compounds

Abstract

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

Description

[Technical field]

[0001] The present invention relates to novel analogs of cytisine and their use in medicine, e.g., for the treatment of addiction. The present invention also relates to the preparation of analogs of cytisine. Manufacturing Improved synthetic method for It also provides the law. [Background technology]

[0002] Nicotinic acetylcholine receptors (nACh R) The various parts of the human brain and the central nervous system nACh is an ionotropic receptor expressed in other parts of the nervous system. R is example For example, cognitive functions, learning and memory, sleep, anxiety, arousal, reward, motor control and other neurological functions. Involved in a variety of physiological functions. nACh R is Also, for example, Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism nACh has been implicated in a number of pathologies, including depression and schizophrenia. R is Also, for example, nicotine addiction (Non-Patent Document 1), alcoholism (Non-Patent Document 2), drug addiction (Non-Patent Document 3), etc. It has been implicated in addiction and dependence on various drugs.

[0003] nACh R There are known to be many subtypes of nicotinic receptors. located at the transmuscular junction) are classified into α, β, γ, δ and a recently discovered additional subunit, ε It is known to be formed by five different substructures:

[0004] Neuronal nACh R( (located in the central nervous system, peripheral ganglia, and adrenal medulla) is a homomer or heteromer TypeTwo classes, named α2-α9 and β2-β9, can be combined into Only the subunits of the protein are displayed. Many neurodegenerative subtypes have been discovered, but heteromers Type Combination (α4)3( β2)2, α3β4 and homomers Type α7 in the brain Notable seems to play a role. Among them, heteromers Type Combination α4β2 is the predominant subtype in the central nervous system. It occupies approximately 90% of the receptors and binds ACh with high affinity. Type combination height is the other major subtype and binds ACh with low affinity.

[0005] Heteromer Type Combination α4β2 has two different stoichiometries: (α4)2(β2)3 and (α4)3(β2)2, which are usually A2B3 and A3B, respectively. The major α4β2 subtype is composed of two α4 and three β2 subunits. It has been proposed that the subtype A2B3 has the structure formed and is the major subtype involved in addiction.

[0006] Nicotine is thought to activate the α4β2 receptor subtype, which may contribute to drug dependence. Dopamine delivery to the nucleus accumbens and prefrontal cortex, specific areas of the human brain that have been linked to Increases the release of.

[0007] Furthermore, the α4β2 receptor subtype is involved in alcoholism (Non-Patent Document 4) and drug addiction. (Non-Patent Document 5)

[0008] nACh R Compounds with the ability to modulate these receptors could be used to treat conditions associated with those receptors. For example, studies have shown that transdermal nicotine is effective in preventing aging. It has been suggested that this could improve cognitive function in people suffering from memory disorders associated with (see reference). However, there are some disadvantages to the use of nicotine even when administered transdermally. For example: For example, nicotine use is known to be addictive, and a 2014 U.S. Surgeon General's report It was noted that nicotine has adverse effects on pregnancy outcome 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. sending reach Products that achieve this have also been developed and are publicly known.

[0010] nACh R Other compounds that regulate it have also been found to be used to treat addiction. Clin is marketed as Chantix® in the United States and Champix® in Europe. It is commercialized by Pfizer Inc. under the brand name EDTA (registered trademark) and approved for use in smoking cessation treatment. Moreover, medicine has lagged behind in the treatment of alcohol and drug dependence (non-specific (Patent document 4 and non-patent document 5).

[0011] Mihalak et al. (Non-Patent Document 7) reported that varenicline is a partial agonist at the α4β2 receptor. It is a weak agonist at α3β4 receptors and partial agonist at α3β2 and α6 receptors. They found that it is an agonist and an effective agonist at the α7 receptor.

[0012] A further drug used in smoking cessation treatment is cytisine. Cytisine is a naturally occurring pyrimidine. Don-containing alkaloids, nACh R Known as a partial agonist. Pharmacologically, cytisine exhibits a high degree of similarity to nicotine and has been used as a smoking cessation aid for many years. The chemical structure of cytisine (or more specifically, the (-) enantiomers) are shown below. [ka]

[0013] While cytisine is a safe and effective smoking cessation treatment, functionalized derivatives of the compound have been Attempts have been made to do so.

[0014] A variety of different numbering systems for cytisines have been used in the past. And for purposes of this disclosure, the following numbering system will be used: [ka]

[0015] In two papers (Non-Patent Document 8 and Non-Patent Document 9), Kozikowski et al. Summarizing previous studies on the introduction of substituents into the cytosine structure (mainly at the 3- and 5-positions) and discloses the synthesis of a racemic analogue that is reported to be novel and contains substituents at the 3-, 4-, and 7-positions. did.

[0016] In a 2006 paper by Kozikowski et al. (Non-Patent Document 8), The substituted compounds showed no activity against the α4β2 receptor subtype despite their high selectivity for this subtype. Operates with Drug activity The results presented in this 2006 paper demonstrated that analogs of cytisine substituted at position 4 are weak antagonists of the α4β2 receptor subtype.

[0017] Thus, the work carried out by Kozikowski et al. The analogues were shown to be significantly different from the known addiction treatments cytisine and varenicline. Ta.

[0018] More recently, work by other teams has focused on substitutions at other positions in the cytisine structure. For example, in US Pat. No. 5,999,513, an analogue of cytisine having the overall structure shown below was synthesized: Ta. [ka] Furthermore, in Patent Document 2, the analogue of cytisine is , on the piperidine ring Placement in 5-position Conversion and / or Nitrogen Contains elementary atoms.

[0019] Rouden et al. (Non-Patent Document 10) have conducted a comprehensive study of different functionalized derivatives of cytisine. The committee produced a comprehensive review of the [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. Pat. No. 5,304,121 [Non-patent literature]

[0021] [Non-Patent Document 1] Schalling and Waller, Acta Physiologica Scandinavica. Supplementum, 1980, volume 479, pages 53-56. [Non-licensed document 2] Holgate et al., Brain Science, 2015, September 5(3), pages 258-274. [Non-licensed document 3] Rahman et al., Frontiers in Neuroscience, 2014, volume 8, article 426.

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

[0022] A substantive search into analogs of cytisine, and cytisine and / or other nAChR binding agents Despite their potential to provide pharmaceuticals with improved properties compared to To our knowledge, no such compounds have been advanced into clinical trials, much less pharmaceuticals. It was never approved as a product. So, for example, As a medicine for treating poisoning, etc. Improved safety and / or Yes Efficacy There remains a need for pharmaceutical agents that have improved properties compared to cytisine, such as: [Means for solving the problem]

[0023] (First aspect) According to a first aspect of the invention, there is provided a compound of formula (I) or ,the Pharmaceutically acceptable Salts, solvates 、 and / Or E Stell is provided. [ka] Here, R 1 From R 4 will be defined later.

[0024] The present invention also provides pharmaceutical compositions comprising such compounds, As a drug Those compounds and composition The messenger For use Provide together.

[0025] Further Aspects Further aspects of the invention, described in more detail below, include 4-substituted analogs of cytisine. Conveniently adjust Manufacturing This is a preparation method for

[0026] The compounds and compositions of the present invention are useful in medicine. For example, they are effective in treating nicotine, amyloidosis, and rheumatoid arthritis. Prevention, treatment, or amelioration of symptoms of disorders of the central nervous system, including addictive disorders such as alcohol and drug addiction It may be used for good. stomach.

[0027] The compounds of this aspect of the invention have been identified by the inventors as being particularly effective in treating the symptoms of drugs, alcohol and / or tobacco. Therapeutic applications in the treatment of addiction and / or dependence for identified as useful for was . A limited number of 4-substituted cytisine analogues have been disclosed to date, but the available The limited binding data for these compounds indicates their applicability for use in medicine. The authors of those disclosures do not claim that these compounds have any neurological effects, including dependence and addiction. They concluded that these compounds showed poor efficacy as modulators of receptors associated with biological diseases. For example, Rouden et al. concluded in Non-Patent Document 10 as follows (Non-Patent Document 10, p. 732). The 4-substituted cytisine analogs tested "showed no agonist activity." sex Show In addition, it inhibits nicotine-activated channel function at both α4β2 and α3β4 receptors. and showed very low efficacy.” However, surprisingly and unexpectedly, the inventors of the present invention have found that Based on the emerging data discussed, these compounds demonstrate previously unnoticed benefits. I discovered that.

[0028] Compounds with a wide range of substitutions at the 4-position of cytisine have been identified by the present inventors as: identified as being therapeutically beneficial.

[0029] As described herein, the compounds of the present invention may be , or Honmei As exemplified by the specific compounds disclosed herein, One or more substituents in Replaced Good .

[0030] As used herein, "aliphatic of The term "aliphatic" refers to the alkyl, aliphatic Included within the terms alkenyl and alkynyl are the terms alkenyl and alkynyl, each of which is optionally substituted as described below.

[0031] As used herein N "Alkyl" groups are 1 to 12 (e.g., 1 to 8, 1 to 6 or 1 to 4) carbon atoms. The alkyl group may be a straight chain alkyl group or a branched chain alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl ... butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl or is 2-ethylhexyl. Alkyl groups may be substituted (i.e., optionally substituted) with one or more of the following substituents: ). Halo, phospho, cycloaliphatic [e.g. cycloalkyl or cycloalkenyl ], heterocycloaliphatic [e.g. heterocycloalkyl or heterocycloalkenyl] Kenil], Ali - Heteroaryl - Aryl, alkoxy, aroyl, heteroaroyl, aroyl S R [For example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or is (heterocycloaliphatic) carbonyl], nitro, cyano, amide, [e.g. (Cycloalkylalkyl)carbonylamino, aryl - Aralkylamino, Carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl (aryl alkyl) carbonyl amino, - Heteroaralkylcarbonylamino arylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylamino Chloroalkylaminocarbonyl, aryl - Aminocarbonyl, or heteroaryl - Ruamino carbonyl], amino [e.g. aliphatic amino, cycloaliphatic amino or heterocycloaliphatic amino], sulfonyl [e.g., aliphatic- SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfa moyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphatic thio oxy, heterocycloaliphatic oxy, aryl - Ruoxy, Heteroaryl - Ruoxi, Aralkyloxy, Heteroaryl - Alkoxy, alkoxycarbonyl, alkylcarbonyl Nyloxy, or hydroxy.

[0032] As used herein N "Alkenyl" groups are from 2 to 12 (e.g., from 2 to 8, It is an aliphatic carbon group containing 6 or 2 to 4) carbon atoms and at least one double bond. Like alkyl groups, alkenyl groups may be straight-chain or branched-chain alkenyl groups. It may also be a group. Examples of alkenyl groups include, but are not limited to, allyl, vinyl, isoprenyl, 1-propenyl, 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 It is. An alkenyl group may contain one or more substituents such as in It may be optionally substituted. Halo, phospho, cycloaliphatic [e.g. cycloalkyl or cycloalkenyl ], heterocycloaliphatic [e.g. heterocycloalkyl or heterocycloalkenyl] Kenil], Ali - Heteroaryl - Aryl, alkoxy, aroyl, heteroaroyl, aroyl S R [For example, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or is [heterocycloaliphatic) carbonyl], nitro, cyano, amino Do [ for example( Cycloalkylalkyl)carbonylamino, aryl - Arylcarbonylamino, Arylca carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl Alkyl)carbonylamino, Heteroaryl - Aralkylamino, heteroarylcarbonylamino, heteroaryl arylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heteroarylamino Chloroalkylaminocarbonyl, aryl - Aminocarbonyl, or heteroaryl - Ruamino carbonyl], amino [e.g. aliphatic amino, cycloaliphatic amino , heterocycloaliphatic amino, or aliphatic sulfonylamino], Sulfonyl [e.g. alkyl-SO2-, cycloaliphatic-SO2-, or aryl - R -SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulf Amoyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphatic Oxy, heterocycloaliphatic oxy, ary - Ruoxy, Heteroaryl - Ruoxi , aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyl Oxy, or hydroxy.

[0033] As used herein N "Alkynyl" groups are 2 to 12 (e.g., 2 to 8, 2 to It is an aliphatic carbon group containing 6 or 2 to 4) carbon atoms and at least one triple bond. The alkynyl group may be a straight-chain alkynyl group or a branched-chain alkynyl group. Examples of alkynyl groups include, but are not limited to, propargyl, butynyl, acetylenyl, 1 -Propynyl, 2-Propynyl, 1-Butynyl, 2-Butynyl, 3-Butynyl, 1-Pentynyl pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 1-hexynyl Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 6-hexynyl It is xynil. An alkynyl group may contain one or more substituents such as in It may be optionally substituted. Aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkoxy Ruoxi, Ali - Ruoxy, Heteroaryl - ruoxy, aralkyloxy, nitro, carbo oxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aryl cycloaliphatic sulfanyl or cycloaliphatic sulfanyl], sulfinyl [e.g. For example, aliphatic sulfinyl or cycloaliphatic sulfinyl], sulfonyl [e.g. aliphatic-SO2-, aliphatic amino-SO2- or cycloaliphatic riphatic-SO2-], amides [e.g. aminocarbonyl, alkylaminocarbonyl Nyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkyl cycloalkylaminocarbonyl, cycloalkylcarbonylamino, aryl - Aminocarbonyl, Ants - arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkyl Bornylamino, Heteroaryl - arylcarbonylamino or heteroaryl - aminocarbonyl] , urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkyl arylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl - Heteroaryl - L, A S (cycloaliphatic) carbonyl or (heteroaryl) cycloaliphatic) carbonyl], amino (e.g. aliphatic amino), Sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (Heterocycloaliphatic)oxy or (Heteroaryl - (r)alkoxy.

[0034] As used herein N , used alone or as "aralkyl", "aralkoxy" "Shi" or "Ari - Used as part of a larger moiety, such as in "alkyloxyalkyl" Ants - The "aryl" group can be monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthyl), tetrahydronaphthyl, tetrahydroindenyl) and tricyclic (e.g. fluorene nyl, tetrahydrofluorenyl, tetrahydroanthracenyl, anthracenyl) ring S Stem refers to monocyclic ring The system is aromatic or bicyclic or tricyclic ring System At least one of the ring is aromatic. The bicyclic and tricyclic groups include benzo-fused 2- to 3-membered carbocyclic rings. For example, a benzo-fused group is 、2 More than C 4-8 The carbocyclic portion of Phenyl fused with has. Ants - The alkyl group may have one or more substituents, including in It is optionally substituted. Aliphatic [e.g., alkyl, alkenyl or alkynyl], cycloaliphatic tic, (cycloaliphatic)aliphatic, heterocycloaliphatic q, (heterocycloaliphatic)aliphatic, aliphatic - Heteroaryl - Ru, Alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy Kiss, Ali - Ruoxy, Heteroaryl - Ruoxy, (araliphatic)oxy, (heterolytic)oxy loralifatic)oxy, aroyl, heteroaroyl, amino, oxo (benzo-abridged) Combined bicyclic or tricyclic aryl - Non-aromatic carbon Ring (above), nitro, carboxy , amide, acyl [e.g. (aliphatic) carbonyl, (cycloaliphatic ) carbonyl, ((cycloaliphatic)aliphatic) carbonyl, (araryl (heterocycloaliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((hetero Cycloaliphatic)aliphatic)carbonyl, or (heteroaliphatic) carbonyl], sulfonyl [e.g., aliphatic-SO2- or amino-S O2-], sulfinyl [e.g., aliphatic-S(O)- or cycloaliphatic sulfanyl [e.g., aliphatic-S(O)-], cyano, hydroxy, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sulf Famido or carbamoyl. Or, Ali - The alkyl group may be unsubstituted.

[0035] Optionally substituted aryl - No restriction on Some examples include: Termites - [e.g. mono-, di- (e.g. p,m-dihalotermes - (Trihalo) and (Trihalo) Ants - (carboxy)aryl - Aryl [e.g. (alkoxycarbonyl)aryl] - le, ( (Aralkyl)carbonyloxy)ari - Aryl and (alkoxycarbonyl)aryl - le], (Amide) Ari - Aryl [e.g., (aminocarbonyl)aryl - Ru, (((alkylamino) Alkyl)aminocarbonyl)ari - Aryl, (alkylcarbonyl)amino aryl - ru, (a R - (aminocarbonyl) aryl - Heteroaryl and - (amino)carbonyl)a R - ru], amino aryl -Aryl [e.g., ((alkylsulfonyl)amino)aryl] - ru or ( (Dialkyl)amino)arylate - Aryl, (cyanoalkyl)aryl - Ru, (alkoxy) aryl - Ru, (sulfamoyl) aryl - (aminosulfonyl)aryl - ru], (Archi arylsulfonyl) - Ru, (cyano) ari - Aryl, (hydroxyalkyl)aryl - le, (( Alkoxy)alkyl)aryl - aryl, (hydroxy)aryl - ru, ((carboxy)alkyl ) Ant - Aryl, (((dialkyl)amino)alkyl)aryl - Aryl, (nitroalkyl)aryl - Aryl, (((alkylsulfonyl)amino)alkyl)aryl - Heterocycloaryl Phatic) Carbonyl) Ari - Aryl, ((alkylsulfonyl)alkyl)aryl - Ru, (Cyanoalkyl) ants - Aryl, (hydroxyalkyl)aryl - ru, (alkylcarbonyl ) Ant - Aryl, alkyl aryl - Aryl, (trihaloalkyl)aryl - p-amino-m-alanyl Coxycarbonyl Ali - Le, p-amino-m-cyanoaryl - p-Halo-m-amino R - m-(heterocycloaliphatic)-o-(alkyl)aryl or (m-(heterocycloaliphatic)-o-(alkyl)aryl - Ru.

[0036] As used herein N"Araliphatic" such as "aralkyl" groups are ants - R Aliphatic groups substituted with groups (e.g., C 1-4 It refers to an alkyl group. "Aliphatic", "Alkyl" and "Aryl - "ru" is defined herein. An example of an ararylphatic such as an aralkyl group is benzyl.

[0037] As used herein N "Aralkyl" groups are ants - Alkyl groups substituted with aryl groups ( For example, C 1-4 It refers to an alkyl group. "Alkyl" and "Aryl" - Both the "rule" and "rule" are defined above. An example of an aralkyl group is benzyl. Aralkyl may optionally be substituted with one or more of the following substituents: in will be replaced. Aliphatic [e.g., alkyl, alkenyl or alkynyl, carboxy including alkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl. of], cycloaliphatic [e.g. cycloalkyl or cycloalkenyl], (cyclo (heterocycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, R - Heteroaryl - alkoxy, cycloalkyloxy, heterocycloalkyloxy Kiss, Ali - Ruoxy, Heteroaryl - aryloxy, aralkyloxy, heteroaralkyloxy oxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkyl Aminocarbonyl, alkylcarbonylamino, silylcarbonyloxy, amido [e.g. aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkylcarbonylamino, aryl - R Carbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonyl Amino, (heterocycloalkylalkyl)carbonylamino, heteroaryl - Lecarboni arylamino or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl , mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl aryl, sulfamido, oxo or carbamoyl.

[0038] As used herein N "Bicyclic ring The "system" consists of two ring Form 8 to 1 2( For example, 9, 10 or 11) member It contains two structures: ring has at least one atom share vinegar (e.g., two atoms share do). bicyclic ring The system is B Cycloaliphatic (e.g. B Cycloalkyl or B Sik alkenyl), B Cycloheteroaliphatic, bicyclic Ants - Ru and bicyclic Heteroa R - Includes

[0039] As used herein N "Carbocycle formula" Or "cycloaliphatic" groups are "cycloalkyl" and "cycloalkenyl" groups, each of which is optionally as defined above. is replaced by.

[0040] As used herein NA "cycloalkyl" group is an alkyl group having 3 to 10 (e.g., 5 to 10 ) a saturated monocyclic carbocyclic ring of carbon atoms formula or bicyclic (fused or bridged) ring Refers to... Examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, butyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octyl cutahydro-indenyl, decahydro-naphthyl, B cyclo[3.2.1]octyl, B cyclo[2.2.2]octyl, B cyclo[3.3.1]nonyl, B Cyclo[3.3.2 ] Desil, B Cyclo[2.2.2]octyl, adamantyl or ((aminocarbonyl) Cycloalkyl)cycloalkyl.

[0041] A "cycloalkenyl" group, as used herein, has one or more double bonds. Non-aromatic carbon atoms of 3 to 10 (e.g., 4 to 8) carbon atoms Ring Point. Examples of cycloalkenyl groups are as follows: Cyclopentenyl, 1,4-cyclohexa-dienyl, cycloheptenyl, cyclooctyl ctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, clopentenyl, B Cyclo[2.2.2]octenyl or B Cyclo[3.3.1]Noneni Ru.

[0042] A cycloalkyl or cycloalkenyl group may have one or more substituents such as in Optional replacement It can be done. Fluorescent, aliphatic [e.g. alkyl, alkenyl or alkynyl], cycloaliphatic Riphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic Tick, (heterocycloaliphatic) aliphatic, ant - Heteroaryl - Alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic) Q) Oxygen, Ali - Ruoxy, Heteroaryl - Ruoxy, (araliphatic)oxy, (Heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g. For example, (aliphatic) carbonylamino, (cycloaliphatic) carbonyl Amino, ((cycloaliphatic)aliphatic)carbonylamino, (aliphatic - (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaryl) ((heterocycloaliphatic)aliphatic) carbonylamino (H) carbonylamino, (heteroaryl - (heteroaryl)carbonylamino, or (heteroaryl (e.g., carbonyl, amino), nitro, carboxy [e.g., HOOC-, alkoxy carbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic (cycloaliphatic)aliphatic) carbonyl, ((cycloaliphatic)aliphatic) carbonyl, (aliphatic) (heterocycloaliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) carbonyl Heterocycloaliphatic)aliphatic)carbonyl, or (heteroarylpha (tic) carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g. , alkyl-SO2- and aryl - sulfinyl [e.g. alkyl-S(O )-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, Sulfamoyl, sulfamido, oxo or carbamoyl.

[0043] As used herein N The term "heterocyclic" or "heterocycloaliphatic" includes heterocycloalkyl and heterocycloalkenyl groups, each of which is as defined above. The following are replaced arbitrarily:

[0044] As used herein N A "heterocycloalkyl" group is a 3- to 10-membered monocyclic ring formula also Bicyclic (fused or bridged) (e.g., 5- to 10-membered monocyclic formula or bicyclic) saturated ring structure Refers to one or more ring The atom may be a heteroatom (e.g., nitrogen, oxygen, sulfur, or a combination thereof). ). Examples of heterocycloalkyl groups include the following: Aziridinyl, piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl , titanyl, oxolanyl, dioxanyl, dioxolanyl, thienyl, dithianyl, thionyl Lithianil, thiomorpholinyl, 1 , 3-Dioxolanyl, imidazolidinyl, oxazo Lysinyl, oxiranyl, oxetanyl, isoxazolidinyl, morpholinyl, pyrrolidinyl donyl, pyrazolidinyl, tetrahydrothiophenyl, oxathioranyl, pyranyl, Thiomorpholyl, Octahydrobenzofuryl, Octahydrochromenyl, Octahydro Thiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinone Linyl, Octahydrobenzo[b]thiophene hmm yl, 2-oxa- BCyclo [2.2.2 ]Octyl, 1-aza- B Cyclo[2.2.2]octyl, 3-aza- B Cyclo [3.2 .1]octyl and 2,6-dioxa-tricyclo[3.3.1.0 3,7 ]Nonyl. The monocyclic heterocycloalkyl group may be fused to a phenyl moiety, such as tetrahydroisoquinol. It forms structures such as heteroaryls. - would be classified as

[0045] A "heterocycloalkenyl" group, as used herein, is an alkyl group containing one or more double bonds. and monocyclic or bicyclic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic rings having the formula: ring Structure It refers to the construction of one or more ring The atom is a heteroatom (eg, nitrogen, oxygen, or sulfur). Monocyclic and bicyclic heterocycloaliphatic Q is Numbered according to standard chemical nomenclature will be done.

[0046] The heterocycloalkyl or heterocycloalkenyl group may optionally be one or more of the following: substituent in It can be substituted. Fluorescent, aliphatic [e.g. alkyl, alkenyl or alkynyl], cycloaliphatic Riphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic Tick, (heterocycloaliphatic) aliphatic, ant - Heteroaryl - Alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic) Q) Oxygen, Ali - Ruoxy, Heteroaryl - Ruoxy, (araliphatic)oxy, (Heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g. For example, (aliphatic) carbonylamino, (cycloaliphatic) carbonyl Amino, ((cycloaliphatic)aliphatic)carbonylamino, (aliphatic - (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaryl) ((heterocycloaliphatic)aliphatic) carbonylamino (H) carbonylamino, (heteroaryl - (heteroaryl)carbonylamino, or (heteroaryl (e.g., carbonyl, amino), nitro, carboxy [e.g., HOOC-, alkoxy carbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic (cycloaliphatic)aliphatic) carbonyl, ((cycloaliphatic)aliphatic) carbonyl, (aliphatic) (heterocycloaliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) carbonyl Heterocycloaliphatic)aliphatic)carbonyl, or (heteroarylpha (tic) carbonyl, nitro, cyano, halo, hydroxy, mercapto, sulfonyl [For example, alkylsulfonyl or aryl - sulfonyl], sulfinyl [e.g. alkyl sulfinyl], sulfanyl [e.g. alkylsulfanyl], sulfoxy, urea , thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

[0047] "Hetero ants - As used herein, a "cycloalkyl" group is a group having 4 to 15 carbon atoms. ring Having atoms Monocyclic, bicyclic or tricyclic ring A system refers to one or more ring The atom is a heteroatom (e.g. nitrogen, oxygen, sulfur or a combination thereof) and ring The system is aromatic or is bicyclic or tricyclic ring At least one of the systems ring is aromatic. Hetero ant - The alkyl group is two to three ring Benzocondensation having The ring Includes the system. For example, the benzo-fused group may be one or two 4- to 8-membered heterocycloaliphatic Moieties (e.g. indolyl, indolyl, isoindolyl, 3H-indolyl, indolyl nyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl or isoquinolinyl ) and benzo condensed thereto. Hetero ant - Some examples of aryls are azetidinyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, -pyridyl, 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl , 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, thiophenyl, oxy Sazolyl, Iso O Xazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiadiazole Azolyl, imidazolyl, diazolyl, triazolyl, tetrazolyl, benzofuryl, isopropyl Soquinolinyl, benzothiazolyl, xanthine, thioxanthine, phenothiazine, dihy Doroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiamine Ophenyl, Indazolyl, Benzimidazolyl, Benzothiazolyl, Puryl, Tinol quinolyl, quinazolyl, tinolyl, phthalazyl, quinazolyl, quinolyl tree Salil, Isoki Noryl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl or 1,8-naphthyl Jill.

[0048] Without limitation, monocyclic heteroaryls - The rules include: Furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imino Dazolyl, pyrazolyl, iso O Xazolyl, isothiazolyl, 1,3,4-thiadiazolyl 2H-pyranyl, 4H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl , pyrazyl or 1,3,5-triazyl. Monocyclic Heteroaryl - The molecules are numbered according to standard chemical nomenclature.

[0049] Without limitation, bicyclic heteroaryls - The rules include: Indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, ben Zo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizinyl nyl, isoindolyl, indolyl, benzo[b]furyl, benzo[b]thiophenyl, Indazolyl, benzimidazyl, benzothiazolyl, purinyl, 4H-quinolizyl, Quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinolyl tree Salil, 1,8 -Naphthyridyl or pteridyl. Bicyclic heteroaryl - The molecules are numbered according to standard chemical nomenclature.

[0050] Hetero ant - The group may optionally be one or more of the following substituents: in will be replaced. Aliphatic [e.g. alkyl, alkenyl or alkynyl], cycloaliphatic (cycloaliphatic)aliphatic, heterocycloaliphatic , (heterocycloaliphatic)aliphatic, ali - Heteroaryl - L, A Alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy S, Ants - Ruoxy, Heteroaryl - Ruoxy, (araliphatic)oxy, (hetero araliphatic)oxy, aroyl, heteroaroyl, amino, oxo(bicyclic or Tricyclic Heteroaryl - Non-aromatic carbocyclic or heterocyclic rings ring (above), carboxy, amine acyl [e.g. (aliphatic) carbonyl, (cycloaliphatic) carboxyl] (cycloaliphatic)aliphatic)carbonyl, (arariphatic) (heterocycloaliphatic) 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 sulfanyl], nitro, cyano, halo, hydroxy, mercapto, Sulfoxy, urea, thiourea, sulfamoyl, sulfamide or carbamoyl. Or, hetero ants - The alkyl group may be unsubstituted.

[0051] Has a substituent R Hetero ant - Non-limiting examples of the rules include: (Halo) Heteroarii - [e.g. mono-, di(halo)heteroaryl - ru], (Carboxy C) Hetero ant - (e.g., (alkoxycarbonyl)heteroaryl - le], cyanohetero Ants - Aminoheteroaryl - ((alkylsulfonyl)amino)heteroaryls R - and ((dialkyl)amino)heteroaryl - (Amido) Heteroaryl - Example For example, aminocarbonyl heteroaryl - ((alkylcarbonyl)amino)heteroaryl - Ru, ( (((alkyl)amino)alkyl)aminocarbonyl)heteroaryl - le, (( (Hetero ant - (aryl)amino)carbonyl)heteroaryl - Heterocycloaliphatic acid (carbonyl)heteroaryl - and ((alkylcarbonyl)amino)heteroaryl - (Cyanoalkyl)heteroaryl - (alkoxy)heteroaryl - Ru, (Sulf Amoil) Hetero ant - (aminosulfonyl)heteroaryl - ru], (sulfo Nil) Heteroari - (e.g., (alkylsulfonyl)heteroaryl - ], (hydroxy Dialkyl)heteroaryl - (alkoxyalkyl)heteroaryl - ru, (hydroxy) Hetero ant - ((carboxy)alkyl)heteroaryl - (((dialkyl)amine No) alkyl] heteroaryl - (Heterocycloaliphatic) Heteroaliphatic - le, ( Cycloaliphatic) Heteroaliphatic -(nitroalkyl)heteroaryl - le, ((( Alkylsulfonyl)amino)alkyl)heteroaryl - Aryl, ((alkylsulfonyl)a Rukill) Heteroari - (Cyanoalkyl)heteroaryl - aryl, (acyl)heteroaryl - (e.g., (alkylcarbonyl)heteroaryl - (alkyl)heteroaryl - Ru and (Haloalkyl)heteroaryl - [e.g., trihaloalkylheteroaryl - [L]

[0052] As used herein, "heteroaraliphatic" (e.g., heteroaralkyl groups) Hetero ants - ruthenium in Replaced Ta Aliphatic groups (e.g., C 1-4 (Alkyl group) vinegar. "Aliphatic", "Alkyl" and "Heteroaryl" - "Rules" are defined above.

[0053] A "heteroaralkyl" group, as used herein, refers to a heteroaryl - ruthenium in Replaced R Ta Alkyl groups (e.g., C 1-4 It refers to an alkyl group. "Alkyl" and "heteroaryl" - Both the "rule" and "rule" are defined above. Heteroaralkyl may optionally be substituted with one or more of the following substituents: in will be replaced. Alkyl (such as carboxyalkyl, hydroxyalkyl and trifluoromethyl) (including haloalkyl), alkenyl, alkynyl, cycloalkyl, (cycloalkenyl) (heterocycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl - R , Hetero ants - alkoxy, cycloalkyloxy, heterocycloalkyloxy, Ants - Ruoxy, Heteroaryl - aryloxy, aralkyloxy, heteroaralkyloxy, Aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyl, carboxycarbonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl arylamino, (cycloalkylalkyl)carbonylamino, aryl - arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)carbonylamino, chloroalkylalkyl)carbonylamino, heteroaryl - carbonylamino, heteroaromatic Ralklylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkyl Sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxy So or carbamoyl.

[0054] As used herein N "Cyclic moiety" and "cyclic group" refer to cycloaliphatic, Heterocycloaliphatic, Aliphatic - Heteroaryl or - Monocyclic, bicyclic or is tricyclic ring It refers to systems, each of which are defined above.

[0055] As used herein N “Bridged Bicyclic ring The "System" ring Bridged Bicyclic Heterocyclic Ring aliphatic ringSystem or bicyclic cycloaliphatic ring Refers to the system. bridged bicyclic ring Examples of systems include, but are not limited to: Adamantanyl, norbornanyl, B cyclo[3.2.1]octyl, B Cyclo [2. 2.2] Octyl, B cyclo[3.3.1]nonyl, B Cyclo[3.2.3]nonyl, 2 -Oxa B Cyclo[2.2.2]octyl, 1-aza B cyclo[2.2.2]octyl, 3-Aza B Cyclo[3.2.1]octyl and 2,6-dioxa-tricyclo[3.3. 1.0 3,7 ]Nonyl. bridged bicyclic ring The system may optionally contain one or more substituents such as in will be replaced. Alkyl (such as carboxyalkyl, hydroxyalkyl and trifluoromethyl) (including haloalkyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl (heterocycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl - Ru, Hetero ant - Alkyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, R - Ruoxy, Heteroaryl - Aroxy, aralkyloxy, heteroaralkyloxy, a Aryl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyl, Nyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl Amino, (cycloalkylalkyl)carbonylamino, aryl - Amino, arylalkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl) (alkyl)carbonylamino, heteroaryl - carbonylamino, heteroara alkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkyls Sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo Or carbamoyl.

[0056] As used herein N "Amide" is a compound of "aminocarbonyl" and "carbonylamino" " This includes both. These terms, whether used alone or in combination with other groups, are used as terminal groups. -N(R x )-C(O)-R Y or -C(O)-N(R X ) 2 refers to an amide group, such as When used in -C(O)-N(R X )-or-N(R X )-C(O)-, where R X and R Y is defined below. Examples of amide groups include alkylamides (alkylcarbonylamides or amylides): (heterocycloaliphatic) amides, (heteroaryl) (raryl)amides, (heteroaryl - (heterocycloalkyl)alkyl amides, Do, Ali - amide, aralkylamide, (cycloalkyl)alkylamide or cyclo Alkyl amide.

[0057] As used herein N The "amino" group is -NR X R Y Here, R Xand R Y Each Each is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic Aliphatic, Ali - aryl, araliphatic, heterocycloaliphatic (heterocycloaliphatic)aliphatic, heteroaliphatic - ru, carboxy , sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (cyclo (cycloaliphatic) aliphatic) carbonyl, Carbonyl, Ali - (aryl)carbonyl, (araliphatic)carbonyl, (heterocycloa aliphatic) carbonyl, ((heterocycloaliphatic)aliphatic) Carbonyl, (heteroaryl - (heteroaraliphatic) carbonyl or (heteroaraliphatic) carbonyl each of which is defined herein and is optionally substituted. Examples of amino groups are alkylamino, dialkylamino or arylamino. - Contains arylamino. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it -NR X - Represented by R, R X has the same meaning as above.

[0058] As used herein N An "acyl" group is a formyl group or R X -C(O)- (e.g. alkyl-C(O)-, also known as "alkylcarbonyl," where R X and "Alkyl" is defined above. Acetyl and pivaloyl are examples of acyl groups.

[0059] As used herein N "Aroyl" or "heteroaroyl" is an aryl - Ru-C(O )- or Heteroaryl - It refers to -C(O)-. Aroyl or heteroaroyl aryl - Heteroaryl and - The position of the pin is as specified above. are arbitrarily substituted as follows:

[0060] As used herein N An "alkoxy" group refers to an alkyl-O- group, where "Lukil" was previously defined.

[0061] As used herein N The "carbamoyl" group is -O-CO-NR X R Y or -NR X -CO-OR Z where R X and R Y is defined above, and R Z Is A Rifatik, Ali - Heterol, araliphatic, heterocycloaliphatic, heterol Roari - It may be heteroaryl or heteroarylphatic.

[0062] As used herein N The "carboxy" group, when used as a terminal group, is -C OOH, -COOR X , -OC(O)H, -OC(O)R X When used internally, refers to -OC(O)- or -C(O)O-.

[0063] As used herein N "Haloaliphatic" groups contain one to three halogen atoms in Replaced Ta Refers to the aliphatic group. For example, the term haloalkyl includes the group --CF.sub.3.

[0064] As used herein N A "mercapto" group refers to a -SH group.

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

[0066] As used herein N When used as a terminal group, the "sulfamide" group is - NR X -S(O)2-NR Y R Z When used internally, it refers to the structure of -NR X -S(O)2 -NR Y -, where R X , R Y and R Z was set out above.

[0067] As used herein N The "sulfonamide" group, when used as a terminal group, -S(O)2-NR X R Y or -NR X -S(O)2-R Z and when used internally - S(O)2-NR X -OR-NR X -S(O)2-, where R X , R Y and R Z is above It was prescribed.

[0068] As used herein N The "sulfanyl" group, when used as a terminal group, is - S.R. X When used internally it refers to -S-, where R X was set out above. Examples of sulfanils are aliphatic-S-, cycloaliphatic-S-, and aliphatic-S-. - Includes Ru-S- etc.

[0069] As used herein N When used as a terminal group, the "sulfinyl" group is - S(O)-R X When used internally it refers to -S(O)-, where R X is above It was prescribed. Example sulfinyl groups are aliphatic -S(O)-, aryl - Ru-S(O)-, (Cycloaliphatic (aliphatic))-S(O)-, cycloalkyl-S( O)-, heterocycloaliphatic-S(O)-, heteroaliphatic-S(O)- - Ru-S(O)- etc. include.

[0070] As used herein N A "sulfonyl" group, when used as a terminal group, is -S (O)2-R X When used internally it refers to -S(O)2-, where R X is above It was prescribed. Example sulfonyl groups are aliphatic -S(O)2-, aryl - Ru-S(O)2-, (Cycloaliphatic (aliphatic))-S(O)2-, cycloaliphatic Heterocycloaliphatic-S(O)2-, Heteroaliphatic-S(O)2-, Heteroaliphatic - Ru-S (O)2-, (cycloaliphatic(amido(aliphatic)))-S(O)2- etc.

[0071] As used herein N The "sulfoxy" group, when used as a terminal group, is -O -SO-R X OR X When used internally it refers to -OS(O)- or -S(O)-O-, where R X is defined above.

[0072] As used herein N A "halogen" or "halo" group is defined as any of fluorine, chlorine, bromine, or iodine. Refers to urinary acid.

[0073] As used herein N The term "alkoxycarbo" encompasses the term "carboxy". "Nyl" can be used alone or in combination with other groups, such as alkyl-OC(O)-. Refers to the base.

[0074] As used herein N "Alkoxyalkyl" means alkyl-O-alkyl-. It refers to such alkyl groups, where alkyl is defined above.

[0075] As used herein N "Carbonyl" refers to -C(O)-.

[0076] As used herein N "Oxo" refers to =O.

[0077] As used herein N The term "phospho" means phosphi Nath and phospho Nath Refers to... Phosphi Nath and phospho Nath An example of -P(O)(R P )2, where R P Yes Phatic, Alkoxy, Ari - Ruoxy, Heteroaryl - Ruoxy, (cycloalipha (heterocycloaliphatic)oxy, (heterocycloaliphatic)oxy, aliphatic - Heteroaryl - It may be aryl, cycloaliphatic or amino.

[0078] As used herein N "Aminoalkyl" is (R X )2N-alkyl- vinegar.

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

[0080] As used herein N The "urea" group is -NR X -CO-NR Y R Z This refers to the structure of "Thiourea" group teeth , -NR when used as a terminal group X -CS-NR Y R Z Structure of When used internally, -NR X -CO-NR Y -OR-NR X -CS-NR Y - Here, R X , R Y and R Z was set out above.

[0081] As used herein N An "aliphatic chain" is a branched or straight chain aliphatic group (e.g., The term refers to an alkyl group, an alkenyl group, or an alkynyl group. A straight aliphatic chain is -[CH2] V-, where v is 1 to 12. The aliphatic chain is substituted with one or more aliphatic groups. Ta It is a straight aliphatic chain. Branched aliphatic chains are -[CQQ] V -, where each Q is 、 Independent hand hydrogen or an aliphatic group, but Q must be an aliphatic group in at least one instance. Aliphatic chains include alkyl chains, alkenyl chains and alkynyl chains, where alkyl, alkynyl, Enyl and alkynyl are defined above.

[0082] The phrase "optionally substituted" is the same as the phrase "substituted or unsubstituted" is used in this sense. As described herein, the compounds of the present invention may be any of those generally described above or of the present invention. One or more of the substituents as exemplified in the particular classes, subclasses and varieties of the disclosure. in Arbitrarily placed can be exchanged. Books statement As described in Included in the chemical formulas described herein R 1 , R 2 , R 3 and R 4 of Possible strange element Reach And other possible strange element is alkyl and aryl - This includes specific groups such as . Unless otherwise noted, Included herein R 1 , R 2 , R 3 and R 4 of Possible strange element Reach Other of Possible strange element Each of the specific groups for may be one or more of the substituents described herein. in Optional replacement It can be done.

[0083] Each of the substituents of the specific groups may further comprise one to three of the following: in It may be substituted. Halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl - Le, Cyclo Aliphatic, heterogeneous Cyclo Aliphatic, heteroaliphatic - aryl, haloalkyl and Alkyl. For example, the alkyl group may be alkylsulfanyl. in may be substituted, alkylsulfanyl being Halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl - Lu, Termite - 1 to 3 alkyl and alkyl in It may be optionally substituted. In further examples, the cycloalkyl portion of the (cycloalkyl)carbonylamino is 1 to 3 of b, cyano, alkoxy, hydroxy, nitro, haloalkyl and alkyl in It may be optionally substituted. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups are The oxy groups, together with the atoms to which they are attached, ring can be formed.

[0084] The compounds of the present invention are useful nACh In R Treatment of disorders of the central nervous system, such as addiction disorders To Contains Can be Useful in medicine.

[0085] (compound) (First aspect (1)) According to the invention, a compound of formula (I) or ,the Pharmaceutically acceptable salts, solvates 、 and / Or An ester is provided. [ka] R 1 teeth, Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic Optionally substituted aryl - Ru, Optionally substituted heteroaryl - Ru, -(CH2) m -NR 6 R 7 R 8 , -(CH2) m -O-(CH2) n -R 10 , -CN, -COOR 12 , -(CH2) O -CO-(CH2) P -R 13 , Amino acids or esters thereof, Acyl chloride, a protecting group, or It's cytisine. Where: R 6 and R 7 are each independently selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Heterocycloalkenyl, or R 6 and R 7 One of them is -CO-R 9 and R 6 and R 7 the other of which is defined above. R 8 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted It may be heterocycloalkenyl, or absent. R 9 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. m is 0, 1, 2, 3, 4 or 5. R 10 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. m and n are each independently 0, 1, 2, 3, 4, or 5. R 12 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. R 13 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. o and p are each independently 0, 1, 2, 3, 4 or 5. R 2 , R 3 and R 4 are each independently selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted may be heterocycloalkenyl, an amino acid or cytisine, or R 4 may be a protecting group, Or, -(CH2) V - a group having the structure of FORMULA 1, where v is 0, 1 , 2, 3, 4, 5 or 6, and FORMULA 1 is a compound represented by formula (I) ) is a compound. R in Formula I 2 , R 3 and R 4 At least one of them is not hydrogen.

[0086] As mentioned above, R 1 The substituent at position is 、 an optionally substituted aliphatic Optionally substituted cycloaliphatic, optionally substituted heterocyclic Chloroaliphatic, optionally substituted 、 Ants - or optionally heteroaryl - R But that's okay.

[0087] In an embodiment of the present invention, R 1 The substituent at position may have a substituent or Unsubstituted C 1-8 , C 1-4 Or C 3-8 Alkyl groups, such as propyl, isopropyl, butyl or may be tert-butyl. In one embodiment of the present invention, R 1 The substituent at the position is 、 Optionally substituted C 1-2 a C which may have an alkyl group or a substituent 3-6 It may be an alkyl group. In such an embodiment, C 1-2 The alkyl group is hydroxymethyl or fluoromethyl. Other substituents may also be used.

[0088] R in the compounds of the present invention 1 The substituents envisaged for use in the substituents at the positions Examples of alkyl groups which may be used include the following: Methyl groups which may have a substituent, for example, aminomethyl, halogenated methyl, e.g. Chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, trifluoromethyl Methyl, bromomethyl, dibromomethyl or tribromomethyl; optionally substituted ethyl groups, e.g. 1- or 2-aminoethyl, hydroxyethyl, halogenated ethyl groups, Examples are 2,2,2-trichloroethyl, 2,2,2-tribromoethyl or 2,2,2 -trifluoroethyl, or , placed optionally substituted propyl groups, such as 1-, 2- or 3-aminomethyl, hydroxypropyl or halogenated propyl.

[0089] In an embodiment of the present invention, R 1 The substituent at position is 、 Unsubstituted or substituted Good ant - It may also be a For example, the substituent may be a phenyl group or an optionally substituted phenyl group. It may be a halogenated phenyl group, for example a chlorophenyl, bromophenyl, nyl, fluorophenyl, perchlorophenyl, perbromophenyl, perfluorophenyl Nil, or tolyl, aniline, phenol, styrene, benzonitrile, anisole, acetophenone It may be a non-, benzaldehyde or benzoic acid group.

[0090] (First aspect (2)) In another embodiment, R 1 The substituent at position is an optionally substituted heteroaryl. - R benzyloxypyridine, pyridone (e.g. 2-pyridone), Pyridine (e.g. 2-pyridine, 3-pyridine or 4-pyridine), phenyltriazo triazole, optionally substituted triazole and triazole methylpivalate groups. That's fine.

[0091] R 1 The substituents may alternatively be optionally substituted cycloalkyl or heterocycloalkyl. It may be alkyl, for example, cyclopentyl, cyclohexyl, morpholinyl, pipetyl, It may be lysyl, piperazyl, tetrahydrofuryl, oxolanyl or dioxanyl. stomach.

[0092] R 1 Examples of optionally substituted alkenyl groups that may be included at position C include 2-8 Arken For example, vinyl, acrylate or -C=C-C6H5 groups.

[0093] R 1 The optionally substituted alkynyl group which may be present at position C 2-8 Alkynyl, or -C≡C-C6H5 or -C≡C-trimethylsilyl group.

[0094] In addition, R of the compound of the present invention 1 Other groups which may be used as substituents include the following groups:

[0095] (-(CH2) m -NR 6 R 7 R 8 ) Here, R 6 、 R 7 、 and R 8 is defined above. In such embodiments, the compounds of the present invention include amines, N-alkylamines, N,N-diamines, Alkylamine and amide groups are represented by R 1 It may be included as a substituent at position. Examples of groups contemplated for inclusion at that position include: amine, methylamine, ethylamine, ethylamine, propylamine, isopropylamine, benzylamine, dimethylamine, Trimethylammonium methyl, dimethylaminomethyl, benzo Z Amides and acetamides In an embodiment of the invention, m is zero and R 8 If does not exist, R 6 and R 7 Both is not hydrogen, and / or R 6 and R 7 Neither of the above is oxo.

[0096] (-(CH2) n -O-(CH2) o -R 10 ) Here, R 10 is defined above. In such embodiments, the compounds of the invention are 1 Contains groups containing ether bonds at position Examples of groups contemplated for inclusion at that position include: Methoxy, ethoxy, propoxy, benzyloxy or trifluoromethylbenzyloxy In embodiments of the present invention, the following conditions apply: R 1 The substituents in are propoxymethyl groups (i.e., -CH2-O-CH2-CH2CH3), Alkoxymethyl group, or -CH2-O-CH2-C6H4-R 12 or -CH2-O-CH2-C 6H 10 -R 12 where R 12 is hydrogen, trifluoromethyl, substituted It is phenyl, halo or fluorine, which may have a group.

[0097] (-CN) (-COOR 12 ) Here, R 12 is defined above. In such embodiments, the compounds of the invention may include a carboxylic acid group or R 1 Esters in position, e.g. For example, ethyl ester, propyl ester, isopropyl ester, butyl ester or It may also contain phenyl esters. In an embodiment of the present invention, R 1 The substituents in 1-3 Alkyl ester group or methyl The substituent may be a substituent other than a ester group.

[0098] (-(CH2) p -CO-(CH2) q -R 13 ) Here, R 13 is defined above. In such an embodiment, the compound of the invention is 、R 1 In position Ketones Is A Aldehyde groups, e.g. For example, acetophenone may be included. In one embodiment, R 1 The substituents in are other than -CO-NH2.

[0099] (-amino acid) For example, naturally occurring amino acids or their esters, such as alanine, arginine, Sparagin, Aspa Ruthart , Cysteine, Glutamine, Gluta mart , Glycine, His Thysine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, Serine, threonine, tryptophan, tyrosine, valine, or methyl or ethyl thereof; Propyl or isopropyl esters.

[0100] The compound of the present invention is R 1 Embodiments of the Invention Comprising an Amino Acid or Ester Thereof at Position In the above, the amino acid (or ester) can be bonded via any atom (e.g., oxygen, carbon, sulfur, etc.). via the oxygen atom in the acid unit), e.g., the acylation of aminocytisine via the oxygen atom in the acid unit. The pyridine of the basic structure of cytisine can be formed by forming an imide or via the nitrogen atom of the amine unit. ring may be coupled to

[0101] (-Acyl chloride) (-protecting group) For example, tert-butyloxycarbonyl (Boc), formyl, acetyl (Ac), Succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl boryl (Cbz), or fluorenylmethoxycarbonyl (Fmoc) or protected boryl Protecting groups, optionally (pinacolato)borane (BPin) and (catecholato)borane (BCat ) has a (RO)2B-structure. In an embodiment of the present invention, any protecting group commonly used in organic synthesis, e.g. The methods outlined in JP-A-2002-113311 and JP-A-2002-113311 can be used, the contents of which are incorporated herein by reference. is incorporated herein by reference.

[0102] (-Cytisinyl) In an embodiment, the compound of the invention may be a cytisine-cytisine dimer. Cytisine compounds may be, for example, substituted via the 3-, 4- or 5-carbon atom of each compound. They may be directly bonded to each other. Alternatively, the two cytisine structures can be linked via a linker, such as a carbon, oxygen or nitrogen atom. They may also be combined. If a linker is used, it itself can be written as e.g. 1-6 It may have a functional group such as alkyl. stomach.

[0103] position R 2 From R 4 The substituents at are defined above. In an embodiment of the present invention, R of formula I 2 and R 3 may be hydrogen. In that case R 2 , R 3 and R 4 At least one of them is not hydrogen. Or, R 2 may be halogen, while R 3 and R 4 is hydrogen. In some embodiments of the present invention, R 4 The substituent of is C 2-6 Even if the substituent is not alkyl good.

[0104] In an embodiment of the present invention, at position R 4 The substituents in may be protecting groups such as . tert-Butyloxycarbonyl (Boc) 、 Formyl, acetyl (Ac), succinyl Succinyl (Suc), Methoxysuccinyl (MeOSuc), Benzyloxycarbonyl (C bz) or fluorenylmethoxycarbonyl (Fmoc), or a boronated protecting group, any B( such as (pinacolato)borane (BPin) and (catecholato)borane (BCat) are also available. Those having OR)2 structure. In an embodiment of the present invention, any protecting group commonly used in organic synthesis, e.g. The methods outlined in JP-A-2002-113311 and JP-A-2002-113311 can be used, the contents of which are incorporated herein by reference. is incorporated herein by reference.

[0105] Unless otherwise indicated, structures depicted herein also include, for example, the chiral groups for each asymmetric center. R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers All isomers of the same structure (e.g., enantiomers, diastereoisomers, geometric (or means that the compound includes three-dimensional (conformational) isomers. Therefore, the single stereochemistry of the compounds of the present application transformation Optical isomers, enantiomers, and diastereoisomers Mixtures of structures and geometries (or conformations) are within the scope of the present application. Unless otherwise stated, all tautomeric forms of the compounds of the present application are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein also may be represented by one or more isotopically enriched forms. The term is meant to include compounds which differ only in the presence of listed atoms. For example, replacement of hydrogen with deuterium or tritium, or 13C- or 14C-enrichment of carbon. Carbon Substitution Except Compounds having the structure of the present application 、 It is within the scope of the present invention.

[0106] (First aspect (3)) Exemplary compounds of the present application include, but are not limited to, the following compounds: 4-Bpin cytisine, 4-hydroxycytisine, (+)4-hydroxycytisine, (-)4-Methoxycytisine, 4-Methoxycytisine, 4-(N-benzylamino)cytisine, (+) 4-(N-benzylamino)cytisine, (-)4-(2,2,2-trifluoroethyl)cytisine, 4-(2,2,2-trifluoroethyl)cytisine (-)4-(perfluorophenyl)cytisine, 4-(perfluorophenyl)cytisine, (-)4-(2-pyridinyl)cytisine, 4-(2-pyridinyl)cytisine, (-)4-(3-pyridinyl)cytisine 4-(3-pyridinyl)cytisine, (-)4-(4-pyridinyl)cytisine, 4-(4-pyridinyl)cytisine, 4-(4-(2-benzyloxy)pyridine)cytisine, 4-(4-(2-pyridone)cytisine, (+)4-(4-(2-pyridone))cytisine (-)4-iodocytisine, (+)4-iodocytisine, (-)4-trifluoromethylcytisine, 4-trifluoromethylcytisine, 4-(N-methylamino)cytisine (+) 4-(N-methylamino)cytisine, 4-(N , N'-dimethylamino)cytisine, (+)4-(N , N'-dimethylamino)cytisine, 4-(N-benzoylamino)cytisine, (+) 4-(N-benzoylamino)cytisine, 4-(N-morpholine)cytisine, (+) 4-(N-morpholine)cytisine, 4-(N-(L-proline methyl ester)cytisine, (+) 4-(N-(L-proline methyl ester)cytisine, (-)4-(N-(L-proline)cytisine, 4-(N-(L-proline)cytisine, (-) 4-carboxylate cytisine, 4-Carboxylic acid cytisine, (-)4-((trifluoromethyl)benzyl)oxycytisine, (-)4-vinylcytisine, (+) 4-vinylcytisine, (-)4-ethylcytisine, (+)4-p-Tolylcytisine, (-)4-(N-2-pyridone)cytisine, 4-(N-2-pyridone)cytisine, 4-(trimethylsilylacetylene)cytisine, (-)4-(acetylenyl)cytisine, 4-(acetylenyl)cytisine, 4-(phenylacetylene)cytisine, (+) 4-(phenylacetylene)cytisine, 4-(E-2-propenoic acid methyl ester)cytisine (+) 4-(E-2-propenoic acid methyl ester) cytisine, 4-(E-(2-phenylethenyl)cytisine, (+) 4-(E-(2-phenylethenyl)cytisine, 4-(1-(4-phenyl)-NH-1,2,3,triazolyl)cytisine, (+) 4-(1-(4-phenyl)-NH-1,2,3,triazolyl)cytisine (-) 4-(1,2,3-triazol-1-yl)methylpivalic acid)cytisine (+) 4-(1,2,3-triazol-1-yl)methylpivalic acid)cytisine, 4-(NH-1,2,3-triazolyl)cytisine, (+) 4-(NH-1,2,3-triazolyl)cytisine, 4-(N-ethylamino)cytisine (+) 4-(N-ethylamino)cytisine, 4-(N-isopropylamino)cytisine, (+) 4-(N-isopropylamino)cytisine, (-)4-cyanocytisine, 4-cyanocytisine, (-)4-aminomethylcytisine, 4-aminomethylcytisine, (-)4-(N-methyl-aminomethyl)cytisine, 4-(N-methyl-aminomethyl)cytisine, (1R,5S,10S,11aR)-10-(aminomethyl)decahydro-8H-1,5 -Methanopyrido[1,2-a][1,5]diazocin-8- O hmm Amino bis(cytisine) derivatives Methylamino bis(cytisine) derivatives (-)4-Tetrazolylcytisine 4-Tetrazolylcytisine, (-)4-(trimethylammonium)methylcytisine, 4-(trimethylammonium)methylcytisine, (-)4-(N-acetyl)aminomethylcytisine, 4-(N-acetyl)aminomethylcytisine, 4-(N-piperazine)cytisine, (+) 4-(N-piperazine)cytisine, (-)3-(trifluoromethyl)-4-bromocytisine 3-(trifluoromethyl)-4-bromocytisine, 3-bromo-4-iodocytisine, (+) 3-bromo-4-iodocytisine, 3-bromo-4-N-methylaminocytisine, (+)3-Bromo-4-methylaminocytisine 。

[0107] (synthesis) Prior art 4-substituted cytisine compounds There was limited disclosure But such a To the best of the inventors' knowledge, no convenient synthesis of this compound has been proposed. No synthetic route to obtain analogs of the 4-substituted cytisine has been proposed so far. Instead, such compounds had to be prepared by total synthesis starting from monocyclic materials. See, for example, Scheme 1 in Non-Patent Document 9 and Non-Patent Document 13.

[0108] Further Aspects According to a further aspect of the invention, there is provided a method for preparing a 4-substituted analogue of cytisine. and includes the following steps:

[0109] Step i: Producing a compound of formula IIa [ka] Here, R 2 , R 3 and R 4 are each independently selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted may be heterocycloalkenyl, an amino acid or cytisine, or R 4 may be a protecting group, Or, -(CH2) V - a group having the structure of FORMULA 1, where v is 0, 1 , 2, 3, 4, 5 or 6, and FORMULA 1 is a compound represented by formula (I) ) is a compound.

[0110] Step ii: Producing a compound of formula IIb [ka] Here, R 2 , R 3 and R 4 is defined above, and BComp is a compound of formula IIa. Boron by contacting with an uration reagent transformation It is a complex.

[0111] (Step iii: BComp to R 1 to form a compound of formula I. P) [ka] Here, R 1 teeth Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic Optionally substituted aryl - Ru, Optionally substituted heteroaryl - Ru, -(CH2) m -NR 6 R 7 R 8 , -(CH2) m -O-(CH2) n -R 10 , -CN, -COOR 12 , -(CH2) O -CO-(CH2) P -R 13 、 a Amino acid or its ester 、 salt Acyl chloride 、 Protection Mamoki, also teeth S It's tysinyl. Where: R 6 and R 7 are each independently selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that -Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted heterocycloalkenyl, or R 6 and R 7 One of them is -CO-R 9 and R 6 and R 7 the other of which is defined above. R 8 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted It may be heterocycloalkenyl, or absent. R 9 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. m is 0, 1, 2, 3, 4 or 5. R 10 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. m and n are each independently 0, 1, 2, 3, 4, or 5. R 12 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. R 13 is selected from the group consisting of: Hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N -Alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfur Hoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto , carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, substituted It's okay to do that - Heteroaryl which may have a substituent - , having a substituent optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic which may be optionally substituted, heteroaryl which may be optionally substituted - Ru, haloalkyl which may have a substituent; aroyl which may have a substituent; Heteroaroyl which may have a substituent, acyl which may have a substituent, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl alkenyl, optionally substituted heterocycloalkyl or substituted Also suitable heterocycloalkenyl. o and p are each independently 0, 1, 2, 3, 4 or 5. Also, R in formula I 2 , R 3 and R 4 At least one of them is not hydrogen.

[0112] The starting material can be any compound encompassed within formula IIa as outlined above. However, one advantage of the present invention is that the preparation method is effective using cytisine as a starting material. It is something that is done for profit. Thus, in the embodiment, R 2 , R 3 and R 4 All of may be hydrogen. Or, position R 4 The substituents in may be protecting groups or may be -(CH2) V -FORMUL A may be a group having the structure 1, where v is 0, 1, 2, 3, 4, 5, or 6; F ORMULA 1 is a compound of formula (I) described herein.

[0113] Thus, in an embodiment, the compound of formula IIa is R 4 and may include a protecting group at The preparation method of the present invention involves adding a protecting group to a compound of formula IIa (which includes cytisine). It may also include a Those skilled in the art would be familiar with techniques for adding protecting groups to secondary amines and would be able to use methods for doing so. Any step of the preparation process is within the scope of the present invention. For example, R 4 The protecting group added at position is Boc (tert-butoxycarbonyl). In one embodiment, the preparation method provides a reagent containing Boc (e.g., (Boc)O), It is dissolved in a suitable solvent (examples include tetrahydrofuran and sodium tricarbonate). thing) Medium with cytisine.

[0114] Thus, in an embodiment of the present invention, R 4 The protecting group at position may be Boc. Other protecting groups that may be used include: Formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOS uc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (F moc), or a boronated protecting group, optionally bis(pinacolato)diborane (B2Pin2) and (RO)2B- such as bis(catecholate)diborane (B2Cat2). B- (OR)2 structure Something that has. In an embodiment of the present invention, any protecting group commonly used in organic synthesis, e.g. The methods outlined in the literature 11 and 12 can be used. is incorporated herein by reference.

[0115] The boronation reagent used in step ii of the preparation method of the present invention is well known in the field of boronation chemistry. It may be any boronating agent known to those skilled in the art. For example, the boronating reagent may be a dialkyloxyborane or an alkylborane. Examples of dialkyloxyboranes are bis(pinacolato)diborane (B2Pin2) and bis( Catecholate)diborane (B2Cat2) And general Formula (RO)2-BB-(OR)2 or H Any other boronization reagent with B(OR)2 medicine, For example, the one disclosed in Non-Patent Document 16 , the contents of which are incorporated herein by reference. An example of an alkylborane boronizing agent is 9-borane. B Cyclo(3.3.1)nonane(9-B BN), B-alkyl-9-oxa-10-borane B Cyclo[3.3.2]decane (OBB D), disiamylborane, thexylborane and HB(cHex)2.

[0116] In an embodiment of the present invention, the molar ratio of boronating reagent to starting material of formula IIa is about 1. The range may be 0 or less:about 1, about 7 or less:about 1, or about 5 or less:about 1. Additionally or alternatively, the molar ratio of boronating reagent to starting material of Formula IIa is about 0.1 or more. Above: about 1, about 0.2 or more: about 1, about 0.3 or more: about 1, about 0.4 or more: about 1 or about 0.5 It may be in the range of about 1.

[0117] In one embodiment of the invention, the boronating reagent is a molar equivalent of the starting material of formula IIa. The ratio may be exceeded. This is preferred in certain embodiments where cytisine is used as the starting material for formula IIa. It may be appropriate.

[0118] In another embodiment of the present invention, the starting material of formula IIa is monofunctional as compared to the boronating reagent. The ratio may be exceeded. This means that a given analogue of cytisine (e.g., N-boc cytisine) is a starting compound of formula IIa It may be suitable in certain embodiments for use as a substance.

[0119] The reaction in step ii of the process of the present invention may be catalyzed using a catalyst known to those skilled in the art. You can take it. In an embodiment of the invention, step ii can be catalyzed, for example using a transition metal catalyst. Receive. In a preferred embodiment, the catalyst used is iridium, palladium, zinc, nickel and and / or rhodium atoms, which are organic coordination complexes. By shape may be provided. A specific example of a catalyst that can be used in the preparation method of the present invention is Ir[(COD)(OMe)]2 , palladium(II) chloride, Pd / P(t-bu)3, Pd(dba)2, nickel chloride ( II), [RhCl(cod)]2 or Et2Zn. Iodine may additionally or alternatively be used as a catalyst.

[0120] Step ii of the process of the present invention may be carried out in a solvent. Any solvent that is compatible with the boronization process to be carried out may be used in the process of the present invention. do. Examples of solvents that can be used are esters (e.g., ethyl acetate), ethers (e.g., diethyl ether), xanthenes, tetrahydrofuran), ketones (e.g. 2-butanone), sulfoxides (e.g. dimethylsulfoxide), aromatics (e.g. toluene), fluorinated aromatics (e.g. trifluorotoluene) and alkanes (e.g. cyclohexane, n-pentane, n-hexane, Includes oxalate.

[0121] In the preparation method of the present invention, a ligand may be used in step ii.

[0122] Examples of ligands that can be used are ,single Aromatic or heteroaromatic compounds which may be cyclic or polycyclic thing , phenanthroline compounds, etc. may also include. Phenanthroline compounds include, but are not limited to, the following: Phenanthroline (phen), dimethylphenanthroline (me2phen), tetrahydrofuran Me4phen and / or 1,10-phenyl-4-methylphenanthroline Phosphorus (bathophen), bipyridyl compounds, e.g. 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(diphenylphosphino)ferrocene (dppf), bis(2- Di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphine 1,2-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe ), hexamethylbenzene (C6Me6), neocuproine and xantphos. Other examples are 1,2-bis(dimethylphosphino)ethane (dmpe) and 6, the contents of which are incorporated herein by reference, and illustrated below. Contains compounds. [ka] Alternatively, examples of ligands that can be used are aromatic or heteroaromatic compounds, which may be polycyclic. Includes. Examples include 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(diphenylphosphino)ethane (dppe), Examples include xamethylbenzene (C6Me6) and xantphos. Other examples are 1,2-bis(dimethylphosphino)ethane (dmpe) and 6, the contents of which are incorporated herein by reference.

[0123] The inventors of the preparation method of the present invention have found that the ligand for the starting material of formula IIa (used The molar ratio of the boron compounds of formula IIb is conversion rate found that it can affect did. In an embodiment of the invention, the molar ratio of ligand: starting material of formula IIa is about 2 less than :1、 Approximately 1.5 Less than: 1, Approximately 1 Less than: 1, Approximately 0.75 Less than: 1, Approximately 0.5 Less than: 1, Approximately 0 .1 Less than: 1, Approximately 0.05 Less than:1 to at least about 0.001:1.

[0124] The boronation reaction step II is suitable for the boronation reaction. Rate If it can be done, what kind of temperature It may be performed at different times. In an embodiment of the invention, the reaction may be carried out at about 0° C., about 10° C., about 20° C., about 30° C., about 40° C. or From about 50℃ 、 It may be carried out at a temperature of about 100°C, about 120°C or about 150°C.

[0125] The inventors of the preparation method of the present invention 、 Molar ratio of boronizing agent to starting material of formula IIa The ratio of boronization of formula IIb did Conversion to compounds conversion rate found that it can affect In an embodiment of the invention, the molar ratio of boronating reagent to starting material of formula IIa is at least at least about 0.5:1, at least about 0.75:1, at least about 1:1, at least about 1 0.5:1, at least about 2:1, at least 2.5:1, or at least 3:1, optionally Optionally, it may be about 5:1 or about 10:1.

[0126] The selective and efficient synthesis of 4-substituted analogues of cytisine requires careful selection of starting materials, solvents, catalysts, and ligands. This was achieved regardless of the order in which the bonds and / or boronating reagents were added.

[0127] In one embodiment of the present invention, the boronating reagent and the starting material of formula IIa are co-present in the reaction zone. The mixture is added at or about the same time. In such embodiments, the reaction zone may be preloaded with solvent, catalyst and / or ligand. , it didn't have to be that way.

[0128] In another embodiment of the invention, the boronating reagent is added prior to the addition of the starting material of formula IIa. may be added to the reaction zone (optionally with solvent, catalyst and / or ligand pre-added) . In such embodiments, the boronating reagent is reacted with the starting material of Formula IIa prior to addition of the starting material of Formula IIa. The reaction zone (optionally solvent, (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 can be easily purified by the method of step ii. The advantage is that it does not require purification before the i begins. Thus, in an embodiment of the present invention, a purification step is carried out between steps ii and iii. The loop is not executed.

[0130] The advantages of the preparation method of the present invention are 、 Step ii) and at least the start of step iii) The aim is to make it possible to carry out the synthesis in the same reaction space, i.e. as a "one-pot synthesis". Thus, in such an embodiment, step iii) comprises reacting a compound of formula II b The boron compounds of tone Manufacturing The reaction may be initiated in the same reaction region where the reaction was started.

[0131] In step iii, BComp is cytisine ring and the 4-position of The specified substituent R 1 To avoid any misunderstanding, the R 1 Substitution with a single This is not required in the replacement step, but it is desirable, as shown in the following example: This is very achievable.

[0132] In an embodiment of the present invention, in step iii, the final R 1 Substituent is cytisine ring Above Before being placed in 4th place, BComp must first win one or more intermediate R 1 Even if substituted with a substituent good. In an embodiment of the present invention, the intermediate R 1 The substituents are halo, (e.g., bromo, chloro young Successfully iodo), benzyloxypyridine, alkyl esters (e.g. methyl esters ), alkenyl (e.g. vinyl), alkynyl (acetylene), trimethylsilylacetate ethylene, 1,2,3-triazol-1-yl)methyl pivalic acid, cyano, aminomethyl , N-Boc-aminomethyl or (benzyloxy)carbonyl)piperazin-1-yl It may be.

[0133] For simplicity, the boronized compounds of formula IIb may optionally contain one or more intermediate R 1 Complete details of how to obtain each of the compounds of formula I via the substituents are provided herein. will not be stated in. The reason is that those skilled in the art will recognize and understand how such substitutions can be made. Because it seems that way. The following examples are reactions that may be used in this regard: conditions Provide further details on:

[0134] In an embodiment, the preparation method of the present invention ring R above 2 , R 3 and / or R 4 By position It may include the additional step of making the substitution. For example, cytisine ring If substitution at the 3- or 5-position above is required, this can be carried out Such steps may be accomplished using any techniques and reagents known to those of skill in the art. If you require advice on how such substitutions can be made, please see the relevant step. See the following example, which illustrates the group: Additional Additionally or alternatively, the following articles may be included in the specification for further guidance in this regard: Reference can be made to non-patent document 16, which provides the above information.

[0135] Additional Additionally or alternatively, the protecting group is R4 In embodiments where the The method is cytisine ring Position 13- of Deprotecting the nitrogen atom is included. This deprotection step is carried out after completion of step ii and before the start of step iii. This may be done during i or after completion of step iii. Those skilled in the art will be familiar with deprotection techniques. Regarding Ren death Any advice please? If necessary, you can refer to the examples below.

[0136] As can be seen from the above, the preparation method of the present invention provides a long-term synthesis of the above compounds. stomach No need for total synthesis Advantageously, and for the first time, convenient preparation of 4-substituted cytisine analogs from cytisine itself. Manufacturing Tolerate do.

[0137] A further advantage of the present invention is that steps ii and iii do not involve chiral rearrangement of the molecule. , and therefore the preparation method is stereoselective. This provides an additional advantage to the industry, resulting in the formation of a racemic analogue of cytisine. 。

[0138] (Preparation, Administration and Use) Thus, in another aspect of the present invention, pharma- ceutically acceptable compositions are provided, The compositions include any of the compounds described herein, optionally in combination with a pharma- ceutically acceptable carrier, Includes adjuvants or delivery vehicles. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0139] Some of the compounds of the present invention may be used for therapeutic purposes. Free in the form or, where appropriate, pharmacopoeias It will be understood that they can exist as acceptable derivatives or prodrugs thereof. According to the present invention, pharma- ceutically acceptable derivatives or prodrugs include, but are not limited to: A pharma- ceutically acceptable salt, ester, salt of such an ester, or When administered, the compound is as described elsewhere herein, or the Metabolites Remaining Straighten the stock can be provided directly or indirectly 、 This includes any other additions or derivatives.

[0140] As used herein N The term "pharmaceutical acceptable salt" is used in accordance with sound medical judgment. Within the range of 100%, there is no excessive toxicity, irritation, allergic reaction, etc., and the substance can be brought into contact with the tissues of humans or lower animals. suitable for use in a clinical setting and has a reasonable benefit / risk ratio is worth Refers to salt. "Pharmaceutically acceptable salt" means , any salt of the compound of the present invention, or a salt of an ester thereof. So, When administering to the recipient 、 Compounds of the Invention or Inhibitory activity the metabolite Or Residue Can provide direct or indirectly thing, means...

[0141] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., in Non-Patent Document 14, describe pharma- ceutical acceptable salts in detail. , which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention can be prepared from suitable inorganic or organic acids or bases. Origin vinegar This includes those that:

[0142] Examples of pharma- ceutically acceptable, non-toxic acid addition salts include, for example, hydrochloric, hydrobromic, phosphoric, Inorganic acids such as sulfuric acid, perchloric acid, or for example acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid , succinic acid, malonic acid, or other organic acids in Formed or used in industries such as ion exchange Use other methods that are Formed by It is a salt of an amino group.

[0143] Other pharma-ceutically acceptable salts include the following: Adipates, alginates, ascorbates, aspartates, benzenesulfonates nate, benzoic acid salt , bisulfate, borate, butyrate, camphor Acid salts , camphorsulfonate , Citric Acid salt , cyclopentane propionate, digluconate, dodecyl sulfate salt , Eta sulfonate, formate, fumarate, glucoheptonate salt , glycerophosphate salt , Guru Con Acid salts , hemisulfate, heptanoic acid salt , hexanoate, hydroiodide, 2-hydroxy -Ethanesulfonate, lactobionic acid salt , lactic acid salt , lauric acid salt , Lauri Ru sulfur acid salt , Li Salts, maleates, malonates salt , methanesulfonic acid salt , 2-naphthalenesulfonic acid salt , nicotinic acid salt , Nitrate, Oleate, Oxalate, Palmitate blood Phosphoric acid salt , pamoic acid salt , P Cutinate, persulfate, 3-phenylpropionate, phosphate salt , Picrate, Pival acid salt , Propionate, Stearate, Succinate salt, sulfuric acid salt , tartrate, thio S An acid Salt, p-Toluenesulfonic acid salt , undecanoate, valerate, etc.

[0144] From the appropriate base Origin The salts that can be used are alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Alkyl )4Contains salt.

[0145] This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, Contains sodium, magnesium, etc. Further pharma- ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium salts. , and an amine cation, For example, halogen ion , hydroxy acid ion , carboxylic acid ion , sulfuric acid ion ,phosphoric acid ion ,nitric acid ion , lower alkyl sulfonic acid ion , and Ants - R Sulfonic Acid ion It is formed using counterions such as R .

[0146] As noted above, the pharma- ceutically acceptable compositions of the present invention may further comprise a pharma- ceutically acceptable carrier, Adjuvants or delivery vehicles, as used herein, include the following: One and all 、 Solvent, diluent, or other liquid vehicle, dispersion or suspension Muddy correction Auxiliary agents, surfactants , isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., which provide desired characteristics. Suitable for a specific dosage form.

[0147] Non-Patent Document 15 describes pharma- ceutical acceptable compositions and their preparation. Manufacturing Known Technology for Formulation A variety of carriers are disclosed for use in the formulation. For example, compositions that produce undesirable biological effects or are pharma- ceutically acceptable. of Other Any conventional delivery medium may be miscible with the compounds of the present invention, such as by interacting in a deleterious manner with the compounds. Except where incompatible, such use is deemed to be within the scope of the present invention.

[0148] Some examples of materials that can serve as pharma- ceutically acceptable carriers include, but are not limited to, This includes the following: Ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g. as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or sorbitol potassium benzoate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes, e.g. As protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride , zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylic acid rate , wax, polyethylene-polyoxypropylene-block polymer, wool fat, Sugars, e.g. lactose, glucose and saccharose; starches, e.g. corn starch; and potato starch, cellulose and its derivatives, e.g. carboxymethylcellulose Sodium cellulose, ethylcellulose and cellulose acetate, powdered tragacanth, malt, Latin, talc, excipients, e.g. cocoa butter, suppository wax, oil, e.g. peanut corn oil, cottonseed oil, rosemary oil, sesame oil, olive oil, corn oil and soybean oil, propylene glycol or polyethylene glycol; esters, e.g. Ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and phosphate buffer, and other non-toxic compatible lubricants, e.g. Sodium uryl sulfate and magnesium stearate, as well as colorants, release agents, coatings The blender may also add flavorings, sweeteners, flavorings and fragrances, preservatives, and antioxidants. It can exist in things.

[0149] The pharma- ceutical acceptable compositions of the present invention may be administered to humans and animals depending on the severity of the infection being treated. To other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (powder, soft It may be administered intravenously, by ointment or drops, bucally, orally or as a nasal spray, etc. do. In some embodiments, the compounds of the invention can be administered in doses of 100 mg / day to achieve the desired therapeutic effect. From about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg of the subject's body weight Administered orally or parenterally at dosage levels of about 25 mg / kg to about 25 mg / kg, one or more times daily. That's fine.

[0150] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, and the like. Includes emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the industry. Examples include water or other solvents, solubilizers and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, Isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoin Benzyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide oil (especially cottonseed oil, peanut oil) oil ,cone oil ,germ oil ,olive oil , castor oil and sesame oil ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sodium Rubitan fatty acid ester, and Mixtures thereof may also be mentioned. Besides inert diluents, the oral compounds also can contain adjuvants, such as wetting agents, emulsifying and suspending agents, Sweeteners, flavoring agents and aromatic agents may be included.

[0151] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be prepared by suitable dispersion. Agent Alternatively, it may be formulated by known techniques using wetting agents and suspending agents. The sterile injectable preparation may also be prepared using a non-toxic parenterally acceptable diluent or solvent. In Extinction It may also be a sterile injectable solution, suspension or emulsion, for example 1,3-butanediol. It may also be in the form of a solution of 1,000g of ethanol. Acceptable transmission media and solvents used Can Water, Ringer's solution, United States Pharmacopoeia and saline solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. do. In addition, fatty acids such as oleic acid are useful for preparing the injectable material. Manufacturing Used in.

[0152] Injectable preparations should be passed through, for example, a bacteria-retaining filter. vinegar By filtration or by sterilizing with water or other The present invention provides a method for the preparation of a sterile injectable medium comprising the steps of: It may be sterilized by incorporating a bactericidal agent.

[0153] In order to prolong the effect of the compounds of the present invention, it is advisable to slow the absorption of the compounds from subcutaneous or intramuscular injection. It is often desirable to This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. do. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. possible. Alternatively, delayed absorption of a parenterally administered compound form may occur by dissolving the compound in an oil vehicle. This is accomplished by dissolving or suspending. Injectable depot forms include, for example, polylactide-polyglycolide. R In biodegradable polymers such as This is made by forming a microencapsulated matrix of the compound. Depending on the ratio of compound to polymer and the nature of the particular polymer used, The release rate of the can be controlled. other biodegradable Examples of polymers include poly(orthoesters) and poly(anhydrides). nothing. Depot-type injectable formulations can also be formulated into liposomes or microemulsions that are compatible with body tissue. It is prepared by incorporating the compound.

[0154] For rectal or vaginal administration composition The product contains the compound of the present invention. , which is solid at ambient temperature It becomes liquid at body temperature and thus melts in the rectum or vaginal cavity releasing the active compound, e.g. A suitable non-irritating excipient, such as cocoa butter, polyethylene glycol, or a suppository wax. Vehicle or carrierSuppositories that can be prepared by mixing are preferred. stomach .

[0155] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is at least one inactive, It is mixed with a pharma- ceutically acceptable excipient or carrier. Sodium citrate or dicalcium phosphate, and / or a) Fillers or extenders, such as starch, lactose, saccharose, glucose, malate nitritol and silicic acid, b) Binders, such as carboxymethylcellulose, alginates, gels, etc. tin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, e.g. glycerol; d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch. Alginic acid, certain silicates, sodium carbonate, e) Dissolution retarders, e.g. paraffin; f) absorption enhancers, e.g. quaternary ammonium compounds; g) humectants, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clays, and i) lubricants, such as talc, calcium stearate, magnesium stearate; Solid polyethylene glycol, sodium lauryl sulfate 、 and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0156] Solid compositions of a similar type also can be prepared using lactose or milk sugar and high molecular weight polyethylene glycol. Ricoh R Used as a filler for soft or hard filled gelatin capsules with excipients such as It's okay to do that. Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared, for example, with an enteric coating. Coatings and shells such as encapsulating agents and other coatings known in the pharmaceutical formulation industry. It can be formulated as follows. They may optionally contain opacifying agents, which may be used to deliver the active ingredient alone, or preferably to the intestinal The composition may be such that it releases at a predetermined location, optionally in a delayed manner. Can be used Embedded type Examples of compositions include polymerized body Includes substances and waxes. Solid compositions of a similar type also can be prepared using lactose or milk sugar and high molecular weight polyethylene glycol. Used as a filler for soft- or hard-filled gelatin capsules with excipients such as recoase It's okay to do that.

[0157] The active compounds may also be in microencapsulated form using one or more of the excipients noted above. is also good. Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared, for example, with an enteric coating. Coatings such as coatings, controlled release coatings and other coatings known in the pharmaceutical formulation industry. The composition may be formulated using coatings and shells. In such fixed dosage forms, the active compound is, for example, sucrose, lactose or starch. The composition may be mixed with at least one inert diluent. Such dosage forms also, in normal practice, Other than inert diluents, Tableting lubricants, e.g. and tableting aids including magnesium stearate and microcrystalline cellulose. Chase of Canada It may contain substances. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. They may optionally contain opacifying agents, which may be used to deliver the active ingredient alone, or preferably to the intestinal The composition may be such that it releases at a predetermined location, optionally in a delayed manner. Can be used Embedded type Examples of compositions include polymerized body Includes substances and waxes.

[0158] Dosage forms for topical or transdermal administration of the compounds of the present invention may be ointments, pastes, creams, lotions, or the like. ions, gels, powders, solutions, sprays, inhalations Agent or a patch. The active ingredient may optionally be combined with a pharma- ceutically acceptable carrier and any necessary preservatives or It is mixed under sterile conditions with a buffer. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which Body Controlling the delivery of compounds to the body This has the further advantage that Such dosage forms can be prepared by dissolving or dispersing the compound in the proper medium. Absorption enhancers also improve the flux of compounds through the skin. R can be used to increase The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. The amount of heat generated can be controlled by adjusting the amount of heat generated.

[0159] The compounds and pharma- ceutical acceptable compositions of the present invention may be used in combination therapy, i.e., The pharmaceutical acceptable composition may be administered either simultaneously or prior to one or more other desired therapeutic or medical procedures. It will also be appreciated that the present invention may be used in which the therapeutic agent can be administered prior to or after administration. The combination of certain therapies (treatments or procedures) using a combination regimen may provide a desirable therapeutic effect. Treatment and / or treatment Placement , the desired therapeutic effect achieved, Compatibility will take into consideration. The treatment used achieves the desired effect on the same disease (e.g. inventive compound). the product can be administered simultaneously with other drugs used to treat the same disease, or It will also be appreciated that different effects may be achieved (eg, controlling adverse effects). As used herein Further treatment options include , to treat or prevent a particular disease or condition However, it is usually administered R, Known as "appropriate for the disease or condition being treated" It is something .

[0160] The amount of additional therapeutic agent present in the compositions of the present invention may vary depending on the amount of additional therapeutic agent present, including when that therapeutic agent is the only active agent. The amount of the active ingredient will be about the same as would normally be administered in a composition containing the active ingredient. Preferably, In this specification The amount of additional therapeutic agent in the disclosed compositions may vary depending on whether that agent is solely In the range of about 50% to 100% of the amount normally present in the composition as a therapeutically active agent It would be.

[0161] The compounds of the present invention or pharma- ceutical acceptable compositions thereof may also be used in the manufacture of, for example, prostheses, artificial valves, replacements, and the like. The composition is used to coat implantable medical devices such as blood vessels, stents, and catheters. It is okay to be absorbed. Thus, in another aspect, the present invention provides the above compounds in the classes and subclasses herein. The compounds of the invention as outlined above and suitable for coating the implantable devices described above. Carrier A composition for coating an implantable device comprising: Things include.

[0162] In yet another aspect, the present invention provides the above-mentioned compounds in the classes and subclasses herein. The compounds of the present invention as outlined in and suitable for coating the above-mentioned implantable devices. CarrierAn implantable device coated with a composition comprising Vessel include. Overall preparation of suitable coatings and coated implantable devices Manufacturing is a patent document The coating is typically a hydrogel polymer. -, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid and biocompatible polymeric materials such as ethylene vinyl acetate and mixtures thereof.

[0163] The coating is composition Optionally, fluorosilane may be added to provide controlled release characteristics in the formulation. Ko - Suitable topcoats of polysaccharides, polyethylene glycols, phospholipids and combinations thereof It may be further covered. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0164] (key Manufacturing and Examples) (Extraction of (-)-cytisine from the seeds of the sedge) As explained above, the preparation method of the present invention advantageously uses cytisine from the cytisus tree. We start with a naturally occurring compound that can be isolated. Cytisine is commercially available, Those skilled in the art will be familiar with the preparation methods for extracting cytisine from natural sources. However, For The following preparation method of offer vinegar do.

[0165] Powdered salicorn seeds (332 g), dichloromethane (465 ml), methanol ( MeOH) and ammonium hydroxide (59 ml, 35% aqueous solution) were stirred at room temperature for 3 days with mechanical stirring. The mixture was vigorously stirred with a stirrer (400 rpm). The mixture was filtered and the solid material was removed when the filtrate became colorless. The filtrate was washed with dichloromethane (4×200 mL) until 3 M Salt acid (330mL) It was acidified to pH 1 and the mixture was stirred (350 rpm) for 2 h. Separate the two layers , the aqueous layer Ammonium hydroxide (70 mL, 35% aqueous solution) to pH 9 ~ Slowly basify to 10 The mixture was stirred for 2 h and extracted with dichloromethane (10 x 70 mL). together did The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan solid. Cytisine (4.76 g) was obtained. Recrystallization from toluene (5 mL) gave a solid ( -)-Cytisine (4.27 g, 1.3%) was obtained.

[0166] (Addition of a protecting group - N-Boc cytisine (56)) [ka] (-)-Cytisine (6.4 mL) in tetrahydrofuran (135 mL) and water (70 mL) 1g, 33.7mmol) and di-tert-butyl dicarbonate (9.3mL, 40.4mmol) ol) was added to an aqueous solution of sodium carbonate (4.28 g, 40.4 mmol, 1 M ) 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 (3×150 mL). Together The organic layer was washed with brine (15 0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The thing is silica gel Le Flash column chromatography [Dichloromethane / methanol ( 3% methanol)]This was purified by hexane distillation to give 56 (9.10 g, 93%) as a colorless solid. I put it out. [ka] The spectroscopic properties of this compound were consistent with the data available in the literature.

[0167] (Removal of Protecting Groups) As exemplified below, a wide range of 4-substituted cytisine derivatives can be prepared by the process of the present invention. More Manufacturing Such compounds may be protected with tert-butoxycarbonyl (Boc) In the following examples, it is desirable to remove the B group present in the 4-substituted cytisine analogs. The oc protecting group was removed by one of two preparative methods.

[0168] (General Procedure A) The cytisine derivative was dissolved in methanol (0.1 M (substrate concentration) within 0.5 M Dissolved in hydrogen chloride solution The reaction mixture was stirred at room temperature for 72 hours, after which the solvent was removed in vacuo. residue The best Dissolve in a small amount of methanol, and slowly add acetone in a volume 10 times that of methanol. The solution was stirred for 2 hours, after which the precipitate was collected by filtration and washed with cold acetone.

[0169] (General Procedure B) The cytisine derivative was dissolved in dioxane (0.1 M (substrate concentration) of 4.0 M Dissolve in hydrogen chloride solution The reaction mixture was stirred at room temperature for 72 hours, after which the solvent was removed in vacuo. residue of The mixture was dissolved in a minimum amount of methanol, and acetone in an amount ten times the volume of the methanol was slowly added thereto. The solution was stirred for 2 h, after which the precipitate was collected by filtration and washed with cold acetone.

[0170] Example 1 - N-Boc-4-Bpin Cytisine (58) [ka] A Schlenk flask was charged with N-Boc-cytisine, 56 (290 mg, 1.00 mmol), -(iridium-cyclooctadienyl-methoxide) (6.6 mg, 0.01 equiv.), 4,4'-2,2'-di-tert-butylbispyridine (5.4 mg, 0.02 equivalents) and bis(pinacolato)-diborane (177 mg, 0.7 equiv.). Schlenk Place the tube under vacuum and flush with nitrogen three times. Backfill Then, tetrahydrofuran (1.4 mL) and the mixture was heated at 80° C. for 24 h. The mixture was cooled to room temperature and concentrated in vacuo. Purification (see below) is possible but not necessary. The crude reaction mixture did not require further purification. It was used in many later transformations without any modification.

[0171] The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / 58 (100 ml) was purified by elution with 5% methanol (5% methanol) to give a pale orange foam. 80mg, 43%, Silica On An unstable compound, only pure fractions were collected, 1 H- The compound was found to be completely converted by NMR. [ka]

[0172] Example 2a - N-Boc-4-hydroxycytisine (66) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.0 mmol scale in As discussed above in Example 1 General procedure for the boronation of cytisine Prepared according to did.

[0173] The boronation reaction mixture was cooled to 0 °C and dissolved in tetrahydrofuran (8.6 mL). 3 M of sodium hydroxide (1.0 mL, 3.0 mmol) was added, followed by 30% Aqueous hydrogen peroxide (1.0 mL) was added slowly over 5 min. The mixture was stirred at 0° C. for 30 min. The mixture was then stirred at room temperature overnight in air. The mixture was diluted with water (3 mL) and the aqueous layer was The aqueous layer was washed with 3×5 mL of dichloromethane. M Salt acid At pH 4 ~ Acidify to 5 and di Extraction was performed with dichloromethane (5×5 mL). Together The organic layer was dried over sodium sulfate. The crude reaction mixture was purified by flash column chromatography on silica gel. The product was purified by filtration [dichloromethane / methanol (5% methanol)] and turned grayish in color. The resulting mixture was concentrated to yield 66 (240 mg, 79%) as a white solid. [ka]

[0174] Example 2b - (+) 4-Hydroxycytisine Hydrochloride (67) [ka] General Procedure A Follow , an off-white solid was obtained from the alcohol 66 (0.79 mmol). Body alcohol The yield was 67 (184 mg, 96%). [ka]

[0175] Example 3a - N-Boc-4-Methoxycytisine (68) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 0.50 mmol in The above-discussed cytidine derivatives in Example 1 General procedure for the boronation reaction of benzene Prepared according to did.

[0176] Newly acquired Manufacturing Copper(II) sulfate pentahydrate (37 mg, 0.01 mL) in methanol (5 mL) was 0.15mmol), potassium hydroxide (84mg, 1.50mmol) and molecular Table 4 Å A solution of (300 mg) was stirred under nitrogen for 5 hours. Syringe Using The reaction mixture was stirred at reflux under an oxygen atmosphere for 18 hours. The reaction mixture was diluted with 10 mL of methanol, filtered through a pad of Celite, and the solvent was removed under vacuum. The crude product was dissolved in ammonia solution (15 mL, 15% aqueous solution) and dichloromethane (15 The organic phase was extracted with dichloromethane (4 x 15 mL). together death The crude reaction mixture was purified by flash column chromatography. The product was purified by chromatography [dichloromethane / methanol (2% methanol)]. Yield 69 (130 mg, 81%) as a colorless solid. [ka]

[0177] Example 3b - (-) 4-Methoxycytisine (69) [ka] Dichloromethane (4 mL, 0.1 M ) in ether 68 (130 mg, 0.42 To the mixture (1 mmol), trifluoroacetic acid (0.3 mL, 10 equiv.) was added in one portion, and the reaction mixture was heated to room temperature. The mixture was stirred at room temperature for 18 hours. Water (10 mL) was added and the aqueous phase was diluted with dichloromethane (3×10 mL). The aqueous phase was basified with ammonia (10 mL, 15% aqueous solution) and The organic phase was extracted with ethyl acetate (3 × 10 mL). together Then, it was dried over magnesium sulfate and filtered. The mixture was concentrated to afford 69 (76 mg, 85%) as a colorless solid. [ka]

[0178] Example 4a - N-Boc-4-(N-benzylamino)cytisine (70) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 5.00 mmol scale in As described in detail in Example 1 above. General procedure for the boronation of cytisine Prepared according to did.

[0179] In a separate container, prepare copper(I) acetate·water in acetonitrile (20 mL). ( 300mg, 1. 5mmol), potassium fluoride (320mg, 5.5mmol) and molecular sieves 4 Å (4g) 15 ~ The mixture was stirred for 20 min. The crude boronation reaction was dissolved in acetonitrile (5 ml L) Dissolution Then, the copper solution Syringe Freshly distilled water was added to the crude reaction mixture via 100 ml of ethyl acetate and stirred for 10 minutes. Benzylamine (1.1 mL, 10.0 mmol) was added and the reaction mixture was heated under an oxygen atmosphere. Heat at reflux for 18 hours. Cool the reaction mixture and filter through Celite®. The reaction crude was diluted with ammonia (25 mL, 15% aqueous solution) and dichloromethane. (25 mL) and the aqueous phase was extracted with dichloromethane (4×15 mL). Together Ta The organic phase was dried over magnesium sulfate, filtered and concentrated. Purified by column chromatography [dichloromethane / methanol (2% methanol)] The resulting colorless solid 70 (1.70 g, 72%) was inseparable Produced with impurities. [ka]

[0180] Example 4b - (+) 4-(N-benzylamino)cytisine (71) [ka] Dichloromethane (43 mL, 0.1 M A solution of secondary amine 70 (1.70 g, 4 Add trifluoroacetic acid (0.4 mL, 10 equiv.) to a mixture of 1.30 mmol) and heat the solution at room temperature for 1 min. Stir for 6 hours. Water was added (20 mL) and the aqueous phase was washed with dichloromethane (3×30 mL). The aqueous phase was then basified with ammonia (10 mL, 15% aqueous solution) and dichloromethane was added. The mixture was extracted with toluene (4×10 mL). Together The organic layer was dried over magnesium sulfate and filtered. Concentrate and filter to obtain a colorless solid. 71 (970 mg, 76%). [ka]

[0181] (Example 5-(-) 4-(2,2,2-trifluoroethyl)cytisine hydrochloride (79 )) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in Details are given in Example 1 above. General procedure for the boronation of cytisine Prepared according to did. To the crude boronation reaction mixture, tris(dibenzylideneacetone)dipalladium(0)(2 3mg, 1mmol%), 2-dicyclohexylphosphino-2',4',6'-triyl Isopropylbiphenyl (Xphos) (47 mg, 2.5 mmol%), Cesium Fluoride (4 Cuprous chloride (99 mg, 1.0 equiv.) and CuCl (50 mg, 3.0 equiv.) were added, and the mixture was cooled to room temperature. Place the tube under vacuum and flush with nitrogen three times. Backfill The reaction mixture was diluted with N,N-dimethylformamide. N-ethylformamide (4.0 mL, 0.25 M ) and 2,2,2-trifluoroethyl iodide Dissolve in dimethylformamide (0.19 mL, 2.0 equiv.) and add water (0.14 mL, 8.0 equiv.). The reaction mixture was stirred at 65° C. for 18 h. The solvent was removed in vacuo and the crude reaction was dissolved in ethyl acetate. The mixture was partitioned between chilled water (15 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate (3 x 15 mL). The organic phase was together The crude reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. Flash column chromatography of the compound [dichloromethane / methanol (2% methanol)] Purification with 2,2,2-trifluoromethylphenyl) gave a colorless solid, N-Boc-4-(2,2,2-trifluoromethylphenyl)-2,4-difluorophenyl The resulting trifluoro-cytisine was obtained. Syn derivatives Follow General Procedure A Deprotection hand Ligand 79 was converted to its hydrochloride salt to give a colorless solid. (93 mg, 34%). [ka]

[0182] Example 6 - (-) 4-(perfluorophenyl)cytisine hydrochloride (75) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in Details are given in Example 1 above. General procedure for the boronation of cytisine Prepared according to did.

[0183] Bromopentafluorobenzene (0.15 mL, 1.2 eq.), dichlorobis(trifluoroacetate) (phenylphosphine)palladium (35 mg, 0.05 equivalents) and cesium carbonate (410 m g, 2.5 equiv.) was added to the crude boronation reaction and the reaction mixture was diluted with tetrahydrofuran (5 mL, 0.2 M The reaction mixture was dissolved in ammonia (25 mL, 15% aqueous solution) and the aqueous phase was extracted with ethyl acetate (4×25 mL). together death The combined organic phase was dried over magnesium sulfate, the solids were filtered and the solvent was evaporated in vacuo. The crude reaction mixture was subjected to flash column chromatography [dichloromethane / methanol (1 Purification with 0.5% methanol gave a colorless solid, 74 (509 mg, 99%). (Dichlorobis(triphenylphosphine)palladium There is some contamination ) was produced. [ka] General Procedure A Follow , N-Boc protected cytisine derivative 74 (1.1 mmol) from, This yielded 4-(perfluorophenyl)-cytisine hydrochloride 75, a colorless solid. . [ka]

[0184] Example 7a - N-Boc 4-(2-pyridinyl)cytisine (100) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in As described above in Example 1, A general procedure for the boronation of cytisine is described. Prepared according to did.

[0185] Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenyl Palladium (phosphine) (35 mg, 5 mol%) was added to the crude boronation reaction mixture. Dry tetrahydrofuran (10 mL) was added, followed by 2-bromopyridine (115 μL). L, 1.2 mmol) was added. The mixture was stirred at 80° C. for 48 h. The reaction was allowed to warm to room temperature. The mixture was cooled, diluted with ethyl acetate (50 mL) and filtered through Celite®. The organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and filtered. The crude product was purified by flash column chromatography on silica gel [Dicyclohexyl]. 4% methanol + 0.1% ammonia (15% aqueous solution)] Purification afforded 100 (205 mg, 56%) as a yellow oil. was used in the next step without [ka]

[0186] Example 7b - (-) 4-(2-pyridinyl)cytisine dihydrochloride (101) [ka] General Procedure A for the Deprotection of Cytisine in accordance with , N-Boc-4-(2-pyridinyl) -Cytisine 100 (0.55 mmol) from A colorless solid, 101 (99.2 mg, 6 3%). [ka]

[0187] Example 8 - (-) 4-(3-pyridinyl)cytisine dihydrochloride (104) [ka] Fill the Schlenk flask with N-Boc-4-bromo-cytisine 61 (370 mg, 1.0 mmol) ), tris(dibenzylideneacetone)dipalladium(0) (9.0 mg, 1 mmol%) ), tricyclohexylphosphine (7.0 mg, 2.4 mmol%) and 3-pyridyl D Charge with boronic acid (140 mg, 1.1 equiv.), place under vacuum and flush with nitrogen three times. Backf Fil The mixture was diluted with dioxane (2.6 mL, 0.4 M ) and dissolve , Li Tricalcium Phosphate water Solution (360g, 1.7 equivalents, 1.3 M )of Syringe The reaction mixture was added dropwise for 10 minutes or more. The mixture was heated at 100° C. for 18 h. The solution was filtered through Celite and the solvent was removed in vacuo. Ammonia solution (5 mL, 15% aqueous solution) was added and the aqueous phase was diluted with dichloromethane (4× 25 mL). Together The organic phase was dried over magnesium sulfate, filtered and concentrated. The obtained N-Boc-4-(3-pyridinyl)-cytisine derivative was General Procedure A Follow Deprotection hand Conversion to the hydrochloride salt afforded 104 (210 mg, 78%) as a colorless solid. . [ka]

[0188] Example 9a - (-) N-Boc-4-(4-pyridinyl)cytisine (102) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in As described in detail in Example 1 above, General procedure for the boronation of cytisine Prepared according to It was done.

[0189] Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenyl Palladium (phosphine) (35 mg, 5 mol%) was added to the crude boronation reaction mixture. Dry tetrahydrofuran (10 mL) was added, followed by 4-iodopyridine (246 mL). g, 1.2 mmol) was added. The mixture was stirred at 80° C. for 48 hours. The mixture was allowed to warm to room temperature. The mixture was cooled, diluted with ethyl acetate (50 mL) and filtered through Celite®. The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol]. ethanol (5% methanol + 0.1% ammonia (15% aqueous solution)] and The product was then subjected to further purification to yield 102 (312 mg, 85%) as an orange oil. was used in step [ka]

[0190] Example 9b - (-) 4-(4-pyridinyl)cytisine dihydrochloride (103) [ka] General Procedure A in accordance with , N-Boc-4-(4-pyridinyl)cytisine 102 (0.85 mmol) from Yield 103 (122 mg, 48%) as a pale orange solid. [ka]

[0191] Example 10a - N-Boc-4-(4-(2-benzyloxy)pyridine)cytidine 105) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in As detailed above in Example 1 General procedure for the boronation of cytisine Prepared according to It was done.

[0192] Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenyl Palladium (phosphine) (35 mg, 5 mol%) was added to the crude boronation reaction mixture. Dry tetrahydrofuran (5.0 mL) was added, followed by dry tetrahydrofuran (5.0mL )of 4-Bromo-2-benzyloxypyridine (316 mg, 1.2 mmol) l ) melt The mixture was stirred at 80° C. for 48 hours. The solution was cooled to room temperature and ethyl acetate was added. The organic layer was diluted with chill (50 mL) and filtered through Celite®. mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane The mixture was purified with ethanol / methanol (4% methanol + 0.1% ammonia (15% aqueous solution)]. The product was a pale yellow oil, and yielded 105 (485 mg, 99%) with almost no impurities. The product was used in the next step without further purification. [ka]

[0193] Example 10b - (+) 4-(4-(2-pyridone)) cytisine hydrochloride (106) [ka] N-Boc 4-(4-(2-benzyloxy)pyridine) in methanol (5.7 mL) ) to a solution of cytisine 105 (448 mg, 0.95 mmol), dark salt acid (2.9m L) of The mixture was heated at reflux for 24 h. After cooling to room temperature, the solvent was removed in vacuo. The crude product was dissolved in methanol (55 mL). Dissolution Then, acetone (550 mL) was added. The mixture was stirred for 2 hours. The solid was filtered, washed with acetone, and dried to give 1, a pale yellow solid. The yield was 06 (254 mg, 84%). [ka]

[0194] Example 11 - (-) N-Boc-4-chlorocytisine (59) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in As outlined in Example 1 above General procedure for the boronation of cytisine Prepared according to It was done.

[0195] The crude boronation reaction mixture was dissolved in methanol (2.5 mL). Dissolved in Water (2.5 mL )of salt Copper chloride (470 mg, 3.5 mmol ) melt The mixture was then left in air at room temperature for 4 days. The mixture was diluted with ammonium hydroxide (10 mL, 15% aqueous solution) and the aqueous phase was Extraction was performed with dichloromethane (3×10 mL). Together The organic layer was dried over sodium sulfate. The crude material was purified by flash column chromatography on silica gel. The mixture was purified with ethyl acetate to give 59 (247 mg, 76%) as an off-white solid. ) was produced. [ka]

[0196] Example 12 - (-) 4-Chlorocytisine (60) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in As outlined above in Example 1 General procedure for the boronation of cytisine Prepared according to It was done.

[0197] In a sealed tube, the crude boronation reaction mixture was diluted with methanol (2.5 mL). Dissolution Copper chloride Aqueous solution of (470 mg, 3.5 mmol, 1.4 M The reaction was heated at 90°C for 18 hours. The reaction was stirred for 1 h. cooling and diluting with ammonium hydroxide (5 mL, 15% in water) The aqueous phase was extracted with dichloromethane (5×5 mL). Together The organic layer was concentrated in vacuo . Residue residue 3 M Salt acid (5 mL) and dichloromethane (5 mL). Wash with methane (2 × 5 mL) Concentrated Water Ammonium oxide solution At pH 10 To Basify and di Extraction was performed with dichloromethane (5×5 mL). Together The organic layer was dried over sodium sulfate. The crude reaction mixture was subjected to flash column chromatography on silica gel. The mixture was purified with raffin [dichloromethane / methanol / ammonia (89:10:1)] and ash was The yield was 60 (179 mg, 80%) as a pale yellow solid. The compound was obtained by recrystallization in toluene. [ka]

[0198] Example 13a - (-) N-Boc-4-iodocytisine (64) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 5.00 mmol scale in Details are given in Example 1 above. General procedure for the boronation of cytisine Prepared according to It was done. Copper(II) nitrate trihydrate (2.4 2g , 10.0 mmol), You Ammonium chloride (1 .45g, 10.0mmol) and molecular sieve 4 Å (500mg) was crude boronized The reaction mixture was added to the Schlenk tube, which was placed under nitrogen and flushed with oxygen three times. Backfill Reaction The mixture was diluted with N,N-dimethylformamide (25 mL )in Dissolve and heat at 80°C for 24 hours. The solvent was removed in vacuo and the residue residue Dichloromethane In The mixture was dissolved in ammonia (3 0 mL, 15% aqueous solution) and the aqueous phase was extracted with dichloromethane (4 x 25 mL). . Together The organic layer was dried over magnesium sulfate, filtered, concentrated, and the crude product was flash-treated. Purified by column chromatography [dichloromethane / methanol (2% methanol)] This afforded the iodide 64 (1.99 g, 95%) as a yellowish solid. [ka]

[0199] Example 13b - (+) 4-Iodocytisine Hydrochloride (65) [ka] General Procedure A in accordance with , N-Boc-4-iodocytisine 64 (0.68 mmol) from Yield 65 (0.18 g, 86%) as a colorless solid. [ka]

[0200] (Example 14a-(-) N-Boc-4-trifluoromethylcytisine (76)) [ka] The Schlenk flask was filled with N-Boc-4-iodocytisine 64 (2.08 g, 5 mmol), Copper uride (4.52g, 23.7mmol), anhydrous Potassium fluoride M( 1.38g, 23.7 mmol) and trimethyl(trifluoromethyl)silane (3.5 mL, 23.7 mmol) The mixture was charged with N,N-dimethylformamide (24 ml) and the reaction mixture was placed under nitrogen. L, 0.2 M ) was added and the reaction mixture was stirred at 50° C. for 16 h. The solvent was removed in vacuo. , remainder residue Partition between dichloromethane (20 mL) and ammonia (20 mL, 15% aqueous solution). The aqueous phase was extracted with dichloromethane (3 x 20 mL). Together The organic phase was dissolved in magnesium sulfate. The crude reaction was dried over silica gel, the solid was filtered and the solvent was evaporated in vacuo. Purification by column chromatography [ethyl acetate / n-hexane (4:1)] gave a colorless The resulting mixture was concentrated to give 76 (1.52 g, 85%) as a solid. [ka]

[0201] (Example 14b-(-) 4-Trifluoromethylcytisine hydrochloride (77)) [ka] General Procedure A in accordance with , N-Boc-4-trifluoromethylcytisine 76 (0.28m mol) from Yield 77 (55 mg, 77%) as a colorless solid. [ka]

[0202] Example 15a-N-Boc-4-bromocytisine (61) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 5.00 mmol scale in Details are given in Example 1 above. General procedure for the boronation of cytisine Prepared according to It was done.

[0203] The crude boronation reaction mixture was dissolved in methanol (12.5 mL). Dissolution and cooled to 0°C. Water (12.5mL )of Copper(II) bromide (3.35g, 15.0mmol ) melt Leave the liquid for more than 5 minutes The ice bath was removed after 30 min and the reaction mixture was allowed to stand at room temperature in the flask in the open air for 2 days. The mixture was diluted with ammonium hydroxide (25 mL, 15% aqueous solution) and the aqueous phase was Extracted with dichloromethane (3×50 mL). Together The organic layer was dried over sodium sulfate. The crude material was purified by flash column chromatography on silica gel. The mixture was purified with ethyl acetate to give 61 (1.54 g, 83 %) was produced. [ka]

[0204] Example 15b - (-) 4-Bromocytisine (62) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-cytisine 58, 1.00 mmol scale in As detailed above in Example 1, General procedure for the boronation of cytisine Prepared according to It was done.

[0205] In a sealed tube, the crude boronation reaction mixture was dissolved in methanol (2.5 mL ) And water (2 .5mL )of Copper(II) bromide (670mg, 3.0mmol ) melt The mixture was stirred for 8 hours. The mixture was heated at 0° C. overnight. The mixture was cooled and washed with ammonium hydroxide (5 mL, 15% aqueous solution). It was diluted and extracted with dichloromethane (5×5 mL). Together The organic layer was concentrated in vacuo. The crude product was M Salt acid (5 mL) and dichloromethane (5 mL). Wash with dichloromethane (2 x 5 mL) Concentrated Water Ammonium oxide aqueous solution Basic up to pH 10 The mixture was concentrated and extracted with dichloromethane (5×5 mL). Together The organic layer was washed with sodium sulfate It was dried, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel. Graphology [dichloromethane / methanol / ammonium hydroxide (89:10:1)] Purification gave bromide 62 (228 m g, 85%). A pure sample was obtained by recrystallization in toluene. [ka]

[0206] Example 16a - N-Boc-4-aminocytisine (80) [ka]

[0207] (Method A) In a Schlenk tube, N-Boc-4-bromobenzene was dissolved in ethanol / water (7:3) (5 mL). bromo-cytisine 61 (184 mg, 0.5 mmol), sodium azide (65 mg, 1 .0 mmol), copper(I) iodide (9 mg, 10 mol%), L-proline (17 mg, A mixture of sodium hydroxide (6 mg, 30 mol%) and sodium hydroxide (6 mg, 30 mol%) was heated at 95°C overnight. The mixture was cooled and partitioned between water and dichloromethane. The aqueous layer was diluted with dichloromethane (2× 10 mL). Together The organic layer was washed with brine, dried over sodium sulfate, The crude material was purified by flash column chromatography on silica gel. Purify with [dichloromethane / methanol / ammonium hydroxide (89:10:1)] and ash Yield amine 80 (116 mg, 76%) as an off-white solid.

[0208] (Method B) In a sealed tube, dark Ammonium hydroxide aqueous solution (0.5mL ) inside N-Boc-4-bromo Bromo-cytisine 61 (92 mg, 0.25 mmol) and copper (2 mg, 10 mol%) The mixture was stirred at 100° C. for 24 h. The mixture was cooled and washed with dichloromethane (5×5 mL). Extraction was carried out. Together Dry the organic layer over sodium sulfate, filter and concentrate in vacuo. The crude product was purified by flash column chromatography on silica gel [dichloromethane / methanol]. ethanol / ammonium hydroxide (89:10:1) to give an off-white solid. The yield was 80 (64 mg, 85%). [ka]

[0209] Example 16b - (+) 4-Aminocytisine dihydrochloride (81) [ka] General Procedure A in accordance with , N-Boc-4-amino-cytisine 80 (1.0 mmol) from Yield amine 81 (273 mg, 98%) as an off-white solid. [ka]

[0210] Example 17 - (-) 4-Fluorocytisine (82) [ka] N-Boc-4-amino- in HF-pyridine complex (70%, 2.0 mL) at -20 °C A solution of cytisine 80 (305 mg, 1.0 mmol) was added to tert-butyl sulfite (0. 18 mL, 1.5 mmol) was added slowly over 1 min. The reaction was stirred at -20 °C for 30 min. The mixture was then warmed to room temperature for 2 hours and finally heated at 60° C. overnight. Cool and Concentrated Water Use ammonium oxide solution to reduce pH to 10 Quench The mixture was diluted with vinegar. The aqueous layer was diluted with ethyl acetate (4 mL) and filtered to remove insoluble salts. × 10 mL). together The organic layer was concentrated in vacuo. M Salt acid (5 mL) and dichloromethane (5 mL). The aqueous layer was partitioned between dichloromethane (2 × 5 mL ) and washed with Concentrated Water Ammonium oxide aqueous solution The solution was basified to pH 10 with dichloromethane. The mixture was extracted using 5×5 mL of ethanol. Together The organic layer was dried over sodium sulfate. The crude material was purified by flash column chromatography on silica gel. Purified with [dichloromethane / methanol / ammonium hydroxide (89:10:1)] Recrystallization in toluene afforded 82 (140 mg, 67%) as a pale yellow solid. This resulted in an analytically pure sample. [ka]

[0211] Example 18a - N-Boc-4-(N-methylamino)cytisine (83) [ka] In a sealed tube, N-Boc-4-bromobenzene was dissolved in 2.0 mL of 40% aqueous methylamine. Bromo-cytisine 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 diluted with dichloromethane (5× Extraction was carried out with 10 mL of ethyl acetate. together The organic layer was dried over sodium sulfate, filtered, and purified. The crude product was purified by flash chromatography on silica gel [dichloromethane / methanol (94:6)] to produce an off-white color Solid 83 (274 mg, 86 %) was produced. [ka]

[0212] Example 18b - (+) 4-(N-methylamino)cytisine dihydrochloride (84) [ka] General Procedure A in accordance with , 4-N-methylamino-N-Boc-cytisine 83 (0.77m mol) from Amine 84 (190 mg, 85%) was yielded as a colorless solid. [ka]

[0213] Example 19a - N-Boc-4(N,N'-dimethylamino)cytisine (85) [ka] In a sealed tube, N-Boc-4- Bromo-cytisine 61 (369 mg, 1.0 mmol) and copper (6 mg, 10 mol%) The mixture was stirred at 100° C. for 24 h. The mixture was cooled and 35% ammonia (2 mL ) and the aqueous phase was extracted with dichloromethane (5×10 mL). Together Sulfurize the organic layer The crude reaction mixture was washed with water, dried over sodium hydroxide, filtered and concentrated in vacuo. Press column chromatography [dichloromethane / methanol / ammonium hydroxide ( 94.5:5:0.5)] to yield 85 (212 mg, 64%) as a white foam. did. [ka]

[0214] (Example 19b - (+) 4-(N,N'-dimethylamino)cytisine dihydrochloride (86 )) [ka] General Procedure A in accordance with , N-Boc-4-N,N'-dimethylamino-cytisine 85 (2 02mg, 0.61mmol) from The yield was amino 86 (174 mg, 93%). [ka]

[0215] Example 20a - N-Boc-4-(N-benzoylamino)cytisine (95) [ka] N-Boc-4-bromo-cytisine 61 (369 mg) in dry toluene (5.0 mL) , 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), benzamide (14 5 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol). Then, N,N'-dimethylethylenediamine (11 μL, 10 mol%) was added. 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 diluted with dichloromethane (HCl). Extracted with methane (5×10 mL). Together The organic layer was dried over sodium sulfate and filtered. The crude reaction mixture was purified by flash column chromatography on silica gel. Purified with dichloromethane / methanol / ammonium hydroxide (95:5:0.1). This gave 95 (425 mg) as a yellow solid. The resulting solid was dissolved in boiling toluene and concentrated. (10 mL) overnight to afford 95 (372 mg, 91%) as a colorless solid. . [ka]

[0216] Example 20b - (+) 4-(N-benzoylamino)cytisine hydrochloride (96) [ka] General Procedure B in accordance with , N-Boc-4-(N-Benzene) Z Amide)-Cytisine 95(363 mg, 0.89 mmol) from Ben, a colorless solid Z Amide 96 (290 mg, 80 %) was produced. [ka]

[0217] Example 21a - N-Boc-4-(N-acetylamino)cytisine (93) [ka] N-Boc-4-bromo-cytisine 61 (369 mg) in dry toluene (5.0 mL) , 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), acetamide (70 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol), N,N'-Dimethylethylenediamine (11 μL, 10 mol%) was added. The mixture was The mixture was heated at 10° C. for 24 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and This was followed by extraction with dichloromethane (5×10 mL). Together The organic layer was washed with sodium sulfate. The crude material was purified by flash column chromatography on silica gel. Chromatography [Dichloromethane / Methanol / Ammonium Hydroxide (95:5:0.1 )] and purified to give a pale yellow foam with almost no impurities, 93 (340 mg, 98%). The product was used in the next step without further purification. [ka]

[0218] Example 21b - (+) 4-(N-acetylamino)cytisine (94) [ka] General Procedure B in accordance with , N-Boc-4-(N-acetamido)cytisine 93 (306m g, 0.88 mmol) from This yielded 94 (250 mg, quantitative) as a pale yellow solid. . [ka]

[0219] Example 22 - (+) 4-N-morpholinecytisine dihydrochloride (92) [ka] The sealed tube was filled with N-Boc-4-bromo-cytisine 61 (370 mg, 1.0 mmol). , charged with copper(II) oxide (15 mg, 0.1 equiv.) and morpholine (0.4 mL, 5 equiv.). The reaction mixture was diluted with water (2.0 mL, 0.5 M ) and is dissolved at 100°C under air for 1 The reaction mixture was cooled to room temperature and the aqueous phase was diluted with dichloromethane (4×25 mL). was extracted. together The organic phase was dried over magnesium sulfate, filtered and concentrated. The N-Boc protected cytisine derivative was Follow General Procedure A Deprotection hand Converted to hydrochloride and no The yield was 92 (180 mg, 85%) as a colored solid. [ka]

[0220] Example 23a - N-Boc-4-(N-(L-proline methyl ester)cytisine (136) [ka] N-Boc-4-bromocytisine 61 (369 mg, 1.0mmol), L-proline methyl ester hydrochloride (198mg, 1.2mmol) , cesium acetate (814 mg, 2.5 mmol), palladium(II) acetate (11 mg, 5mol%) and (±)-binap (BINAP) (44 mg, 7 mol%) mixture The mixture was stirred at 0° C. for 48 hours. The mixture was cooled to room temperature and short Celite pad (Registered trademark )of The crude material was filtered through ethyl acetate, washed with ethyl acetate and concentrated in vacuo. Press column chromatography [dichloromethane / methanol / ammonium hydroxide ( 95:5:0.1)] and is an off-white foam with almost no impurities. The yield was 136 (371 mg, 89%). [ka]

[0221] Example 23b - (+) 4-(N-(L-proline methyl ester) cytisine dihydrochloride Salt (137) [ka] General Procedure B in accordance with , N-Boc-4-(N-(L-proline methyl ester)-cysteine Synth 136 (0.88 mmol) from 137 (304 mg, 89%) was obtained as a colorless solid. It was born. [ka]

[0222] Example 24-(-) 4-(N-(L-proline)cytisine dihydrochloride (138)) [ka] salt Acid (3 7% aqueous solution N-Boc-4-(N-(L-proline methyl ester) A mixture of 138 (341 mg, 0.82 mmol) and 139 (1.0 mmol) of cytisine 138 was refluxed for 48 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude was dissolved in methanol (4 mL ) Dissolved inThen, acetone was slowly added (40 mL). The resulting suspension was stirred for 1 h. The solid was filtered, washed with acetone, and dried under vacuum to give 138 ( The yield was 261 mg (85%). [ka]

[0223] Example 25a—N-Boc-4-(carboxymethyl)cytisine (119) [ka] N-Boc-4 in N,N-dimethylformamide / methanol (1:1) (5 mL) -Bromo-cytisine 61 (369 mg, 1.0 mmol), triethylamine (0.4 m L, 2.5 mmol), 1,3-bis(diphenylphosphino)propane (82 mg, 0 A solution of palladium(II) acetate (45 mg, 0.2 mmol) and palladium(II) acetate (45 mg, 0.2 mmol) was added to 80 The mixture was stirred at 1 atm of carbon monoxide for 24 h at 20 °C. The mixture was cooled to room temperature and filtered through a Celite ( The crude material was purified by filtration through a silica gel flash column. Purification by chromatography [ethyl acetate] gave 119 (300 mg, 86%). [ka]

[0224] Example 25b - (-) 4-Carboxymethylcytisine (120) [ka] N-Boc-4-methyl-ester-cytisine 11 in dichloromethane (1.3 mL) A solution of 9 (95 mg, 0.27 mmol) was diluted with trifluoroacetic acid (0.21 mL, 2.7 mM The mixture was stirred for 24 h and then concentrated in vacuo. M of salt acid (5 mL) and dichloromethane (5 mL). The aqueous layer was diluted with dichloromethane (2× 5 mL), basified to pH 9 with sodium carbonate, and then dichloromethane (5 × 5 mL). together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Concentration at 37° C. afforded 120 (55 mg, 81%) as an off-white solid. An analytically pure sample was obtained by recrystallization in toluene. [ka]

[0225] (Example 26-(-) 4-Cytisine Carboxylic Acid Hydrochloride (229)) [ka] salt acid N-Boc-4-methyl-ester-cytisine in water (37% in water, 7.5 mL) A solution of 119 (263 mg, 0.75 mmol) was heated at reflux for 24 h. The crude reaction mixture was diluted with methanol (30 mL) and concentrated in vacuo. Dissolution Then acetone was slowly added (300 mL). The resulting suspension was stirred for 1 h. The solid was filtered, washed with acetone and dried under vacuum to give 229 (164 mg, 81%). [ka]

[0226] Example 27a - N-Boc-4-(hydroxymethyl)cytisine (121) [ka] N-Boc-4-methyl ester-cytisine 119 in tetrahydrofuran (4 mL) (350 mg, 1.00 mmol) was added to a solution of lithium aluminum hydroxide (diethyl ether Teru, 1.0 M ) was added dropwise at -78°C for 5 minutes and the reaction mixture was stirred for 3.5 hours. Ethyl acetate (2 mL) was added dropwise, followed by saturated Rochelle's salt solution (10 mL). The reaction mixture was stirred for 30 min and the aqueous phase was extracted with ethyl acetate (3×25 mL). together did The organic phase was dried over magnesium sulfate, filtered and concentrated. Flash column chromatography Raffinate [dichloromethane / methanol (2% methanol to 5% methanol)] Purification afforded 121 (194 mg, 62%) as a colorless foam. [ka] No quaternary carbon of the Boc group was found.

[0227] Example 27b - (-) 4-(hydroxymethyl)cytisine hydrochloride (122) [ka] General Procedure A in accordance with , N-Boc-4-hydroxymethylcytisine 121 (0.60m mol) from This yielded the alcohol 122 (120 mg, 90%) as a colorless solid. [ka]

[0228] Example 28a -N-Boc-4-(4-(trifluoromethyl)benzyl)oxy Cytisine (123) [ka] Dry tetrahydrofuran (7.5 mL )of Alcohol 121 (240 mg, 0.75 m Mol ) melt Sodium hydride (33 mg, 1.1 equivalents, 60% dispersion in mineral oil) was added to the solution. The mixture was stirred at 0° C. After 30 min, tetrabutylammonium iodide (14 mg , 0.05 equiv.) and 4-(trifluoromethyl)benzyl bromide (358 mg, 2 equiv.) The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was diluted with water (10 mL). Quench The aqueous phase was then extracted with ethyl acetate (3×15 mL). together The organic layer was diluted with sulfuric acid. The crude reaction mixture was washed with silica gel, dried over magnesium, filtered and concentrated in vacuo. The mixture was purified by column chromatography [dichloromethane / methanol (1% methanol)]. The product was purified to give 123 (250 mg, 71%) as a colorless solid, which was purified without further purification. was used in the next step without [ka]

[0229] (Example 28b-(-) 4-(4-(trifluoromethyl)benzyl)oxythiocyanate N(124) [ka] Ether 123 (0.25 g, 0.52 mmol) was converted to the hydrochloride salt using general procedure A. to afford 124 (110 mg, 60%) as a colorless solid. [ka]

[0230] Example 29a - N-Boc-4-methylcytisine (109) [ka] N-Boc-4-bromo-cytisine 61 (369 mg) in dry toluene (5.0 mL) , 1.0 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg To a mixture of 5 mol% tetramethyltin (0.35 mL, 2.5 mmol) was added The mixture was stirred under nitrogen at 100° C. for 24 h. The mixture was cooled to room temperature and The mixture was filtered through ethyl acetate (50 mL) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel [dichloromethane / methanol The resulting pale yellow solid 109 (308 The yield was 1.2 mg (quantitative). [ka]

[0231] Example 29b - (-) 4-Methylcytisine hydrochloride (110) [ka] General Procedure A in accordance with , N-Boc-4-methylcytisine 109 (1.40 mmol) A more colorless solid 110 (337 mg, quantitative) was obtained. [ka]

[0232] (Example 30a-(-) N-Boc-4-vinylcytisine (115)) [ka] N-Boc-4-bromo-cytisine 61 in dioxane / water (8:2) (5.0 mL) (369mg, 1.0mmol), 2,4,6-trivinylcyclotriboroxane pyridinyl complex (194 mg, 1.2 mmol), potassium carbonate (276 mg, 2.0 mmol) and and 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 The organic layer was filtered through a filter paper (Trademark) and washed with ethyl acetate (50 mL). , washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol]. The mixture was purified with 100% methanol (97:3)] to give 115 (271 mg, 86%) as a pale yellow foam. which was used in the next step without further purification. [ka]

[0233] Example 30b - (+) 4-Vinylcytisine Hydrochloride (116) [ka] General Procedure B in accordance with , N-Boc-4-vinyl-cytisine 115 (271 mg, 0.8 6mmol) from Yield 116 (214 mg, 99%) as a colorless solid. [ka]

[0234] Example 31a-N-Boc-4-ethylcytisine (117) [ka] Methanol (22 mL )of 4-Vinyl-N-Boc-cytisine 115 (353 mg, 1 .1mmol ) melt Palladium / carbon 10% w / w (35 mg) was added to the solution. Place under vacuum and rinse with hydrogen three times. Backfill The mixture was heated under 1 atm of hydrogen for 24 hours. The mixture was filtered through Celite® and diluted with ethyl acetate (50 1 mL) and concentrated in vacuo to give 117 (337 mg, 95%). [ka]

[0235] Example 31b - (-) 4-Ethylcytisine hydrochloride (118) [ka] General Procedure A in accordance with , N-Boc-4-ethyl-cytisine 117 (0.92 mmol) from 118 was obtained as a colorless solid (227 mg, 97%). [ka]

[0236] Example 32a-N-Boc-4-p-tolylcytisine (72) [ka] Fill the Schlenk flask with N-Boc-4-bromo-cytisine 61 (370 mg, 1.0 mmol) ), potassium carbonate (250 mg, 1.8 equiv.), tetrakis(triphenylphosphine) Palladium(0) (58 mg, 5 mol%) and 4-methylphenylboronic acid (160 m g, 1.2 equiv.) and add a mixture of diethyl ether / water (5:1, 10 mL). The reaction mixture was heated at 80° C. for 18 h. The solution was cooled and the solvent was removed in vacuo. The crude reaction was partitioned between water (15 mL) and dichloromethane (15 mL) and the aqueous phase was The mixture was extracted with ethanol (3×15 mL). together The organic phase was dried over magnesium sulfate and filtered. The crude reaction mixture was purified by flash column chromatography [dichloromethane / Purification with methanol (1.5% methanol) afforded 72 as a colorless solid. The crude material was recrystallized in hot toluene to give 72 (260 mg, 71 %) was produced. [ka]

[0237] Example 32b - (+)4-p-Tolylcytisine (73) [ka] In a Schlenk tube, N-Boc-4-p-tolyl-cytisine 72 (270 mg, 0.7 1 mmol) in dichloromethane (7.0 mL) and trifluoroacetic acid (0.3 mL , 10 equiv.) was added. The reaction mixture was stirred at room temperature for 18 h. Then, water (10 mL) was added to the reaction mixture and the aqueous phase was washed with dichloromethane (3×15 mL). Monia solution (20 mL, 15% aqueous solution) was added and the aqueous phase was diluted with dichloromethane (3 × 15 mL). was extracted. togetherThe organic phase was dried over magnesium sulfate, filtered and concentrated to a colorless solution. Recrystallization of the product in hot toluene afforded 73 (140 mg, 74%) as a solid. Conversion to 73 gave 73 (73 mg, 40%) as a colorless solid. [ka]

[0238] Example 33a - N-Boc-4-(N-2-pyridone)cytisine (107) [ka] N-Boc-4-bromo-cytisine 61 (369 mg) in dry toluene (5.0 mL) , 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), 2-hydroxypyridine gin (114 mg, 1.2 mmol) and potassium carbonate (277 mg, 2.0 mmol) To the solution was added N-N'-dimethylethylenediamine (22 μL, 20 mol%). The mixture was heated under nitrogen at 110° C. for 24 h. Copper(I) iodide (19 mg, 1 0 mol%) and N-N'-dimethylethylenediamine (DMEDA) (22 μL, 20 mol%) was added and the mixture was stirred for 36 hours. After cooling, the mixture was diluted with ethyl acetate (50 mL). The organic layer was diluted with ammonium hydroxide ( 2×10 mL, 15% aqueous solution). together The aqueous layer was diluted with dichloromethane (5 × 10 The mixture was extracted with 1 mL. together The organic layer (ethyl acetate and dichloromethane) was dissolved in sodium sulfate. The crude reaction mixture was dried over ice, filtered and concentrated in vacuo. The product was purified by column chromatography [dichloromethane / methanol (95:5)] to give a pale yellow color. The resulting product was 107 (336 mg, 88%), which was then subjected to the next step without further purification. was used. [ka]

[0239] Example 33b - (-) 4-(N-2-pyridone)cytisine hydrochloride (108) [ka] General Procedure B in accordance with , N-Boc-4-(N-2-pyridone)-cytisine 107 (28 9 mg, 0.75 mol) from 108 (182 mg, 76%) as a pale orange solid was produced. [ka]

[0240] Example 34a - N-Boc-4-(trimethylsilylacetylene)cytisine (125 )) [ka] N-Boc-4-bromo-cytisine 61 in dry tetrahydrofuran (10.0 mL) (369 mg, 1.0 mmol), copper(I) iodide (19 mg, 10 mol%) and dichloromethane A solution of triphenylphosphine palladium (35 mg, 5 mol%) was added to Isopropylamine (0.42 mL, 3.0 mmol) followed by trimethylsilylacetate Len (0.16 mL, 1.1 mmol The mixture was then incubated at room temperature under nitrogen for 24 hours. The mixture was diluted with dichloromethane (50 mL). The organic layer was extracted with ammonium chloride. Wash with methanol (10 mL, saturated solution), brine (10 mL), dry over sodium sulfate, and filter. The crude product was purified by flash column chromatography on silica gel [ ethyl acetate] and purified. (Palladium catalyst) Most of Light Dark brown foam The product was used in the next step without further purification to yield 125 (406 mg, quantitative). was used. [ka]

[0241] Example 34b - N-Boc-4-(acetylene)cytisine 126) [ka] N-Boc-4-( A solution of (trimethylsilylacetylene)-cytisine 125 (379 mg, 0.98 mmol) To the solution was added potassium carbonate (270 mg, 1.96 mmol). The mixture was stirred for 24 hours. Water was added (10 mL) and the aqueous phase was extracted with dichloromethane (3×20 mL). together To The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel. Purify the impurities by flash column chromatography on gel [ethyl acetate] (Para Catalyst) Most of White The product was a colored solid, 126 (275 mg, 89%). The product was used in the next step without further purification. [ka]

[0242] Example 34c - (-) 4-(acetylenyl)cytisine hydrochloride (127) [ka] General Procedure B in accordance with , N-Boc-4-(acetylene)cytisine 126 (0.77 Milli moles from 127 (150 mg, 78%) was obtained as a pale yellow solid. [ka]

[0243] Example 35a - N-Boc-4-(phenylacetylene)cytisine (128) [ka] N-Boc-4-bromocytisine 61 (3 69 mg, 1.0 mmol), copper(I) iodide (38 mg, 20 mol%) and dichloro A mixture of bis(triphenylphosphine)palladium (70 mg, 10 mol%) was Isopropylamine (0.42 mL, 3.0 mmol), followed by phenylacetylene (0 The mixture was stirred at room temperature under nitrogen for 24 hours. The mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with ammonium chloride (10 mL). , saturated solution), brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo The crude product was purified by flash column chromatography on silica gel [ethyl acetate] Refining and removing impurities (Palladium catalyst) Most of Light 128(3 Yield: 76 mg, 96%). The product was used in the next step without further purification. [ka]

[0244] Example 35b - (+) 4-(Phenylacetylene)cytisine Hydrochloride (129) [ka] General Procedure B in accordance with , N-Boc-4-(phenylacetylene)cytisine 128 (0. 88 Milli moles from 129 (267 mg, 92%) was obtained as a pale yellow solid. [ka]

[0245] Example 36a - N-Boc-4-(E-2-propenoic acid methyl ester) Cytisine (111) [ka] N-Boc-4-bromocytisine 61 (369 mg) in dry dioxane (5.0 mL) , 1.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (12 m g, 2.5 mol%) was added to a mixture of N,N-dicyclohexylmethylamine (0.2 mL , 1.1mmol), tri-tert-butylphosphine (dioxane solution 0.1 M , 0 .5mL, 5mol%) and ethyl acrylate (0.2mL, 2.0mmol) were added. The mixture was stirred at room temperature under nitrogen for 24 hours. Tris(dibenzylideneacetone) Dipalladium(0) (12 mg, 2.5 mol%), tri-tert-butylphosphine (Dioxane solution 0.1 M , 0.50 mL, 5 mol%) and ethyl acrylate (0.2 HCl (mL, 2.0 mmol) was added again and the mixture was stirred for an additional 24 h. The crude was filtered through silica gel, washed with ethyl acetate and concentrated in vacuo. Flash column chromatography [dichloromethane / methanol (97:3 )] to afford 111 (321 mg, 83%) as a pale yellow solid. [ka]

[0246] (Example 36b - (+) 4-(E-2-propenoic acid methyl ester) Cytisine hydrochloride (112) [ka] General Procedure B in accordance with , 111 (1.00 mmol) from 112(3 00mg, 92%). [ka]

[0247] Example 37a-N-Boc-4-(E-(2-phenylethenyl))cytisine(1 13) [ka] N-Boc-4-bromo-cytisine 61 (369 mM) in dry dioxane (5.0 mL) g, 1.0 mmol) and tris(dibenzylideneacetone)dipalladium(0)(12 A mixture of N,N-dicyclohexylmethylamine (0.2 mg, 2.5 mol%) , 1.1mmol), tri-tert-butylphosphine (dioxane solution 0.1 M , 0 0.50 mL, 5 mol%) and styrene (0.2 mL, 2.0 mmol) were added. The mixture was stirred at room temperature under nitrogen for 24 hours. Dium(0) (12 mg, 2.5 mol%), tri-tert-butylphosphine (di Kisan solution 0.1 M , 0.50 mL, 5 mol%) and styrene (0.2 mL, 2.0 m mol) was added again and the mixture was stirred for another 24 h. The mixture was then filtered through Celite® The crude was filtered through silica gel, washed with ethyl acetate and concentrated in vacuo. The extract was purified by column chromatography [dichloromethane / methanol (97:3)] to give a pale yellow color. The product was subjected to further purification without yielding 113 (373 mg, 95%) as a yellow foam. was used in step [ka]

[0248] Example 37b --(+)4-(E-(2-phenylethenyl))cytisine hydrochloride (1 14) [ka] General Procedure B in accordance with , 113 (0.88 mmol) from It is an off-white solid The yield was 114 (259 mg, 89%). [ka]

[0249] Example 38a - N-Boc-4-(1-(4-phenyl)-NH-1,2,3-trimethylsilyl) Azolyl)cytisine (134) [ka] N-Boc-4-bromo-cytisine 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 , 10 mol%) was added to a mixture of N,N'-dimethylethylenediamine (22 μL, 20 mM vol%), followed by the addition of phenylacetylene (132 μL, 1.2 mmol). The mixture was stirred at 50° C. under nitrogen for 24 hours. The mixture was cooled to room temperature and ammonium hydroxide was added. Dilute with ethanol solution (20 mL, 15% in water) and then extract with ethyl acetate (3 × 50 mL). I went out. together The organic layer was washed with brine (20 mL) and dried over sodium sulfate. The crude product ( 1 86 based on H NMR ~ 93% conversion) Flash column chromatography (ethyl acetate, then dichloromethane / methanol) The product was purified with methanol / ammonium hydroxide (97:3:0.1) and turned grayish white. The solid 134 (214 mg, 49%) was subjected to further purification without further purification. Used in Tepp. [ka]

[0250] Example 38b - (+) 4-(1-(4-phenyl)-NH-1,2,3-triazo (lyl)cytisine dihydrochloride (135) [ka] General Procedure B in accordance with , N-Boc-4-((4-phenyl)-NH-1,2,3,Tri Azole)-Cytisine 134 (0.46 mmol) from , a colorless solid, 135 (15 The yield was 1 mg, 81%). [ka]

[0251] Example 39a - N-Boc-4-(1,2,3-triazol-1-yl)methyl Pivalic acid) Cytisine (131)) [ka] N-Boc- in a mixture of tert-butyl alcohol / water (1:1) (8.6 mL) A solution of 4-(acetylene)-cytisine 126 (544 mg, 1.73 mmol) was added to the solution in succession. 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 h. The mixture was diluted with ammonium hydroxide (10 mL, The mixture was diluted with 15% aqueous solution of ethyl acetate (15% in water) and then extracted with ethyl acetate (3×20 mL). together death The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel [dichloromethane / The mixture was purified with methanol / ammonium hydroxide (95:5:0.1) to remove most of the impurities. The resulting mixture was purified by HPLC to yield 131 (722 mg, 89%) as a pale yellow oil that was purified without further purification. was used in the next step. [ka]

[0252] Example 39b - N-Boc-4-(NH-1,2,3-triazolyl)-cytisine (132) [ka] Methanol (3.2 mL )of N-Boc-4-(1,2,3-triazol-1-yl) )Methyl pivalate)-cytisine 131 (688 mg, 1.46 mmol ) melt In the liquid, hydroxide Sodium (3.2 mL, 1 M Aqueous solution) was added. The mixture was stirred at room temperature for 12 hours. Add salt to the food acid (3.2mL, 1 M aqueous solution), diluted with water (30 mL), and ethyl acetate Extraction was performed with (5×20 mL). together The organic layer was washed with brine (20 mL) and sulfuric acid The crude material was purified by flash column chromatography on silica gel. Column chromatography [dichloromethane / methanol / ammonium hydroxide (97:3 0.1)] to give 132 (461 mg, 88%) as an off-white solid. It was born. [ka]

[0253] (Example 39c - (+) 4-(NH-1,2,3-triazolyl) Cytisine Dihydrochloride Salt 133(A) [ka] General Procedure A in accordance with , N-Boc-4-(NH-1,2,3-triazole)-cysteine 132 (1.22 mmol) Using General Procedure A Deprotection hand Converted to hydrochloride and no The yield was 133 (352 mg, 87%) as a yellow solid. [ka]

[0254] Example 40 - (+) 4-(N-ethylamino)cytisine (87) [ka] In a sealed tube, add ethylamine (2.0 mL, tetrahydrofuran solution 2.0 M ) in N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol) and copper (7 mg A mixture of 10 mol%) of 1,2-dichlorophenyl ether (10 mol%) was stirred in water (1 mL) at 100° C. for 24 hours. The mixture was cooled and extracted with dichloromethane (5×10 mL). together The organic layer was diluted with sulfuric acid. The crude material was purified by flash elution with silica gel. Purified by column chromatography [dichloromethane / methanol (6% methanol)] The mixture was collected by filtration to yield 87 (102 mg, 42%) as an off-white solid. [ka]

[0255] Example 41 - (+) 4-(N-isopropylamino)cytisine 88 [ka] In a sealed tube, N-Boc-4-bromo in 40% iPrH2 solution (2.0 mL) was -Cytisine 61 (369 mg, 1.0 mmol) and copper (7 mg, 10 mol%) mixture The mixture was stirred at 100° C. for 24 h. The mixture was cooled and diluted with dichloromethane (5×10 mL). Extraction was performed. togetherThe organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel [dichloromethane / methan The mixture was purified with ethanol (6% methanol) to give an off-white solid, 88 (88 mg, 33%). [ka]

[0256] Example 42a-N-Boc-4-Cyanocytisine (139) [ka] The Schlenk flask was filled with N-Boc-4-bromo-cytisine 61 (1.85 g, 5.00 mmol). l), tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.20 (3.00 mmol) and zinc cyanide (350 mg, 3.00 mmol) and placed under nitrogen. N,N-Dimethylformamide (6.2 mL) was added and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled and the solvent was removed in vacuo. Column chromatography [dichloromethane:methanol (1% methanol)] Purification afforded 139 (1.6 g, 99%) as a colorless solid. [ka]

[0257] Example 43 - (-) 4-Cyanocytisine (140) [ka] In a Schlenk tube, N-Boc-4-cyano-cytisine 139 (140 mg, 0.46 0.1 mmol) in dichloromethane (3.0 mL, 0.1 M) and dissolved in trifluoroacetic acid ( 0.3 mL, 10 eq.) was added. The solution was stirred at room temperature for 16 h. Water was added (10 mL ) and the aqueous phase was washed with dichloromethane (3×20 mL). Ammonia was added (10 mL, 15% aqueous solution), and the aqueous phase was extracted with dichloromethane (4×20 mL). together The organic layer was dried over magnesium sulfate, filtered and concentrated to give a colorless solid 140 (86 mg, 86%). [ka]

[0258] Example 44a—N-Boc-4-(carboxyamido)cytisine (141) [ka] N-Boc-4-cyano-cytisine 1 in an equimolar mixture of ethanol / water (5 mL) A solution of 39 (320 mg, 1.0 mmol) was added with sodium borohydride (33 mg, 0 0.75 mmol) was added and the reaction mixture was stirred at 75° C. for 18 hours. Cool and dilute with water (5 mL). Quench The ethanol was removed in vacuo. The aqueous phase was then Extract with dichloromethane (3 x 15 mL) together The organic phase was dried over magnesium sulfate. The crude reaction mixture was purified by flash column chromatography [dichloro by purification with 2% to 4% methanol] , nothing In color solid Yield 141 (150 mg, 46%) It was recrystallized from toluene. Ta. [ka]

[0259] Example 44b - (-) 4-(Carboxamido)cytisine hydrochloride (142) [ka] General Procedure A in accordance with , N-Boc-4-amido-cytisine 141 (0.44 mmol) from The resulting mixture was stirred for 30 min at rt to give 142 (90 mg, 88%) as a colorless solid. [ka]

[0260] Example 45a—N-Boc-4-(aminomethyl)cytisine (143) [ka] Ethanol (10 mL, 0.1 M N-Boc-4-cyano-cytisine 139 (3 (20 mg, 1.0 mmol) and potassium hydroxide (84 mg, 1.5 mmol). Raney Nickel (0.3 mL, slurry in water) was added. The reaction vessel was placed under vacuum. , 3 times with hydrogen Backfill The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through a pad of Celite (registered trademark). The crude reaction mixture was filtered through toluene (Trademark) and concentrated. Flash column chromatography [Dichloromethane:methanol (10% methanol) + 0.1% ammonia (35% aqueous solution) Purification by HPLC yielded the amine 143 (260 mg, 82%) as a colorless solid. did. [ka]

[0261] Example 45b - (-) 4-(aminomethyl)cytisine dihydrochloride (144) [ka] General Procedure According to A , N-Boc-4-methylamino-cytisine 143 (0.76 mm ol) was converted to the hydrochloride salt to afford 144 (150 mg, 89%) as a colorless solid. [ka]

[0262] Example 46a - N-Boc-4-(N-Boc-aminomethyl)cytisine [ka] Tetrahydrofuran (8 mL )of N-Boc-4-aminomethyl-cytisine 143(2 64mg, 0.83mmol ) melt The liquid was diluted with di-tert-butyl dicarbonate (0.2 mL, 0.9 1 mmol) and triethylamine (0.16 mL, 1.16 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 18 hours. After that, water (15 mL) was added and the aqueous phase was diluted with dichloromethane. (3×25 mL). together The organic phase was dried over magnesium sulfate and filtered. The mixture was concentrated by flash column chromatography [dichloromethane:methanol (3% Purification with methanol gave a colorless oil, N-Boc-4-(N-Boc-amine). The product was purified by HPLC to yield 280 mg (6H, 82%) of cytisine. [ka]

[0263] Example 46b—(−) 4-((N-methyl)aminomethyl)cytisine (152) [ka] Tetrahydrofuran (6.0 mL )of N-Boc-4-(N-Boc-aminomethyl) -Cytisine (255 mg, 0.61 mmol) ) melt The solution contained sodium hydride (17 mg, 0 .70 mmol, 60% dispersion in oil) was added and the solution was stirred for 30 minutes. 0.05 mL, 0.70 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. Partition between water (10 mL) and ethyl acetate (10 mL), and then wash the aqueous phase with ethyl acetate (3 × 10 mL). was extracted. together The organic phase was washed with magnesium sulfate, filtered and concentrated. The compound Using General Procedure A Deprotection hand Convert it to the hydrochloride salt, 152, which is a colorless solid. (89 mg, 65%). [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]diazocin-3(4H)-carbo Xylate (153) [ka] N-Boc-4-cyano-cytisine 139 (200 mg, 0.63 mmol) was pyridinium Dissolve sodium phosphinate in a mixture of ethanol, 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® The crude material was partitioned between water (15 mL) and dichloromethane (15 mL) and The aqueous phase was extracted with dichloromethane (3×25 mL). together The organic phase was dissolved in magnesium sulfate. The crude reaction mixture was purified by column chromatography [dichloromethane]. methane / methanol (4% methanol)] to give a colorless, pale yellow solid. The yield was 153 (170 mg, 86%). [ka]

[0265] Example 47b - Amine bis(cytisine) derivative (154) [ka] General Procedure A in accordance with , tert-butyl(1R,5R)-10-(hydroxymethyl) -8-Oxo-1,5,6,8,-tetrahydro-2H-1,5-methano-pyrido[1, 2-a][1,5]diazocin-3(4H)-carbo Xylate 153 (0.53 mm l) from , yielding 154 (113 mg, 97%) as a colorless solid. [ka]

[0266] Example 48-Methylamino bis(cytisine) derivative (156) [ka] 153 (200 mg, 0.32 mmol) in a solution of formaldehyde (0.14 mL, 6 equiv., 37% in water) ), followed by the addition of sodium cyanoborohydride (74 mg, 3.5 equiv.) and the reaction mixture The mixture was stirred for 24 h. The solution was concentrated and the crude product was dissolved in ammonia (20 mL, 15% aqueous solution). Partition into dichloromethane (20 mL) and extract the aqueous phase with dichloromethane (3 x 20 mL). Ta. together The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography [dichloromethane / methanol (3% methanol)] This gave the corresponding N-Boc protected bis(cytisine) derivative (160 mg) as a colorless solid. , 82%). General procedure B was used Deprotection and Salt Conversion to the salt This afforded 156 (89 mg, 87%) as a colorless solid. [ka]

[0267] (Example 49 - (-) 4-Tetrazolylcytisine dihydrochloride (149)) [ka] The Schlenk flask was filled with N-Boc-4-cyano-cytisine 139 (240 mg, 0.75 mm ol), zinc bromide (170 mg, 0.75 mmol) and sodium azide (58 mg, 0.90 mmol) and placed under nitrogen. M ) and iso Propanol (0.8 mL, 1.0 M ) was added and the reaction mixture was heated at 60° C. for 18 h. The solvent was removed in vacuo and the residue residue Dissolve in dichloromethane (20 mL) and add water (20 mL). The mixture was poured into salt. acid (0.1 M (aqueous solution) pH ≒ 4 ~ Acidify to 5 and dichloromethane The aqueous phase was acidified to pH ≈ 1 and washed with dichloromethane (3 × 20 mL). 5 mL). together The organic phase was dried over magnesium sulfate, filtered and the solvent was removed. Evaporate in vacuo. The product was converted to the hydrochloride salt using general procedure A to give a colorless solid. The yield was 149 (102 mg, 53%). [ka]

[0268] (Example 50-N-Boc-4-(dimethylamino)methyl-cytisine, and 4-( Dimethylamino)methyl-(-)-cytisine dihydrochloride (151) [ka] Amine 143 (320 mg, 1.0 mmol) was added to a solution of formaldehyde (480 mg, 6 equivalents, 35% aqueous solution) and Then sodium cyanoborohydride (219 mg, 3.5 equiv.) was added successively. The mixture was stirred at room temperature for 18 hours. The reaction was diluted with 10 mL of water. Quench The aqueous phase was then extracted with ethyl acetate. (3×25 mL). together The organic layer was dried over magnesium sulfate and filtered. The crude reaction mixture was purified by flash column chromatography on silica gel. Purify with [dichloromethane / methanol (1% methanol)] and color Oil products (2 07 mg, 60%). [ka] General Procedure A in accordance with , N-Boc-4-(dimethylamino)methyl-cytisine (0.6 0mmol) from The product was analyzed by HPLC to yield 151 (120 mg, 81%) as a colorless solid, which was then analyzed by HPLC. After several days under reduced pressure, it turned into a viscous oil. [ka]

[0269] Example 51-(-) 4-((trimethylammonium)methyl)cytisine iodide Salt(150) [ka] Ethanol (6.3 mL )of Amine 143 (220 mg, 0.63 mmol) ) melt Into the liquid, Iodomethane (0.1 mL, 1.3 eq) was added and the reaction was stirred at 60° C. for 18 h. The solution was concentrated. Using General Procedure A Deprotection hand Hydrochloride fart conversion death ,green color Indefinite The yield was 150 (80 mg, 42%) as a solid. [ka]

[0270] (Example 52-(-)4-(N-acetyl)aminomethyl)cytisine (148) [ka] Amine 143 (310 mg, 1.0 mmol) was dissolved in isopropenyl acetate (0.33 mL, 3 equivalents) and stirred at room temperature for 24 hours. The reaction was then concentrated. Flash column chromatography (dichloromethane / methanol (3% methanol) Purification by ethanol (HCl) afforded the product as a colorless solid (330 mg, 92%). common Using Procedure A Deprotection hand conversion Things to do The result is a colorless foam of 148 (237 ml). g, 80%). [ka]

[0271] Example 53-N-Boc-4-(4-((benzyloxy)carbonyl)piperazine cytisine (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 equiv.) and 1-Z-piperazine (0.5 mL, 2.5 mm The solution of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether) was stirred at 100° C. for 18 hours. The reaction was cooled and the residue was residue ethyl acetate (3× 25 mL). together The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo The crude reaction mixture was purified by flash column chromatography on silica gel [Zik The solid was purified in 100 mL of 1,000 mL of ethyl acetate / methanol (2% methanol) to give a colorless solid (220 mg, 89 %) which was used in the next step without further purification. [ka]

[0272] Example 54 - N-Boc-4-(piperazin-1-yl)cytisine [ka] Methanol (5 mL )of 89 (160 mg, 0.32 mmol) ) melt The liquid was placed under nitrogen. Palladium on activated carbon 10 wt% (5 mg, 0.1 equiv.) was added. The vessel was placed under vacuum. Place and hydrogen three times Backfill The reaction mixture was stirred for 18 hours at 37° C. for 18 hours. The mixture was filtered through a filter (Trademark) and the solvent was concentrated to give a colorless solid, the piperazinyl derivative (85 mg). , 71%), which was used in the next step without further purification. [ka]

[0273] Example 55 - (+) 4-(N-piperazinyl)cytisine trihydrochloride (90) [ka] Methanol (6.4 mL )of N-Boc-4-N-(N'-benzyloxycarbonyl A solution of 2-piperazine-cytisine (323 mg, 0.64 mmol) was placed under nitrogen and Palladium on carbon (10 wt%) (6.5 mg, 0.1 equiv.) was added. The vessel was placed under vacuum. and hydrogen three times. Backfill The mixture was cooled to room temperature and stirred for 24 hours. The mixture was filtered through ethyl acetate and concentrated in vacuo. Using General Procedure A Deprotection hand Hydrochloride fart strange exchange Things to do This afforded 90 (237 mg, 96%) as a colorless solid. [ka]

[0274] Example 56a - N-Boc-3-(trifluoromethyl)-4-bromocytisine 161) [ka] N-Boc-4 in a mixture of dimethyl sulfoxide (3.8 mL) and water (1.6 mL) A solution of 10-bromo-cytisine 61 (370 mg, 1.0 mmol) was cooled to 0° C. and diluted with trichloroethylene. Sodium fluoromethylsulfonate (470 mg, 3.0 mmol) was added. t-Butyl hydroperoxide (0.7 mL, 70% aqueous solution) was added dropwise over 5 min, and the solution was then cooled to room temperature. The mixture was allowed to warm to room temperature and stirred for 24 hours. The solvent was removed in vacuo. The crude material was dissolved in ammonia (15 The aqueous phase was partitioned between 15 mL of 15% aqueous solution and dichloromethane (15 mL). (3×25 mL). together The organic phase was dried over magnesium sulfate and filtered. The crude product was purified by flash column chromatography on silica gel [n-hexane / ethyl acetate (1:1)] to give a colorless solid, 161 (130 mg, 30%). , together with 3% N-Boc-5-trifluoromethyl-4-bromo-cytisine. [1H NMR: 98% (C3 substitution), 2% (C5 substitution; 87% conversion)] [ka]

[0275] (Example 56b-(-) 3-(trifluoromethyl)-4-bromocytisine hydrochloride ( 162) [ka] General Procedure A in accordance with , bromide 161 (0.25 mmol) from 162 (0.45 mg, 48%) was produced. [ka]

[0276] Example 57a - N-Boc-3-bromo-4-iodocytisine (159) [ka] N-Boc-4-iodo-cytisine 65 (120 mg, 0.286 mmol) was added to tetrahydrofuran. Hydrofuran (6 mL, 0.05 M) Dissolve and add N-bromosuccinimide (51 mg, 0.286 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction was diluted with water (1 5 mL) and the aqueous phase was extracted with ethyl acetate (3×25 mL). together The organic phase was The mixture was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel. The product was purified by column chromatography [n-hexane / ethyl acetate (1:1)] and N-Boc- 159 (91 mg, 65%). [ka]

[0277] Example 57b - (+) 3-Bromo-4-iodocytisine hydrochloride (160) [ka] General Procedure A in accordance with , iodide 159 (0.16 mmol) from , 5-bromo-4-io 160 (57 mg, 81%) was produced that was contaminated with do-cytisine (ratio 22:3). . [ka]

[0278] Example 58a - N-Boc-3-bromo-4-methylaminocytisine (157) [ka] Tetrahydrofuran (6.0 mL )of N-Methylamine 83 (96 mg, 0.30 mm ol ) melt N-bromosuccinimide (54 mg, 0.30 mmol) was added to the solution and reacted. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with water (15 mL) and the aqueous phase was washed with ethyl acetate (3 × 25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel [dichloromethane / Methanol (2% methanol)] and 157 (N-Boc-3-bromo-4-methyl N-Boc-5-bromo-4-methylamino-cytisine (84 mg, 70%) was obtained. The ethylamino (27 mg, 22%) was used in the next step without further purification. [ka]

[0279] Example 58b - (+) 3-Bromo-4-N-methylaminocytisine hydrochloride (158 )) [ka] General Procedure A in accordance with , N-methylamine 157 (0.21 mmol) from , 9% of 5- 158 (45 mg, 73%). [ka]

[0280] Example 59 - Iridium-catalyzed CH borylation of (-)-cytisine Synthesis of 4-Bpin cytisine The Schlenk flask was charged with (-)-cytisine (190 mg, 1.0 mmol), [Ir(COD) (OMe)]2 (6.6 mg, 0.01 equiv.), 4,4'-2,2'-di-tert-butyl Tylbispyridine (5.4 mg, 0.02 equivalents) and bis(pinacolato)diboron (38 The mixture was charged with nitrogen. purge Then, tetrahydrofuran (1.4 1 mL) was added and the reaction mixture was heated at reflux for 24 h. After this time, the volatile materials were removed under reduced pressure The 4-Bpin cytisine was partially characterized without further purification and was identified as brown. It was obtained as a foam. [ka] [ka] To confirm the identity of 4-Bpin cytisine, the compound was further brominated in methanol. Treatment with an aqueous solution of copper(II) converted it to 4-bromocytisine. The spectroscopic properties of ticine were consistent with data available in the literature.

[0281] (Example 60 - Iridium-catalyzed CH borylation reaction of (-)-cytisine) (Synthesis of 4-Bpin cytisine) The same molar amounts, equipment, solvents, catalysts and ligands were used as outlined above. The preparation method of Example 59 was carried out, with the difference being that tetramethyl-1,10-phenanthro The use of phosphorus as a ligand and the boronation reaction reagent 3.00 equivalents of bis(pina) The preparation method was from cytisine to 4-BPin cytosine. This resulted in 100% conversion to ticine.

[0282] Example 61 - Iridium-catalyzed CH borylation of (-)-cytisine (Synthesis of 4-Bpin cytisine) The same molar amounts, equipment, solvents, catalysts and ligands were used as outlined above. The preparation method of Example 59 was carried out, with the difference that neocuproine was used as the ligand. The preparation method resulted in 100% conversion of cytisine to 4-BPincytisine. This proved to be a success.

[0283] (Example 62-Iridium-catalyzed CH borylation of N-Boc-cytisine) 56) (Synthesis of N-Boc-4-Bpin cytisine (58)) The Schlenk flask was charged with N-Boc cytisine (56) (290 mg, 1.0 mmol), [Ir (COD)(OMe)]2 (6.6 mg, 0.01 equiv.), 4,4'-2,2'-di-t ert-Butylbispyridine (5.4 mg, 0.02 eq.) and bis(pinacolato)diborate The mixture was charged with 178 mg of 1,000 mL ... purge After that, tetrahydrofuran C. (1.4 mL) was added and the reaction mixture was heated at reflux for 18 h. NMR showed nearly 100% conversion and the volatile materials were removed under reduced pressure. The crude N-Boc-4-Bpin cytisine (58) was essentially It is shown to be pure, but further purification is possible. However , which is N-Boc-4-BPin It is not necessary to use cytisine (58) as a reactant prior to this. Further purification of the crude N-Boc-4-B-cytisine (58) was performed by chromatography. (dichloromethane-methanol, 95:5) to produce a pale yellow foam. The product yielded pure N-Boc-4-BPin cytisine (58) (180 mg, 43%). [ka]

[0284] (Example 63-Iridium-catalyzed CH borylation of N-Boc-cytisine) 56) (Synthesis of N-Boc-4-Bpin cytisine (58)) The same molar amounts, equipment, solvents, catalysts and ligands were used as outlined above. The preparation method of Example 62 was carried out, except that N-methylcytisine was replaced with the compound of formula IIa. The preparation method was 9-methylcytisine converted to 4-BPincytisine. This resulted in an 8% conversion.

[0285] (Example 64-Iridium-catalyzed CH borylation of N-Boc-cytisine) 56) (Synthesis of N-Boc-4-Bpin cytisine (58)) The same molar amounts, equipment, solvents, catalysts and ligands were used as outlined above. The preparation method of Example 62 was carried out, with the difference being N-benzyloxycarbonylcytisine The starting material for the compound of formula IIa was cytisine to 4-BP. This resulted in 88% conversion to cytisine.

[0286] (Example 65-N-Boc-4-p-tolylcytisine (72)) N-Boc-4-Bpin cytisine 58, 0.5 mmol scale in The general Target Procedure Prepared according to The crude N-Boc-4-Bpin cytisine was dissolved in potassium carbonate (1 24mg, 0.90mmol), tetrakis(triphenylphosphine)palladium(0 ) (28 mg, 0.05 equiv.) and 4-bromotoluene (0.25 mL, 1.0 mmol ) and a mixture of dimethyl ether / water (5:1) (5 mL, 0.1 M ) was added. The mixture was heated at 80° C. for 24 h, then cooled to room temperature and diluted with water (15 mL). was extracted with dichloromethane (3×15 mL) together The organic phase was dried over magnesium sulfate. The mixture was dried, filtered and concentrated. Purification with ethanol (1.5% methanol) gave a colorless solid, N-Boc-4 -(p-tolyl)cytisine (104 mg, 55%) was obtained.

[0287] Example 66-N-Boc-4-methylcytisine (109) N-Boc-4-Bpin cytisine 58, 0.5 mmol scale in The method of Cytisine The general procedure for the oxidation reaction is as discussed above. Prepared according to did. Using a modification of the relevant procedure, crude N-Boc-4-Bpin cytisine 58 was purified by trichloroethylene. Tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.025 equiv.), Tri(p-tolyl)phosphine (7.6 mg, 0.05 equivalents), potassium carbonate (138 mg , 2.0 equiv.), iodomethane (0.03 mL, 1.0 equiv.), and the vessel was placed under vacuum. and rinsed with nitrogen three times. Backfill N,N-dimethylformamide / water (9:1, 5 ml A mixture of 1,2-dichlorophenyl ether (L) was added and the reaction mixture was stirred at 60° C. for 18 hours. The mixture was cooled to room temperature. The solvent was then removed in vacuo. residue Partition between ethyl acetate (15 mL) and water (15 mL), The aqueous phase was extracted with ethyl acetate (3×15 mL). together The organic phase was washed with magnesium sulfate. The mixture was dried, filtered, concentrated, and purified by flash column chromatography on silica gel [Dichloro The resulting pale yellow solid, N-Boc- The yield was 4-methylcytisine (98 mg, 64%).

[0288] Example 67a - N-Boc(3-bromo-4-hydroxy)cytisine [ka] Tetrahydrofuran (32 mL )of N-Boc-4-aminocytisine (512 mg, 1 .67mmol ) melt The solution was cooled to 0°C and N-bromosuccinimide (312 mg, 1. 76 mmol) was added and the reaction mixture was stirred at 0° C. for 18 h. Water (25 mL) was added and The aqueous phase was extracted with ethyl acetate (3×25 mL). together The organic phase was washed with magnesium sulfate. The crude reaction mixture was purified by flash column chromatography [AcOEt The resulting colorless solid, N-Boc(3 1-Bromo-4-hydroxycytisine (350 mg, 55%) was obtained. [ka]

[0289] (Example 67b)-(-)-(3-bromo-4-hydroxy)cytisine hydrochloride (BS7 0)) [ka] General Procedure A in accordance with , N-Boc(3-bromo-4-hydroxy)cytisine (0.83 mmol) from This afforded BS70 (236 mg, quantitative) as a colorless solid. [ka]

[0290] Example 68a - N-Boc(3-bromo-4-amino)cytisine [ka] Tetrahydrofuran (16 mL )of 4-Aminocytisine (250 mg, 0.82 mmol) l ) melt The solution was cooled to 0°C and N-bromosuccinimide (153 mg, 0.86 mmol) was added. ) was added and the reaction mixture was stirred at 0° C. for 18 h. Water (25 mL) was added and the aqueous phase was diluted with ethyl acetate. Extracted with chill (3 x 25 mL). together The organic phase was dried over magnesium sulfate and filtered. The crude reaction mixture was purified by flash column chromatography [ethyl acetate]. The colorless solid N-Boc(3-bromo-4-amino)cytisine (9 The yield was 5 mg, 30%). [ka]

[0291] Example 68b - (+)-(3-Bromo-4-amino)cytisine hydrochloride (BS71) ) [ka] General Procedure A in accordance with , N-Boc(3-bromo-4-amino)cytisine from Colorless solid The yield was BS71 (62 mg, 64%). [ka]

[0292] (Example 69a -N-Boc(3-bromo-4-ethyl)cytisine) [ka] Tetrahydrofuran (20 mL )of N-Boc-4-ethyl-cytisine (341 mg, 1.07mmol ) melt The solution was cooled to 0°C and N-bromosuccinimide (190 mg, 1 0.07 mmol) was added and the reaction mixture was stirred at 0° C. for 18 h. Water (25 mL) was added. The aqueous phase was then extracted with ethyl acetate (3×25 mL). together The organic phase was diluted with magnesium sulfate. The crude reaction mixture was dried at 40° C., filtered and concentrated. Dichloromethane / methanol (2% methanol) gave a colorless solid. The yield was N-Boc(3-bromo-4-ethyl)cytisine (296 mg, 70%). [ka]

[0293] Example 69b - (-)-(3-bromo-4-ethyl)cytisine (BS74) [ka] General Procedure A in accordance with , N-Boc(3-bromo-4-ethyl)cytisine (296 mg, 0.75mmol) from , yielding BS74 (80 mg, 37%) as a colorless solid. [ka]

[0294] Example 70 - Binding to Nicotinic Receptor Subtypes Regarding affinity for different nAChR subtypes, specifically α4β2, α3β4, and α7 The binding of the panel of compounds mentioned above was tested. The protocols for these tests are described below. The results are shown in Tables 1 to 9 below.

[0295] (Binding to heterologously expressed α4β2 and α3β4 human subtypes) HEK293 cells , 10% fetal bovine serum, 1% L-glutamine, 100 units / ml penicillin G and 100 μg streptomycin. Dulbecco modification In Eagle medium 、1 In a humid environment containing 0% carbon dioxide Cultured α3 and β4, or α4 and β2 coding I'm The cDNA was transfected into HEK293 cells at 30% confluency. transfected). cell Transfection was performed using 30 μL of JetPay (quotient mark ) (Polypass, France) (1 mg / ml, pH 7.2) and 3 μg of each cDNA were used. and was performed in a 100 mm Petri dish. After 24 hours of transfection, cell Collect Therefore, the cells were washed with phosphate-buffered saline by centrifugation and used for binding analysis. HEK-transfected α3β4 or α4β2 receptors 3 H]-Epiva Epibatidine saturation binding experiments were performed in the presence of 100 nM cold epibatidine (specifically different Bond) or absence Existence (complete) complete conclusion In the mixture, 50 mM Tris-HCl, pH 7, 150 mM sodium chloride , 5 mM potassium chloride, 1 mM magnesium chloride, 2.5 mM calcium chloride, and Buffer containing 2mg / ml bovine serum albumin Inside, Concentrations ranging from 0.005 to 1 nM The assay was carried out by incubation at 4°C overnight at room temperature. different Ligand binding is 100 nM away from full binding. was defined as the reduced binding in the presence of cold epibatidine.

[0296] Induced by compounds or nicotinic ligands 3 Inhibition of [H]-epibatidine binding was Incubate the medium with increasing concentrations of test compound (10 pM to 10 mM) for 30 min at room temperature (rt). Then, 3 The final concentration of [H]-epibatidine was 0.25 nM (α4β2 subtype 0.5nM (α3β4 subtype) or 0.5nM (α3β4 subtype) at 4°C overnight. After incubation, HEK cells transfected with α4β2 or α3β4 subtypes were The membrane of Ice cold Gel filtration chromatography using phosphate buffered saline The gel filtration chromatography filter was presoaked in polyethyleneimine. and filtered through a harvesting device. 3 H]-epibatidine binding is a beta counter - liquid Determined by scintillation counting.

[0297] (Binding to heterologously expressed α7 subtype) Human α7 cDNA was transfected into SH-SY5Y human neuroblastoma cells. . cell Transfection was performed using 30 μL of JetPay (quotient (Polypass, France) ) (1 mg / ml, pH 7.2) and 6 μg of α7 cDNA were used in a 100 mm petri dish. After 24 hours of transfection, cell The cells were collected and centrifuged. The plates were washed with phosphate-buffered saline and used for binding assays.

[0298] [ 125 I]-α-bungarotoxin (PerkinElmer, Boston, MA) (purchased from Epson) The saturated bond is 0.1 at room temperature. ~ 10 nM concentration of [ 125 I]-α-Bungarotiki This was performed by overnight incubation of SH-SY5Y membranes with lysine. different Binding is 1 μM This was determined in parallel by incubation in the presence of unlabeled α-bungarotoxin. After incubation, samples were filtered as above and the bound radioactivity was assayed in a gamma counter. Noh Directly The test compound was 125 Inhibition of I-α-bungarotoxin binding was SH- SY5Y membrane Concentration (10M ~ 1mM) of test agent for 30 minutes at room temperature Pre-culture hand, So After that, at room temperature 125 I]-α-bungarotoxin at a final concentration of 2 to 3 nM and incubated overnight. This was measured by performing the following:

[0299] After overnight incubation, the membranes of α7-transfected SH-SY5Y cells were Ice cold Phosphate buffer The mixture was washed by filtration through a gel filtration chromatography filter using aqueous saline. Gel filtration chromatography filters were presoaked in polyethyleneimine and passed through a harvesting device. Filtered. 125 I]-α-bungarotoxin binding was measured by gamma counter in By direct counting It was decided.

[0300] (Data Analysis) Ligand binding data were obtained using Prism version 5 (GraphPad Software, Calif.) The data were analyzed by nonlinear regression using the Ki The value is the unit of the conflict location. Calculated from experimental 50% inhibitory concentration values ​​using the Cheng-Prusoff equation for a population: .K i =IC 50 / [1+(L / K d ), where L is the number of radioligands used in each experiment. is the concentration, K d Values ​​were determined by saturation binding experiments. All assays were performed in duplicate and at least Both were repeated two or 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 compounds of the present invention inhibit both the α3β4 subtype and the α7 (in both murine and human cells, when tested) compared with human α4β2 It shows high selectivity for receptor subtypes, Off-target " effect was minimized.

[0301] Example 71 - Nicotinic Receptor Subtypes in(Relative effectiveness of The compounds of the present invention were synthesized by the method comprising the steps of: 3β4 and α7 nicotinic acetylcholine R Cholinergic receptors (nACh R) Test the effect of the function Human α4β2nACh receptors are either (α4)3(β2)2 (low ACh sensitivity) or (α4)2(β2)3 receptors (highly sensitive to ACh) or Reference 16). Expression in oocytes was obtained as follows. Human α4, β2, β4 or α Contains 7 complementary DNA pCI (Promega, UK) Plasmi The previous literature Injected like (Non-Patent Document 16). In order to express (α4)3(β2)2nACh receptors, 10α A mixture of 4:1 cDNA for β2 and (α4)2(β2)3 receptors was injected into the nuclei of oocytes. For the α4:10β2 cDNA ratio injected was 1α4:10β2.

[0302] (Functional research) Geneclamp amplifier (Molecular Devices, USA) Manually, using or Using the automated HiClamp system Note Record but In both cases, the oocytes 3 M With two electrodes filled with potassium chloride Stab , cell was held at -60mV throughout the experiment. did.

[0303] Isolation of oocytes and voltage clamp recording with two electrodes Previous literature It is carried out as follows The concentration-response curves of the agonists were determined to maximize the activity of all the receptors tested (Non-Patent Documents 16, 17). The ratio of the compound to the response elicited by 1 mM ACh, the concentration of ACh that activates Correct the reaction of the object Rules This was achieved by synthesizing the To ensure reliable recording, a minimum interval of 5 min was allowed between agonist applications. The mice were then exposed to increasing concentrations of compound until no further increase in response amplitude was obtained. The concentrations were interpreted as those that produced the maximal response of the receptor tested. The data captured is at least of 3 different donor A small number of studies were performed on oocytes obtained from from at least five experiments.

[0304] ((a):(α4)3(β2)2nACh R( Low sensitivity of the stoichiometry of the compound effect) (Maximum gating efficacy of compound) (α4)3(β2)2nACh heterologously expressed in Xenopus oocytes R Maximum activity The concentration of the compound of the present invention that causes activation is 、 Determined using a two-electrode voltage clamp. The maximum current elicited by the compound was the maximum response to (α4)3(β2)2 receptors. (c) Relativized to the maximal concentration elicited by 1 mM ACh. [Table 10]

[0305] ((b):(α4)2(β2)3nACh R Effects related to (The maximum gating of the compound for the (α4)2(β2)3 receptor (high sensitivity receptor) (ing efficacy) (α4)2(β2)3nACh heterologously expressed in Xenopus oocytes R Maximum activity The concentration of compounds that produced activation was determined using a two-electrode voltage clamp. The maximal current elicited by this would then elicit the maximal response to (α4)2(β2)3 receptors. ) relative to the maximal concentration elicited by 1 mM ACh. [Table 11]

[0306] (c):α3β4nACh R (Effect of the compound on (α3β4nACh R (maximum gating efficacy of compound for α3β4nACh heterologously expressed in Xenopus oocytes R Produces maximum activation The concentration of compound that induces the agonist effect was determined using a two-electrode voltage clamp. The maximal current was then induced by 1 mM ACh (leading to the maximal response to α3β4 receptors). The concentrations were then relativized to the maximum concentration derived from the [Table 12]

[0307] ((d):α7nACh R (Effect of the compound on (α7nACh R (relative potency of compounds with respect to The amplitude of the current elicited by the compounds at 100 μM was measured and then α7nACh R Relativized to the amplitude of response to 1 mM ACh, the concentration producing maximal activity. It was done. [Table 13] The data in Table 13 show that the compounds of the present invention have a higher α7 It was found to exhibit low relative potency for the receptor. The present application provides the following aspects of the invention. (Aspect 1) A compound represented by formula I, or a pharma- ceutically acceptable salt, solvate, and / or salt thereof, More preferably, it is an ester, (chemical 1) TIFF2025028923000474.tif51170 R of Formula I 1 teeth, Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic Optionally substituted aryl; optionally substituted heteroaryl; -(CH 2 ) m -NR 6 R 7 R 8 (side chain 1), -(CH 2 ) m -O-(CH 2 ) n -R 10 (side chain 2), -CN, -COOR 12 (side chain 3), -(CH 2 ) O -CO-(CH 2 ) P -R 13 (side chain 4), Amino acids or esters thereof, Acyl chloride, a protecting group, or cytisinyl, R of Side Chain 1 6 and R 7 each independently represents hydrogen, halo, hydroxy, oxo, amino , amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino No, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulf Anil, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethyl aryl, aryl silyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl optionally having a substituent, heteroaroyl optionally having a substituent, Optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, aralkyl, and cycloalkyl. cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heptyl A group consisting of a heterocycloalkyl or a heterocycloalkenyl which may have a substituent. Selected from the group, or The R of the side chain 1 6 and the above R 7 One of them is -CO-R 9 (side chain 5), and R 6 and the above R 7 the other is selected from the group R of Side Chain 1 8 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl, or is absent; R of the side chain 5 9 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; m of the side chain 1 is 0, 1, 2, 3, 4 or 5; R of the side chain 2 10 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; m and n of the side chain 2 each independently represent 0, 1, 2, 3, 4, or 5; R of the side chain 3 12 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; R of the side chain 4 13 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; o and p of the side chain 4 each independently represent 0, 1, 2, 3, 4, or 5; R of Formula I 2 、R 3 and R 4 each independently represents hydrogen, halo, hydroxy, or oxo , amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkyl alkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl , sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, Trimethylsilyl, urea, thiourea, aryl which may have a substituent, Heteroaryl which may have a substituent, alkyl which may have a substituent, cycloaliphatic which may be substituted, heterocycloaliphatic which may be substituted aryl, optionally substituted heteroaryl, optionally substituted haloaryl alkyl, an optionally substituted aroyl, an optionally substituted heteroaroyl, Optionally substituted acyl, optionally substituted alkenyl, alkynyl which may be substituted, aralkyl which may be substituted, cycloalkyl, optionally substituted cycloalkenyl, Heterocycloalkyl or heterocycloalkenyl, amino acid or cytisine, or R 4 is a protecting group, or -(CH 2 ) V -FORMU LA 1 (referred to as chemical formula A) is a group having a structure, wherein v in the chemical formula A is 0, 1, 2, 3, 4, 5 or 6, wherein FORMULA 1 is a compound of formula I; The R of Formula I 2 , R 3 and the above R 4 At least one of the is not hydrogen. The compound or a pharma- ceutically acceptable salt, solvate, and / or ester thereof. (Aspect 2) A compound represented by formula I, or a pharma- ceutically acceptable salt or solvent thereof, for use in a drug. solvates and / or esters, (Case 2) TIFF2025028923000475.tif51170 R of Formula I 1 teeth, Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic Optionally substituted aryl; optionally substituted heteroaryl; -(CH 2 ) m -NR 6 R 7 R 8 (side chain 1), -(CH 2 ) m -O-(CH 2 ) n -R 10 (side chain 2), -CN, -COOR 12 (side chain 3), -(CH 2 ) O -CO-(CH 2 ) P-R 13 (side chain 4), Amino acids or esters thereof, Acyl chloride, a protecting group, or cytisinyl, R of Side Chain 1 6 and R 7 each independently represents hydrogen, halo, hydroxy, oxo, amino , amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino No, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulf Anil, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethyl aryl, aryl silyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl optionally having a substituent, heteroaroyl optionally having a substituent, Optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, aralkyl, and cycloalkyl. cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heptyl A group consisting of a heterocycloalkyl or a heterocycloalkenyl which may have a substituent. Selected from the group, or The R of the side chain 1 6 and the above R 7 One of them is -CO-R 9 (side chain 5), and R 6 and the above R 7 the other is selected from said group, R of Side Chain 1 8 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl, or is absent; R of the side chain 5 9 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; m of the side chain 1 is 0, 1, 2, 3, 4 or 5; R of the side chain 2 10 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; m and n of the side chain 2 each independently represent 0, 1, 2, 3, 4, or 5; R of the side chain 3 12 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; R of the side chain 4 13 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; o and p of the side chain 4 each independently represent 0, 1, 2, 3, 4, or 5; R of Formula I 2 、R 3 and R 4 each independently represents hydrogen, halo, hydroxy, or oxo , amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkyl alkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl , sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, Trimethylsilyl, urea, thiourea, aryl which may have a substituent, Heteroaryl which may have a substituent, alkyl which may have a substituent, cycloaliphatic which may be substituted, heterocycloaliphatic which may be substituted aryl, optionally substituted heteroaryl, optionally substituted haloaryl alkyl, an optionally substituted aroyl, an optionally substituted heteroaroyl, Optionally substituted acyl, optionally substituted alkenyl, alkynyl which may be substituted, aralkyl which may be substituted, cycloalkyl, optionally substituted cycloalkenyl, Heterocycloalkyl or heterocycloalkenyl, or selected from Group 7 consisting of amino acid, cytisine, or 4 is a protecting group, or - (CH 2 ) V - a group having the structure of FORMULA 1 (referred to as chemical formula A), In formula A, v is 0, 1, 2, 3, 4, 5 or 6, and said FORMULA 1 is a compound represented by the formula I, or a pharma- ceutically acceptable salt, solvate, and / or a compound thereof. Or esters. (Aspect 3) R 1 includes substituted methyl groups, substituted ethyl groups, and substituted propyl groups. , replaced C 1-8 is an alkyl group, The substituted methyl groups include aminomethyl and halogenated methyl groups. Methyl is chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, trimethyl Includes fluoromethyl, bromomethyl, dibromomethyl, and tribromomethyl. The substituted ethyl group may be 1- or 2-aminoethyl, hydroxyethyl, halogen, The ethyl halide may be 2,2,2-trichloroethyl, 2,2,2 -tribromoethyl or 2,2,2-trifluoroethyl, The substituted propyl group is 1-, 2- or 3-aminomethyl, hydroxypropyl or a propyl halide. (Aspect 4) R 1 is an unsubstituted C containing propyl, isopropyl, butyl or tert-butyl 3 -8 The compound according to any one of the preceding aspects, wherein the compound is an alkyl group. (Aspect 5) R 1 is an unsubstituted or substituted aryl, a phenyl group or a chlorophenyl group; phenyl, bromophenyl, fluorophenyl, perchlorophenyl, perbromophenyl, substituted phenyl groups, including halogenated phenyl groups, including trifluorophenyl; , aniline, phenol, styrene, benzonitrile, anisole, acetophenone, The compound according to any one of the preceding aspects, comprising benzaldehyde or benzoic acid. (Aspect 6) R 1 benzyloxypyridine, pyridones including 2-pyridone, 2-pyridines, Pyridines including 3-pyridine or 4-pyridine, phenyltriazoles, Optionally substituted triazoles and triazole methyl pivalates. 3. The compound according to embodiment 1 or 2, which is preferably heteroaryl. (Aspect 7) R 1 are cyclopentyl, cyclohexyl, morpholinyl, piperidyl, piperazine, aryl, tetrahydrofuryl, oxolanyl or dioxanyl, The compound according to any one of the preceding embodiments, wherein R is cycloalkyl or heterocycloalkyl. (Aspect 8) R 1 is vinyl, acrylate, -C=CC 6 H 5 , acetylenic, -C≡CC 6 H 5 or -C≡C-trimethylsilyl group, 2-8 Arken or C which may have a substituent 2-8 Compound according to any one of the preceding claims, wherein the compound is alkynyl. 。 (Aspect 9) R 1 is an amine, an N-alkylamine, an N,N-dialkylamine or an amide. 3. The compound according to claim 1 or 2, (Aspect 10) R 1 amine, methylamine, ethylamine, propylamine, isopropylamine amine, benzylamine, dimethylamine, trimethylammonium methyl, dimethylamine 10. The compound according to embodiment 9, wherein the aryl group is any one of monomethyl, benzamido, or acetamido. (Aspect 11) R 1 is methoxy, ethoxy, propoxy, benzyloxy or trifluoromethyl 3. The compound according to any one of the preceding claims, wherein the compound is any one of: (Aspect 12) R 1 Ethyl ester, propyl ester, isopropyl ester, butyl ester 3. The compound according to claim 1 or 2, which is a carboxylic acid or ester, including a tert- or phenyl ester. compound. (Aspect 13) R 1 are alanine, arginine, asparagine, aspartate, cysteine, and glucan. glutamine, glutamate, glycine, histidine, isoleucine, leucine, lysine, methionine Thionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine , valine or their methyl, ethyl, propyl or isopropyl esters. 3. The compound according to embodiment 1 or 2, which is a naturally occurring amino acid or an ester thereof. (Aspect 14) R 1 are tert-butyloxycarbonyl (Boc), formyl, and acetyl (A c), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (BOC), fluorenyl (Cbz), or fluorenylmethoxycarbonyl (Fmoc), or (Pinacolato)borane (BPin) and (Catecholato)borane (BCat) (RO) 2 B - 1 - 10 - 15 - 16 - 17 - 18 - 19 - 20 - 21 - 22 - 23 - 24 - 25 - 26 - 27 - 28 - 29 - compound. (Aspect 15) R 2 and the above R 3 The compound according to any one of the preceding aspects, wherein is hydrogen. (Aspect 16) R 4 16. The compound according to any one of the preceding aspects, wherein is a protecting group or hydrogen. (Aspect 17) (-)4-methylcytisine, (-)4-(hydroxymethyl)cytisine, (-)4-bromocytisine, (-)4-chlorocytisine, (+)4-trylcytisine, (-)4-ethylcytisine, (+) 4-vinylcytisine, A compound selected from (-) 4-fluorocytisine. (Aspect 18) 18. A compound according to embodiment 17 for use in medicine. (Aspect 19) 19. A compound according to any one of the preceding aspects for use in the prevention or treatment of addiction. (Aspect 20) The addiction is any one of nicotine addiction, alcohol addiction, and drug addiction. 19. The compound according to claim 19. (Aspect 21) A compound according to any one of aspects 1 to 20, and a pharma- ceutically acceptable excipient. composition. (Aspect 22) 22. The composition according to aspect 21, for use in the prevention or treatment of addiction. (Aspect 23) 23. The composition according to claim 22, wherein the addiction is nicotine addiction, alcohol addiction, and drug addiction. thing. (Aspect 24) 21. A method for preventing or treating addiction in a subject in need of treatment, comprising administering an effective amount of any one of claims 1 to 20 to a subject in need of treatment. A compound according to any one of claims 21 to 23 or a composition according to any one of claims 21 to 23, A method for preventing or treating addiction, comprising a step of administering to a subject. (Aspect 25) 1. A process for preparing a 4-substituted cytisine analogue, comprising the steps of: Step i to produce a compound of formula IIa; (C3) TIFF2025028923000476.tif51170 Step ii to produce a compound of formula IIb; (C4) TIFF2025028923000477.tif51170 CompB of the formula IIb is R 1 to produce a compound of formula I. iii) (C5) TIFF2025028923000478.tif50170 R of Formula IIa 2 、R 3 and R 4 each independently represents hydrogen, halo, hydroxy, Oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N- Dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulf phenyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpiva aryl, trimethylsilyl, urea, thiourea, optionally substituted aryl, Heteroaryl which may have a substituent; alkyl which may have a substituent; Cycloaliphatic groups which may have a substituent, heterocycloaliphatic groups which may have a substituent, phatic, optionally substituted heteroaryl, optionally substituted haloaryl aroyl optionally having a substituent; heteroaroyl optionally having a substituent; yl, optionally substituted acyl, optionally substituted alkenyl, alkynyl which may have a substituent; aralkyl which may have a substituent; cycloalkyl which may be substituted, cycloalkenyl which may be substituted, Heterocycloalkyl optionally having a substituent or heterocycloalkenyl optionally having a substituent. R is selected from Group 1 consisting of cyclic alkyl, cyclic alkyl, cyclic aryl ... 4 is a protecting group, or is -(CH 2 ) V - a group having the structure of FORMULA 1 (referred to as chemical formula A), In the formula A, v is 0, 1, 2, 3, 4, 5 or 6, and the formula 1 is A compound of formula I, The R of formula IIb 2 , R 3 and the above R 4 is selected from group 1, CompB is a boronated complex obtained by contacting the compound of formula IIa with a boronating agent. and The R of Formula I 1 teeth, Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic Optionally substituted aryl; optionally substituted heteroaryl; -(CH 2 ) m -NR 6 R 7 R 8 (side chain 1), -(CH 2 ) m -O-(CH 2 ) n -R 10 (side chain 2), -CN, -COOR 12 (side chain 3), -(CH 2 ) O -CO-(CH 2 ) P -R 13 (side chain 4), Amino acids or esters thereof, Acyl chloride, a protecting group, or cytisinyl, R of Side Chain 1 6 and R 7 each independently represents hydrogen, halo, hydroxy, oxo, or amino; No, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkyla Amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfur phenyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trime aryl, aryl having a substituent, optionally substituted heteroaryl, optionally substituted alkyl, Optionally substituted heterocycloaliphatic , optionally substituted heteroaryl, optionally substituted haloalkyl, Optionally substituted aroyl, optionally substituted heteroaroyl, substituted acyl; optionally substituted alkenyl; optionally substituted alkynyl which may be substituted, aralkyl which may be substituted, cycloalkyl which may be substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted A group consisting of heterocycloalkyl or heterocycloalkenyl which may have a substituent. Selected from Loop 2, or R of Side Chain 1 6 and R 7 One of them is -CO-R 9 (side chain 5), and R 6 and the above R 7 the other is selected from group 2; R of Side Chain 1 8 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl, or is absent; R of the side chain 5 9 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; m of the side chain 1 is 0, 1, 2, 3, 4 or 5; R of the side chain 2 10 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; m and n of the side chain 2 each independently represent 0, 1, 2, 3, 4, or 5; R of the side chain 3 12 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano. No, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl , carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thio Urea, optionally substituted aryl, optionally substituted heteroaryl , alkyl which may have a substituent, cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted Aroyl, optionally substituted heteroaroyl, optionally substituted acyl , optionally substituted alkenyl, optionally substituted alkynyl, arylalkyl optionally having a substituent; cycloalkyl optionally having a substituent; optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkenyl; R of the side chain 4 13 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, optionally substituted aryl, optionally substituted heteroaryl alkyl optionally having a substituent; cycloaliphatic heterocycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl which may be substituted, haloalkyl which may be substituted, aroyl, heteroaroyl which may have a substituent, aryl which may have a substituent aryl, optionally substituted alkenyl, optionally substituted alkynyl, substituted arylalkyl which may have a group; cycloalkyl which may have a group; Optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or is selected from optionally substituted heterocycloalkenyl; o and p of the side chain 4 each independently represent 0, 1, 2, 3, 4, or 5; The R of Formula I 2 , R 3 and the above R 4 At least one of the compounds is not hydrogen. Manufacturing method. (Aspect 26) The compound of formula IIa provided in step i is 4 A hydrogen atom at the position Including, The step further comprises: 4 with a protecting group. 25. The preparation method according to claim 25. (Aspect 27) 27. The method according to claim 26, wherein the protecting group is tert-butyloxycarbonyl (Boc). Preparation method. (Aspect 28) 28. The method according to claim 26 or 27, wherein the compound of formula IIa is cytisine. 。 (Aspect 29) The boronizing reagent has the formula (RO) 2 -BB-(OR) 2 OrHB(OR) 2 Represented by 29. The method of any one of embodiments 25 to 28, wherein the compound has a chemical structure as follows: (Aspect 30) The boronation reagent is bis(pinacolato)diboron (B 2 Pin 2 ), or Bis(catechol Diboron (B 2 Cat 2 29. The method according to any one of aspects 25 to 28, wherein (Aspect 31) the molar ratio of boronating reagent to starting material of 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 31. The method according to any one of aspects 25 to 30, wherein the ratio of 1:1 is at least 2:1. (Aspect 32) 32. Any of aspects 25 to 31, wherein the reaction in step ii is carried out in the presence of a catalyst. The preparation method according to any one of claims 1 to 5. (Aspect 33) 33. The process according to embodiment 32, wherein the catalyst is a transition metal catalyst. (Aspect 34) The transition metal catalyst may include iridium, palladium, zinc, nickel, and / or rhodium. 34. The method of preparation according to embodiment 33, comprising: (Aspect 35) 35. The method of any one of aspects 25 to 34, wherein the reaction in step ii is carried out in a solvent. The preparation method described in paragraph . (Aspect 36) The solvent may be an ester solvent, an ether solvent, a ketone solvent, a sulfoxide solvent, an aromatic solvent, or the like. 36. The method of claim 35, further comprising the step of: Manufacturing method. (Aspect 37) 37. The method according to any one of aspects 25 to 36, wherein step ii is carried out in the presence of a ligand. The preparation method described. (Aspect 38) The ligand is tetramethyl-1,10-phenanthroline (Me4phen), -tert-Butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (b py), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2- Di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphine 1,2-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe ), hexamethylbenzene (C6Me6), xantphos, or 1,2-bis(dimethyl 38. The method according to embodiment 37, wherein the compound is any one of: (Aspect 39) The ligands are phenanthroline (phen), dimethylphenanthroline (me2 phen), tetramethyl-1,10-phenanthroline (me4phen), Anthroline (bathophen), di-tert-butyl-2,2'-bipyridyl ( dtbpy), 2,2'-bipyridine (bpy), dimethoxy-2,2'-bipyridyl ( MeO-bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), Bis(2-di-tert-butylphosphinophenyl)ether, 1,3-bis(diphenyl 1,2-Bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), neocuproine, xanthophos, 1,2-bis(dimethylphosphino)ethane (dmpe), or a compound according to formula 6 38. The method according to claim 37, wherein the method is any one of (6) TIFF2025028923000479.tif207170 。 (Aspect 40) The molar ratio of boronating agent to starting material of 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: 40. The ratio of the ... The preparation method according to any one of claims 1 to 4. (Aspect 41) The boronization in step ii is carried out at a temperature of 50° C. to 100° C. 41. A method for preparing the composition according to any one of claims 25 to 40. (Aspect 42) Prior to the commencement of step iii, the compound of formula IIb is and / or step ii) is not separated from the product mixture formed in step ii) 42. The method according to any one of aspects 25 to 41, wherein no purification step is carried out between i. 。 (Aspect 43) Step iii is initiated in the same reaction region in which step ii was carried out. 43. The method of preparation according to any one of aspects 25 to 42. (Aspect 44) In the step iii, the CompB is R 1 The first intermediate of the substituent is replaced 44. The method of preparation according to any one of aspects 25 to 43. (Aspect 45) R 1 The first intermediate of the substituent is R 1 or R 1 replacement 45. The method of claim 44, wherein said compound of formula I is formed by substituting a group with R 1 . (Aspect 46) R 1 The second intermediate of the substituent is R 1 or R 1 replacement A method according to embodiment 45, wherein said compound of formula I is produced by substituting with a group. (Aspect 47) R 1 The first, second and third intermediates of the substituents are bromo, chloro, iodo and benzyloxy. pyridine, alkyl esters including methyl esters, alkenyls including vinyl, acetyl Alkynyl including phenyl, trimethylsilylacetylene, 1,2,3-triazole-1 -ylmethyl pivalic acid, cyano, aminomethyl, N-Boc-aminomethyl or (benzoylmethyl) 47. The method according to claim 46, wherein the aryl group is independently selected from the group consisting of (oxy)carbonyl)piperazin-1-yl. Preparation method. (Aspect 48) The compound of formula IIb or formula I is 4 a protecting group at position The preparation method further comprises the step of: 4 Deprotection of the group 48. The method according to any one of aspects 25 to 47, comprising the step of: (Aspect 49) R of the compound of formula IIb or formula I 4 The step of deprotecting the group After the completion of step ii, or before the start of step iii, or The method according to aspect 48, wherein the method is carried out during or after completion of step iii.

Claims

1. 1. A compound represented by formula I, or a pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 1】 R of Formula I 1 teeth, Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic optionally substituted allyl; optionally substituted heteroaryl; - (CH 2 ) m -NR 6 R 7 R 8 (side chain 1), - (CH 2 ) m -O-(CH 2 ) n -R 10 (side chain 2), - C.N., -COOR 12 (side chain 3), - (CH 2 ) O -CO-(CH 2 ) P -R 13 (side chain 4) Amino acids or esters thereof, Acyl chloride, a protecting group, or cytisinyl, R of Side Chain 1 6 and R 7 each independently represents hydrogen, halo, hydroxy, oxo, amino , amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino No, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulf Anil, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethyl aryl, urea, thiourea, optionally substituted allyl, optionally substituted optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted silyl Cycloaliphatic, optionally substituted heterocycloaliphatic, substituted Heteroaryl which may have a group, haloalkyl which may have a substituent, aroyl which may have a substituent, heteroaroyl which may have a substituent, substituted acyl, optionally substituted alkenyl, optionally substituted aryl alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl alkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclo A group consisting of a cycloalkyl or an optionally substituted heterocycloalkenyl group. or The R of the side chain 1 6 and the above R 7 One of the groups is -CO-R 9 (side chain 5), and R 6 and the above R 7 the other is selected from the group of groups described above, R of Side Chain 1 8 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted heterocycloalkenyl optionally bearing a group, or absent; R of the side chain 5 9 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, m of the side chain 1 is 0, 1, 2, 3, 4 or 5; R of Side Chain 2 10 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, m and n of the side chain 2 each independently represent 0, 1, 2, 3, 4, or 5; R of the side chain 3 12 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, R of the side chain 3 13 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, o and p in the side chain 3 each independently represent 0, 1, 2, 3, 4, or 5; R of Formula I 2 , R 3 and R 4 each independently represents hydrogen, halo, hydroxy, or oxo , amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkyl alkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl , sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, Trimethylsilyl, urea, thiourea, allyl which may have a substituent, optionally substituted heteroaryl; optionally substituted alkyl; cycloaliphatic which may be substituted, heterocycloaliphatic which may be substituted aryl, optionally substituted heteroaryl, optionally substituted haloalkyl, Optionally substituted aroyl, optionally substituted heteroaroyl, substituted acyl; optionally substituted alkenyl; optionally substituted alkynyl which may be substituted, aralkyl which may be substituted, cycloalkyl which may be substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Heterocycloalkyl or optionally substituted heterocycloalkenyl, amino acid or cytisine, or R 4 is a protecting group, or -(CH 2 ) V -FORMULA 1 (referred to as chemical formula A), where v in the chemical formula A is 0, 1, 2, 3, 4 , 5 or 6, and said FORMULA 1 is a compound of formula I, The R of Formula I 2 , the R 3 and the R 4 At least one of the compounds is not hydrogen. Compound.

2. A compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in medicine. There was, 【Chemistry 2】 R of Formula I 1 teeth, Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic optionally substituted allyl; optionally substituted heteroaryl; - (CH 2 ) m -NR 6 R 7 R 8 (side chain 1), - (CH 2 ) m -O-(CH 2 ) n -R 10 (side chain 2), - C.N., -COOR 12 (side chain 3), - (CH 2 ) O -CO-(CH 2 ) P -R 13 (side chain 4) Amino acids or esters thereof, Acyl chloride, a protecting group, or cytisinyl, R of Side Chain 1 6 and R 7 each independently represents hydrogen, halo, hydroxy, oxo, amino , amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino No, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulf Anil, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethyl aryl, urea, thiourea, optionally substituted allyl, optionally substituted optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted silyl Cycloaliphatic, optionally substituted heterocycloaliphatic, substituted Heteroaryl which may have a group, haloalkyl which may have a substituent, aroyl which may have a substituent, heteroaroyl which may have a substituent, substituted acyl, optionally substituted alkenyl, optionally substituted aryl alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl alkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclo A group consisting of a cycloalkyl or an optionally substituted heterocycloalkenyl group. or The R of the side chain 1 6 and the above R 7 One of the groups is -CO-R 9 (side chain 5), and R 6 and the above R 7 the other is selected from the group of groups described above; R of Side Chain 1 8 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted heterocycloalkenyl optionally bearing a group, or absent; R of the side chain 5 9 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, m of the side chain 1 is 0, 1, 2, 3, 4 or 5; R of Side Chain 2 10 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, m and n of the side chain 2 each independently represent 0, 1, 2, 3, 4, or 5; R of the side chain 3 12 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, R of the side chain 4 13 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, o and p in the side chain 4 each independently represent 0, 1, 2, 3, 4, or 5; R of Formula I 2 , R 3 and R 4 each independently represents hydrogen, halo, hydroxy, or oxo , amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkyl alkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl , sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, Trimethylsilyl, urea, thiourea, allyl which may have a substituent, optionally substituted heteroaryl; optionally substituted alkyl; cycloaliphatic which may be substituted, heterocycloaliphatic which may be substituted aryl, optionally substituted heteroaryl, optionally substituted haloalkyl, Optionally substituted aroyl, optionally substituted heteroaroyl, substituted acyl; optionally substituted alkenyl; optionally substituted alkynyl which may be substituted, aralkyl which may be substituted, cycloalkyl which may be substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Heterocycloalkyl or optionally substituted heterocycloalkenyl, amino acid or cytisine, or 4 is a protecting group, or -( CH 2 ) V -FORMULA 1 (chemical formula A) A's v is 0, 1, 2, 3, 4, 5 or 6, and said FORMULA 1 is a compound of formula I is a compound of The R of Formula I 2 , the R 3 and the R 4 At least one of the compounds is not hydrogen. Compound.

3. The R 1 represents an optionally substituted methyl group, an optionally substituted ethyl group , optionally substituted C including an optionally substituted propyl group 1-8 Alkyl It is based on The optionally substituted methyl group includes aminomethyl and halogenated methyl. The methyl halide may be chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, or the like. Contains bromomethyl, trifluoromethyl, bromomethyl, dibromomethyl, and tribromomethyl. fruit, The optionally substituted ethyl group is 1- or 2-aminoethyl, hydroxyethyl, ethyl, and ethyl halide, the ethyl halide being 2,2,2-trichloroethylene 2,2,2-tribromoethyl or 2,2,2-trifluoroethyl, The optionally substituted propyl group is 1-, 2- or 3-aminomethyl, hydroxypropyl, 3. The compound of claim 1 or 2, comprising an alkoxypropyl or a propyl halide.

4. The R 1 is an unsubstituted C including propyl, isopropyl, butyl or tert-butyl. 3 -8 3. The compound according to claim 1 or 2, which is an alkyl group.

5. The R 1 is an unsubstituted or unsubstituted phenyl group containing a phenyl group or an optionally substituted phenyl group. Allyl which may have a substituent, such as chlorophenyl, bromophenyl, fluorophenyl, phenyl, perchlorophenyl, perbromophenyl, perfluorophenyl, or tolyl , aniline, phenol, styrene, benzonitrile, anisole, acetophenone, 3. The compound according to claim 1 or 2, which comprises a halogenated phenyl group containing benzoic acid or benzoyl aldehyde. Compound.

6. The R 1 benzyloxypyridine, pyridones including 2-pyridone, 2-pyridines, Pyridines including 3-pyridine or 4-pyridine, phenyltriazoles, The triazole and triazole methyl pivalic acid may be substituted with a group.

3. The compound according to claim 1 or 2, which is optionally heteroaryl.

7. The R 1 are cyclopentyl, cyclohexyl, morpholinyl, piperidyl, piperazine, substituted with groups including aryl, tetrahydrofuryl, oxolanyl, or dioxanyl; 3. The compound according to claim 1 or 2, which is optionally cycloalkyl or heterocycloalkyl. 。

8. The R 1 is vinyl, acrylate or -C=C-C 6 H 5 Acetinyl, -C≡C-C 6 H 5 or a -C≡C-trimethylsilyl group which may have a substituent; 2-8 Alkenyl or substituted C which may have a substituent 2-8 3. The compound of claim 1 or 2, which is alkynyl.

9. The R 1 is an amine, an N-alkylamine, an N,N-dialkylamine or an amide. The compound according to claim 1 or 2.

10. The R 1 amine, methylamine, ethylamine, propylamine, isopropylamine amine, benzylamine, dimethylamine, trimethylammonium methyl, dimethylamine 10. The compound of claim 9, which is any one of: benzamido, benzamido, or acetamido. 。

11. The R 1 is methoxy, ethoxy, propoxy, benzyloxy or trifluoromethyl 3. The compound according to claim 1 or 2, which is any one of:

12. The R 1 Ethyl ester, propyl ester, isopropyl ester, butyl ester 3. The compound according to claim 1 or 2, which is a carboxylic acid or ester, including a terephthalic acid or phenyl ester. Compound.

13. The R 1 are alanine, arginine, asparagine, aspartate, cysteine, Glutamine, Glutamate, Glycine, Histidine, Isoleucine, Leucine, Lysine , methionine, phenylalanine, proline, serine, threonine, tryptophan, Contains oleic acid, valine or their methyl, ethyl, propyl or isopropyl esters 3. The compound according to claim 1 or 2, which is a naturally occurring amino acid or an ester thereof.

14. The R 1 is tert-butyloxycarbonyl (Boc), formyl, acetyl (A c), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Boc), carboxyl (Cbz), or fluorenylmethoxycarbonyl (Fmoc) or protected boryl protecting groups, such as (pinacolato)borane (BPin) and (catecholato)borane (BPin). ) Borane (BCat) (RO) 2 The compound of claim 1 or 2, comprising the B-structure.

15. The R 2 and the R 3 The compound according to any one of claims 1 to 14, wherein is hydrogen.

16. The R 4 is a protecting group or hydrogen.

17. (+) 4-trylcytisine, (-) 4-ethylcytisine, A compound selected from (+) 4-vinylcytisine.

18. 18. A compound according to claim 17 for use in medicine.

19. A compound according to any one of claims 1 to 18 for use in the prevention or treatment of poisoning. 。

20. The addiction is any one of nicotine addiction, alcohol addiction, and drug addiction. Item 20. The compound according to item 19.

21. A method for treating a pulmonary disease comprising administering to a patient a compound according to any one of claims 1 to 20, and a pharma- ceutically acceptable excipient. A composition comprising:

22. 22. The composition of claim 21 for use in the prevention or treatment of poisoning.

23. 23. The method of claim 22, wherein the addiction is nicotine addiction, alcohol addiction, and drug addiction. Composition.

24. A method for preventing or treating poisoning in a subject (other than a human) in need of treatment, comprising administering an effective amount of A compound according to any one of claims 1 to 20 or any one of claims 21 to 23. A method for preventing or treating poisoning, comprising the step of administering the composition described above to the subject.

25. 1. A process for preparing a 4-substituted cytisine analogue, comprising the steps of: Step i to produce a compound of formula IIa; 【Chemistry 3】 Step ii to produce a compound of formula IIb; 【Chemistry 4】 CompB of the formula IIb is R 1 to produce a compound of formula I. iii. 【Chemistry 5】 R of Formula IIa 2 , R 3 and R 4 each independently represents hydrogen, halo, hydroxy, Oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N- Dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulf phenyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpiva aryl acid, trimethylsilyl, urea, thiourea, optionally substituted allyl, Heteroaryl which may have a group, alkyl which may have a substituent, optionally substituted cycloaliphatic; optionally substituted heterocycloaliphatic aryl, optionally substituted heteroaryl, optionally substituted haloaryl alkyl, an optionally substituted aroyl, an optionally substituted heteroaroyl, Optionally substituted acyl, optionally substituted alkenyl, alkynyl which may be substituted, aralkyl which may be substituted, cycloalkyl, optionally substituted cycloalkenyl, Heterocycloalkyl or heterocycloalkenyl, or R is selected from Group 1 of the group consisting of amino acid and cytisine; 4 is a protecting group, or , -(CH 2 ) V -FORMULA 1 (chemical formula A) In the formula A, v is 0, 1, 2, 3, 4, 5 or 6, and the formula 1 is is a compound of formula I, The R of Formula IIb 2 , the R 3 and the R 4 is selected from group 1 of the above groups and CompB is a boron complex obtained by contacting the compound of formula IIa with a boronizing agent. It is a body, The R of Formula IIa 1 teeth, Hydroxy, halogen, an optionally substituted aliphatic Optionally substituted cycloaliphatic optionally substituted heterocycloaliphatic optionally substituted allyl; optionally substituted heteroaryl; - (CH 2 ) m -NR 6 R 7 R 8 (side chain 1), - (CH 2 ) m -O-(CH 2 ) n -R 10 (side chain 2), - C.N., -COOR 12 (side chain 3), - (CH 2 ) O -CO-(CH 2 ) P -R 13 (side chain 4) Amino acids or esters thereof, Acyl chloride, a protecting group, or cytisinyl, R of Side Chain 1 6 and R 7 are each independently halo, hydroxy, oxo, amino, or a amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, Phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanilic aryl, sulfamide, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl allyl, urea, thiourea, allyl which may have a substituent, Heteroaryl which may be substituted, alkyl which may be substituted, cyclo which may be substituted Aliphatic, optionally substituted heterocycloaliphatic, Heteroaryl which may have a substituent; haloalkyl which may have a substituent; aroyl which may be substituted, heteroaroyl which may be substituted, acyl which may be substituted, alkenyl which may be substituted, alkyl which may be substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl , optionally substituted cycloalkenyl, optionally substituted heterocyclo Group 2 of the group consisting of alkyl or optionally substituted heterocycloalkenyl or R of Side Chain 1 6 and R 7 One of the groups is -CO-R 9 (side chain 5), and R 6 and the above R 7 The other is selected from group 2 of the above groups, R of Side Chain 1 8 is halo, hydroxy, oxo, amino, amido, nitro, cyano, Alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulf E, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea A. An optionally substituted aryl, an optionally substituted heteroaryl, a optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic groups optionally having a group, heterocycloaliphatic groups optionally having a substituent Allyl, optionally substituted haloalkyl, optionally substituted aroyl, Heteroaroyl which may have a substituent, acyl which may have a substituent, Alkenyl which may have a substituent, alkynyl which may have a substituent, arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or heterocycloalkenyl, optionally having 1 or no aryl group; R of the side chain 5 9 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, m of the side chain 1 is 0, 1, 2, 3, 4 or 5; R of Side Chain 2 10 is halo, hydroxy, oxo, amino, amido, nitro, cyano, Alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulf E, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea A. An optionally substituted aryl, an optionally substituted heteroaryl, a optionally substituted alkyl, optionally substituted cycloaliphatic, Heterocycloaliphatic groups optionally having a group, heterocycloaliphatic groups optionally having a substituent Allyl, optionally substituted haloalkyl, optionally substituted aroyl, Heteroaroyl which may have a substituent, acyl which may have a substituent, Alkenyl which may have a substituent, alkynyl which may have a substituent, arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or heterocycloalkenyl, m and n of the side chain 2 each independently represent 0, 1, 2, 3, 4, or 5; R of the side chain 3 12 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano. No, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl , carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, Sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thio Urea, optionally substituted allyl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic Heterocycloaliphatic which may be substituted, Heterocycloaliphatic which may be substituted aryl, haloalkyl which may have a substituent, alloy which may have a substituent aryl, optionally substituted heteroaroyl, optionally substituted acyl, substituted Alkenyl which may have a group, alkynyl which may have a substituent, arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or and selected from heterocycloalkenyl which may have the formula: R of the side chain 4 13 is hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyclohexyl Ano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl aryl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido , sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiamine aurea, an optionally substituted allyl, an optionally substituted heteroaryl, Optionally substituted alkyl, optionally substituted cycloaliphatic , optionally substituted heterocycloaliphatic, optionally substituted Heteroaryl, optionally substituted haloalkyl, optionally substituted allo aryl, optionally substituted heteroaroyl, optionally substituted acyl, Optionally substituted alkenyl, optionally substituted alkynyl, substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or substituted is selected from heterocycloalkenyl optionally bearing a group, o and p in the side chain 4 each independently represent 0, 1, 2, 3, 4, or 5; The R of Formula I 2 , the R 3 and the R 4 At least one of the hydrogen atoms is not hydrogen. Manufacturing method.

26. The compound of formula IIa provided in step i is 4 A hydrogen atom at the position Including, Step i further comprises reacting said R 4 Substitution of a hydrogen atom at position 26. The method of claim 25, comprising:

27. 27. The method of claim 26, wherein the protecting group is tert-butyloxycarbonyl (Boc). Method for preparation of

28. 28. The method of claim 26 or 27, wherein the compound of formula IIa is cytisine. Law.

29. The boronizing reagent has the formula (RO): 2 -B-B-(OR) 2 Or HB (OR) 2 Represented by 29. The method of any one of claims 25 to 28, having a chemical structure as follows:

30. The boronation reagent is bis(pinacolato)diboron (B 2 Pin 2 ), or Bis(catechol G) Diboron (B 2 Cat 2 29. The process according to any one of claims 25 to 28, 。

31. the molar ratio of the boronating reagent, said formula IIa, to the starting material 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 31. The method of any one of claims 25 to 30, wherein the ratio of glycerol to glycerol is at least 2:

1.

32. 32. The method of claim 25, wherein the reaction in step ii is carried out in the presence of a catalyst. The preparation method according to any one of claims 1 to 4.

33. 33. The process according to claim 32, wherein the catalyst is a transition metal catalyst.

34. The transition metal catalyst may include iridium, palladium, zinc, nickel and / or rhodium.

34. The method of claim 33, comprising:

35. 35. Any of claims 25 to 34, wherein the reaction in step ii is carried out in a solvent. The preparation method according to claim 1.

36. The solvent may be an ester solvent, an ether solvent, a ketone solvent, a sulfoxide solvent, an aromatic solvent, or the like.

36. The method of claim 35, comprising the step of: Preparation method.

37. 37. Any one of claims 25 to 36, wherein step ii is carried out in the presence of a ligand. The preparation method described in

38. The ligand is tetramethyl-1,10-phenanthroline (Me4phen), di -tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (b py), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2- Di-tert-butylphosphinophenyl)ether, 1,3-bis(diphenylphosphine 1,2-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe ), hexamethylbenzene (C6Me6), xantphos, or 1,2-bis(dimethyl 38. The method of claim 37, wherein the aryl group is one of aryl phosphino)ethane (dmpe).

39. The ligands are phenanthroline (phen), dimethylphenanthroline (me2 phen), tetramethyl-1,10-phenanthroline (me4phen), Anthroline (bathophen), di-tert-butyl-2,2'-bipyridyl ( dtbpy), 2,2'-bipyridine (bpy), dimethoxy-2,2'-bipyridyl ( MeO-bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), Bis(2-di-tert-butylphosphinophenyl)ether, 1,3-bis(diphenylphosphinophenyl)ether 1,2-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), neocuproine, xantphos, 1,2-bis(dimethylphosphino)ethane (dmpe), or a compound according to formula 6 38. The method of claim 37, wherein the method is any one of the following: 【Chemistry 6】

40. The molar ratio of the boronation reaction to the starting material of formula IIa is less than 2:1, or less than 1.5: Less than 1, or less than 1:1, or less than 0.75:1, or less than 0.5:1, or 0.1:1 40. The method of claim 37, wherein the ratio of ...

2. The preparation method according to claim 1 .

41. The boronation reaction in step ii is carried out at a temperature of 50° C. to 100° C.

41. The method of claim 25 .

42. Prior to the commencement of step iii, the compound of formula IIb is and / or the step ii) is not separated from the product mixture formed by the step ii) 42. The process according to any one of claims 25 to 41, wherein no purification step is carried out between i. Law.

43. Step iii is initiated in the same reaction region in which step ii is carried out.

43. A method for preparing a composition according to any one of claims 25 to 42.

44. In step iii, CompB is 1 The first intermediate of the substituent and the 44. The method of any one of claims 25 to 43,

45. The R 1 The first intermediate of the substituent is R 1 The second intermediate of the substituent is replaced or Record R 1 45. The preparation of claim 44, wherein the compound of formula I is substituted with a substituent. method.

46. The R 1 The second intermediate of the substituent is 1 or R 1 46. ​​The method of claim 45, wherein the compound of formula I is prepared by the steps of: Law.

47. The R 1 The first intermediate, the second intermediate, and the third intermediate of the substituent are bromo, chloro, b, iodo, benzyloxypyridine, alkyl ester, methyl ester, alkenyl , vinyl, alkynyl, acetylenyl, trimethylsilylacetylene, 1,2,3-trimethylsilylacetylene Azol-1-ylmethyl pivalic acid, cyano, aminomethyl, N-Boc-aminomethyl or (benzyloxy)carbonyl)piperazin-1-yl, Item 47. The preparation method according to item 46.

48. The compound of formula IIb or formula I is 4 a protecting group at position The preparation method further comprises the step of: 4 Deprotection of the group 48. The method of any one of claims 25 to 47, further comprising the steps of:

49. The R of the compound of formula IIb or formula I 4 The step of deprotecting the group , after completion of step ii, or before the start of step iii, or 49. The process according to claim 48, wherein the process is carried out during step i or after completion of step iii.

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