer with salt water and dry it with sodium sulfate. The product was filtered and concentrated under vacuum. The crude product was subjected to flash column chromatography using silica gel. Purified with [dichloromethane / methanol / ammonium hydroxide (89:10:1)], then ash It produced amine 80 (116 mg, 76%), a colored white solid. 【0208】 (Method B) In a sealed tube, dark Ammonium hydroxide aqueous solution (0.5mL ) inside N-Boc-4-B Romocythicine 61 (92 mg, 0.25 mmol) and copper (2 mg, 10 mol%) The mixture was stirred at 100°C for 24 hours. The mixture was cooled and dichloromethane (5 × 5 mL) was added. Extraction was performed using this method. Together The organic layer was dried with sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to flash column chromatography using silica gel [dichloromethane / methane]. Purified with tanol / ammonium hydroxide (89:10:1), yielding a grayish-white solid. It produced 80 (64 mg, 85%). [ka] 【0209】 (Example 16b-(+)4-aminocyticin dihydrochloride (81)) [ka] General Procedure A in accordance with N-Boc-4-aminocyticine 80 (1.0 mmol) from It produced amine 81 (273 mg, 98%), a grayish-white solid. [ka] 【0210】 (Example 17-(-)4-fluorocyticin(82)) [ka] N-Boc-4-amino- To a solution of cyticine 80 (305 mg, 1.0 mmol), add tert-butyl sulfite (0. 18 mL (1.5 mmol) was slowly added for more than 1 minute. The reaction mixture was stirred at -20°C for 30 minutes. Then, it was heated for 2 hours until it reached room temperature, and finally heated overnight at 60°C. The mixture was then heated to 0°C. Cool, concentrated water Use an ammonium oxide aqueous solution to bring the pH down to 10. Quench I did. Mix the ingredients with vinegar. Diluted with ethyl acetate (10 mL) and filtered to remove insoluble salts. The aqueous layer was separated by ethyl acetate (4 mL). Extracted using 10 mL of solution. together The resulting organic layer was concentrated in a vacuum. The crude product was divided into three parts. M salt acid The aqueous layer was divided into (5 mL) and dichloromethane (5 mL). ) is washed, concentrated water Ammonium oxide aqueous solution It is then basicized to pH 10, and dichlorometh Extraction was performed using a 5x5 mL solution. Together The organic layer was dried with sodium sulfate. The crude product was filtered and concentrated in a vacuum. The crude product was then subjected to flash column chromatography using silica gel. Purified with FIE [dichloromethane / methanol / ammonium hydroxide (89:10:1)] This produced 82 (140 mg, 67%), a pale yellow solid. Recrystallization in toluene was performed. A more analytically pure sample was obtained. [ka] 【0211】 (Example 18a-N-Boc-4-(N-methylamino)cyticine(83)) [ka] In a sealed tube, N-Boc-4- Romocythinine 61 (369 mg, 1.0 mmol) and copper (7 mg, 10 mol%) The mixture was stirred at 100°C for 24 hours. The mixture was cooled to room temperature and then treated with dichloromethane (5× Extraction was performed using 10 mL. together The resulting organic layer was dried with sodium sulfate and filtered to obtain the true Concentrated in air. Crude product was flash-chromatographed on silica gel [dichloromethane]. Purified with methanol (94:6), resulting in a grayish-white color. color Solid 83 (274 mg, 86 It produced %). [ka] 【0212】 (Example 18b-(+)4-(N-methylamino)cyticine dihydrochloride (84)) [ka] General Procedure A in accordance with , 4-N-methylamino-N-Boc-cyticine 83 (0.77m mol) from A colorless solid, amine 84 (190 mg, 85%), was produced. [ka] 【0213】 (Example 19a-N-Boc-4(N,N'-dimethylamino)cyticine(85)) [ka] In a sealed tube, N-Boc-4- in a 40% aqueous solution of dimethylamine (2.0 mL) Bromocythicine 61 (369 mg, 1.0 mmol) and copper (6 mg, 10 mol%) The mixture was stirred at 100°C for 24 hours. The mixture was cooled and 35% ammonia (2 mL) was added. The solution was diluted with ) and the aqueous phase was extracted with dichloromethane (5 × 10 mL). Together Sulfurize the organic layer The crude reaction mixture was dried with sodium phosphate, filtered, and concentrated under vacuum. Column chromatography [Dichloromethane / Methanol / Ammonium hydroxide ( It is purified using the 94.5:5:0.5 method to produce 85g (212mg, 64%) of a white foam. did. [ka] 【0214】 (Example 19b-(+)4-(N,N'-dimethylamino)cyticine dihydrochloride (86 )) [ka] General Procedure A in accordance with N-Boc-4-N,N'-dimethylaminocyticine 85(2 (0.2 mg, 0.61 mmol) from Amino 86 (174 mg, 93%) was produced. [ka] 【0215】 (Example 20a-N-Boc-4-(N-benzoylamino)cyticine (95)) [ka] N-Boc-4-bromocythicine 61 (369 mg) in dried toluene (5.0 mL) , 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), benzamide (14 A mixture of 5 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) Then, N,N'-dimethylethylenediamine (11 μL, 10 mol%) was added to the mixture. The mixture was heated at 110°C for 3 days. After cooling, the mixture was diluted with water (10 mL), and the aqueous phase was treated with dichloromethyl chlorophosphate. Extraction was performed using methane (5 x 10 mL). Together The organic layer was dried with sodium sulfate and filtered. The mixture was then concentrated under vacuum. The crude reaction mixture was subjected to flash column chromatography using silica gel. Purified with [Dichloromethane / Methanol / Ammonium Hydroxide (95:5:0.1)] This produced 95 (425 mg) of a yellow solid. The obtained solid was boiled in toluene. Washed overnight with (10 mL), a colorless solid of 95 (372 mg, 91%) was obtained. . [ka] 【0216】 (Example 20b-(+)4-(N-benzoylamino)cyticine hydrochloride (96)) [ka] General Procedure B in accordance with N-Boc-4-(N-ben Z Amid)-Cyticine 95(363 mg, 0.89 mmol) from Ben, a colorless solid Z Amido 96 (290 mg, 80 %) was produced. [ka] 【0217】 (Example 21a-N-Boc-4-(N-acetylamino)cyticine(93)) [ka] N-Boc-4-bromocythicine 61 (369 mg) in dried toluene (5.0 mL) , 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), acetamide (70 A mixture of (mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol), N,N'-dimethylethylenediamine (11 μL, 10 mol%) was added. Mixture 1 The mixture was heated at 10°C for 24 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and then... Extraction was then performed with dichloromethane (5 × 10 mL). Together The organic layer is sodium sulfate The crude product was dried in a vacuum, filtered, and concentrated in a vacuum. The crude product was then subjected to flash column chromatography using silica gel. Mathematics [Dichloromethane / Methanol / Ammonium Hydroxide (95:5:0.1 )] is purified to produce a pale yellow foam with almost no impurities, 93 (340 mg, 98%) It produced [product name]. The product was used in the next step without further purification. [ka] 【0218】 (Example 21b-(+)4-(N-acetylamino)cyticine(94)) [ka] General Procedure B in accordance with N-Boc-4-(N-acetamide)cyticine 93(306m (g, 0.88 mmol) from It produced 94 (250 mg, quantitative), a pale yellow solid. . [ka] 【0219】 (Example 22 - (+) 4-N-morpholine cyticine dihydrochloride (92)) [ka] The sealed tube contains N-Boc-4-bromocyticine 61 (370 mg, 1.0 mmol) The solution is filled with copper(II) oxide (15 mg, 0.1 equivalent) and morpholine (0.4 mL, 5 equivalents). Fill the container and add water (2.0 mL, 0.5 mL) to the reaction mixture. M Dissolve in ) and heat in air at 100°C The mixture was heated for 8 hours. The reaction mixture was cooled to room temperature, and the aqueous phase was converted to dichloromethane (4 × 25 mL). Extracted using [this method]. together The resulting organic phase was dried with magnesium sulfate, filtered, and concentrated. A modified N-Boc-protected cyticine derivative Follow General Procedure A Deprotect hand Convert to hydrochloride salt, It produced a solid of color 92 (180 mg, 85%). [ka] 【0220】 (Example 23a-N-Boc-4-(N-(L-Proline Methyl Ester)Cyticine) (136)) [ka] N-Boc-4-bromocythinine 61 (369 mg) in dried toluene (5.0 mL) (1.0 mmol), L-proline methyl ester hydrochloride (198 mg, 1.2 mmol) , Cesium acetate (814 mg, 2.5 mmol), Palladium(II) acetate (11 mg, 5 mol%) and (±)-Binap (BINAP) (44 mg, 7 mol) mixture 10 The mixture was stirred at 0°C for 48 hours. The mixture was then cooled to room temperature. short Celite pad (Registered trademark) )of The mixture was filtered, washed with ethyl acetate, and concentrated under vacuum. The crude product was then frothed in silica gel. Column chromatography [Dichloromethane / Methanol / Ammonium hydroxide ( It is a grayish-white foam refined using the 95:5:0.1) process, with virtually no impurities. It produced 136 (371 mg, 89%). [ka] 【0221】 (Example 23b-(+)4-(N-(L-proline methyl ester)cyticine dihydrochloride) Salt (137) [ka] General Procedure B in accordance with N-Boc-4-(N-(L-proline methyl ester)-cyth Syn-136 (0.88 mmol) from 137 (304 mg, 89%) is a colorless solid. It was produced. [ka] 【0222】 (Example 24-(-)4-(N-(L-proline)cyticine dihydrochloride (138)) [ka] salt Acid (3 7% aqueous solution N-Boc-4-(N-(L-prolinemethyl methyl ester in 8.2 mL) A mixture of ester-cyticine 138 (341 mg, 0.82 mmol) was refluxed for 48 hours. The mixture was heated. It was cooled to room temperature and concentrated under vacuum. The crude product was treated with methanol (4 mL). ) Dissolve Then, acetone was slowly added (40 mL). The resulting suspension was stirred for 1 hour. The solid is filtered, washed with acetone, and dried under vacuum to obtain a pale brown solid, 138( It produced 261 mg, 85%. [ka] 【0223】 (Example 25a-N-Boc-4-(carboxymethyl)cyticine(119)) [ka] N,N-dimethylformamide / methanol (1:1) (5 mL) contains N-Boc-4 - Bromocyticine 61 (369 mg, 1.0 mmol), triethylamine (0.4 mg) L, 2.5 mmol), 1,3-bis(diphenylphosphino)propane (82 mg, 0 A solution of 0.2 mmol) and palladium(II) acetate (45 mg, 0.2 mmol) for 80 The mixture was stirred at °C for 24 hours under 1 atmosphere of carbon monoxide. The mixture was cooled to room temperature and then coated with Celite ( The crude product was filtered through a registered trademark and concentrated under vacuum. The crude product was then processed through a silica gel flash column. Purified by chromatography [ethyl acetate], 119 (300 mg, It produced 86%. [ka] 【0224】 (Example 25b-(-)4-carboxymethylcyticine(120)) [ka] N-Boc-4-methyl-ester-cyticine-11 in dichloromethane (1.3 mL) 9 (95 mg, 0.27 mmol) solution with trifluoroacetic acid (0.21 mL, 2.7 mL) (mol) was added. The mixture was stirred for 24 hours and then concentrated under vacuum. The crude product was 3 M of salt acid The aqueous layer was divided into (5 mL) and dichloromethane (5 mL). The aqueous layer was divided into dichloromethane (2 × Wash with 5 mL of sodium carbonate, base to pH 9, and then dichloromethane (5 mL) Extracted using 5 mL of solution. together The resulting organic layer was dried with sodium sulfate, filtered, and then vacuum-sealed. It was concentrated and yielded 120 (55 mg, 81%), a grayish-white solid. Recrystallization within the ene yielded an analytically pure sample. [ka] 【0225】 (Example 26-(-)4-carboxylate cyticine hydrochloride (229)) [ka] salt acid N-Boc-4-methyl-ester-cyticine in (37% aqueous solution, 7.5 mL) A solution of 119 (263 mg, 0.75 mmol) was heated under reflux for 24 hours. The mixture was then heated in a chamber. The mixture was cooled to warm temperature and then concentrated under vacuum. The crude reaction mixture was then diluted with methanol (30 mL). Dissolution Then, acetone was slowly added (300 mL). The resulting suspension was stirred for 1 hour. The solid is filtered, washed with acetone, and dried under vacuum, resulting in a colorless solid 229(164) It produced mg, 81%. [ka] 【0226】 (Example 27a-N-Boc-4-(hydroxymethyl)cyticine(121)) [ka] N-Boc-4-methyl ester-cyticine 119 in tetrahydrofuran (4 mL) (350 mg, 1.00 mmol) of lithium aluminum hydroxide (diethyl A) in a solution. Inside the tel, 1.0 M Add ) dropwise at -78°C for 5 minutes, and stir the reaction mixture for 3.5 hours. Acetic acid Ethyl (2 mL) was added dropwise, followed by the addition of saturated Rochelle salt solution (10 mL). The mixture was stirred for 30 minutes, and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). together did The organic phase was dried with magnesium sulfate, filtered, and concentrated. Flash column chromatography Raffy [dichloromethane / methanol (2% methanol to 5% methanol)] Refining yielded 121 (194 mg, 62%), a colorless foam. [ka] No quaternary carbon atoms were found in the Boc group. 【0227】 (Example 27b-(-)4-(hydroxymethyl)cyticine hydrochloride (122)) [ka] General Procedure A in accordance with N-Boc-4-hydroxymethylcyticine-121 (0.60m mol) from It produced a colorless solid called alcohol-122 (120 mg, 90%). [ka] 【0228】 (Example 28a-N-Boc-4-(4-(trifluoromethyl)benzyl)oxy Shichishin (123)) [ka] Dry tetrahydrofuran (7.5 mL) )of Alcohol 121 (240mg, 0.75mg) mol ) melt Add sodium hydride (33 mg, 1.1 equivalents, 60% dispersed in mineral oil) to the liquid. The mixture was stirred at 0°C. After 30 minutes, tetrabutylammonium iodide (14 mg) (0.05 equivalents) and 4-(trifluoromethyl)benzyl bromide (358 mg, 2 equivalents) The reaction mixture was heated to room temperature and stirred for 18 hours. The reaction mixture was then diluted with water (10 mL). Quench The aqueous phase was then extracted with ethyl acetate (3 × 15 mL). together Various types of sulfuric acid The crude reaction mixture was dried with magnesium, filtered, and concentrated in a vacuum. Purification by sugar column chromatography [dichloromethane / methanol (1% methanol)] It is prepared to produce a colorless solid called 123 (250 mg, 71%), which is then further purified. It was used in the next step without being used. [ka] 【0229】 (Example 28b-(-)4-(4-(trifluoromethyl)benzyl)oxycicy (124)) [ka] Prepare the hydrochloride of ether 123 (0.25 g, 0.52 mmol) using general procedure A. This was converted to produce 124 (110 mg, 60%), a colorless solid. [ka] 【0230】 (Example 29a-N-Boc-4-methylcythicine(109)) [ka] N-Boc-4-bromocythicine 61 (369 mg) in dried toluene (5.0 mL) , 1.0 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg To the mixture of 5 mol%, tetramethyltin (0.35 mL, 2.5 mmol) was added. The mixture was stirred at 100°C under nitrogen for 24 hours. The mixture was cooled to room temperature and then ceramic. Filtered through Ito (registered trademark), washed with ethyl acetate (50 mL), and concentrated under vacuum. The crude product was subjected to flash column chromatography using silica gel [dichloromethane / methano It is purified with (97:3) and is a pale yellow solid with almost no impurities, 109 (308 It produced mg (quantitatively). [ka] 【0231】 Example 29b-(-)4-methylcyticine hydrochloride (110) [ka] General Procedure A in accordance with , N-Boc-4-methylcyticine 109 (1.40 mmol) A more colorless solid, 110 (337 mg, quantitative), was obtained. [ka] 【0232】 (Example 30a-(-)N-Boc-4-vinylcyticine(115)) [ka] N-Boc-4-bromocythicine 61 in dioxane / water (8:2) (5.0 mL) (369 mg, 1.0 mmol), 2,4,6-trivinylcyclotriboloxane pyri Zin complex (194 mg, 1.2 mmol), potassium carbonate (276 mg, 2.0 mmol), and A mixture of dichlorobis(triphenylphosphine)palladium (35 mg, 5 mol%) The mixture was stirred at 90°C under nitrogen for 24 hours. The mixture was cooled to room temperature and then coated with Celite (a type of mineral). The organic layer was filtered through a registered trademark and washed with ethyl acetate (50 mL). The sample was washed with saline solution (10 mL), dried with sodium sulfate, filtered, and concentrated under vacuum. Flash column chromatography of crude reaction mixture with silica gel [dichloromethane / methicone] Purified with Tanol (97:3), resulting in a pale yellow foam, 115 (271 mg, 86%) It produced a substance that was used in the next step without further purification. [ka] 【0233】 (Example 30b-(+)4-vinylcyticine hydrochloride (116)) [ka] General Procedure B in accordance with N-Boc-4-vinylcyticine 115 (271 mg, 0.8 6 mmol) from It produced 116 (214 mg, 99%), a colorless solid. [ka] 【0234】 (Example 31a-N-Boc-4-ethylcyticine(117)) [ka] Methanol (22 mL) )of 4-Vinyl-N-Boc-Cyticine 115 (353 mg, 1 0.1 mmol ) melt Palladium / carbon 10% w / w (35 mg) was added to the solution. The reaction vessel was... Placed under vacuum, and treated with hydrogen three times. Backfill The mixture was then subjected to 24 hours under 1 atmosphere of hydrogen. The mixture was stirred at room temperature. The mixture was filtered through Celite® and ethyl acetate (50%). Wash in mL and concentrate in a vacuum to obtain a grayish-white solid of 117 (337 mg, It produced 95%. [ka] 【0235】 (Example 31b-(-)4-ethylcyticine hydrochloride (118)) [ka] General Procedure A in accordance with N-Boc-4-ethyl-cyticine 117 (0.92 mmol) from A colorless solid, 118 (227 mg, 97%), was obtained. [ka] 【0236】 (Example 32a-N-Boc-4-p-trilcyticine(72)) [ka] Schlenk tube N-Boc-4-bromocyticine 61 (370 mg, 1.0 mmol) ), potassium carbonate (250 mg, 1.8 equivalents), tetrakis(triphenylphosphine) Palladium (0) (58 mg, 5 mol%) and 4-methylphenylboronic acid (160 mg) Fill with g (1.2 equivalents) and add a mixture of dimethyl ether / water (5:1, 10 mL). The reaction mixture was heated at 80°C for 18 hours. The solution was cooled, and the solvent was removed under vacuum. The crude reaction mixture was partitioned into water (15 mL) and dichloromethane (15 mL), and the aqueous phase was converted to dichloromethane. Extraction was performed using a 3 x 15 mL solution. together The resulting organic phase was dried with magnesium sulfate and filtered. The mixture was concentrated. Flash column chromatography of the crude reaction mixture [dichloromethane / Purification with methanol (1.5% methanol) yields a colorless solid, 72. The crude product was recrystallized in high-temperature toluene to obtain a colorless foam, 72 (260 mg, 71 It produced %). [ka] 【0237】 (Example 32b-(+)4-p-trilcyticine(73)) [ka] In the Schlenk tube, N-Boc-4-p-tril-cyticine 72 (270 mg, 0.7 Dissolve 1 mmol) in dichloromethane (7.0 mL) and trifluoroacetic acid (0.3 mL) (10 equivalents) was added. The reaction mixture was stirred at room temperature for 18 hours. Then, water (10 mL) The reaction mixture was then added, and the aqueous phase was washed with dichloromethane (3 × 15 mL). After that, the reaction mixture was completed. Add Monia solution (20 mL, 15% aqueous solution) and add dichloromethane (3 × 15 mL) to the aqueous phase. Extracted using [this method]. togetherThe resulting organic phase was dried with magnesium sulfate, filtered, and concentrated, producing a colorless sample. Solid 73 (140 mg, 74%) was produced. Recrystallization of the product in high-temperature toluene. The chemical reaction yielded a colorless solid called 73 (73 mg, 40%). [ka] 【0238】 Example 33a -N-Boc-4-(N-2-pyridone)cytidine (107)) [ka] N-Boc-4-bromocythicine 61 (369 mg) in dried toluene (5.0 mL) , 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), 2-hydroxypyrrhizate Zin (114 mg, 1.2 mmol) and potassium carbonate (277 mg, 2.0 mmol) N-N'-dimethylethylenediamine (22 μL, 20 mol%) was added to the solution. The mixture was heated under nitrogen at 110°C for 24 hours. Furthermore, copper(I) iodide (19 mg, 1 0 mol%) and N-N'-dimethylethylenediamine (DMEDA) (22 μL, 20 Add mol% and stir for 36 hours. After cooling, the mixture was dissolved in ethyl acetate (50 mL). Diluted and then filtered through Celite®. The organic layer was ammonium hydroxide ( Washed with 2 x 10 mL (15% aqueous solution). together The resulting aqueous layer was treated with dichloromethane (5 × 10 Extracted in mL. together The resulting organic layer (ethyl acetate and dichloromethane) is then treated with sodium sulfate. The crude reaction mixture was dried in a vacuum, filtered, and concentrated in a vacuum. Purified by chromatography [dichloromethane / methanol (95:5)], resulting in a pale yellow color. It yields color 107 (336 mg, 88%), which is then used in the next step without further purification. It was used. [ka] 【0239】 (Example 33b-(-)4-(N-2-pyridone)cyticine hydrochloride (108)) [ka] General Procedure B in accordance with N-Boc-4-(N-2-pyridone)-cyticine-107(28 (9 mg, 0.75 mol) from 108 (182 mg, 76%) is a pale orange solid. It produced [something]. [ka] 【0240】 Example 34a-N-Boc-4-(trimethylsilylacetylene)cyticine (125 )) [ka] N-Boc-4-bromocyticine 61 in dried tetrahydrofuran (10.0 mL) (369 mg, 1.0 mmol), copper(I) iodide (19 mg, 10 mol%) and diclofenac In a solution of lorobis (triphenylphosphine) palladium (35 mg, 5 mol%), Isopropylamine (0.42 mL, 3.0 mmol) followed by trimethylsilylacetyl Len (0.16 mL, 1.1 mmol ) was added. The mixture was left at room temperature under nitrogen for 24 hours. Stirring was continued. The mixture was diluted with dichloromethane (50 mL). The organic layer was ammonium chloride. Wash with 10 mL of saturated solution and 10 mL of saline solution, dry with sodium sulfate, and filter. The crude product was concentrated under vacuum. Flash column chromatography was performed on silica gel. Purified with ethyl acetate, impurities (Palladium catalyst) most of pale light brown foam 125 (406 mg, quantitative) was produced. The product was then processed in the next step without further purification. It was used. [ka] 【0241】 Example 34b-N-Boc-4-(acetylene)cytidine 126) [ka] N-Boc-4-( Dissolution of trimethylsilylacetylene)-cyticine 125 (379 mg, 0.98 mmol) Potassium carbonate (270 mg, 1.96 mmol) was added to the solution. The mixture was stirred for 24 hours. The solution was then mixed with water (10 mL) and the aqueous phase was extracted with dichloromethane (3 × 20 mL). together to The resulting organic layer was dried with sodium sulfate, filtered, and concentrated under vacuum. The crude product was silica. Purified by flash column chromatography of the gel [ethyl acetate], removing impurities. (para (Dium catalyst) most of white It produced 126 (275 mg, 89%), which is a solid of color. The product was used in the next step without further purification. [ka] 【0242】 Example 34c-(-)4-(acetylenyl)cyticine hydrochloride (127) [ka] General Procedure B in accordance with N-Boc-4-(acetylene)cytidine-126(0.77 Milli Mol) from A pale yellow solid, 127 (150 mg, 78%), was obtained. [ka] 【0243】 Example 35a-N-Boc-4-(phenylacetylene)cyticine(128)) [ka] N-Boc-4-bromocytisine 61(3) in dried tetrahydrofuran (5.0 mL) 69 mg, 1.0 mmol), copper(I) iodide (38 mg, 20 mol%) and dichloro A mixture of bis(triphenylphosphine)palladium (70 mg, 10 mol%) contains Isopropylamine (0.42 mL, 3.0 mmol), then phenylacetylene (0 Add 0.22 mL (2.0 mmol). Stir the mixture under nitrogen at room temperature for 24 hours. The mixture was diluted with ethyl acetate (50 mL). The organic layer was diluted with ammonium chloride (10 mL). Wash with saturated solution, salt water (10 mL), dry with sodium sulfate, filter, and vacuum. The product was concentrated using [ethyl acetate]. The crude product was then subjected to flash column chromatography on silica gel. Purified by removing impurities (Palladium catalyst) most of pale 128(3) is a light brown foam. 76 mg, 96% was produced. The product was used in the next step without further purification. [ka] 【0244】 (Example 35b-(+)4-(phenylacetylene)cyticine hydrochloride (129)) [ka] General Procedure B in accordance with N-Boc-4-(phenylacetylene)cyticine-128(0. 88 Milli Mol) from A pale yellow solid, 129 (267 mg, 92%), was obtained. [ka] 【0245】 (Example 36a-N-Boc-4-(E-2-Methyl Propenate)Cyticine) (111)) [ka] N-Boc-4-bromocytisine 61 (369 mg) in dried dioxane (5.0 mL) , 1.0 mmol) and Tris(dibenzylideneacetone) dipalladium(0)(12m A mixture of g, 2.5 mol%) contains N,N-dicyclohexylmethylamine (0.2 mL) , 1.1 mmol), tri-tert-butylphosphine (dioxane solution 0.1 M , 0 0.5 mL, 5 mol%) and ethyl acrylate (0.2 mL, 2.0 mmol) were added. The mixture was stirred under nitrogen at room temperature for 24 hours. Tris(dibenzylideneacetone) Dipalladium (0) (12 mg, 2.5 mol%), tri-tert-butylphosphine (Dioxane solution 0.1 M , 0.50 mL, 5 mol%) and ethyl acrylate (0.2 Add the remaining 2.0 mmol (mL) and stir the mixture for another 24 hours. The crude product was filtered through (registered trademark), washed with ethyl acetate, and concentrated under vacuum. Kagel flash column chromatography [dichloromethane / methanol (97:3 The substance was purified using the following method, yielding a pale yellow solid called 111 (321 mg, 83%). [ka] 【0246】 (Example 36b-(+)4-(E-2-Methyl Propenate)Cyticine Hydrochloride) (112)) [ka] General Procedure B in accordance with , 111 (1.00 mmol) from 112(3) is a pale yellow solid. It produced 00mg, 92%. [ka] 【0247】 (Examples) 37a-N-Boc-4-(E-(2-phenylethenyl))cyticine (1 13)) [ka] N-Boc-4-bromocythicine 61 (369m) in dried dioxane (5.0 mL) g, 1.0 mmol) and Tris(dibenzylideneacetone) dipalladium(0)(12 A mixture of mg, 2.5 mol%) contains N,N-dicyclohexylmethylamine (0.2 mL) , 1.1 mmol), tri-tert-butylphosphine (dioxane solution 0.1 M , 0 0.50 mL, 5 mol%) and styrene (0.2 mL, 2.0 mmol) were added. Mixing was performed. The substance was stirred under nitrogen at room temperature for 24 hours. Tris(dibenzylideneacetone)dipara Dium (0) (12 mg, 2.5 mol%), tri-tert-butylphosphine (Gio) Kizhan solution 0.1 M , 0.50 mL, 5 mol%) and styrene (0.2 mL, 2.0 m The mixture was then stirred again for another 24 hours. The crude product was filtered through a filter, washed with ethyl acetate, and concentrated under vacuum. The crude product was then flushed with silica gel. Purified by dichloromethane / methanol (97:3) column chromatography, and then palpable 113 units (373 mg, 95%) of yellow foam were produced. The product was then processed without further purification. It was used in the following step. [ka] 【0248】 Example 37b --(+)4-(E-(2-phenylethenyl))cyticine hydrochloride (1 14)) [ka] General Procedure B in accordance with , 113 (0.88 mmol) from It is a grayish-white solid. It produced 114 (259 mg, 89%). [ka] 【0249】 Example 38a-N-Boc-4-(1-(4-phenyl)-NH-1,2,3-tri Azolyl (Citicine (134)) [ka] N-Boc-4-bromocyticine 61 in ethanol / water (7:3) (5.0 mL) (369 mg, 1.00 mmol), sodium azide (130 mg, 2.0 mmol) , sodium ascorbate (20 mg, 10 mol%) and copper(I) iodide (19 mg In a mixture of 10 mol%, add N,N'-dimethylethylenediamine (22 μL, 20 m %) Then phenylacetylene (132 μL, 1.2 mmol) was added. Mixture The mixture was stirred at 50°C for 24 hours under nitrogen. The mixture was cooled to room temperature, and ammonium hydroxide was added. Dilute with a 20 mL 15% aqueous solution, then extract with ethyl acetate (3 × 50 mL). They went out. together The prepared organic layer was washed with 20 mL of salt water and dried with sodium sulfate. It was filtered and concentrated in a vacuum. Crude product ( 1 Based on 1H NMR, 86 ~ (93% conversion) Kagel flash column chromatography [ethyl acetate, then dichloromethane / methicone] Purified with tanol / ammonium hydroxide (97:3:0.1), resulting in a grayish-white color. It produces 134 (214 mg, 49%) solid, which is then used in the next step without further purification. It was used in the step. [ka] 【0250】 (Example 38b-(+)4-(1-(4-phenyl)-NH-1,2,3-triazo (Ril)Citicine dihydrochloride (135) [ka] General Procedure B in accordance with N-Boc-4-((4-phenyl)-NH-1,2,3, Tri Azole-Citrice 134 (0.46 mmol) from , a colorless solid 135(15 It produced 1 mg, 81%. [ka] 【0251】 (Example 39a-N-Boc-4-(1,2,3-triazol-1-yl)methyl Pivalic acid (cyticine (131)) [ka] N-Boc- in a mixture of tert-butyl alcohol / water (1:1) (8.6 mL) In a solution of 4-(acetylene)-cyticine 126 (544 mg, 1.73 mmol), Azidomethyl pivalate (0.3 mL, 2.08 mmol), copper(II) sulfate pentahydrate (22 mg, 5 mol%) and sodium ascorbate (102 mg, 30 mol%) The mixture was stirred at room temperature for 48 hours. The mixture was then mixed with ammonium hydroxide (10 mL, The solution was diluted with a 15% aqueous solution, and then extracted with ethyl acetate (3 × 20 mL). together death The organic layer was washed with brine (20 mL), dried with sodium sulfate, filtered, and concentrated in a vacuum. Shrinkage occurred. Crude material was subjected to silica gel flash column chromatography [dichloromethane / It was purified with methanol / ammonium hydroxide (95:5:0.1) to remove most impurities. It produces a pale yellow oil called 131 (722 mg, 89%), which is not further refined. It was used in the next step. [ka] 【0252】 (Example 39b-N-Boc-4-(NH-1,2,3-triazolyl)-cyticine) (132)) [ka] Methanol (3.2 mL) )of N-Boc-4-(1,2,3-triazole-1-yl) (Methylpivalate)-Cyticine 131 (688 mg, 1.46 mmol) ) melt In the liquid, hydroxide Sodium (3.2 mL, 1 M An aqueous solution was added. The mixture was stirred at room temperature for 12 hours. Salt acid (3.2 mL, 1 M Neutralize with aqueous solution, dilute with water (30 mL), and ethyl acetate Extraction was performed using (5 × 20 mL) solution. together Wash the prepared organic layer with salt water (20 mL) and sulfuric acid. The crude product was dried with sodium, filtered, and concentrated in a vacuum. Rum chromatography [dichloromethane / methanol / ammonium hydroxide (97:3 Purified using :0.1), the grayish-white solid 132 (461 mg, 88%) It was produced. [ka] 【0253】 (Example 39c-(+)4-(NH-1,2,3-triazolyl))cyticine dihydrochloride Salt 133(A)) [ka] General Procedure A in accordance with N-Boc-4-(NH-1,2,3-triazole)-citish N132 (1.22 mmol) Using General Procedure A Deprotect hand Convert to hydrochloride salt, It produced a solid of color 133 (352 mg, 87%). [ka] 【0254】 (Example 40-(+)4-(N-ethylamino)cyticine(87)) [ka] In a sealed tube, ethylamine (2.0 mL, tetrahydrofuran) solution 2.0 M ) N-Boc-4-bromocyticine 61 (369 mg, 1.0 mmol) and copper (7 mg A mixture of 10 mol% was stirred in water (1 mL) at 100°C for 24 hours. The material was cooled and extracted with dichloromethane (5 × 10 mL). together The resulting organic layer was treated with sulfuric acid. The crude product was dried with magnesium, filtered, and concentrated in a vacuum. The crude product was then flushed with silica gel. Purified by column chromatography [dichloromethane / methanol (6% methanol)]. It yielded 87 (102 mg, 42%) of a grayish-white solid. [ka] 【0255】 (Example 41-(+)4-(N-isopropylamino)cythicine 88) [ka] In a sealed tube, N-Boc-4-bromo in 40% iPrH2 solution (2.0 mL) - A mixture of cyticine 61 (369 mg, 1.0 mmol) and copper (7 mg, 10 mol%) The mixture was stirred at 100°C for 24 hours. The mixture was cooled and then dissolved in dichloromethane (5 × 10 mL). Extraction was performed. togetherThe resulting organic layer was dried with sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to flash column chromatography of silica gel [dichloromethane / meth Purified with [6% methanol], it is a grayish-white solid 88 (88 mg, It produced 33%. [ka] 【0256】 (Example 42a-N-Boc-4-cyanocyticine (139)) [ka] Schlenk tube filled with N-Boc-4-bromocyticine 61 (1.85g, 5.00mmo l) Tetrakis(triphenylphosphine)palladium (0) (230 mg, 0.20 Filled with mmol) and zinc cyanide (350 mg, 3.00 mmol), and placed under nitrogen. Then, N,N-dimethylformamide (6.2 mL) was added, and the reaction mixture was heated at 80°C for 18 minutes. The mixture was heated for a specified time. The reaction mixture was cooled, and the solvent was removed under vacuum. The crude reaction mixture was flushed. By column chromatography [dichloromethane:methanol (1% methanol)] Refinement yielded a colorless solid, 139 (1.6g, 99%). [ka] 【0257】 (Example 43-(-)4-cyanocyticine (140)) [ka] In the Schlenk tube, N-Boc-4-cyanocyticine 139 (140 mg, 0.46 mmol) is dichloromethane (3.0 mL, 0.1 MIt is dissolved in trifluoroacetic acid ( 0.3 mL (10 equivalents) was added. The solution was stirred at room temperature for 16 hours. Water was added (10 mL). The aqueous phase was washed with dichloromethane (3 × 20 mL). Ammonia was added (10 mL, A 15% aqueous solution was prepared, and the aqueous phase was extracted with dichloromethane (4 × 20 mL). together organic layer It is dried with magnesium sulfate, filtered and concentrated to obtain a colorless solid of 140 (86 mg, It produced 86%. [ka] 【0258】 (Example 44a-N-Boc-4-(carboxamide)cyticine (141)) [ka] N-Boc-4-cyanocyticine 1 in an equimolar mixture of ethanol / water (5 mL) In a solution of 39 (320 mg, 1.0 mmol), sodium borohydride (33 mg, 0 mmol) was added. Add 0.75 mmol) and stir the reaction mixture at 75°C for 18 hours. Allow the reaction mixture to cool to room temperature. Cool and add water (5 mL) Quench The ethanol was removed in a vacuum. Then the aqueous phase was Extract with dichloromethane (3 x 15 mL), together The resulting organic phase was dried with magnesium sulfate. The mixture was filtered and concentrated. Flash column chromatography of the crude reaction mixture [Dichloro Purification with lomethane / methanol (2% to 4% methanol) , nothing solid of color It produces 141 (150 mg, 46%) It was recrystallized from toluene. Ta. [ka] 【0259】 (Example 44b-(-)4-(carboxamide)cyticine hydrochloride (142)) [ka] General Procedure A in accordance with N-Boc-4-amide-cyticine 141 (0.44 mmol) from A colorless solid, 142 (90 mg, 88%), was obtained. [ka] 【0260】 (Example 45a-N-Boc-4-(aminomethyl)cyticine (143)) [ka] Ethanol (10 mL, 0.1 M ) N-Boc-4-cyanocyticine 139(3 In a solution of 20 mg (1.0 mmol) and potassium hydroxide (84 mg, 1.5 mmol) Then, Raney nickel (0.3 mL, slurry in water) was added. The reaction vessel was placed under vacuum. , with hydrogen 3 times Backfill The mixture was stirred at room temperature for 18 hours. The reaction mixture was then mixed with Celite (registered The crude reaction mixture was filtered through a (trademark) and concentrated using flash column chromatography. [Dichloromethane: methanol (10% methanol) + 0.1% ammonia (35% aqueous solution) Purification using (liquid) yields a colorless solid amine 143 (260 mg, 82%). did. [ka] 【0261】 (Example 45b-(-)4-(aminomethyl)cyticine dihydrochloride (144)) [ka] General procedure According to A N-Boc-4-methylaminocyticine-143 (0.76 mm The ol) was converted to hydrochloride salt, yielding a colorless solid, 144 (150 mg, 89%). [ka] 【0262】 (Example 46a-N-Boc-4-(N-Boc-aminomethyl)cyticine) [ka] Tetrahydrofuran (8mL) )of N-Boc-4-aminomethylcyticine 143(2 64 mg, 0.83 mmol ) melt Add di-tert-butyl dicarbonate (0.2 mL, 0.9 Add 1 mmol) and triethylamine (0.16 mL, 1.16 mmol) and mix the reaction mixture. The mixture was stirred at room temperature for 18 hours. Then, water (15 mL) was added, and the aqueous phase was converted to dichloromethane. Extraction was performed using (3 × 25 mL) solution. together The resulting organic phase was dried with magnesium sulfate and filtered. It was concentrated. Flash column chromatography [dichloromethane:methanol (3%) By purification with methanol, a colorless oil called N-Boc-4-(N-Boc-Ammonia) is obtained. It produced (280 mg, 82%) nomethyl-cyticine. [ka] 【0263】 (Example 46b-(-)4-((N-methyl)aminomethyl)cyticine(152)) [ka] Tetrahydrofuran (6.0 mL) )of N-Boc-4-(N-Boc-aminomethyl) -Citicine (255 mg, 0.61 mmol) ) melt In the liquid, add sodium hydride (17 mg, 0 Add 0.70 mmol of 60% dispersed oil and stir the solution for 30 minutes. Iodomethane (0. Add 0.5 mL (0.70 mmol) and stir the reaction mixture at room temperature for 18 hours. The crude product was prepared. The aqueous phase was divided into water (10 mL) and ethyl acetate (10 mL), and the aqueous phase was divided into ethyl acetate (3 × 10 mL). Extracted using [this method]. together The resulting organic phase was washed with magnesium sulfate, filtered, and concentrated. The compound Using General Procedure A Deprotect hand Converted to hydrochloride, 152 is a colorless solid. (89 mg, 65%) was produced. [ka] 【0264】 (Example 47a-Tert-butyl(1R,5R)-10-(hydroxymethyl)- 8-Oxo-1,5,6,8-Tetrahydro-2H-1,5-methanopyrido[1,2- a][1,5]diazosin-3(4H)-carb Xylart (153)) [ka] N-Boc-4-cyanocyticine 139 (200 mg, 0.63 mmol) is pyridized Dissolve sodium phosphinate in a mixture of acetic acid and water in a ratio of 2:1:1. (340 mg, 3.27 mmol) and Raney nickel (1.0 mL, slurry in water) The reaction mixture was stirred at 50°C for 6 hours. The solution was passed through Celite®. It was filtered and concentrated. The crude product was divided into water (15 mL) and dichloromethane (15 mL). The aqueous phase was extracted with dichloromethane (3 × 25 mL). together The resulting organic phase is converted to magnesium sulfate The mixture was dried, filtered, and concentrated. Column chromatography of the crude reaction mixture [dichloro Purification with methane / methanol (4% methanol) yields a colorless, pale yellow solid. It produced 153 (170 mg, 86%). [ka] 【0265】 (Example 47b-amine bis(cyticine) derivative (154)) [ka] General Procedure A in accordance with tert-butyl(1R,5R)-10-(hydroxymethyl) -8-oxo-1,5,6,8-tetrahydro-2H-1,5-methanopyrido[1, 2-a][1,5]diazosin-3(4H)-carb Xylart 153(0.53mmo l) from It produced 154 (113 mg, 97%), which is a colorless solid. [ka] 【0266】 (Example 48 - Methylamino bis(cyticine) derivative (156)) [ka] 153 (200 mg) in an equimolar mixture of methanol / tetrahydrofuran (3 mL) (0.32 mmol) solution, formaldehyde (0.14 mL, 6 equivalents, 37% aqueous solution) ), then sodium cyanoborohydride (74 mg, 3.5 equivalents) was added, and the reaction mixture was prepared. The mixture was stirred for 24 hours. The solution was concentrated, and the crude product was mixed with ammonia (20 mL, 15% aqueous solution) The mixture is divided into 20 mL of dichloromethane, and the aqueous phase is extracted with 3 x 20 mL of dichloromethane. Ta. together The resulting organic layer was dried with magnesium sulfate, filtered, and concentrated. Purification by Rum chromatography [dichloromethane / methanol (3% methanol)] Therefore, the corresponding N-Boc-protected bis(cyticine) derivative (160 mg) is a colorless solid. It produced 82% of the following Using General Procedure B Deprotection and salt By conversion to salts It produced 156 (89 mg, 87%), which is a colorless solid. [ka] 【0267】 (Example 49-(-)4-tetrazoylcyticine dihydrochloride (149)) [ka] Schlenk tube N-Boc-4-cyanocyticine 139 (240 mg, 0.75 mm) (ol), zinc bromide (170 mg, 0.75 mmol) and sodium azide (58 mg, It was filled with 0.90 mmol of water and placed under nitrogen. M ) and iso Propanol (0.8 mL, 1.0 M The reaction mixture was then heated at 60°C for 18 hours. Remove the solvent in a vacuum, and the remaining residue Dissolve it in dichloromethane (20 mL) and add water (20 mL). Poured the mixture into the salt acid (0.1 M pH ≈ 4 (in aqueous solution) ~ Acidify to level 5, dichlorometh Washed with (3 x 20 mL). Acidified the aqueous phase to pH ≈ 1, and then dichloromethane (3 x 2 Extracted using 5 mL. together The resulting organic phase was dried with magnesium sulfate and filtered to remove the solvent. It was evaporated in a vacuum. The product was converted to hydrochloride using general procedure A, and was a colorless solid. It produced 149 (102 mg, 53%). [ka] 【0268】 (Example 50-N-Boc-4-(dimethylamino)methylcyticine, and 4-( Dimethylaminomethyl-(-)-cyticine dihydrochloride (151) [ka] Amine 143 (320 mg) in an equimolar mixture of tetrahydrofuran / water (12 mL) To a 1.0 mmol solution, add formaldehyde (480 mg, 6 equivalents, 35% aqueous solution) and Sodium cyanoborohydride (219 mg, 3.5 equivalents) was added in succession. The mixture was stirred at room temperature for 18 hours. The reaction mixture was dissolved in 10 mL of water. Quench Then, the aqueous phase is converted to ethyl acetate. Extraction was performed using (3 × 25 mL) solution. together The resulting organic layer was dried with magnesium sulfate and filtered. The crude reaction mixture was concentrated in a vacuum. Flash column chromatography of silica gel. Purified with [dichloromethane / methanol (1% methanol)], green color The product is an oil (2 It produced 0.7 mg, 60%. [ka] General Procedure A in accordance with , N-Boc-4-(dimethylamino)methylcythicine (0.6 0 mmol) from It produces 151 (120 mg, 81%) which is a colorless solid, and it is air After several days, it transformed into a viscous oil. [ka] 【0269】 (Example 51-(-)4-((trimethylammonium)methyl)cytic iodide) Salt (150) [ka] Ethanol (6.3mL) )of Amine 143 (220 mg, 0.63 mmol) ) melt In the liquid, Iodomethane (0.1 mL, 1.3 equivalents) was added, and the reaction mixture was stirred at 60°C for 18 hours. The solution was concentrated. Using General Procedure A Deprotect hand Hydrochloride fart conversion death ,green color Gaku-karu Mutei It produced 150 units (80 mg, 42%) of solid form. [ka] 【0270】 (Example 52-(-)4-(N-acetyl)aminomethyl)cyticine (148)) [ka] Amine 143 (310 mg, 1.0 mmol) is mixed with isopropenyl acetate (0.33 mL, Dissolve in 3 equivalents and stir at room temperature for 24 hours. Then concentrate the reaction mixture. The crude product was silicified. Kagel Flash Column Chromatography [Dichloromethane / Methanol (3% Methane)] The product was purified using [NOL] and yielded a colorless solid product (330 mg, 92%). common Using Procedure A Deprotect hand conversion to do Therefore, the colorless foam is 148 (237m It produced g, 80%). [ka] 【0271】 (Example 53-N-Boc-4-(4-((benzyloxy)carbonyl)piperazi n-1-il)shichishin(89)) [ka] In a sealed tube, bromide 61 (180 mg, 0.5 mmol) in water (1.0 mL) Copper(I) oxide (8 mg, 0.1 equivalent) and 1-Z-piperazine (0.5 mL, 2.5 mm) The solution of ol) was stirred at 100°C for 18 hours. The reaction mixture was cooled, and the remainder residue ethyl acetate (3× Extracted using 25 mL. together The resulting organic layer was dried with magnesium sulfate, filtered, and vacuum-sealed. Concentrated within the body. Crude reaction mixture was subjected to flash column chromatography of silica gel. Purified with lolomethane / methanol (2% methanol), it becomes a colorless solid (220 mg, 89 It produced 89% of the product, which was used in the next step without further refinement. [ka] 【0272】 (Example 54-N-Boc-4-(piperazin-1-yl)cyticine) [ka] Methanol (5 mL) )of 89 (160 mg, 0.32 mmol) ) melt Place the liquid under nitrogen. Then, palladium (5 mg, 0.1 equivalent) was added on 10 wt% activated carbon. The container was then placed under vacuum. Place it and use hydrogen three times Backfill The mixture was stirred for 18 hours. The reaction mixture was then prepared using Celite (registered The piperazinyl derivative (85 mg) is filtered through a (trademark) and the solvent is concentrated, becoming a colorless solid. It yielded 71%, which was used in the next step without further purification. [ka] 【0273】 (Example 55-(+)4-(N-piperazinyl)cyticine trihydrochloride (90)) [ka] Methanol (6.4 mL) )of N-Boc-4-N-(N'-benzyloxycarbonyl A solution of )-piperazine-cyticine (323 mg, 0.64 mmol) is placed under nitrogen. Palladium / carbon (10% by weight) (6.5 mg, 0.1 equivalent) was added. The container was then placed under vacuum. Place it and use hydrogen three times Backfill The mixture was then stirred for 24 hours. The sample was filtered through a standard filter and concentrated under vacuum. Using General Procedure A Deprotect hand Hydrochloride fart strange exchange to do This yielded 90 (237 mg, 96%), a colorless solid. [ka] 【0274】 (Example 56a-N-Boc-3-(trifluoromethyl)-4-bromocyticin 161) [ka] N-Boc-4 in a mixture of dimethyl sulfoxide (3.8 mL) and water (1.6 mL) -A solution of bromocyticine 61 (370 mg, 1.0 mmol) was cooled to 0°C, and then... Sodium fluoromethylsulfonate (470 mg, 3.0 mmol) was added. Add t-butyl hydroperoxide (0.7 mL, 70% aqueous solution) dropwise for 5 minutes, and then immerse the solution in the room. The mixture was heated to a temperature of 15°C and stirred for 24 hours. The solvent was removed under vacuum. The crude product was treated with ammonia (15°C). The aqueous phase is divided into (15 mL, 15% aqueous solution) and dichloromethane (15 mL), and the aqueous phase is divided into dichloromethane. Extraction was performed using (3 × 25 mL) solution. together The resulting organic phase was dried with magnesium sulfate and filtered. The crude product was concentrated. The crude product was subjected to flash column chromatography on silica gel [n-hexane]. Purified with ethyl acetate (1:1), the colorless solid 161 (130 mg, 30%) was obtained. It was produced along with 3% N-Boc-5-trifluoromethyl-4-bromocyticine. [¹H NMR: 98% (C3 substitution), 2% (C5 substitution; 87% conversion)] [ka] 【0275】 (Example 56b-(-)3-(trifluoromethyl)-4-bromocyticine hydrochloride ( 162)) [ka] General Procedure A in accordance with Bromide 161 (0.25 mmol) from 162 (0.45 mg, 48% was produced. [ka] 【0276】 (Example 57a-N-Boc-3-bromo-4-iodocyticine (159)) [ka] N-Boc-4-iodocyticine 65 (120 mg, 0.286 mmol) tetra Hydrofuran (6 mL, 0.05 M) Dissolve and N-bromosuccinimide (51 mg, 0.286 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then mixed with water (1 The solution was diluted with 5 mL, and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). together The organic phase The crude product was dried with magnesium sulfate, filtered, and concentrated. The crude product was then flashed in silica gel. Purified by microchromatography [n-hexane / ethyl acetate (1:1)], and N-Boc- 159 (91 mg, 5-bromo-4-iodocyticine in a 22:3 ratio) contaminated with 5-bromo-4-iodocyticine. It produced 65%. [ka] 【0277】 (Example 57b-(+)3-bromo-4-iodocyticine hydrochloride (160)) [ka] General Procedure A in accordance with , iodide 159 (0.16 mmol) from , 5-bromo-4-yo 160 (57 mg, 81%) contaminated with docythicine (ratio 22:3) was produced. . [ka] 【0278】 (Example 58a-N-Boc-3-bromo-4-methylaminocyticin(157)) [ka] Tetrahydrofuran (6.0 mL) )of N-methylamine 83 (96 mg, 0.30 mm) OL ) melt Add N-bromosuccinimide (54 mg, 0.30 mmol) to the solution and react. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (15 mL), and the aqueous phase was mixed with ethyl acetate (3 mL). Extracted using 25 mL of solution. together The resulting organic phase was dried with magnesium sulfate and filtered to concentrate Shrinkage occurred. Crude material was subjected to silica gel flash column chromatography [dichloromethane / Purified with methanol (2% methanol), 157(N-Boc-3-bromo-4-methyl It produces (84 mg, 70%) N-Boc-5-bromo-4-methyl Chilamino (27 mg, 22%) was used in the next step without further purification. [ka] 【0279】 (Example 58b-(+)3-bromo-4-N-methylaminocyticine hydrochloride (158 )) [ka] General Procedure A in accordance with N-methylamine 157 (0.21 mmol) from , 9% of 5- 158 (45 mg, ) is a colorless solid contaminated with bromo-4-methylaminocyticine. It produced 73%. [ka] 【0280】 (Example 59 - Iridium-catalyzed borylation reaction of (-)-cyticine) Synthesis of 4-Bpin cyticine Schlenk tube (-)-cyticine (190 mg, 1.0 mmol), [Ir(COD) (OMe)]2 (6.6 mg, 0.01 equivalent), 4,4'-2,2'-di-tert-b Tilbispyridine (5.4 mg, 0.02 equivalents) and bis(pinacolato)diborone (38 Filled with 0 mg (1.50 equivalents). purge Afterwards, tetrahydrofuran (1.4 Add (mL) and heat the reaction mixture under reflux for 24 hours. After this time, the volatile material was removed under reduced pressure. Removed below, 4-Bpin cyticine was partially characterized without further purification, and brown It was obtained as a foam. [ka] [ka] To confirm the uniqueness of 4-Bpin cyticine, the compound was further subjected to bromidation in methanol. It was converted to 4-bromocytisine by treatment with an aqueous solution of copper(II). The spectral properties of thisine were consistent with data available in the literature. 【0281】 (Example 60 - Iridium-catalyzed borylation reaction of (-)-cyticine with CH) (Synthesis of 4-Bpin cytisine) Using the same molar quantities, apparatus, solvent, catalyst, and ligand as outlined above... The preparation method of Example 59 was performed, but the difference was tetramethyl-1,10-phenanthr The use of phosphorus as a ligand and the boronation reaction reagent As a 3.00 equivalent screw (pina The presence of (Corato)diborone was confirmed. The preparation method involved using cyticine to 4-BPin The result was a 100% conversion to thysine. 【0282】 (Example 61 - Iridium-catalyzed borylation reaction of (-)-cyticine with CH) (Synthesis of 4-Bpin cytisine) Using the same molar quantities, apparatus, solvent, catalyst, and ligand as outlined above... The preparation method of Example 59 was performed, but the difference was that neocuproin was used as the ligand. The preparation method involved 100% conversion of cytidine to 4-BPin cytidine. It was the result. 【0283】 (Example 62: Iridium-catalyzed CH borylation reaction of N-Boc-cyticine) 56)) (Synthesis of N-Boc-4-Bpin cytisine (58)) Schlenk tubes are treated with N-Boc cyticine (56) (290 mg, 1.0 mmol), [Ir (COD)(OMe)]2 (6.6 mg, 0.01 equivalent), 4,4'-2,2'-di-t ert-butylbispyridine (5.4 mg, 0.02 equivalents) and bis(pinacolato)dibo Filled with ron (178 mg, 0.70 equivalents). purge After that, tetrahydroflu Add (1.4 mL) and heat the reaction mixture under reflux for 18 hours. After this time, 1H NMR showed nearly 100% conversion, indicating that the volatile material was removed under reduced pressure. The crude product of N-Boc-4-Bpincyticine (58) is essentially determined by 1H NMR. It is shown to be pure, but further purification is possible. ruga This is N-Boc-4-BPin This step is unnecessary before using cyticine (58) as a reagent. Further purification of crude N-Boc-4-BPin cyticine (58) is performed by chromatography. This is achieved using (dichloromethane-methanol, 95:5) and is a pale yellow foam. Pure N-Boc-4-BPin cyticine (58) (180 mg, 43%) was produced. [ka] 【0284】 (Example 63: Iridium-catalyzed CH borylation reaction of N-Boc-cyticine) 56)) (Synthesis of N-Boc-4-Bpin cytisine (58)) Using the same molar quantities, apparatus, solvent, catalyst, and ligand as outlined above... The preparation method of Example 62 was performed, but the difference was that N-methylcytisine was used as the chemical formula IIa. It was used as the excipient. The preparation method involved converting cytidine to 4-BPin cytidine. The result was an 8% conversion. 【0285】 (Example 64: Iridium-catalyzed CH borylation reaction of N-Boc-cyticine) 56)) (Synthesis of N-Boc-4-Bpin cytisine (58)) Using the same molar quantities, apparatus, solvent, catalyst, and ligand as outlined above... The preparation method of Example 62 was performed, but the difference was N-benzyloxycarbonylcyticine The starting material was of chemical formula IIa. The preparation method involved using cytidine to produce 4-BP. The result was an 88% conversion to cyticine. 【0286】 (Example 65-N-Boc-4-p-trilcyticine (72)) N-Boc-4-Bpin cytisine 58 in 0.5 mmol scale in The general discussion above Procedure Prepared according to It was done. To crude N-Boc-4-Bpin cyticine, potassium carbonate (1 24 mg, 0.90 mmol), tetrakis(triphenylphosphine)palladium (0 (28 mg, 0.05 equivalent) and 4-bromotoluene (0.25 mL, 1.0 mmol) Add ) and a dimethyl ether / water mixture (5:1) (5 mL, 0.1 M ) was added. The mixture was heated at 80°C for 24 hours, then cooled to room temperature and diluted with water (15 mL). Aqueous phase Extract with dichloromethane (3 x 15 mL), together The resulting organic phase was dried with magnesium sulfate. The solution was dried, filtered, and concentrated. Flash column chromatography [dichloromethane / methicone] Purification with tanol (1.5% methanol) yields a colorless solid, N-Boc-4. -(p-tril)cyticine (104 mg, 55%) was produced. 【0287】 (Example 66-N-Boc-4-methylcythicine (109)) N-Boc-4-Bpin cytisine 58 in 0.5 mmol scale in The seven-sin method The general procedure for the chemical reaction discussed above Prepared according to did. Using the related procedure modifications, crude N-Boc-4-Bpin cyticine 58 is used. Lith (dibenzylideneacetone) dipalladium (0) (11 mg, 0.025 equivalents), Li(p-tril)phosphine (7.6 mg, 0.05 equivalent), potassium carbonate (138 mg) Add 2.0 equivalents of iodomethane (0.03 mL, 1.0 equivalent) and place the container under vacuum. Leave it and sterilize it with nitrogen three times. Backfill It was done. N,N-dimethylformamide / water (9:1, 5m Add the mixture of (L) and stir the reaction mixture at 60°C for 18 hours. Cool the mixture to room temperature. The solvent was removed under vacuum. residue Distribute it into ethyl acetate (15 mL) and water (15 mL), The aqueous phase was extracted with ethyl acetate (3 × 15 mL). together The resulting organic phase was treated with magnesium sulfate. Dry, filter and concentrate, then flash column chromatography on silica gel [diclo Purified with lomethane / methanol (3% methanol), the pale yellow solid N-Boc- It produced 4-methylcyticine (98 mg, 64%). 【0288】 (Example 67a-N-Boc(3-bromo-4-hydroxy)cyticine) [ka] Tetrahydrofuran (32mL) )of N-Boc-4-aminocytisine (512 mg, 1 0.67 mmol ) melt Cool the solution to 0°C and add N-bromosuccinimide (312 mg, 1. Add 76 mmol) and stir the reaction mixture at 0°C for 18 hours. Add water (25 mL) The aqueous phase was extracted with ethyl acetate (3 × 25 mL). together The resulting organic phase was treated with magnesium sulfate. The crude reaction mixture was dried, filtered, and concentrated. Flash column chromatography was performed on the crude reaction mixture [vinegar]. Purified with ethyl acid / methanol (1% methanol), the colorless solid N-Boc(3) It produced -bromo-4-hydroxy)cyticine (350 mg, 55%). [ka] 【0289】 (Example 67b-(-)-(3-bromo-4-hydroxy)cyticine hydrochloride (BS7) 0)) [ka] General Procedure A in accordance with , N-Boc(3-bromo-4-hydroxy)cyticine (0.83 mmol) from This produced BS70 (236 mg, quantitative), a colorless solid. [ka] 【0290】 (Example 68a-N-Boc(3-bromo-4-amino)cyticine) [ka] Tetrahydrofuran (16mL) )of 4-aminocytisine (250 mg, 0.82 mmol) l ) melt Cool the solution to 0°C and add N-bromosuccinimide (153 mg, 0.86 mmol). Add ) and stir the reaction mixture at 0°C for 18 hours. Add water (25 mL) and combine the aqueous phase with acetate. Extraction was performed using chill (3 x 25 mL). together The resulting organic phase was dried with magnesium sulfate and filtered. The mixture was concentrated by passing it through. Flash column chromatography of the crude reaction mixture was performed using [ethyl acetate]. By purification, a colorless solid N-Boc(3-bromo-4-amino)cyticine (9 It produced 5 mg, 30%. [ka] 【0291】 (Example 68b-(+)-(3-bromo-4-amino)cyticine hydrochloride (BS71)) ) [ka] General Procedure A in accordance with N-Boc(3-bromo-4-amino)cyticine from Colorless solid It produced BS71 (62 mg, 64%). [ka] 【0292】 (Example 69a-N-Boc(3-bromo-4-ethyl)cyticine)) [ka] Tetrahydrofuran (20 mL) )of N-Boc-4-ethylcyticine (341 mg, 1.07 mmol ) melt Cool the solution to 0°C, then add N-bromosuccinimide (190 mg, 1 Add 0.07 mmol) and stir the reaction mixture at 0°C for 18 hours. Add water (25 mL). The aqueous phase was extracted with ethyl acetate (3 × 25 mL). together The resulting organic phase is converted to magnesium sulfate The mixture was dried, filtered, and concentrated. Flash column chromatography of the crude reaction mixture [ Purification with dichloromethane / methanol (2% methanol) yields a colorless solid. N-Boc(3-bromo-4-ethyl)cyticine (296 mg, 70%) was produced. [ka] 【0293】 (Example 69b-(-)-(3-bromo-4-ethyl)cyticine (BS74)) [ka] General Procedure A in accordance with , N-Boc(3-bromo-4-ethyl)cyticine (296 mg, (0.75 mmol) from It produced BS74 (80 mg, 37%), a colorless solid. [ka] 【0294】 (Example 70 - Binding to nicotinic receptor subtypes) Regarding affinity for different nAChR subtypes, particularly α4β2, α3β4, and α7 The binding of the group of compounds described above was tested. The protocols for these tests are described below. The results are shown in Tables 1 through 9 below. 【0295】 (Binding to heterologously expressed α4β2 and α3β4 human subtypes) HEK293 cells 10% fetal bovine serum, 1% L-glutamine, 100 units The treatment was supplemented with penicillin G at a dose of / ml and streptomycin at a dose of 100μg. Dalbecco modification In a medium 、1 In a humid environment containing 0% carbon dioxide cultured α3 and β4, Alternatively, code α4 and β2 doing cDNA (at a density of 30%) is introduced into HEK293 cells. (Lancefected). cell Transfection is performed using 30 μL of jet paint. (quotient mark (Polypass, France) (1 mg / ml, pH 7.2) and 3 μg of cDNA were used. This was done in a 100mm Petri dish. After 24 hours of transfection, cell Gather The samples were then washed with phosphate-buffered saline by centrifugation and used for binding analysis. HEK-transfected α3β4 or α4β2 receptors [ 3 H]-Epiva The thidine saturation binding experiment was performed in the presence of 100 nM cold epibatidine ( different (Combined) or Non-existent Existence (complete) complete conclusion In the mixture, 50 mM Tris-HCl, pH 7, and 150 mM sodium chloride are used. , 5 mM potassium chloride, 1 mM magnesium chloride, 2.5 mM calcium chloride and Buffer containing 2 mg / ml bovine serum albumin Inside, Concentrations in the range of 0.005 to 1 nM This was performed by overnight incubation at 4°C. different Ligand binding is 100 nM from complete binding. It was defined as the reduced binding in the presence of cold epibatidine. 【0296】 Induced by compounds or nicotine ligands [ 3 Inhibition of H]-epivatidine binding, The test compound was cultured at room temperature (rt) for 30 minutes, gradually increasing the concentration (from 10 pM to 10 mM). To nourish, and then, [ 3 The final concentration of [H]-epivathidine was set to 0.25 nM (α4β2 subtype). (In this case) or 0.5 nM (for α3β4 subtype) and measured by overnight incubation at 4°C. HEK cells were transfected with either the α4β2 or α3β4 subtype after culturing. The membrane, Ice-cold Gel filtration chromatography using phosphate-buffered saline The filters were washed by filtration. The gel filtration chromatography filters were pre-soaked in polyethyleneimine. Then, it was filtered through a harvesting device. 3 The H]-epivatidine bond is a beta counter. - liquid Determined by scintillation count. 【0297】 (Binding to heterologously expressed α7 subtypes) Human α7 cDNA was transfected into SH-SY5Y human neuroblastoma cells. . cell Transfection is performed using 30 μL of jet paint. (quotient (Polypass, France) Using 1 mg / ml (pH 7.2) and 6 μg of α7 cDNA, a 100 mm petrochemical solution was used. It was done in a dish. After 24 hours of transfection, cell Collect the material and use centrifugal separation to extract the The samples were washed with nitrate-buffered saline and used for binding analysis. 【0298】 [ 125 I]-α-Bungarotoxin (PerkinElmer Company, Bost, Massachusetts) (Purchased from) Saturated bond, 0.1 at room temperature ~ 10 nM concentration [ 125 I]-α-Bungarottoki This was performed by overnight incubation of SH-SY5Y membranes using Syn. different The bond is 1 μM This was determined in parallel by culturing in the presence of unlabeled α-bungarotoxin. After fermentation, the sample was filtered as described above, and the coupled radiation was measured using a gamma counter. Noh But directly Counted. By the test compound [ 125 Inhibition of I]-α-bungarotoxin binding is SH- High SY5Y film Concentration (10M ~ 1mM) The test drug was left at room temperature for 30 minutes. Pre-culture hand, So Afterwards at room temperature [ 125 Incubate overnight with a final concentration of 2 to 3 nM of [I]-α-bungarotoxin. It was measured by performing the following procedure. 【0299】 After culturing overnight, the membrane of SH-SY5Y cells transfected with α7 was... Ice-cold Slow phosphate The samples were washed by filtration using a gel filtration chromatography filter with saline solution. The gel filtration chromatography filter is pre-soaked in polyethyleneimine and then passed through the harvesting apparatus. It was filtered. 125 [I]-α-Bungarotoxin binding is gamma counter in By direct counting It was decided. 【0300】 (Data analysis) Ligand binding data is from Prism Version 5 (GraphPad Software, Inc., Calif The analysis was performed using nonlinear regression with K (La Jolla, Walnia).i The value is a single location of the conflict. Calculated from experimental 50% inhibitory concentration values ​​using the following Chen-Prusov formula for a single population. K i =IC 50 / [1+(L / K d ), where L is the radioactive ligand used in each experiment. It is concentration, K d The values ​​were determined by saturated bond experiments. All analyses were performed twice, with less than two values. Each instance was repeated two to three times. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] As can be seen from this data, the compound of the present invention is compatible with both the α3β4 subtype and α7 subtype. Compared to (when tested, in both mouse and human cells), human α4β2 It shows high selectivity in receptor subtypes, Off-target The potential for this effect was minimized. 【0301】 (Example 71 - Nicotinic receptor subtype) in(Relative effect of) The compounds of the present invention were heterologously expressed in African clawed frog oocytes, and human α4β2, α 3β4 and α7 nicotinic acetyl Ru Cholinergic receptor (nACh R) Testing the effects of the function I tested it. The human α4β2nACh receptor is (α4)3(β2)2 (low ACh sensitivity) or It was expressed as either the (α4)2(β2)3 receptor (which has high sensitivity to ACh) (unpatented). Reference 16). Expression in oocytes was obtained as follows. Human α4, β2, β4 or α 7 Contains complementary DNA pCI (Promega, UK) Plasmi Do is the first document Injected like this (Non-patent document 16). In order to express the (α4)3(β2)2nACh receptor, 10α A mixture of 4:1β2 cDNA was injected into the nucleus of an oocyte, while the (α4)2(β2)3 receptor was also injected. The ratio of injected cDNA was 1α4:10β2. 【0302】 (Functional research) Geneclamp amplifier (Molecular Devices, USA) Using manually, or Using the automated HiClamp system Note Record but It was done. In both cases, oocytes 3 M With two electrodes filled with potassium chloride Stitch , cell Maintain -60mV during the experiment. did. 【0303】 The isolation of oocytes and the recording of voltage fixation on oocytes using two electrodes are Previous literature It will be executed as follows. (Non-patent documents 16, 17). The concentration-response curve of the agonist maximizes all receptors being tested. The reaction derived from the concentration of ACh that activates the chemicals is 1 mM ACh. Correct reactions caused by substances Rules Obtained by (Non-Patent Documents 16 to 18). Reproducible To ensure accurate recording, a minimum interval of 5 minutes was permitted between the application of the agonist. Oocytes The compound concentration was increased until no further increase in response amplitude was obtained. The concentration was interpreted as the concentration that elicited the maximum response from the tested receptor. See Tables 1 to 13. The data that was stopped was at least 3 different donor A small amount of work was performed on oocytes obtained from At the very least, it was obtained from five experiments. 【0304】 ((a):(α4)3(β2)2nACh R( Compounds related to low-sensitivity stoichiometry effect) (Maximum gating potency of the compound) (α4)3(β2)2nACh heterologously expressed in African clawed frog oocytes R Maximum activity The concentration of the compound of the present invention that causes transformation is 、 This was determined using voltage fixation at two electrodes. The maximum current derived from the compound leads to the maximum response to the (α4)3(β2)2 receptor. (k) It was relativized to the maximum concentration derived from 1 mM ACh. [Table 10] 【0305】 ((b):(α4)2(β2)3nACh R (Effects related to) (Maximum gate of compounds related to the (α4)2(β2)3 receptor (a highly sensitive receptor) (Effectiveness) (α4)2(β2)3nACh heterologously expressed in African clawed frog oocytes R Maximum activity The concentration of the compound that causes the transformation was determined using voltage fixation at two electrodes. The resulting maximum current then leads to the maximum response to the ((α4)2(β2)3 receptor. )This was relative to the maximum concentration derived from 1 mM ACh. [Table 11] 【0306】 ((c):α3β4nACh R (Effects of the compound) (α3β4nACh R (Maximum gating potency of the compound) α3β4nACh heterologously expressed in African clawed frog oocytes R Produces maximum activation The concentration of the compound was determined using voltage fixation at two electrodes. The maximum current subsequently evolves due to 1 mM ACh (which leads to the maximum response to the α3β4 receptor). It was relativized with respect to the maximum concentration derived from it. [Table 12] 【0307】 ((d):α7nACh R (Effects of the compound) (α7nACh R (The relative potency of the compounds concerned) The amplitude of the current induced by the compound at 100 μM was measured, followed by α7nACh R Relativizing the reaction amplitude relative to 1 mM ACh, the concentration that produces maximum activity. It was done. [Table 13] The data in Table 13 shows that the compound of the present invention is α7 compared to cyticine and varenicline. It was found to exhibit low relative efficacy with respect to receptors. This application provides the invention in the following embodiments. (Aspect 1) Compounds represented by chemical formula I, or pharmaceutically acceptable salts, solvates thereof, and / or 'k' is ester, (chemical 1) TIFF0007873509000234.tif51170 R of the aforementioned chemical formula I 1 teeth, Hydroxy, halogen, Aliphatic which may have substituents, Cycloaliphatic, which may have substituents, Heterocycloaliphatic, which may have substituents aryls which may have substituents, heteroaryls which may have substituents, -(CH 2 ) m -NR 6 R 7 R 8 (Let's call this side chain 1), -(CH 2 ) m -O-(CH 2 ) n -R 10 (Let's call it side chain 2), -CN, -COOR 12 (Assuming side chain 3), -(CH 2 ) O -CO-(CH 2 ) P -R 13 (Let's call it side chain 4), Amino acids or their esters, Acyl chloride, Protecting group, or Selected from cyticinyl, R of the side chain 1 6 and R 7 These are, independently, hydrogen, halo, hydroxyl, oxo, and amino acids. amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino No, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulf Anyl sulfamide sulfo mercapto carbamoyl methyl pivalate, trimeth Lucilyl, urea, thiourea, optionally substituted aryl, substituted A heteroaryl that may have substituents, an alkyl that may have substituents cycloaliphatic, heterocycloaliphatic having substituents, A heteroaryl which may have substituents, a haloalkyl which may have substituents, an alloyl which may have a substitution group, a heteroaloyl which may have substituents, a substituent acyl which may have substituents, alkenyl which may have substituents A good alkynyl, optionally substituted aralkyl, optionally substituted sic Roalkyl, optionally substituted cycloalkenyl, optionally substituted he Glucose comprising telocycloalkyl or optionally substituted heterocycloalkenyl Selected from the options, or The R of the side chain 1 6 and R 7 One of them is -CO-R 9 (Let's call it side chain 5), and the R 6 and R 7 The other is selected from the aforementioned group, R of the side chain 1 8 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or is selected from heterocycloalkenyls which may have substituents, or which may not have substituents. R of the side chain 5 9 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The m of the side chain 1 is 0, 1, 2, 3, 4, or 5. R of the side chain 2 10 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The values ​​of m and n in the side chain 2 are independently 0, 1, 2, 3, 4, or 5. R of the side chain 3 12 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, R of the side chain 4 13 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The o and p of the side chain 4 are independently 0, 1, 2, 3, 4, or 5. R of the aforementioned chemical formula I 2 、R 3 and R 4 These are independently hydrogen, halo, hydroxyl, and oxo. , amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dial Killamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl Sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, Trimethylsilyl, urea, thiourea, optionally substituted aryl, substituted A heteroaryl which may have a substituent, an alkyl which may have a substituent cycloaliphatic which may have substituents, heterocycloaliphatic which may have substituents ick, optionally substituted heteroaryl, optionally substituted haloaryl Kill, optionally substituted alloyl, optionally substituted heteroaloyl, optionally substituted acyl, optionally substituted alkenyl, substituted alkynyl which may have substituents, aralkyl which may have substituents A good cycloalkyl, a cycloalkenyl which may have substituents, and A heterocycloalkyl or heterocycloalkenyl which may have substituents, Selected from mino acids or cyticine, or R 4 is a protecting group, or -(CH 2 ) V -FORMU LA 1 (referred to as chemical formula A) is a group having the structure, where v in chemical formula A is 0, 1, 2, 3, 4, 5, or 6, and FORMULA 1 is a compound of the chemical formula I. The R of the aforementioned chemical formula I 2 , the R 3 and R 4 At least one of them is not hydrogen. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, and / or ester thereof. (Aspect 2) Compounds represented by chemical formula I used in pharmaceuticals, or their pharmaceutically acceptable salts, solvents. Japanese compounds and / or esters, (Case 2) TIFF0007873509000235.tif51170 R of the aforementioned chemical formula I 1 teeth, Hydroxy, halogen, Aliphatic which may have substituents, Cycloaliphatic, which may have substituents, Heterocycloaliphatic, which may have substituents aryls which may have substituents, heteroaryls which may have substituents, -(CH 2 ) m -NR 6 R 7 R 8 (Let's call this side chain 1), -(CH 2 ) m -O-(CH 2 ) n -R 10 (Let's call it side chain 2), -CN, -COOR 12 (Assuming side chain 3), -(CH 2 ) O -CO-(CH 2 ) P-R 13 (Let's call it side chain 4), Amino acids or their esters, Acyl chloride, Protecting group, or Selected from cyticinyl, R of the side chain 1 6 and R 7 These are, independently, hydrogen, halo, hydroxyl, oxo, and amino acids. amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino No, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulf Anyl sulfamide sulfo mercapto carbamoyl methyl pivalate, trimeth Lucilyl, urea, thiourea, optionally substituted aryl, substituted A heteroaryl that may have substituents, an alkyl that may have substituents cycloaliphatic, heterocycloaliphatic having substituents, A heteroaryl which may have substituents, a haloalkyl which may have substituents, an alloyl which may have a substitution group, a heteroaloyl which may have substituents, a substituent acyl which may have substituents, alkenyl which may have substituents A good alkynyl, optionally substituted aralkyl, optionally substituted sic Roalkyl, optionally substituted cycloalkenyl, optionally substituted he Glucose comprising telocycloalkyl or optionally substituted heterocycloalkenyl Selected from the options, or The R of the side chain 1 6 and R 7 One of them is -CO-R 9 (Let's call it side chain 5), and the R 6 and R 7 The other is selected from the aforementioned group, R of the side chain 1 8 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or is selected from heterocycloalkenyls which may have substituents, or which may not have substituents. R of the side chain 5 9 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The m of the side chain 1 is 0, 1, 2, 3, 4, or 5. R of the side chain 2 10 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The values ​​of m and n in the side chain 2 are independently 0, 1, 2, 3, 4, or 5. R of the side chain 3 12 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, R of the side chain 4 13 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The o and p of the side chain 4 are independently 0, 1, 2, 3, 4, or 5. R of the aforementioned chemical formula I 2 、R 3 and R 4 These are independently hydrogen, halo, hydroxyl, and oxo. , amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dial Killamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl Sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, Trimethylsilyl, urea, thiourea, optionally substituted aryl, substituted A heteroaryl which may have a substituent, an alkyl which may have a substituent cycloaliphatic which may have substituents, heterocycloaliphatic which may have substituents ick, optionally substituted heteroaryl, optionally substituted haloaryl Kill, optionally substituted alloyl, optionally substituted heteroaloyl, optionally substituted acyl, optionally substituted alkenyl, substituted alkynyl which may have substituents, aralkyl which may have substituents A good cycloalkyl, a cycloalkenyl which may have substituents, and A heterocycloalkyl or heterocycloalkenyl which may have substituents, Selected from group 7 consisting of amino acids or cyticine, or the R 4 is a protecting group, or - (CH 2 ) V -A group having the structure of FORMULA 1 (chemical formula A), and the chemical In formula A, v is 0, 1, 2, 3, 4, 5, or 6, and FORMULA 1 is the chemical formula Compound I, the aforementioned compound, or a pharmaceutically acceptable salt, solvate thereof, and / or Or ester. (Aspect 3) The aforementioned R 1 This includes substituted methyl groups, substituted ethyl groups, and substituted propyl groups. , replaced C 1-8 It is an alkyl group, The substituted methyl group includes aminomethyl and halogenated methyl groups. Methyl includes chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, and tri It contains fluoromethyl, bromomethyl, dibromomethyl, and tribromomethyl. The substituted ethyl group may be 1- or 2-aminoethyl, hydroxyethyl, or halogen. It contains ethyl halogen, and the ethyl halogen is 2,2,2-trichloroethyl, 2,2,2 - Containing tribromoethyl or 2,2,2-trifluoroethyl, The substituted propyl group is 1-, 2-, or 3-aminomethyl, or hydroxypropyl. Or the compound according to embodiment 1 or 2, comprising a propyl halogenated compound. (Aspect 4) The aforementioned R 1 This includes unsubstituted C containing propyl, isopropyl, butyl, or tert-butyl. 3 -8 The compound according to embodiment 1 or 2, wherein the compound is an alkyl group. (Aspect 5) The aforementioned R 1 is an unsubstituted or substituted aryl group, and is a phenyl group or chlorophenyl group. bromophenyl, fluorophenyl, perchlorophenyl, perbromophenyl, pe Substituted phenyl groups containing halogenated phenyl groups including fluorophenyl, or tri Aniline, phenol, styrene, benzonitrile, anisole, acetophenone, A compound according to embodiment 1 or 2, comprising benzaldehyde or benzoic acid. (Aspect 6) The aforementioned R 1 This includes benzyloxypyridine, pyridone containing 2-pyridone, 2-pyridine, Pyridine containing 3-pyridine or 4-pyridine, phenyltriazole, having substituents Triazoles and triazolemethylpivalic acid may be present, even if they have substituents. The compound according to embodiment 1 or 2, which is a good heteroaryl compound. (Aspect 7) The aforementioned R 1 These are cyclopentyl, cyclohexyl, morpholinyl, piperidyl, and piperadi. Even if it has substituents including tetrahydrofuryl, oxolanil, or dioxanil The compound according to embodiment 1 or 2, which is a good cycloalkyl or heterocycloalkyl. (Pattern 8) The aforementioned R 1 Vinyl, acrylate, -C=CC 6 H 5 Acetinyl, -C≡CC 6 H 5 , or a substituent containing a -C≡C-trimethylsilyl group, which may have a C 2-8 Alkeni C may have a substituent or other substituent. 2-8 The compound described in embodiment 1 or 2 is an alkynyl compound. 。 (Aspect 9) The aforementioned R 1 These are amines, N-alkylamines, N,N-dialkylamines, or amides. The compound according to embodiment 1 or 2. (Aspect 10) The aforementioned R 1 These include amines, methylamines, ethylamines, propylamines, and isopropylamines. methylamine, benzylamine, dimethylamine, trimethylammonium methyl, dimethylamine The compound according to embodiment 9, which is one of nomethyl, benzamide, or acetamide. (Aspect 11) The aforementioned R 1 These are methoxy, ethoxy, propoxy, benzyloxy or trifluoromethyl A compound according to embodiment 1 or 2, which is any one of rubenzyloxy. (Aspect 12) The aforementioned R 1 These include ethyl esters, propyl esters, isopropyl esters, and butyl esters. The carboxylic acid or ester containing tel or phenyl ester, as described in Embodiment 1 or 2. compound. (Aspect 13) The aforementioned R 1 It contains alanine, arginine, asparagine, aspartate, cysteine, and Glutamate, Glycine, Histidine, Isoleucine, Leucine, Lysine, Me Thionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine containing valine or their methyl, ethyl, propyl or isopropyl esters, The compound according to embodiment 1 or 2, which is a naturally occurring amino acid or an ester thereof. (Aspect 14) The aforementioned R 1 It is tert-butyloxycarbonyl (Boc), formyl, acetyl (A c) succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxyca Rubonyl (Cbz), or fluorenyl methoxycarbonyl (Fmoc), or ( (RO) of pinacoratoborane (BPin) and catecoratoborane (BCat) 2 B - Any one of the protected boryl protecting groups that optionally include the structure, as described in Embodiment 1 or 2. compound. (Aspect 15) The aforementioned R 2 and R 3 The compound is hydrogen, as described in any one of embodiments 1 to 14. (Aspect 16) The aforementioned R 4 The compound according to any one of embodiments 1 to 15, wherein is a protecting group or hydrogen. (Aspect 17) (-)4-methylcyticine, (-)4-(hydroxymethyl)cyticine, (-)4-bromocyticine, (-)4-chlorocyticine, (+)4-trilcyticine, (-)4-ethylcyticine, (+)4-vinyl cyticine, A compound selected from (-)4-fluorocyticine. (Aspect 18) A compound as described in embodiment 17, used in pharmaceuticals. (Aspect 19) A compound according to any one of embodiments 1 to 18, used for the prevention or treatment of poisoning. (Aspect 20) The aforementioned poisoning is one of the following: nicotine poisoning, alcohol poisoning, or drug poisoning. The compound described in 19. (Aspect 21) The present invention comprises a compound according to any one of embodiments 1 to 20, and a pharmaceutically acceptable excipient. composition. (Aspect 22) The composition according to embodiment 21, used for the prevention or treatment of poisoning. (Aspect 23) The poisoning is nicotine poisoning, alcohol poisoning, and drug poisoning, according to the composition described in embodiment 22. thing. (Aspect 24) Methods for preventing or treating poisoning of a target requiring treatment, wherein the effect size is as described in 1 to 20 of the embodiments. A compound described in any one of the items, or a composition described in any one of the embodiments 21 to 23, A method for preventing or treating poisoning, comprising a step of administering an agent to a target for treatment. (Aspect 25) A method for preparing a 4-position cyticine analog, Step i, which involves generating a compound of chemical formula IIa, (3) TIFF0007873509000236.tif51170 Step ii, which involves generating a compound of chemical formula IIb, (C4) TIFF0007873509000237.tif51170 CompB of the above chemical formula IIb is R 1 A step to generate a compound of chemical formula I by substitution. iii and (C5) TIFF0007873509000238.tif50170 R of the aforementioned chemical formula IIa 2 、R 3 and R 4 These are, independently, hydrogen, halo, hydroxyl, Oxo, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N- Dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulf Honyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methylpiva uric acid, trimethylsilyl, urea, thiourea, aryl which may have substituents, A heteroaryl which may have a substitution group, an alkyl which may have a substituent, and a substituent cycloaliphatic which may have substituents, heterocycloaliphatic which may have substituents Fatic, optionally substituted heteroaryl, optionally substituted Roalkyl, optionally substituted aroyl, optionally substituted heteroalloyl Iyl, optionally substituted acyl, optionally substituted alkenyl, substituent Alkynyl which may have a substituent, aralkyl which may have a substituent Optional cycloalkyl, optionally substituted cycloalkenyl, substituted A heterocycloalkyl or a heterocycloalkyl which may have substituents Selected from group 1 consisting of R, amino acids, or cyticine, or the aforementioned R 4 is a protecting group, also is, -(CH 2 ) V -A group having the structure of FORMULA 1 (chemical formula A), In chemical formula A, v is 0, 1, 2, 3, 4, 5, or 6, and FORMULA 1 is the same as above. It is a compound of chemical formula I, The R of the aforementioned chemical formula IIb 2 , the R 3 and R 4 The above is selected from group 1, CompB is a boronation complex obtained by contacting the compound of chemical formula IIa with a boronation reagent. And, The R of the aforementioned chemical formula I 1 teeth, Hydroxy, halogen, Aliphatic which may have substituents, Cycloaliphatic, which may have substituents, Heterocycloaliphatic, which may have substituents aryls which may have substituents, heteroaryls which may have substituents, -(CH 2 ) m -NR 6 R 7 R 8 (Let's call this side chain 1), -(CH 2 ) m -O-(CH 2 ) n -R 10 (Let's call it side chain 2), -CN, -COOR 12 (Assuming side chain 3), -(CH 2 ) O -CO-(CH 2 ) P -R 13 (Let's call it side chain 4), Amino acids or their esters, Acyl chloride, Protecting group, or It is one of the following: R of the side chain 1 6 and R 7 These are, independently, hydrogen, halo, hydroxyl, oxo, and amine. No, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkyla Mino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sul Fanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trim cyyl, urea, thiourea, optionally substituted aryl, substituted A heteroaryl which may have substituents, an alkyl which may have substituents, even if it has substituents Good cycloaliphatic, domestic heterocycloaliphatic having substituents , optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted alloyl, optionally substituted heteroaloyl, substituent acyl which may have substituents, alkenyl which may have substituents A good alkynyl, an aralkyl which may have substituents, a cy chloroalkyl, optionally substituted cycloalkenyl, optionally substituted G Selected from Loop 2, or R of the side chain 1 6 and R 7 One of them is -CO-R 9 (Let's call it side chain 5), and the R 6 and the above R 7 The other is selected from group 2, R of the side chain 1 8 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or is selected from heterocycloalkenyls which may have substituents, or which may not have substituents. R of the side chain 5 9 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The m of the side chain 1 is 0, 1, 2, 3, 4, or 5. R of the side chain 2 10 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The values ​​of m and n in the side chain 2 are independently 0, 1, 2, 3, 4, or 5. R of the side chain 3 12 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and shea. No, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thio Urea, optionally substituted aryl, optionally substituted heteroaryl , alkyl which may have substituents, cycloaliphatic which may have substituents C, heterocycloaliphatic, which may have substituents, A heteroaryl, a substituted haloalkyl, a substituted Aroyl, optionally substituted heteroaloyl, optionally substituted acyl , optionally substituted alkenyl, optionally substituted alkynyl, substituent Aralkyl which may have substituents, cycloalkyl which may have substituents cycloalkenyl which may have substituents, heterocycloalkyl which may have substituents or Selected from heterocycloalkenyls which may have substituents, R of the side chain 4 13 These are hydrogen, halo, hydroxy, oxo, amino, amide, nitro, and cy Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbony carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, th Aurea, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted alkyl, optionally substituted cycloaliphatic buck, heterocycloaliphatic, which may have substituents, A good heteroaryl, a haloalkyl which may have substituents, may have substituents aroyl, heteroaloyl which may have substituents, ac which may have substituents Alkenyl, which may have substituents, alkynyl, which may have substituents, substitution Aralkyl groups which may have a group, cycloalkyl groups which may have a substituent Optionally having a cycloalkenyl, or optionally having a heterocycloalkyl or It is selected from heterocycloalkenyls which may have substituents, The o and p of the side chain 4 are independently 0, 1, 2, 3, 4, or 5. The R of the aforementioned chemical formula I 2 , the R 3 and R 4 At least one of them is not hydrogen Manufacturing method. (Aspect 26) The compound of chemical formula IIa provided in step i is R 4 A hydrogen atom at this position Includes, The above step further includes the R 4 an embodiment that includes substituting the hydrogen atom at the position with a protecting group. Preparation method as described in 25. (Aspect 27) The protecting group is tert-butyloxycarbonyl (Boc), as described in embodiment 26. Preparation method. (Aspect 28) The preparation method according to embodiment 26 or 27, wherein the compound of chemical formula IIa is cyticine. 。 (Aspect 29) The boronating reagent has the chemical formula (RO) 2 -BB-(OR) 2 or HB (OR) 2 Represented by A preparation method according to any one of embodiments 25 to 28, having a chemical structure. (Aspect 30) The boronating reagent is bis(pinacorato)diboron(B 2 pin 2 ), or Bis (category) (B) Diboron (B) 2 Cat 2 The preparation method described in any one of embodiments 25 to 28. (Aspect 31) Boronating reagent: The molar ratio of the starting material of chemical formula IIa is at least 0.5:1, or At least 0.75:1, or at least 1:1, or at least 1.5:1, or less A preparation method according to any one of embodiments 25 to 30, wherein the ratio is at least 2:1. (Aspect 32) The reaction in step ii is carried out in the presence of a catalyst, according to any of embodiments 25 to 31. The preparation method described in any one of the items. (Aspect 33) The preparation method according to embodiment 32, wherein the catalyst is a transition metal catalyst. (Aspect 34) The transition metal catalyst is iridium, palladium, zinc, nickel and / or rhodium. The preparation method described in embodiment 33. (Aspect 35) The reaction in step ii is carried out in a solvent, according to any one of embodiments 25 to 34. Preparation method as described in the section. (Aspect 36) The aforementioned solvents include ester solvents, ether solvents, ketone solvents, sulfoxide solvents, and aromatic solvents. The preparation according to embodiment 35, comprising a medium, a fluorinated aromatic solvent, an alkane solvent, or a mixture thereof. Manufacturing method. (Aspect 37) Step ii is performed in the presence of a ligand, in any one of embodiments 25 to 36. The preparation method described. (Aspect 38) The ligand is tetramethyl-1,10-phenanthroline (Me4phen), di -tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (b py), 1,1'-bis(diphenylphosphin)ferrocene (dppf), bis(2- Di-tert-butylphosphinofenyl) ether, 1,3-bis(diphenylphosphinofenyl) (dppp)propane, 1,2-bis(diphenylphosphin)ethane (dppe ), hexamethylbenzene (C6Me6), xanthophos, or 1,2-bis(dimethyl) The preparation method according to embodiment 37, wherein the solution is one of phosphino)ethane (DMPE). (Aspect 39) The ligands are phenanthroline (phen) and dimethylphenanthroline (me2 phen), tetramethyl-1,10-phenanthroline (me4phen), batfe Nanthroline (bathophen), di-tert-butyl-2,2'-bipyridyl dtbpy), 2,2'-bipyridine (bpy), dimethoxy-2,2'-bipyridyl ( MeO-bpy), 1,1'-bis(diphenylphosphin)ferrocene (dppf), Bis(2-di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenyl Nylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), neocuproine, xanthophos, 1,2-Bis(dimethylphosphin)ethane (DMPE), or the compound described in chemical formula 6. The preparation method according to embodiment 37, which is one of the following. (6) TIFF0007873509000239.tif207170 。 (Approach 40) Boronating reagent: The molar ratio of the starting material of chemical formula IIa is less than 2:1, or less than 1.5. :1, or less than 1:1, or less than 0.75:1, or less than 0.5:1, or less than 0.1: 1, or less than 0.05:1, and at least 0.001:1, in embodiments 37 to 39 The preparation method described in any one of the items. (Aspect 41) The boration in step ii is carried out at a temperature of 50°C to 100°C. Preparation method as described in any one of items 25 to 40. (Aspect 42) Before the commencement of step iii, the compound of chemical formula IIb is formed in step ii. The resulting mixture is not separated from and / or the mixture from step ii. The preparation method according to any one of embodiments 25 to 41, wherein the purification step is not performed during i. 。 (Aspect 43) Step iii is initiated in the same reaction region in which step ii was performed. or the preparation method described in any one of embodiments 25 to 42. (Aspect 44) In step iii above, CompB is R 1 Substituted with the first intermediate of the substituent or the preparation method described in any one of embodiments 25 to 43. (Aspect 45) The aforementioned R 1 The first intermediate of the substituent is R 1 Substituting with a second intermediate of the substituent, or R 1 replacement The preparation method according to embodiment 44, wherein the group is substituted to produce the compound of chemical formula I. (Aspect 46) The aforementioned R 1 The second intermediate of the substituent is R 1 Substituting with a third intermediate of the substituent, or R 1 replacement The preparation method according to embodiment 45, wherein the group is substituted to produce the compound of chemical formula I. (Aspect 47) The aforementioned R 1 The first, second, and third intermediates of the substituent are bromo, chloro, iodine, and benzyl oxyl. Cypyridine, alkyl esters containing methyl esters, alkenyls containing vinyl, acetyl Alkinyl containing renyl, trimethylsilylacetylene, 1,2,3-triazole-1 -Ilmethylpivalic acid, cyano, aminomethyl, N-Boc-aminomethyl or (benzyl A method independently selected from (ruoxy)carbonyl)piperazine-1-yl, as described in embodiment 46. Preparation method. (Aspect 48) The compound of chemical formula IIb or chemical formula I is R 4 Equipped with a protective group at the position, The preparation method further involves the R of the compound of chemical formula IIb or chemical formula I. 4 Deprotect the base A preparation method according to any one of embodiments 25 to 47, comprising the step of [doing something]. (Aspect 49) R of the compound of chemical formula IIb or chemical formula I 4 The above deprotection step of the base is before After the completion of step ii, or before the start of step iii, or the completion of step iii The preparation method according to embodiment 48, which is performed during or after the completion of step iii.

Claims

[Claim 1] A method for preparing a cyticine analog of formula (I) with a 4-position substitution, or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 1】 (In the formula, R １ teeth, ・ OH, Halogen, ・Ayl, • Alkyl, Alkenil, Alkinil, -NR ６ R ７ Here, R ６ and R ７ Each is independently selected from the group consisting of hydrogen, aryl, and alkyl. ・-NH(C=O)R ９ Here, R ９ It is an aryl or alkyl, ・ -(CH ２ )-NR ６ R ７ , where R ６ and R ７ are each independently selected from the group consisting of hydrogen, a protecting group, and alkyl, ・ Alkoxy, ・ -CH ２ -O-CH ２ -R １０ Here, R １０ It is Ariel, -CN, -COOR １２ Here, R １２ is hydrogen or alkyl, • Amino acids, or their methyl, ethyl, propyl, or isopropyl esters, Acyl chloride, ・ Protecting group, or 4-cyticinyl, and R ２ These are hydrogen, halogens, or haloalkyls. R ３ is hydrogen, and R ４ is hydrogen or a protecting group, Here, the protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Cbz), fluorenyl methoxycarbonyl (Fmoc), (pinacolate)borane (BPin), and (catecolate)borane (BCat). (i) Formula (IIa): 【Chemistry 2】 (In the formula, R ２ , R ３ , and R ４ The step of preparing the compound (as identified above), (ii) Formula (IIb): 【Transformation 3】 (In the formula, R ２ , R ３ , and R ４ The steps include: producing a compound of formula (IIa) (where CompB is a boron complex) by contacting the compound of formula (IIa) with a boronating reagent, (iii) CompB to R １ Substituting this, we get equation (I) 【Chemistry 4】 The step of generating the compound, The preparation method comprising the above. [Claim 2] The compound of formula (IIa) prepared in step (i) above has hydrogen atoms R ４ The step includes the position of, and the step further includes R ４ The preparation method according to claim 1, comprising substituting the hydrogen atom at the position with a protecting group. [Claim 3] The preparation method according to claim 2, wherein the protecting group is Boc. [Claim 4] The preparation method according to any one of claims 1 to 3, wherein the compound of formula (IIa) is cyticine. [Claim 5] The boronating reagent is of formula (RO) ２ -B-B-(OR) ２ OR HB (OR) ２ A preparation method according to any one of claims 1 to 4, wherein the preparation method is characterized by having the following: [Claim 6] The boronating reagent is B ２ Pin ２ or B ２ Cat ２ The preparation method according to any one of claims 1 to 4. [Claim 7] The preparation method according to any one of claims 1 to 6, wherein the molar ratio of the boronating reagent to the starting material of formula (IIa) is at least 0.5:1, at least 0.75:1, at least 1:1, at least 1.5:1, or at least 2:

1. [Claim 8] The preparation method according to any one of claims 1 to 7, wherein the reaction in step (ii) is carried out in the presence of a catalyst. [Claim 9] The preparation method according to claim 8, wherein the catalyst is a transition metal catalyst. [Claim 10] The preparation method according to claim 9, wherein the transition metal catalyst includes iridium, palladium, zinc, nickel, and / or rhodium. [Claim 11] The preparation method according to any one of claims 1 to 10, wherein the reaction in step (ii) is carried out in a solvent selected from an ester solvent, an ether solvent, a ketone solvent, a sulfoxide solvent, an aromatic solvent, a fluorinated aromatic solvent, an alkane solvent, and a mixture thereof. [Claim 12] The preparation method according to any one of claims 1 to 11, wherein step (ii) is carried out in the presence of a ligand. [Claim 13] The preparation method according to claim 12, wherein the ligand is selected from tetramethyl-1,10-phenanthroline (Me4phen), di-tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), xanthophos, and 1,2-bis(dimethylphosphino)ethane (dmpe). [Claim 14] The ligands include phenanthroline (phen), dimethylphenanthroline (me2phen), tetramethyl-1,10-phenanthroline (me4phen), batphenanthroline (bathophen), di-tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bpy), dimethoxy-2,2'-bipyridyl (MeO-bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), neocuproine, xanthophos, 1,2-bis(dimethylphosphino)ethane (dmpe), and the following: 【Transformation 5】 【change】 The preparation method according to claim 12, wherein one of the compounds is selected. [Claim 15] The preparation method according to any one of claims 12 to 14, wherein the molar ratio of the ligand to the starting material of formula (IIa) is less than 2:1, less than 1.5:1, less than 1:1, less than 0.75:1, less than 0.5:1, less than 0.1:1, less than 0.05:1, or less than 0.001:

1. [Claim 16] The preparation method according to any one of claims 1 to 15, wherein the boration in step (ii) is carried out at a temperature of 50°C to 100°C. [Claim 17] The preparation method according to any one of claims 1 to 16, wherein the compound of formula (IIb) is not separated from the product mixture formed in step (ii) before the start of step (iii), and / or no purification step is performed between step (ii) and step (iii). [Claim 18] The preparation method according to any one of claims 1 to 17, wherein step (iii) is initiated in the same reaction region in which step (ii) was performed. [Claim 19] In step (iii), CompB is the first intermediate R １ A preparation method according to any one of claims 1 to 18, wherein the substituent is substituted. [Claim 20] The first intermediate R １ The substituent is the second intermediate R. １ Substituting with a substituent, or R １ The preparation method according to claim 19, wherein the substituent is substituted to produce the compound of formula (I). [Claim 21] The first intermediate R １ The substituent is the second intermediate R. １ The preparation method according to claim 20, wherein the substituent is substituted. [Claim 22] The second intermediate R １ The substituent is the third intermediate R １ Substituting with a substituent, or R １ The preparation method according to claim 21, wherein the substituent is substituted to produce the compound of formula (I). [Claim 23] The first, second, or third intermediate R １ The preparation method according to any one of claims 19 to 22, wherein the substituent is independently selected from halo (e.g., bromo, chloro, or iodine), benzyloxypyridinyl, alkyl ester (e.g., methyl ester), alkenyl (e.g., vinyl), alkynyl (e.g., acetylenyl), trimethylsilylacetylenyl, (1,2,3-triazole-1-yl) pivalate, cyano, aminomethyl, N-Boc-aminomethyl, and ((benzyloxy)carbonyl)piperazine-1-yl. [Claim 24] The compound of formula (IIb) or the compound of formula (I) is R ４ The preparation method further comprises a protecting group at the position of the compound of formula (IIb) or the compound of formula (I) ４ A preparation method according to any one of claims 1 to 23, comprising the step of deprotecting a group. [Claim 25] The compound of formula (IIb) or the compound of formula (I), the R ４ The preparation method according to claim 24, wherein the step of deprotecting the group is performed after the completion of step (ii), before the start of step (iii), during step (iii), or after the completion of step (iii).

Images