Compound

Abstract

The present invention provides novel analogs of cytisine, methods for their use in medicine, such as the treatment of addiction, and improved synthetic methods for preparing analogs of cytisine. The present invention provides novel analogs of cytisine, processes for preparing the analogs, pharmaceutical compositions containing the analogs, and methods for using the novel analogs of cytisine in the prevention or treatment of central nervous system disorders, including addictive disorders. The chemical structure of the novel analogs of cytisine of the present invention is shown in Formula I. [Formula 1] TIFF2022159381000240.tif37170

Description

[Technical field]

[0001] The present invention relates to novel analogs of cytisine and to their use in medicine, for example in the treatment of addiction. The present invention also relates to the preparation of analogs of cytisine. Manufacturing Also provided is an improved synthetic method for [Background technology]

[0002] Nicotinic acetylcholine receptors (nACh R) nACh is an ionotropic receptor expressed in various parts of the human brain and other parts of the central nervous system. R is It is involved in a variety of physiological functions, such as cognitive function, learning and memory, sleep, anxiety, arousal, reward, motor control and other neurological functions. nACh R is It has also been implicated in a number of disease states, such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism and schizophrenia. R is It has also been implicated in various drug addictions and dependences, such as nicotine addiction (Non-Patent Document 1), alcohol addiction (Non-Patent Document 2), and drug dependency (Non-Patent Document 3).

[0003] nACh R Numerous subtypes are known to exist. Muscle-type nicotinic receptors (located at the neuromuscular junction) are known to be formed by five distinct substructures: α, β, γ, δ, and a recently discovered additional subunit, ε.

[0004] Neuronal nACh R( (located in the central nervous system, peripheral ganglia, and adrenal medulla) are either homomeric or heteromeric. Type Only two classes of subunits, designated α2-α9 and β2-β9, that can be combined into Many neurodegenerative subtypes have been discovered, but heteromers Type Combination (α4)3(β2)2, α3β4 and homomers Type α7 in the brain NotableAmong them, heteromers Type Combination α4β2 is the predominant subtype in the central nervous system, accounting for approximately 90% of receptors, and binds ACh with high affinity. Type Combination is the other major subtype and binds ACh with low affinity.

[0005] Heteromer Type Combination α4β2 can be assembled into two different stoichiometries, (α4)2(β2)3 and (α4)3(β2)2, which are usually referred to as A2B3 and A3B2, respectively. The major α4β2 subtype has been proposed to have the structure A2B3, formed from two α4 and three β2 subunits, and is the main subtype involved in addiction.

[0006] Nicotine is thought to activate this α4β2 receptor subtype, thereby increasing the release of dopamine into the nucleus accumbens and prefrontal cortex, specific parts of the human brain that have been linked to drug addiction.

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

[0008] nACh R Compounds with the ability to modulate have been found to be effective in treating conditions associated with these receptors. For example, studies suggest that transdermally administered nicotine can improve cognitive function in people suffering from age-related memory impairment (see, for example, Non-Patent Document 6). However, there are several disadvantages to the use of nicotine, even when administered transdermally: for example, nicotine use is known to be addictive, and a 2014 U.S. Surgeon General's report noted that nicotine has adverse effects on pregnancy outcomes and fetal brain development.

[0009] In the field of smoking cessation therapy, nicotine is used to help smokers quit smoking, either via the oral route (e.g., tablets or chewing gum) or transdermally. deliveryProducts that achieve this have also been developed and are publicly known.

[0010] nACh R Other compounds that modulate the agonist have also been found to be used in the treatment of addiction. Varenicline has been commercialized by Pfizer under the brand name Chantix® in the United States and Champix® in Europe and has been approved for use in smoking cessation treatment. Additionally, the drug has lagged behind in the treatment of alcohol and drug dependence (Non-Patent Document 4 and Non-Patent Document 5).

[0011] Mihalak et al. (Non-Patent Document 7) discovered that varenicline is a partial agonist at the α4β2 receptor, a weak agonist at the α3β4 receptor, a partial agonist at the α3β2 and α6 receptors, and a potent agonist at the α7 receptor.

[0012] A further drug used in smoking cessation treatment is cytisine. Cytisine is a naturally occurring, pyridone-containing alkaloid that inhibits the action of nACh R Known as a partial agonist. Pharmacologically, cytisine exhibits a high degree of similarity to nicotine and has been successfully used as a smoking cessation aid for many years now. The chemical structure of cytisine (or more specifically, the (-) enantiomer of cytisine) is shown below: [ka]

[0013] While cytisine is a safe and effective smoking cessation treatment, there have been attempts to generate functionalized derivatives of the compound.

[0014] A variety of different numbering systems for cytisine have been used in the past. For purposes of this discussion, and of the present 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. summarized previous work on the introduction of substituents in the cytisine structure (mainly at the 3- and 5-positions) and disclosed the synthesis of racemic analogs that are reportedly new and contain substituents at the 3-, 4-, and 7-positions.

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

[0017] Thus, the studies conducted by Kozikowski et al. demonstrated that analogs of cytisine substituted at the 4-position were significantly different from the known addiction treatments cytisine and varenicline.

[0018] More recently, work by other teams has focused on substitutions at other positions in the cytisine structure. For example, in US Pat. No. 5,399,633, an analogue of cytisine was synthesized having the overall structure shown below. [ka] Furthermore, in Patent Document 2, the analogue of cytisine is , on the piperidine ring Substituents at the 5-position and / or Nitrogen Contains elementary atoms.

[0019] Rouden et al. (Non-Patent Document 10) have produced a comprehensive review of all the different studies on functionalized derivatives of cytisine. [Prior art documents] [Patent documents]

[0020] [Patent Document 1] International Publication No. 2014 / 001318 [Patent Document 2] Specification of Chinese Patent Gazette No. 103509021 [Patent Document 3 Specification of US Patent No. 6,099,562 [Patent Document 4 Specification of US Patent No. 5,886,026 [Patent Document 5 Specification of US Patent No. 5,304,121 [Non-Patent Document

[0021] [Non-Patent Document 1 Schalling and Waller, Acta Physiologica Scandinavica. Supplementum, 1980, volume 479, pages 53-56. [Non-Patent Document 2 Holgate et al., Brain Science, 2015, September 5(3), pages 258-274. [Non-Patent Document 3 Rahman et al., Frontiers in Neuroscience, 2014, volume 8, article 426. [Non-Patent Document 4 Mitchell et al., Pyschopharmacology, October 2012, 223 3, pages 299 to 306. [Non-Patent Document 5 Crunelle et al., European Neuropsychopharmacology,February 2010,20,2,pages 69 to 79. [Non-Patent Document 6 White et al., Psychopharmacology, February 2004, 171, 4, pages 465 to 471. [Non-Patent Document 7 Mihalak et al. (Molecular Pharmacology, 2006, September, 70(3), pages 801 to 805. [Non-licensed document 8] Kozikowski et al., Journal of Medical Chemistry, 2006, 49, pages 2673 to 2676.

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

[0022] Despite substantial research into analogs of cytisine and their potential to provide pharmaceutical agents with improved properties compared to cytisine and / or other nAChR binding agents, to the inventors' knowledge, no such compounds have progressed into clinical trials, let alone been approved as a pharmaceutical product. So, for example, As a medicine for treating poisoning, etc. Improved safety and / or Yes There remains a need for pharmaceutical agents that have improved properties compared to cytisine, such as efficacy. [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 useProvide together.

[0025] Further Aspects A further aspect of the invention, described in more detail below, provides a method for conveniently preparing 4-substituted analogs of cytisine. Manufacturing This is a preparation method for

[0026] The compounds and compositions of the invention are useful in medicine. For example, they may be used to prevent, treat, or ameliorate symptoms of disorders of the central nervous system, including addictive disorders such as nicotine, alcohol, and drug addiction. stomach.

[0027] The compounds of this aspect of the invention have been identified by the inventors as having therapeutic suitability, particularly in the treatment of drug, alcohol and / or tobacco addiction and / or dependence. for identified as useful for was . A limited number of 4-substituted analogs of cytisine have been previously disclosed, but the limited binding data available for these compounds did not indicate their applicability for use in medicine, and the authors of those disclosures concluded that these compounds showed poor efficacy as modulators of receptors associated with neurological disorders, including dependence and addiction. For example, Rouden et al. concluded in Non-Patent Document 10 that the 4-substituted cytisine analogs tested "did not show agonist activity." sex "It showed no effect on nicotine-activated channel function at both α4β2 and α3β4 receptors." However, surprisingly and unexpectedly, the present inventors have discovered, based on emerging data, discussed in more detail below, that these compounds exhibit previously unnoticed advantages.

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

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

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

[0031] As used herein N An "alkyl" group refers to an aliphatic saturated hydrocarbon group containing 1 to 12 (eg, 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, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. Alkyl groups can be substituted (ie, optionally substituted) with one or more substituents such as the following. Halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, - Heteroaryl - Aryl, alkoxy, aroyl, heteroaroyl, aroyl S aryl [e.g. (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido, [e.g. (cycloalkylalkyl)carbonylamino, aryl - arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroaryl - arylcarbonylamino, heteroarakylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, aryl - Aminocarbonyl, or heteroaryl - aminocarbonyl], amino [e.g. aliphatic amino, cycloaliphatic amino, or heterocycloaliphatic amino], sulfonyl [e.g. aliphatic-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryl - Ruoxy, Heteroaryl - aryloxy, aralkyloxy, heteroaryloxy - alkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.

[0032] As used herein N An "alkenyl" group is an aliphatic carbon group containing 2 to 12 (eg, 2 to 8, 2 to 6, or 2 to 4) carbon atoms and at least one double bond. Like the alkyl group, the alkenyl group may be a straight-chain or branched-chain alkenyl group. Examples of alkenyl groups include, but are not limited to, allyl, vinyl, isoprenyl, 1-propenyl, 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. 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], aryl, - Heteroaryl - Aryl, alkoxy, aroyl, heteroaroyl, aroyl S [e.g. (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or (heterocycloaliphatic) carbonyl], nitro, cyano, amino Do [ For example, (cycloalkylalkyl)carbonylamino, aryl - arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroaryl - arylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylcarbonylamino, heteroaralkylcarbonylamino ... arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, arylcarbonylamino, - Aminocarbonyl, or heteroaryl - aminocarbonyl], amino [e.g. aliphatic amino, cycloaliphatic amino, heterocycloaliphatic amino, or aliphatic sulfonylamino], sulfonyl [e.g. alkyl-SO2-, cycloaliphatic-SO2-, or arylamino], - -SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryl - Ruoxy, Heteroaryl - Aroxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.

[0033] As used herein N An "alkynyl" group is an aliphatic carbon group containing 2 to 12 (eg, 2 to 8, 2 to 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, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 6-hexynyl. An alkynyl group may contain one or more substituents such as inIt may be optionally substituted. Aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl - Ruoxy, Heteroaryl - aryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g. aliphatic sulfanyl or cycloaliphatic sulfanyl], sulfinyl [e.g. aliphatic sulfinyl or cycloaliphatic sulfinyl], sulfonyl [e.g. aliphatic-SO2-, aliphatic amino-SO2- or cycloaliphatic-SO2-], amido [e.g. aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, aryl - Aminocarbonyl, Aryl - heterocycloalkylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroaryl - arylcarbonylamino or heteroaryl - aminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl - Heteroaryl - L, A S [e.g. (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino (e.g. aliphatic amino), sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaliphatic)oxy. - (r)alkoxy.

[0034] As used herein N , used alone or in combination with "aralkyl", "aralkoxy", or "aryl" -"Aryl" used as part of a larger moiety, such as in "aryloxyalkyl" - "aryl" groups include monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl) and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, tetrahydroanthracenyl, anthracenyl) groups. ring Refers to the system, monocyclic ring The system is aromatic or bicyclic or tricyclic ring At least one of the systems 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, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aliphatic - Heteroaryl - Aryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryl - Ruoxy, Heteroaryl - aryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, oxo (benzo-fused bicyclic or tricyclic aryl - Non-aromatic carbon Ringabove), nitro, carboxy, amido, acyl [e.g. (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], sulfonyl [e.g. aliphatic-SO2- or amino-SO2-], sulfinyl [e.g. aliphatic-S(O)- or cycloaliphatic-S(O)-], sulfanyl [e.g. aliphatic-S-], cyano, halo, hydroxy, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, or carbamoyl. Or, Ali - The alkyl group may be unsubstituted.

[0035] Optionally substituted aryl - Non-limiting examples of the rules include: Termites - [e.g. mono-, di- (e.g. p,m-dihalotermes - (Halogen) and (Trihalo) ants - (carboxy)aryl - Aryl [e.g. (alkoxycarbonyl)aryl] - Aryl, ((aralkyl)carbonyloxy)aryl - Aryl and (alkoxycarbonyl)aryl - Aryl], (amide) aryl - Aryl [e.g., (aminocarbonyl)aryl - Aryl, (((alkylamino)alkyl)aminocarbonyl)aryl - Aryl, (alkylcarbonyl)amino aryl - Ru, (Ari - (aminocarbonyl) aryl - Heteroaryl and - (aryl)amino)carbonyl)aryl - ru], amino aryl - Aryl [e.g., ((alkylsulfonyl)amino)aryl] -Aryl or ((dialkyl)amino)aryl - Aryl, (cyanoalkyl)aryl - Ru, (alkoxy) aryl - Ru, (sulfamoyl) ari - Aryl [e.g., (aminosulfonyl)aryl] - Aryl], (alkylsulfonyl) aryl - Ru, (cyano) ari - Aryl, (hydroxyalkyl)aryl - Aryl, ((alkoxy)alkyl)aryl - aryl, (hydroxy)aryl - Aryl, ((carboxy)alkyl)aryl - Aryl, (((dialkyl)amino)alkyl)aryl - Aryl, (nitroalkyl)aryl - Aryl, (((alkylsulfonyl)amino)alkyl)aryl - ((heterocycloaliphatic)carbonyl)aryl - Aryl, ((alkylsulfonyl)alkyl)aryl - Aryl, (cyanoalkyl)aryl - Aryl, (hydroxyalkyl)aryl - Aryl, (alkylcarbonyl) aryl - Aryl, alkyl aryl - Aryl, (trihaloalkyl)aryl - p-amino-m-alkoxycarbonyl aryl - Le, p-amino-m-cyanoaryl - p-Halo-m-amino aryl - m-(heterocycloaliphatic)-o-(alkyl)aryl or (m-(heterocycloaliphatic)-o-(alkyl)aryl - Ru.

[0036] As used herein N "Araliphatic" such as "aralkyl" groups are ants - Aliphatic groups substituted with alkyl 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 alkyl groups (e.g., 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, including carboxyalkyl, hydroxyalkyl, or haloalkyl, such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, - Heteroaryl - aryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl - Ruoxy, Heteroaryl - aryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g. aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkylcarbonylamino, aryl - arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroaryl - Aralkylcarbonylamino or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo or carbamoyl.

[0038] As used herein N “Bicyclic ring The "system" consists of two ring Form 8 to 12( For example, 9, 10 or 11) member It contains two structures: ring has at least one atom share (e.g., two atoms share do). bicyclic ring The system is B Cycloaliphatic (e.g. B Cycloalkyl or B cycloalkenyl), B Cycloheteroaliphatic, bicyclic Ants - Ru and bicyclic Hetero ant - Includes

[0039] As used herein N "Carbocycle formula" Or, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which is optionally substituted as previously described.

[0040] As used herein N A "cycloalkyl" group is a saturated carbocyclic monocyclic ring of 3 to 10 (e.g., 5 to 10) carbon atoms. formula or bicyclic (fused or bridged) ring Refers to... Examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-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]decyl, B cyclo[2.2.2]octyl, adamantyl or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0041] A "cycloalkenyl" group, as used herein, refers to a non-aromatic cycloalkenyl group of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Ring Point. Examples of cycloalkenyl groups are as follows: Cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, B Cyclo[2.2.2]octenyl or B Cyclo[3.3.1]nonenyl.

[0042] A cycloalkyl or cycloalkenyl group may have one or more substituents such as in It may be optionally substituted. Fluorescent, aliphatic [e.g. alkyl, alkenyl or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aliphatic - Heteroaryl - Aryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryl - Ruoxy, Heteroary - alkyoxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aliphatic)carbonylamino, - (heterocycloaliphatic)carbonylamino, (heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, (heteroaryl)carbonylamino, (heteroaryl)carbonylamino, (heteroaryl)carbonylamino, -(cycloaliphatic)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO2- and aryl]. - aryl-SO2-], 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 "heterocycle" or "heterocycloaliphatic" embraces heterocycloalkyl and heterocycloalkenyl groups, each of which is optionally substituted as previously described.

[0044] As used herein N A "heterocycloalkyl" group is a 3- to 10-membered monocyclic ring formula or bicyclic (fused or bridged) (e.g., 5- to 10-membered monocyclic formula or bicyclic) saturated ring It refers to a structure, one or more ring The atom is a heteroatom (eg, 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, trithianyl, thiomorpholinyl, 1 ,3-Dioxolanyl, imidazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, isoxazolidinyl, morpholinyl, pyrrolidonyl, pyrazolidinyl, tetrahydrothiophenyl, oxathiolanyl, pyranyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiophene hmm yl, 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. Monocyclic heterocycloalkyl groups can be fused to a phenyl moiety to form structures such as tetrahydroisoquinoline, which are heteroaryl groups. - would be classified as

[0045] A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicyclic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring system having one or more double bonds. ring It refers to a structure, one or more ring The atom is a heteroatom (eg, nitrogen, oxygen, or sulfur). Monocyclic and bicyclic heterocycloaliphatic Q is They are numbered according to standard chemical nomenclature.

[0046] A heterocycloalkyl or heterocycloalkenyl group may optionally contain one or more substituents such as in It can be substituted. Fluorescent, aliphatic [e.g. alkyl, alkenyl or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aliphatic - Heteroaryl -Aryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryl - Ruoxy, Heteroary - alkyoxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aliphatic)carbonylamino, - (heterocycloaliphatic)carbonylamino, (heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, (heteroaryl)carbonylamino, (heteroaryl)carbonylamino, (heteroaryl)carbonylamino, - (cycloaliphatic)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or aryl]. - sulfonyl], sulfinyl [eg alkylsulfinyl], sulfanyl [eg alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo or carbamoyl.

[0047] "Hetero ants - As used herein, a "cycloalkyl" group is a group having 4 to 15 carbon atoms. ring Monocyclic, bicyclic or tricyclic rings having atoms ring Refers to a system, one or more ring The atoms are heteroatoms (e.g., nitrogen, oxygen, sulfur, or combinations thereof) and are monocyclic. ring The system is aromatic or bicyclic or tricyclic ring At least one of the systems ringis aromatic. Hetero ant - The alkyl group is two to three ring Benzocondensation having The ring Includes the system. For example, a benzo-fused group contains benzo fused to one or two 4- to 8-membered heterocycloaliphatic moieties (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Hetero ant - Some examples of aryl are azetidinyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, thiophenyl, oxazolyl, isophenyl, and phenyl. O Xazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, diazolyl, triazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzothiazolyl, xanthine, thioxanthine, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, puryl, tinolyl, quinolyl, quinazolyl, tinolyl, phthalazyl, quinazolyl, quinolyl tree Salyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl or 1,8-naphthyridyl.

[0048] Without limitation, monocyclic heteroaryls - The rules include: Furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, 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: Indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazyl, benzothiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinolyl tree Salyl, 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, aliphatic - Heteroaryl - Aryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryl - Ruoxy, Heteroary - aryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, oxo (bicyclic or tricyclic heteroaryl) - Non-aromatic carbocyclic or heterocyclic rings ringabove), carboxy, amido, acyl [e.g. (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)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 - (carboxy)heteroaryl - (e.g., (alkoxycarbonyl)heteroaryl - le], cyanoheteroaryl - Aminoheteroaryl - ((alkylsulfonyl)amino)heteroaryl - and ((dialkyl)amino)heteroaryl - (Amido) Heteroaryl - Aminocarbonyl heteroaryl - ((alkylcarbonyl)amino)heteroaryl - Ru, ( (((alkyl)amino)alkyl)aminocarbonyl)heteroaryl - Heteroaryl - (aryl)amino)carbonyl)heteroaryl - ((heterocycloaliphatic)carbonyl)heteroaryl - and ((alkylcarbonyl)amino)heteroaryl - (Cyanoalkyl)heteroaryl - (alkoxy)heteroaryl - (Sulfamoyl) Heteroaryl - (aminosulfonyl)heteroaryl - (sulfonyl)heteroaryl - (e.g., (alkylsulfonyl)heteroaryl - (hydroxyalkyl)heteroaryl - (alkoxyalkyl)heteroaryl - (hydroxy)heteroaryl - ((carboxy)alkyl)heteroaryl - (((dialkyl)amino)alkyl]heteroaryl - (Heterocycloaliphatic) Heteroaliphatic - (cycloaliphatic) heteroaryl - (nitroalkyl)heteroaryl - (((alkylsulfonyl)amino)alkyl)heteroaryl - ((alkylsulfonyl)alkyl)heteroaryl - (cyanoalkyl)heteroaryl - aryl, (acyl)heteroaryl - (e.g., (alkylcarbonyl)heteroaryl - (alkyl)heteroaryl - and (haloalkyl)heteroaryl - [e.g., trihaloalkylheteroaryl - [L]

[0052] As used herein, "heteroaraliphatic" (e.g., heteroaralkyl group) refers to a heteroaryl group. - ruthenium in Replaced Ta Aliphatic groups (e.g., C 1-4 It refers to an alkyl group. "Aliphatic", "Alkyl" and "Heteroaryl" - "Rules" are defined above.

[0053] A "heteroaralkyl" group, as used herein, refers to a heteroaryl - ruthenium in Replaced 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 (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, - Heteroaryl - aryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl - Ruoxy, Heteroaryl - aryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, ...aryloxy, aryloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, aryloxy, aryloxy, heteroaralkyloxy, - arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroaryl - Examples of the arylcarbonylamino include heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, and carbamoyl.

[0054] As used herein N "Cyclic moiety" and "cyclic group" include cycloaliphatic, heterocycloaliphatic, and aryl groups. - Heteroaryl or - Monocyclic, bicyclic or tricyclic rings 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 Aliphatic ring System 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 (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, - Heteroaryl - aryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl - Ruoxy, Heteroaryl - aryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, ...aryloxy, aryloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, aryloxy, aryloxy, heteroaralkyloxy, -arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroaryl - Examples of the arylcarbonylamino include heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, and carbamoyl.

[0056] As used herein N "Amido" includes both "aminocarbonyl" and "carbonylamino". These terms, whether used alone or in combination with other groups, are used as -N(R x )-C(O)-R Y or -C(O)-N(R X )2, and when used internally it refers to an amide group such as -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 (such as alkylcarbonylamides or alkylaminocarbonyls), (heterocycloaliphatic)amides, (heteroaralkyl)amides, (heteroaryl)amides, - (heterocycloalkyl)alkylamides, (heterocycloalkyl)alkylamides, - aryl amide, aralkyl amide, (cycloalkyl)alkyl amide or cycloalkyl amide.

[0057] As used herein N The "amino" group is -NR X R Y Here, R X and R Y each independently represents hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aliphatic, - Heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaliphatic, heteroaliphatic - aryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, aryl - (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaliphatic - (heteroaraliphatic)carbonyl or (heteroaraliphatic)carbonyl, each of which is defined herein and 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 is -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 - Heteroaryl-C(O)- or Heteroaryl - It refers to -C(O)-. Aroyl or heteroaroyl aryl - Heteroaryl and - The position of the ring is optionally substituted as defined above.

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

[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 aliphatic, ali - araryphatic, heterocycloaliphatic, heteroaryphatic - It may be heteroaryl or heteroarylphatic.

[0062] As used herein N The "carboxy" group, when used as a terminal group, is -COOH, -COOR X , -OC(O)H, -OC(O)R X When used internally it 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 -SO3H or -SO3R. X When used internally it refers to -S(O)3-.

[0066] As used herein N The "sulfamide" group, when used as a terminal group, is -NR X -S(O)2-NR Y R ZWhen 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 A "sulfonamide" group, when used as a terminal group, is -S(O)-NR X R Y or -NR X -S(O)2-R Z When used internally, it refers to -S(O)2-NR X -OR-NR X -S(O)2-, where R X , R Y and R Z was set out above.

[0068] As used herein N The "sulfanyl" group, when used as a terminal group, is -SR 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 was set out above. Example sulfinyl groups are aliphatic -S(O)-, aryl - Aryl-S(O)-, (cycloaliphatic (aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl ... - Ru-S(O)- and the like.

[0070] As used herein N A "sulfonyl" group, when used as a terminal group, is -S(O)-R X When used internally it refers to -S(O)2-, where R X was set out above. Example sulfonyl groups are aliphatic -S(O)2-, aryl - Cycloaliphatic-S(O)2-, (cycloaliphatic (aliphatic))-S(O)2-, cycloaliphatic-S(O)2-, heterocycloaliphatic-S(O)2-, heteroaliphatic - This includes aryl-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 refers to fluorine, chlorine, bromine or iodine.

[0073] As used herein N "Alkoxycarbonyl", which is encompassed by the term carboxy, used alone or in combination with other groups, refers to groups such as alkyl-OC(O)-.

[0074] As used herein N "Alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, 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 is aliphatic, alkoxy, ari - Ruoxy, Heteroaryl - aryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy - Heteroaryl - It may be aryl, cycloaliphatic or amino.

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

[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 The structure of the thiourea group teeth , -NR when used as a terminal group X -CS-NR Y R Z When used internally, -NR X -CO-NR Y -OR-NR X -CS-NR Y -, where R X , R Y and R Z was set out above.

[0081] As used herein N "Aliphatic chain" refers to a branched or straight-chain aliphatic group (eg, an alkyl, alkenyl, or alkynyl group). A straight aliphatic chain is -[CH2] V -, where v is 1 to 12. The branched 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 It may be hydrogen or an aliphatic group, but Q must in at least one instance be an aliphatic group. Aliphatic chains include alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

[0082] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." As described herein, the compounds of the invention may contain one or more substituents as generally described above or as exemplified within specific classes, subclasses and genuses of the invention. in It may be optionally substituted. 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 aryl. 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. inIt may be optionally substituted.

[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 - Cycloaliphatic, heterocyclic Cyclo Aliphatic, heteroaliphatic - Ar, haloalkyl and alkyl. For example, the alkyl group may be alkylsulfanyl. in The alkylsulfanyl may be substituted with halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, or aryl groups. - Lu, Termite - 1 to 3 alkyl and alkyl in It may be optionally substituted. In further examples, the cycloalkyl portion of the (cycloalkyl)carbonylamino can be selected from one to three of halo, 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 together with the atoms to which they are bonded 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -aryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; - and optionally substituted aryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, or not present. 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -aryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, an amino acid or cytisine, or R 4 may be a protecting group or -(CH2) V It may also be a group having the structure -FORMULA 1, where v is 0, 1, 2, 3, 4, 5 or 6, and FORMULA 1 is a compound of formula (I) as described herein. 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 、 Optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted 、 Ants - or optionally heteroaryl - Lu is also fine.

[0087] In an embodiment of the present invention, R 1 The substituent at position C may be substituted or unsubstituted. 1-8 , C 1-4 Or C 3-8 It may be an alkyl group, for example propyl, isopropyl, butyl or tert-butyl. In one embodiment of the present invention, R 1 The substituent at the position is 、 Optionally substituted C 1-2 C which may have an alkyl group or a substituent 3-6 It may be an alkyl group. In such an embodiment, C1-2 The alkyl group may have substituents other than hydroxymethyl or fluoromethyl.

[0088] R in the compounds of the present invention 1 Examples of optionally substituted alkyl groups contemplated for use as the substituent at position include the following: Optionally substituted methyl groups, such as aminomethyl, methyl halides, for example chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl or tribromomethyl; optionally substituted ethyl groups, for example 1- or 2-aminoethyl, hydroxyethyl, ethyl halides, for example 2,2,2-trichloroethyl, 2,2,2-tribromoethyl or 2,2,2-trifluoroethyl, or , placed an optionally substituted propyl group, for example 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 optionally substituted aryl - It may also be a For example, the substituent may be a phenyl group or an optionally substituted phenyl group, such as a halogenated phenyl group, e.g., a chlorophenyl, bromophenyl, fluorophenyl, perchlorophenyl, perbromophenyl, perfluorophenyl, or It may be a tolyl, aniline, phenol, styrene, benzonitrile, anisole, acetophenone, benzaldehyde or benzoic acid group.

[0090] (First aspect (2)) In another embodiment, R 1 The substituent at position is an optionally substituted heteroaryl. -It may be, for example, a benzyloxypyridine, a pyridone (for example, 2-pyridone), a pyridine (for example, 2-pyridine, 3-pyridine or 4-pyridine), a phenyltriazole, an optionally substituted triazole or a triazole methylpivalate group.

[0091] R 1 The substituent may alternatively be an optionally substituted cycloalkyl or heterocycloalkyl, such as cyclopentyl, cyclohexyl, morpholinyl, piperidyl, piperazyl, tetrahydrofuryl, oxolanyl, or dioxanyl.

[0092] R 1 Examples of optionally substituted alkenyl groups that may be included at position C include 2-8 Alkenyl, for example, includes 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, i.e., -C≡C-C6H5 or -C≡C-trimethylsilyl groups.

[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 amine, N-alkylamine, N,N-dialkylamine and amide groups in R 1 It may be included as a substituent at position. Examples of groups contemplated for inclusion at that position include: amine, methylamine, ethylamine, propylamine, isopropylamine, benzylamine, dimethylamine, trimethylammoniummethyl, dimethylaminomethyl, benzyl ... Z Amide and acetamide groups. In an embodiment of the invention, m is zero and R 8 If does not exist, R 6 and R 7 are not both 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 Examples of groups contemplated for inclusion at that position include: Methoxy, ethoxy, propoxy, benzyloxy or trifluoromethylbenzyloxy groups. In embodiments of the invention, the following proviso applies: R 1 The substituents in are propoxymethyl groups (i.e., -CH2-O-CH2-CH2CH3), alkoxymethyl groups, or -CH2-O-CH2-C6H4-R 12 or -CH2-O-CH2-C6H 10 -R 12 where R 12 is hydrogen, trifluoromethyl, optionally substituted phenyl, halo or fluorine.

[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 1It may also include esters at any position, such as ethyl ester, propyl ester, isopropyl ester, butyl ester or phenyl ester. In an embodiment of the present invention, R 1 The substituents in 1-3 The substituent may be other than an alkyl ester group or a methyl 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 It may also contain an aldehyde group, for example acetophenone. 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, asparagine, Ruthart , Cysteine, Glutamine, Gluta mart , glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or their methyl, ethyl, propyl or isopropyl esters.

[0100] The compound of the present invention is R 1 In embodiments of the invention that include an amino acid or an ester thereof at a position, the amino acid (or ester) may be linked via any atom (e.g., via an oxygen, carbon, sulfur or nitrogen atom), such as via an oxygen atom in the acid unit to form an amide of aminocytisine, or via a nitrogen atom in the amine unit to form a pyridine of the basic structure of cytisine. ring may be coupled to

[0101] (-Acyl chloride) (-protecting group) For example, tert-butyloxycarbonyl (Boc), formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Cbz), or fluorenylmethoxycarbonyl (Fmoc) or protected boryl protecting groups, optionally having a (RO)2B-structure such as (pinacolato)borane (BPin) and (catecholato)borane (BCat). In embodiments of the present invention, any protecting group commonly used in organic synthesis can be used, such as those outlined in Non-Patent Documents 11 and 12, the contents of which are incorporated herein by reference.

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

[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 2-6Substituents other than alkyl may also be used.

[0104] In an embodiment of the present invention, at position R 4 The substituent in may be a protecting group such as the following: tert-Butyloxycarbonyl (Boc) 、 Formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc), or boronated protecting groups, optionally with the B(OR)2 structure, such as (pinacolato)borane (BPin) and (catecholato)borane (BCat). In embodiments of the present invention, any protecting group commonly used in organic synthesis can be used, such as those outlined in Non-Patent Documents 11 and 12, the contents of which are incorporated herein by reference.

[0105] Unless otherwise specified, structures depicted herein are also meant to include all isomers (e.g., enantiomers, diastereoisomers, geometric (or conformational) isomers) of the structure, such as, for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, the single stereochemistry of the compounds of the present application transformation Optical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures, are within the scope of this 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 are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or replacement of carbon with 13C- or 14C-enriched carbon. 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 However, a convenient synthesis of such compounds has not been proposed. To the best of the inventors' knowledge, no synthetic route has been proposed to obtain 4-substituted analogs of cytisine starting from cytisine. Instead, such compounds have had to be prepared from total synthesis starting from monocyclic materials. See, for example, Scheme 1 of Non-Patent Document 9 and Non-Patent Document 13.

[0108] Further Aspects According to a further aspect of the invention, there is provided a preparative method for making a 4-substituted cytisine analogue, comprising the steps of:

[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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -aryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, an amino acid or cytisine, or R 4 may be a protecting group or -(CH2) V It may also be a group having the structure -FORMULA 1, where v is 0, 1, 2, 3, 4, 5 or 6, and FORMULA 1 is a compound of formula (I) as described herein.

[0110] Step ii: Producing a compound of formula IIb [ka] Here, R 2 , R 3 and R 4 is defined above, and BComp is the boronization reaction product of contacting a compound of formula IIa with a boronizing agent. transformation It is a complex.

[0111] (Step iii: BComp to R 1 to produce a compound of formula I. [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 Mamoru, 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -aryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; - and optionally substituted aryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, or not present. 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl - Heteroaryl which may have a substituent - an alkyl group which may have a substituent; a cycloaliphatic group which may have a substituent; a heterocycloaliphatic group which may have a substituent; a heteroaryl group which may have a substituent; -

[0133] In the present invention, the term "aryl" refers to any of the following: optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, or optionally substituted 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 advantageously carried out using cytisine as the starting material. 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) VIt may also be a group having the structure -FORMULA 1, where v is 0, 1, 2, 3, 4, 5 or 6, and FORMULA 1 is a compound of formula (I) as described herein.

[0113] Thus, in an embodiment, the compound of formula IIa is R 4 The process of the invention may include a protecting group at , and the process of the invention may include the step of adding a protecting group to a compound of formula IIa (including cytisine). One of ordinary skill in the art would be familiar with techniques for adding protecting groups to secondary amines, and any steps in the preparation process for doing so are within the scope of the present invention. For example, R 4 In embodiments where the protecting group added at position is Boc (tert-butoxylcarbonyl), the preparation method involves providing a Boc-containing reagent (e.g., (Boc)O) and dissolving it in a suitable solvent (e.g., one that includes tetrahydrofuran and sodium tricarbonate). Medium with cytisine.

[0114] Thus, in an embodiment of the present invention, R 4 The protecting group present at position may be Boc. Other protecting groups that may be used include: protecting groups such as formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc), or boronated protecting groups, optionally (RO)2B- such as bis(pinacolato)diborane (B2Pin2) and bis(catecholato)diborane (B2Cat2); B- Those having (OR)2 structure. In embodiments of the present invention, any protecting group commonly used in organic synthesis can be used, such as those outlined in Non-Patent Documents 11 and 12, the contents of which are incorporated herein by reference.

[0115] The boronating reagent used in step ii of the process of the present invention may be any boronating reagent known to those skilled in the art of boronating chemistry. For example, the boronating reagent may be a dialkyloxyborane or an alkylborane. Examples of dialkyloxyboranes are bis(pinacolato)diborane (B2Pin2) and bis(catecholato)diborane (B2Cat2). And general Any other boronation reagent having the formula (RO)2-BB-(OR)2 or HB(OR)2 medicine, See, for example, "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-BBN), B-alkyl-9-oxa-10-borane B These include cyclo[3.3.2]decane (OBBD), disiamylborane, thexylborane, and HB(cHex)2.

[0116] In embodiments of the invention, the molar ratio of boronating reagent to starting material of Formula IIa may range from about 10 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 can be in the range of about 0.1 or more: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 or more:about 1.

[0117] In some embodiments of the present invention, the boronating reagent may be in molar excess compared to the starting material of Formula IIa. This may be preferred in certain embodiments where cytisine is used as the starting material for Formula IIa.

[0118] In other embodiments of the present invention, the starting material of Formula IIa may be in molar excess compared to the boronating reagent. This may be preferred in certain embodiments where certain analogs of cytisine (eg, N-boc cytisine) are used as the starting material for Formula IIa.

[0119] The reaction in step ii of the process of the present invention may be catalysed using catalysts known to those skilled in the art. In an embodiment of the invention, step ii is catalysed, for example using a transition metal catalyst. In a preferred embodiment, the catalyst used contains iridium, palladium, zinc, nickel and / or rhodium atoms in an organic coordination complex. By shape may be provided. Specific examples of catalysts that may be used in the preparation method of the present invention include Ir[(COD)(OMe)]2, palladium(II) chloride, Pd / P(t-bu)3, Pd(dba)2, nickel(II) chloride, [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. Examples of solvents that may be used include esters (e.g., ethyl acetate), ethers (e.g., dioxane, 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).

[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 , phenanthroline compounds, etc. may also include. Phenanthroline compounds include, but are not limited to, the following: Phenanthroline (phen), dimethylphenanthroline (me2phen), tetramethyl-1,10-phenanthroline (me4phen) and / or bathophenanthroline (bathophen), bipyridyl compounds such as bipyridyl (bby), di-tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bpy), dimethoxy-2,2'-bipyridyl (MeO-bpy), and / or other compounds such as 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl)ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), neocuproine and xantphos. Other examples include 1,2-bis(dimethylphosphino)ethane (dmpe), and those disclosed in J. Chem. Soc. 1999, 14, 1311-1322, the contents of which are incorporated herein by reference, and include the compounds illustrated below. [ka] Alternatively, examples of ligands that may be used include aromatic or heteroaromatic compounds, which may be polycyclic. Examples include tetramethyl-1,10-phenanthroline (Me4phen), di-tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl)ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), and xantphos. Other examples include 1,2-bis(dimethylphosphino)ethane (dmpe) and those disclosed in J. Chem. Soc. 1999, 14, 1311-1322, the contents of which are incorporated herein by reference.

[0123] The inventors of the present process have determined that the molar ratio of ligand (if used) to starting material of formula IIa is proportional to the conversion to boronated compound of formula IIb. conversion rate found that it can affect 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 The process may be carried out at any temperature as long as the process can proceed smoothly. In an embodiment of the invention, the reaction may be carried out at a temperature of from about 0° C., about 10° C., about 20° C., about 30° C., about 40° C., or about 50° C. 、 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 、 The molar ratio of boronizing reagent to starting material of formula IIa is did Conversion to compounds conversion rate found that it can affect In embodiments of the invention, the molar ratio of boronating reagent to starting material of Formula IIa is at least about 0.5:1, at least about 0.75:1, at least about 1:1, at least about 1.5:1, at least about 2:1, at least 2.5:1, or at least 3:1, and optionally about 5:1 or about 10:1.

[0126] Selective and efficient synthesis of 4-substituted analogs of cytisine was achieved regardless of the order in which starting materials, solvents, catalysts, ligands 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 added to the reaction zone simultaneously or nearly simultaneously. In such embodiments, the reaction zone may or may not be preloaded with solvent, catalyst and / or ligand.

[0128] In another embodiment of the invention, the boronating reagent may be added to the reaction zone (optionally pre-loaded with solvent, catalyst and / or ligand) before the starting material of Formula IIa is added. In such embodiments, the boronating reagent may be present in the reaction zone (optionally along with a solvent, catalyst and / or ligand) for a period of time, such as about 1 minute or more, about 2 minutes or more, or about 5 minutes or more, before the starting material of Formula IIa is added.

[0129] One advantage of the process of the present invention is that the crude product obtained in step ii does not require purification before step iii begins. Thus, in an embodiment of the invention, no purification step is carried out between steps ii and iii.

[0130] The advantages of the preparation method of the present invention are 、 The advantage is that step ii) and at least step iii) can be carried out in the same reaction zone, i.e. as a "one-pot synthesis". Thus, in such an embodiment, step iii) comprises reacting a compound of formula II b Boron compounds are available 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 a substituent R 1 To avoid any misunderstanding, the R 1 It is not necessary to perform the substitution with in a single substitution step, although this may be desirable and can be achieved as shown in the example below.

[0132] In an embodiment of the present invention, in step iii, the final R 1 Substituent is cytisine ring Before being placed in the top four, BComp must first win one or more intermediate R 1 It may be substituted with a substituent. In an embodiment of the present invention, the intermediate R1 The substituents are halo, (e.g., bromo, chloro Young may be iodo), benzyloxypyridine, alkyl ester (e.g. methyl ester), alkenyl (e.g. vinyl), alkynyl(acetylene), trimethylsilylacetylene, 1,2,3-triazol-1-yl)methylpivalate, cyano, aminomethyl, N-Boc-aminomethyl or (benzyloxy)carbonyl)piperazin-1-yl.

[0133] For simplicity, the boronized compounds of formula IIb may optionally contain one or more intermediate R 1 The complete details of how each of the compounds of Formula I is arrived at via the substituents are not provided herein. This is because one of ordinary skill in the art would recognize and understand how such substitutions could be performed. 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 It may include the additional step of performing substitutions at positions. For example, cytisine ring If substitution at the 3- or 5-position above is required, this can be carried out. Such steps can be accomplished using any of the techniques and reagents known to those of skill in the art. If guidance is needed as to how such substitutions can be made, reference can be made to the following example in which such steps are illustrated. Follow up Additionally or alternatively, reference may be made to non-patent document 16, which contains the articles referenced herein and provides further guidance in this regard.

[0135] Follow up Additionally or alternatively, the protecting group is R 4 In an embodiment, the preparation method of the present invention is ringPosition 13- of Deprotecting the nitrogen atom is included. This deprotection step may be carried out after completion of step ii, before the start of step iii, during step iii or after completion of step iii. Those skilled in the art will be familiar with deprotection techniques. Regarding Ren death If you need any advice, you can refer to the following examples:

[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 Advantageously and for the first time, convenient preparation of 4-substituted cytisine analogs from cytisine itself without the need for total synthesis. Manufacturing is permitted.

[0137] A further advantage of the present invention is that steps ii and iii do not involve chiral rearrangement of the molecule and hence the process 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, there are provided pharma- ceutically acceptable compositions comprising any of the compounds described herein, and optionally a pharma- ceutically acceptable carrier, adjuvant, or delivery vehicle. 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 It will be understood that the compounds may be present in their original form or, where appropriate, as pharma- ceutically acceptable derivatives or prodrugs thereof. According to the present invention, a pharma- ceutically acceptable derivative or prodrug includes, but is not limited to, a pharma- ceutically acceptable salt, ester, salt of such an ester, or a compound described elsewhere herein that, upon administration to a subject in need thereof, is the Metabolites RemainingCan provide distillates directly or indirectly 、 This includes any other additions or derivatives.

[0140] As used herein N The term "pharmaceutical acceptable salt" means, within the bounds of sound medical judgment, a substance suitable for use in contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic reaction, etc., and which 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, When administering to the recipient 、 Compounds of the Invention or Inhibitory activity the metabolite Or Residues can be provided directly or indirectly thing, means...

[0141] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharma- ceutically acceptable salts in detail in Non-Patent Document 14, 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 This includes those who

[0142] Examples of pharma-ceutically acceptable, non-toxic acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, and the like. in formed or using other methods used in the industry, such as ion exchange. Formed by It is a salt of an amino group.

[0143] Other pharma-ceutically acceptable salts include the following: Adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates salt , bisulfate, borate, butyrate, camphor Acid salts , camphorsulfonate, citric acid salt, cyclopentane propionate, digluconate, dodecyl sulfate salt , ethanesulfonate, formate, fumarate, glucoheptonate salt , glycerophosphate salt , Glucon 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 , malate, maleate, malonate salt , methanesulfonic acid salt , 2-naphthalenesulfonic acid salt , nicotinic acid salt , Nitrate, Oleate, Oxalate, Palmitate blood Phosphoric acid salt , pamoic acid salt , pectinate, persulfate, 3-phenylpropionate, phosphate salt , Picrate, Pivalic acid salt , Propionate, Stearate, Succinate salt , sulfuric acid salt , tartrate, thio S Anhydride, 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, magnesium, and the like. Further pharma- ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, 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 - sulfonic acid ion It is formed using counterions such as R .

[0146] As noted above, the pharma- ceutically acceptable compositions of the present invention further comprise a pharma- ceutically acceptable carrier, adjuvant or delivery vehicle, which as used herein include the following: an anabolic agent; One and all 、 Solvent, diluent, or other liquid vehicle, dispersion or suspension Muddy correction Auxiliaries, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., as appropriate to the particular dosage form desired.

[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 Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, such as by interacting in a deleterious manner with other compounds, its use is contemplated as being 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, the following: Ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, e.g. human serum albumin, buffer substances, e.g. phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylonitrile ... rate , waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and saccharose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, powdered tragacanth, malt, gelatine, talc, excipients such as cocoa butter , suppository waxes, oils such as peanut oil, cottonseed oil, rosemary oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as propylene glycol or polyethylene glycol, esters such as 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 such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavorings and perfuming agents, preservatives, and antioxidants can also be present in the composition, according to the discretion of the formulator.

[0149] The pharma- ceutical acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (by powders, ointments or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection to be treated. In some embodiments, the compounds of the invention may be administered orally or parenterally, one or more times per day, at dosage levels of from about 0.01 mg / kg to about 50 mg / kg, preferably from about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, to obtain the desired therapeutic effect.

[0150] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, 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, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, oil ,cone oil ,germ oil ,olive oil , castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and Mixtures thereof may also be mentioned. Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[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 They may be sterile injectable solutions, suspensions or emulsions, for example as solutions in 1,3-butanediol. Acceptable transmission media and solvents used Can The solutions used are water, Ringer's solution, USP and normal saline. 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. 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 They may be sterilized by filtration or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium, prior to use.

[0153] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. 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. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms include, for example, polylactide-polyglycolide. R These can be made by forming a matrix of microencapsulated compounds in biodegradable polymers such as polyethylene glycol. Depending on the ratio of compound to polymer, and the nature of the particular polymer employed, the rate of compound release can be controlled. other biodegradable Examples of polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissue.

[0154] For rectal or vaginal administration composition The product contains the compound of the present invention. and a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and will melt in the rectum or vaginal cavity releasing the active compound. Suppositories 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 admixed with at least one inert pharma- ceutically acceptable excipient or carrier such as: pharmaceutical agents such as cereals, vegetable oils, and the like; Sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, saccharose, glucose, mannitol and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, e.g. glycerol; d) disintegrants, such as agar-agar, calcium carbonate, potato 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 glycols. R It may also be used as a filler for soft or hard filled gelatin capsules using excipients such as: The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a predetermined location in the intestinal tract, 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 may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glucoses.

[0157] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be formulated with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such fixative forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms also, in normal practice, Other than inert diluents, Tableting lubricants and tableting aids including magnesium stearate and microcrystalline cellulose. Chase of It may contain additives. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a predetermined location in the intestinal tract, 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 a compound of the present invention may be ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or the like. Agent or a patch. The active component is admixed under sterile conditions with a pharma- ceutically acceptable carrier and any needed preservatives or buffers as may be required. 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 This has the added advantage of controlling the delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in the proper medium. Absorption enhancers also increase 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.

[0159] It will also be understood that the compounds and pharma- ceutically acceptable compositions of the invention may be used in combination therapies, i.e., the compounds and pharma- ceutically acceptable compositions may be administered simultaneously with, prior to, or following one or more other desired therapies or medical procedures. The combination of a particular therapy (treatment or procedure) using a combination dosing regimen may be used to improve the quality of the desired treatment and / or procedure. Placement , the desired therapeutic effect achieved, Compatibility will take into consideration. It will also be understood that the treatments used may achieve the same desired effect against the same disease (e.g., an inventive compound may be administered simultaneously with other agents used to treat the same disease) or may achieve a different effect (e.g., controlling an adverse effect). As used herein Further treatment options include , which are normally administered to treat or prevent a particular disease or condition. R, Known as "appropriate for the disease or condition being treated" It is something .

[0160] The amount of an additional therapeutic agent present in the compositions of this invention will be about the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, In this specification The amount of additional therapeutic agent in the disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0161] The compounds of the invention or pharma- ceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents or catheters. The present invention therefore in another aspect provides compounds of the invention as outlined above in the classes and subclasses herein. and a carrier suitable for coating the implantable device as described above. A composition for coating an implantable device comprising: Things include.

[0162] In yet another aspect, the present invention relates to compounds of the invention as outlined above in the classes and subclasses herein. and a carrier suitable for coating the implantable device as described above. An implantable device coated with a composition comprising Vessel include. Overall preparation of suitable coatings and coated implantable devices Manufacturing are described in U.S. Patent Nos. 5,393, 5,439, 5,563, and 6,641. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.

[0163] The coating is composition Optionally, fluorosilicone may be used to provide controlled release characteristics in the formulation. - The nanoparticles may be further coated with a suitable topcoat of polysaccharides, polysaccharides, polyethylene glycol, phospholipids and combinations thereof. 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 starts with cytisine, a naturally occurring compound that can be isolated from the scutellaria tree. Cytisine is commercially available, and those skilled in the art will be familiar with the preparation methods for extracting cytisine from natural sources. However, The following preparation method of offer vinegar do.

[0165] Powdered salicornia seeds (332 g), dichloromethane (465 ml), methanol (MeOH) and ammonium hydroxide (59 ml, 35% aqueous solution) were vigorously stirred with a mechanical stirrer (400 rpm) at room temperature for 3 days. The mixture was filtered and the solid material was washed with dichloromethane (4×200 mL) until the filtrate was colorless. The filtrate was diluted with 100 ml of dichloromethane and 100 ml of ammonium hydroxide. M Salt acid (330 mL) to pH 1 and the mixture was stirred (350 rpm) for 2 h. Separate the two layers The aqueous layer was adjusted to pH 9 with ammonium hydroxide (70 mL, 35% aqueous solution). ~ It was slowly basified to 10. The mixture was stirred for 2 hours and extracted with dichloromethane (10×70 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford cytisine (4.76 g) as a tan solid. Recrystallization from toluene (5 mL) afforded solid (-)-cytisine (4.27 g, 1.3%).

[0166] (Addition of a protecting group - N-Boc cytisine (56)) [ka] A solution of (-)-cytisine (6.41 g, 33.7 mmol) and di-tert-butyl dicarbonate (9.3 mL, 40.4 mmol) in tetrahydrofuran (135 mL) and water (70 mL) was diluted with an aqueous solution of sodium carbonate (4.28 g, 40.4 mmol, 1 M ) was added. 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) and TogetherThe organic layer was washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Le Flash column chromatography [Dichloromethane / methanol (3% methanol)] to afford 56 (9.10 g, 93%) as a colorless solid. [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 preparation method of the present invention. Manufacturing In such compounds, it may be desirable to remove the tert-butoxycarbonyl (Boc) protecting group. In the examples below, the Boc protecting groups present in the 4-substituted cytisine analogs were 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 Hydrogen chloride solution was added and the reaction mixture was stirred at room temperature for 72 hours. The solvent was then removed in vacuo. residue was dissolved in a minimum amount of methanol, and acetone was slowly added in a volume 10 times that of methanol. The solution was stirred for 2 hours. The precipitate was then 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 Hydrogen chloride solution was added and the reaction mixture was stirred at room temperature for 72 hours. The solvent was then removed in vacuo. residue was dissolved in a minimum amount of methanol, and acetone was slowly added in a volume 10 times that of methanol. The solution was stirred for 2 hours. The precipitate was then collected by filtration and washed with cold acetone.

[0170] Example 1 - N-Boc-4-Bpin Cytisine (58) [ka] A Schlenk tube was charged with N-Boc-cytisine, 56 (290 mg, 1.00 mmol), bis-(iridium-cyclooctadienyl-methoxide) (6.6 mg, 0.01 equiv.), 4,4'-2,2'-di-tert-butylbispyridine (5.4 mg, 0.02 equiv.) and bis(pinacolato)-diborane (177 mg, 0.7 equiv.). The Schlenk tube was placed under vacuum and flushed with nitrogen three times. Backfill Tetrahydrofuran (1.4 mL) was added 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) was possible but not necessary. The crude reaction mixture was used in numerous subsequent transformations without further purification.

[0171] The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol (5% methanol)] to give 58 (180 mg, 43%, silica gel) as a pale orange foam. On An unstable compound, only pure fractions were collected, 1 The resulting mixture was converted to 1H-NMR (complete conversion). [ka]

[0172] Example 2a - N-Boc-4-hydroxycytisine (66) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-cytisine 58 was added in a 1.0 mmol scale in General Procedure for the Cytisine Borylation Reaction Discussed Above in Example 1 Prepared according to did.

[0173] The boronation reaction mixture was cooled to 0° C. and dissolved in tetrahydrofuran (8.6 mL). M of sodium hydroxide (1.0 mL, 3.0 mmol) was added, followed by the slow addition of 30% aqueous hydrogen peroxide (1.0 mL) over 5 min. The mixture was stirred at 0° C. for 30 min and then at room temperature overnight under air. The mixture was diluted with water (3 mL) and the aqueous layer was washed with dichloromethane (3×5 mL). M Salt acid At pH 4 ~ It was acidified to 5 and extracted with dichloromethane (5×5 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol (5% methanol)] to afford 66 (240 mg, 79%) as an off-white solid. [ka]

[0174] Example 2b - (+) 4-Hydroxycytisine Hydrochloride (67) [ka] General Procedure A Follow , an off-white solid was prepared from alcohol 66 (0.79 mmol). 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-dioxaborolan-2-yl)-cytisine 58, 0.50 mmol inGeneral Procedure for the Cytisine Borylation Reaction Discussed Above in Example 1 Prepared according to did.

[0176] Newly acquired Manufacturing The mixture was dissolved in 100 mL of methanol (5 mL) and 100 mL of copper(II) sulfate pentahydrate (37 mg, 0.15 mmol), potassium hydroxide (84 mg, 1.50 mmol), and 40 mL of molecular sieves. Å A solution of (300 mg) was stirred under nitrogen for 5 hours. Syringe The crude was transferred to the boronation reaction using HCl. The reaction mixture was stirred at reflux under oxygen atmosphere for 18 h. The reaction was diluted with 10 mL of methanol, filtered through a pad of Celite, and the solvent was removed under vacuum. The crude was partitioned between ammonia solution (15 mL, 15% aqueous solution) and dichloromethane (15 mL) and the aqueous phase was extracted with dichloromethane (4 x 15 mL). The organic phase was together The crude reaction mixture was purified by flash column chromatography [dichloromethane / methanol (2% methanol)] to afford 69 (130 mg, 81%) as a colorless solid. [ka]

[0177] Example 3b - (-) 4-Methoxycytisine (69) [ka] Dichloromethane (4 mL, 0.1 M To a solution of ether 68 (130 mg, 0.42 mmol) in ethyl acetate (HCl), trifluoroacetic acid (0.3 mL, 10 equiv.) was added in one portion and the reaction mixture was stirred at room temperature for 18 h. Water (10 mL) was added and the aqueous phase was washed with dichloromethane (3×10 mL). The aqueous phase was basified with ammonia (10 mL, 15% aqueous solution) and extracted with dichloromethane (3×10 mL). The organic phase was together The mixture was stirred for 30 min at 40° C. for 1 hour, dried over magnesium sulfate, filtered and 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-dioxaborolan-2-yl)-cytisine 58 was added in a 5.00 mmol scale. in General procedure for the boronation reaction of cytisine as detailed in Example 1 above. 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 sieve 4 Å (4g) 15 ~ The mixture was stirred for 20 min. The crude boronation reaction was dissolved in acetonitrile (5 mL). Dissolution Then, the copper solution Syringe to the crude reaction and stirred for 10 minutes. Freshly distilled benzylamine (1.1 mL. 10.0 mmol) was added and the reaction mixture was heated at reflux under oxygen atmosphere for 18 hours. The reaction mixture was cooled, filtered through Celite® and concentrated. The reaction crude was partitioned between ammonia (25 mL, 15% aqueous solution) and dichloromethane (25 mL) and the aqueous phase was extracted with dichloromethane (4×15 mL). Together The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude reaction mixture was purified by flash column chromatography [dichloromethane / methanol (2% methanol)] to give 70 (1.70 g, 72%) as a colorless solid. inseparable Produced with impurities. [ka]

[0180] Example 4b - (+) 4-(N-benzylamino)cytisine (71) [ka] Dichloromethane (43 mL, 0.1 M To a solution of secondary amine 70 (1.70 g, 4.30 mmol) in 10 mL of ethyl acetate was added trifluoroacetic acid (0.4 mL, 10 equiv.) and the solution was stirred at room temperature for 16 h. 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 extracted with dichloromethane (4×10 mL). Together The organic layer was dried over magnesium sulfate, filtered and concentrated to give 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-dioxaborolan-2-yl)-cytisine 58 was added in a 1.00 mmol scale in General procedure for the boronation reaction of cytisine as detailed in Example 1 above. Prepared according to did. To the crude boronation reaction mixture, tris(dibenzylideneacetone)dipalladium(0) (23 mg, 1 mmol%), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (47 mg, 2.5 mmol%), cesium fluoride (450 mg, 3.0 equiv.), and CuCl cuprous chloride (99 mg, 1.0 equiv.) were added and the Schlenk tube was placed under vacuum and flushed with nitrogen three times. Backfill The reaction mixture was diluted with N,N-dimethylformamide (4.0 mL, 0.25 mL). MThe crude reaction mixture was dissolved in 2,2,2-trifluoroethyl iodide (0.19 mL, 2.0 equiv.) and water (0.14 mL, 8.0 equiv.) was added. The reaction mixture was stirred at 65° C. for 18 h. The solvent was removed in vacuo and the crude reaction was partitioned between ethyl acetate (15 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate (3×15 mL). The organic phase was together The crude reaction mixture was purified by flash column chromatography [dichloromethane / methanol (2% methanol)] to afford N-Boc-4-(2,2,2-trifluoroethyl)cytisine (190 mg, 50%) as a colorless solid. The resulting trifluoro-cytisine derivative was Follow General Procedure A Deprotection hand Conversion to the hydrochloride salt afforded ligand 79 (93 mg, 34%) as a colorless solid. [ka]

[0182] Example 6 - (-) 4-(perfluorophenyl)cytisine hydrochloride (75) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-cytisine 58 was added in a 1.00 mmol scale in General procedure for the boronation reaction of cytisine as detailed in Example 1 above. Prepared according to did.

[0183] Bromopentafluorobenzene (0.15 mL, 1.2 equiv.), dichlorobis(triphenylphosphine)palladium (35 mg, 0.05 equiv.) and cesium carbonate (410 mg, 2.5 equiv.) were added to the crude boronation reaction and the reaction mixture was diluted with tetrahydrofuran (5 mL, 0.2 M ) and stirred for 18 h at 80° C. The reaction mixture was diluted with ammonia (25 mL, 15% aqueous solution) and the aqueous phase was extracted with ethyl acetate (4×25 mL). TogetherThe organic phase was dried over magnesium sulfate, the solids were filtered and the solvent was evaporated in vacuo. Purification of the crude reaction mixture by flash column chromatography [dichloromethane / methanol (1.5% methanol)] afforded a colorless solid, 74 (509 mg, 99%) (dichlorobis(triphenylphosphine)palladium 2, 81; 98.5 mg, 99.5%). 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 as 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-dioxaborolan-2-yl)-cytisine 58 was added in a 1.00 mmol scale in General procedure for the boronation reaction of cytisine detailed above in Example 1 Prepared according to did.

[0185] Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg, 5 mol%) were added to the boronation reaction crude mixture. Dry tetrahydrofuran (10 mL) was added followed by 2-bromopyridine (115 μL, 1.2 mmol). The mixture was stirred at 80° C. for 48 h. The reaction was cooled to room temperature, 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, filtered and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel [dichloromethane / methanol (4% methanol) + 0.1% ammonia (15% in water)] to afford 100 (205 mg, 56%) as a yellow oil. The product was used in the next step without further purification. [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 Yield 101 (99.2 mg, 63%) as a colorless solid. [ka]

[0187] Example 8 - (-) 4-(3-pyridinyl)cytisine dihydrochloride (104) [ka] A Schlenk tube was charged 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. Backfill 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 Over 10 min, the reaction 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% aq.) was added and the aqueous phase was extracted with dichloromethane (4×25 mL). Together The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting N-Boc-4-(3-pyridinyl)-cytisine derivative was Follow General Procedure A 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-dioxaborolan-2-yl)-cytisine 58 was prepared on a 1.00 mmol scale. in General procedure for the boronation reaction of cytisine as detailed in Example 1 above. Prepared according to It was done.

[0189] Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg, 5 mol%) were added to the boronation reaction crude mixture. Dry tetrahydrofuran (10 mL) was added followed by 4-iodopyridine (246 mg, 1.2 mmol). The mixture was stirred at 80° C. for 48 h. The mixture was cooled to room temperature, 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 (5% methanol) + 0.1% ammonia (15% in water)] to afford 102 (312 mg, 85%) as an orange oil. The product was used in the next step without further purification. [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)cytisine 105 [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-cytisine 58 was prepared on a 1.00 mmol scale. inGeneral procedure for the boronation reaction of cytisine as detailed above in Example 1 Prepared according to It was done.

[0192] Anhydrous cesium acetate (814 mg, 2.5 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg, 5 mol%) were added to the crude boronation reaction mixture. Dry tetrahydrofuran (5.0 mL) was added, followed by dry tetrahydrofuran (5.0 mL). )of 4-Bromo-2-benzyloxypyridine (316 mg, 1.2 mmol) ) melt The mixture was stirred at 80° C. for 48 h. The solution was cooled to room temperature, 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, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol (4% methanol)+0.1% ammonia (15% in water)] to afford 105 (485 mg, 99%) as a pale yellow oil with little impurities. The product was used in the next step without further purification. [ka]

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

[0194] Example 11 - (-) N-Boc-4-chlorocytisine (59) [ka] N-Boc-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-cytisine 58 was prepared on a 1.00 mmol scale. in General procedure for the boronation reaction of cytisine as outlined in Example 1 above. 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 Copper chloride (470 mg, 3.5 mmol) ) melt The mixture was stirred at room temperature under air for 4 days, and the mixture was diluted with ammonium hydroxide (10 mL, 15% aqueous solution) and the aqueous phase was extracted with dichloromethane (3×10 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [ethyl acetate] to afford 59 (247 mg, 76%) as an off-white solid. [ka]

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

[0197] In a sealed tube, the crude boronation reaction mixture was diluted with methanol (2.5 mL). Dissolution Then, an aqueous solution of copper chloride (470 mg, 3.5 mmol, 1.4 M ) was added. The reaction was stirred at 90° C. for 18 hours. cooling The mixture was then diluted with ammonium hydroxide (5 mL, 15% aqueous solution) and the aqueous phase was extracted with dichloromethane (5×5 mL). Together The organic layer was concentrated in vacuo. residue 3 M Salt acid (5 mL) and dichloromethane (5 mL). The aqueous layer was washed with dichloromethane (2×5 mL) and Concentrated Water Ammonium oxide solution At pH 10 To It was basified and extracted with dichloromethane (5×5 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonia (89:10:1)] to afford 60 (179 mg, 80%) as an off-white solid. A pure sample 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-dioxaborolan-2-yl)-cytisine 58 was prepared on a 5.00 mmol scale. in General procedure for the boronation reaction of cytisine as detailed in Example 1 above. Prepared according to It was done. Copper(II) nitrate trihydrate (2.42g , 10.0 mmol), You Ammonium chloride (1.45 g, 10.0 mmol) and molecular sieves 4 Å (500 mg) was added to the crude boronation reaction mixture, the Schlenk tube was placed under nitrogen and flushed with oxygen three times. Backfill The reaction mixture was diluted with N,N-dimethylformamide (25 mL )in The mixture was dissolved and heated at 80° C. for 24 hours. The solvent was removed in vacuo and the residue was residue Dichloromethane In The mixture was poured onto ammonia (30 mL, 15% aqueous solution) and the aqueous phase was extracted with dichloromethane (4×25 mL). Together The organic layer was dried over magnesium sulfate, filtered and concentrated, and the crude was purified by flash column chromatography [dichloromethane / methanol (2% methanol)] to afford 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 charged with N-Boc-4-iodocytisine 64 (2.08 g, 5 mmol), copper iodide (4.52 g, 23.7 mmol), anhydrous Potassium fluoride M( The reaction mixture was charged with N,N-dimethylformamide (24 mL, 0.2 M ) was added and the reaction mixture was stirred at 50° C. for 16 h. The solvent was removed in vacuo and the residue residue The mixture was partitioned between dichloromethane (20 mL) and ammonia (20 mL, 15% aqueous solution). The aqueous phase was extracted with dichloromethane (3×20 mL). Together The organic phase was dried over magnesium sulfate, the solid was filtered and the solvent was evaporated in vacuum. Purification of the crude reaction by flash column chromatography [ethyl acetate / n-hexane (4:1)] afforded 76 (1.52 g, 85%) as a colorless solid. [ka]

[0201] (Example 14b-(-) 4-Trifluoromethylcytisine hydrochloride (77)) [ka] General Procedure A in accordance with , N-Boc-4-trifluoromethylcytisine 76 (0.28 mmol) 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-dioxaborolan-2-yl)-cytisine 58 was prepared on a 5.00 mmol scale. in General procedure for the boronation reaction of cytisine as detailed in Example 1 above. Prepared according to It was done.

[0203] The crude boronation reaction mixture was dissolved in methanol (12.5 mL). Dissolution The mixture was cooled to 0°C. Water (12.5 mL) )of Copper(II) bromide (3.35g, 15.0mmol ) melt The solution was added over 5 min. The ice bath was removed after 30 min and the reaction mixture was stirred at room temperature in the open-air flask 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, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [ethyl acetate] to afford 61 (1.54 g, 83%) as an off-white solid. [ka]

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

[0205] In a sealed tube, the crude boronation reaction mixture was dissolved in methanol (2.5 mL ) Then, add water (2.5 mL )of Copper(II) bromide (670mg, 3.0mmol ) melt The mixture was heated at 80° C. overnight. The mixture was cooled, diluted with ammonium hydroxide (5 mL, 15% aqueous solution) and extracted with dichloromethane (5×5 mL). Together The organic layer was concentrated in vacuo. M Salt acid (5 mL) and dichloromethane (5 mL). The aqueous layer was washed with dichloromethane (2×5 mL) and Concentrated Water Ammonium oxide aqueous solution to pH 10 and extracted with dichloromethane (5×5 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (89:10:1)] to give bromide 62 (228) as an off-white solid. m g, 85%). A purer sample was obtained by recrystallization in toluene. [ka]

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

[0207] (Method A) In a Schlenk tube, a mixture of N-Boc-4-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, 30 mol%), and sodium hydroxide (6 mg, 30 mol%) in ethanol / water (7:3) (5 mL) was heated at 95° C. overnight. The mixture was cooled and partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (2×10 mL). Together The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (89:10:1)] to afford the amine 80 (116 mg, 76%) as an off-white solid.

[0208] (Method B) In a sealed tube, dark Ammonium hydroxide aqueous solution (0.5mL ) insideA mixture of N-Boc-4-bromo-cytisine 61 (92 mg, 0.25 mmol) and copper (2 mg, 10 mol%) was stirred for 24 h at 100° C. The mixture was cooled and extracted with dichloromethane (5×5 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (89:10:1)] to afford 80 (64 mg, 85%) as an off-white solid. [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] To a solution of N-Boc-4-amino-cytisine 80 (305 mg, 1.0 mmol) in HF-pyridine complex (70%, 2.0 mL) at -20° C., 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, then warmed to room temperature for 2 h and finally heated at 60° C. overnight. The mixture was cooled to 0° C. and Concentrated Water Use ammonium oxide solution to reduce pH to 10 QuenchThe mixture was diluted with ethyl acetate (10 mL) and filtered to remove insoluble salts. The aqueous layer was extracted with ethyl acetate (4×10 mL). together The organic layer was concentrated in vacuo. M Salt acid (5 mL) and dichloromethane (5 mL). The aqueous layer was washed with dichloromethane (2×5 mL) and Concentrated Water Ammonium oxide aqueous solution The mixture was basified to pH 10 with and extracted with dichloromethane (5×5 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (89:10:1)] to afford 82 (140 mg, 67%) as a pale yellow solid. An analytically pure sample was obtained by recrystallization in toluene. [ka]

[0211] Example 18a - N-Boc-4-(N-methylamino)cytisine (83) [ka] In a sealed tube, a mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol) and copper (7 mg, 10 mol%) in a 40% aqueous solution of methylamine (2.0 mL) was stirred for 24 h at 100° C. The mixture was cooled to room temperature and extracted with dichloromethane (5×10 mL). together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel [dichloromethane / methanol (94:6)] to give an off-white solid. color Yield was 274 mg (86%) of solid 83. [ka]

[0212] Example 18b - (+)4-(N-methylamino)cytisine dihydrochloride (84) [ka] General Procedure A in accordance with , 4-N-methylamino-N-Boc-cytisine 83 (0.77 mmol) 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, a mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol) and copper (6 mg, 10 mol%) in a 40% aqueous solution of dimethylamine (2.0 mL) was stirred for 24 h at 100° C. The mixture was cooled, diluted with 35% ammonia (2 mL) and the aqueous phase was extracted with dichloromethane (5×10 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (94.5:5:0.5)] to afford 85 (212 mg, 64%) as a white foam. [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 (202 mg, 0.61 mmol) fromThe yield was amino 86 (174 mg, 93%). [ka]

[0215] Example 20a - N-Boc-4-(N-benzoylamino)cytisine (95) [ka] To a mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), benzamide (145 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) in dry toluene (5.0 mL) was added N,N'-dimethylethylenediamine (11 μL, 10 mol%). 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 extracted with dichloromethane (5×10 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (95:5:0.1)] to afford 95 (425 mg) as a yellow solid. The resulting solid was washed with boiling toluene (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 The yield was amide 96 (290 mg, 80%). [ka]

[0217] Example 21a - N-Boc-4-(N-acetylamino)cytisine (93) [ka] To a mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), acetamide (70 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) in dry toluene (5.0 mL) was added N,N'-dimethylethylenediamine (11 μL, 10 mol%). The mixture was heated at 110° C. for 24 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and then extracted with dichloromethane (5×10 mL). Together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (95:5:0.1)] to afford 93 (340 mg, 98%) as a clean pale yellow foam. 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 (306 mg, 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] A sealed tube was charged with N-Boc-4-bromo-cytisine 61 (370 mg, 1.0 mmol), copper(II) oxide (15 mg, 0.1 equiv.) and morpholine (0.4 mL, 5 equiv.), and the reaction mixture was diluted with water (2.0 mL, 0.5 M ) and heated under air at 100° C. for 18 h. The reaction mixture was cooled to room temperature and the aqueous phase was extracted with dichloromethane (4×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting N-Boc protected cytisine derivative was Follow General Procedure A Deprotection hand Conversion to the hydrochloride salt afforded 92 (180 mg, 85%) as a colorless solid. [ka]

[0220] Example 23a - N-Boc-4-(N-(L-proline methyl ester)cytisine (136)) [ka] N-Boc-4-bromocytisine 61 (369 mg, 1.0 mmol), L-proline methyl ester hydrochloride (198 mg, 1.2 mmol), cesium acetate (814 mg, 2.5 mmol), palladium(II) acetate (11 mg, 5 mol%) and (±)-binap in dry toluene (5.0 mL). (BINAP) (44 mg, 7 mol%) was stirred at 100° C. for 48 h. The mixture was cooled to room temperature and short Celite pad (Registered trademark )ofThe crude material was filtered through hexane, washed with ethyl acetate and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (95:5:0.1)] to afford 136 (371 mg, 89%) as a clean off-white foam. [ka]

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

[0222] Example 24-(-) 4-(N-(L-proline)cytisine dihydrochloride (138)) [ka] salt Acid (3 7% aqueous solution A mixture of N-Boc-4-(N-(L-proline methyl ester)-cytisine 138 (341 mg, 0.82 mmol) in N-Boc-4-(N-(L-proline methyl ester)-cytisine 138) (8.2 mL) was heated at reflux for 48 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude was dissolved in methanol (4 mL). Dissolved in Then acetone was added slowly (40 mL). The resulting suspension was stirred for 1 h. The solid was filtered, washed with acetone, and dried under vacuum to afford 138 (261 mg, 85%) as a light brown solid. [ka]

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

[0224] Example 25b - (-) 4-Carboxymethylcytisine (120) [ka] To a solution of N-Boc-4-methyl-ester-cytisine 119 (95 mg, 0.27 mmol) in dichloromethane (1.3 mL) was added trifluoroacetic acid (0.21 mL, 2.7 mmol). The mixture was stirred for 24 h and then concentrated in vacuo. The crude product was 3 M Salt acid (5 mL) and dichloromethane (5 mL). The aqueous layer was washed with dichloromethane (2×5 mL), basified with sodium carbonate to pH 9, and then extracted with dichloromethane (5×5 mL). together The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 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 A solution of N-Boc-4-methyl-ester-cytisine 119 (263 mg, 0.75 mmol) in (37% aqueous solution, 7.5 mL) was heated at reflux for 24 h. The mixture was cooled to room temperature and then concentrated in vacuo. The crude reaction mixture was diluted with methanol (30 mL). 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 afford 229 (164 mg, 81%) as a colorless solid. [ka]

[0226] Example 27a - N-Boc-4-(hydroxymethyl)cytisine (121) [ka] A solution of N-Boc-4-methyl ester-cytisine 119 (350 mg, 1.00 mmol) in tetrahydrofuran (4 mL) was diluted with lithium aluminum hydroxide (1.0 M ) was added dropwise at -78°C over 5 min and the reaction mixture was stirred for 3.5 h. 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 x 25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography [dichloromethane / methanol (2% methanol to 5% methanol)] 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 (0.60 mmol) from This yielded the alcohol 122 (120 mg, 90%) as a colorless solid. [ka]

[0228] Example 28a - N-Boc-4-(4-(trifluoromethyl)benzyl)oxycytisine (123) [ka] Dry tetrahydrofuran (7.5 mL )of Alcohol 121 (240 mg, 0.75 mmol) ) melt To the solution was added sodium hydride (33 mg, 1.1 equiv., 60% dispersion in mineral oil) and 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.) were added. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was diluted with water (10 mL) and washed with 1 mL of water. Quench The aqueous phase was then extracted with ethyl acetate (3×15 mL). together The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol (1% methanol)] to afford 123 (250 mg, 71%) as a colorless solid, which was used in the next step without further purification. [ka]

[0229] (Example 28b - (-) 4-(4-(trifluoromethyl)benzyl)oxycytisine (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] To a mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg, 5 mol%) in dry toluene (5.0 mL) was added tetramethyltin (0.35 mL, 2.5 mmol). The mixture was stirred at 100° C. under nitrogen for 24 h. The mixture was cooled to room temperature, filtered through Celite®, washed with ethyl acetate (50 mL), and concentrated under vacuum. The crude was purified by flash column chromatography on silica gel [dichloromethane / methanol (97:3)] to afford 109 (308 mg, quantitative) as a light yellow solid with little impurity. [ka]

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

[0232] (Example 30a-(-) N-Boc-4-vinylcytisine (115)) [ka] A mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex (194 mg, 1.2 mmol), potassium carbonate (276, 2.0 mmol) and dichlorobis(triphenylphosphine)palladium (35 mg, 5 mol%) in dioxane / water (8:2) (5.0 mL) was stirred at 90° C. for 24 h under nitrogen. The mixture was cooled to room temperature, filtered through Celite® and washed with ethyl acetate (50 mL). The organic layer was washed with water (10 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 / methanol (97:3)] to afford 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, 0.86 mmol) 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, 1.1 mmol) ) melt To the solution was added palladium / carbon 10% w / w (35 mg). The reaction vessel was placed under vacuum and pressurized with hydrogen three times. Backfill The mixture was stirred under 1 atm of hydrogen for 24 h at room temperature. The mixture was filtered through Celite®, washed with ethyl acetate (50 mL) and concentrated in vacuo to afford 117 (337 mg, 95%) as an off-white solid. [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] A Schlenk tube was charged 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 mg, 1.2 equiv) and a mixture of diethyl ether / water (5:1, 10 mL) was added. The reaction mixture was heated at 80° C. for 18 h. The solution was cooled and the solvent removed in vacuo. The crude reaction was partitioned between water (15 mL) and dichloromethane (15 mL) and the aqueous phase was extracted with dichloromethane (3×15 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude reaction mixture by flash column chromatography [dichloromethane / methanol (1.5% methanol)] afforded 72 as a colorless solid. The crude material was recrystallized in hot toluene to afford 72 (260 mg, 71%) as a colorless foam. [ka]

[0237] Example 32b - (+)4-p-Tolylcytisine (73) [ka] In a Schlenk tube, N-Boc-4-p-tolyl-cytisine 72 (270 mg, 0.71 mmol) was dissolved 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). Then, ammonia solution (20 mL, 15% aqueous solution) was added and the aqueous phase was extracted with dichloromethane (3×15 mL). together The combined organic phase was dried over magnesium sulfate, filtered and concentrated to afford 73 (140 mg, 74%) as a colorless solid. Recrystallization of the product in hot toluene afforded 73 (73 mg, 40%) as a colorless solid. [ka]

[0238] Example 33a - N-Boc-4-(N-2-pyridone)cytisine (107) [ka] To a solution of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol), copper(I) iodide (19 mg, 10 mol%), 2-hydroxypyridine (114 mg, 1.2 mmol) and potassium carbonate (277 mg, 2.0 mmol) in dry toluene (5.0 mL) was added N-N'-dimethylethylenediamine (22 μL, 20 mol%). The mixture was heated at 110° C. under nitrogen for 24 h. Further copper(I) iodide (19 mg, 10 mol%) and N-N'-dimethylethylenediamine (DMEDA) (22 μL, 20 mol%) were added and stirred for 36 h. After cooling, the mixture was diluted with ethyl acetate (50 mL) and then filtered through Celite®. The organic layer was washed with ammonium hydroxide (2×10 mL, 15% aqueous solution). together The combined aqueous layer was extracted with dichloromethane (5×10 mL). together The combined organic layers (ethyl acetate and dichloromethane) were dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol (95:5)] to afford pale yellow 107 (336 mg, 88%), which was used in the next step without further purification. [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 (289 mg, 0.75 mol) fromYield 108 (182 mg, 76%) as a pale orange solid. [ka]

[0240] Example 34a - N-Boc-4-(trimethylsilylacetylene)cytisine (125) [ka] A solution of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol), copper(I) iodide (19 mg, 10 mol%) and dichlorobis(triphenylphosphine)palladium (35 mg, 5 mol%) in dry tetrahydrofuran (10.0 mL) was added with diisopropylamine (0.42 mL, 3.0 mmol) followed by trimethylsilylacetylene (0.16 mL, 1.1 mmol). mmol ) was added. The mixture was stirred at room temperature under nitrogen for 24 hours. The mixture was diluted with dichloromethane (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 was purified by flash column chromatography on silica gel [ethyl acetate] to remove impurities. (Palladium catalyst) Most of Light This yielded 125 (406 mg, quantitative) as a light brown foam which was used in the next step without further purification. [ka]

[0241] Example 34b - N-Boc-4-(acetylene)cytisine 126) [ka] To a solution of N-Boc-4-(trimethylsilylacetylene)-cytisine 125 (379 mg, 0.98 mmol) in a mixture of methanol (14 mL) and dichloromethane (7 mL) was added potassium carbonate (270 mg, 1.96 mmol). The mixture was stirred for 24 h. Water was added (10 mL) and the aqueous phase was extracted with dichloromethane (3×20 mL). together The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [ethyl acetate] to remove impurities. (Palladium catalyst) Most of White 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] To a mixture of N-Boc-4-bromocytisine 61 (369 mg, 1.0 mmol), copper(I) iodide (38 mg, 20 mol%) and dichlorobis(triphenylphosphine)palladium (70 mg, 10 mol%) in dry tetrahydrofuran (5.0 mL) was added diisopropylamine (0.42 mL, 3.0 mmol) followed by phenylacetylene (0.22 mL, 2.0 mmol). The mixture was stirred at room temperature under nitrogen for 24 h. 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] to remove impurities. (Palladium catalyst) Most of Light This yielded 128 (376 mg, 96%) as a light brown foam which 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 was obtained as a pale yellow solid (267 mg, 92%). [ka]

[0245] Example 36a - N-Boc-4-(E-2-propenoic acid methyl ester)cytisine (111) [ka] A mixture of N-Boc-4-bromocytisine 61 (369 mg, 1.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (12 mg, 2.5 mol%) in dry dioxane (5.0 mL) was diluted with N,N-dicyclohexylmethylamine (0.2 mL, 1.1 mmol), tri-tert-butylphosphine (dioxane solution 0.1 M , 0.5 mL, 5 mol%), and ethyl acrylate (0.2 mL, 2.0 mmol) were added. The mixture was stirred at room temperature under nitrogen for 24 h. 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 mL, 2.0 mmol) were added again and the mixture was stirred for another 24 h. The mixture was filtered through Celite®, washed with ethyl acetate and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel [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 Yield 112 (300 mg, 92%) as a pale yellow solid. [ka]

[0247] Example 37a-N-Boc-4-(E-(2-phenylethenyl))cytisine (113)) [ka] A mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (12 mg, 2.5 mol%) in dry dioxane (5.0 mL) was diluted with N,N-dicyclohexylmethylamine (0.2 mL, 1.1 mmol), tri-tert-butylphosphine (dioxane solution 0.1 M , 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. Tris(dibenzylideneacetone)dipalladium(0) (12 mg, 2.5 mol%), tri-tert-butylphosphine (dioxane solution 0.1 M , 0.50 mL, 5 mol%) and styrene (0.2 mL, 2.0 mmol) were added again and the mixture was stirred for another 24 h. The mixture was filtered through Celite®, washed with ethyl acetate and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel [dichloromethane / methanol (97:3)] to afford 113 (373 mg, 95%) as a pale yellow foam. The product was used in the next step without further purification. [ka]

[0248] Example 37b—(+)4-(E-(2-phenylethenyl))cytisine hydrochloride (114) [ka] General Procedure B in accordance with , 113 (0.88 mmol) from Yield 114 (259 mg, 89%) as an off-white solid. [ka]

[0249] Example 38a - N-Boc-4-(1-(4-phenyl)-NH-1,2,3-triazolyl)cytisine (134) [ka] To a mixture of N-Boc-4-bromo-cytisine 61 (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%) in ethanol / water (7:3) (5.0 mL) was added N,N'-dimethylethylenediamine (22 μL, 20 mol%) followed by phenylacetylene (132 μL, 1.2 mmol). The mixture was stirred at 50° C. under nitrogen for 24 h. The mixture was cooled to room temperature and diluted with ammonium hydroxide solution (20 mL, 15% aqueous solution) and then extracted with ethyl acetate (3×50 mL). together The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. 1 86 based on H NMR ~ The crude product (93% conversion) was purified by flash column chromatography on silica gel [ethyl acetate, then dichloromethane / methanol / ammonium hydroxide (97:3:0.1)] to afford 134 (214 mg, 49%) as an off-white solid, which was used in the next step without further purification. [ka]

[0250] Example 38b - (+) 4-(1-(4-phenyl)-NH-1,2,3-triazolyl)cytisine dihydrochloride (135) [ka] General Procedure B in accordance with , N-Boc-4-((4-phenyl)-NH-1,2,3,triazole)-cytisine 134 (0.46 mmol) from The resulting mixture was concentrated to afford 135 (151 mg, 81%) as a colorless solid. [ka]

[0251] Example 39a - N-Boc-4-(1,2,3-triazol-1-yl)methylpivalic acid cytisine (131) [ka] To a solution of N-Boc-4-(acetylene)-cytisine 126 (544 mg, 1.73 mmol) in a mixture of tert-butyl alcohol / water (1:1) (8.6 mL) was added successively 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, 15% aqueous solution) and then extracted with ethyl acetate (3×20 mL). together The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (95:5:0.1)] to afford 131 (722 mg, 89%) as a clean pale yellow oil, which was used in the next step without further purification. [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)methylpivalate)-cytisine 131 (688 mg, 1.46 mmol ) melt The solution was added with sodium hydroxide (3.2 mL, 1 MAqueous solution) was added. The mixture was stirred at room temperature for 12 hours. acid (3.2mL, 1 M The mixture was neutralized with water (aqueous solution), diluted with water (30 mL), and extracted with ethyl acetate (5×20 mL). together The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol / ammonium hydroxide (97:3:0.1)] to afford 132 (461 mg, 88%) as an off-white solid. [ka]

[0253] (Example 39c - (+) 4-(NH-1,2,3-triazolyl) cytisine dihydrochloride 133(A)) [ka] General Procedure A in accordance with , N-Boc-4-(NH-1,2,3-triazole)-cytisine 132 (1.22 mmol) Using General Procedure A Deprotection hand Conversion to the hydrochloride salt afforded 133 (352 mg, 87%) as a colorless 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 A mixture of N-Boc-4-bromo-cytisine 61 (369 mg, 1.0 mmol) and copper (7 mg, 10 mol%) in 1 mL of water was stirred at 100° C. for 24 h. The mixture was cooled and extracted with dichloromethane (5×10 mL). together The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol (6% methanol)] to afford 87 (102 mg, 42%) as an off-white solid. [ka]

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

[0256] Example 42a-N-Boc-4-Cyanocytisine (139) [ka] A Schlenk tube was charged with N-Boc-4-bromo-cytisine 61 (1.85 g, 5.00 mmol), tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.20 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 removed in vacuo. Purification of the crude reaction mixture by flash column chromatography [dichloromethane:methanol (1% methanol)] 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 mmol) was dissolved in dichloromethane (3.0 mL, 0.1 M ) and trifluoroacetic acid (0.3 mL, 10 equiv.) 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 x 20 mL). Ammonia was added (10 mL, 15% aqueous solution) and the aqueous phase was extracted with dichloromethane (4 x 20 mL). together The combined organic layer was dried over magnesium sulfate, filtered and concentrated to afford 140 (86 mg, 86%) as a colorless solid. [ka]

[0258] Example 44a—N-Boc-4-(carboxyamido)cytisine (141) [ka] To a solution of N-Boc-4-cyano-cytisine 139 (320 mg, 1.0 mmol) in an equimolar mixture of ethanol / water (5 mL), sodium borohydride (33 mg, 0.75 mmol) was added and the reaction mixture was stirred at 75° C. for 18 h. The reaction mixture was cooled to room temperature and washed with water (5 mL). Quench The ethanol was removed in vacuo. The aqueous phase was then extracted with dichloromethane (3×15 mL) and together The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude reaction mixture by flash column chromatography [dichloromethane / methanol (2% to 4% methanol)] gave , nothing The yield was 141 (150 mg, 46%), a colored solid. 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 To a solution of N-Boc-4-cyano-cytisine 139 (320 mg, 1.0 mmol) and potassium hydroxide (84 mg, 1.5 mmol) in 10 mL of ethyl acetate was added Raney nickel (0.3 mL, slurry in water). The reaction vessel was placed under vacuum and purged with hydrogen three times. BackfillThe mixture was stirred at room temperature for 18 h. The reaction mixture was filtered through Celite® and the crude reaction mixture was concentrated. Purification by flash column chromatography [dichloromethane:methanol (10% methanol) + 0.1% ammonia (35% in water)] afforded the amine 143 (260 mg, 82%) as a colorless solid. [ka]

[0261] Example 45b - (-) 4-(aminomethyl)cytisine dihydrochloride (144) [ka] General Procedure According to A N-Boc-4-methylamino-cytisine 143 (0.76 mmol) 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 (264 mg, 0.83 mmol) ) melt To the solution were added di-tert-butyl dicarbonate (0.2 mL, 0.91 mmol) and triethylamine (0.16 mL, 1.16 mmol), and the reaction mixture was stirred at room temperature for 18 hours, after which water (15 mL) was added and the aqueous phase was extracted with dichloromethane (3×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography [dichloromethane:methanol (3% methanol)] afforded N-Boc-4-(N-Boc-aminomethyl)-cytisine (280 mg, 82%) as a colorless oil. [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 To the liquid was added sodium hydride (17 mg, 0.70 mmol, 60% dispersion in oil) and the solution was stirred for 30 min. Iodomethane (0.05 mL, 0.70 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The crude material was partitioned between water (10 mL) and ethyl acetate (10 mL) and the aqueous phase was extracted with ethyl acetate (3×10 mL). together The organic phase was washed with magnesium sulfate, filtered and concentrated. Using General Procedure A Deprotection hand Conversion to the hydrochloride salt afforded 152 (89 mg, 65%) as a colorless solid. [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 dissolved in a mixture of pyridine, acetic acid and water in a ratio (2:1:1) and sodium phosphinate (340 mg, 3.27 mmol) and Raney nickel (1.0 mL, slurry in water) were added. The reaction mixture was stirred at 50° C. for 6 h. The solution was filtered through Celite® and concentrated. The crude 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 dried over magnesium sulfate, filtered and concentrated. Purification of the crude reaction mixture by column chromatography [dichloromethane / methanol (4% methanol)] afforded 153 (170 mg, 86%) as a colorless, pale yellow solid. [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(0.53mmol) from , yielding 154 (113 mg, 97%) as a colorless solid. [ka]

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

[0267] (Example 49 - (-) 4-Tetrazolylcytisine dihydrochloride (149)) [ka] A Schlenk flask was charged with N-Boc-4-cyano-cytisine 139 (240 mg, 0.75 mmol), zinc bromide (170 mg, 0.75 mmol) and sodium azide (58 mg, 0.90 mmol) and placed under nitrogen. Water (2.5 mL, 0.3 M ) and isopropanol (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 was dissolved in dichloromethane (20 mL) and poured into water (20 mL). acid (0.1 M (aqueous solution) pH ≒ 4 ~ The aqueous phase was acidified to pH ≈ 1 and extracted with dichloromethane (3×25 mL). togetherThe organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The product was converted to the hydrochloride salt using general procedure A to afford 149 (102 mg, 53%) as a colorless solid. [ka]

[0268] Example 50 - N-Boc-4-(dimethylamino)methyl-cytisine, and 4-(dimethylamino)methyl-(-)-cytisine dihydrochloride (151) [ka] To a solution of amine 143 (320 mg, 1.0 mmol) in an equimolar mixture of tetrahydrofuran / water (12 mL) was added formaldehyde (480 mg, 6 equiv., 35% aqueous solution) and sodium cyanoborohydride (219 mg, 3.5 equiv.) successively. The reaction mixture was stirred at room temperature for 18 h. 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, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol (1% methanol)] to give green eluate. color The product was an oil (207 mg, 60%). [ka] General Procedure A in accordance with , N-Boc-4-(dimethylamino)methyl-cytisine (0.60 mmol) from This yielded 151 (120 mg, 81%) as a colorless solid, which turned into a viscous oil after standing in air for several days. [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 To the solution was added iodomethane (0.1 mL, 1.3 equiv.) and the reaction was stirred for 18 h at 60° C. The solution was concentrated. Using General Procedure A Deprotection hand Hydrochloride fart conversion death ,green color The product was dried at 37° C. The yield was 150 (80 mg, 42%) as a yellowish amorphous 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 equiv.) and stirred at room temperature for 24 h. The reaction was then concentrated. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol (3% methanol)] to afford the product (330 mg, 92%) as a colorless solid. Using General Procedure A Deprotection hand conversion Things to do to yield 148 (237 mg, 80%) as a colorless foam. [ka]

[0271] Example 53-N-Boc-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)cytisine (89) [ka] In a sealed tube, a solution of bromide 61 (180 mg, 0.5 mmol), copper(I) oxide (8 mg, 0.1 equiv.), and 1-Z-piperazine (0.5 mL, 2.5 mmol) in water (1.0 mL) was stirred at 100 °C for 18 h. The reaction was cooled and the residue was residue was extracted with ethyl acetate (3×25 mL). together The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography on silica gel [dichloromethane / methanol (2% methanol)] to afford 89 as 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 solution was placed under nitrogen and palladium on activated carbon 10 wt% (5 mg, 0.1 equiv.) was added. The vessel was placed under vacuum and flushed with hydrogen three times. Backfill The mixture was filtered through Celite® and the solvent was concentrated to afford the piperazinyl derivative (85 mg, 71%) as a colorless solid, 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 )ofA solution of N-Boc-4-N-(N'-benzyloxycarbonyl)-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 flushed with hydrogen three times. Backfill The mixture was filtered through Celite® and concentrated in vacuo. Using General Procedure A Deprotection hand Hydrochloride fart conversion 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] A solution of N-Boc-4-bromo-cytisine 61 (370 mg, 1.0 mmol) in a mixture of dimethylsulfoxide (3.8 mL) and water (1.6 mL) was cooled to 0° C. and sodium trifluoromethylsulfonate (470 mg, 3.0 mmol) was added. Tert-butyl hydroperoxide (0.7 mL, 70% aqueous solution) was added dropwise over 5 min and the solution was allowed to warm to room temperature and stirred for 24 h. The solvent was removed in vacuo. The crude was partitioned between ammonia (15 mL, 15% aqueous solution) and dichloromethane (15 mL) and the aqueous phase was extracted with dichloromethane (3×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel [n-hexane / ethyl acetate (1:1)] to afford 161 (130 mg, 30%) as a colorless solid, along 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%) were yielded. [ka]

[0276] Example 57a - N-Boc-3-bromo-4-iodocytisine (159) [ka] N-Boc-4-iodo-cytisine 65 (120 mg, 0.286 mmol) was dissolved in tetrahydrofuran (6 mL, 0.05 M) The mixture was dissolved and 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 (15 mL) and the aqueous phase was extracted with ethyl acetate (3×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel [n-hexane / ethyl acetate (1:1)] to afford 159 (91 mg, 65%) contaminated with N-Boc-5-bromo-4-iodo-cytisine (22:3 ratio). [ka]

[0277] Example 57b - (+) 3-Bromo-4-iodocytisine hydrochloride (160) [ka] General Procedure A in accordance with , iodide 159 (0.16 mmol) from, yielding 160 (57 mg, 81%) contaminated with 5-bromo-4-iodo-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 mmol) ) melt To the solution was added N-bromosuccinimide (54 mg, 0.30 mmol) and the reaction was stirred at room temperature for 24 h. The reaction was diluted with water (15 mL) and the aqueous phase was extracted with ethyl acetate (3×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel [dichloromethane / methanol (2% methanol)] to afford 157 (N-Boc-3-bromo-4-methylamino-cytisine) (84 mg, 70%), and N-Boc-5-bromo-4-methylamino (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 to yield 158 (45 mg, 73%) as a colorless solid contaminated with 9% 5-bromo-4-methylamino-cytisine. [ka]

[0280] Example 59 - Iridium-catalyzed CH borylation of (-)-cytisine Synthesis of 4-Bpin cytisine A Schlenk tube 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-butylbispyridine (5.4 mg, 0.02 equiv.) and bis(pinacolato)diboron (380 mg, 1.50 equiv.). purge Then, tetrahydrofuran (1.4 mL) was added and the reaction mixture was heated at reflux for 24 h, after which time the volatile materials were removed under reduced pressure to give 4-Bpin cytisine as a brown foam which was partially characterized without further purification. [ka] [ka] To confirm the identity of 4-Bpincytisine, the compound was further converted to 4-bromocytisine by treatment with an aqueous solution of copper(II) bromide in methanol. The spectroscopic properties of 4-bromocytisine were consistent with data available in the literature.

[0281] (Example 60 - Iridium-catalyzed CH borylation reaction of (-)-cytisine) (Synthesis of 4-Bpin cytisine) The preparation of Example 59 was carried out using the same molar amounts, equipment, solvents, catalysts and ligands as outlined above, with the difference being that tetramethyl-1,10-phenanthroline was used as the ligand and the boronation reaction was carried out in the same manner as described above. reagent The presence of 3.00 equivalents of bis(pinacolato)diboron as a cytisine derivative was confirmed by the preparation of 4-BPin cytisine, which resulted in 100% conversion of cytisine to 4-BPin cytisine.

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

[0283] Example 62 - Iridium-catalyzed CH borylation of N-Boc-cytisine (56) (Synthesis of N-Boc-4-Bpin cytisine (58)) A Schlenk tube 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-tert-butylbispyridine (5.4 mg, 0.02 equiv.) and bis(pinacolato)diboron (178 mg, 0.70 equiv.). purge Then, tetrahydrofuran (1.4 mL) was added and the reaction mixture was heated at reflux for 18 h, after which time 1H NMR showed nearly 100% conversion and the volatile materials were removed under reduced pressure. The crude N-Boc-4-Bpin cytisine (58) was shown to be essentially pure by 1H NMR, but further purification was possible. However , which is unnecessary prior to using N-Boc-4-BPin cytisine (58) as the reactant. Further purification of the crude N-Boc-4-BPincytisine (58) was achieved using chromatography (dichloromethane-methanol, 95:5) to yield pure N-Boc-4-BPincytisine (58) (180 mg, 43%) as a pale yellow foam. [ka]

[0284] Example 63 - Iridium-catalyzed CH borylation of N-Boc-cytisine (56) (Synthesis of N-Boc-4-Bpin cytisine (58)) The method of preparation of Example 62 was carried out using the same molar amounts, equipment, solvents, catalysts and ligands as outlined above, with the difference being that N-methylcytisine was used as the starting material of formula IIa. The method of preparation resulted in 98% conversion of cytisine to 4-BPincytisine.

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

[0286] (Example 65-N-Boc-4-p-tolylcytisine (72)) N-Boc-4-Bpin cytisine 58, 0.5 mmol scale in The general procedure discussed above Prepared according to To the crude N-Boc-4-Bpin cytisine was added potassium carbonate (124 mg, 0.90 mmol), tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.05 equiv.) and 4-bromotoluene (0.25 mL, 1.0 mmol), and the mixture was diluted with a mixture of diethyl 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). The aqueous phase was extracted with dichloromethane (3×15 mL) and together The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by flash column chromatography [dichloromethane / methanol (1.5% methanol)] afforded N-Boc-4-(p-tolyl)cytisine (104 mg, 55%) as a colorless solid.

[0287] Example 66-N-Boc-4-methylcytisine (109) N-Boc-4-Bpin cytisine 58, 0.5 mmol scale in The general procedure discussed above for the boronation reaction of cytisine Prepared according to did. Using a modification of the relevant procedure, crude N-Boc-4-Bpin cytisine 58 was added with tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.025 equiv.), tri(p-tolyl)phosphine (7.6 mg, 0.05 equiv.), potassium carbonate (138 mg, 2.0 equiv.), and iodomethane (0.03 mL, 1.0 equiv.), and the vessel was placed under vacuum and flushed with nitrogen three times. Backfill A mixture of N,N-dimethylformamide / water (9:1, 5 mL) was added and the reaction mixture was stirred at 60° C. for 18 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. residue The mixture was partitioned between ethyl acetate (15 mL) and water (15 mL) and the aqueous phase was extracted with ethyl acetate (3×15 mL). together The combined organic phase was dried over magnesium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel [dichloromethane / methanol (3% methanol)] to afford N-Boc-4-methylcytisine (98 mg, 64%) as a pale yellow solid.

[0288] Example 67a - N-Boc(3-bromo-4-hydroxy)cytisine [ka] Tetrahydrofuran (32 mL )of N-Boc-4-aminocytisine (512 mg, 1.67 mmol) ) melt The solution was cooled to 0° C., N-bromosuccinimide (312 mg, 1.76 mmol) was added, and the reaction mixture was stirred for 18 h at 0° C. Water (25 mL) was added and the aqueous phase was extracted with ethyl acetate (3×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude reaction mixture was purified by flash column chromatography [ethyl acetate / methanol (1% methanol)] to afford N-Boc(3-bromo-4-hydroxy)cytisine (350 mg, 55%) as a colorless solid. [ka]

[0289] Example 67b - (-)-(3-bromo-4-hydroxy)cytisine hydrochloride (BS70) [ka] General Procedure A in accordance with , N-Boc(3-bromo-4-hydroxy)cytisine (0.83mmol) 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) ) melt The solution was cooled to 0° C., N-bromosuccinimide (153 mg, 0.86 mmol) was added, and the reaction mixture was stirred for 18 h at 0° C. Water (25 mL) was added and the aqueous phase was extracted with ethyl acetate (3×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude reaction mixture by flash column chromatography [ethyl acetate] afforded N-Boc(3-bromo-4-amino)cytisine (95 mg, 30%) as a colorless solid. [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 Yield BS71 (62 mg, 64%) as a colorless solid. [ka]

[0292] (Example 69a -N-Boc(3-bromo-4-ethyl)cytisine) [ka] Tetrahydrofuran (20 mL )of N-Boc-4-ethyl-cytisine (341 mg, 1.07 mmol) ) melt The solution was cooled to 0° C., N-bromosuccinimide (190 mg, 1.07 mmol) was added, and the reaction mixture was stirred for 18 h at 0° C. Water (25 mL) was added and the aqueous phase was extracted with ethyl acetate (3×25 mL). together The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude reaction mixture by flash column chromatography [dichloromethane / methanol (2% methanol)] afforded N-Boc(3-bromo-4-ethyl)cytisine (296 mg, 70%) as a colorless solid. [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, 0.75 mmol) from , yielding BS74 (80 mg, 37%) as a colorless solid. [ka]

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

[0295] (Binding to heterologously expressed α4β2 and α3β4 human subtypes) HEK293 cells , supplemented with 10% fetal bovine serum, 1% L-glutamine, 100 units / ml penicillin G, and 100 μg streptomycin. In Dulbecco's modified Eagle's medium 、1 In a humid environment containing 0% carbon dioxide Cultured . Encodes α3 and β4, or α4 and β2 I'm cDNA (transfected into HEK293 cells at 30% confluency). cell Transfection was performed using 30 μL of JetPay (quotient The transfection was carried out in 100 mm Petri dishes using 100 μg of each cDNA and 100 μl of ... cell were collected, washed with phosphate-buffered saline by centrifugation, and used for binding assays. HEK-transfected α3β4 or α4β2 receptors 3 H]-epibatidine saturation binding experiments were performed in the presence of 100 nM cold epibatidine (specifically different (combination) or absence (complete complete conclusion In each case, a buffer containing 50 mM Tris-HCl, pH 7, 150 mM sodium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 2.5 mM calcium chloride, and 2 mg / ml bovine serum albumin was used. Inside, The experiments were carried out at concentrations ranging from 0.005 to 1 nM, with overnight incubation at 4°C. different Ligand binding was defined as total binding minus binding in the presence of 100 nM cold epibatidine.

[0296] Induced by compounds or nicotinic ligands 3Inhibition of [H]-epibatidine binding was determined by incubation with increasing concentrations of test compound (10 pM to 10 mM) for 30 min at room temperature (rt), followed by [ 3 The final concentration of [H]-epibatidine was 0.25 nM (for the α4β2 subtype) or 0.5 nM (for the α3β4 subtype) and incubated overnight at 4°C. After incubation, the membranes of HEK cells transfected with the α4β2 or α3β4 subtype were Ice cold The gel filtration chromatography filter was presoaked in polyethyleneimine and filtered through a harvesting device. 3 H]-epibatidine binding is a beta counter - Determined by liquid 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 The transfection was carried out in a 100 mm Petri dish using α7 cDNA and 6 μg of α7 (Polypas, France) (1 mg / ml, pH 7.2). After 24 hours of transfection, cell were collected, washed with phosphate-buffered saline by centrifugation, and used for binding assays.

[0298] [ 125 I]-α-bungarotoxin (purchased from PerkinElmer, Boston, Massachusetts) had a saturation binding of 0.1 at room temperature. ~ 10 nM concentration of [ 125 This was performed by overnight incubation of SH-SY5Y membranes with [I]-α-bungarotoxin. different Binding was determined in parallel by incubation in the presence of 1 μM unlabeled α-bungarotoxin. After incubation, samples were filtered as above and bound radioactivity was assayed in a gamma counter. Noh was directly counted. 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, Then, at room temperature, 125 I]-α-bungarotoxin at a final concentration of 2 to 3 nM was incubated overnight.

[0299] After overnight incubation, the membranes of α7-transfected SH-SY5Y cells were Ice cold The gel filtration chromatography filter was presoaked in polyethyleneimine and filtered through a harvesting device. 125 I]-α-bungarotoxin binding was measured by gamma counter in was determined by direct counting.

[0300] (Data Analysis) Ligand binding data were analyzed by nonlinear regression using Prism version 5 (GraphPad Software, La Jolla, CA). i Values ​​were calculated from experimental 50% inhibitory concentration values ​​using the Cheng-Prusoff equation for single populations at competing sites: K i =IC 50 / [1+(L / K d ), where L is the concentration of radioligand used in each experiment and K d Values ​​were determined by saturation binding experiments. All assays were performed in duplicate and repeated at least two to three times. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] As can be seen from this data, the compounds of the present invention exhibit high selectivity for the human α4β2 receptor subtype compared to both the α3β4 subtype and α7 (in both murine and human cells, when tested). 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 synthesis of human α4β2, α3β4 and α7 nicotinic acetylcholinesterases heterologously expressed in Xenopus oocytes. R Cholinergic receptors (nACh R) The effect of α4β2nACh receptors on the function of the α4β2nACh receptors was examined. Human α4β2nACh receptors were expressed as either (α4)3(β2)2 (low ACh sensitivity) or (α4)2(β2)3 receptors (high ACh sensitivity) (Non-Patent Document 16). Expression in oocytes was obtained as follows. Contains human α4, β2, β4 or α7 complementary DNA pCI (Promega, UK) Plasmi The previous literature (Non-Patent Document 16). To express the (α4)3(β2)2 nACh receptor, a mixture of 10α4:1β2 cDNA was injected into the oocyte nuclei, whereas for the (α4)2(β2)3 receptor, the ratio of injected cDNA was 1α4:10β2.

[0302] (Functional research) Geneclamp amplifier (Molecular Devices, USA) Manually, using Or use the automated HiClamp system Note Record but In both cases, oocytes were incubated for 3 MWith two electrodes filled with potassium chloride Stab , cell was held at −60 mV throughout the experiment.

[0303] Isolation of oocytes and voltage clamp recording with two electrodes Previous literature Agonist concentration-response curves were performed as previously described (16, 17). The concentration-response curves of the agonists were plotted against the responses elicited by the compounds relative to the responses elicited by 1 mM ACh, the concentration of ACh that maximally activated all receptors tested. Rules The data were obtained by synthesizing the agonist activity of oocytes in the presence of agonists (Non-Patent Documents 16 to 18). To ensure reproducible recordings, a minimum interval of 5 min was allowed between agonist applications. Oocytes were exposed to increasing concentrations of compound until no further increase in response amplitude was obtained. This concentration was interpreted as the concentration that produced the maximal response of the receptor tested. The data summarized in Tables 1 to 13 show that at least of 3 different donor Results were obtained from at least five experiments performed on oocytes obtained from

[0304] ((a):(α4)3(β2)2nACh R( Effect of compounds on stoichiometry of low sensitivity (Maximum gating efficacy of compound) (α4)3(β2)2nACh heterologously expressed in Xenopus oocytes R The concentration of the compound of the present invention that produces maximum activation is 、 Two-electrode voltage clamp was used to determine the maximal current elicited by the compounds, which was relativized to the maximal concentration elicited by 1 mM ACh (eliciting a maximal response at (α4)3(β2)2 receptors). [Table 10]

[0305] ((b):(α4)2(β2)3nACh R Effects related to (Maximum gating efficacy of the compound for the (α4)2(β2)3 receptor (high sensitivity receptor)) (α4)2(β2)3nACh heterologously expressed in Xenopus oocytes R The concentration of compound producing maximal activation was determined using a two-electrode voltage clamp. The maximal current elicited by the compound was then relativized to the maximal concentration elicited by 1 mM ACh (which elicits a maximal response at (α4)2(β2)3 receptors). [Table 11]

[0306] (c):α3β4nACh R Effects of compounds on (α3β4nACh R (maximum gating efficacy of compound for α3β4nACh heterologously expressed in Xenopus oocytes R The concentration of compound producing maximal activation was determined using a two-electrode voltage clamp. The maximal current elicited by the compound was then relativized to the maximal concentration elicited by 1 mM ACh (which elicits a maximal response at α3β4 receptors). [Table 12]

[0307] ((d):α7nACh R Effects of compounds 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 The amplitude of the response was relativized to 1 mM ACh, the concentration producing maximal activity. [Table 13] The data in Table 13 show that compounds of the present invention exhibit lower relative potency for the α7 receptor compared to cytisine and varenicline. 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 ester thereof, (chemical 1) TIFF0007668016000234.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 7are 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl; 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, or is absent; R of the side chain 5 9 is selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl; R of the side chain 4 13 is selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 are each independently selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, an amino acid or cytisine; or R 4 is a protecting group, or -(CH 2 ) V - a group having the structure of FORMULA 1 (formula A), where v in formula A is 0, 1, 2, 3, 4, 5 or 6, and FORMULA 1 is a compound of formula I, The R of Formula I 2 , R 3 and the above R 4 or a pharma- ceutically acceptable salt, solvate, and / or ester thereof, wherein at least one of: (Aspect 2) A compound of formula I, or a pharma- ceutically acceptable salt, solvate, and / or ester thereof, for use in medicine, comprising (Case 2) TIFF0007668016000235.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 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, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl; 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, or is absent; R of the side chain 5 9 is selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl; R of the side chain 4 13 is selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 are each independently selected from Group 7 consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, an amino acid or cytisine, or 4 is a protecting group, or -(CH 2 ) V - a group having the structure FORMULA 1 (formula A), wherein v in formula A is 0, 1, 2, 3, 4, 5 or 6, and wherein formula 1 is a compound of formula I, or a pharma- ceutically acceptable salt, solvate, and / or ester thereof. (Aspect 3) R 1 is a substituted C, including a substituted methyl group, a substituted ethyl group, and a substituted propyl group. 1-8 is an alkyl group, The substituted methyl group includes aminomethyl and halogenated methyl groups, and the halogenated methyl groups include chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, and tribromomethyl; the substituted ethyl group includes 1- or 2-aminoethyl, hydroxyethyl, and ethyl halide, the ethyl halide including 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, or 2,2,2-trifluoroethyl; The compound according to any one of the preceding aspects, wherein the substituted propyl group comprises 1-, 2-, or 3-aminomethyl, hydroxypropyl, or halogenated propyl. (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, comprising a phenyl group or a substituted phenyl group, including a halogenated phenyl group, including chlorophenyl, bromophenyl, fluorophenyl, perchlorophenyl, perbromophenyl, perfluorophenyl, or a compound according to embodiment 1 or 2, comprising tolyl, aniline, phenol, styrene, benzonitrile, anisole, acetophenone, benzaldehyde or benzoic acid. (Aspect 6) R 1 is an optionally substituted heteroaryl, including benzyloxypyridine, pyridone including 2-pyridone, pyridine including 2-pyridine, 3-pyridine or 4-pyridine, phenyltriazole, optionally substituted triazole and triazole methylpivalate. (Aspect 7) R 1 A compound according to any one of the preceding aspects, wherein is an optionally substituted cycloalkyl or heterocycloalkyl, including cyclopentyl, cyclohexyl, morpholinyl, piperidyl, piperazyl, tetrahydrofuryl, oxolanyl, or dioxanyl. (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 Alkenyl or optionally substituted C 2-8 The compound according to any one of the preceding aspects, wherein said compound is alkynyl. (Aspect 9) R 1 is an amine, an N-alkylamine, an N,N-dialkylamine, or an amide. (Aspect 10) R 1 is any one of amine, methylamine, ethylamine, propylamine, isopropylamine, benzylamine, dimethylamine, trimethylammoniummethyl, dimethylaminomethyl, benzamide, or acetamide. (Aspect 11) R 1 A compound according to any one of aspects 1 to 2, wherein is any one of methoxy, ethoxy, propoxy, benzyloxy, or trifluoromethylbenzyloxy. (Aspect 12) R 1 is a carboxylic acid or ester, including an ethyl ester, a propyl ester, an isopropyl ester, a butyl ester, or a phenyl ester. (Aspect 13) R 1 is a naturally occurring amino acid or an ester thereof, including alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or their methyl, ethyl, propyl, or isopropyl esters. (Aspect 14) R 1 is tert-butyloxycarbonyl (Boc), formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Cbz), or fluorenylmethoxycarbonyl (Fmoc), or (RO) of (pinacolato)borane (BPin) and (catecholato)borane (BCat). 2 The compound according to any one of the preceding aspects, which is any one of the protected boryl protecting groups optionally comprising the B-structure. (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) 20. The compound according to embodiment 19, wherein the addiction is one of nicotine addiction, alcohol addiction, or drug addiction. (Aspect 21) A composition comprising a compound according to any one of aspects 1 to 20, and a pharma- ceutically acceptable excipient. (Aspect 22) 22. The composition according to aspect 21, for use in the prevention or treatment of addiction. (Aspect 23) 23. The composition of claim 22, wherein the addiction is nicotine addiction, alcohol addiction, and drug addiction. (Aspect 24) 23. A method for preventing or treating intoxication in a subject in need of treatment, comprising administering to said subject an effective amount of a compound according to any one of aspects 1 to 20, or a composition according to any one of aspects 21 to 23. (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; (3) TIFF0007668016000236.tif51170 Step ii to produce a compound of formula IIb; (C4) TIFF0007668016000237.tif51170 CompB of the formula IIb is R 1 and iii) replacing the compound with H to produce a compound of formula I, (C5) TIFF0007668016000238.tif50170 R of Formula IIa 2 、R 3 and R 4 are each independently selected from Group 1 consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, an amino acid or cytisine, or 4 is a protecting group, or -(CH 2 ) V - a group having the structure of FORMULA 1 (formula A), where v in formula A is 0, 1, 2, 3, 4, 5 or 6, and FORMULA 1 is a compound of formula I, The R of formula IIb 2 , R 3 and the above R4 is selected from Group 1, and CompB is a boronated complex obtained by contacting the compound of formula IIa with a boronating agent; 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 are each independently selected from Group 2 consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl; 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, or is absent; R of the side chain 5 9 is selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl; R of the side chain 4 13 is selected from hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamido, sulfo, mercapto, carbamoyl, methylpivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or 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 A preparation method in which at least one of the above is not hydrogen. (Aspect 26) The compound of formula IIa provided in step i is 4 containing a hydrogen atom at the position The step further comprises: 4 26. The method according to embodiment 25, comprising replacing the hydrogen atom at position with a protecting group. (Aspect 27) 27. The process according to embodiment 26, wherein the protecting group is tert-butyloxycarbonyl (Boc). (Aspect 28) The method according to any one of claims 26 to 27, wherein said compound of formula IIa is cytisine. (Aspect 29) The boronizing reagent has the formula (RO) 2 -BB-(OR) 2 OrHB(OR) 2 29. The method of any one of embodiments 25 to 28, wherein the compound has a chemical structure represented by: (Aspect 30) The boronation reagent is bis(pinacolato)diboron (B 2 Pin 2 ), or bis(catecholato)diboron (B 2 Cat 2 29. The method according to any one of aspects 25 to 28, wherein (Aspect 31) 31. The process according to any one of aspects 25 to 30, wherein 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 at least 2:1. (Aspect 32) 32. The process according to any one of aspects 25 to 31, wherein the reaction in step ii is carried out in the presence of a catalyst. (Aspect 33) 33. The process according to embodiment 32, wherein the catalyst is a transition metal catalyst. (Aspect 34) 34. The process according to embodiment 33, wherein the transition metal catalyst comprises iridium, palladium, zinc, nickel and / or rhodium. (Aspect 35) A process according to any one of aspects 25 to 34, wherein the reaction in step ii is carried out in a solvent. (Aspect 36) 36. The process according to aspect 35, wherein the solvent comprises an ester solvent, an ether solvent, a ketone solvent, a sulfoxide solvent, an aromatic solvent, a fluorinated aromatic solvent, an alkane solvent or a mixture thereof. (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. (Aspect 38) 38. The method according to embodiment 37, wherein the ligand is any one of tetramethyl-1,10-phenanthroline (Me4phen), di-tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl)ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), xantphos, or 1,2-bis(dimethylphosphino)ethane (dmpe). (Aspect 39) 38. The method according to claim 37, wherein the ligand is any one of phenanthroline (phen), dimethylphenanthroline (me2phen), tetramethyl-1,10-phenanthroline (me4phen), bathophenanthroline (bathophen), di-tert-butyl-2,2'-bipyridyl (dtbpy), 2,2'-bipyridine (bpy), dimethoxy-2,2'-bipyridyl (MeO-bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl)ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), neocuproine, xantphos, 1,2-bis(dimethylphosphino)ethane (dmpe), or a compound according to formula 6. (6) TIFF0007668016000239.tif207170 。 (Aspect 40) 40. The process according to any one of aspects 37 to 39, wherein the molar ratio of boronating reagent to starting material of formula IIa is from less than 2:1, or less than 1.5:1, or less than 1:1, or less than 0.75:1, or less than 0.5:1, or less than 0.1:1, or less than 0.05:1 to at least 0.001:1. (Aspect 41) 41. A process according to any one of aspects 25 to 40, wherein the boronation in step ii is carried out at a temperature of from 50° C. to 100° C. (Aspect 42) 42. The process according to any one of aspects 25 to 41, wherein the compound of formula IIb is not separated from the product mixture formed in step ii prior to the start of step iii, and / or no purification step is carried out between step ii and step iii. (Aspect 43) 43. The process according to any one of aspects 25 to 42, wherein step iii is initiated in the same reaction zone in which step ii is carried out. (Aspect 44) In the step iii, the CompB is R 1 44. The process according to any one of aspects 25 to 43, wherein the first intermediate is substituted with a substituent. (Aspect 45) R 1 The first intermediate of the substituent is R 1 or R 1 45. The method of claim 44, wherein said compound of formula I is substituted with a substituent. (Aspect 46) R 1 The second intermediate of the substituent is R 1 or R 1 46. ​​The method of claim 45, wherein said compound of formula I is substituted with a substituent. (Aspect 47) R 1 The process according to aspect 46, wherein the first, second and third intermediate substituents are independently selected from bromo, chloro, iodo, benzyloxypyridine, alkyl ester including methyl ester, alkenyl including vinyl, alkynyl including acetylenyl, trimethylsilylacetylene, 1,2,3-triazol-1-ylmethylpivalate, cyano, aminomethyl, N-Boc-aminomethyl or (benzyloxy)carbonyl)piperazin-1-yl. (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 48. A method according to any one of aspects 25 to 47, comprising deprotecting a group. (Aspect 49) R of the compound of formula IIb or formula I 4 A process according to aspect 48, wherein said deprotecting step is carried out after completion of step ii, or before the start of step iii, or during step iii, or after completion of step iii.

Claims

1. A compound represented by formula (I), 【Chemistry 1】 In formula (I), R 1 teeth, Hydroxy, halogen, Aryl, Alkyl, Alkenyl, Alkynyl, -NR 6 R 7 (Here, R 6 and R 7 each is independently selected from hydrogen, aryl, and alkyl; -NH(C=O)R 9 (Here, R 9 is aryl or alkyl); -CH 2 -NR 6 R 7 (Here, R 6 and R 7 each is independently selected from hydrogen and alkyl; Alkoxy, -CH 2 -O-CH 2 -R 10 (Here, R 10 is aryl), - C.N., -COOR 12 (Here, R 12 is hydrogen or alkyl; an amino acid or its methyl, ethyl, propyl, or isopropyl ester; Acyl chloride, or 4-cytisinyl, R 2 is hydrogen, halogen, or haloalkyl; R 3 is hydrogen, and R 4 is hydrogen or a protecting group, wherein the protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), (pinacolato)borane (BPin), and (catecholato)borane (BCat); R 2 and R 3 is hydrogen and R 4 When is Boc, R 1 is methyl or -CH 2 Not OH and R 2 , R 3 and R 4 At least one of the following is not hydrogen: The compound or a pharma- ceutically acceptable salt or solvate thereof, which is a single stereochemical isomer.

2. R 1 The compound of claim 1 , wherein is alkyl.

3. R 2 and R 3 The compound of claim 1 , wherein is hydrogen.

4. R 4 The compound of claim 1 , wherein:

5. (+) 4-trylcytisine, (-) 4-ethylcytisine, and A compound selected from (+) 4-vinylcytisine.

6. A compound according to any one of claims 1 to 3 and 5, or a pharma- ceutically acceptable salt or solvate thereof, for use in the prophylaxis or treatment of an addiction selected from nicotine addiction, alcohol addiction, or drug addiction.

7. 7. A composition comprising a compound according to any one of claims 1 to 3, 5 and 6, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

8. 8. The composition of claim 7, for use in the prevention or treatment of an addiction selected from nicotine addiction, alcohol addiction, or drug addiction.

9. 10. A method for the prevention or treatment of addiction in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 3, 5 and 6, or a composition according to claim 7 or 8, wherein the addiction is selected from nicotine addiction, alcohol addiction, or drug addiction.

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