compound

Abstract

We provide an improved synthesis method for preparing cytishine analogs that have improved properties compared to cytishine. [Solution] A method for preparing a cyticine analog with 4-position substitution as shown below (Chemical Formula I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 = Hydrogen compounds R 1 = After conversion to a boron complex compound, R 1 The method comprises the step of generating the compound of formula (I) by substitution. TIFF2026143488000246.tif51170

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. The present invention also relates to the use of these. The present invention also relates to an improved synthetic method for preparing cyticine analogs. We also provide legal information. [Background technology]

[0002] Nicotinic acetylcholine receptors (nAChRs) are located in various parts of the human brain and central nervous system. nAChR is an ion channel-embedded receptor expressed in other parts of the ion system. For example, cognitive function, learning and memory, sleep, anxiety, arousal, reward, motor control and other neurological functions. It is involved in various physiological functions. nAChR is also used in conditions such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, and autism. nAChR has been involved in numerous medical conditions, including schizophrenia and other illnesses. nAChR is also involved in, 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] Numerous subtypes of nAChR 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] Neural nAChRs (located in the central nervous system, peripheral ganglia, and adrenal medulla) are homomer Alternatively, two classes named α2-α9 and β2-β9 can be combined in a heteromer form. Only the subunits of the S will be displayed. Many neural subtypes have been discovered, but heteromer combination (α4)3( β2)2, α3β4, and homomeric α7 are thought to play significant roles in the brain. Of these, the heteromeric combination α4β2 is the major subtype in the central nervous system. It accounts for approximately 90% of receptors and binds to ACh with high affinity. α7 homomeric combination Se is another major subtype that binds to ACh with low affinity.

[0005] The heteromeric combination α4β2 is two different stoichiometric combinations (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] Compounds that have the ability to modulate nAChRs 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 delivered via the oral route (e.g., tablets or chewing gum) or transdermally. Products that achieve this level have also been developed and are publicly known.

[0010] Other compounds that modulate nAChR have also been 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 a dong-containing alkaloid and is known as a partial agonist of nAChR. 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 It was reported that the drug did not show agonist activity in Ip. This result was presented in a 2006 paper. A cyticine analog with a substitution at position 4 is a weak antagonist of the α4β2 receptor subtype. He presented this.

[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 cyticine analog is located at the 5- position on the piperidine ring. Contains a composting agent and / or a nitrogen atom.

[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-Patent Document 2] Holgate et al., Brain Science, 2015, September 5(3), pages 258-274. [Non-Patent Document 3] Rahman et al., Frontiers in Neuroscience, 2014, volume 8, article 426.

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

[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, improved safety and / or efficacy as a pharmaceutical product in the treatment of poisoning, etc. 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 a pharmaceutically acceptable compound thereof Salts, solvates, and / or esters are provided. [ka] Here, R 1 From R 4 This will be specified later.

[0024] The present invention also provides pharmaceutical compositions containing such compounds as pharmaceuticals, and Provided together with the use of the composition.

[0025] (Further aspects) Further aspects of the present invention, described in more detail below, relate to a 4-substituted cyticene analogue. This is a preparation method for conveniently preparing [the substance].

[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 may be used for good.

[0027] Compounds in this embodiment of the present invention are, in particular, drugs, alcohols and / or tobaccos, as determined by the inventors. It has been identified as useful for therapeutic application in the treatment of addiction and / or dependence. 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-substituted cyticine analogs tested "showed agonist activity." 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 as described herein. As exemplified by the specific compounds disclosed in the document, substituted with one or more substituents That's good too.

[0030] As used herein, the term “aliphatic” refers to alkyl, a The terms lukenil and alkinil are included, and each may be optionally substituted as described below.

[0031] The "alkyl" groups used herein are 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 Kenyl, aryl, heteroaryl, alkoxy, aroyl, heteroaloyl, acyl [For example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, and [Heterocycloaliphatic]carbonyl, nitro, cyano, amide, for example (Cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkyl Carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl (alkyl)carbonylamino, heteroarylcarbonylamino, heteroarachilcylcarbonylamino Bonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterosyl Chloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylamino 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 oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, Aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbon Nyloxy, or hydroxy.

[0032] The “alkenyl” group as used herein is 2 to 12 (e.g., 2 to 8, 2 to 8) 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 can be optionally substituted with one or more substituents as follows: Halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl] ], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloal Kenyl, aryl, heteroaryl, alkoxy, aroyl, heteroaloyl, acyl [For example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, and is [heterocycloaliphatic)carbonyl], nitro, cyano, amide [e.g. ( Cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylca Carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl Alkyl)carbonylamino, heteroarylcarbonylamino, heteroaryl(alkyl) Bonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterosyl Chloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylamino 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 aryl] -SO2-], sulfinyl, sulfoxy, urea, thiourea, sulf Amoyl sulfamide oxo carboxy, carbamoyl, cycloaliphatic Oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy , aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyl Oxy, or hydroxy.

[0033] The "alkynyl" group as used herein is 2 to 12 (e.g., 2 to 8, 2 to 8) 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 can be optionally substituted with one or more substituents as follows: Aroyl, heteroaloyl, alkoxy, cycloalkyloxy, heterocycloalkyl Aryloxy, heteroaryloxy, 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, arylaminocarbonyl, Arylcarbonylamino, Aralkylcarbonylamino, (heterocycloalkyl) Carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarboxy [Bonylamino, heteroarylcarbonylamino, or heteroarylaminocarbonyl] Urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkyl Lucarbonyloxy, cycloaliphatic, heterocycloaliphatic, ally yl, heteroaryl, acyl [e.g., (cycloaliphatic) carbonyl or (heteroaryl) [Rocycloaliphatic)carbonyl], amino (e.g., aliphatic amino), Sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (Heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

[0034] As used herein, when used alone, or as "Aralquil", "Aralcoquil" Used as part of a larger part, such as in "C" or "aryloxyalkyl". The "aryl" 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 cy This refers to a stem, and whether the monocyclic ring system is aromatic, or whether it is a bicyclic or tricyclic ring system. At least one ring of the molecule is aromatic. The bicyclic and tricyclic groups contain benzo-condensed 2- to 3-membered carbon rings. For example, a benzo-condensed group consists of two or more C 4-8 The phenyl compound is condensed with the carbon ring portion of the phenyl compound. It holds. The aryl group may be optionally substituted with one or more substituents, including the following: Aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic Tick, (cycloaliphatic)aliphatic, heterocycloaliphatic K, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, Alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy oxy, aryloxy, heteroaryloxy, (alariphatic)oxy, (hetero) (Roalariphatic) oxy, aroyl, heteroaloyl, amino, oxo (benzo contraction) (On the non-aromatic carbon rings of combined bicyclic or tricyclic aryls), 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. Alternatively, the aryl group may remain unsubstituted.

[0035] The restriction does not limit aryl compounds that may have substituents (optionally substituted, the same applies below). Examples include the following: Haloaryls [e.g., mono-, di(e.g., p,m-dihaloaryls) and (trihalo) (aryl), (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ( (aralkyl)carbonyloxy)aryl and (alkoxycarbonyl)aryl], (Amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino) Alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (A ((((heteroaryl)amino)carbonyl)aryl and (((heteroaryl)amino)carbonyl) [Lill], aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ( (Dialkyl)amino)aryl, (Cyanoalkyl)aryl, (Alkoxy)aryl (Sulfamoyl)aryl [e.g., (aminosulfonyl)aryl], (alkyl (Sulfonyl)aryl, (cyano)aryl, (hydroxyalkyl)aryl, (( Alkoxy)alkyl)aryl, (hydroxy)aryl, ((carboxy)alkyl )aryl, (((dialkyl)amino)alkyl)aryl, (nitroalkyl)aryl aryl, (((alkylsulfonyl)amino)alkyl)aryl, ((heterocycloaryl Fatic)carbonyl)aryl, ((alkylsulfonyl)alkyl)aryl, (cyanoalkyl)aryl, (hydroxyalkyl)aryl, (alkylcarbonyl )aryl, alkylaryl, (trihaloalkyl)aryl, p-amino-m-aryl Coxycarbonylaryl, p-amino-m-cyanoaryl, p-halo-m-aminoaryl Reel or (m-(heterocycloaliphatic)-o-(alkyl)aryl.

[0036] The term "ararylphatic," as used herein, refers to groups such as the "aralkyl" group. Aliphatic groups substituted with a group (e.g., C 1-4 This refers to an alkyl group. "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an araryl group, such as benzyl, is benzyl.

[0037] As used herein, the "aralkyl" group is an alkyl group substituted with an aryl group. For example, C 1-4 This refers to an alkyl group. Both "alkyl" and "aryl" are defined above. An example of an aralkyl group is benzyl. The aralkyl molecule can be optionally substituted with one or more substituents as follows: 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 Reel, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkylo Xy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkylo Xy, alloyl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkyl Carbonyl oxy, amide [e.g., aminocarbonyl, alkylcarbonylamino, cy Chloalkylcarbonylamino, (cycloalkylalkylcarbonylamino, aryl Carbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonyl Amino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbon [Duamino or heteroalkylcarbonylamino], cyano, halo, hydroxy, acyl mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamyo Sulfamide, oxo, or carbamoyl.

[0038] A “biring ring system” as used herein refers to a system of 8 to 12 rings forming two rings. For example, a structure comprising 9, 10, or 11 members, wherein two rings share at least one atom. (For example, by sharing two atoms). Bicyclic ring systems are bicycloaliphatic (e.g., bicycloalkyl or bicycloalkyl) Roalkenyl), bicycloheteraliphatic, bicyclic aryl and bicyclic hetero Includes reel.

[0039] The "carbocyclic" or "cycloaliphatic" group as used herein is a "cy It includes both a "chloroalkyl" group and a "cycloalkenyl" group, each of which is optional as described above. It will be replaced with.

[0040] The "cycloalkyl" group as used herein is 3 to 10 (for example, 5 to 10) This refers to a monocyclic or bicyclic (fused or bridged) ring of a saturated carbon ring of carbon atoms. Examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopropyl thyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, o Decahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bi Cyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2 ]decyl, bicyclo[2.2.2]octyl, adamantyl or ((aminocarbonyl) Cycloalkyl) Cycloalkyl.

[0041] The "cycloalkenyl" group, as used herein, has one or more double bonds. This refers to a non-aromatic carbon ring consisting of 3 to 10 (for example, 4 to 8) carbon atoms. Examples of cycloalkenyl groups are as follows: Cyclopentenyl, 1,4-cyclohexa-dienyl, cycloheptenyl, cycloo Ctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cy Clopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl Ru.

[0042] The cycloalkyl or cycloalkenyl group may be optionally substituted with one or more substituents as follows: It is possible. Phosphors, aliphatic [e.g., alkyl, alkenyl or alkynyl], cyclo Liphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic Tick, (heterocycloaliphatic)aliphatic, aryl, heteroali alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic) (C)oxy, aryloxy, heteroaryloxy, (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 (k) Carbonylamino, (heteroaryl)carbonylamino, or (heteroaryl) [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 aryl-SO2-], sulfinyl [e.g., alkyl-S(O )-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, Sulfamoyl, sulfamide, oxo, or carbamoyl.

[0043] The terms “heterocyclic ring” or “heterocycloaliphatic” as used herein It includes heterocycloalkyl groups and heterocycloalkenyl groups, each of which is as described above. It can be replaced as you like.

[0044] The "heterocycloalkyl" group as used herein is a monocyclic or monocyclic group with 3 to 10 members. This is a bicyclic (fused or bridged) saturated ring structure (e.g., monocyclic or bicyclic with 5 to 10 members). This refers to a ring atom in which one or more ring atoms are heteroatoms (e.g., nitrogen, oxygen, sulfur, or a combination 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]thiophenyl, 2-oxa-bicyclo[2.2.2 ]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[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 forms a structure such as an n-membered ring, which would be classified as heteroaryl.

[0045] A "heterocycloalkenyl" group, as used herein, refers to one or more double bonds monocyclic or bicyclic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure, wherein one or more ring atoms is a heteroatom (e.g., nitrogen, oxygen or sulfur). Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature .

[0046] A heterocycloalkyl or heterocycloalkenyl group is optionally substituted with one or more of the following substituents. Phosphor, aliphatic [e.g. alkyl, alkenyl or alkynyl], cycloalipa phatic, (cycloaliphatic)aliphatic, heterocycloalipha tic, (heterocycloaliphatic)aliphatic, aryl, heteroary l, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphat ic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido[e.g. for example, (aliphatic)carbonylamino, (cycloaliphatic)carbonyl amino, ((cycloaliphatic)aliphatic)carbonylamino, (ary l)carbonylamino, (araliphatic)carbonylamino, (heterocycloali phatic)carbonylamino, ((heterocycloaliphatic)aliphat ic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaralipha [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 arylsulfonyl], sulfinyl [for example, alkyl Sulfinyl, Sulfanyl [e.g., alkylsulfanyl], Sulfoxy, Urea , thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

[0047] The "heteroaryl" group has 4 to 15 ring atoms, as used herein. This refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring atoms are heteroatoms (for example) It is nitrogen, oxygen, sulfur, or a combination thereof, and the monocyclic ring system is aromatic, or This refers to a biring or triring ring system in which at least one ring is aromatic. Heteroaryl groups contain a benzo-condensed ring system having two to three rings. 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 ) Some examples of heteroaryls are azetidinyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl). -Pyridyl, 4-pyridyl), pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl , 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, thiophenyl, oxy Sazolyl, isoxazolyl, 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, quinazolyl, quinoxalyl, isoqui Noryl, 4H-Quinolidyl, Benzo-1,2,5-Thiasiazolyl or 1,8-Naphthyl Jill.

[0048] Without restriction, monocyclic heteroaryls include the following: Furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, im Dazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl Pyrazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, pyridadyl, pyrimidyl, pyrazolyl , pyrazyl or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0049] Without restriction, bicyclic heteroaryls include the following: 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, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolyl, isoquinolyl, cinnolyl, phthalazinyl, quinazolyl, quinoxalinyl, 1,8 -naphthyridyl or pteridyl. Bicyclic heteroaryl is numbered according to standard chemical nomenclature.

[0050] Heteroaryl is optionally substituted with one or more substituents as follows. aliphatic [e.g. alkyl, alkenyl or alkynyl], cycloaliphat ic, (cycloaliphatic)aliphatic, heterocycloaliphatic , (heterocycloaliphatic)aliphatic, aryl, heteroaryl, a lkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)ox y, aryloxy, heteroaryloxy, (araliphatic)oxy, (hetero araliphatic)oxy, aroyl, heteroaroyl, amino, oxo (on a bicyclic or tricyclic heteroaryl on a non-aromatic carbocyclic or heterocyclic ring), carboxy, ami de, acyl [e.g. (aliphatic)carbonyl, (cycloaliphatic)carb onyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphat ic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocyclo aliphatic)aliphatic)carbonyl, or (heteroaraliphatic) 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. Alternatively, the heteroaryl may remain unsubstituted.

[0051] Examples of heteroaryls with substituents that are not limited include the following: (halo)heteroaryl [e.g., mono-, di-(halo)heteroaryl], (carbboxy (C) Heteroaryl [e.g., (alkoxycarbonyl) heteroaryl], cyanohetero Aryl, aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl] [Examples:] Reels and ((dialkyl)amino) heteroaryls, (amide) heteroaryls For example, aminocarbonyl heteroaryl, ((alkylcarbonyl)amino)heteroaryl rl, (((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (( (heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic) ((C)carbonyl)heteroaryl and ((alkylcarbonyl)amino)heteroaryl [Sulfur], (cyanoalkyl) heteroaryl, (alkoxy) heteroaryl, (sulf (Amoyl) heteroaryl [e.g., (aminosulfonyl) heteroaryl], (sulfo (Nyl) heteroaryl [e.g., (alkylsulfonyl) heteroaryl], (hydrox (Cyalkyl)heteroaryl, (alkoxyalkyl)heteroaryl, (hydroxy) Heteroaryl, ((carboxy)alkyl)heteroaryl, (((dialkyl)amine ()alkyl]heteroaryl, (heterocycloaliphatic)heteroaryl, ( Cycloaliphatic) heteroaryl, (nitroalkyl) heteroaryl, ((( (Alkylsulfonyl)amino)alkyl)heteroaryl, ((Alkylsulfonyl)a (Cyanoalkyl) heteroaryl, (Acyl) heteroaryl [For example, (alkylcarbonyl) heteroaryl], (alkyl) heteroaryl and (Haloalkyl) heteroaryl [e.g., trihaloalkyl heteroaryl].

[0052] "Heteroararylphatic" (heteroaralkyl group, etc.) as used herein This refers to an aliphatic group substituted with a heteroaryl group (e.g., C 1-4 (Alkyl group) vinegar. "Aliphatic," "alkyl," and "heteroaryl" are defined above.

[0053] The "heteroaralkyl" group is substituted with a heteroaryl group, as used herein. A modified alkyl group (for example, C 1-4 This refers to an alkyl group. Both "alkyl" and "heteroaryl" are defined above. The heteroaralkyl group can be optionally substituted with one or more substituents as follows: Alkyl (carboxyalkyl, hydroxyalkyl, and trifluoromethyl) (containing haloalkyls), alkenyls, alkynyls, cycloalkyls, (cycloal (Kyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl , heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, Aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, Aroyl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyl Bonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl ruamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocyc cloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroar alkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkyl sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxy so or carbamoyl.

[0054] As used herein, "cyclic moiety" and "cyclic group" refer to cycloaliphatic, heterocycloaliphatic, monocyclic, bicyclic or refers to a tricyclic ring system, each of which is as defined above.

[0055] As used herein, "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system. Examples of bridged bicyclic ring systems include, but are not limited to, the following. adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2. 2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2 -oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl and 2,6-dioxa-tricyclo[3.3. 1.0 3,7 nonyl. The bridged bicyclic ring system is optionally substituted with one or more substituents as follows. alkyl (such as carboxyalkyl, hydroxyalkyl and trifluoromethyl (containing haloalkyls), alkenyls, alkynyls, cycloalkyls, (cycloalkyl (aryl), alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, Heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, a Reeloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, A Royl, heteroaloyl, nitro, carboxy, alkoxycarbonyl, alkylcarbon Nyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl Amino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, A Lalkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl (L-alkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaryl Lukylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkyls Ruphanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo Or carbamoyl.

[0056] As used herein, "amide" refers to "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 (Larkyl)amide, (heteroaryl)amide, (heterocycloalkyl)alkylamide , arylamide, aralkylamide, (cycloalkyl)alkylamide or cyclo Alkylamide.

[0057] The "amino" group as used herein is -NR X R Y This refers to R X and R Y Each These are independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic (Aliphatic, aryl, arylphatic, heterocycloaliphatic) (Heterocycloaliphatic)aliphatic, heteroaryl, carboxy , sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycline (Cycloaliphatic) carbonyl, ((cycloaliphatic)aliphatic) ca Rubonyl, arylcarbonyl, (alariphatic)carbonyl, (heterocycloa (riphatic)carbonyl, ((heterocycloaliphatic)aliphatic) Carbonyl, (heteroaryl)carbonyl, or (heteroarylphatic)carbonyl These are terms, each of which is defined herein and may be optionally substituted. Examples of amino groups include alkylaminos, dialkylaminos, or arylaminos. If the term "amino" is not a terminal group (for example, alkylcarbonylamino), -NR X - is represented by R X This has the same meaning as above.

[0058] The "acyl" group as used herein 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 herein, "alloyl" or "heteroalloyl" refers to aryl-C(O) )- or heteroaryl-C(O)- refers to this. The positions of the aryl and heteroaryl in aroyl or heteroaloyl are as defined above. Uni can be arbitrarily substituted.

[0060] As used herein, the “alkoxy” group refers to an alkyl-O- group, where “A "Lukil" was defined previously.

[0061] The "carbamoyl" group as used herein 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 Refractic, aryl, alariphatic, heterocycloaliphatic, hetero It may be a loaryl or heteroalariphatic.

[0062] As used herein, 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 herein, a "haloaliphatic" group consists of one to three halogen atoms. This refers to an aliphatic group substituted with [a specific group]. For example, the term haloalkyl refers to a group containing a -CF3 group.

[0064] As used herein, the "mercapto" group refers to the -SH group.

[0065] The "sulfo" group as used herein, when used as a terminal group, is -SO3 H or -SO3R X It refers to -S(O)3- when used internally.

[0066] The "sulfamide" group as used herein, 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] The "sulfonamide" group as used herein, when 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 stipulated.

[0068] The "sulfanyl" group as used herein, 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 alli Includes Ru-S- etc.

[0069] The "sulfinyl" group as used herein, 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 stipulated. Examples of sulfinyl groups include aliphatic-S(O)- and aryl-S(O)-. (cycloaliphatic (aliphatic))-S(O)-, cycloalkyl-S( O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, etc. include.

[0070] The "sulfonyl" group as used herein 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 stipulated. Examples of sulfonyl groups include aliphatic-S(O)2- and aryl-S(O)2-. (cycloaliphatic (aliphatic))-S(O)2-, cycloaliphatic S(O)2-, heterocycloaliphatic-S(O)2-, heteroaryl-S (O)2-, (cycloaliphatic(amide(aliphatic)))-S(O)2- Includes, etc.

[0071] The "sulfoxy" group as used herein 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 herein, the "halogen" or "halo" group refers to fluorine, chlorine, bromine, or yo. It refers to the element U.

[0073] The term "alkoxycarb" as used herein encompasses the term carboxyl. "Nyl" can be used alone or in combination with other groups, such as alkyl-OC(O)- It refers to the base.

[0074] As used herein, "alkoxyalkyl" refers to alkyl-O-alkyl- This refers to an alkyl group, where alkyl is defined above.

[0075] As used herein, "carbonyl" refers to -C(O)-.

[0076] As used herein, "oxo" refers to =O.

[0077] The term "phospho" as used herein refers to phosphinates and phosphonates. It refers to. Examples of phosphinates and phosphonates include -P(O)(R P )2, where R P Yes Phatic, alkoxy, aryloxy, heteroaryloxy, (cycloalipha (tic)oxy, (heterocycloaliphatic)oxy, aryl, heteroali It is chloroalyphatic or amino.

[0078] The term "aminoalkyl" as used herein refers to (R X ) Refers to the 2N-alkyl- structure vinegar.

[0079] As used herein, "cyanoalkyl" refers to the (NC)-alkyl- structure. .

[0080] The "urea" group as used herein is -NR X -CO-NR Y R Z It refers to the structure, The "thiourea" group, when used as a terminal group, is -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 herein, "aliphatic chain" refers to a branched or linear aliphatic group (e.g., 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. An aliphatic chain is a linear aliphatic chain substituted with one or more aliphatic groups. Branched aliphatic chains are -[CQQ] V - has the structure, where each Q is independently a 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 Optionally, one or more substituents as exemplified in the specific classes, subclasses, and types of the present invention. It can be exchanged. As described herein, the R contained in the chemical formula described herein 1 , R 2 , R 3 and R 4 The variable elements and other variable elements include certain groups such as alkyl and aryl groups. . Unless otherwise specified, the R included in this specification 1 , R 2 , R 3 and R 4 The variable elements and other variable elements Each of the specific groups for a variant element may be optionally substituted with one or more substituents as described herein. It is possible.

[0083] Each substituent of a particular group may be further substituted with one to three of the following: Halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cyclo Aliphatic, heterocycloaliphatic, heteroaryl, haloalkyl and Alkyl. For example, alkyl groups can be substituted with alkylsulfanils, and alkylsulfanils are Halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, halotermite The ion may be optionally substituted with 1 to 3 alkyl groups. In further examples, the cycloalkyl portion of (cycloalkyl)carbonylamino is ro, cyano, alkoxy, hydroxy, nitro, haloalkyl and 1 to 3 may be optionally substituted with. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atoms to which they are bonded.

[0084] The compounds of the present invention are useful nAChRs, and are included in the treatment of central nervous system disorders such as addiction disorders and are useful in the drugs mentioned.

[0085] (Compound) (First aspect (1)) According to the present invention, there is provided a compound of chemical formula (I), or a pharmaceutically acceptable salt, solvate thereof, and / or ester thereof.

Chemical Formula

[0086] As mentioned above, R 1 The substituent at the position may have a substituent, or may be an aliphatic. cycloaliphatic, which may have substituents, heterosymmetric, which may have substituents Cloaliphatic, optionally substituted, aryl, or optionally heteroaryl 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 C3-8 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 position C may have a substituent. 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 optionally substituted propyl groups, for example, 1-,2- Alternatively, 3-aminomethyl, hydroxypropyl, or halogenated propyl.

[0089] In embodiments of the present invention, R 1 The substituent at this position is either unsubstituted or has a substituent. It can be a good aryl. 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 this position may have a substituent or be a heteroaryl 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 cyclic alkyl or heterocyclo Alkyl compounds are also acceptable, for example, cyclopentyl, cyclohexyl, morpholinyl, pipette 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, benzamide, and acetamide 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. R1 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 is R 1 Ketone or aldehyde group at position, 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 Sparagine, aspartate, cysteine, glutamine, glutamate, 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. They may be joined to a ring.

[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 may also 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 stereochemical isomer, enantiomer, and diastereoisomer of the compound of the present application 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. Compounds having the structure of this invention, except for carbon substitution, fall 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))cytidine, (+)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 cytisine, (-)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)methylpivalate)cyticine, (+)4-(1,2,3-triazol-1-yl)methylpivalate)cyticine, 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 -methanopyrid[1,2-a][1,5]diazosin-8-one, Aminobis(cyticine) derivatives, Methylaminobis(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-bromocyticine, 3-(trifluoromethyl)-4-bromocyticine, 3-bromo-4-iodocyticine, (+)3-bromo-4-iodocyticine, 3-bromo-4-N-methylaminocyticine, (+)3-bromo-4-N-methylaminocyticine.

[0107] (synthesis) Although there was limited prior art disclosure of 4-substituted cyticine compounds, such chemical 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 aryl which may have substituents, heteroaryl which may have substituents, rest A alkyl group which may have substituents, a cycloaliphatic which may have substituents A heterocycloaliphatic which may have substituents, a heteroaryl which may have substituents, 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 compound is identified above, and CompB is a boron complex. (This step involves generating the compound by contacting a 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 aryls which may have substituents, heteroaryls which may have substituents, -(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 , Amino acids or their esters, Acyl chloride, Protecting group, or It is cyticinyl. 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 aryl which may have substituents, heteroaryl which may have substituents, rest A alkyl group which may have substituents, a cycloaliphatic which may have substituents A heterocycloaliphatic which may have substituents, a heteroaryl which may have substituents, 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 aryl which may have substituents, heteroaryl which may have substituents, rest A alkyl group which may have substituents, a cycloaliphatic which may have substituents A heterocycloaliphatic which may have substituents, a heteroaryl which may have substituents, 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 aryl which may have substituents, heteroaryl which may have substituents, rest A alkyl group which may have substituents, a cycloaliphatic which may have substituents A heterocycloaliphatic which may have substituents, a heteroaryl which may have substituents, 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 aryl which may have substituents, heteroaryl which may have substituents, rest A alkyl group which may have substituents, a cycloaliphatic which may have substituents A heterocycloaliphatic which may have substituents, a heteroaryl which may have substituents, 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 aryl which may have substituents, heteroaryl which may have substituents, rest A alkyl group which may have substituents, a cycloaliphatic which may have substituents A heterocycloaliphatic which may have substituents, a heteroaryl which may have substituents, 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 aryl which may have substituents, heteroaryl which may have substituents, rest A alkyl group which may have substituents, a cycloaliphatic which may have substituents A heterocycloaliphatic which may have substituents, a heteroaryl which may have substituents, 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). The process includes bringing the material into contact with cyticine.

[0114] Therefore, in the embodiment of the present invention, R 4 The protecting group present at that position may be Boc. i. Other protective groups that may be used 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 the (RO)2B-B-(OR)2 structure of bis(catecorato)diborane (B2Cat2), etc. 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( Catecoratodiborane (B2Cat2) and general formula (RO)2-BB-(OR)2 or H Any other boronating reagent having B(OR)2, for example, those 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-borabicyclo(3.3.1)nonane(9-B BN), B-alkyl-9-oxa-10-borabicyclo[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 The compounds contain a rhodium atom, which may be provided in the form of organic coordination complexes. 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 include aromatic or heteroaromatic compounds, which may be monocyclic or polycyclic. It may contain substances, phenanthroline compounds, etc. 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), 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 ( We discovered that the molar ratio (in this case) can affect the conversion rate to the boronated compound of chemical formula IIb. did. In embodiments of the present invention, the molar ratio of ligand to starting material of chemical formula IIa is less than approximately 2. :1, less than approximately 1.5:1, less than approximately 1:1, less than approximately 0.75:1, less than approximately 0.5:1, approximately 0 The ratio is less than 0.1:1, and less than approximately 0.05:1, and at least approximately 0.001:1.

[0124] Boration reaction step II can proceed at any temperature if the boration reaction proceeds at the appropriate rate. 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 The process may be carried out at temperatures ranging from approximately 50°C to approximately 100°C, 120°C, or 150°C.

[0125] The inventors of the preparation method of the present invention have determined the molar amount of the boronating agent relative to the starting material of chemical formula IIa. We discovered that the ratio can affect the conversion rate to the boronated compound of chemical formula IIb. 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 advantage of the preparation method of the present invention is that 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 a borated compound of chemical formula IIb The reaction may be initiated in the same prepared reaction region.

[0131] In step iii, BComp is removed from the 4-position substitution of the cyticine ring, and the above conditions 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 on the cyticine ring. 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 halogens, (for example, bromo, chloro, etc.) (or 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 provide further details on reaction conditions that may be used in this regard.

[0134] In one embodiment, the preparation method of the present invention is R on the cytidine ring 2 , R 3 and / or R 4 location It may include an additional step of performing a substitution. For example, if substitution at the 3- or 5-position on the cyticine ring is required, this can be performed. 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 or alternative advice in this regard may include the articles referenced herein. Non-patent document 16 provided is available for reference.

[0135] Additionally or alternatively, the protecting group is R4 In an embodiment where the present invention is positioned, preparation of the present invention The method includes the step of deprotecting the nitrogen atom at position 13- of the cyticine ring. 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, if there is any advice in this regard... If needed, the following examples can be referenced.

[0136] As can be seen from the above, the preparation method of the present invention does not require the lengthy total synthesis of the above compound. This advantageously and for the first time allows for the convenient preparation of cyticine analogs with 4-position substitution from cyticine itself. 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, leading to the formation of racemic analogs of cytsine.

[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 available in free form for therapeutic use, or, where appropriate, pharmaceutically. 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, take any of the compounds, metabolites, or residues described elsewhere in this specification directly. This includes any other adducts or derivatives that can be provided indirectly or directly.

[0140] The term “pharmaceutically acceptable salt” as used herein is based on legitimate medical judgment. Within the specified range, without excessive toxicity, irritation, allergic reactions, etc., and without contact with human or lower animal tissue. This refers to a salt that is suitable for use and has a reasonable effect / risk ratio. "Pharmacologically acceptable salt" is any salt of the compound of the present invention, or a salt of its ester. Therefore, when administering the compound of the present invention or its metabolites or residues that have inhibitory activity, It means something that can provide goods directly or indirectly.

[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. The pharmaceutically acceptable salts of the compounds of the present invention are derived from suitable inorganic or organic acids or bases. 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. , formed from organic acids such as succinic acid or malonic acid, or used in industries such as ion exchange. It is a salt of an amino group formed by other methods.

[0143] Other pharmaceutically acceptable salts include the following: Adipine salt, alginate, ascorbate, aspartate, benzenesulfonate Nat, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfonates , citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanol Sulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluc Conate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy - Ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, li Ngo salts, maleates, malons, methanesulfonates, 2-naphthalenesulfonic acid Salt, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe Cutinate, persulfate, 3-phenylpropionate, phosphate, picrate, pival Salts, propionates, stearates, succinates, sulfates, tartrates, thiocyanates Salts, p-toluenesulfonate, undecanoate, valerate, etc.

[0144] Salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 Contains alkyl tetrasalt.

[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 amine cations, for example halogen ions, hydroxide ions, carboxylate ions, Sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl ions It is formed using counterions such as sulfonate ions.

[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: One and all of the following: solvents, diluents, or other liquid solvents, dispersion or suspension aids, 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 a pharmaceutically acceptable composition and a known technique for its preparation. Various carriers used in formation are disclosed. For example, producing undesirable biological effects or altering the composition to make it pharmaceutically acceptable. 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, e.g., cocoa butter, suppository wax, oil, e.g., peanut butter 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 Oils (especially cottonseed oil, peanut oil, corn oil, wheat germ oil, olive oil, castor oil, and sesame oil) ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and so Examples include fatty acid esters of rubitan, and mixtures thereof. 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 a suitable dispersant. Alternatively, it may be formed by known techniques using wetting agents and suspending agents. Sterilized injectable preparations can also be sterilized with a non-toxic, parenterally acceptable diluent or solvent. 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. Of the acceptable transfer media and solvents, only water, Ringer's solution, and the United States Pharmacopeia may be used. 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 are used in the preparation of the injected substance.

[0152] Injectable preparations are filtered, for example, through a bacterial-retaining filter, or purified with sterile water or other materials before use. 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. The injectable depot form is, for example, within a biodegradable polymer such as polylactide-polyglycolide. 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 examples of biodegradable 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] The composition for rectal or vaginal administration comprises the compound of the present invention, which is 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. Suppositories that can be formulated by mixing with a modifier or carrier are preferred.

[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. Used as a filler for soft or hard gelatin capsules using excipients such as Recall. 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. Examples of embedding compositions that may be used include polymeric 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 also, in common practice, use substances other than inert diluents, such as tablet lubricants. In addition, the addition of tableting aids such as magnesium stearate and microcrystalline cellulose. 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. Examples of embedding compositions that may be used include polymeric 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. Includes ointments, gels, powders, solutions, sprays, inhalants, or patches. 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 account the use of transdermal patches, which control the delivery of compounds to 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 may also be used to increase the flow of compounds through the skin. 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. The suitability of the treatment and / or procedure for achieving the desired therapeutic effect will be taken 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). Further therapeutic agents used herein are intended to treat or prevent specific diseases or conditions. It is commonly administered and is known to be "appropriate for the disease or condition being treated." .

[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, the amount of further therapeutic agents in the compositions disclosed herein 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 compounds of the present invention, outlined in the text, and are suitable for coating the above-mentioned portable devices. The present invention includes a composition for coating an implantable device containing a carrier.

[0162] In yet another embodiment, the present invention relates to the classes and subclasses described herein, as described above. The compounds of the present invention, outlined in the text, and suitable for coating the above-mentioned portable devices. Includes implantable devices coated with a composition containing a carrier. Suitable coatings and the overall preparation of coated portable devices are described in the 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 optionally contains fluorosilicone to give controlled release properties within the composition. Suitable topcoats of corn, polysaccharides, polyethylene glycol, phospholipids, and combinations thereof. It's fine if it's covered even more. [Modes for carrying out the invention] [Examples]

[0164] (Preparation 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 presumably familiar with the preparation methods for extracting cyticine from natural sources, but just in case... The following preparation method is provided.

[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). The filtrate was treated with 3M hydrochloric acid (330 mL). The mixture was acidified to pH 1 and stirred for 2 hours (350 rpm). The two layers were separated, and the aqueous layer was... Slowly base the pH to 9-10 using ammonium hydroxide (70 mL, 35% aqueous solution). The mixture was stirred for 2 hours and extracted with dichloromethane (10 x 70 mL). The resulting organic layer was 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) Add an aqueous solution of sodium carbonate (4.28 g, 40.4 mmol, 1 M) to the solution of (ol). The mixture was stirred for 3 days, and then diluted with ethyl acetate (200 mL) and brine (70 mL). The aqueous layer was extracted with ethyl acetate (3 x 150 mL), and the combined organic layer was dissolved in brine (15 Washed with 0 mL, dried with sodium sulfate, filtered, and concentrated under vacuum. Crude reaction mixture. The material is silica gel flash column chromatography [dichloromethane / methanol ( Purified with 3% methanol, it yields 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 protective group) As illustrated below, a wide range of 4-substituted cyticine derivatives can be used in the preparation method of the present invention. Further preparations are possible. Such compounds may be protected with tert-butoxycarbonyl (Boc) protection. 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) Dissolve the cyticine derivative in a 0.5 M hydrogen chloride solution in methanol (at a substrate concentration of 0.1 M). The reaction mixture was stirred at room temperature for 72 hours. The solvent was then removed under vacuum. 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) Dissolve the cyticine derivative in a 4.0 M hydrogen chloride solution in dioxane (at a substrate concentration of 0.1 M). The reaction mixture was stirred at room temperature for 72 hours. The solvent was then removed under vacuum. The residue was then collected. 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 Place the tube under vacuum and backfill it three times with nitrogen, then add 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 80 mg, 43%, a compound unstable on silica, only the pure fraction was 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-yl)-cyticine 58 was used in a 1.0 mmol scale as discussed above in Example 1. It was prepared according to the general procedure for the borylation reaction of cyticene.

[0173] The boration reaction mixture was cooled to 0°C and dissolved in tetrahydrofuran (8.6 mL). Then, 3M sodium hydroxide (1.0 mL, 3.0 mmol) was added, followed by 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). Acidified the aqueous layer with 3 M hydrochloric acid to pH 4-5, and then... Extraction was performed with chloromethane (5 x 5 mL). The combined 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] Following general procedure A, a grayish-white solid is obtained from 66 (0.79 mmol) alcohol. It produced 67mg of alcohol (184mg, 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 was added in 0.50 mmol to the cyticine discussed above in Example 1. It was prepared according to the general procedure for the boration reaction of .

[0176] Newly prepared, copper(II) sulfate pentahydrate (37 mg, 0) in methanol (5 mL) (0.15 mmol), potassium hydroxide (84 mg, 1.50 mmol) and molecular syrup A solution of -4 Å (300 mg) was stirred under a nitrogen atmosphere for 5 hours, and then used a syringe to... 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 mixture was divided into (mL) and the aqueous phase was extracted with dichloromethane (4 × 15 mL). The organic phase was then combined. 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] A solution of ether 68 (130 mg, 0.42) in dichloromethane (4 mL, 0.1 M) 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 combined, dried with magnesium sulfate, and filtered. 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-Cyticine 58 is shown in detail in Example 1 above on a 5.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[0179] In a separate container, copper(I) acetate in acetonitrile (20 mL) and water (300 mg, 1. Potassium fluoride (320 mg, 5.5 mmol) and molecular sieves 4 Å (4 g) was stirred for 15-20 minutes. The crude product of the boration reaction was mixed with acetonitrile (5 ml). Dissolve in (L), add the copper solution to the crude reaction mixture using a syringe, and stir 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 mixture was divided into (25 mL) and the aqueous phase was extracted with dichloromethane (4 × 15 mL). 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)] This yielded a colorless solid, 70 (1.70g, 72%), along with inseparable impurities. [ka]

[0180] (Example 4b-(+)4-(N-benzylamino)cyticine(71)) [ka] Solution of secondary amine 70 in dichloromethane (43 mL, 0.1 M) (1.70 g, 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 tan (4 x 10 mL). The combined organic layers were dried with magnesium sulfate and filtered. After thawing and concentration, 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-yl)-cyticine 58 is shown in detail in Example 1 above on a 1.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine. 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 was placed under vacuum and backfilled three times with nitrogen. The reaction mixture was N,N-dimethyl Sulfurformamide (4.0 mL, 0.25 M) and 2,2,2-trifluoroethyl iodide 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). The reaction mixture was extracted. The organic phases were combined, dried over 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 The syn derivative was deprotected according to general procedure A to convert it to a hydrochloride salt, and the colorless solid ligand 79 was obtained. (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-yl)-cyticine 58 is shown in detail in Example 1 above on a 1.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[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 Dissolve in mL, 0.2 M and stir at 80°C for 18 hours. The reaction mixture was then mixed with ammonia (25 The solution was diluted (mL, 15% aqueous solution), and the aqueous phase was extracted with ethyl acetate (4 × 25 mL). The resulting 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%). (Containing dichlorobis(triphenylphosphine)palladium) was produced. [ka] Following general procedure A, cyticine derivative 74 (1.1 mmol) protected with N-Boc was prepared. From this, a colorless solid, 4-(perfluorophenyl)-cyticine hydrochloride 75, was produced. . [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-Cyticine 58 was used in a 1.00 mmol scale in Example 1 as described above. It was prepared according to the general procedure for the borylation reaction of cytidine described above.

[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] Following the general procedure A for deprotection of cyticine, N-Boc-4-(2-pyridinyl) - From cyticine 100 (0.55 mmol), a colorless solid 101 (99.2 mg, 6 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-pyridin Fill with ruboronic acid (140 mg, 1.1 equivalents), place under vacuum, and backfill with nitrogen three times. The mixture was dissolved in dioxane (2.6 mL, 0.4 M) and tricalcium phosphate. The aqueous solution (360g, 1.7 equivalents, 1.3M) was added dropwise using a syringe for at least 10 minutes. The reaction was then mixed. 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 × Extraction was performed using 25 mL of solution. The combined organic phase was dried with magnesium sulfate, filtered, and concentrated. The obtained N-Boc-4-(3-pyridinyl)-cyticine derivative was then subjected to general procedure A. Therefore, it was deprotected and converted to hydrochloride, yielding a colorless solid 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-Cyticine 58 is described in detail in Example 1 above at a 1.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[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] Following general procedure A, N-Boc-4-(4-pyridinyl)cyticine 102 (0.85 A pale orange solid, 103 (122 mg, 48%), was produced from mmol. [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-Cyticine 58 was described in detail above in Example 1 on a 1.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[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. (5.0 mL) 4-bromo-2-benzyloxypyridine (316 mg, 1.2 mmol) l) Add the solution. Stir the mixture at 80°C for 48 hours. Cool the solution to room temperature and add acetic acid. 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) ) Add concentrated hydrochloric acid (2.9 mL) to a solution of cyticine 105 (448 mg, 0.95 mmol) The mixture was heated under reflux for 24 hours. After cooling to room temperature, the solvent was removed under vacuum. The crude product was dissolved in methanol (55 mL) and acetone (550 mL) was added. 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)-Cyticine 58 is schematically shown in Example 1 above on a 1.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[0195] The boronation reaction crude mixture was dissolved in methanol (2.5 mL). Salt was added to water (2.5 mL). Add copper(II, 3.5 mmol) solution and leave the mixture in the air at room temperature 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 with chloromethane (3 x 10 mL). The combined organic 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-Cyticine 58 is shown in a schematic manner in Example 1 at a 1.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[0197] In a sealed tube, dissolve the crude boronation mixture in methanol (2.5 mL) and copper chloride. An aqueous solution (470 mg, 3.5 mmol, 1.4 M) was added. The reaction mixture was incubated at 90°C for 18 hours. Stirring was maintained. The reaction mixture was cooled and diluted with ammonium hydroxide (5 mL, 15% aqueous solution). The aqueous phase was extracted with dichloromethane (5 × 5 mL). The combined organic layers were concentrated under vacuum. The residue was partitioned into 3M hydrochloric acid (5 mL) and dichloromethane (5 mL). The aqueous layer was divided into dichloromethane. Wash with methane (2 x 5 mL), base to pH 10 with concentrated ammonium hydroxide solution, and di Extraction was performed with chloromethane (5 x 5 mL). The combined 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-yl)-cyticine 58 is shown in detail in Example 1 above on a 5.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine. Copper(II) nitrate trihydrate (2.42 g, 10.0 mmol), ammonium iodide (1 Crude borylation of 0.45g (10.0 mmol) and molecular sieve 4 Å (500 mg) In addition to the reaction mixture, the Schlenk tube was placed under nitrogen and backfilled three times with oxygen. Dissolve the mixture in N,N-dimethylformamide (25 mL) and heat at 80°C for 24 hours. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane. The mixture was then dissolved in ammonia (3 The aqueous phase was poured over (0 mL, 15% aqueous solution) and extracted with dichloromethane (4 × 25 mL). The combined organic layers are dried over 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] Following general procedure A, from N-Boc-4-iodocytisine 64 (0.68 mmol) 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 ionide (4.52g, 23.7mmol), anhydrous potassium fluoride (1.38g, 23.7mmol) 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 Add L, 0.2M) and stir the reaction mixture at 50°C for 16 hours. Remove the solvent under vacuum. The residue was then partitioned into dichloromethane (20 mL) and ammonia (20 mL, 15% aqueous solution). The aqueous phase was extracted with dichloromethane (3 x 20 mL), and the combined organic phase was extracted with 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] Following general procedure A, N-Boc-4-trifluoromethylcyticine 76 (0.28m From mol, a colorless solid of 77 (55 mg, 77%) was produced. [ka]

[0202] (Example 15a-N-Boc-4-bromocyticine (61)) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cyticine 58 is shown in detail in Example 1 above on a 5.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[0203] The crude mixture for the boration reaction was dissolved in methanol (12.5 mL) and cooled to 0°C. A solution of copper(II) bromide (3.35 g, 15.0 mmol) in water (12.5 mL) was steeped for at least 5 minutes. 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 with dichloromethane (3 x 50 mL). The combined organic layer was dried 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-Cyticine 58 is shown in detail above in Example 1 on a 1.00 mmol scale. It was prepared according to the general procedure for the borylation reaction of cyticine.

[0205] In a sealed tube, dissolve the boronation reaction crude mixture in methanol (2.5 mL) and water (2 0.5 mL of copper(II) bromide (670 mg, 3.0 mmol) solution was added to the mixture. The mixture was heated overnight at 0°C. The mixture was cooled and then treated with ammonium hydroxide (5 mL, 15% aqueous solution). The mixture was diluted and extracted with dichloromethane (5 x 5 mL). The combined organic layers were concentrated under vacuum. The crude product was partitioned into 3M hydrochloric acid (5 mL) and dichloromethane (5 mL). The aqueous layer was then divided into dichloromethane. Wash with lolomethane (2 x 5 mL) and rinse with concentrated ammonium hydroxide solution until pH 10 is basic. The mixture was then extracted with dichloromethane (5 x 5 mL). The combined organic layer was then treated with 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)] Upon purification, bromide 62 (228 mg, 85%), a grayish-white solid, was obtained. 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 with 10 mL. The combined organic layers were washed with brine and dried 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, N-Boc-4- 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 carried out. The combined organic layers were 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] Following general procedure A, from N-Boc-4-amino-cytisine 80 (1.0 mmol) 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. The mixture was cooled and quenched to pH 10 using a concentrated ammonium hydroxide solution. Diluted with ethyl acetate (10 mL) and filtered to remove insoluble salts. The aqueous layer was separated by ethyl acetate (4 mL). Extraction was performed with 10 mL of x 10 mL of solution. The combined organic layers were concentrated under vacuum. The crude product was treated with 3 M hydrochloric acid. The aqueous layer was divided into (5 mL) and dichloromethane (5 mL). It is washed with ) and basicized to pH 10 with concentrated ammonium hydroxide solution, and dichlorometh Extraction was performed using (5 x 5 mL). The combined organic layers were 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-B in a 40% aqueous solution (2.0 mL) of methylamine 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 with 10 mL. The combined organic layers were dried with sodium sulfate and filtered to obtain the true solution. Concentrated in air. Crude product was flash-chromatographed on silica gel [dichloromethane]. Purified with methanol (94:6), a grayish-white solid 83 (274 mg, 86 It produced %). [ka]

[0212] (Example 18b-(+)4-(N-methylamino)cyticine dihydrochloride (84)) [ka] Following general procedure A, 4-N-methylamino-N-Boc-cyticine 83 (0.77m A colorless solid, amine 84 (190 mg, 85%), was produced from (mol). [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 aqueous phase was diluted with ( ) and extracted with dichloromethane (5 × 10 mL). The combined organic layers were then sulfurized. 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] Following general procedure A, N-Boc-4-N,N'-dimethylaminocythicine 85(2 Amino 86 (174 mg, 93%) was produced from 0.2 mg (0.61 mmol). [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 with methane (5 x 10 mL). The combined organic layers were 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] Following general procedure B, N-Boc-4-(N-benzamide)-cyticine 95(363 From mg, 0.89 mmol) to the colorless solid benzamide 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 carried out with dichloromethane (5 × 10 mL). The combined organic layer was then treated with 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] Following general procedure B, N-Boc-4-(N-acetamide)cyticine 93(306m From g, 0.88 mmol, a pale yellow solid of 94 (250 mg, quantitative) was produced. . [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, dissolve the reaction mixture in water (2.0 mL, 0.5 M), and heat in air at 100°C for 1 minute. 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). Extraction was performed. The combined organic phase was dried with magnesium sulfate, filtered, and concentrated. The N-Boc-protected cyticine derivative is deprotected according to general procedure A and converted 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, A mixture of 5 mol% and (±)-BINAP (44 mg, 7 mol%) is 10 The mixture was stirred at 0°C for 48 hours. The mixture was cooled to room temperature and short Celite pads (registered trademark) were prepared. The crude product was filtered through a filtration medium, washed with ethyl acetate, and concentrated under vacuum. The crude product was then furrowed 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] Following general procedure B, N-Boc-4-(N-(L-proline methyl ester)-cyth From Syn 136 (0.88 mmol), a colorless solid, 137 (304 mg, 89%), is obtained. It was produced. [ka]

[0222] (Example 24-(-)4-(N-(L-proline)cyticine dihydrochloride (138)) [ka] N-Boc-4-(N-(L-prolinemethyl in hydrochloric acid (37% aqueous solution, 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 in ) and slowly add acetone (40 mL). Stir the resulting suspension 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 flash-coated in silica gel. 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 in a vacuum. The crude product was 3M The aqueous layer was partitioned into hydrochloric acid (5 mL) and dichloromethane (5 mL). The aqueous layer was then partitioned into dichloromethane (2 × Wash with 5 mL of sodium carbonate, base to pH 9, and then dichloromethane (5 mL) Extraction was performed using 5 mL of solution. The combined organic layer was dried with sodium sulfate and filtered under vacuum. 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] N-Boc-4-methyl-ester-cyticine in hydrochloric acid (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 dissolved in methanol (30 mL). 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. In a thermometer, 1.0 M acetic acid was added dropwise at -78°C for 5 minutes, and the reaction mixture was stirred for 3.5 hours. 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). 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] Following general procedure A, N-Boc-4-hydroxymethylcythicine 121 (0.60m Alcohol 122 (120 mg, 90%), a colorless solid, was produced from (mol) of it. [ka]

[0228] (Example 28a-N-Boc-4-(4-(trifluoromethyl)benzyl)oxy Shichishin (123)) [ka] Dry tetrahydrofuran (7.5 mL) with alcohol 121 (240 mg, 0.75 mg) To the mol) solution, add sodium hydride (33 mg, 1.1 equivalents, 60% dispersed in mineral oil). 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). Quenched, the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were then mixed with sulfate. 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] Following general procedure A, N-Boc-4-methylcythicine 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] Following general procedure B, N-Boc-4-vinyl-cyticine 115 (271 mg, 0.8 A colorless solid, 116 (214 mg, 99%), was obtained from 6 mmol. [ka]

[0234] (Example 31a-N-Boc-4-ethylcyticine(117)) [ka] 4-vinyl-N-Boc-cyticine 115 (353 mg, 1) in methanol (22 mL) To a 0.1 mmol solution, palladium / carbon 10% w / w (35 mg) was added. The reaction vessel was... The mixture was placed under vacuum and backfilled three times with hydrogen. The mixture was left under 1 atmosphere of hydrogen for 24 hours. 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] Following general procedure A, N-Boc-4-ethyl-cyticine 117 (0.92 mmol) From this, 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. The combined 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 [method]. The combined organic phase was dried with magnesium sulfate, filtered, and concentrated, resulting in a colorless [result]. 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 × 10 mL of 15% aqueous solution. The combined aqueous layer was then mixed with dichloromethane (5 × 10 Extracted with (mL). The combined organic layer (ethyl acetate and dichloromethane) was 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] Following general procedure B, N-Boc-4-(N-2-pyridone)-cyticine 107(28 9 mg, 0.75 mol) to a pale orange solid 10⁸ (182 mg, 76%) 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. A pale brown foam purified with ethyl acetate, with virtually no impurities (palladium catalyst). 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. We added water (10 mL) and extracted the aqueous phase with dichloromethane (3 × 20 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated in a vacuum. The crude product was silica. Purified by flash column chromatography of the gel [ethyl acetate], removing impurities (para It produced 126 (275 mg, 89%), a white solid with almost no zinc catalyst. The product was used in the next step without further purification. [ka]

[0242] Example 34c-(-)4-(acetylenyl)cyticine hydrochloride (127) [ka] Following general procedure B, N-Boc-4-(acetylene)cytidine 126 (0.77 mm) From the moles, 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. It is purified to produce a pale brown foam with almost no impurities (palladium catalyst) 128(3 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] Following general procedure B, N-Boc-4-(phenylacetylene)cyticine 128(0. From 88 mmol, 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 0.1M, 0.50mL, 5mol%) 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] Following general procedure B, 112(3) is a pale yellow solid obtained from 111(1.00 mmol). It produced 00mg, 92%. [ka]

[0247] (Example 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) Xanthane solution 0.1M, 0.50mL, 5mol%) and styrene (0.2mL, 2.0m) 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] Following general procedure B, 113 (0.88 mmol) yields 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). The soil was then removed. The combined organic layers were washed with salt water (20 mL) and dried with sodium sulfate. It was filtered and concentrated in a vacuum. Crude product ( 1 Based on H NMR, 86-93% conversion is achieved. 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] Following general procedure B, N-Boc-4-((4-phenyl)-NH-1,2,3, tri From azole-cyticine 134 (0.46 mmol), 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, Diluted with a 15% aqueous solution, then extracted with ethyl acetate (3 x 20 mL). 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] N-Boc-4-(1,2,3-triazol-1-yl) methanol (3.2 mL) (Methylpivalic acid)-Cyticine 131 (688 mg, 1.46 mmol) solution, hydroxyl Sodium (3.2 mL, 1 M aqueous solution) was added. The mixture was stirred at room temperature for 12 hours. The solution was neutralized with hydrochloric acid (3.2 mL, 1 M aqueous solution), diluted with water (30 mL), and ethyl acetate was used. Extraction was performed using (5 × 20 mL). The combined organic layers were washed 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] Following general procedure A, N-Boc-4-(NH-1,2,3-triazole)-citacy N132 (1.22 mmol) is deprotected and converted to hydrochloride using general procedure A, and 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 samples were cooled and extracted with dichloromethane (5 × 10 mL). The combined organic layers were then 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. The combined organic layers were 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 dissolved in dichloromethane (3.0 mL, 0.1 M), and 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, (15% aqueous solution), the aqueous phase was extracted with dichloromethane (4 × 20 mL). The combined 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. The solution was cooled and quenched with water (5 mL). Ethanol was removed under vacuum. The aqueous phase was then... Extraction was performed with dichloromethane (3 x 15 mL), and the combined organic phase was dried with magnesium sulfate. The mixture was filtered and concentrated. Flash column chromatography of the crude reaction mixture [Dichloro Purification with romethane / methanol (2% to 4% methanol) yields a colorless solid. It yielded a certain 141 (150 mg, 46%), which was recrystallized from toluene. [ka]

[0259] (Example 44b-(-)4-(carboxamide)cyticine hydrochloride (142)) [ka] Following general procedure A, N-Boc-4-amide-cyticine 141 (0.44 mmol) From this, a colorless solid, 142 (90 mg, 88%), was obtained. [ka]

[0260] (Example 45a-N-Boc-4-(aminomethyl)cyticine (143)) [ka] N-Boc-4-cyanocyticine 139 (3) in ethanol (10 mL, 0.1 M) 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. The mixture was backfilled three times with hydrogen and stirred at room temperature for 18 hours. The reaction mixture was then prepared using 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] Following general procedure 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 (8 mL) N-Boc-4-aminomethyl-cyticine 143 (2 (64 mg, 0.83 mmol) solution with 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). The combined 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] N-Boc-4-(N-Boc-aminomethyl) in tetrahydrofuran (6.0 mL) -Cyticine (255 mg, 0.61 mmol) solution, 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). Extraction was performed. The combined organic phase was washed with magnesium sulfate, filtered, and concentrated. The compound was deprotected using general procedure A to convert it to a hydrochloride salt, which is a colorless solid 152. (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)-carboxylate(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). The combined organic phase was then extracted with 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] Following general procedure A, 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)-carboxylate 153(0.53mmo From (1), a colorless solid, 154 (113 mg, 97%), was obtained. [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. The combined organic layers were 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. 82% was produced. Subsequent deprotection and conversion to hydrochloride using general procedure B 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, The container was filled with 0.90 mmol of water and placed under nitrogen. Water (2.5 mL, 0.3 M) and iso Propanol (0.8 mL, 1.0 M) was added, and the reaction mixture was heated at 60°C for 18 hours. Remove the solvent under vacuum, dissolve the residue in dichloromethane (20 mL), and add water (20 mL). It was poured into the container. The mixture was acidified with hydrochloric acid (0.1M aqueous solution) to a pH of approximately 4-5, and then dichlorometh Washed with (3 x 20 mL). Acidified the aqueous phase to pH ≈ 1, and then dichloromethane (3 x 2 Extraction was performed using 5 mL of solution. The combined 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 quenched with 10 mL of water, and the aqueous phase was converted to ethyl acetate. Extraction was performed using (3 × 25 mL). The combined organic layers were dried with magnesium sulfate and filtered. The crude reaction mixture was concentrated in a vacuum. Flash column chromatography of silica gel. The product is refined with [dichloromethane / methanol (1% methanol)] and is a green oil (2 It produced 0.7 mg, 60%. [ka] Following general procedure A, N-Boc-4-(dimethylamino)methylcythicine (0.6 From 0 mmol), 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] In a solution of amine 143 (220 mg, 0.63 mmol) in ethanol (6.3 mL), 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. It was deprotected and converted to the hydrochloride using general procedure A, resulting in a greenish amorphous solution. 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)] Purified using [NOL], a colorless solid product (330 mg, 92%) was obtained. By deprotecting and converting using procedure A, a colorless foam is obtained: 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 residue was removed using ethyl acetate (3× Extraction was performed using 25 mL. The combined organic layers were dried over 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] A 5 mL solution of methanol (160 mg, 0.32 mmol) was placed under nitrogen. Then, palladium (5 mg, 0.1 equivalent) was added on 10 wt% activated carbon. The container was then placed under vacuum. The mixture was placed in a container, backfilled three times with hydrogen, and 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] N-Boc-4-N-(N'-benzyloxycarbonyl) of methanol (6.4 mL) 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. The mixture was placed in a container and backfilled three times with hydrogen and stirred for 24 hours. The solution was filtered through a standard filter and concentrated under vacuum. It was then deprotected and converted to hydrochloride using general procedure A. By conversion, a colorless solid, 90 (237 mg, 96%), was produced. [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). The combined 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] Following general procedure A, from bromide 161 (0.25 mmol) to 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 Dissolve in hydrofuran (6 mL, 0.05 M) 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). The combined organic phase was then extracted. 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] Following general procedure A, 5-bromo-4-iodide was obtained from iodide 159 (0.16 mmol). 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) containing N-methylamine 83 (96 mg, 0.30 mg) 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). Extraction was performed using 25 mL of water. The combined 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] Following general procedure A, 9% 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 cytisine 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 It was filled with 0 mg (1.50 equivalents). After purging with nitrogen, 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 3.00 equivalents of bis(pina) as a boronation reagent 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 cyticine (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 178 mg (0.70 equivalents) of chlorine. After purging with nitrogen, tetrahydrofluid was used. 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, but 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 cyticine (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 cyticine (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 as discussed above. Prepared according to the following procedure. Crude N-Boc-4-Bpin cyticine was mixed with 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). The mixture was heated at 80°C for 24 hours, then cooled to room temperature and diluted with water (15 mL). Aqueous phase The organic phase was extracted with dichloromethane (3 x 15 mL), and the combined 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. The preparation was carried out according to the general procedure for the chemical reaction described above. 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. It was left standing and backfilled three times with nitrogen. 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. The residue was partitioned into ethyl acetate (15 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic phase was then extracted 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 (32 mL) contains N-Boc-4-aminocyticine (512 mg, 1 Cool the 0.67 mmol) 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). The combined organic phase was then extracted 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] Following general procedure A, N-Boc(3-bromo-4-hydroxy)cyticine (0.83 A colorless solid, BS70 (236 mg, quantitative), was produced from mmol. [ka]

[0290] (Example 68a-N-Boc(3-bromo-4-amino)cyticine) [ka] Tetrahydrofuran (16 mL) containing 4-aminocytisine (250 mg, 0.82 mmol) l) 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). The combined 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] A colorless solid was obtained from N-Boc(3-bromo-4-amino)cyticine following general procedure A. It produced BS71 (62 mg, 64%). [ka]

[0292] (Example 69a-N-Boc(3-bromo-4-ethyl)cyticine)) [ka] Tetrahydrofuran (20 mL) contains N-Boc-4-ethyl-cyticine (341 mg, Cool the 1.07 mmol) solution to 0°C, and 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). The combined organic phase was extracted with 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] Following general procedure A, N-Boc(3-bromo-4-ethyl)cyticine (296 mg, From 0.75 mmol, a colorless solid, BS74 (80 mg, 37%), was produced. [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 were mixed with 10% fetal bovine serum, 1% L-glutamine, and 100 units. Dulbecco's modified formula supplemented with penicillin G at 1 / ml and streptomycin at 100 μg. The cells were cultured in a humid environment containing 10% carbon dioxide in a medium called Ogle. α3 and β4, Alternatively, cDNA encoding α4 and β2 (is 30% densely packed into HEK293 cells) (Lancetified). Cell transfection is performed with 30 μL of Jetpay (trademark). (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, the cells were collected. 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 (specific binding) or absence of 100 nM cold epibatidine. In the present state (complete bonding), 50 mM Tris-HCl, pH 7, 150 mM sodium chloride , 5 mM potassium chloride, 1 mM magnesium chloride, 2.5 mM calcium chloride and In a buffer containing 2 mg / ml of bovine serum albumin, concentrations ranging from 0.005 to 1 nM were observed. The procedure was performed by overnight incubation at 4°C. Specific ligand binding was measured from complete binding to 100 nM. 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 is 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 was subjected to gel filtration chromatography using ice-cold 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 Jetpay® (Polypass, France). Using 1 mg / ml (pH 7.2) and 6 μg of α7 cDNA, a 100 mm petrochemical solution was used. The procedure was performed in a dish. After 24 hours of transfection, the cells were collected and separated by centrifugation. The samples were washed with nitrate-buffered saline and used for binding analysis.

[0298] [ 125I]-α-Bungarotoxin (PerkinElmer Company, Bost, Massachusetts) (Purchased from) Saturated bonds, at room temperature, at a concentration of 0.1~10 nM [ 125 I]-α-Bungarottoki This was performed by overnight incubation of SH-SY5Y membranes using Syn. Nonspecific binding was observed at 1 μM. This was determined in parallel by culturing in the presence of unlabeled α-bungarotoxin. After fermentation, the sample is filtered as described above, and the bound radioactivity is directly measured in a gamma counter. Counted. By the test compound [ 125 Inhibition of I]-α-bungarotoxin binding is SH- The SY5Y membrane was pre-cultured at room temperature for 30 minutes with a high concentration (10M~1mM) of the test agent, and then... 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 overnight culture, the membranes of α7-transfected SH-SY5Y cells were subjected to ice-cold phosphate saturation. 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 determined by direct counting with a gamma counter. 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 demonstrated high selectivity across receptor subtypes, minimizing the potential for "off-target" effects.

[0301] (Example 71 - Relative potency in nicotinic receptor subtypes) The compounds of the present invention were heterologously expressed in African clawed frog oocytes, and human α4β2, α We tested the effects on the function of 3β4 and α7 nicotinic acetylcholine receptors (nAChRs). 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. A pCI (Promega, UK) plasmid containing complementary DNA is injected as described in the previous literature. (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) Manually using a Geneclamp amplifier (Molecular Devices, USA), or Recording was performed using an automated HiClamp system. In both cases, oocytes The cells were punctured with two electrodes filled with 3M potassium chloride, and the cells were kept at -60mV during the experiment. did.

[0303] The isolation of oocytes and the recording of voltage fixation on the oocytes using two electrodes were performed as described in the previous literature. (Non-patent documents 16, 17). The concentration-response curve of the agonist maximizes all receptors being tested. The reaction derived from 1 mM ACh, which is the concentration of ACh that activates the chemical This was obtained by normalizing the reaction involving substances (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 obtained were from small amounts of oocytes obtained from at least three different donors. At the very least, it was obtained from five experiments.

[0304] ((a): Compounds related to (α4)3(β2)2nAChR (low sensitivity stoichiometry) effect) (Maximum gating potency of the compound) Maximum activity of (α4)3(β2)2nAChR heterologously expressed in African clawed frog oocytes The concentration of the compound of the present invention that causes the transformation 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): Effects on (α4)2(β2)3nAChR) (Maximum gate of compounds related to the (α4)2(β2)3 receptor (a highly sensitive receptor) (Effectiveness) Maximum activity of (α4)2(β2)3nAChR heterologously expressed in African clawed frog oocytes 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): Effects of compounds on α3β4nAChR) (Maximum gating efficacy of compounds related to α3β4nAChR) This resulted in the maximum activation of heterologously expressed α3β4nAChR in African clawed frog oocytes. 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): Effects of compounds on α7nAChR) (Relative potency of compounds with respect to α7nAChR) The amplitude of the current induced by the compound at 100 μM was measured, followed by α7nACh The amplitude of the reaction is relative to the 1 mM ACh concentration, which is the concentration that produces the maximum activity of R. 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) TIFF2026143488000234.tif51170 The R of the above 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, -(CH2) m -NR 6 R 7 R 8 (Let's call this side chain 1), -(CH2) m -O-(CH2) n -R 10 (Let's call it side chain 2), -CN, -COOR 12 (Assuming side chain 3), -(CH2) O -CO-(CH2) 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 m and n of 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 4These 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 pivalic acid, 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 -(CH2) 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) TIFF2026143488000235.tif51170 The R of the above 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, -(CH2) m -NR 6 R 7 R 8 (Let's call this side chain 1), -(CH2) m -O-(CH2) n -R 10 (Let's call it side chain 2), -CN, -COOR 12 (Assuming side chain 3), -(CH2) O -CO-(CH2) 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 m and n of 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 pivalic acid, 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 - (CH2) 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 C3 containing propyl, isopropyl, butyl, or tert-butyl. -8 The compound according to embodiment 1 or 2, wherein the compound is an alkyl group. (Appendix 5) The aforementioned R 1is 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=C-C6H5, acetylene, -C≡C-C6H 5, or a C which may have substituents including a -C≡C-trimethylsilyl group. 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)2B of (Pinacolato) volan (BPin) and (Catecolato) volan (BCat) - 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 cytisine, 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) Step II of generating the compound of chemical formula IIb, (C4) TIFF2026143488000237.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) TIFF2026143488000238.tif50170 The R of the above 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, -(CH2) 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, -(CH2) m -NR 6 R 7 R 8 (Let's call this side chain 1), -(CH2) m -O-(CH2) n -R 10 (Let's call it side chain 2), -CN, -COOR 12 (Assuming side chain 3), -(CH2) O -CO-(CH2) 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 R7 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 413 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 is represented by the chemical formula (RO)2-BB-(OR)2 or HB(OR)2. 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 (B2Pin2), or bis(catecolato) (t) The preparation method according to any one of embodiments 25 to 28, wherein the material is diboron (B2Cat2). (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) TIFF2026143488000239.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 1Substituting 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

1. A cyticine analog of formula (I) with a 4-position substitution, or a pharmaceutically acceptable salt or solvent thereof. A method for preparing Japanese food, 【Chemistry 1】 (In the formula, R １ teeth, ・ OH, Halogen, ・Ayl, • Alkyl, Alkenil, Alkinil, -NR ６ R ７ Here, R ６ and R ７ These are, independently, hydrogen, aryl, and aryl. Selected from a group consisting of kills, ・-NH(C=O)R ９ Here, R ９ It is an aryl or alkyl, ・-(CH ２ )-NR ６ R ７ , wherein R ６ and R ７ are each independently hydrogen, a protecting group Selected from the group consisting of , 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 tert-butyloxycarbonyl (Boc), formyl, acetyl Lu (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyl o Xycarbonyl (Cbz), Fluorenyl Methoxycarbonyl (Fmoc), (Pinacola Select from the group consisting of (BPin) borane and (Catecolate) borane (BCat). (to be selected) (i) Formula (IIa): 【Chemistry 2】 (In the formula, R ２ , R ３ , and R ４ Prepare the compound (as identified above). Step, (ii) Formula (IIb): 【Transformation 3】 (In the formula, R ２ , R ３ , and R ４ As identified above, CompB is a boron complex. The compound of formula (IIa) is produced by contacting the compound of formula (IIa) with a boronating reagent. Steps, and, (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.

2. The compound of formula (IIa) prepared in step (i) above has hydrogen atoms R ４ Location The step includes, and the step further includes R ４ This includes replacing the hydrogen atom at the position with a protecting group. The preparation method described in item 1.

3. The preparation method according to claim 2, wherein the protecting group is Boc.

4. The compound of formula (IIa) is cyticine, according to any one of claims 1 to 3. Manufacturing method.

5. The boronating reagent is of formula (RO) ２ -B-B-(OR) ２ OR HB (OR) ２ has The preparation method according to any one of claims 1 to 4.

6. The boronation reagent is B ２ Pin ２ or B ２ Cat ２ The following is a statement of any one of claims 1 to 4. Preparation method as described in item 1.

7. The boronating reagent: The molar ratio of the starting material in formula (IIa) is at least 0.5:1, and at least At least 0.75:1, at least 1:1, at least 1.5:1, or at least 2:1 The preparation method according to any one of claims 1 to 6.

8. The reaction in step (ii) is carried out in the presence of a catalyst, which of claims 1 to 7 The preparation method described in any one of the items.

9. The preparation method according to claim 8, wherein the catalyst is a transition metal catalyst.

10. The transition metal catalyst may include iridium, palladium, zinc, nickel, and / or rhodium. The preparation method according to claim 9, wherein mu is included.

11. The reaction in step (ii) above involves ester solvent, ether solvent, ketone solvent, and Alphoxide solvents, aromatic solvents, fluorinated aromatic solvents, alkane solvents, and mixtures thereof A preparation method according to any one of claims 1 to 10, carried out in a solvent selected from the following.

12. The above step (ii) is carried out in the presence of a ligand, any one of claims 1 to 11. The preparation method described above.

13. 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) (Diphenylphosphin)propane (dppp), 1,2-bis(diphenylphosphin)ethane (dppe) ), hexamethylbenzene (C6Me6), xanthophos, and 1,2-bis(dimethyl The preparation method according to claim 12, wherein the phosphino-ethane (dmpe) is selected from the following:

14. The ligands are phenanthroline (phen) and dimethylphenanthroline (me2). phen), tetramethyl-1,10-phenanthroline (me4phen), batfe Nanthroline (bathopen), 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), and the following: 【Transformation 5】 【change】 The preparation method according to claim 12, wherein one of the compounds is selected.

15. The molar ratio of the ligand to the starting material of formula (IIa) is less than 2:1, less than 1.5:1, 1 Less than: 1, Less than 0.75: 1, Less than 0.5: 1, Less than 0.1: 1, Less than 0.05: 1, Also The preparation method according to any one of claims 12 to 14, wherein is less than 0.001:

1.

16. The boration in step (ii) is carried out at a temperature of 50°C to 100°C. The preparation method described in any one of the requirements 1 to 15.

17. Before the start of step (iii), the compound of formula (IIb) is formed in step (ii). The resulting mixture is not separated from and / or from step (ii) and step (iii) The preparation method according to any one of claims 1 to 16, wherein the purification step is not performed during the following steps.

18. Step (iii) is initiated in the same reaction region where step (ii) was performed. The preparation method according to any one of claims 1 to 17.

19. In step (iii), CompB is the first intermediate R １ Substitutings are used to replace claims. The preparation method described in any one of items 1 to 18.

20. The first intermediate R １ The substituent is the second intermediate R. １ Substituting with a substituent, or R １ substituent The preparation method according to claim 19, wherein the compound of formula (I) is produced by substitution with the above.

21. The first intermediate R １ The substituent is the second intermediate R. １ Substituting with a substituent, as described in claim 20 The method for preparing it.

22. The second intermediate R １ The substituent is the third intermediate R １ Substituting with a substituent, or R １ substituent The preparation method according to claim 21, wherein the compound of formula (I) is produced by substitution with the above.

23. The first, second, or third intermediate R １ The substituent is a halo (e.g., bromo, chloro, or (e.g., iodine), benzyloxypyridinyl, alkyl ester (e.g., methyl ester) ), alkenyl (e.g., vinyl), alkynyl (e.g., acetylenyl), trimethyl Silylacetylenyl, (1,2,3-triazole-1-yl)methyl pivalate, cyano , aminomethyl, N-Boc-aminomethyl, and ((benzyloxy)carbonyl) A preparation according to any one of claims 19 to 22, independently selected from perazine-1-yl. Manufacturing method.

24. The compound of formula (IIb) or the compound of formula (I) is R ４ A protective group is provided at the position, The preparation method further involves the compound of formula (IIb) or the compound of formula (I) R ４ Destroy the foundation A preparation method according to any one of claims 1 to 23, comprising a protective step.

25. The compound of formula (IIb) or the compound of formula (I), the R ４ Deprotect the base The steps are: after the completion of step (ii), before the start of step (iii), and step (iii). The preparation method according to claim 24, which is performed during or after the completion of step (iii).

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