HK1074573B

HK1074573B - Tetrahydroquinoline analogues as muscarinic agonists

Info

Publication number: HK1074573B
Application number: HK05106785.1A
Authority: HK
Inventors: 尼尔斯．肖杰埃贝克; 克瑞斯蒂恩．鲁普．科克; 博．伦纳特．米卡埃尔．弗里贝里; 博-拉格纳．托尔夫
Original assignee: 阿卡蒂亚药品公司
Priority date: 2001-12-28
Filing date: 2002-12-23
Publication date: 2009-05-22

Description

Tetrahydroquinoline analogs as muscarinic agonists

Technical Field

[0001]The present invention relates to compounds that affect cholinergic receptors, particularly muscarinic receptors. The present invention provides compounds which are agonists of cholinergic receptors, including muscarinic receptors, particularly M of muscarinic receptors₁And M₄The subtype is. The invention also provides methods of using the provided compounds to modulate diseases associated with cholinergic receptors, inter aliaIs used for treating or alleviating diseases related to muscarinic receptors, such as M₁And/or M₄Receptor subtype associated diseases.

Background

[0002]Muscarinic cholinergic receptors mediate the response of the neurotransmitter acetylcholine in the central and peripheral nervous systems. Muscarinic receptors play a key role, in the central nervous system they mediate higher cognitive functions and in the peripheral parasympathetic nervous system they mediate cardiac, respiratory, digestive and endocrine and exocrine responses. Five different muscarinic receptor subtypes have been identified: m₁-M₅. Muscarinic radicals M₁Receptor subtypes are predominantly expressed in the cerebral cortex and are thought to be involved in the control of higher cognitive functions; m₂Receptors are the major subtype found in the heart, which is involved in the control of heart rate; m₃Receptors are widely expressed in many peripheral tissues and are thought to be involved in gastrointestinal and urinary tract stimulation and in sweating and salivation; m₄Receptors are present in the brain and may be associated with locomotion; m₅Receptors are present in the brain and their function is currently uncertain. M₁And M₄Of particular relevance is the dopaminergic system.

[0003] Diseases associated with cognitive impairment such as Alzheimer's disease are accompanied by a decrease in acetylcholine content in the brain. This is thought to be a result of the degeneration of cholinergic neurons of the basal forebrain, which are innervated by various regions of the brain, including the cortex and hippocampus, which are primarily associated with higher-order processes.

[0004] Efforts to increase acetylcholine levels have focused on increasing choline (acetylcholine synthesis precursor) levels and blocking acetylcholinesterase (AChE), an enzyme that metabolizes acetylcholine. Attempts to enhance central cholinergic function by choline or lecithin administration have proven unsuccessful. While AChE inhibitors have been shown to have therapeutic efficacy, they are often found to have cholinergic side effects due to stimulation with peripheral acetylcholine, including abdominal cramps, nausea, vomiting, and diarrhea. These gastrointestinal side effects are observed in about one-third of the patients treated. In addition, it has been found that significant hepatotoxicity due to elevated hepatic transaminase is observed in about 30% of patients with some AChE inhibitors, such as tetrahydroaminoacridine. The adverse effects of AChE inhibitors severely limit their clinical utility.

[0005] The dopamine hypothesis of schizophrenia suggests that increased dopamine neurotransmission is responsible for the positive symptoms of this disease and is supported by evidence that dopamine receptor blockers are effective in ameliorating the symptoms of this disease. In addition, drugs that enhance dopamine neurotransmission in the brain can cause humans to develop conditions similar to psychosis and exacerbate psychotic symptoms in schizophrenic patients. In animal studies, drugs that increase dopamine neurotransmission have behavioral effects such as hyperactivity, climbing and prepulse inhibition deficits. Known antipsychotic and dopamine receptor antagonists block these behavioral effects. Unfortunately, dopamine receptor antagonists also cause severe extrapyramidal side effects in patients, as predicted by the induction of severe syncope in animal models, including tremor, bradykinesia, difficulty sitting still, and tardive dyskinesia.

[0006]Due in part to these observations, there is M₁Agents with receptor agonist activity have been found to be useful in the treatment of dementia. However, the action of existing agents on different muscarinic receptor subtypes lacks specificity. Also found are known M₁Muscarinic agonists such as arecoline which is M₂And M₃Weak agonists of the receptor subtype and no effect in the treatment of cognitive impairment due largely to dose-limiting M₂And M₃Side reactions mediated by the receptor.

[0007]Nalmerine (Xanomeline) (Shannon et al, J.Pharmacol. exp. Ther.1994, 269, 271; Shannon et al, Schizophrenia Res.2000, 42, 249) is an M₁/M₄Preferred muscarinic receptor agonists, while capable of inhibiting a10 but not a9 dopamine cells, have little or no affinity for dopamine receptors. Thiadiazole derivatives PTAC (Shannon et al, European Journal of Pharmacology, 1998, 356, 109) have been reported to antagonize muscarinic M₂And M₄The receptor has partial agonist action on M₁、M₃And M₅The receptor has antagonist action and simultaneously shows functional dopamine antagonist.

[0008] More recently, muscarinic agonists, including manocorine, have been shown to have activity in animal models similar to known antipsychotics, but without causing catalepsy (Bymaster et al, Eur. J. Pharmacol.1998, 356, 109, Bymaster et al, Life Sci.1999, 64, 527, Shannon et al, J Pharmacol. Exp. Ther.1999, 290, 901, Shannon et al, Schizophra Res.2000, 42, 249). Furthermore, pennomalin appears to alleviate psychotic behavioral symptoms such as delusions, hallucinations, quarries and hallucinations in patients with alzheimer's disease (Bodick et al, arch. neurol.1997, 54, 465), yet the clinical use of this compound is severely restricted by side effects caused by treatment.

[0009] It has been reported (Sauerberg et al, j.med chem.1998, 41, 4378) that 1, 2, 5-thiadiazole analogs have high affinity and selectivity for central muscarinic receptors, while exhibiting functional dopamine antagonism despite a lack of affinity for dopamine receptors.

[0010]The present investigators have in part worked to design a molecule that ameliorates negative symptoms and cognitive impairment while alleviating positive symptoms associated with schizophrenia as a novel drug for the treatment of psychotic disorders. The aim of the investigator of the present application is to demonstrate D with a combination₂Antagonist active muscarinic M₁And/or M₄Agonists have a better antipsychotic effect without producing high doses of D alone₂Side effects associated with antagonists. D of some compounds of the invention₂Antagonist properties help to alleviate the positive symptoms of the disease.

[0011]Based on M₁And M₄Distribution of receptors in the cerebral cortex and hippocampus (the region associated with higher cognitive function), M of these compounds₁And/or M₄Agonist attributes may alleviate cognitive dullness and possibly improve the negative symptoms associated with schizophrenia (Friedman, biol. psychohistory, 1999, 45, 1; Rowley, j.med. chem.2001, 44, 477; Felder, j.med chem.2000, 43, 4333). This unique combination of central nervous system behavior in a molecule is unprecedented and may lead to an entirely new class of antipsychotics with better clinical attributes without limiting side effects.

[0012] U.S. Pat. Nos. 3,324,137 and 3,365,457 disclose N- [ indolyl-lower-alkanoyl ] -1, 5-iminocycloalkanes and iminocycloalkanes not encompassed by the present invention.

[0013] EP 0584487 discloses 4, 5-dihydro-4-oxo-pyrroles linked to a piperazine ring which are not encompassed by the present invention.

[0014] Mokrosz et al (Pharmazie, 52, 1997, 6, p423) disclose N- [3- (4-aryl) -1-piperazinyl ] propyl ] derivatives of indolin-2 (1H) -one, quinolin-2- (1H) -one and isoquinolin-1- (2H) -one which are not encompassed by the present invention.

Disclosure of Invention

[0015] The invention provides a novel compound shown as a general formula I, and salts and isomers thereof

Wherein R is¹Is a monovalent radical selected from optionally substituted C_1-6-alkyl, optionally substituted C_2-6Alkylene, optionally substituted C_2-6-alkenyl, optionally substituted C_2-6-alkynyl, optionally substituted O-C_1-6-alkyl, optionally substituted O-C_2-6-alkenyl, optionally substituted O-C_2-6-alkynyl, optionally substituted S-C_1-6-alkyl, optionally substituted S-C_2-6-alkenyl, optionally substituted S-C_2-6-an alkynyl group;

m is O, 1 or 2;

C₃-C₄is CH₂-CH or CH ═ C, or C₄Is CH and C₃Is absent;

R²and R³Independently selected from hydrogen, optionally substituted C_1-6Alkyl, optionally substituted O-C_1-6Alkyl, halogen, hydroxy, or R²And R³Together form a ring system;

R⁴and R⁵Each of which is independently selected from hydrogen, halogen, hydroxy, optionally substituted C_1-6-alkyl, optionally substituted O-C_1-6Alkyl, optionally substituted aryl-C_1-6Alkyl and optionally substituted arylheteroalkyl;

L¹and L²Is a divalent group independently selected from-C (R)⁶)＝C(R⁷)、-C(R⁶)＝N-、-N＝C(R⁶) -, -S-, -NH-and-O-; wherein L is¹And L²Only one of which may be selected from-S-, -NH-, and-O-;

y is selected from O, S and H₂；

X is a divalent group selected from-C (R)⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁷)-O-、-S-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-S-、-N(R^N)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-N(R^N)-、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、-O-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、S-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、N(R^N)-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-O、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-S、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-N(R^N)-、-C(R⁶)(R⁷)-C(R⁶)＝C(R⁷) -and-C (R)⁶)＝C(R⁷)-C(R⁶)(R⁷) Wherein R is⁶And R⁷Independently selected from hydrogen, halogen, hydroxy, nitro, cyano, NR^NR^N、N(R^N)-C(O)N(R^N) Optionally substituted C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, optionally substituted O-C_1-6-alkyl, optionally substituted O-aryl, optionally substituted O-C_2-6-alkenyl, optionally substituted O-C_2-6-an alkynyl group,

wherein R is^NSelected from hydrogen and optionally substituted C_1-6-an alkyl group.

[0016] The invention also provides compositions comprising

i) One or more compounds of the formula I, and

ii) at least one pharmaceutically acceptable excipient or carrier.

[0017] The invention also provides methods of treating a disease in a mammal, such as a human, wherein modulation of cholinergic receptor activity is associated with a physiologically beneficial response in the disease in the mammal. In one embodiment, the method comprises administering an effective amount of a compound of formula I.

[0018]Thus, the present invention provides methods for treating or preventing or alleviating one or more symptoms associated with an aberration in a mammal, such as a human, which is associated with a muscarinic receptorRelating, e.g. to M₁Muscarinic receptor subtypes are related. In one embodiment, the method comprises administering an effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing. Disorders that are particularly treatable by the methods of the present invention include, for example, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friedreich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Niemann Pick's disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, amnesia, confusion, memory loss, attention deficit, vision deficit, depression, pain, sleep disorders, psychosis, sudden infant death Syndrome, increased intraocular pressure, and glaucoma.

[0019]The invention also provides a method of treating a psychotic disorder in which the physiologically beneficial response is due to a response to M₁Agonism, M₁And M₄Agonism, M₁Agonism and D₂Antagonism, or M₁And M₄Agonism and D₂Modulation of antagonism.

[0020] The invention also provides the use of a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing, in the manufacture of a medicament for the treatment of a disease or disorder associated with a cholinergic receptor or a ligand thereof.

[0021] Thus the invention provides a method for the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of alzheimer's disease, parkinson's disease, schizophrenia, huntington's chorea, friedreich's ataxia, gilles de la tourette's syndrome, down syndrome, niemann-pick disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, amnesia, confusion, memory loss, attention deficit, vision loss, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.

[0022] The invention also provides methods of increasing cholinergic receptor activity. In one embodiment, the method comprises contacting a cholinergic receptor or a cholinergic receptor-containing system with an effective amount of at least one compound of formula I to increase the activity of the cholinergic receptor.

[0023]The invention provides kits comprising one or more compounds of the invention and instructions for performing the methods of the invention. In one embodiment, the instructions are for treating or preventing or alleviating one or more symptoms associated with an aberration in a mammal, such as a human, associated with a muscarinic receptor, such as M₁Muscarinic receptor subtypes are related. In another embodiment, the instructions are to increase cholinergic receptor activity or activate a cholinergic receptor.

Description of the invention

[0024] For the purpose of explanation, the following definitions will be used to define technical terms in their entirety.

[0025] The term "agonist" is defined as a compound that, when contacted with a receptor, enhances the activity of the receptor.

[0026] The term "antagonist" is defined as a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby inhibiting or blocking the effect of the agonist or inverse agonist on the receptor. However, antagonists (also known as "neutral" antagonists) have no effect on intrinsic receptor activity.

[0027]The term "inverse agonist" is defined as a compound that decreases the basal activity of a receptor (i.e., a signal mediated through the receptor). Such compounds are also known as negative antagonists. Inverse agonists are ligands for a receptor that render the receptor inactive relative to a basal state that occurs in the absence of any ligand. Thus, when an antagonist inhibits the activity of an agonist, an inverse agonist is a ligand that can alter the conformation of the receptor in the absence of the agonist. Concept of inverse agonistsIs produced by Bond et al in Nature 374: 272 (1995). More specifically, Bond et al propose non-coordinating β₂The adrenergic receptors are in equilibrium between an inactive conformation and a spontaneous active conformation. Agonists are believed to stabilize the receptor in the active conformation. Conversely, inverse agonists are believed to stabilize inactive receptor conformations. Thus, when an antagonist exhibits activity against an agonist, an inverse agonist also exhibits activity in the absence of the agonist by inhibiting the spontaneous conversion of the non-coordinating receptor to an active conformation.

[0028]“M₁The receptor is defined as the activity and M₁The corresponding receptors of the muscarinic receptor subtype, which can be characterized by molecular clonology and pharmacology.

[0029] The term "subject" refers to an animal, e.g., a mammal, such as a human, who is the subject of treatment, observation or experiment.

[0030] The term "selective" is defined as the property of a compound in an amount sufficient to affect the desired response of a particular receptor type, subtype, species or subspecies with substantially little or no effect on the activity of other receptor types.

[0031]EC of agonist₅₀Is intended to mean the concentration of the compound required to achieve 50% of the maximum reaction observed in an in vitro assay such as R-SAT. EC of inverse agonist₅₀Is intended to mean the concentration of the desired compound at which 50% inhibition of the R-SAT reaction is achieved at a basal level in the absence of the compound.

[0032] The term "co-administration" of pharmacologically active compounds as used herein refers to the delivery of two or more separate chemical agents, whether in vitro or in vivo. Co-administration refers to the simultaneous delivery of separate agents; simultaneous delivery of the medicament mixture; and delivering one agent followed by a second or other agent. In each case, the co-administered agents act in combination with each other.

[0033]In the context of the present invention, the term "C_1-6By alkyl is meant straight chainOr a branched saturated hydrocarbon chain, wherein the longest chain has 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.

[0034]In the context of the present invention, the term "C_2-8-alkenyl "means a straight or branched hydrocarbon group having 2 to 8 carbon atoms and containing one or more double bonds. C_2-8Illustrative examples of-alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl. C containing more than one double bond_2-8Illustrative examples of alkenyl groups include butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl, and octatrienyl, and branched forms thereof. The unsaturated bond (double bond) may be located anywhere in the carbon chain.

[0035]In the context of the present invention, the term "C_2-8-alkynyl "means a branched or linear hydrocarbon radical containing from 2 to 8 carbon atoms and containing one or more triple bonds. C_2-8Illustrative examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl and branched forms thereof. The unsaturated bond (triple bond) may be located at any position of the carbon chain. The unsaturated bond may be more than one, so that C_2-8Alkynyl may be a diyne or an enediyne as known to the person skilled in the art.

[0036]In the context of the present invention, the term "C_3-8-cycloalkyl "includes 3-, 4-, 5-, 6-, 7-and 8-membered rings containing only carbon atoms, while the term" heterocyclyl "means 3-, 4-, 5-, 6-, 7-and 8-membered rings in which carbon atoms and 1 to 3 heteroatoms form said rings. The heteroatoms of such heterocyclic groups are independently selected from oxygen, sulfur and nitrogen.

[0037] The term "heterocyclyl" also contains one or more carbonyl or thiocarbonyl functional groups such that the definition includes both O-and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates and the like.

[0038]C_3-8-cycloalkyl and heterocyclyl optionally contain one or more unsaturated bonds which are present in such a way that no aromatic pi-electron system is produced.

[0039] Heterocycles may alternatively be fused to aromatic rings, such that this definition includes bicyclic structures. Such fused heterocyclic groups share a single bond with the optionally substituted phenyl ring. Examples of benzo-fused heterocycles include, but are not limited to, benzimidazolone, tetrahydroquinoline, and methylenedioxybenzene ring structures.

[0040]“C_3-8Illustrative examples of "cycloalkyl" are the carbocyclic rings cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1, 3-cyclohexadiene, 1, 4-cyclohexadiene, cycloheptane, cycloheptene, 1, 2-cycloheptadiene, 1, 3-cycloheptadiene, 1, 4-cycloheptadiene, and 1, 3, 5-cycloheptatriene.

[0041] Illustrative examples of "heterocyclyl" are heterocyclic tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1, 3-dioxins, 1, 3-dioxans, 1, 4-dioxins, 1, 4-dioxans, piperazines, 1, 3-oxathianes, 1, 4-oxathianes, tetrahydro-1, 4-thiazines, 2H-1, 2-oxazines, maleimides, succinimides, barbituric acid, thiobarbituric acid, dioxopiperazines, hydantoins, dihydrouracils, morpholines, trioxanes, hexahydro-1, 3, 5-triazines, tetrahydrothiophenes, tetrahydrofurans, pyrrolines, pyrrolidinones, pyrrolidinediones (pyrollidinones), pyrazolines, imidazolines, imidazolidines, 1, 3-dioxole, 1, 3-dioxolane, 1, 3-dithienolone, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, 1, 3-oxathiapentane. The bond to the heterocycle may be at a heteroatom, or through a carbon atom of the heterocycle, or through a carbon of the phenyl ring for benzo-fused derivatives.

[0042]In the context of the present invention, the term "aryl" is meant to refer to a carbocyclic aromatic ring or ring system. In addition, theThe term "aryl" includes fused ring systems wherein at least two aromatic rings or at least one aryl group is joined to at least one C_3-8-the cycloalkyl groups share at least one chemical bond. Illustrative examples of "aryl" rings include optionally substituted phenyl, naphthyl, phenanthryl, anthracyl, tetrahydronaphthyl, fluorenyl, indenyl, and indanyl. An example of aryl is phenyl. The term "aryl" refers to an aromatic group, typically a phenyl-type group, attached through one ring-forming carbon atom, and optionally bearing one or more substituents selected from: halogen, hydroxy, amino, cyano, nitro, alkylamido, acyl, C_1-6Alkoxy radical, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Aminoalkyl radical, C_1-6Alkylamino, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl. As mentioned, aryl may be phenyl, more suitably substituted phenyl with one or two, the same or different substituents as listed above. The substituted positions are para and/or meta. Representative examples of aryl groups include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, trifluoromethylphenyl, alkoxyphenyl.

[0043]In the context of the present invention, the term "aryl (C)_1-6-alkyl) "means through C as defined above_1-6-an alkyl-linked carbocyclic aromatic ring.

[0044]The term arylheteroalkyl should be construed as an aryl group as defined above, which is interrupted by C_1-6The alkyl chain is linked as a substituent and also contains in the chain at least one atom chosen from oxygen, sulphur and nitrogen.

[0045] In the context of the present invention, the term "heteroaryl" means a heterocyclic aromatic group in which one or more carbon atoms in the aromatic ring are replaced by one or more heteroatoms selected from nitrogen, sulfur, phosphorus and oxygen.

[0046]In addition, the term "heteroaryl" includes fused ring systems wherein at least one aromatic ring is joined to at least one heteroaromatic ring, at least two heteroaromatic rings, at least one heteroaromatic ring is joined to at least one heterocyclic group, or at least one heteroaromatic ring is joined to at least one C_3-8The cycloalkyl rings share at least one chemical bond.

[0047]The term "heteroaryl" is understood to mean an aromatic C also containing one O or S atom, or up to four N atoms, or a combination of one O or S atom and up to two N atoms_2-6Cyclic groups, substituted and benzo-and pyrido-fused derivatives thereof, and are typically attached through a ring-forming carbon atom. The heteroaryl group may bear one or more substituents selected from: halogen, hydroxy, amino, cyano, nitro, alkylamido, acyl, C_1-6-alkoxy, C_1-6Alkyl radical, C_1-6-hydroxyalkyl, C_1-6Aminoalkyl radical, C_1-6-alkylamino, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl. Particular heteroaryl groups are 5-and 6-membered aromatic heterocyclic systems which carry 0, 1 or 2 substituents, which are identical or different from one another, selected from the substituents listed above. Representative examples of heteroaryl groups include, but are not limited to, unsubstituted, mono-or di-substituted derivatives of: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, furazan (furazan), 1, 2, 3-oxadiazole, 1, 2, 3-thiadiazole, 1, 2, 4-thiadiazole, triazole, benzotriazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, pteridine, pyrrole, phenoxazole, oxazole, isoxazole, oxadiazole, benzopyrazole, indazole, quinolizine, cinnoline, 2, 3-naphthyridine, quinazoline, and quinoxaline. The most common substituents are halogen, hydroxy, cyano, O-C_1-6Alkyl radical, C_1-6-alkyl, hydroxy-C_1-6Alkyl, amino-C_1-6-an alkyl group.

[0048]The term "O-C" as used herein_1-6-alkyl "means C_1-6Alkoxy (alkyloxy) or alkoxy (alkyloxyy), such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy and hexyloxy.

[0049] The term "halogen" includes fluorine, chlorine, bromine and iodine.

[0050]The term "optionally substituted" as used herein means that the target group may be substituted one or several times, such as 1 to 5 times, 1 to 3 times or 1 to 2 times, with one or more substituents selected from C_1-6Alkyl radical, C_1-6Alkoxy, oxo (which may be the tautomeric enol form), carboxy, amino, hydroxy (which may be the tautomeric keto form when the enol system is present), nitro, alkylsulfonyl, alkylsulfinyl, C_1-6-alkoxycarbonyl, C_1-6Alkylcarbonyl, formyl, mono-and bis (C)_1-6-alkyl) amino, carbamoyl, mono and bis (C)_1-6-alkyl) aminocarbonyl, amino-C_1-6-alkyl-aminocarbonyl, mono-and bis (C)_1-6-alkyl) amino-C_1-6-alkylaminocarbonyl radical, C_1-6Alkylcarbonylamino, cyano, guanidino, ureido, C_1-6-alkanoyloxy, C_1-6-alkylsulfonyloxy, -dihalo-C_1-6Alkyl, trihalo-C_1-6-alkyl and halogen. Typically, the above substituents can also be optionally substituted.

[0051] The term "salt" means a pharmaceutically acceptable acid addition salt, which can be obtained by treating a functional group in basic form, such as ammonia, with a suitable acid, such as an inorganic acid, e.g. a hydrohalic acid, typically hydrochloric, hydrobromic, hydrofluoric or hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, (Z) -2-butenedioic acid, (E) -butenedioic acid, 2-hydroxysuccinic acid, 2, 3-dihydroxysuccinic acid, 2-hydroxy-1, 2, 3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexylsulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and others known to those skilled in the art.

[0052]The methods of the invention involve modulation of cholinergic receptors. Typically, the cholinergic receptor is a muscarinic receptor; an example of a cholinergic receptor is M₁-muscarinic receptors of the receptor subtype. As can be seen from the examples, in suitable embodiments, the cholinergic receptor may be a muscarinic M₁Receptors and muscarinic M₄One or both of the receptor subtypes. Physiologically beneficial responses in the methods of the invention are generally associated with M₁Receptor subtype vs. M₂Or M₃Specific activation of receptor subtypes, or with M₁-and M₄Receptor subtype vs. M₂Or M₃Specific activation of receptor subtypes. Furthermore, the physiologically beneficial response in the methods of the invention is generally associated with agonist activity of the compounds of formula I or IA. Thus, in one embodiment, the compounds of formula I or IA are muscarinic agonists, such as M₁Agonists or M₁And M₄An agonist.

[0053] Another aspect of the invention relates to methods of increasing cholinergic receptor activity. In one embodiment, the method comprises contacting a cholinergic receptor or a cholinergic receptor-containing system with an effective amount of at least one compound of formula I or IA as defined above.

[0054]A related aspect of the invention relates to a method of treating or preventing or alleviating one or more symptoms associated with an aberration in a mammal, such as a human. In one embodiment, the method comprises administering an effective amount of a compound of formula I or IA, wherein the aberration is associated with a muscarinic receptor, such as M₁Muscarinic receptor subtypes are related.

[0055]And M₁Disorders associated with muscarinic receptor subtypes are typically psychotic disorders. The psychiatric disorder suitable for treatment with the methods of the invention is selected from cognitive impairmentInjuries, forgetfulness, confusion, memory loss, attention deficit, vision loss, depression, pain, sleep disturbances, psychosis, and increased intraocular pressure.

[0056]And M₁Disorders associated with muscarinic receptor subtypes are not necessarily psychotic disorders. Such as increased intraocular pressure and M₁Muscarinic receptor subtypes are related. Thus, disorders to which the methods of the invention are directed include non-psychotic disorders.

[0057] The disorder to which the methods of the invention relate may also be selected from neurodegenerative-related disorders, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, Friedreich's ataxia, Gilles de la Tourette's syndrome, Down's syndrome, Niemann pick's disease, dementia, clinical depression, age-related cognitive decline, attention deficit, sudden infant death syndrome and glaucoma.

[0058]As mentioned above, the compounds of the invention are active against muscarinic M₁Receptor subtypes have high selectivity and affinity. As can be seen from the examples, the compound pair M₁And M₄One or both of the receptor subtypes has high affinity and binds to other receptors such as M₂、M₃And M₅Receptor subtypes are highly selective. The compounds of the invention are generally used at least in part as M₁Agonists or as M₁And M₄An agonist.

[0059]The compounds of the invention are also useful against dopamine D₂The receptor has an affinity. As discussed above in the dopamine hypothesis associated with schizophrenia, compounds that are simultaneously useful as muscarinic agonists and dopamine antagonists are critical for the adequate treatment of a variety of psychiatric disorders. The invention thus also relates to methods of treating psychotic disorders using the compounds of the invention, for use as D₂Antagonists or D₂Inverse agonists and muscarinic agonists, particularly useful as M₁Agonists or M₁And M₄An agonist. Thus, the methods of the invention can be used to treat disorders in mental disorders in which a physiologically beneficial response is due to a response to M₁Agonism, M₁And M₄Agonism, M₁Agonism and D₂Antagonism, or M₁And M₄Agonism and D₂Modulation of antagonism.

[0060]In one aspect of the invention, the compounds of the invention are antipsychotics and the antipsychotic activity is due to the utility of the compounds of the invention as M₁Agonists, or M₁And M₄Agonists, or as M₁Agonists and D₂Antagonists, or M₁And M₄Agonists and D₂An antagonist.

[0061] Another aspect of the present invention relates to the use of a compound of formula IA, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, in the manufacture of a medicament for the treatment of a disease or disorder associated with a cholinergic receptor or a ligand thereof. The medicament may be for the treatment of a receptor-related disease as discussed above or a disorder as discussed above. A related aspect of the invention relates to a pharmaceutical composition comprising an effective amount of a compound of general formula I as defined above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutical composition comprising any of the foregoing, and a pharmaceutically acceptable carrier or excipient.

[0062] The invention provides a novel compound shown as a general formula I, and salts and isomers thereof

m is0, 1 or 2;

C₃-C₄is CH₂-CH or CH ═ C, or C₄Is CH and C₃Is absent;

R⁴and R⁵Each of which is independently selected from hydrogen, halogen, hydroxy, optionally substituted C_1-6Alkyl, O-C_1-6Alkyl, aryl-C_1-6Alkyl and aryl heteroalkyl;

y is selected from O, S and H₂；

[0063]The present investigators have found that the present compounds are directed to M₁Muscarinic receptors have high affinity and specificity. The compounds of the invention are also useful in a series of reactions with M₁In diseases associated with modulation of muscarinic receptor subtypes.

[0064]In general, R in the compounds of the formula I¹Selected from optionally substituted C_1-6-alkyl, optionally substituted C_1-6Alkylene, optionally substituted C_2-6-alkenyl, optionally substituted C_2-6-alkynyl, optionally substituted O-C_1-6Alkyl and optionally substituted O-C_2-6-alkenyl. R¹May be selected from optionally substituted C_1-6-alkyl, optionally substituted C_1-6Alkylene, optionally substituted C_2-6-alkenyl and optionally substituted O-C_1-6-an alkyl group. R¹May generally be selected from optionally substituted C_1-6-alkyl, optionally substituted C_1-6Alkylene and optionally substituted O-C_1-6-an alkyl group. Most generally, R¹Is selected from the alternativesSubstituted C₄-alkyl, optionally substituted C₅-alkyl, optionally substituted C₄Alkylene and optionally substituted O-C_1-6-an alkyl group. In a preferred embodiment, R¹May be unsubstituted C₄Alkyl, unsubstituted C₅Alkyl or unsubstituted O-C₃Alkyl, such as n-butyl, n-pentyl or n-propoxy.

[0065]In a particular embodiment of the invention, in the compounds of the formula I R¹Is optionally substituted C_1-6-alkyl selected from unsubstituted C_1-6-alkyl and C_1-6-alkoxyalkyl groups. C_1-6The alkoxyalkyl group may be C_1-3Alkoxy radical C_1-3An alkyl group. In general, C_1-6-alkoxyalkyl is selected from methoxypropyl, ethoxyethyl, propoxymethyl and methoxyethyl.

[0066]In one embodiment of the invention, the compound of formula I is piperidine, bicyclic piperidine, 3-4-unsaturated piperidine or bicyclic 3-4-unsaturated piperidine. In this embodiment, C₃-C₄The bond may be a single bond, thereby forming a piperidine ring or bicyclic piperidine. Alternatively, the piperidine may be 3-4 unsaturated. I.e. C₃-C₄May be a double bond (C)₃＝C₄) Thereby forming a 3-4-unsaturated piperidine or a bicyclic 3-4-unsaturated piperidine.

[0067]In another embodiment of the invention, m is0, C₃Is absent, while C₄Is CH, thereby forming an azetidine ring. Bicyclic analogs of azetidine are also included.

[0068]In an alternative embodiment, m is0, such that when C is₃-C₄A single bond or a double bond forms a pyrrolidine ring or 3-pyrroline, respectively. Bicyclic analogs of the pyrrolidine ring or 3-pyrroline are also included. More suitably, m is 2, thereby forming a 7 membered ring. In a particular embodiment, m is 1.

[0069]In one embodiment, R²And R³Together form a bicyclic ring system, thereby

Is selected from

Wherein R is⁸Is present 0, 1 or 2 times and is independently selected from optionally substituted C_1-6Alkyl, optionally substituted O-C_1-6Alkyl, halogen, hydroxy.

[0070]In this embodiment, R is preferably selected²And R³So that R²And R³Together form a ring system, thereby

Is selected from

[0071]In a more preferred embodiment, the substituent R is selected²And R³Making the bicycle 3-substituted 8-azabicyclo [3.2.1]]Octane.

[0072]However, in particular embodiments, R²And R³Independently selected from hydrogen, optionally substituted C_1-6Alkyl, optionally substituted O-C_1-6Alkyl, halogen and hydroxyl.

[0073]Thus, in the general formulaIn combinations of embodiments of the compounds of I, C₃-C₄Is a single bond, R²And R³Independently selected from hydrogen, optionally substituted C_1-6Alkyl, optionally substituted O-C_1-6Alkyl, halogen and hydroxy, m is 1. Preferably, R²And R³Is hydrogen.

[0074]In another combination, m may be 0, C₃May be absent, C₄May be CH, such that

Is that

[0075]In another combination of embodiments, C₃-C₄And m is such that a piperidine ring is formed, e.g. wherein R²And R³Is hydrogen. In other embodiments, C₃-C₄And m is such that a piperidine ring is formed, R²And R³Is hydrogen, R¹Is unsubstituted C₄Alkyl, unsubstituted C₅Alkyl or O-C₃Alkyl radicals, such as the butyl, pentyl or propoxy radical.

[0076] Thus, in one embodiment,

is 4-butylpiperidine.

[0077] In a further embodiment of the process of the present invention,

is 4-butylpiperidine.

[0078]In one embodiment of the invention, C₃-C₄And m is such that an azetidine ring is formed,

[0079]R²and R³Is hydrogen, R¹Selected from unsubstituted C₄Alkyl, unsubstituted C₅Alkyl and O-C₃-an alkyl group. Thus, in one embodiment,

is 4-butylazetidine.

[0080] In one aspect of the invention, the 3-carbon chain connects two nitrogen atoms of two ring systems of the compound of formula I. The present investigators have found that such an optionally substituted propylene spacer unit provides compounds with the ability to efficiently bind cholinergic receptors. More specifically, the compounds of the present invention exhibit agonist properties at cholinergic receptors, especially at muscarinic receptors.

[0081] In one embodiment, the chain

Is unsubstituted, meaning that all R are⁴And R⁵Are all hydrogen.

[0082]In another embodiment, the substituent R⁴One of them is selected from C_1-6Alkyl, O-C_1-6Alkyl and halogen, and the substituents R⁴The other two ofIs hydrogen.

[0083]In a combination of embodiments, the substituent R⁴One of them is selected from C_1-6Alkyl, O-C_1-6Alkyl and halogen, and the substituents R⁴The other two of (A) are hydrogen, and all R's are⁵Are all hydrogen.

[0084]In a preferred embodiment, the substituent R⁴One of which is selected from methyl, methoxy, ethyl and fluoro, and the remaining R' s⁴And R⁵Are all hydrogen.

[0085]In general, when the substituent R is⁴Is one of C_1-6Alkyl, O-C_1-6Alkyl or halogen, the chain is 2-substituted-1, 3-propylene.

[0086]In a more suitable embodiment, the chain is a2, 2-disubstituted-1, 3-propylene group, wherein R⁴And R⁵Is usually C_1-6-alkyl or fluoro.

[0087] In certain embodiments of the invention, the propylene chain bears one or more substituents and the propylene chain contains stereoisomeric atoms. As set out in the examples, such chiral compounds are preferably in racemic or enantiomeric form. Pure enantiomers and racemates are included in the present invention.

[0088]X may be a straight chain unit of 1-, 2-or 3-atoms which, together with the atoms in the ring containing X, forms a 5-, 6-or 7-membered ring. As mentioned above, X in the ring is a divalent group selected from the group consisting of-C (R)⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁷)-O-、-S-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-S-、-N(R^N)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-N(R^N)-、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、-O-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、S-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、N(R^N)-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-O、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-S、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-N(R^N)-、-C(R⁶)(R⁷) -CH ═ CH-and-CH ═ CH-C (R)⁶)(R⁷)。

[0089]In a preferred embodiment, X is selected from the group consisting of-C (R)⁶)(R⁶)C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁸)-O-、-S-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-S-、-N(R^N)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-N(R^N)-。

[0090]In a more preferred embodiment, X is selected from the group consisting of-C (R)⁶)(R⁷)C(R⁶)(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁸) -O-and-C (R)⁶)＝C(R⁷)-。

[0091]R⁶And R⁷Are optional substituents of the ring system. A range of substituents are contemplated by the investigator of the present invention and are well known to those skilled in the art. Substituent R⁶And R⁷Can be independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, NR^NR^N、N(R^N)-C(O)N(R^N) Optionally substituted C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, optionally substituted O-C_1-6-alkyl, optionally substituted O-aryl, optionally substituted O-C_2-6-alkenyl, optionally substituted O-C_2-6-alkynyl.

[0092]Preferably, when the substituent R is⁶And R⁷Exist in a predetermined placeIn the meaning of X, they are usually selected from hydrogen, halogen, hydroxy and C_1-6-an alkyl group. More generally, when R⁶And R⁷When they form part of the defined X, they are all hydrogen.

[0093]In one embodiment, Y is selected from O, S and H₂。

[0094] In a preferred embodiment, Y is O.

[0095]As described above, L¹And L²Is a divalent group independently selected from-C (R)⁷)＝C(R⁸)、-C(R⁷)＝N-、-N＝C(R⁷) -, -S-, -NH-and-O-; wherein L is¹And L²Only one of which may be selected from-S-and-O-. In general, L¹And L²So that

Is an aromatic or heteroaromatic ring. In one embodiment, L¹And L²Independently selected from-C (R)⁶)＝C(R⁷)、-C(R⁶)＝N-、-N＝C(R⁷) -and-S-, wherein L¹And L²Only one of which is-S-. In another embodiment, L¹And L²Is C (R)⁶)＝C(R⁷). In another embodiment, L¹And L²So that a 6-membered ring is formed. In another embodiment, L¹And L²Are all-C (R)⁶)＝C(R⁷)-。

[0096]Preferably, when the substituent R is⁶And R⁷Present in defined

When in middle, they areIs generally selected from hydrogen, halogen, hydroxy, C_1-6Alkyl and O-C_1-6-an alkyl group.

[0097]Preferably, when the substituent R is⁶And R⁷Present in defined

When in (1), they are selected from hydrogen, fluorine, chlorine, methyl and methoxy.

[0098] Thus, in one combination of embodiments, the compounds of the present invention are represented by the following formula Ia

Wherein R is¹Selected from optionally substituted C_1-6-alkyl, optionally substituted C_1-6Alkylene, optionally substituted C_2-6-alkenyl, optionally substituted C_2-6-alkynyl, optionally substituted O-C_1-6Alkyl and optionally substituted O-C_2-6-an alkenyl group; and R²、R³、R⁴、X、Y、R⁶And R⁷As defined above.

[0099]In another combination of embodiments, the compounds of the present invention are represented by formula Ia wherein X is selected from the group consisting of-C (R)⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁸)-O-、-S-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-S-、-N(R^N)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-N(R^N) -, wherein R⁶And R⁷Hydrogen is preferred.

[0100] In another combination of embodiments, the compounds of the present invention are represented by formula Ia, wherein Y is O.

[0101]In another combination of embodiments, the compounds of the present invention are of formula Ia, wherein R is⁴Selected from hydrogen, C_1-6Alkyl, O-C_1-6-alkyl and halogen.

[0102]In another combination of embodiments, the compounds of the present invention are of formula Ia, wherein R is⁶And R⁷Selected from hydrogen, halogen, hydroxy, C_1-6Alkyl and O-C_1-6-an alkyl group.

[O103]In another combination of embodiments, the compounds of the present invention are of formula Ia wherein C is optionally substituted_1-6-alkyl is selected from unsubstituted C_1-6-alkyl and C_1-6Alkoxyalkyl, wherein Y is selected from O and H₂Wherein X is selected from-C (R)⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁷)-O-、-S-C(R⁶)(R⁷)-、-C(R⁶)(R⁷) -S-, wherein L¹And L²Independently selected from-C (R)⁶)＝C(R⁷)-、-C(R⁶) N-and-N ═ C (R)⁷) -, and wherein R⁴Selected from hydrogen, halogen, hydroxy, optionally substituted C_1-6-alkyl and optionally substituted O-C_1-6An alkyl group.

[0104] In another combination of embodiments, the compounds of the invention are optionally substituted 1- [3- (4-alkylpiperidin-1-) propyl ] -1, 2, 3, 4-tetrahydroquinoline; optionally substituted 1- [3- (4-alkylpiperidin-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; an optionally substituted 1- [3- (4-alkylpiperidin-1-) propyl ] -1H-quinolin-2-one; an optionally substituted 4- [3- (4-alkylpiperidin-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; an optionally substituted 4- [3- (4-alkylpiperidin-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; optionally substituted 1- [3- (3-alkyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -1, 2, 3, 4-tetrahydroquinoline; optionally substituted 1- [3- (3-alkyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; optionally substituted 1- [3- (3-alkyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -1H-quinolin-2-one; an optionally substituted 4- [3- (3-alkyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; an optionally substituted 4- [3- (3-alkyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] thiazin-3-one; optionally substituted 1- [3- (3-alkylazetidin-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; optionally substituted 1- [3- (3-alkylazetidin-1-) propyl ] -1H-quinolin-2-one; optionally substituted 1- [3- (3-alkylazetidin-1-) propyl ] -1, 2, 3, 4-tetrahydroquinoline; an optionally substituted 4- [3- (3-alkylazetidin-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; an optionally substituted 4- [3- (3-alkylazetidin-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one.

[0105] Compounds of suitable embodiments of the present invention may be selected from 1- [3- (4-butyl-piperidinyl-1) -propyl ] -1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -2-methyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -8-methyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -7-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methoxy-3, 4-dihydro-1H-quinolin-2-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; 6-acetyl-4- [3- (4-butyl-piperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methyl-3, 4-dihydro-2H-benzo [1, 4] oxazine; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -6-ethyl-3, 4-dihydro-2H-benzo [1, 4] oxazine; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [3- (4-butylidene-piperidinyl-1) -2-methyl-propyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [3- (3-butyl-8-aza-bicyclo [3.2.1] octyl-8) -2-methyl-propyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [ 2-methyl-3- (3-pentyl-8-aza-bicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6, 8-dichloro-7-methyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butyl-piperidinyl-1-) propyl ] -6, 8-dimethyl-4H-benzo [1, 4] oxazin-3-one (81MF 2237F); 6-tert-butyl-4- [3- (4-butyl-piperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -5-methyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7-methyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6-chloro-7-nitro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7-chloro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7, 8-difluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -4H-pyrido [4, 3-b ] [1, 4] thiazin-3-one; 4- [3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylidenepiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-butylidenepiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (3-butylidene-8-aza-bicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6, 8-dichloro-7-ethyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -8-fluoro-4H-benzo [1, 4] oxazin-3-one; 6-bromo-4- [3- (4-butylpiperidinyl-1-) propyl ] -8-fluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -8-isopropyl-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl ] -4H-benzo [1, 4] oxazin-3-one; (-) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidine) -2-methoxypropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-hydroxy-3- (3-pentylbicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [2- (4-butylpiperidinyl-1-methyl) allyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-fluoropropyl ] -4H-benzo [1, 4] oxazin-3-one; (S) -4- [3- (4-butyl-piperidinyl-1) -2-methyl-propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-aza-bicyclo [3.2.1] octyl-8) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -6-fluoro-4- [ 2-methyl-3- (4-propoxy-piperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methyl-propyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -6-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1-) 2-methylpropyl ] -7-fluoro-4 h-benzo [1, 4] oxazin-3-one; (R) -7-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -7-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -7-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -7-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methyl-propyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R) -6-methoxy-4- [ 2-methyl-3- (3-pentyl-8-aza-bicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -6-methoxy-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -6-methyl-4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; 1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-3, 4-dihydro-1H-quinolin-2-one; 6-fluoro-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-3, 4-dihydro-1H-quinolin-2-one; (R, S) -6-fluoro-1- [3- (4-propoxypiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-chloro-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-methyl-3, 4-dihydro-1H-quinolin-2-one; 6-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -5-methyl-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-methyl-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-6-methyl-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one; 6, 7-difluoro-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one; (R, S) -6, 7-difluoro-1- [3- (4-propoxypiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one; 6-fluoro-7-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one; (R, S) -6-fluoro-7-methyl-1- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butyl-piperidinyl-1-) propyl ] -6-fluoro-5-methyl-3, 4-dihydro-1H-quinolin-2-one; 6-fluoro-5-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -1H-quinolin-2-one; 1- [3- (4-propoxypiperidinyl-1-) propyl ] -1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-methyl-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-methoxy-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-chloro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -5-methyl-1H-quinolin-2-one; 1- [3- (4-butyl-piperidinyl-1-) propyl ] -7-methyl-1H-quinolin-2-one; (R) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -1H-quinolin-2-one; (R) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -1H-quinolin-2-one; 1- [3- (4-allyloxypiperidin-1-) propyl ] -1H-quinolin-2-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -6-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -6-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -7-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -7-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1-) -2-methylpropyl ] -7-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -7-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -7-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -3- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -3H-benzothiazol-2-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -3H-benzothiazol-2-one; (R, S) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -3H-benzothiazol-2-one; (R, S) -3- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -3H-benzothiazol-2-one; (R, S) -3- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -3H-benzothiazol-2-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylidenepiperidin-1-yl) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -6-methoxy ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6, 7-difluoro-4H-benzo [1, 4] oxazin-3-one; (R, S) -6, 7-difluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butoxy-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R, S) -6-fluoro-4- {3- [3- (2-methoxyethyl) -8-azabicyclo [3.2.1] octyl-8- ] -2-methylpropyl } -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butylazetidin-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R, S) -6-fluoro-4- [ 2-methyl-3- (3-propoxyazetidin-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butylazetidin-1) -2-methoxypropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butyl-3-fluoropiperidinyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one.

[0106]The compounds of the present invention have the ability to increase cholinergic receptor activity or activate cholinergic receptors. Cholinergic receptor activity includes signaling activity or any other activity that is directly or indirectly associated with cholinergic signaling or activation. Cholinergic receptors include muscarinic receptors, especially M of muscarinic receptors₁Or M₄The subtype is. Muscarinic receptors may be found, for example, in the central nervous system, peripheral nervous system, gastrointestinal system, heart, endocrine glands or lung. Muscarinic receptors may be of various types, including truncated, variant or modified cholinergic receptors.

[0107] Also provided are kits comprising a compound of the invention and instructions for performing a method of the invention, e.g., increasing cholinergic receptor activity or activating a cholinergic receptor.

[0108] A system comprising cholinergic receptors may be, for example, a subject, such as a mammal, a non-human primate or a human. The system may also be an in vivo or in vitro experimental model, such as a cell culture model system expressing cholinergic receptors, and extracts or purified receptors containing cholinergic receptors but not cells. Non-limiting examples of such systems are tissue culture cells expressing the receptor, or extracts or lysates thereof.

[0109]The cells used in the methods of the invention include cells capable of passing cholinergic receptors such as M₁Muscarinic receptors, or by endogenous expression of receptors (e.g. certain types of neuronal cell lines may naturally express M₁Receptor), or any cell in which signaling is mediated by the introduction of an exogenous gene into the cell (e.g., by transfecting the cell with a plasmid containing the receptor gene).Since lower life forms of cells often lack the appropriate signal transduction pathways for this purpose, such cells are often mammalian cells (or other eukaryotic cells, such as insect cells or Xenopus oocytes). Specific non-limiting examples of suitable cells include: mouse fibroblast cell line NIH 3T3(ATCC CRL1658) which can be transfected with M by enhanced growth₁(ii) receptor reaction; RAT 1 cells (Pace et al, Proc. Natl. Acad. Sci. USA 88: 7031-35 (1991)); pituitary cells (Vallar et al, Nature 330: 556-58 (1987)). Other suitable mammalian cells include, but are not limited to, HEK 293 cells, CHO cells, and COS cells.

[0110] The compounds of the present invention also have the ability to lower intraocular pressure and are therefore useful in the treatment of intraocular pressure related diseases, such as glaucoma. Glaucoma is a disease in which abnormalities are observed in the circulatory control mechanism of the aqueous fluid that fills the anterior chamber, i.e., the formation of a space between the cornea and the lens. This causes an increase in the volume of watery fluid and an increase in intraocular pressure, which in turn causes visual field defects and even blindness due to compression and contraction of the optic nerve papillae.

[0111]Thus, the present invention also provides a method of treating a disease in a mammal, such as a human, wherein modulation of cholinergic receptor activity is associated with a physiologically beneficial response in said disease in said mammal. In one embodiment, the method comprises administering an effective amount of a compound of formula I as defined above to obtain a physiologically beneficial response. Typically the cholinergic receptor is a muscarinic receptor, more typically the cholinergic receptor muscarinic M₁-receptor subtype. Alternatively, the cholinergic receptor is muscarinic M₄-receptor subtype.

[0112]The invention also provides methods of treating or preventing or alleviating symptoms associated with an aberration in a mammal, such as a human. In one embodiment, the method comprises administering an effective amount of a compound of formula I, wherein the aberration is associated with a muscarinic receptor, such as M₁Muscarinic receptor subtypes to treat or prevent or alleviate one or more symptoms associated with the disorder.

[0113]Physiologically beneficial reactions are usually associated with muscarinic M₁Receptor subtype vs. muscarinic M₂-or M₃Selective modulation of receptor subtypes. In one embodiment, the compounds in the methods of the invention are muscarinic agonists.

[0114]The diseases or disorders treated by the compounds of the present invention are typically psychiatric disorders and the physiologically beneficial response is due to a response to M₁Agonism, M₁And M₄Agonism, M₁Agonism and D₂Antagonism, or M₁And M₄Agonism and D₂Modulation of antagonism.

[0115] Another related aspect of the invention relates to methods of increasing cholinergic receptor activity. In one embodiment, the method comprises contacting a cholinergic receptor or a cholinergic receptor-containing system with an effective amount of at least one compound as defined above to increase the activity of the cholinergic receptor.

[0116] As can be determined from the above discussion, the compounds of the present invention are at least partially useful as pharmaceutical agents. Accordingly, the present invention provides a composition comprising I) one or more compounds of formula I as defined above; and ii) at least one pharmaceutically acceptable excipient or carrier. Since the present invention relates to the use of a compound of general formula I as defined above, the present invention also provides the use of a compound of general formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing, for the manufacture of a medicament for the treatment of a disease or disorder associated with a cholinergic receptor or a ligand thereof.

[0117]The invention thus relates in part to methods of treating or preventing or alleviating one or more symptoms associated with an aberration in a mammal, such as a human. In one embodiment, the method comprises administering an effective amount of a compound of formula I, wherein the aberration is associated with a muscarinic receptor, such as M₁Muscarinic receptor subtypes are associated to prevent or alleviate one or more symptoms. The disorder is selected fromThose of the following: cognitive impairment, amnesia, confusion, memory loss, attention deficit, vision loss, depression, pain, sleep disturbances, psychosis and increased intraocular pressure. Aberrations also include those selected from the following: neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friedreich's ataxia, Gilles de la Tourette's syndrome, Down's syndrome, Niemann pick's disease, dementia, clinical depression, age-related cognitive decline, attention deficit, sudden infant death syndrome and glaucoma. Thus, the present invention also relates to the use of a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing, in the manufacture of a medicament for use in a disease or disorder selected from: alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, Friedreich's ataxia, Gilles de la Tourette's syndrome, Down's syndrome, Niemann pick's disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, amnesia, confusion, memory loss, attention deficit, vision loss, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.

[0118]The compounds of the invention may be used alone in suitable dosages, as determined by routine experimentation, to treat muscarinic receptors, particularly muscarinic M₁Or M₄Optimal pharmacological effects are obtained for the receptor subtype while minimizing any potential toxic or other undesirable effects. In addition, co-administration or continuous administration of other agents that may enhance the action of the compounds may be desirable in certain circumstances.

[0119] The pharmacological profile and selectivity of the compounds of the invention for a particular muscarinic receptor subtype may be demonstrated by a number of different assays using recombinant receptor subtypes, such as the available human receptors, e.g. conventional second messenger or binding assays. One particularly convenient functional detection system is the receptor selection and amplification detection system disclosed in U.S. Pat. No. 5,707,798, which describes a method for screening for biologically active compounds using the ability of cells to amplify in the presence of receptor ligands, wherein the cells are transfected with, for example, receptor DNA encoding different muscarinic subtypes. Cell expansion is detected by an increased level of a marker expressed by the cell.

[0120] The present invention is disclosed in more detail below by way of examples.

Examples

Example 1

Synthetic chemistry

LC-MS general analysis method

The method comprises the following steps:

[0121] spectra were obtained using an HP1100 LC/MSD instrument. Equipment with dual pumps, autosampler, column oven, diode array detector, electroplating sputter ionization interface was used. A reversed phase column (C18 Luna 3. mu. 75X 4.6mm ID) with a guard column cartridge system was used. The mobile phase was MeCN/8mM ammonium acetate in water. A 15 minute gradient program was used with an initial 70% MeCN, 12 minutes later 95% MeCN, 1 minute later 70% MeCN for 2 minutes. The flow rate was 0.6 ml/min.

The method 2 comprises the following steps:

[0122] spectra were obtained using a Waters LC/ZMD instrument. An apparatus with a 600 gradient pump, 2700 sample manager, 996 diode array detector, electroplating sputter ionization interface was used. A reversed phase column (C18X-Terra 5. mu. 50X 4.6mm ID) with a guard column cartridge system was used. The mobile phase was MeCN/10mM ammonium acetate in water. A 14 minute gradient program was used with an initial 30% MeCN, 95% MeCN after 10 minutes for 2 minutes, 30% MeCN after 0.5 minutes for 4.5 minutes. The flow rate was 1 ml/min.

LC-MS general preparation method

The method comprises the following steps:

[0123] preparative purification was performed on a Waters automated purification system (600 pump, 2700 sample manager, 996 PDA detector, ZMD mass spectrometer).

[0124] The column used was YMC C18J' sphere ODS H80. Buffer A was 0.15% TFA in water and buffer B was 0.15% TFA in MeCN/water 95/5. The column was run at 17 ml/min. The compounds were first loaded with 30% buffer B for 2.5min, followed by a 30-100% gradient of buffer B for 8.5 min. When one column is running, the other is balanced with a double column equipped with two pumps.

The method 2 comprises the following steps:

[0125]preparative purification was performed on a Waters Delta 4000 preparative system, a Waters 2487 double absorbance detector, a Waters fraction collector II. The column used was Luna 15. mu. m C18, 250X 21.2 mm. Using the following mobile phase H₂O/MeCN ammonium acetate buffer (25nM) or H₂O/MeCN TFA buffer (25 nM).

[0126] Heating was performed by microwave irradiation with a Smith Creator Single Cavity (Personal Chemistry AB, Uppsala, Sweden) which produced continuous radiation at 2.45 GHz. The microwave-assisted reactions were performed in covered Smith process vials equipped with magnetic stir bars. To ensure adequate radiation absorption, the liquid sample volume was ≧ 0.5 mL.

[0127]Cation exchange CC was performed using a Varian BOND ELUT (mega BE-SCX, 1g, 6ml) column. After the compound was applied to the column, the column was first washed with MeOH (2 column volumes) and then with NH 2 column volumes₄OH(H₂25% NH in O₃) The column was eluted with MeOH mixture (1: 9) to give the desired compound.

(R, S) -1- (4-butylpiperidinyl-1) -3-chloroprop-2-ol (101IS93-1)

[0128]A4 mL vial was charged with 4-butylpiperidine (0.29g, 2.0mmol) and epichlorohydrin (C0.190g, 2.1mmol) and shaken at room temperature for 4 h. By flash chromatography (SiO)₂；CH₂Cl₂acetone/MeOH 85/10/5) to give the title compound as an oil (0.31g, 64%).¹H NMR(CDCl₃)δ3.95-3.85(m，1H)，3.60-3.48(m，1H)，2.97-2.88(m，1H)，2.82-2.72(m，1H)，2.46-2.35(m，1H)，2.30-2.20(m，1H)，1.98-1.88(m，1H)，1.70-1.58(m，2H)，1.35-1.08(m，9H)，0.88(t，J＝6.8Hz，3H)；¹³CNMR(CDCl₃)δ66.7，61.5，55.9，53.1，47.4，36.4，35.8，32.9，32.6，29.2，23.1，14.3。

(R, S) -4-butyl-1- (3-chloro-2-fluoropropyl) piperidine (101IS93-2)

[0129]DAST (1.9mmol, 230. mu.L) was added dropwise to 1- (4-butylpiperidinyl-1) -3-chloroprop-2-ol (101IS93) (0.31g, 1.28mmol) dissolved in CH₂Cl₂(5mL) in the resulting solution. After 2h, quench the reaction with water (5mL) and CH₂Cl₂The organic phases were extracted (2X 15mL), combined and dried (Na)₂SO₄) Filtering, concentrating under reduced pressure, and subjecting the residue to flash chromatography (SiO)₂(ii) a heptane/EtOAc 60: 40) to give the title compound as an oil (0.025g, 9%);¹H NMR(CDCl₃)δ4.79(dm，J＝48Hz，1H)，3.78-3.60(m，2H)，2.92-2.83(m，2H)，2.72-2.56(m，2H)，2.15-2.00(m，2H)，1.69-1.58(m，2H)，1.35-1.16(m，9H)，0.88(t，J＝6.8Hz)；¹³C N MR(CDCl₃)δ91.1(d，J＝111Hz)，59.9(d，J＝22Hz)，55.2，54.9，44.9(d，J＝25Hz)，36.4，35.6，32.7，32.6，29.2，23.1，14.3。

general method 1(GP1)

[0130]To a flask or vial was added 2-aminophenol (1.0 equivalent) (0.1g/mL) dissolved in DMF and 2-chloroacetyl chloride (1.1 equivalent) was added. The reaction is stirred at room temperature for 12-20 hours, K is added₂CO₃(2.1 equiv.). The reaction was stirred at room temperature for another 12-20 hours, then evaporated to dryness and dissolved in waterTo (10mL), extract with EtOAc (3X 20 mL). The organic phases were combined and concentrated to give the crude product, which was used as such or purified with CC (heptane: EtOAc).

4H-pyrido [4, 3-b][1, 41 thiazin-3-one (81MF939a)

[0131]3-amino-4-thiopyridine (0.10g, 0.79mmol), 2-chloroacetyl chloride (0.098g, 0.87mmol) and K were mixed according to GP1₂CO₃(0.23g, 1.66mmol) to give the title compound as a crude product (81MF939a) (0.087 g).

8-fluoro-4H-benzo [1, 4]]Oxazin-3-one (95MF45)

[0132]2-amino-6-fluorophenol (95MF2085) (0.256g, 2.0mmol), 2-chloroacetyl chloride (0.25g, 2.2mmol) and K were mixed according to GP1₂CO₃(0.583g, 4.2mmol) to give the title compound as a crude product (95MF45) (0.29 g).

7-fluoro-4H-benzo [1, 4]]Oxazin-3-one (111MF12)

[0133]2-amino-5-fluorophenol (111MF10) (10.3g, 81mmol), 2-chloroacetyl chloride (10.1g, 89mmol) and K were mixed according to GP1₂CO₃(23.5g，170mmol)。CC(SiO₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF12) (12.6g, 93%);¹H NMR(DMSO)δ10.68(s，1H)，6.83-6.91(m，2H)，6.75-6.80(m，1H)，4.57(s，2H)；¹³CNMR(DMSO)δ164.2，157.8(d，J＝238.6Hz)，144.0(d，J＝12.4Hz)，123.9(d，J＝2.7Hz)，116.3(d，J＝9.6Hz)，108.6(d，J＝22.7Hz)，104.0(d，J＝26.5Hz)，66.7。

7, 8-difluoro-4H-benzo [1, 4]]Oxazin-3-one (81MF2082A)

[0134]6-amino-2, 3-difluorophenol (81KK30a) (0.113g, 0.78mmol), 2-chloroacetyl chloride (0.10g, 0.89mmol) and K were mixed in accordance with GP1₂CO₃(0.226g, 1.6mmol) to give the title compound as a crude product (81MF2082A) (0.12 g).

6-bromo-8-fluoro-4H-benzo [1, 4]]Oxazin-3-one (95MF44)

[0135]2-amino-4-bromo-6-fluorophenol (95MF2084) (0.078g, 0.38mmol), 2-chloroacetyl chloride (0.048g, 0.42mmol) and K were mixed according to GP1₂CO₃(0.11g, 0.79mmol) to give the title compound as a crude product (95MF44) (0.091 g).

8-isopropyl-4H-benzo [1, 4]]Oxazin-3-one (95MF83)

[0136]The crude 2-amino-6-isopropylphenol (95MF80(2240) (0.16g, 1.1mmol), 2-chloroacetyl chloride (0.14g, 1.2mmol) and K were mixed according to GP1₂CO₃(0.32g, 2.3mmol) to give the title compound as a crude product (95MF83) (0.115 g).

6, 8-dichloro-7-methyl-4H-benzo [1, 4]]Oxazine-3-one (81MF2225)

[0137]6-amino-2, 4-dichloro-3-metyl-phenol (1.9g, 10mmol), 2-chloroacetyl chloride (1.2g, 11mmol) and K were mixed in accordance with GP1₂CO₃(3.0g, 22mmol) to give the title compound as a crude product (80MF2225) (2.33 g).

6, 8-dichloro-7-ethyl-4H-benzo [1, 4]]Oxazin-3-one (95MF46)

[0138]6-amino-2.4-dichloro-3-ethylphenol (95MF2226) (0.293g, 1.5mmol), 2-chloroacetyl chloride (0.19g, 1.7mmol) and K were mixed according to GP1₂CO₃(0.44g, 3.2mmol) to give the title compound as a crude product (95MF46) (0.34 g).

7-fluoro-6-methyl-3, 4-dihydro-1H-quinolin-2-one (97KK40)

[0139]3-fluoro-4-methylaniline (1.247g, 9.96mmol), 3-chloropropionyl chloride (1.269g, 9.99mmol) and K dissolved in MeCN (10mL) were stirred at 40 deg.C₂CO₃(1.450g, 10.5mmol) for 3 h. Quench the reaction mixture with 4M HCl and extract the product into CH₂Cl₂. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The residue (1.168g) was heated to 145 ℃ and AlCl was added portionwise over 30min₃(3.538g, 26.5 mmol). The reaction mixture was then cooled, 4M HCl added with stirring, and then CH was extracted₂Cl₂. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Rapid CC (SiO) for residue₂；CH₂Cl₂MeOH 40: 1) to give the title compound (97KK40) (0.201g, 11% overall yield).¹H NMR(CDCl₃)δ8.15(brs，1H)，6.94(d，J＝7.8Hz，1H)，6.47(d，J＝10.0Hz，1H)，2.91-2.87(m，2H)，2.62-2.60(m，2H)，2.19(d，J＝1.8Hz，CH₃)。

6-fluoro-1H-quinolin-2-one (97KK38)

[0140]DDQ (0.38g, 1.7mmol) was added to a solution of 6-fluoro-3, 4-dihydro-1H-quinolin-2-one (0.18g, 1.1mmol) in dioxane (25mL) and the resulting solution refluxed for 16H. Concentrating the mixture, adding saturated Na₂CO₃(25mL) aqueous solution, then organic mixture (MeOH: CH)₂Cl₂(ii) a 1: 10, 3X 50 mL). The organic phases were combined with Na₂SO₄Drying, filtering, concentrating under reduced pressure, and purifying with quick CC (SiO)₂；CH₂Cl₂MeOH 20: 1) to give the title compound (0.056g, 31%).¹H NMR(DMSO-D₆)δ11.8(brs，1H)，7.85(d，J＝9.4Hz)，7.50(dd，J＝2.8，9.2Hz)，7.43-7.37(m，1H)，7.37-7.25(m，1H)，6.54(d，J＝9.4Hz)。

7-fluoro-1H-quinolin-2-one (97KK34)

[0141]DDQ (0.42g, 1.9mmol) was added to a solution of 7-fluoro-3, 4-dihydro-1H-quinolin-2-one (0.20g, 1.2mmol) in dioxane (25mL) and the resulting mixture was refluxed under argon for 16H. The mixture was concentrated under reduced pressure and saturated Na was added₂CO₃(25mL) aqueous solution and organic mixture (MeOH: CH)₂Cl₂(ii) a 1: 10, 3X 50 mL). Is combined withOrganic phase, with Na₂SO₄Drying, filtering, concentrating under reduced pressure, and purifying with composite fast LC (SiO)₂；CH₂Cl₂MeOH 10: 1) to yield the title compound (0.037g, 18%).¹H NMR(DMSO-D₆)δ11.8(s，1H)，7.88(d，J＝9.6Hz，1H)，7.74-7.65(m，1H)，7.05-6.95(m，2H)，6.43(d，J＝9.6Hz)；¹³CNMR(CDMSO-D₆)δ163.0(d，J＝247Hz)，161.9，140.4(d，J＝13Hz)，130.4(d，J＝11Hz)，120.9，116.1，109.8(d，J＝23)，101.0(d，J＝25Hz)。

6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (10LH75-1) and 6-fluoro-5-methyl-3, 4-dihydro -1H-quinolin-2-one (107LH75-2)

[0142]3-chloro-N- (4-fluoro-3-methyl-phenyl) -propionamide (3.8g, 30mmol), 3-chloropropionyl chloride (2.9mL, 30mmol) and K₂CO₃(5.0g, 36mmol) was added to CH₃CN (50mL), the mixture was stirred at room temperature for 44 h. The reaction was then diluted with EtOAc (50mL) and washed with water (20mL), HCl (20mL, 4N) and brine (20 mL). With Na₂SO₄The organic phase was dried, filtered and concentrated under reduced pressure. Heating the residue (5.9g) to 135 deg.C, adding AlCl in portions during 30min₃(11g, 82mmol) and the reaction was cooled to 50 deg.C, HCl (4N 20mL) was added and the resulting mixture was stirred for 15 min. The mixture was extracted with EtOAc (50mL) and the organic phase was washed with water (20 mL). Drying (Na)₂SO₄) The resulting organic phase was filtered, concentrated under reduced pressure, and purified by preparative HPLC to give 6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (0.76g, 14%) and 6-fluoro-5-methyl-3, 4-dihydro-1H-quinolin-2-one (0.190g, 4%). 6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH 75-1):¹HNMR(CDCl₃) δ 8.86(brs, 8.86, 1H), 6.81(d, J ═ 9.2Hz, 1H), 6.62(d, J ═ 6.8Hz, 1H), 2.91(brt, J ═ 7.6Hz, 3H), 2.94-2.87(m, 2H), 2.20(d, J ═ 2.0 Hz). 6-fluoro-5-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH 75-2):¹H NMR(CDCl₃)δ8.78(brs，1H)，6.85(t，J＝8.8Hz，1H)，6.62(dd，J＝4.5，8.8Hz，1H)，2.92(brt，J＝7.6Hz，2H)，2.64-2.58(m，2H)，2.20(d，J＝2.4Hz，3H)。

(R) -4- (3-hydroxy-2-methylpropyl-4H-benzo [1, 4]]Oxazine-3-one (1008LM40-37)

[0143]A25 mL flask was charged with 4H-benzo [1, 4] in MeCN (10mL)]Oxazin-3-one (0.100g, 0.670mmol), (S) -3-bromo-2-methylpropanol (0.103g, 0.670mmol) and cesium carbonate (0.208g, 0.670mmol) and stirred at 40 ℃ for 2 days. The reaction mixture was quenched with water (5mL) and the product extracted with EtOAc (2X 10 mL). The organic layers were combined and dried (Na)₂SO₄) Evaporation gave the title compound (108LM40-37) as a crude product (0.219 g).

General method 2(GP2)

[0144]To a dry 50mL flask were added the corresponding heterocyclic compound (1.1 equiv), (R) - (3-bromo-2-methyl-propoxy) -tert-butyl-dimethylsilane (95MF94) (1 equiv) and cesium carbonate (2.5 equiv) dissolved in DMF (20mL) and stirred at 55 ℃ for 20 h. The reaction mixture was quenched with water (10mL) and the product extracted with EtOEt (3X 20 mL). The combined organic layers were washed with brine and dried (Na)₂SO₄) By evaporation, with fast CC (SiO)₂(ii) a EtOAc/heptane 1: 10).

(S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-4H-benzo [1, 4]]Oxazin-3-ones (108LM24-21)

[0145]4H-benzo [1, 4] in DMF (20mL) according to GP2]Oxazin-3-one (2.47g, 16.5mmol), (R) - (3-bromo-2-methyl-propoxy) -tert-butyldimethylsilane (95MF94) (4.01g, 15.0mmol) and Cs₂CO₃(12.2g, 37.6mmol) to give the title compound (108LM24-21) (3.92g, 78%).¹H NMR(CDCl₃)δ7.15-7.11(m，1H)，6.99-6.91(m，3H)，4.60-4.50(m，2H)，3.98(dd，J＝8.3Hz，J＝12.4Hz，1H)，3.81(dd，J＝5.5Hz，J＝12.4Hz，1H)，3.51(dd，J＝4.1Hz，J＝9.7Hz，1H)，3.40(dd，J＝6.9Hz，J＝9.7Hz，1H)，2.12-2.02(m，1H)，0.90-0.82(m，12H)，0.02(s，6H)。

(A) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-4H-benzo [1, 4]]Thiazin-3-ones (108LM25-22)

[0146]4H-benzo [1, 4] in DMF (20mL) according to GP2]Thiazin-3-one (2.75g, 16.7mmol), (R) - (3-bromo-2-methylpropyloxy) -tert-butyldimethylsilane (95MF94) (4.04g, 15.1mmol) and cesium carbonate (12.3g, 37.9mmol) were reacted to give the title compound (108LM25-22) (3.74g, 70%).¹H NMR(CDCl₃)δ7.35(d，J＝7.6Hz，1H)，7.28-7.18(m，2H)，6.99(t，J＝7.6Hz，1H)，4.13(dd，J＝8.9Hz，J＝13.3Hz，1H)，3.95(dd，J＝5.9Hz，J＝13.3Hz，1H)，3.52-3.40(m，2H)，3.37(s，CH₂)，1.96-2.07(m，1H)，0.92-0.83(m，12H)，0.02(s，6H)。

General method 3(GP3)

[0147]To a 50mL flask were added the corresponding heterocyclic compound (1 equivalent) dissolved in THF (30mL) and tetrabutylammonium fluoride (TBAF) (1.3 equivalents), and stirred at room temperature for 20 h. The reaction mixture was concentrated to a syrup and dissolved in EtOAc (30 mL). The mixture was washed with brine (2X 20 mL). The organic layers were combined and dried (Na)₂SO₄) By evaporation, with fast CC (SiO)₂(ii) a EtOAc/heptane 7: 3).

(S) -4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4%]Oxazine-3-one (108LM26-23)

[0148]Compound (S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl dissolved in THF (30mL) according to GP3]-4H-benzo [1, 4]]Oxazin-3-one (108LM24-21) (3.92g, 11.7mmol) and TBAF (4.78g, 15.2mmol) were reacted to give the title compound (108LM26-23) (2.52g, 98%).¹H NMR(CDCl₃)δ7.05-6.95(m，4H)，4.63(s，CH₂)，4.23(dd，J＝10.3Hz，J＝13.9Hz，1H)，3.56(dd，J＝4.8Hz，J＝13.9Hz，1H)，3.52-3.49(m，1H)，3.46-3.38(m，1H)，2.92-2.85(m，1H)，2.09-1.97(m，1H)，1.06(d，J＝7.3Hz，CH₃)。

(S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-4H-benzo [1, 4]]Thiazin-3-ones

[0149]Compound (108LM25-22) (3.69g, 10.5mmol) and TBAF (4.30g, 13.6mmol) in THF (30mL) were reacted according to GP 3. By fast CC (SiO)₂(ii) a EtOAc/heptane 7: 3) to yield the title compound (108LM34-31) (2.36g, 95%).¹H NMR(CDCl₃)δ7.38(d，J＝7.9Hz，1H)，7.28-7.18(m，2H)，7.03(t，J＝7.0Hz，1H)，4.32(dd，J＝9.0Hz，J＝15.2Hz，1H)，3.70(dd，J＝5.5Hz，J＝15.2Hz，1H)，3.52(dd，Jn＝3.4Hz，J＝11.7Hz，1H)，3.34-3.42(m，3H)，2.82(bs，OH)，1.92-1.83(m，1H)，0.98(d，J＝6.9Hz，CH₃)。

General method 4(GP4)

[0150]A50 mL flask was charged with CHCl in solution₃(30mL), triphenylphosphine (2 equivalents) and imidazole (2.5 equivalents). When all the material had dissolved, iodine (3 equivalents) was added with stirring. Stirring was continued for 20h at room temperature. The reaction mixture was washed with saturated aqueous sodium thiosulfate (30mL) and dried (Na)₂SO₄) By evaporation, with fast CC (SiO)₂(ii) a EtOAc/heptane 3: 1).

(S) -4-iodo-2-methylpropyl) -4H-benzo [1, 4]Oxazine-3-one (108LM27-24)

[0151]Dissolving in CHCl according to GP4₃(30mL) of Compound (S) -4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4]]Oxazin-3-one (108LM26-23) (2.52g, 11.4mmol), triphenylphosphine (6.12g, 23.3mmol), imidazole (1.98g, 29.1mmol) and iodine (8.88g, 35.0mmol) reacted to give the title compound (108LM27-24) (3.02g, 80%).¹H NMR(CDCl₃)δ7.07-7.00(m，4H)，4.65-4.55(m，2H)，3.94(dd，J＝1.7Hz，J＝6.7Hz，CH₂)，3.23-3.14(m，2H)，2.18-2.07(m，1H)，1.05(d，J＝6.1Hz，CH₃)。

(R) -4- (3-iodo-2-methylpropyl) -4H-benzo [14]Oxazin-3-one (108LM46-43)

[0152]Dissolving in CHCl according to GP4₃(R) -4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4] in (30mL)]Oxazin-3-one (108LM40-37) (1.040g) crude product, triphenylphosphine (0.99g, 3.77mmol), imidazole (0.32g, 4.71mmol) and iodine (1.43g, 5.65mmol) reacted to give the title compound (108LM46-43) as a crude product (0.312 g).

(S) -4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4%]Thiazine-3-one (108LM37-34)

[0153]Dissolving in CHCl according to GP4₃(30mL) of Compound (S) -4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4]]Thiazin-3-one (108LM34-31) (2.33g, 9.82mmol), triphenylphosphine (5.15g, 19.7mmol), imidazole (1.67g, 24.6mmol), and iodine (7.48g, 29.5mmol) reacted to give the title compound (108LM37-34) (2.57g, 75%).¹H NMR(CDCl₃)δ7.37(d，J＝7.8Hz，1H)，7.24(t，J＝7.8Hz，1H)，7.16(d，J＝7.8Hz，1H)，7.02(t，J＝7.8Hz，1H)，4.02(d，J＝6.8Hz，CH₂)，3.37(s，CH₂)，3.15-3.05(m，CH₂)，1.95(m，1H)，0.97(d，J＝6.2Hz，CH₃)。

General method 5(GP5)

[0154]In a4 or 7mL vial was added 4H-benzo [1, 4] benzo dissolved in 3mL dry MeCN]Oxazin-3-one (1.0 equiv.), Cs₂CO₃(1.5 equiv.) and 3-chloro-1-iodopropane (1.1 equiv.) and shaken at room temperature for 66-72 h. Using 10mL of H₂The reaction mixture was diluted with O and CH₂Cl₂Or EtOAc (3X 30 mL). The organic layers were combined and MgSO₄Dried or filtered through a PTFF Whatman filter and concentrated. The residue was purified with CC (heptane/EtOAc) or used in the next step without further purification.

6-bromo-4- (3-chloropropyl) -8-fluoro-4H-benzo [1, 4%]Oxazin-3-ones (95MF50(2084))

[0155]Mixing 6-bromo-8-fluoro-4H-benzo [1, 4] according to GP5]Oxazin-3-one (95MF44) (0.091g, 0.37mmol), Cs₂CO₃(0.180g, 0.55mmol) and 3-chloro-1-iodopropane (0.083g, 0.41 mmol). CC (SiO)₂(ii) a heptane/EtOAc 9: 1-4) to give the title compound (95MF50(2084)) (0.086g, 72%).¹H NMR(CDCl₃)δ7.02-6.96(m，1H)，6.85(d，J＝5.2Hz，1H)，4.65(s，2H)，4.04-4.11(m，2H)，3.62(t，J＝6.2Hz，2H)，2.10-2.18(m，2H)；¹³C NMR(CDCl₃)δ163.8，151.7(d，J＝250.9Hz)，133.1(d，J＝14.6Hz)，131.5(d，J＝3.8Hz)，115.1(d，J＝21.5Hz)，114.2(d，J＝10.0Hz)，113.4(d，J＝3.4Hz)，67.6，42.2，39.5，30.0。

4- (3-chloropropyl) -8-fluoro-4H-benzo [1, 4]]Oxazin-3-ones (95MF51(2085))

[0156]Mixing 8-fluoro-4H-benzo [1, 4] according to GP5]Oxazin-3-one (95MF45) (0.290g, 1.74mmol), Cs₂CO₃(0.848g, 2.6mmol) and 3-chloro-1-iodopropane (0.390g, 1.91 mmol). CC (SiO)₂(ii) a heptane/EtOAc 9: 1-4) to give the title compound (95MF51(2082)) (0.254g, 60%).¹H NMR(CDCl₃)δ7.01-6.95(m，1H)，6.88-6.82(m，2H)，4.66(s，2H)，4.13-4.08(m，2H)，3.63(t，J＝6.0Hz，2H)，2.19-2-12(m，2H)；¹³C NMR(CDCl₃)δ164.2，152.1(d，J＝246.8Hz)，133.9(d，J＝15.0Hz)，130.6(d，J＝3.1Hz)，122.6(d，J＝8.1Hz)，111.8(d，J＝18.4Hz)，110.1(d，J＝3.4Hz)，67.8，42.4，39.5，30.1。

6, 8-dichloro-4- (3-chloropropyl) -7-ethyl-4H-benzo [1, 4]Oxazin-3-ones ((95MF52(2226))

[0157]Mixing 6, 8-dichloro-7-ethyl-4H-benzo [1, 4] according to GP5]Oxazin-3-one (95MF46) (0.342g, 1.39mmol), Cs₂CO₃(0.678g，2.08mmol) and 3-chloro-1-iodopropane (0.313g, 1.52 mmol). CC (SiO)₂(ii) a heptane/EtOAc 9: 1-4) to give the title compound (95MF52(2226)) (0.301g, 67%).¹H NMR(CHCl₃)δ7.01(s，1H)，4.68(s，2H)，4.06(t，J＝7.2Hz，2H)，3.62(t，J＝6.0Hz，2H)，2.91(q，J＝7.6Hz，2H)，2.10-2.18(m，2H)，1.16(t，J＝7.6Hz，3H)；¹³C NMR(CDCl₃)δ163.8，140.6，135.8，127.9，127.7，123.6，113.8，67.9，42.2，39.3，30.0，24.7，12.7。

4- (3-chloropropyl) -8-isopropyl-4H-benzo [1, 4]]Oxazin-3-one (95MF98)

[0158]Mixing 8-isopropyl-4H-benzo [1, 4] according to GP5]Oxazin-3-one (95MF83) (0.115g, 0.60mmol), CS₂CO₃(0.293g, 0.90mmol) and 3-chloro-1-iodopropane (0.135g, 0.66 mmol). CC (SiO)₂(ii) a heptane/EtOAc 9: 1-4) to give the title compound (95MF98) (0.112g, 70%).¹H NMR(CDCl₃)δ7.03-6.95(m，2H)，6.93-6.90(m，1H)，4.57(s，2H)，4.09(m，2H)，3.62(t，J＝6.2Hz，2H)，3.33-3.25(m，1H)，2.20-2.13(m，2H)，1.22(d，J＝7.2Hz，6H)；¹³C NMR(CDCl₃)δ164.9，142.8，137.8，128.5，122.8，121.4，112.5，67.7，42.5，39.3，30.3，27.2，22.7。

4- (3-chloropropyl) -6-fluoro-4H-benzo [1, 4]Oxazin-3-one (8173MF55b)

[0159]Mixing 6-fluoro-4H-benzo [1, 4] according to GP5]Oxazin-3-one (8173MF55b) (0.090g, 0.54mmol), Cs₂CO₃(0.263g, 0.81mmol) and 3-chloro-1-iodopropane (0.121g, 0.59 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (8173MF55b) (0.102g, 78%).¹H NMR(CDCl₃)δ6.95-6.91(m，1H)，6.82-6.78(m，1H)，6.72-6.67(m，1H)，4.57(s，1H)，4.05(t，J＝7.2Hz，2H)，3.62(t，J＝6.2Hz，2H)，2.19-2.11(m，2H)；¹³C NMR(CDCl₃)δ164.6，158.6(d，J＝240.7Hz)，141.5(d，J＝2.3Hz)，129.6(d，J＝10.5Hz)，118.0(d，J＝9.3Hz)，110.0(d，J＝23.1Hz)，102.7(d，J＝28.8Hz)，67.8，42.3，39.3，30.0。

4- (3-chloropropyl) -7, 8-difluoro-4H-benzo [1, 4]]Oxazin-3-one (81MF2082b)

[0160]Mixing 7, 8-difluoro-4H-benzo [1, 4] according to GP5]Oxazin-3-one (81MF2082a) (0.119g, 0.64mmol), Cs₂CO₃(0.314g, 0.96mmol) and 3-chloro-1-iodopropane (0.144g, 0.70mmol) to give the title compound (0.156g) as a crude product;¹HNMR(CDCl₃)δ6.89-6.82(m，1H)，6.78-6.74(m，1H)，4.68(s，2H)，4.08(t，J＝7.2Hz，2H)，3.62(t，J＝6.4Hz，2H)，2.18-2.10(m，2H)；¹³C NMR(CDCl₃)δ163.5，147.7(q，J＝245.6Hz，J＝10.4Hz)，141.0(q，J＝249.4Hz，J＝15.7Hz)，135.5，126.2，109.9(d，J＝18.4Hz)，108.6(q，J＝7.6Hz，J＝4.2Hz)，67.8，42.3，39.4，30.0。

4- (3-chloropropyl) -6-methoxy-4H-benzo [1, 4]]Oxazine-3-one (81MF2249b)

[0161]Mixing 6-methoxy-4H-benzo [1, 4] according to GP5]Oxazin-3-one (81MF2249a) (0.212g, 1.18mmol), Cs₂CO₃(0.578g, 1.77mmol) and 3-chloro-1-iodopropane (0.265g, 1.3 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-2) to give the title compound (81MF2249b) (0.127g, 42%).¹H NMR(CDCl₃)δ6.88(d，J＝8.8Hz，1H)，6.62(d，J＝2.8Hz，1H)，6.50(dd，J＝2.8Hz，J＝8.8Hz，1H)，4.50(s，2H)，4.05-4.01(m，2H)，3.76(s，3H)，3.59(t，J＝6.2Hz，2H)，2.16-2.09(m，2H)；¹³CNMR(CDCl₃)δ164.8，155.5，139.3，129.2，117.4，107.8，101.9，67.8，55.8，42.4，38.9，30.0。

4- (3-chloropropyl) -7-fluoro-4H-benzo [1, 4%]Oxazin-3-one (81MF763b)

[0162]Mixing 7-fluoro-4H-benzo [1, 4] according to GP5]Oxazines-3-one (81MF763) (0.263g, 1.57mmol), Cs₂CO₃(0.769g, 2.36mmol) and 3-chloro-1-iodopropane (0.354g, 1.73mmol) to give the title compound (0.40g) as a crude product;¹H NMR(CDCl₃)δ7-01-6.91(m，1H)，6.79-6.73(m，2H)，4.60(s，2H)，4.08(t，J＝7.2Hz，2H)，3.62(t，J＝6.4Hz，2H)，2.18-2.11(m，2H)。

4- (3-chloropropyl) -4H-pyrido [4, 3-b][1，4]Thiazine-3-one (81MF939b)

[0163]Mixing 4H-pyrido [4, 3-b ] according to GP5][1，4]Thiazin-3-one (81MF939a) (0.087g, 0.52mmol), Cs₂CO₃(0.256g, 0.78mmol) and 3-chloro-1-iodopropane (0.116g, 0.57mmol) to give the title compound (0.139g) as a crude product.¹H NMR(CDCl₃)δ8.43(s，1H)，8.17(d，J＝5.2Hz，1H)，7.25(d，J＝5.2Hz，1H)，4.20-4.15(m，2H)，3.55(t，J＝6.2Hz，2H)，3.41(s，2H)，2.17-2.10(m，2H)。

General method 6(GP6)

[0164]A100 mL flask was charged with 4H-benzo [1, 4] in 50mL dry MeCN]Oxazin-3-one (1.0 equiv.), Cs₂CO₃(1.5 eq.) and 3-chloro-1-iodopropane (1.1 eq.) and stirred at room temperature for 72 h. The reaction mixture was evaporated to dryness and taken up in 100mL of H₂Diluted O and extracted with EtOAc (3X 100 mL). The organic layers were combined and MgSO₄Dried, filtered, evaporated to dryness and purified with CC (heptane/EtOAc).

6, 8-dichloro-4- (3-chloropropyl) -7-methyl-4H-benzo [1, 4-]Oxazin-3-one (81MF2225b)

[0165]Mixing 6, 8-dichloro-7-methyl-4H-benzo [1, 4] according to GP6]Oxazin-3-one (81MF2225a) (2.33g, 10.0mmol), CS₂CO₃(4.88g, 15.0mmol) and 3-chloro-1-iodopropane (2.25g, 11.0 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (81MF2225b) (2.44g, 79%).¹H NMR(CDCl₃)δ7.02(s，1H)，4.67(s，2H)，4.06(t，J＝7.2Hz，2H)，3.62(t，J＝6.2，2H)，2.43(s，3H)，2.18-2.10(m，2H)；¹³CNMR(CDCl₃)δ163.7，140.5，130.3，128.3，127.6，124.1，113.5，67.9，42.2，39.3，30.0，17.2。

4- (3-chloropropyl) -6, 8-dimethyl-4H-benzo [1, 4]]Oxazin-3-one (81MF2237b)

[0166]Mixing 6, 8-dimethyl-4H-benzo [1, 4] according to GP6]Oxazin-3-one (81MF2237a) (1.70g, 9.60mmol), Cs₂CO₃(4.69g, 14.4mmol) and 3-chloro-1-iodopropane (2.15g, 10.6 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (81MF2237b) (0.96g, 39%).¹H NMR(CDCl₃)δ6.72-6.69(m，2H)，4.56(s，2H)，4.07(t，2H)，3.62(t，J＝6.4Hz，2H)，2.30(s，3H)，2.20(s，3H)，2.19-2.12(m，2H)；¹³C NMR(CDCl₃)δ164.9，141.5，131.9，128.0，126.7，126.4，113.1，67.8，42.5，39.0，30.3，21.2，15.5。

6-tert-butyl-4- (3-chloropropyl) -4H-benzo [1, 4%]Oxazine-3-one (81MF2248b)

[0167]Mixing 6-tert-butyl-4H-benzo [1, 4] according to GP6]Oxazin-3-one (81MF2248a) (2.07g, 10.0mmol), Cs₂CO₃(4.88g, 15.0mmol) and 3-chloro-1-iodopropane (2.25g, 11.0 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (81MF2248b) (1.39g, 49%).¹H NMR(CDCl₃)δ7.12(d，J＝2.0Hz，1H)，7.03(dd，J＝8.4Hz，J＝2.0Hz，1H)，6.92(d，J＝8.4Hz，1H)，4.54(s，2H)，4.14(t，J＝7.2Hz，2H)，3.65(t，J＝6.0Hz，2H)，2.21-2.14(m，2H)，1.32(s，9H)；¹³CNMR(CDCl₃)δ164.8，146.4，143.1，127.9，120.9，116.7，112.2，67.8，42.6，38.9，34.8，31.6，30.2。

6-chloro-4- (3-chloropropyl) -7-nitro-4H-benzo [1, 4%]Oxazin-3-one (81MF2253b)

[0168]Mixing 6-chloro-7-nitro-4H-benzo [1, 4] according to GP6]Crude product (2.60g, 10.0mmol) of oxazin-3-one (81MF2253a), Cs₂CO₃(4.88g, 15.0mmol) and 3-chloro-1-iodopropane (2.25g, 11.0 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (81MF2253b) (1.23g, 36%).¹H NMR(CDCl₃)δ7.66(s，1H)，7.20(s，1H)，4.70(s，2H)，4.12(t，J＝7.6Hz，2H)，3.67-3.59(m，2H)，2.21-2.13(m，2H)；¹³CNMR(CDCl₃)δ163.6，143.5，133.3，133.2，122.4，117.2，115.2，67.4，42.1，39.6，29.8。

7-chloro-4- (3-chloropropyl) -4H-benzo [1, 4%]Oxazin-3-one (81MF2271b)

[0169]Mixing 7-chloro-4H-benzo [1, 4] according to GP6]Oxazin-3-one (81MF2271a) (1.74g, 9.47mmol), Cs₂CO₃(4.63g, 14.2mmol) and 3-chloro-1-iodopropane (2.13g, 10.4 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (81MF2271b) (1.95g, 79%).¹H NMR(CHCl₃)δ7.03-6.96(m，3H)，4.59(s，2H)，4.07(t，J＝7.2Hz，2H)，3.61(t，J＝6.4Hz，2H)，2.17-2.10(m，2H)；¹³C NMR(CDCl₃)δ164.0，146.0，129.1，127.3，123.0，117.8，115.5，67.7，42.4，39.2，30.0。

4- (3-chloropropyl) -5-methyl-4H-benzo [1, 4]]Oxazin-3-one (81MF941b)

[0170]Mixing 5-methyl-4H-benzo [1, 4] according to GP6]Oxazin-3-one (81MF941a) (1.514g, 9.28mmol), Cs₂CO₃(4.53g, 13.9mmol) and 3-chloro-1-iodopropane (2.09g, 10.21 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (81MF941b) (1.07g, 48%).¹H NMR(CHCl₃)δ6.99-6.87(m，3H)，4.42(s，2H)，4.17(t，J＝7.2Hz，2H)，3.45(t，J＝6.4Hz，2H)，2.41(s，3H)，2.04-1.97(m，2H)；¹³C NMR(CHCl₃)δ168.3，149.9，129.1，128.7，126.9，125.1，115.0，69.4，42.2，42.1，30.6，20.9。

4- (3-chloropropyl) -7-methyl-4H-benzo [1, 4]]Oxazine-3-one (81MF2246b)

[0171]Mixing 7-methyl-4H-benzo [1, 4] according to GP6]Oxazin-3-one (81MF2246a) (1.42g, 8.7mmol), Cs₂CO₃(4.24g, 13.0mmol) and 3-chloro-1-iodopropane (1.95g, 9.5 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-5) to give the title compound (81MF2246b) (1.64g, 79%).¹H NMR(CHCl₃)δ6.98-6.81(m，3H)，4.59(s，2H)，4.06-4.03(m，2H)，3.63-3.60(m，2H)，2.26(s，2H)，2.20-2.15(m，2H)；¹³CNMR(CHCl₃)δ164.8，145.8，134.3，123.9，118.1，114.9，68.0，42.8，39.4，30.5，21.0。

(R, S) -6-methyl-4-oxiranylmethyl-4H-benzo [1, 4]Oxazin-3-one (101IS84F1)

[0172]In a dry 7mL vial was added 6-methyl-4H-benzo [1, 4]]Oxazin-3-one (160mg, 1.0mmol), epichlorohydrin (0.147g, 1.6mmol), Cs₂CO₃(0.820g, 2.5mmol) and dry DMF (1mL) and the mixture was shaken at 60 ℃ for 36 h. The mixture was diluted with ether (20mL) and washed with water and brine (10mL), dried, filtered, and concentrated under reduced pressure to give an oil. By fast CC (SiO)₂，CH₂Cl₂acetone/MeOH 95: 3: 2) to yield the title compound (0.127g, 39%).¹H NMR(CHCl₃)δ7.01(d，J＝1.2Hz，1H)，6.84(d，J＝8.4Hz)，6.80(dm，J＝8.4Hz)，4.58(ABq J＝15.2，21.2Hz，2H)，4.50(dd，J＝3.2，15.2Hz，1H)，3.66(dd，J＝6，15.2Hz)，3.23(m，1H)，2.86(dd，J＝4，4.4Hz，1H)，2.69(dd，J＝2.8，4.8Hz，1H)，2.33(s，3H)；¹³C NMR(CHCl₃)δ156.2，143.3，132.9，129.0，124.9，116.9，116.6，68.0，50.2，25.8，44.0，21.3。

General method 7(GP7)

[0173]To a dry 100mL flask was added 4H-benzo [1, 4] benzo dissolved in dry DMF (40mL)]Oxazin-3-one (1.0 eq), (3-bromo-2-methyl-propoxy) -tert-butyldimethylsilane (1.0 eq), Cs₂CO₃(2.5 equivalents) and stirred at 50 ℃ for 20-28 hours under an inert gas. Water (100mL) was added to the reaction, and extracted with ether (3X 150 mL). The combined organic layers were washed with brine (100mL), Na₂SO₄Dried, concentrated and then purified with CC (heptane/EtOAc).

(S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-6-fluoro-4H-benzo [1, 4]]Oxazine-3- Ketones (111MF01)

[0174]Mixing 6-fluoro-4H-benzo [1, 4] according to GP7]Oxazin-3-one (95MF88) (2.54g, 15.2mmol), (R) -3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.07g, 15.2mmol) and Cs₂CO₃(12.38g，38mmol)。CC(SiO₂(ii) a heptane/EtOAc 9: 1) to give the title compound (111MF01) (4.09g, 76%).¹H NMR(CHCl₃)δ6.93-6.87(m，1H)，6.92-6.88(m，1H)，6.68-6.63(m，1H)，4.56(m，2H)，4.01(m，1H)，3.78(m，1H)，3.58(m，1H)，3.45(m，1H)，2.11(m，1H)，0.92(s，12H)，0.06(d，J＝0.8Hz，6H)；¹³CNMR(CDCl₃)δ164.8，158.5(d，J＝239.9Hz)，141.6(d，J＝2.7Hz)，130.1(d，J＝10.7Hz)，117.6(d，J＝9.3Hz)，109.6(d，J＝23.1Hz)，103.6(d，J＝28.8Hz)，67.8，65.9，44.2，34.5，26.0，18.4，14.9，-5.4，-5.4。

(S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-7-fluoro-4H-benzo [1, 4]]Oxazine-3- Ketones (111MF14)

[0175]Mixing 7-fluoro-4H-benzo [1, 4] according to GP7]Oxazin-3-one (111MF12) (2.52g, 15.1mmol), (S) -3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03g, 15.1mmol) and Cs₂CO₃(12.3g，38mmol)。CC(SiO₂(ii) a heptane/EtOAc 9: 1) to yield the title compound(111MF14)(3.79g，71％)。¹H NMR(CDCl₃)δ7.12(dd，J＝5.2Hz，J＝8.8Hz，1H)，6.67-6.34(m，2H)，4.60(q，J＝14.8Hz，J＝25.4Hz，2H)，4.03(dd，J＝8.4Hz，J＝14.0Hz，1H)，3.82(dd，J＝5.6Hz，J＝14.0Hz，1H)，3.57(dd，J＝4.8Hz，J＝10.0Hz，1H)，3.45(dd，J＝7.0Hz，J＝9.8Hz，1H)，2.15-2.05(m，1H)，0.93-0.89(m，12H)，0.06(s，6H)；¹³C NMR(CHCl₃)δ164.1，158.9(d，J＝243.7Hz)，146.4(d，J＝11.6Hz)，125.3(d，J＝3.0Hz)，116.4(d，J＝9.6Hz)，109.1(d，J＝22.7Hz)，105.1(d，J＝25.8Hz)，67.8，66.0，44.1，34.5，26.0，18.4，14.9，-5.3，-5.4。

(S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-6-methoxy-4H-benzo [1, 4]]Oxazole (oxazole) (I) Oxazin-3-ones (111MF32)

[0176]Mixing 6-methoxy-4H-benzo [1, 4] according to GP7]Oxazin-3-one (111MF24) (2.7g, 15.1mmol), (S) -3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03g, 15.1mmol) and Cs₂CO₃(12.3g，38mmol)。CC(SiO₂(ii) a heptane/EtOAc 9: 1) to give the title compound (111MF32) (4.03g, 80%).¹H NMR(CDCl₃)δ6.89(d，J＝8.8Hz，1H)，6.71(d，J＝2.8Hz，1H)，6.50(dd，J＝2.8Hz，J＝8.6Hz，1H)，4.53(q，J＝14.8Hz，J＝29.2Hz，2H)，3.98(dd，J＝8.8Hz，J＝14.0Hz，1H)，3.85(dd，J＝5.8Hz，J＝14.2Hz，1H)，3.77(s，3H)，3.57(dd，J＝9.2Hz，J＝10.0Hz，1H)，3.47(dd，J＝7.2Hz，J＝10.0Hz，1H)，2.20-2.12(m，1H)，0.91(s，12H)，0.05(d，J＝1.2Hz，6H)；¹³C NMR(CHCl₃)δ165.3，155.6，139.7，129.8，117.2，107.4，103.3，68.0，66.2，55.9，43.9，34.3，26.1，18.5，14.7，-5.3，-5.4。

General method 8(GP8)

[0177] 4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one (1.0 equiv.) and tetrabutylammonium fluoride monohydrate (1.3 equiv.) were added to a 100mL flask and dissolved in 40mL dry THF. The reaction is stirred at room temperature under an inert gas for 20 to 24 hours. The reaction mixture was concentrated and purified with CC (heptane/EtOAc).

(S) -6-fluoro-4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4]Oxazin-3-one (111MF03)

[0178]Mixing the compound (S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl according to GP8]-6-fluoro-4H-benzo [1, 4]]Oxazin-3-one (111MF01) (4.09g, 11.6mmol) and tetrabutylammonium fluoride monohydrate (4.30g, 15.4 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF03) (2.63g, 95%).¹H NMR(CHCl₃)δ6.92(dd，J＝5.2Hz，J＝8.8Hz，1H)，6.80(dd，J＝2.8Hz，J＝10.0Hz，1H)，6.71-6.66(m，1H)，4.59(d，J＝0.8Hz，2H)，4.17-4.11(m，1H)，3.58-3.40(m，3H)，2.79(s，1H)，2.08-1.96(m，1H)，1.04(d，J＝7.2Hz，3H)；¹³C NMR(CHCl₃)δ165.3，158.4(d，J＝238.44Hz)，141.5(d，J＝2.7Hz)，129.5(d，J＝10.4Hz)，117.9(d，J＝9.3Hz)，110.2(d，J＝23.1Hz)，103.1(d，J＝28.4Hz)，67.5，63.85，43.8，34.0，14.9。

(S) -7-fluoro-4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4]Oxazin-3-one (111MF18)

[0179]Mixing the compound (S) -4- [3- (tert-butyldimethylsilyloxy) -2-methyl-propyl ] according to GP8]-7-fluoro-4H-benzo [1, 4]]Oxazin-3-one (111MF14) (3.79g, 10.7mmol) and tetrabutylammonium fluoride monohydrate (3.99g, 14.3 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF18) (2.57g, 100%).¹H NMR(CHCl₃)δ6.99-6.95(m，1H)，7.77-7.72(m，2H)，4.63(m，2H)，4.23-4.16(m，1H)，3.58-3.40(m，3H)，2.86(s，1H)，2.05-1.97(m，1H)，1.04(d，J＝6.8Hz，3H)；¹³C NMR(CHCl₃)164.6，159.2(d，J＝244.5Hz)，146.4(d，J＝11.6Hz)，124.9(d，J＝3.1Hz)，115.9(d，J＝9.6Hz)，109.4(d，J＝22.7Hz)，105.3(d，J＝26.1Hz)，67.5，63.8，43.8，34.0，15.0。

(S) -4- (3-hydroxy-2-methylpropyl) -6-methoxy-4H-benzo [1, 4]Oxazin-3-one (111MF34)

[0180]Mixing the compound (S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl according to GP8]-6-methoxy-4H-benzo [1, 4]]Oxazin-3-one (111MF32) (4.03g, 12.0mmol) and tetrabutylammonium fluoride monohydrate (4.46g, 16.0 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF34) (2.70g, 100%).¹H NMR(CHCl₃)66.91(d，J＝8.8Hz，1H)，6.63(d，J＝2.8Hz，1H)，6.54(dd，J＝2.8Hz，J＝8.8Hz，1H)，4.57(s，2H)，4.19(dd，J＝9.4Hz，J＝14.6Hz，1H)，3.78(s，3H)，3.56-3.39(m，3H)，2.84(s，1H)，2.09-1.99(m，1H)，1.05(d，J＝7.2Hz，3H)；¹³C NMR(CHCl₃)165.8，155.5，139.5，129.4，117.4，107.7，103.0，67.7，63.8，56.0，43.6，34.1，15.0。

General method 9(GP9)

[0181]A250 mL flask was charged with CHCl₃4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4] in (100mL)]Oxazin-3-one (1.0 equiv). Triphenylphosphine (2.2 equivalents) and imidazole (2.4 equivalents) were then added. Adding I to the solution₂(2.8 equivalents) and the reaction stirred at room temperature for 15-18 hours. The reaction mixture is washed with Na₂S₂O₃(saturated aqueous solution) (100mL) was quenched. Separating the phases, using CH for the aqueous phase₂Cl₂(150mL) washed. The organic layers were combined and washed with Na₂SO₄Dried, concentrated and purified with CC (heptane/EtOAc).

(S) -6-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4]Oxazin-3-one (111MF04)

Mixing the compound (S) -6-fluoro-4- (3-hydroxy-2-methyl-propyl) -4H-benzo [1, 4] according to GP9]Oxazin-3-one (111MF03) (2.63g, 11.0mmol) Triphenylphosphine (6.35g, 24.2mmol), imidazole (1.8g, 26.4mmol) and I₂(7.81g，30.8mmol)。CC(SiO₂(ii) a heptane/EtOAc 9: 1-4) to give the title compound (111MF04) (3.86g, 100%).¹H NMR(CHCl₃)δ6.97-6.93(m，1H)，6.82-6.78(m，1H)，6.73-6.68(m，1H)，4.63-4.53(m，2H)，3.90(d，J＝6.8Hz，2H)，3.20-3.16(m，2H)，2.15-2.04(m，1H)，1.06(d，J＝6.4Hz，3H)；¹³CNMR(CHCl₃)δ165.0，158.5(d，J＝240.2Hz)，141.7(d，J＝2.3Hz)，129.6(d，J＝10.4Hz)，118.1(d，J＝9.2Hz)，110.1(d，J＝23.4Hz)，103.1(d，J＝28.7Hz)，67.8，46.3，33.5，18.9，11.6。

(S) -7-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4]Oxazin-3-one (111MF20)

[0182]Mixing the compound (S) -7-fluoro-4- (3-hydroxy-2-methylpropyl) -4H-benzo [1, 4] according to GP9]Oxazin-3-one (111MF18) (2.57g, 11.0mmol), triphenylphosphine (6.61g, 23.7mmol), imidazole (1.76g, 25.8mmol) and I2(7.64g, 30.1 mmol). CC (SiO)₂(ii) a heptane/EtOAc 9: 1-4) to give the title compound (111MF20) (3.31g, 89%).¹H NMR(CDCl₃)δ7.00-6.96(m，1H)，6.78-6.74(m，2H)，4.65-4.56(m，2H)，3.92(d，J＝7.6Hz，2H)，3.21-3.13(m，2H)，2.13-2.03(m，1H)，1.04(d，J＝6.4Hz，3H)；¹³C NMR(CHCl₃)δ164.3，159.0(d，J＝244.4Hz)，146.6(d，J＝12.0Hz)，125.0(d，J＝3.0Hz)，115.9(d，J＝9.7Hz)，109.4(d，J＝22.5Hz)，105.5(d，J＝26.0Hz)，67.8，46.3，33.6，18.9，11.8。

(S) -4- (3-iodo-2-methylpropyl) -6-methoxy-4H-benzo [1, 4-]Oxazin-3-one (111MF36)

[0183]Mixing the compound (S) -4- (3-hydroxy-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] according to GP9]Oxazin-3-one (111MF34) (2.70g, 12.0mmol), triphenylphosphine (6.92g, 26.4mmol), imidazole (1.96g, 28.8mmol) and I2(8.53g, 33.6 mmol). CC (SiO)₂(ii) a heptane/EtOAc 9: 1-4) to obtain the titled compoundCompound (111MF36) (3.54g, 82%).¹H NMR(CDCl₃)δ6.92(d，J＝8.4Hz，1H)，6.63(d，J＝2.8Hz，1H)，6.53(dd，J＝2.8Hz，J＝8.8Hz，1H)，4.54(q，J＝14.8Hz，J＝23.6Hz，2H)，3.92(d，J＝7.4Hz，2H)，3.80(s，3H)，3.18(dd，J＝1.0Hz，J＝6Hz，2H)，2.17-2.08(m，1H)，1.05(d，J＝6.8Hz，3H)；¹³CNMR(CHCl₃)δ165.4，155.6，139.6，129.4，117.7，108.0，102.5，68.0，56.1，46.1，33.6，18.9，12.0。

(S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-6-methyl-4H-benzo [1, 4]]Oxazines -3-one (101IS60-1)

[0184]To a dry 50mL round bottom flask was added 6-methyl-4H-benzo [1, 4]]Oxazin-3-one (0.59g, 3.6mmol), (R) - (3-bromo-2-methylpropoxy) -tert-butyldimethylsilane (1.0g, 3.6mmol), Cs₂CO₃(2.9g, 8.9mmol) and 10mL of dry DMF. The mixture was stirred at 50 ℃ overnight (15h), dissolved in ether (50mL), washed with water (20mL) and the aqueous phase extracted with ether (20 mL). The combined organic phases were washed with brine and dried (Na)₂SO₄) Filtering, concentrating under reduced pressure, and flash-chromatography (SiO) the obtained oil₂(ii) a heptane/EtOAc 85: 15) to give the title compound as an oil (1.1g, 88%).¹H NMR(CHCl₃)δ6.87(d，J＝1.6Hz，1H)，6.81(d，J＝8.0Hz，1H)，6.72(dm，J＝8.0Hz，1H)，4.5(bars，2H)，3.93(dd，J＝8.8，14.0Hz，1H)，3.81(dd，J＝5.6，14.0Hz，1H)，3.53(dd，J＝4.8，10.2Hz，1H)，3.41(ddJ＝7.2，10.2Hz，1H)，2.25(s，3H)，2.18(m，1H)，0.87(s，9H)，0.83(d，J＝6.8Hz，3H)，0.01(s，6H)；¹³C NMR(CHCl₃)δ170.5，148.9，137.8，129.6，122.2，121.6，73.3，71.6，49.0，39.7，31.5，26.6，23.8，20.1，0.0。

(S) -4- (3-hydroxy-2-methylpropyl) -6-methyl-4H-benzo [1, 4]Oxazin-3-one (101IS60-2)

[0185]The compound (S) -4- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-6-methyl-4H-benzo [1, 4]]Oxazin-3-one (101IS60-1) (1.0g, 2.9mmol) was dissolved in dry THF (12mL) and TBAF (1.2g, 3.8mmol) was added. The reaction was stirred at room temperature overnight, the solution was concentrated under reduced pressure, and the remaining oil was diluted with EtOAc (60mL), washed with brine (3X 30mL), and dried (Na)₂SO₄) Filtering, and concentrating under reduced pressure. Flash chromatography of the remaining oil (SiO)₂(ii) a heptane/EtOAc 30: 70) to give an oil which crystallizes on standing (0.69g, 76%).¹H NMR(CHCl₃)δ6.88(d，J＝8.4Hz，1H)，6.83-6.78(m，2H)，4.59(brs 2H)，4.22(dd J＝10.0，14.4Hz)，3.57-3.38(m，3H)，2.9(vbrs，1H)，2.33(s，3H)，2.04(m，1H)，1.08(d，J＝7.2Hz)；¹³C NMR(CHCl₃)δ165.7，143.4，132.3，124.9，117.1，115.9，67.6，63.7，43.5，34.2，21.3，15.1。

(S) -4- (3-iodo-2-methylpropyl) -6-methyl-4H-benzo [1, 4-]Oxazin-3-one (101IS70)

[0186]To a dry 50mL round bottom flask was added (S) -4- (3-hydroxy-2-methylpropyl) -6-methyl-4H-benzo [1, 4]]Oxazin-3-one (1.0g, 4.2mmol), PPh₃(2.2g, 8.5mmol), imidazole (0.58g, 8.5mmol), and dissolved in CH₂Cl₂(25 mL). Iodine (2.2g, 8.4mmol) was then added in portions over 4 h. After the last addition, the reaction was poured onto SiO₂And filtering. Concentration under reduced pressure gave the title compound as a crude product (1.5g), which was used without further purification.

1- (3-chloropropyl) -3, 4-dihydro-1H-quinolin-4-one (85LM31)

[0187]A50 mL flask was charged with 3, 4-dihydro-1H-quinolin-2-one (2.00g, 13.6mmol) and sodium hydride (60% in oil, 0.712g, 16.3mmol) dissolved in DMF (50mL, dry) and stirred at 0 deg.C for 1H, then 1-chloro-3-iodo-propane (2.77g, 13.6mmol) was added and stirred at room temperature for 20H. The reaction mixture was quenched with water (10mL) and the product extracted with EtOEt (3X 25 mL). Incorporating organic matterLayer, drying (Na)₂SO₄) By evaporation, with fast CC (SiO)₂(ii) a EtOAc/heptane 1: 4) to yield the crude product (2.25g) of the title compound (85LM 31).¹H NMR(CHCl₃)δ7.29-7.22(m，1H)，7.17(d，J＝7.4Hz，1H)，7.08-6.98(m，2H)，4.10(t，J＝7.3Hz，CH₂)，3.62(t，J＝5.9Hz，CH₂)，2.88(t，J＝7.3Hz，CH₂)，2.63(t，J＝7.3Hz，CH₂)，2.19-2.10(m，2H)；¹³C NMR(CDCl₃)δ170.5，140.0，128.2，127.8，126.3，123.2，115.0，43.3，40.2，32.2，30.5，26.0。

1- (3-chloropropyl) -6-fluoro-3, 4-dihydro-1H-quinolin-2-one (92LH79)

[0188]To the reaction flask was added 6-fluoro-3, 4-dihydro-1H-quinolin-2-one (0.180g, 1.09mmol) dissolved in dry DMF (2mL) under argon. NaH (60% in oil, 0.048g, 1.20mmol) was added and the mixture was stirred at room temperature for 0.5 h. 1-bromo-3-chloropropane (0.180g, 1.14mmol) was then added and the mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a DCM) to give the title compound (92LH79) (0.193g, 73%).¹H NMR(CHCl₃)δ7.02-6.88(m，3H)，4.09-4.05(m，2H)，3.61(t，J＝6.3Hz，CH₂)，2.87(t，J＝6.7Hz，CH₂)，2.65-2.61(m，2H)，2.16-2.09(m，2H)；¹³C NMR(CDCl₃)δ169.8，158.4(J＝242.9Hz)，135.7(J＝2.7Hz)，128.5(J＝7.7Hz)，115.7(J＝8.1Hz)，115.1(J＝22.7)，113.8(J＝22.3Hz)，42.6，40.3，31.5，30.1，25.5。

(R, S) -1- (3-chloro-2-methylpropyl) -6-fluoro-3, 4-dihydro-1H-quinolin-2-one (107LH68)

[0189]To the reaction flask was added 6-fluoro-3, 4-dihydro-1H-quinolin-2-one (0.496g, 3.0mmol) dissolved in dry DMF (3mL) under argon. NaH (60% in oil, 0.132g, 3.3mmol) was added,the mixture was stirred at room temperature for 45 min. Then (R, S) -1-bromo-3-chloro-2-methylpropane (0.513g, 3.0mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for crude product₂(ii) a EtOAc/n-heptane 1: 1) to yield the crude product (0.308g) of the title compound (107LH 68).

1- (3-chloropropyl) -6-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH14)

[0190]To the reaction flask was added 6-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH05) (0.300g, 1.26mmol) dissolved in dry DMF (5mL) under argon. NaH (60% in oil, 0.055g, 1.38mmol) was added and the mixture was stirred at room temperature for 1 h. 1-bromo-3-chloropropane (0.198g, 1.24mmol) was then added and the mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for crude product₂(ii) a DCM) to give the crude product (0.257g) of the title compound (107LH 14).

1- (3-chloropropyl) -7-fluoro-6-methyl-3, 4-dihydro-1H-quinolin-2-one (112KK01)

[0191]To the reaction flask was added 7-fluoro-6-methyl-3, 4-dihydro-1H-quinolin-2-one (97KK40) (0.102g, 0.57mmol) dissolved in dry DMF (5mL) under argon. Washed NaH (0.015g, 0.63mmol) was added and the mixture was stirred at room temperature for 1 h. 1-chloro-3-iodopropane (0.104g, 0.51mmol) in DMF (1mL) was then added. Then stirred at room temperature for 20 h. The reaction mixture was quenched with water and the product was Et₂And (4) extracting. Combine the organic layers with 4% MgSO₄Washing with aqueous solution, and adding Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a DCM/n-heptane 2: 1, DCM, MeOH/DCM 1: 10) gave the title compound (112KK01) (0.050g, 38%).¹H NMR(CHCl₃)δ6.95-6.93(m，1H)，6.73(d，J＝11.5Hz，1H)，4.03-4.00(m，2H)，3.59(t，J＝6.5Hz，CH₂)，2.83-2.79(m，2H)，2.62-2.58(m，2H)，2.20(d，J＝1.8Hz，CH₃)，2.13-2.07(m，2H)。

1- (3-chloropropyl) -6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (112KK03)

[0192]To the reaction flask was added 6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (97KK47) (0.181g, 0.99mmol) dissolved in dry DMF (5mL) under argon. Washed NaH (0.026g, 1.08mmol) was added and the mixture was stirred at room temperature for 0.5 h. Then 3-chloro-1-iodopropane (0.205g, 1.00mmol) dissolved in DMF (1mL) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was Et₂And (4) extracting. Combine the organic layers with 4% MgSO₄Washing with aqueous solution, and adding Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a DCM) to give the title compound (112KK03) (0.122g, 47%).¹H NMR(CD₃OD)δ6.99-6.86(m，2H)，4.03-3.99(m，2H)，3.60(t，J＝6.1，CH₂)，2.84-2.81(m，2H)，2.63-2.59(m，2H)，2.13-2.06(m，2H)。

1- (3-chloropropyl) -5-methyl-3, 4-dihydro-1H-quinolin-2-one and 1- (3-chloropropyl) -7-methyl-3, 4-di hydro-1H-quinolin-2-ones

[0193]Pure 2-chloro-N-m-tolylacetamide (92LH85) (1.7g, 8.5mmol) was heated to 135 deg.C and AlCl was added portionwise over 30min under argon₃(3.4mg, 26 mmol). The reaction was cooled to 60 ℃ and then HCl (10mL, 4M) was added. The mixture was extracted with EtOAc (2X 30mL), and the organic phases were combined and Na₂SO₄Drying, filtering, and concentrating under reduced pressure. Flash chromatography of the residue (SiO)₂；CH₂Cl₂MeOH 9: 1) to give the compounds 7-methyl-3, 4-dihydro-1H-quinolin-2-one and 5-methyl-3, 4-dihydro-1H-quinolin-2-one (1.1 g). The mixture was dissolved in dry DMF (8mL), NaH (60% in oil, 310mg, 7.7mmol) was added and the solution was taken up in N₂Stirred at room temperature for 45 min. Then adding 1-bromo-3-chloropropane, and reactingIt should be stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50mL) and washed with water (10 mL). Na for organic phase₂SO₄Drying, filtration, concentration under reduced pressure and purification of the residue by preparative RP-HPLC gave 1- (3-chloropropyl) -5-methyl-3, 4-dihydro-1H-quinolin-2-one (0.057g, 3%) and 1- (3-chloropropyl) -7-methyl-3, 4-dihydro-1H-quinolin-2-one (0.12g, 6%). 1- (3-chloropropyl) -5-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH 27-11.7): the retention time is 11.7min,¹H NMR(CD₃OD)δ7.12(vbrt，7.7Hz，1H)，6.98(d，J＝8.0Hz，1H)，6.90(d，J＝7.2Hz，1H)，4.09-4.02(m，2H)，3.59(t，＝6.4Hz，2H)，2.85-2.78(m，2H)，2.58-2.50(m，2H)，2.27(s，3H)，2.10-2.01(m，2H)；¹³C NMR(CD₃OD) δ 171.5, 139.2, 135.9, 126.9, 125.4, 125.3, 113.1, 42.2, 40.1, 31.1, 30.3, 21.2, 18.5. 1- (3-chloropropyl) -7-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH 27-13.1): the retention time is 13.1min,¹H NMR(CD₃OD)δ7.02(brd，J＝7.6Hz，1H)，6.94(brs，1H)，6.81(brd，J＝7.6Hz，1H)，4.03(brt，J＝7.2Hz，2H)，3.58(t，J＝6.2Hz，2H)，2.78(t，J＝7.4Hz，2H)，2.51(t，J＝7.4Hz)，2.30(s，3H)，2.09-2.00(m，2H)；¹³C NMR(CD₃OD)δ171.6，139.0，137.4，127.8，123.9，115.7，42.3，39.8，31.7，30.3，24.6，20.4。

(S) -1- [3- (tert-butyldimethylsilyl) -2-methylpropyl]-3, 4-dihydro-1H-quinolin-2-one (122LH13)

[0194]To the reaction flask was added 3, 4-dihydro-1H-quinolin-2-one (1.60g, 10.9mmol) dissolved in dry DMF (30mL) under argon. NaH (60% in oil, 0.480g, 12.0mmol) was added and the mixture was stirred at room temperature for 1 h. Then (R) - (3-bromo-2-methylpropoxy) -tert-butyldimethylsilane (3.0g, 10.9mmol) was added, followed by stirring at room temperature for 4 days. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a DCM purification to give the title compound (122LH13)(2.685g，74％)。

(S) -1- (3-hydroxy-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (122LH16)

[0195]To the reaction flask was added (S) -1- [3- (tert-butyldimethylsilyl) -2-methylpropyl dissolved in dry THF (20mL) under argon]-3, 4-dihydro-1H-quinolin-2-one (122LH13) (2.685g, 8.05mmol) and tetrabutylammonium fluoride (2.70g, 10.3mmol) and stirred at room temperature for 20H. The reaction mixture was concentrated and the product was purified using fast CC (SiO)₂(ii) a n-heptane/EtOAc 1: 1) to yield the title compound (122) (1.54g, 87%).

(S) -1- (3-iodo-2-methylpropyl) -34-dihydro-1H-quinolin-2-one (122LH18)

[0196]To the reaction flask was added (S) -1- (3-hydroxy-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (122LH16) (1.54g, 7.0mmol) dissolved in 50mL DCM. Addition of PPh₃(4.04g, 15.4mmol) and imidazole (1.14g, 16.7mmol), followed by stirring at room temperature for 15 min. The mixture was cooled in an ice bath and then I was added₂(5.00g, 19.7 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture is washed with Na₂S₂O₃Washing with Na₂SO₄Drying and concentrating. Fast CC (SiO) for product₂(ii) a n-heptane/EtOAc 1: 1) to yield the title compound (122LH18) (2.140g, 93%).

1- (3-chloropropyl) -1H-quinolin-2-one (107LH80)

[0197]A7 mL vial was charged with 1H-quinolin-2-one (0.62g, 4.2mmol), 4mL dry DMF, and NaH (60% in oil, 0.200g, 5.1 mmol). Mixture in N₂After stirring at room temperature for 45min, 1-bromo-3-chloropropane (0.42mL, 4.2mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with EtOAc (50mL) and washed with water (15 mL). The aqueous phase was extracted with EtOAc (25mL), and the organic phases were combined and dried (Na)₂SO₄) Filtering, concentrating under reduced pressure, and subjecting the residue to flash chromatography (SiO)₂；CH₂Cl₂) Purification gave the title compound (0.38g, 41%) which contained 15% of 1- (3-bromopropyl) -1H-quinolin-2-one.¹H NMR(CD₃OD)δ7.90(d，J＝9.4Hz，1H)，7.73-7.57(m，3H)，7.34-7.28(m，1H)，6.66(d，J＝9.4Hz)，4.46(t，J＝7.4Hz，2H)，3.71(t，J＝6.4Hz，2H)，2.21-2.02(m，2H)；¹³C NMR(CD₃OD)δ163.2，140.7，138.8，131.3，129.3，122.8，121.4，120.2，114.4，42.18，40.2，30.5。

1- (3-chloropropyl) -5-methyl-1H-quinolin-2-one (107LH39)

[0198]To a microwave vial was added 1- (3-chloropropyl) -5-methyl-3, 4-dihydro-1H-quinolin-2-one (0.081g, 0.34mmol), DDQ (0.116g, 0.51mmol), dioxane (2mL), and sealed. After microwave irradiation at 175 ℃ for 10min, the reaction was diluted with EtOAc (50mL) and saturated NaHCO₃The aqueous solution (2X 15mL) was washed and the organic phase was dried (Na)₂SO₄) Filtered, concentrated under reduced pressure and the residue purified by preparative RP-HPLC to give the title compound as a crude product (0.053g), which was used without further purification. HPLC-MS (ammonium acetate) [ M + H ]]⁺＝236.2。

1- (3-chloropropyl) -7-methyl-1H-quinolin-2-one (107LH40)

[0199]To a microwave vial was added 1- (3-chloropropyl) -7-methyl-3, 4-dihydro-1H-quinolin-2-one (0.21g, 0.88mmol), DDQ (0.30g, 1.3mmol), dioxane (4mL), and sealed. After microwave irradiation at 175 ℃ for 10min, the reaction was diluted with EtOAc (50mL) and saturated NaHCO₃Aqueous solution (2X 15mL) was washed with Na₂SO₄The organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give the title compound as a crude product (0.130g), which was used without further purification. HPLC-MS (ammonium acetate) [ M + H ]]⁺＝236.2。

(S) -1- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-1H-quinolin-2-one (107LH43)

[0200]1H-quinolin-2-one (1.9g, 13mmol) and NaH (60% in oil, 0.58g, 15mmol) were added to dry DMF (30mL) and reacted under N₂Stirred at room temperature for 45 min. Then (R) - (3-bromo-2-methylpropyl) -tert-butyldimethylsilane (3.7g, 13mmol) was added and the reaction stirred at 50 ℃ for 72 h. The reaction was poured into water, extracted with EtOAc (2X 50mL), and the organic phases were combined, dried, filtered, and concentrated under reduced pressure. Flash chromatography of the residue (SiO)₂；CH₂Cl₂) Purification gave the title compound (2.10g, 6.4mmol, 48%).¹H NMR(CDCl₃)δ7.60-7.53(m，2H)，7.49-7.40(m，2H)，7.12(dt，J＝0.9，7.6Hz，1H)，6.62(d，J＝9.6Hz，1H)，4.39(dd，J＝8.4，14.0Hz，1H)，4.15(dd，J＝5.4，14.0Hz)，3.54(dd，J＝4.4，10.2Hz，1H)，3.45(dd，J＝7.6，10.2Hz)，2.27-2.12(m，1H)，0.88(s，12H)，0.01(s，6H)；¹³CNMR(CHCl₃)δ168.2，145.2，144.5，135.8，134.3，127.3，127.2，126.4，120.5，71.7，50.4，40.9，31.4，23.8，20.4，0.0。

(S) -1- (3-hydroxy-2-methylpropyl) -1H-quinolin-2-one (107LH62)

[0201]TBAF (1.2g, 4.6mmol) and (S) -1- [3- (tert-butyldimethylsilyloxy) -2-methylpropyl]-1H-quinolin-2-one (0.31g, 0.93mmol) is dissolved in THF (5mL) and stirred under argon at room temperature overnight. The mixture was concentrated under reduced pressure and dissolved in EtOAc (30 mL). The solution was washed with water (15mL) and Na₂SO₄Drying, and concentrating under reduced pressure. The residue was filtered through silica to give a crude product (0.19g) of the title compound, which was used without further purification.

(S) -1- (3-iodo-2-methylpropyl) -1H-quinolin-2-one (107LH64)

[0202]Imidazole (0.14g, 2.1mmol), (S) -1- (3-hydroxy-2-methyl-propyl) -1H-quinolin-2-one crude product (0.19g, 0.87mmol) and PPh₃(0.50g, 1.9mmol) was dissolved in CH₂Cl₂(5mL) and dissolvingCooling to 0 deg.C, and adding I₂(0.61g, 2.4mmol), the reaction was allowed to proceed overnight at room temperature. By CH reaction₂Cl₂(25mL) diluted with saturated Na₂SO₄Aqueous solution (2X 25mL) was washed with Na₂SO₄The organic phase was dried, filtered and concentrated under reduced pressure to give the crude product, which was used without further purification. HPLC-MS (ammonium acetate) [ M + H ]]⁺＝328.1。

General method 10(GP10)

[0203] To a 4mL vial was added the corresponding heterocyclic compound (1 equivalent) and the corresponding piperidine (1.2 or 2 equivalents) dissolved in dry MeCN (1/2mL) and shaken. The reaction mixture was quenched with water (1mL) and the product was extracted with EtOAc (2X 1 mL). The organic layers were combined and purified with cation exchange CC and flash CC.

(R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl]-4H-benzo [1, 4]]Thiazin-3-ones (108LM43-40)

[0204]Compound (S) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP10]Thiazin-3-one (108LM37-34) (0.105g, 0.304mmol) and 4-butyl-piperidine (0.052g, 0.369mmol) were reacted and shaken at 60 ℃ for 3 days. Exchange of CC and fast CC (SiO) with cations₂(ii) a MeOH/DCM 1: 20) to afford the title compound (108LM43-40) (0.082g, 75%).¹H NMR(CHCl₃)δ7.34(d，J＝9.1Hz，1H)，7.25-7.17(m，2H)，7.02-6.95(m，1H)，4.15-3.99(m，2H)，3.35(s，CH₂)，2.83(bd，J＝10.4Hz，1H)，2.68(bd，J＝10.4Hz，1H)，2.20-2.05(m，2H)，2.00-1.85(m，2H)，1.82-1.73(m，1H)，1.67-1.55 (m，2H)，1.30-1.14(m，9H)，0.88(t，J＝7.2，CH₃)，0.82(d，J＝6.5Hz，CH₃)；¹³C NMR(CHCl₃) δ 166.0, 139.2, 128.8, 127.1, 124.8, 123.5, 118.9, 63.8, 55.5, 54.4, 47.7, 36.6, 36.1, 32.9, 32.8, 32.1, 29.4, 29.3, 23.2, 16.7, 14.4; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

(R) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Thiazin-3-ones (108LM49-46)

[0205]Compound (S) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP10]Thiazin-3-one (108LM37-34) (0.433g, 1.25mmol) and 4-propoxypiperidine (79KS66) (0.225g, 1.55mmol) were reacted and shaken at 60 ℃ for 4 days. Exchange of CC and fast CC (SiO) with cations₂(ii) a MeOH/DCM 1: 20) to afford the title compound (108LM49-46) (0.220g, 49%).¹H NMR(CDCl₃)δ7.37(d，J＝8.1Hz，1H)，7.25-7.20(m，2H)，7.05-6.97(m，1H)，4.18-4.00(m，2H)，3.42-3.35(m，4H)，3.30-3.20(m，1H)，2.80-2.70(m，1H)，2.65-2.55(m，1H)，2.20-2.05(m，3H)，2.00-1.82(m，4H)，1.62-1.50(m，4H)，0.92(t，J＝7.4，CH₃)，0.82(d，J＝6.8Hz，CH₃)，¹³C NMR(CHCl₃) δ 166.1, 139.2, 128.8, 127.1, 124.9, 123.5, 118.8, 75.5, 69.8, 63.3, 52.7, 51.9, 47.6, 32.1, 32.0, 29.6, 23.5, 16.6, 10.9; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.3。

(R) -4- [3- (4-butylidene-piperidinyl-1) -2-methyl-propyl]-4H-benzo [1, 4]]Thiazin-3-ones (108LM50-47)

[0206]Compound (S) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP10]Thiazin-3-one (108LM37-34) (0.432g, 1.25mmol) and 4-butylidenepiperidine (111MF05) (0208g, 1.49mmol) were reacted and shaken at 60 ℃ for 4 days. Exchange of CC and fast CC (SiO) with cations₂(ii) a MeOH/DCM 1: 20) to afford the title compound (108LM50-47) (0.267g, 60%).¹H NMR(CHCl₃)δ7.35(d，J＝7.5Hz，1H)，7.26-7.18(m，2H)，6.98(t，J＝7.5Hz，1H)，5.10(t，J＝7.4Hz，CH)，4.17-4.03(m，2H)，3.36(s，CH₂)，2.43-2.33(m，2H)，2.30-2.08(m，8H)，2.00-1.90(m，3H)，1.28-1.38(m，2H)，0.90-0.80(m，6H)；¹³C NMR(CDCl₃)δ1660, 139.2, 136.4, 128.8, 127.1, 124.8, 123.5, 122.7, 118.8, 63.4, 56.4, 55.6, 47.7, 36.4, 32.1, 29.5, 29.4, 28.6, 23.4, 16.7, 14.0; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝359.3。

(R) -4- [3- (3-butyl-8-aza-bicyclo [3.2.1]]Octyl-8) -2-methyl-propyl]-4H-benzo [1, 4]]Thia-methyl Oxazin-3-ones (108LM51-48)

[0207]Compound (S) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP10]Thiazin-3-one (108LM37-34) (0.093g, 0.269mmol) and 3-butyl-8-aza-bicyclo [3.2.1]Octane (104KS29) (0.054g, 0.323mmol) reacted and shaken at 40 ℃ for 5 days. Exchange of CC and fast CC (SiO) with cations₂(ii) a MeOH/DCM 1: 10) to afford the title compound (108LM51-48) (0.042g, 40%).¹H NMR(CHCl₃)δ7.38(d，J＝7.8Hz，1H)，7.33(d，J＝8.1Hz，1H)，7.22(t，J＝7.9Hz，1H)，7.00(t，J＝8.0Hz，1H)，4.18-4.10(m，2H)，3.38(s，CH₂)，3.15-3.00(m，2H)，2.30-2.22(m，1H)，2.20-2.10(m，1H)，1.90-1.75(m，3H)，1.60-1.40(m，5H)，1.40-1.15(m，8H)，0.90-0.82(m，6H)；¹³C NMR(CHCl₃) δ 166.1, 139.2, 128.7, 127.2, 124.7, 123.5, 119.1, 61.4, 60.1, 57.3, 47.6, 38.3, 36.9, 32.1, 31.2, 29.9, 29.4, 28.2, 27.2, 26.5, 23.1, 16.7, 14.3; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝387.3。

(R) -4- [ 2-methyl-3- (3-pentyl-8-aza-bicyclo [3.2.1]]Octyl-8-) propyl]-4H-benzo [1, 4]]Thia-methyl Oxazin-3-ones (108LM52-49)

[0208]Compound (S) -4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP10]Thiazin-3-one (108LM37-34) (0.080g, 0.231mmol) and 3-pentyl-8-azabicyclo [3.2.1]Octane (104KS32-2) (0.050g, 0.276mmol) reacted and shaken at 40 ℃ for 5 days. Exchange of CC and fast CC (SiO) with cations₂；MeOH/DCM 1∶50+1％Et₃N) purification to give the title compound(108LM52-49)(0.045g，49％)。¹H NMR(CHCl₃)δ7.36(d，J＝7.6Hz，1H)，7.32(d，J＝7.7Hz，1H)，7.22(t，J＝7.6Hz，1H)，7.00(t，J＝7.6Hz，1H)，4.16(d，J＝7.3Hz，CH₂)，3.34(s，CH₂)，3.10-2.95(m，2H)，2.25-2.17(m，1H)，2.15-2.03(m，3H)，1.94-1.75(m，3H)，1.70-1.60(m，1H)，1.60-1.50(m，2H)，1.40-1.15(m，10H)，0.90-0.80(m，6H)；¹³C NMR(CDCl₃) δ 166.1, 139.2, 128.7, 127.1, 124.7, 123.4, 119.1, 60.5, 59.0, 57.4, 47.5, 38.4, 36.4, 32.2, 32.1, 31.4, 29.9, 28.5, 28.4, 27.9, 27.2, 22.9, 16.7, 14.3; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝401.3。

General method 11(GP11)

[0209]Into a 100mL flask was added 4- (3-chloropropyl) -4H-benzo [1, 4] in 25mL dry MeCN]Oxazin-3-one (1.0 equiv.), K₂CO₃(2.0 equiv.), NaI (2.0 equiv.), and 4-butylpiperidine (1.05 equiv.) in the presence of N₂Stir at room temperature for 168 h. The reaction mixture was evaporated to dryness, using 100mL of H₂Diluted O and extracted with EtOAc (3X 120 mL). The organic layers were combined and MgSO₄Dried, evaporated to dryness, and treated with CC (heptane: EtOAc or CH)₂Cl₂MeOH).

4- [3- (4-Butylpiperidinyl-1-) propyl]-6, 8-dichloro-7-methyl-4H-benzo [1, 4]]Oxazin-3-ones (81MF2225F)

[0210]Mixing 6, 8-dichloro-4- (3-chloropropyl) -7-methyl-4H-benzo [1, 4] according to GP11]Oxazin-3-one (81MF2225b) (2.44g, 7.92mmol), K₂CO₃(2.19g, 15.84mmol), NaI (2.37g, 15.84mmol) and 4-butylpiperidine (1.172g, 8.3 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF2225F) (1.55g, 47%).¹HNMR(CHCl₃)δ7.11(s，1H)，4.65(s，2H)，3.93(t，2H)，2.86，(d，2H)，2.41(s，3H)，2.41(s，3H)，2.33(t，2H)，1.92-1.77(m，4H)，1.65(d，2H)，1.31-1.19(m，9H)，0.88(t，3H)；¹³C NMR(CHCl₃)δ163.5，140.5，129.9，128.1，123.7，114.0，67.9，55.8，54.4，40.1，36.4，36.0，32.6，29.2，24.8，23.1，17.2，14.2。

[0211]To the pure compound (0.235g, 0.50mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.047g, 0.52mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.24g, 94%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝413.2。

4- [3- (4-butyl-piperidinyl-1-) propyl]-6, 8-dimethyl-4H-benzo [1, 4]]Oxazin-3-ones (81MF2237F)

[0212]Mixing 4- (3-chloropropyl) -6, 8-dimethyl-4H-benzo [1, 4] according to GP11]Oxazin-3-one (81MF2237b) (0.96g, 3.78mmol), K₂CO₃(1.05g, 7.57mmol), NaI (1.14g, 7.57mmol) and 4-butylpiperidine (0.56g, 3.97 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF2237F) (0.98g, 72%).¹H NMR(CDCl₃)δ6.71(s，1H)，6.65(s，1H)，4.52(s，2H)，3.93(t，J＝7.2，2H)，2.87(d，J＝11.2，2H)，2.36(t，J＝7.2Hz，2H)，2.27(s，3H)，2.18(s，3H)，1.81-1.89(m，4H)，1.65(d，J＝9.6Hz，2H)，1.28-1.17(m，9H)，0.87(t，J＝6-8Hz，3H)；¹³C NMR(CDCl₃)δ164.6，141.4，131.6，128.3，126.3，126.1，113.4，67.8，56.1，54.3，39.8，36.4，35.9，32.7，29.1，25.0，23.0，21.1，15.5，14.2。

[0213]To the pure compound (0.193g, 0.54mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.051g, 0.57mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.22g, 91%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝359.3。

6-tert-butyl-4- [3- (4-butylz-piperidinyl-1-) propyl-4H-benzo [1, 4-]Oxazin-3-ones (81MF2248F)

[0214]Mixing 6-tert-butyl-4- (3-chloropropyl) -4H-benzo [1, 4] according to GP11]Oxazin-3-one (81MF2248b) (1.39g, 4.93mmol), K₂CO₃(1.36g, 9.85mmol), NaI (1.48g, 9.85mmol) and 4-butylpiperidine (0.73g, 5.17 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF2248F) (1.66g, 87%).¹H NMR(CHCl₃)δ7.01-6.98(m，2H)，6.91-6.88(m，1H)，4.55(s，2H)，3.99(t，J＝7.2Hz，2H)，2.89(d，J＝6.4Hz，2H)，2.42(t，J＝6.8Hz，2H)，1.92-1.82(m，4H)，1.65(d，J＝9.6Hz 2H)，1.31(s，9H)，1.29-1.17(m，9H)，0.88(t，J＝6.8Hz，3H)；¹³CNMR(CDCl₃)δ164.6，146.1，143.3，128.1，120.6，116.6，112.2，67.9，56.5，54.4，39.8，36.4，35.9，34.7，32.6，31.6，29.2，24.8，23.1，14.2。

[0215]To the pure compound (0.178g, 0.46mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.044g, 0.49mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.19g, 87%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝387.4。

4- [3- (4-Butylpiperidinyl-1-) propyl]-5-methyl-4H-benzo [1, 4]]Oxazin-3-one (81MF941x)

[0216]Mixing 4- (3-chloropropyl) -5-methyl-4H-benzo [1, 4] according to GP11]Oxazin-3-one (81MF941b) (1.08g, 4.48mmol), K₂CO₃(1.24g, 8.95mmol), NaI (1.34g, 8.95mmol) and 4-butylpiperidine (0.66g, 4.70 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF941x) (0.814g, 53%).¹H NMR(CDCl₃)δ6.97-6.83(m，3H)，4.41(s，2H)，4.07(t，J＝7.2Hz，2H)，2.67(d，J＝10.8Hz，2H)，2.39(s，3H)，2.18(t，J＝7.2Hz，2H)，1.76(t，J＝10.8Hz，2H)，1.69-1.62(m，2H)，1.58(d，J＝10.0Hz，2H)，1.30-1.06(m，9H)，0.87(t，J＝6.8Hz，3H)；¹³CNMR(CDCl₃)δ168.3，150.0，129.2，128.9，126.8，124.8，114.8，69.5，55.7，54.2，42.6，36.4，35.9，32.6，29.2，25.3，23.0，20.9，14.2。

[0217]To the pure compound (0.177g, 0.52mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.047g, 0.49mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.21g, 92%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.1。

4- [3- (4-Butylpiperidinyl-1-) propyl-7-methyl-4H-benzo [1, 4-]Oxazine-3-one (81MF2246F)

[0218]Mixing 4- (3-chloropropyl) -7-methyl-4H-benzo [1, 4] according to GP11]Oxazin-3-one (81MF2246b) (1.64g, 6.84mmol), K₂CO₃(1.89g, 13.68mmol), NaI (2.05g, 13.68mmol) and 4-butylpiperidine (1.02g, 7.18 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF2246F) (1.85g, 79%).¹H NMR(CDCl₃)δ6.97(d，J＝8.0Hz，1H)，6.82-6.78(m，2H)，4.54(s，2H)，3.94(t，J＝7.2Hz，2H)，2.86(d，J＝10.8Hz，2H)，2.37(t，J＝7.0Hz，2H)，2.28(s，3H)，1.92-1.79(m，4H)，1.66(d，J＝9.2Hz，2H)，1.31-1.18(m，9H)，0.88(t，J＝7.2Hz，3H)；¹³C NMR(CDCl₃)δ164.2，145.3，133.9，126.3，123.3，117.7，115.0，67.8，56.0，54.3，39.7，36.5，36.0，32.7，29.2，24.9，23.1，20.8，14.2。

[0219]To the pure compound (0.156g, 0.45mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.042g, 0.47mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.192g, 97%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.1。

4- [3- (4-Butylpiperidinyl-1-) propyl]-6-chloro-7-nitro-4H-benzo [1, 4]]Oxazin-3-ones (81MF2253x)

[0220]Mixing 6-chloro-4- (3-chloro) according to GP11Propyl) -7-nitro-4H-benzo [1, 4]Oxazin-3-one (81MF2253b) (1.23g, 4.05mmol), K₂CO₃(1.12g, 8.09mmol), NaI (1.21g, 8.09mmol), and 4-butylpiperidine (0.60g, 4.24 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF2253x) (0.698g, 42%).¹H NMR(CDCl₃)δ7.61(s，1H)，7.36(s，1H)，4.66，(s，2H)，3.99(t，J＝6.8Hz，2)，2.85(d，J＝11.2Hz，2H)，2.34(t，J＝6.4Hz，2H)，1.94-1.80(m，4H)，1.67(d，J＝10.0Hz，2H)，1.31-1.20(m，9H)，0.88(t，J＝6.4Hz，3H)；¹³C NMR(CHCl₃)δ163.4，143.4，141.9，133.9，122.1，117.7，114.8，67.5，55.5，54.4，40.5，36.4，36.0，32，6，29.2，24.6，23.0，14.2。

[0221]To the pure compound (0.128g, 0.31mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.029g, 0.33mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.125g, 80%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝410.1。

4- [3- (4-Butylpiperidinyl-1-) propyl]-7-chloro-4H-benzo [1, 4]]Oxazin-3-one (81MF2271x)

[0222]Mixing 7-chloro-4- (3-chloropropyl) -4H-benzo [1, 4] according to GP11]Oxazin-3-one (81MF2271b) (1.953g, 7.49mmol), K₂CO₃(2.07g, 14.9mmol), NaI (2.24g, 14.9mmol) and 4-butylpiperidine (1.11g, 7.86 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF2271x) (2.46g, 90%).¹H NMR(CHCl₃)δ7.08-6.96(m，3H)，4.57(s，2H)，3.95(t，J＝7.2Hz，2H)，2.85(d，J＝10.8Hz，2H)，2.35(t，J＝7.2Hz，2H)，1.93-1.78(m，4H)，1.66(d，J＝9.2Hz，2H)，1.31-1.18(m，9H)，0.88(t，J＝6.4Hz，3H)；¹³C NMR(CHCl₃)δ163.7，146.0，128.7，127.7，122.7，117.6，116.1，67.7，55.9，54.3，39.9，36.5，36.0，32.7，29.2，24.8，23.1，14.2。

[0223]To the pure compound (0.171g, 0.47mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.043g, 0.49mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.206g, 97%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝365.1。

General method 12(GP12)

[0224]To a 4mL vial was added 4- (3-chloropropyl) -4H-benzo [1, 4] in 3mL dry MeCN]Oxazin-3-one (1.0 equiv.), K₂CO₃(2.0 equiv.), NaI (2.0 equiv.), and amine (1.05 equiv.), and shaken at 60 ℃ for 100 h. The reaction mixture was evaporated to dryness, using 4mL of H₂Diluting with O and CH₂Cl₂(3X 10mL) and filtered through a PTFF Whatman filter. The combined organic layers were evaporated to dryness and washed with CC (heptane/EtOAc or CH)₂Cl₂MeOH) or preparative TLC (heptane/EtOAc or CH)₂Cl₂MeOH).

4- [3- (4-Butylpiperidinyl-1-) propyl]-6-fluoro-4H-benzo [1, 4]]Oxazin-3-one (8173MF55F)

[0225]Mixing 4- (3-chloropropyl) -6-fluoro-4H-benzo [1, 4] according to GP12]Oxazin-3-one (8173MF55b) (0.102g, 0.42mmol), K₂CO₃(0.12g, 0.84mmol), NaI (0.13g, 0.84mmol) and 4-butylpiperidine (0.06g, 0.44 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (8183MF55F) (0.12g, 80%).¹H NMR(CHCl₃)δ6.96(dd，J＝10.4Hz，J＝2.8Hz，1H)，6.87(dd，J＝9.6Hz，J＝5.2Hz，1H)，6.66-6.12(m，1H)，4.51(s，2H)，3.91(t，J＝7.2Hz，2H)，2.84(d，J＝11.2Hz，2H)，2.32(t，J＝7.2Hz，2H)，1.91-1.77(m，4H)，1.64(d，J＝9.6Hz，2H)，1.29-1.16(m，9H)，0.86(t，J＝6.8Hz，3H)；¹³C NMR(CHCl₃)δ164.2，158.5(d，J＝239.5Hz)，141.4(d，J＝2.7Hz)，130.0(d，J＝10.4Hz)，117.5(J＝9.3Hz)，109.5(d，J＝23.5Hz)，103.2(d，J＝28.8Hz)，67.7，55.7，54.3，40.0，36.4，35.9，32.6，29.1，24.7，23.0，14.2。

[0226]To the pure compound (0.12g, 0.34mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.032g, 0.37mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.128g, 87%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.2。

4- [3- (4-Butylpiperidinyl-1-) propyl]-7, 8-difluoro-4H-benzo [1, 4]]Oxazin-3-ones (81MF2082x)

[0227]Mixing 4- (3-chloropropyl) -7, 8-difluoro-4H-benzo [1, 4] according to GP12]Oxazin-3-one (81MF2082b) (0.16g, 0.60mmol), K₂CO₃(0.17g, 11.9mmol), NaI (0.18g, 11.9mmol) and 4-butylpiperidine (0.09g, 0.63 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF2082x) (0.14g, 65%).¹H NMR(CHCl₃)δ6.88-6.76(m，2H)4.66(s，2H)，3.96(t，J＝7.2Hz，2H)，2.84(d，J＝11.2，2H)，2.34(t，J＝6.8Hz，2H)，1.91-1.78(m，4H)，1.67(d J＝9.6Hz，2H)，1.30-1.15(m，9H)；¹³C NMR(CDCl₃)δ163.1，147.4(q，J＝245.0Hz，J＝10.6Hz)，140.1(q，J＝248.7Hz，J＝15.7Hz)，135.4(d，J＝12.0Hz)，126.5，109.5(d，J＝18.4Hz)，109.0(q，J＝7.6Hz，J＝3.8Hz)，67.8，55.8，52.3，40.1，36.4，35.9，32.7，29.1，24.8，23.0，14.2。

[0228]To the pure compound (0.14g, 0.39mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.042g, 0.46mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.16g, 89%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝367.3。

4- [3- (4-Butylpiperidinyl-1-) propyl]-4H-pyrido [4, 3-b][1，4]Thiazine-3-one (81MF939)

[0229]Mixing 4- (3-chloropropyl) -4H-pyrido [4, 3-b ] according to GP12][1，4]Thiazin-3-one (81MF939b) (0.14g, 0.57mmol), K₂CO₃(0.16g, 11.4mmol), NaI (0.18g, 11.4mmol) and 4-butylpiperidine (0.09g, 0.60 mmol). CC (SiO)₂(ii) a heptane/EtOAc 10: 1-4) to give the title compound (81MF939) (0.064g, 32%).¹H NMR(CDCl₃)δ8.48(s，1H)，8.17(d，J＝5.2Hz，1H)，7.25(d，J＝4.8Hz，1H)，4.06-4.12(m，2H)，3.41(s，2H)，2.82(d，7＝11.2，2H)，2.33(t，J＝6.8Hz，2H)，1.83-1.89(m，4H)，1.64(d，J＝9.2Hz，2H)，1.16-1.29(m，9H)，0.87(t，J＝6.8Hz，3H)；¹³C NMR(CDCl₃)δ163.91，143.84，138.92，136.20，134.04，122.31，55.80，54.32，43.29，36.43，35.99，32.68，30.78，29.19，25.20，23.05，14.24。

[0230]To the pure compound (0.064g, 0.18mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.020g, 0.22mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.16g, 89%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝348.2。

4- [3- (4-Propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Thiazine-3-one (81MF07KS)

[0231]Mixing 4- (3-chloropropyl) -4H-benzo [1, 4] according to GP12]Thiazin-3-one (81MF07) (0.18g, 0.74mmol), K₂CO₃(0.20g, 14.8mmol), NAI (0.22g, 14.8mmol) and 4-propoxypiperidine (0.12g, 0.81 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (81MF07KS) (0.205g, 79%).¹H NMR(CHCl₃)δ7.33(d，J＝7.6Hz，2H)，7.21(d，J＝3.2Hz，2H)，7.00-6.96(m，1H)，4.03(t，J＝7.2Hz，2H)，3.38-3.34(m，4H)，3.26-3.21(m，1H)，2.69(t，J＝5.6Hz，2H)，2.33(t，J＝7.2Hz，2H)，2.04(t，J＝9.8Hz，2H)，1.86-1.76(m，4H)，1.58-1.51(m，4H)，0.90(t，J＝7.2Hz，3H)；¹³C NMR(CHCl₃)δ165.2，139.7，128.5，127.2，124.1，123.4，118.1，75.2，69.7，55.4，51.5，43.2，31.8，31.7，25.3，23.4，10.8。

[0232]To the pure compound (0.205g, 0.58mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.058g, 0.64mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.192g, 74%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.2。

4- [3- (4-Propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Oxazin-3-one (81MF08KS)

[0233]Mixing 4- (3-chloropropyl) -4H-benzo [1, 4] according to GP12]Oxazin-3-one (81MF08) (0.13g, 0.58mmol), K₂CO₃(0.16g, 1.15mmol), NaI (0.17g, 1.15mmol), and 4-propoxypiperidine (0.089g, 0.60 mmol). CC (SiO)₂(ii) a Heptane/EtOAc 4: 1-4) to yield the title compound (81(81MF08KS)) (0.147g, 76%).¹HNMR(CDCl₃)δ7.11-7.08(m，1H)，7.01-6.94(m，3H)，4.55(s，2H)，3.96(t，J＝7.2Hz，2H)，3.37(t，J＝6.8Hz，2H)，3.28-3.21(m，1H)，2.74-2.69(m，2H)，2.36(t，J＝7.2Hz，2H)，2.10-2.03(m，2H)，1.90-1.77(m，4H)，1.61-1.51(m，4H)，0.90(t，J＝7.2Hz，3H)；¹³C NMR(CDCl₃)δ164.3，145.4，128.7，123.8，122.8，117.1，115.1，75.1，69.6，67.7，55.5，51.5，39.6，31.6，24.9，23.4，10.7。

[0234]To the pure compound (0.147g, 0.44mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.048g, 0.53mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.160g, 86%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝333.3。

4- [3- (4-Butylpiperidinyl-1-) propyl]-7-fluoro-4H-benzo [1, 4]]Oxazine-3-one (81MF763)

[0235]Mixing 4- (3-chloropropyl) -7-fluoro-4H-benzo [1, 4] according to GP12]Oxazin-3-one (81MF763b) (0.40g, 1.6mmol), K₂CO₃(0.44g, 3.2mmol), NaI (0.48g, 3.2mmol) and 4-butylpiperidine (0.24g, 1.70 mmol). CC (SiO)₂(ii) a Heptane/EtOAc 4: 1-4) purificationTo give the title compound (81MF763) (0.26g, 46%).¹H NMR(CDCl₃)δ7.09-7.04(m，1H)，6.74-6.69(m，2H)，4.58(s，2H)，3.95(t，J＝7.2Hz，2H)，2.84(d，J＝11.2Hz，2H)，3.45(t，J＝6.8Hz，2H)，1.91-1.78(m，4H)，1.66(d，J＝9.2Hz，2H)，1.29-1.16(m，9H)，0.88(t，7.2Hz，3H)；¹³C NMR(CDCl₃)δ163.6，158.9(d，J＝243.7Hz)，146.3(d，J＝11.5Hz)，125.2(d，J＝3.0Hz)，115.9(d，J＝9.7Hz)，109.1(d，J＝22.8Hz)，105.1(d，J＝26.1Hz)，67.8，55.9，54.3，39.9，36.5，36.0，32.7，29.2，24.8，23.1，14.2。

[0236]To the pure compound (0.26g, 0.74mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.073g, 0.818mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.26g, 78%), HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.3。

4- [3- (4-Butylidenepiperidyl-1-) propyl]-4H-benzo [1, 4]]Thiazine-3-one (81MF26)

[0237]Mixing 4- (3-chloropropyl) -4H-benzo [1, 4] according to GP12]Thiazin-3-one (81MF07) (0.073g, 0.30mmol), K₂CO₃(0.12g, 0.90mmol), NaI (0.090g, 0.6mmol) and 4-butylidenepiperidine (0.050g, 0.28 mmol). Preparative TLC (SiO)₂；CH₂Cl₂MeOH 10: 1) to yield the title compound (81MF26) (0.034g, 33%).¹HNMR(CDCl₃)δ7.34-7.31(m，1H)，7.23-7.20(m，1H)，7.00-6.95(m，1H)，5.10(t，J＝7.2Hz，1H)，4.04(t，J＝7.2Hz，2H)，3.34(s，2H)，2.37-2.32(m，6H)，2.23-2.14(m，2H)，1.96-1.90(m，2H)，1.86-1.78(m，2H)，1.37-1.27(m，2H)，0.86(t，J＝7.2Hz，3H)；¹³C NMR(CHCl₃)δ165.1，139.6，136.0，128.5，127.2，124.1，123.4，122.7，118.1，55.6，55.4，54.8，43.2，36.1，31.7，29.2，28.3，25.2，23.2，13.8。

[0238]To the pure compound (0.034g, 0.10mmol) dissolved in diethyl ether (4mL) was addedOxalic acid (0.010g, 0.10mmol) in diethyl ether (2mL) was added. The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.030g, 69%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.2。

4- [3- (4-Butylidenepiperidyl-1-) propyl]-4H-benzo [1, 4]]Oxazin-3-one (81MF25)

[0239]Mixing 4- (3-chloropropyl) -4H-benzo [1, 4] according to GP12]Oxazin-3-one (81MF08) (0.068g, 0.30mmol), K₂CO₃(0.12g, 0.90mmol), NaI (0.090g, 0.60mmol) and 4-butylidenepiperidine (0.050g, 0.28 mmol). Preparative TLC (SiO)₂；CH₂Cl₂MeOH 10: 1) to yield the title compound (81MF25) (0.070g, 71%).¹HNMR(CDCl₃)δ7.12(d，J＝6.8Hz，1H)，7.03-6.95(m，3H)，5.12(J＝7.4Hz，1H)，4.56(s，1H)，3.99(t，J＝7.6Hz，2H)，2.41-2.36(m，6H)，2.26-2.17(m，2H)，1.98-1.81(m，4H)，1.38-1.28(m，2H)，0.87(t，J＝7.2Hz，3H)；¹³C NMR(CDCl₃)δ164.3，145.5，136.0，128.7，123.8，122.8，122.8，117.1，115.2，67.7，55.7，55.6，54.9，39.7，36.1，29.2，28.4，24.8，23.2，13.8。

[0240]To the pure compound (0.070g, 0.21mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.020g, 0.22mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.087g, 97%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝329.3。

4- [3- (3-Butylene-8-aza-bicyclo [3.2.1]]Octyl-8) -propyl-4H-benzo [1, 4]]Oxazin-3-ones (81MF24)

[0241]Mixing 4- (3-chloropropyl) -4H-benzo [1, 4] according to GP12]Oxazin-3-one (81MF08) (0.030g, 0.13mmol), K₂CO₃(0.037g, 0.26mmol), NaI (0.040g, 0.27mmol) and 3-butylidene-8-azabicyclo [3.2.1]Octane (0.029g, 0.17 mmol). Preparative TLC (SiO)₂；CH₂Cl₂/MeOH 10∶1) Purification yielded the title compound (81MF24) (0.019g, 41%).¹H NMR(CDCl₃)δ7.22-7.19(m，1H)，7.05-6.96(m，3H)，5.24(t，J＝7.2Hz，1H)，5.08(s，2H)，4.06(t，J＝6.4Hz，2H)，2.61(t，J＝6.8Hz，2H)，2.30(s，2H)，2.03-1.83(m，7H)，1.58-1.43(m，2H)，1.39-1.22(m，3H)，0.89(m，3H)；¹³C NMR(CDCl₃)δ164.5，145.5，131.4，128.7，127.9，124.0，123.0，117.1，115.5，67.8，60.4，60.2，48.8，41.0，39.6，33.7，29.5，26.8，26.4，25.8，23.2，13.9。

[0242]To the pure compound (0.019g, 0.05mmol) dissolved in diethyl ether (2mL) was added oxalic acid (0.005g, 0.006mmol) dissolved in diethyl ether (1 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.012g, 50%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝355.3。

4- [3- (4-Butylpiperidinyl-1-) propyl]-6-methoxy-4H-benzo [1, 4]]Oxazine-3-one (81MF2249)

[0243]Mixing 4- (3-chloropropyl) -6-methoxy-4H-benzo [1, 4] according to GP12]Oxazin-3-one (81MF2249b) (0.127g, 0.50mmol), K₂CO₃(0.137g, 1.0mmol), NaI (0.149g, 1.0mmol), and 4-butylpiperidine (0.075g, 0.52 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (81MF2249) (0.14g, 85%).¹H NMR(CHCl₃)δ6.88(d，J＝8.8Hz，1H)，6.67(d，J＝2.4Hz，1H)，6.49(dd，J＝8.8Hz，J＝2.4Hz，1H)，4.51(s，2H)，3.93(t，7.2Hz，2H)，3.77(s，3H)，2.86(d，J＝10.8Hz，2H)，2.36(t，J＝7.2Hz，2H)，1.90-1.80(m，4H)，1.64(d J＝8.8Hz，2H)，1.29-1.17(m，9H)，0.88(t，J＝6.2Hz，3H)；¹³C NMR(CHCl₃)δ168.8，155.6，139.6，129.7，117.2，107.2，102.9，68.0，56.1，56.0，54.4，39.9，36.5，35.9，32.6，29.2，24.9，23.0，14.2。

[0244]To the pure compound (0.14g, 0.37mmol) in diethyl ether (4mL) was added oxalic acid (2mL) in diethyl ether (2mL)0.037g, 0.41 mmol). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.15g, 90%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

General method 13(GP13)

[0245]To a 7mL vial was added 4- (3-chloropropyl) -4H-benzo [1, 4] in 5mL dry MeCN]Oxazin-3-one (1.0 equiv.), K₂CO₃(2.0 equiv.), NaI (2.0 equiv.), and 4-butylpiperidine (1.05 equiv.), and shaken for 48h at 60 ℃. The reaction mixture was evaporated to dryness and taken up in 10mLH₂Diluting with O and CH₂Cl₂(3X 13mL) and filtered through a PTFF Whatman filter. The combined organic layers were evaporated to dryness and washed with CC (heptane/EtOAc or CH)₂Cl₂MeOH) or preparative TLC (heptane/EtOAc or CH)₂Cl₂MeOH).

4- [3- (4-Butylpiperidinyl-1-) propyl]-6, 8-dichloro-7-ethyl-4H-benzo [1, 4]]Oxazin-3-ones (95MF60)

[0246]Mixing 6, 8-dichloro-4- (3-chloro-propyl) -7-ethyl-4H-benzo [1, 4] according to GP13]Oxazin-3-one ((95MF52(2226)) (0.30g, 0.93mmol), K₂CO₃(0.26g, 1.86mmol), NaI (0.28g, 1.86mmol) and 4-butylpiperidine (0.14g, 0.98 mmol). CC (SiO)₂；CH₂Cl₂MeOH 10: 0.2-4) to give the title compound (95MF60) (0.24g, 59%).¹HNMR(CDCl₃)δ7.10(s，1H)，4.65(s，2H)，3.93(t，J＝6.8Hz，2H)，2.95-2.81(m，4H)，2.33(t，J＝6.8Hz，2H)，1.90-1.78(m，4H)，1.66(d，J＝10.0Hz，2H)1.30-1.13(m，12H)，0.88(s，3H)；¹³C NMR(CDCl₃) δ 163.5, 140.6, 135.3, 128.2, 127.7, 123.2, 114.3, 67.9, 55.8, 54.4, 40.1, 36.4, 36.0, 32.7, 29.2, 24.8, 24.6, 23.1, 14.2, 12.7; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝427.2。

4- [3- (4-Butylpiperidinyl-1-) propyl]-8-fluoro-4H-benzo [1, 4]]Oxazin-3-one (95MF59)

[0247]Mixing 4- (3-chloropropyl) -8-fluoro-4H-benzo [1, 4] according to GP13]Oxazin-3-one (95MF51(2085)) (0.25g, 1.04mmol), K₂CO₃(0.29g, 2.1mmol), NaI (0.31g, 2.1mmol) and 4-butylpiperidine (0.15g, 1.1 mmol). CC (SiO)₂；CH₂Cl₂MeOH 10: 0.2-4) to give the title compound (95MF59) (0.29g, 80%).¹H NMR(CHCl₃)δ6.92-6.84(m，2H)，6.79-6.74(m，1H)，4.59(s，2H)，3.93(t，J＝7.4Hz，2H)，2.81(d，J＝10.8Hz，2H)，2.31(t，J＝7.0Hz，2H)，1.87-1.75(m，4H)，1.62(d，J＝9.2Hz，2H)，1.27-1.12(m，9H)，0.84(t，J＝6.8Hz，3H)；¹³C NMR(CDCl₃)δ163.7，151.8(d，J＝246.0Hz)，133.8(d，J＝14.6Hz)，130.7(d，J＝3.5Hz)，122.1(d，J＝8.0Hz)，111.2(d，J＝18.4Hz)，110.4(d，J＝3.4Hz)，67.6，55.8，54.2，40.0，36.4，35.8，32.6，29.0，24.8，22.9，14.1。

[0248]To the pure compound (0.29g, 0.83mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.078g, 0.86mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.31g, 85%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.3。

6-bromo-4- [3- (4-butylpiperidinyl-1-) propyl]-8-fluoro-4H-benzo [1, 4]]Oxazin-3-one (95MF58)

[0249]Mixing 6-bromo-4- (3-chloropropyl) -8-fluoro-4H-benzo [1, 4] according to GP13]Oxazin-3-one (95MF50(2084)) (0.086g, 0.27mmol), K₂CO₃(0.074g, 0.53mmol), NaI (0.080g, 0.53mmol) and 4-butylpiperidine (0.039g, 0.28 mmol). CC (SiO)₂；CH₂Cl₂MeOH 10: 0.2-4) to give the title compound (95MF58) (0.040g, 35%).¹H NMR(CDCl₃)δ6.92-6.84(m，2H)，6.79-6.74(m，1H)，4.59(s，2H)，3.93(t，J＝7.4Hz，2H)，2.81(d，J＝10.8Hz，2H)，2.31(t，J＝7.0Hz，2H)，1.87-1.75(m，4H)，1.62(d，J＝9.2Hz，2H)，1.27-1.12(m，9H)，0.84(t，J＝6.8Hz，3H)；¹³C NMR(CHCl₃)δ163.7，151.8(d，J＝246.0Hz)，133.8(d，J＝14.6Hz)，130.7(d，J＝3.5Hz)，122.1(d，J＝8.0Hz)，111.2(d，J＝18.4Hz)，110.4(d，J＝3.4Hz)，67.6，55.8，54.2，40.0，36.4，35.8，32.6，29.0，24.8，22.9，14.1。

[0250]To the pure compound (0.040g, 0.09mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.009g, 0.098mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.040g, 82%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝427.2。

4- [3- (4-Butylpiperidinyl-1-) propyl]-8-isopropyl-4H-benzo [1, 4]]Oxazin-3-one (111MF02)

[0251]Mixing 4- (3-chloropropyl) -8-isopropyl-4H-benzo [1, 4] according to GP13]Oxazin-3-one (95MF98) (0.112g, 0.42mmol), K₂CO₃(0.115g, 0.84mmol), NaI (0.125g, 0.84mmol) and 4-butylpiperidine (0.062g, 0.44 mmol). Preparative TLC (SiO)₂；CH₂Cl₂MeOH 10: 1) to yield the title compound (111MF02) (0.06g, 39%).¹HNMR(CHCl₃)δ6.99-6.91(m，3H)，4.55(s，2H)，3.96(t，J＝7.4Hz，2H)，3.27(m，1H)，2.89(d，J＝11.2Hz，2H)，2.40(t，J＝7.2Hz，2H)，1.93-1.83(m，4H)，1.66(d，J＝9.6Hz，2H)；1.27-1.20(m，15H)，0.88(t，J＝6.8Hz，3H)；¹³C NMR(CHCl₃)δ164.7，142.9，137.5，128.7，122.6，121.1，112.9，67.7，56.0，54.2，39.9，36.4，35.9，32.5，29.1，27.2，24.9，23.0，22.7，14.2。

[0252]To the pure compound (0.06g, 0.16mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.016g, 0.18mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.07g, 88%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝373.3。

(R, S) -4- [3- (4-butylpiperidine)1) -2-hydroxy-propyl]-6-methyl-4H-benzo [1, 4]]Oxazin-3-ones (101IS86)

[0253]In a 4mL vial was added (R, S) -6-methyl-4-oxiranylmethyl-4H-benzo [1, 4]]Oxazin-3-one (0.090g, 0.41mmol), 4-butylpiperidine (0.090g, 0.60mmol), K₂CO₃(0.097g, 0.70mmol) and dry THF (2 mL). The mixture was shaken at 40 ℃ for 74h, then concentrated under reduced pressure, and the residue was diluted with EtOAc (20mL), washed with water (10mL), brine, and washed with Na₂SO₄And (5) drying. Filtering, concentrating under reduced pressure, and subjecting the residue to flash chromatography (SiO)₂；CH₂Cl₂acetone/MeOH 85: 10: 5) to give the title product as an oil (0.080g, 54%).¹H NMR(CD₃OD)δ7.12(s，1H)，6.85(d，J＝8.2Hz，1H)，6.81(brd，J＝8.2Hz，1H)，4.53(ABq，14.8，18.0Hz，2H)，4.12-4.02(m，2H)，3.95-3.85(m，1H)，3.05-2.98(m，1H)，2.92-2.84(m，1H)，2.48-2.40(m，2H)，2.31(s，3H)，2.10-1.98(m，2H)，1.71-1.62(m，2H)，1.35-1.15(m，9H)，0.90(t，J＝6.8Hz)；¹³C NMR(CD₃OD)δ166.0，143.7，132.4，128.8，124.4，116.5，116.4，67.5，65.9，62.8，54.6，54.5，46.1，36.3，35.6，32.2(br)，29.0，22.8，20.0，13.3。

[0254]The product was dissolved in diethyl ether and oxalic acid (1.1 eq) dissolved in diethyl ether was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.033 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

(R, S) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl]-4H-benzo [1, 4]]Oxazin-3-one (101IS85)

[0255]Epichlorohydrin (0.48g, 5.2mmol) in dry DMF (7mL), Cs₂CO₃(2.3g, 7.0mmol), 4H-benzo [1, 4]]Oxazin-3-one (0.52g, 3.5mmol) was stirred for 22 h. The mixture was then diluted with ether (50mL), washed with water (10mL) and brine (10 mL). With Na₂SO₄Drying the organic phase, filtering, concentrating under reduced pressure, and subjecting the residue to flash chromatographyMethod (SiO)₂；CH₂Cl₂acetone/MeOH 95: 3: 2). The resulting oil (0.50g, 2.5mmol) was dissolved in THF, 4-butylpiperidine (0.43g, 3.0mmol) and K were added₂CO₃(0.83g, 6.0mmol) and the reaction shaken at 40 ℃ for 72 h. The reaction was then concentrated under reduced pressure and the residue was washed with quick CC (SiO)₂；CH₂Cl₂acetone/MeOH 85: 10: 5) to give the title compound (0.43g, 1.2mmol, 35%).¹H NMR(CD₃OD)δ7.32(brd，J＝7.2Hz，1H)，7.06-6.94(m，3H)，4.58(ABq，J＝14.8，17.6Hz，2H)，4.13-4.03(m，2H)，3.91(dd，J＝8.8，15.2Hz)，3.97(brd，J＝10.7Hz，1H)，2.87(brd，J＝10.1Hz)，2.43(d，J＝6Hz，2H)，2.09-1.96(m，2H)，1.69-1.60(m，2H)，1.34-1.16(m，9H)，0.90(t，J＝6.8Hz)；¹³C NMR(CD₃OD)δ165.8，145.8，129.2，124.0，122.6，116.7，116.2，67.4，65.9，54.7，54.5，46.2，36.3，35.6，32.2(br)，29.0，22.8，13.3。

[0256]The product was dissolved in diethyl ether and oxalic acid (1.1 eq) dissolved in diethyl ether was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.037 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝347.3。

(-) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl]-4H-benzo [1, 4]]Oxazin-3-one (101IS95)

[0257]According to the above for (R/S) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl]-4H-benzo [1, 4]]Oxazin-3-one procedure using (R) - (-) -epichlorohydrin (97%) (instead of racemic epichlorohydrin) gave the title compound. The optical purity was determined to be 96.3% by HPLC analysis (Chiralpak AD, 250X 4.6, 5. mu.M; hexane/i-PrOH/diethylamine 95: 4.7: 0.3, 0.5 mL/min). ([ alpha ])]_D ²⁰＝-6，c＝0.5，EtOH)。

¹H NMR、¹³The C NMR and HPLC-MS spectral data are identical to those of the racemic compound.

(R，S)-4- [3- (4-Butylpiperidine) -2-methoxypropyl radical]-4H-benzo [14 ]]Oxazin-3-one (101IS91)

[0258]A dry 4mL vial was charged with NaH (6.5mg, 0.15mmol) followed by (R, S) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl dissolved in dry THF (1mL)]-4H-benzo [1, 4]]A solution of oxazin-3-one (101IS85) (0.043g, 0.12mmol) was stirred at room temperature for 2 h. Pure MeI (7.5. mu.l, 0.12mmol) was then added and after an additional 2h at room temperature, the reaction mixture was quenched with water (2mL) and extracted with EtOAc (3X 10 mL). With Na₂SO₄Drying the organic phase, filtering, concentrating under reduced pressure, and subjecting the residue to flash chromatography (SiO)₂；CH₂Cl₂acetone/MeOH 90: 6: 4) to give the title compound as an oil (5.1mg, 12%).¹H NMR(CD₃OD)δ7.25(dm，J＝7.2Hz，1H)，7.00-6.88(m，3H)，4.49(ABq，J＝15.2，18.8Hz，2H)，4.06-3.94(m，2H)，3.69-3.61(m，1H)，3.25(s，3H)，2.94-2.82(m，2H)，2.54-2.36(m，2H)，2.10-1.94(m，2H)，1.64-1.55(m，2H)，1.25-1.05(m，9H)，0.81(t，J＝6.8Hz)；¹³CNMR(CD₃OD) delta 165.9, 146.0, 129.1, 124.2, 122.7, 116.8, 116.1, 76.0, 67.5, 60.2, 57.2, 54.6, 54.5, 43.7, 36.2, 35.3, 31.8, 28.9, 22.8, 13.2; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

(R, S) -4- [ 2-hydroxy-3- (3-pentylbicyclo [3.2.1]]Octyl-8) -propyl]-4H-benzo [1, 4]]Oxazin-3-ones (123IS03)

[0259]Epichlorohydrin (0.48g, 5.2mmol) in dry DMF (7mL), Cs₂CO₃(2.3g, 7.0mmol), 4H-benzo [1, 4]]Oxazin-3-one (0.52g, 3.5mmol) was stirred for 22 h. The mixture was then diluted with ether (50mL), washed with water (10mL) and brine (10 mL). With Na₂SO₄Drying the organic phase, filtering, concentrating under reduced pressure, and filtering the residue with quick CC (SiO)₂；CH₂Cl₂acetone/MeOH 95: 3: 2). The resulting oil (0.060g, 0.29mmol) was dissolved in DMF (1.5mL) and 3-pentyl-8-azabicyclo [3.2.1] was added]Octane (0.060g, 0.33 m)mol) and Cs₂CO₃(0.30g, 0.8lmmol), the mixture was shaken at 65 ℃ for 72 h. The mixture was then poured into diethyl ether (25mL), washed with water (10mL), and the aqueous phase extracted with diethyl ether (20 mL). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying, filtering, concentrating under reduced pressure, purifying the residue with cation exchange CC followed by flash CC (SiO)₂；CH₂Cl₂Acetone MeOH 85/10/5 to give the title compound (0.060g, 33% (as 4H-benzo [1, 4 ])]Oxazin-3-one).¹H NMR(CHCl₃)δ7.42(dm，J＝7.2Hz，1H)，7.05-6.94(m，3H)，4.60(ABq，J＝14.8，16.8Hz，2H)，4.15(dd，J＝3.2，14.0Hz，1H)，3.86-3.78(m，3H)，3.14(m，2H)，2.54(dd，J＝4.8，12.5Hz，1H)，2.22(dd，J＝9.2，12.4Hz)，2.16-1.98(m，2H)，1.98-1.83(m，2H)，1.72-1.55(m，3H)，1.43-1.34(m，2H)，1.42-1.15(m，8H)，0.87(t，J＝7.2Hz)。¹³C NMR(CDCl₃) δ 165.3, 145.5, 129.7, 124.2, 122.9, 117.0, 116.6, 67.9, 67.4, 60.9, 58.6, 56.7, 46.7, 38.3, 36.7, 36.5, 28.5, 28.3, 28.2, 27.1, 22.9, 14.3. HPLC-MS (ammonium acetate) [ M + H ]]⁺＝387.3。

4- [2- (4-Butylpiperidinyl-1-methyl) allyl]-4H-benzo [1, 4 oxazin-3-one (123IS02)

[0260]3-chloro-2-chloromethyl-1-propene (0.20g, 1.5mmol), 4H-benzo [1, 4]]Oxazin-3-one (0.15g, 1.0mmol) and Cs₂CO₃(0.65g, 2.0mmol) were mixed in 1mL DMF and shaken at 65 ℃ for 5 h. The mixture was diluted with ether (20mL), washed with water (20mL), and the aqueous phase extracted with ether (20 mL). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying, filtering, concentrating under reduced pressure, and purifying the residue with quick CC (SiO)₂(ii) a heptane/EtOAc 70: 30). The product (0.080g, 0.34mmol) was dissolved in DMF (1mL) followed by the addition of 4-butylpiperidine (0.053g, 0.37mmol) and Cs₂CO₃(0.23g, 0.71mmol) and the mixture was shaken at 65 ℃ for 24 h. The mixture was then poured into diethyl ether (25mL), washed with water (10mL), and the aqueous phase was washed with ethyl etherExtraction with ether (20 mL). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying, filtering, concentrating under reduced pressure, purifying the residue with cation exchange CC followed by flash CC (SiO)₂；EtOAc/MeOH/NH₄OH (25% NH in water)₃) 97.5: 2: 0.5) to give the title compound (0.075g, 21%).¹H NMR(CHCl₃)δ7.05-2.92(m，4H)，5.01(brs，1H)，4.82(brs，1H)，4.64(brs 2H)，4.57(brs，2H)，2.94(brs，2H)，2.86(brd，J＝10.4Hz，2H)，1.93-1.82(m，2H)，1.71-1.62(m，2H)，1.34-1.15(m，9H)，0.89(t，J＝6.2Hz，3H)；¹³C NMR(CHCl₃) δ 1.64.5, 145.4, 129.2, 123.9, 122.8, 116.9, 113.2, 67.9, 63.2, 54.4, 44.8, 36.6, 36.0, 32.8, 29.3, 23.1, 14.3; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.3。

(R, S) -4- [3- (4-butylpiperidinyl-1-) 2-fluoropropyl]-4H-benzo [1, 4]]Oxazin-3-one (101IS96)

[0261]A4 mL vial was charged with (R, S) -4-butyl-1- (3-chloro-2-fluoropropyl) piperidine (0.020g, 85. mu. mol), 4H-benzo [1, 4] benzo]Oxazin-3-one (0.023g 0.16mmol) and CH₃CN (1 mL). The mixture was stirred at 60 ℃ for 70h, the mixture was diluted with MeOH and filtered through a small pad of silica placed over the cation CC. Concentrating under reduced pressure to obtain oil, and performing flash chromatography (SiO)₂(ii) a Heptane: EtOAc 50/50) to give the title compound as an oil (0.011g, 38%).¹HNMR(CD₃OD)δ7.28-7.24(m，1H)，7.07-6.96(m，3H)，5.05(dm，J＝50.4Hz)，(ABq，J＝15.2，20.0Hz)，4.29-4.12(m，2H)，3.00-2.92(m，2H)，2.78-2.60(m，2H)，2.14-2.05(m，2H)，1.73-1.63(m，2H)，1.35-1.16(m，10H)，0.90(t，J＝6.8Hz，3H)。¹³C NMR(CD₃OD)δ165.8，145.8，129.0，124.2，122.7，116.8，117.0，116.8，89.5(d，J＝174Hz)，67.4，60.1(d，J＝21Hz)，54.5，43.8(d，J＝23Hz)，36.2，35.4，32.0，31.9，28.9，22.8，13.2。

[0262]Dissolving the product in diethyl ether, adding the solutionOxalic acid (1.1 equivalents). The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.037 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.3。

(S) -4- [3- (4-butyl-piperidinyl-1) -2-methyl-propyl-4H-benzo [1, 4]]Oxazin-3-ones (108LM53-50)

[0263]To a 4mL vial was added (R) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] in dry MeCN (1/2mL)]Crude product of oxazin-3-one (108LM46-43) (0.312g) and 4-butyl-piperidine (0.210g, 1.49mmol) and shaken at 60 ℃ for 3 days. The reaction mixture was quenched with water (1ml) and the product extracted with EtOAc (2X 1 ml). The organic layers were combined and loaded onto cation exchange. The column was washed with MeOH (2 column volumes) and then eluted with 8% ammonium hydroxide in MeOH (2 column volumes) to give the product. Fast CC (SiO) for product₂(ii) a MeOH/DCM 1: 20) to afford the title compound (108LM53-50) (0.193g, 17% -3 steps).¹H NMR(CHCl₃)δ7.18(d，J＝7.8Hz，1H)，7.03-6.96(m，3H)，4.58(ABq，J＝14.3Hz，J＝33.9Hz，CH₂)，4.05-3.90(m，2H)，2.88(bd，J＝10.4Hz，1H)，2.71(bd，J＝10.4Hz，1H)，2.25-2.01(m，3H)，2.00-1.92(m，1H)，1.83-1.75(m，1H)，1.68-1.56(m，2H)，1.33-1.12(m，9H)，0.95-0.85(m，6H)；¹³C NMR(CHCl₃) δ 164.9, 145.7, 128.9, 123.8, 122.7, 117.2, 115.8, 67.8, 64.2, 55.8, 54.4, 45.4, 36.6, 36.1, 33.0, 32.8, 29.3, 23.2, 17.1, 14.4; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.3。

(R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl]-4H-benzo [1, 4]]Oxazin-3-ones (108LM22-20)

[0264]Compound (S) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP10]Oxazin-3-one (108LM27-24) (0.063g, 0.19mmol) and 4-butyl-piperidine (0.053g, 0.38mmol) were reacted and shaken at 50 ℃ for 1 day and 70 ℃ for 2 days. Exchange of CC and fast CC (SiO) with cations₂(ii) a MeOH/DCM 1: 50) to afford the title compound (108LM22-20) (0.051g, 79%).¹H NMR(CDCl₃)δ7.18-7.15(m，1H)，7.02-6.96(m，3H)，4.60(ABq，J＝15.0Hz，J＝31.3Hz，CH₂) 3.99(dd, J ═ 8.1Hz, 13.8Hz, 1H), 3.92(dd, J ═ 5.0Hz, 13.8Hz, 1H), 2.88(bd, J ═ 10.0Hz, 1H), 2.72(bd, J ═ 10.0Hz, 1H), 2.26-2.02(m, 3H), 2.00-1.92(m, 1H), 1.85-1.75(m, 1H), 1.70-1.59(m, 2H), 1.32-1.14(m, 9H), 0.92-0.85(m, 6H); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.3。

General method 14(GP14)

[0265]To a 4mL vial was added the corresponding heterocyclic compound (1 eq) and the corresponding piperidine (1.1 eq) and shaken at 60 ℃ for 2 days. Et was added₃N (1/2mL), shaking was continued for 1 day. The reaction mixture was quenched with water (1mL) and Et was added₂O (1mL) and sodium hydroxide (until pH 10). The product is treated with Et₂O (2X 1 mL). The organic layers were combined and washed with Na₂SO₄Drying and concentrating. The product was purified using cation exchange CC followed by fast CC (SiO)₂(ii) a MeOH/DCM 1: 50).

(R) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl]-4H-benzo [1, 4]]Oxazin-3-ones (108LM32-29)

[0266]Compound (S) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP14]Oxazin-3-one (108LM27-24) (0.202g, 0.61mmol) and 4-propoxy-piperidine (79KS66) (0.097g, 0.67mmol) reacted to give the title compound (108LM32-29) (0.136g, 65%).¹H NMR(CHCl₃)δ7.15(bd，J＝7.3Hz，1H)，7.03-6.95(m，3H)，4.60(ABq，J＝13.9Hz，J＝31.6Hz，CH₂)，4.05-3.90(m，2H)，3.48(t，J＝7.0Hz，CH₂)，3.28-3.20(m，1H)，2.79(bs，1H)，2.63(bs，1H)，2.27-2.11(m，3H)，2.10-1.93(m，2H)，1.92-1.83(m，2H)，1.63-1.52(m，4H)，0.94-0.86(m，6H)；¹³C NMR(CHCl₃)δ164.5，145.4，128.5, 123.4, 122.3, 116.9, 115.2, 75.0, 69.4, 67.4, 63.2, 52.5, 51.5, 45.0, 31.6, 31.5, 29.1, 23.1, 16.6, 10.5; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝347.3。

(R) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-4H-benzo [1, 4]]Oxazin-3-ones (108LM33-30)

Compound (S) -4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP14]Oxazin-3-one (108LM27-24) (0.441g, 1.33mmol) and 4-butylidenepiperidine (111MF05) (0.204g, 1.47mmol) reacted to give the title compound (108LM33-30) (0.293g, 64%).¹H NMR(CDCl₃)δ7.19(bd，J＝7.0Hz，1H)，7.04-6.97(m，3H)，5.13(t，J＝7.9Hz，CH)，4.60(ABq，J＝14.1Hz，J＝16.2Hz，CH₂)，4.00(d，J＝7.0Hz，CH₂)，2.50-2.38(m，2H)，2.35-2.05(m，9H)，1.95(dt，J＝7.0Hz，CH₂)，1.50-1.40(m，2H)，0.94-0.86(m，6H)；¹³C NMR(CHCl₃) δ 165.0, 145.8, 136.3, 128.9, 123.8, 122.8, 122.7, 117.3, 115.7, 67.9, 63.7, 56.5, 55.7, 45.5, 36.4, 29.4, 28.6, 23.4, 17.1, 13.9; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.3。

General method 15(GP15)

[0267]Add dissolved Et to 7mL vial₃The corresponding heterocyclic compound (1 equivalent) and the corresponding piperidine (1.1 equivalent) in N (1/2mL) were shaken at 60 ℃ for 4 days. The reaction mixture was quenched with water (1mL) and Et was added₂O (1mL) and sodium hydroxide (until pH 10). The product is treated with Et₂O (10X 1mL) and EtOAc (10X 1 mL). The organic layers were combined and dried (Na)₂SO₄) And (4) concentrating. The product was purified using cation exchange CC followed by fast CC (SiO)₂(ii) a MeOH/DCM 1: 20).

(R) -4- [3- (3-butyl-8-aza-bicyclo [3.2.1]]Octyl-8]-2-methylpropyl-4H-benzo [1, 4]]Oxazines -3-one (108LM38-35)

[0268]Et dissolution according to GP15₃Compound (S) -4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] in N (1/2mL)]Oxazin-3-one (108LM27-24) (0.092g, 0.28mmol) and 3-butyl-8-aza-bicyclo [3.2.1]Octane (104KS29) (0.051g, 0.31mmol) reacted to give the title compound (108LM38-35) (0.068g, 64%).¹H NMR(CHCl₃)δ7.32(d，J＝6.7Hz，1H)，7.03-6.95(m，3H)，4.60(ABq，J＝7.2Hz，J＝10.8Hz，CH₂)，4.12-4.00(m，2H)，3.16(bs，1H)，3.07(bs，1H)，2.33(dd，J＝6.1Hz，J＝2.1Hz，1H)，2.12(t，J＝4.7Hz，1H)，2.01-1.78(m，2H)，1.58-1.40(m，5H)，1.38-1.13(m，9H)，0.92-0.84(m，6H)；¹³C NMR(CHCl₃) δ 164.9, 145.7, 128.9, 123.7, 122.7, 117.1, 116.2, 67.9, 61.8, 60.0, 58.1, 45.4, 38.7, 38.6, 37.1, 31.6, 29.4, 28.2, 27.4, 26.5, 23.1, 17.1, 14.3; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝371.3。

(R) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1]]Octyl-8-) propyl]-4H-benzo [1, 4]]Oxazole (oxazole) (I) Oxazin-3-ones (108LM39-36)

Et dissolution according to GP15₃Compound (S) -4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] in N (1/2mL)]Oxazin-3-one (108LM27-24) (0.083g, 0.25mmol) and 3-pentyl-8-aza-bicyclo [3.2.1]Octane (104KS32-2) (0.051g, 0.28mmol) reacted to give the title compound (108LM39-36) (0.061g, 63%).¹H NMR(CDCl₃)δ7.33-7.29(m，1H)，7.03-6.96(m，3H)，4.60(ABq，J＝14.8Hz，J＝37.1Hz，CH₂)，4.14-4.00(m，2H)，3.13(bs，1H)，3.05(bs，1H)，2.63-2.50(m，1H)，2.17-2.03(m，3H)，2.00-1.80(m，3H)，1.72-1.53(m，3H)，1.42-1.15(m，10H)，0.93-0.85(m，6H)；¹³CNMR(CHCl₃) δ 165.0, 145.7, 128.9, 123.7, 122.6, 117.1, 116.1, 67.9, 60.9, 58.9, 58.2, 45.3, 38.4, 37.0, 36.8, 32.2, 31.7, 28.5, 28.3, 27.2, 22.9, 17.1, 14.3; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝385.3。

General method 16(GP16)

[0269]To a 7mL vial was added 4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4]]Oxazin-3-one (1.0 eq) and amine (1.0 eq) and shaken at 60 ℃ for 20 h. Et was added to the reaction mixture₃N (2.5 equiv.) and shaken at 60 ℃ for 60-80 hours. The reaction mixture was concentrated and dissolved in 1M NaOH (10mL) with CH₂Cl₂Extracted (3X 15mL) and dried on a PTFF Whatman filter. The organic layers were combined, concentrated, and purified using cation exchange CC and CC (heptane/EtOAc) or preparative HPLC.

(R) -6-fluoro-4- [ 2-methyl-3- (4-propoxy-piperidinyl-1) -propyl]-4H-benzo [1, 4]]Oxazin-3-ones (108LM30-27)

[0270]Compound (S) -6-fluoro-4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] dissolved in MeCN (1/2mL) according to GP10]Oxazin-3-one (111MF04) (0.400g, 1.15mmol) and 4-propoxy-piperidine (79KS66) (0.332g, 2.29mmol) were reacted and shaken at 60 ℃ for 3 days and 70 ℃ for 1 day. Exchange of CC and fast CC (SiO) with cations₂(ii) a MeOH/DCM 1: 50 → 1: 20) to give the title compound (108LM30-27) (0.263g, 63%).¹H NMR(CHCl₃)δ6.96(dd，J＝9.7Hz，J＝2.9Hz，1H)，6.91(dd，J＝8.9Hz，J＝4.9Hz，1H)，6.66(dt，J＝8.9Hz，J＝2.9Hz，1H)，4.56(ABq，J＝15.5Hz，J＝31.7Hz，CH₂)，3.95(dd，J＝13.5Hz，J＝8.1Hz，1H)，3.88(dd，J＝13.5Hz，J＝4.7Hz，1H)，3.38(t，J＝6.7Hz，CH₂)，3.32-3.23(m，1H)，2.79(bs，1H)，2.62(bs，1H)，2.26-2.12(m，3H)，2.19-1.95(m，2H)，1.94-1.84(m，2H)，1.66-1.53(m，4H)，0.95-0.85(m，6H)；¹³C NMR(CHCl₃)δ164.9，158.5(d，J＝952.8Hz，1H)，141.7(d，J＝9.2Hz，1H)，130.0(d，J＝42.4Hz，1H)，117.7(d，J＝38.4Hz，1H)，109.6(d，J＝93.2Hz，1H)，103.4(d，J＝114.4Hz，1H)，75.2，69.8，67.9，63.7，52.8，52.0，45.7，31.8，31.6，29.5，23.5，17.1，10.9；HPLC-MS(ammonium acetate) [ M + H ]]⁺＝365.3。

(R) -4- [3- (4-Butylidenepiperidinyl-1) -2-methyl-propyl]-6-fluoro-4H-benzo [1, 4]]Oxazin-3-ones (1111MF06)

[0271]Mixing the compound (S) -6-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF04) (0.718g, 2.06mmol) and 4-butylidenepiperidine (0.301g, 2.16 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF06) (0.40g, 54%).¹H NMR(CHCl₃)δ7.01(dd，J＝3.0Hz，J＝10.2Hz，1H)，6.90(dd，J＝5.4Hz，J＝8.6Hz，1H)，6.89-6.63(m，1H)，5.12(t，J＝7.4Hz，1H)，4.63-4.51(m，2H)，4.02-3.89(m，1H)，2.51-2.44(m，2H)，2.32-2.23(m，5H)，2.21-2.15(m，5H)，2.11-2.03(m，1H)，1.98-1.93(m，2H)，1.39-1.29(m，2H)，0.91-0.86(m，6H)；¹³C NMR(CHCl₃)δ164.8，158.5(d，J＝239.4Hz)，141.6(d，J＝2.7Hz)，136.2，130.0(d，J＝10.8Hz)，122.7，117.6(d，J＝9.3Hz)，109.5(d，J＝23.1Hz)，103.4(d，J＝29.1Hz)，67.8，63.7，56.6，55.8，45.7，36.2，29.4，29.3，28.4，23.3，17.0，13.9。

[0272]To the pure compound (0.38g, 1.0mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.104g, 1.15mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.44g, 92%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.4。

(R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl]-6-fluoro-4H-benzo [1, 4]]Oxazin-3-ones (111MF08)

[0273]Mixing the compound (S) -6-fluoro-4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF04) (0.873g, 2.50mmol) and 4-butylpiperidine (0.371g, 2.63 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF08) (0.53g, 58%).¹H NMR(CDCl₃)δ7.01(d，J＝10.0Hz，1H)，6.92-6.88(m，1H)，6.68-6.64(m，1H)，5.57(q，J＝32.4Hz，J＝15.2Hz，2H)，4.02-3.83(m，2H)，2.92-2.70(m，2H)，2.23-2.10(m，2H)，2.04-1.97(m，2H)，1.81(t，J＝10.8Hz，1H)，1.72-1.61(m，2H)，1.36-1.19(m，9H)，0.90-0.88(m，6H)；¹³C NMR(CHCl₃)δ164.8，158.5(d，J＝239.4Hz)，141.6(d，J＝2.3Hz)，130.0(d，J＝10.4Hz)，117.6(d，J＝9.6Hz)，109.4(d，J＝23.1Hz)，103.5(d，J＝29.3Hz)，67.8，64.1，56.0，54.3，45.7，36.5，36.0，33.0，32.5，29.5，29.2，23.1，17.1，14.3。

[0274]To the pure compound (0.53g, 1.5mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.104g, 1.15mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.614g, 93%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.3。

(R) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-6-fluoro-4H-benzo [1, 4]] Oxazin-3-one (111MF26)

[0275]Mixing the compound (S) -6-fluoro-4- (3-iodo-2-methyl-propyl) -4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF04) (0.219g, 0.6mmol) and 3-butyl-8-azabicyclo [3.2.1]Octane (0.10g, 0.6 mmol). CC (SiO)₂(ii) a Heptane/EtOAc (4: 1-4) purification afforded the title compound (111MF26) (0.16g, 58%).¹H NMR(CHCl₃)δ7.16(dd，J＝2.8Hz，J＝10.0Hz，1H)，6.90(dd，J＝5.0Hz，J＝9.0Hz，1H)，6.69-6.63(m，1H)，4.58(q，J＝14.8Hz，J＝38.0Hz，2H)，4.10-3.93(m，2H)，3.16-3.06(m，2H)，2.33(dd，J＝4.0Hz，J＝12.8Hz，1H)，2.05(t，J＝11.6Hz，1H)，1.94-1.82(m，2H)，1.58-1.43(m，6H)，1.39-1.32(m，2H)，1.31-1.15(m，6H)，0.90-0.87(m，6H)；¹³C NMR(CDCl₃)δ164.9，158.5(d，J＝239.4Hz)，141.6(d，J＝2.7Hz)，130.0(d，J＝10.4Hz)，117.5(d，J＝9.3Hz)，109.4(d，J＝23.5Hz)，103.9(d，J＝28.9Hz)，67.8，61.9，60.1，58.2，45.6，38.6，38.5，36.9，31.8，29.4，28.2，27.4，26.5，23.1，17.1，14.3。

[0276]To the pure compound (0.16g, 0.41mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.039g, 0.43mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.173g, 88%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝389.3。

(R) -6-fluoro-4- (2-methyl-3- (3-pentyl-8-azabicyclo [ 3.2.1)]Octyl-8]-propyl-4H-benzo [1, 4]] Oxazin-3-one (111MF27)

[0277]Mixing the compound (S) -6-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF04) (0.208g, 0.6mmol) and 3-pentyl-8-azabicyclo [3.2.1]Octane (0.10g, 0.56 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF27) (0.16g, 58%).¹H NMR(CDCl₃)δ7.13(dd，J＝2.8Hz，J＝10.0Hz，1H)，6.90(dd，J＝5.2Hz，J＝8.8Hz，1H)，6.68-6.63(m，1H)，4.57(q，J＝14.8Hz，J＝40.0Hz，1H)，4.11-3.94(m，2H)，3.14-3.04(m，2H)，2.30(dd，J＝4.0Hz，J＝12.8Hz，1H)，2.20-2.09(m，2H)，2.06-2.00(m，1H)，1.95-1.82(m，3H)，1.71-1.52(m，3H)，1.40-1.34(m，2H)，1.32-1.19(m，8H)，0.89-0.85(m，6H)；¹³C NMR(CHCl₃)δ164.9，158.5(d，J＝239.4Hz)，141.6(d，J＝2.6Hz)，130.0(d，J＝10.8Hz)，117.5(d，J＝9.3Hz)，109.4(d，J＝23.4Hz)，103.8(d，J＝28.9Hz)，67.8，61.0，59.0，58.2，45.5，38.4，36.6，36.5，32.8，31.8，28.4，28.4，28.2，27.2，22.8，7.0，14.2。

[0278]To the pure compound (0.16g, 0.41mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.039g, 0.43mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.198g, 97%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝403.3。

(R) -4- [3- (4-butylpiperidinyl-1) -2-methylCyclopropyl radical]-7-fluoro-4H-benzo [1, 4]]Oxazin-3-ones (112KK04)

[0279]To a microwave vial was added (S) -7-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] in MeCN (4mL)]Oxazin-3-one (111MF20) (0.274g, 0.78mmol) and 4-butylpiperidine (0.226g, 1.60mmol) and sealed. After microwave irradiation at 100 ℃ for 60min, the reaction mixture was purified with cation exchange CC and then with fast CC (SiO)₂；CH₂Cl₂MeOH 50: 1) to give the title compound (112KK04) (0.180g, 63%).¹H NMR(CD₃OD)δ7.24-7.21(m，1H)，6.81-6.76(m，2H)，4.60(ABq，J＝17.4Hz，J＝15.1Hz，CH₂)，3.98(dd，J＝14.3Hz，J＝5.9Hz，1H)，3.87(dd，J＝14.3Hz，J＝7.6Hz，1H)，2.86(d，J＝11.0Hz，1H)，2.73(d，J＝9.8Hz，1H)，2.28-2.23(m，1H)，2.16-2.08(m，2H)，1.93-1.81(m，2H)，1.79-1.62(m，2H)，1.32-1.13(m，9H)，0.93-0.88(m，2CH₃)；¹³C NMR(CD₃OD)δ166.1，160.3(d，J＝242.3Hz)，148.1(d，J＝11.9Hz)，126.4(d，J＝2.9Hz)，117.8(d，J＝9.4Hz)，109.9(d，J＝22.9Hz)，105.7(d，J＝26.1Hz)，68.6，65.1，56.3，55.4，46.6，37.5，37.0，33.6，33.4，30.1，29.9，24.0，17.2，14.4。

[0280]The product was dissolved in MeOH/Et₂O, adding dissolved Et₂Oxalic acid in O. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.176 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.29。

(R) -7-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Oxazin-3-ones (111MF28)

[0281]Mixing the compound (S) -7-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF20) (0.501g, 1.43mmol) and 4-propoxypiperidine (0.205g, 1.43 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF28) (0.375g, 71%).¹H NMR(CDCl₃)δ7.12-7.08(m，1H)，6.74-6.69(m，2H)，4.59(q，J＝15.0Hz，J＝31.0Hz，2H)，4.01-3.88(m，2H)，3.39(t，J＝6.8Hz，2H)，3.29-3.22(m，1H)，2.77(t，J＝6.3Hz，1H)，2.63(t，J＝5.6Hz，1H)，2-26-2.12(m，3H)，2.04-1.96(m，2H)，1.88-1.84(m，2H)，1.62-1.50(m，4H)，0.93-0.87(m，6H)；¹³C NMR(CDCl₃)δ164.2，158.9(d，J＝241.9Hz)，146.5(d，J＝12.1Hz)，125.2(d，J＝3.0Hz)，116.1(d，J＝9.6Hz)，109.0(d，J＝22.3Hz)，105.2(d，J＝25.8Hz)，75.2，69.8，67.8，63.5，52.8，51.8，45.5，31.9，31.8，29.4，23.5，17.0，10.8。

[0282]To the pure compound (0.375g, 1.03mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.097g, 1.08mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.41g, 88%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝365.3。

(R) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-7-fluoro-4H-benzo [1, 4]]Oxazin-3-ones (111MF29)

[0283]Mixing the compound (S) -7-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF20) (0.515g, 1.47mmol) and 4-butylidenepiperidine (0.205g, 1.47 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF29) (0.393g, 73%).¹H NMR(CDCl₃)δ7.17-7.12(m，1H)，6.74-6.69(m，2H)，5.15-5.11(t，J＝7.2Hz，1H)，4.61(q，J＝15.2Hz，2H)，4.04-3.92(m，2H)，2.48-2.40(m，2H)，2.32-2.13(m，9H)，1.96(q，J＝7.2Hz，2H)，1.38-1.30(m，2H)，0.91-0.86(m，6H)；¹³C NMR(CDCl₃)δ164.1，158.9(d，J＝243.4Hz)，146.5(d，J＝11.9Hz)，136.1，125.2(d，J＝3.0Hz)，128.9，116.2(d，J＝22.7Hz)，109.0(d，J＝22.7Hz)，105.2(d，J＝26.2Hz)，67.8，63.7，56.5，55.7，54.6，36.3，29.3，28.5，23.3，17.1，13.9。

[0284]To the pure compound (0.393g, 1.09mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.103g, 1.14mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.46g, 94%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

(R) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-7-fluoro-4H-benzo [1, 4]] Oxazin-3-ones (112KK05)

[0285]To a microwave vial was added (S) -7-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] dissolved in MeCN (2mL)]Oxazin-3-one (111MF20) (0.047g, 0.13mmol) and 3-butyl-8-azabicyclo [3.2.1]Octane (0.039g, 0.23mmol) and sealed. After microwave irradiation at 100 ℃ for 60min, the reaction mixture was purified with cation exchange CC and then with fast CC (SiO)₂；CH₂Cl₂MeOH 50: 1) to give the title compound (112KK05) (0.017g, 33%).¹HNMR(CD₃OD)δ7.34-7.30(m，1H)，6.80-6.75(m，2H)，4.61(ABq，J＝18.8Hz，J＝15.1Hz，CH₂)，4.04(dd，J＝14.3Hz，J＝5.9Hz，1H)，3.93(dd，J＝14.3Hz，J＝8.2Hz，1H)，3.18-3.10(m，2H)，2.36-2.23(m，2H)，2.03-1.85(m，3H)，1.62-1.45(m，5H)，1.36-1.14(m，8H)，0.92-0.87(m，2CH₂)；¹³C NMR(CD₃OD)δ166.2，160.4(d，J＝242.3Hz)，148.1(d，J＝11.9Hz)，126.3(d，J＝2.9Hz)，118.1(d，J＝9.7Hz)，109.8(d，J＝22.9Hz)，105.7(d，J＝26.5Hz)，68.6，62.5，61.2，58.3，46.4，39.0，37.9，32.1，30.2，29.0，27.8，27.2，23.9，17.2，14.4。

[0286]The product was dissolved in MeOH/Et₂O, adding dissolved Et₂Oxalic acid in O. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.016 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝389.34。

(R) -7-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [ 3.2.1)]Octyl-8) -propyl-4H-benzo [1, 4]] Oxazin-3-one (111MF30)

[0287]Mixing the compound (S) -7-fluoro-4- (3-iodo-2-methylpropyl) -4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF20) (0.208g, 0.59mmol) and 3-pentyl-8-azabicyclo [3.2.1]Octane (0.106g, 0.58 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) and preparative HPLC purification gave the title compound (111MF30) (0.070g, 29%).¹H NMR(CDCl₃)δ7.23-7.19(m，1H)，6.66-6.60(m，2H)，4.60-4.46(m，2H)，4.05-3.99(m，1H)，3.95-3.90(m，1H)，3.06-3.03(m，1H)，2.99-2.96(m，1H)，2.24-2.19(m，1H)，2.07-1.94(m，3H)，1.90-1.73(m，3H)，1.60-1.45(m，3H)，1.33-1.25(m，2H)，1.24-1.12(m，8H)，0.83-0.78(m，6H)；¹³C NMR(CDCl₃)δ164.1，158.8(d，J＝243.3Hz)，146.4(d，J＝11.5Hz)，125.1(d，J＝3.1Hz)，116.6(d，J＝9.3Hz)，108.9(d，J＝22.8Hz)，105.0(d，J＝25.7Hz)，67.7，60.9，58.8，58.1，45.4，38.3，36.8，36.6，32.1，31.6，28.5，28.4，28.1，27.0，22.8，17.0，14.2。

[0288]To the pure compound (0.070g, 0.17mmol) dissolved in diethyl ether (1mL) was added oxalic acid (0.016g, 0.18mmol) dissolved in diethyl ether (1 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.082g, 96%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝402.56。

(R) -4- [3- (4-butylpiperidinyl-1) -2-methyl-propyl]-6-methoxy-4H-benzo [1, 4]]Oxazin-3-ones (111MF38)

[0289]Mixing the compound (S) -4- (3-iodo-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] according to GP16]Oxazin-3-one (11MF36) (0.636g, 1.77mmol) and 4-butylpiperidine (0.226g, 1.6 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) and preparative HPLC purification gave the title compound (111MF38) (0.245g, 27%).¹H NMR(CDCl₃)δ6.89(d，J＝8.8Hz，1H)，6.72(d，J＝2.4Hz，1H)，6.50(dd，J＝2.8，J＝8.8Hz，1H)，4.54(q，J＝32.4，J＝14.8，2H)，3.94-3.90(m，2H)，3.77(s，3H)，2.90(d，J＝11.2Hz，1H)，2.72(d，J＝10.8Hz，1H)，2.25-2.10(m，3H)，1.93(t，J＝11.2Hz，1H)，1.80(t，J＝11.2Hz，1H)，1.61(d，J＝10.8Hz，2H)，1.31-1.19(m，9H)，0.90-0.86(m，6H)；¹³C NMR(CDCl₃)δ165.3，155.5，139.7，129.8，117.2，107.1，103.3，68.0，64.2，55.9，55.7，54.5，45.5，36.5，36.0，32.9，32.5，29.2，29.2，23.1，16.9，14.3。

[0290]To the pure compound (0.245g, 0.65mmol) dissolved in diethyl ether (2mL) was added oxalic acid (0.062g, 0.68mmol) dissolved in diethyl ether (2 mL). The crystals formed were filtered and washed with diethyl ether to give the oxalate salt of the title compound (0.229g, 75%); HPLC-MS (ammonium acetate) [ M + H ]]⁺＝375.3。

(R) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-6-methoxy-4H-benzo [1, 4]]Oxazine-3- Ketones (111MF39)

[0291]Mixing the compound (S) -4- (3-iodo-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF36) (0.612g, 1.69mmol) and 4-butylidenepiperidine (0.212g, 1.5 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound 111MF39) (0.489g, 77%).¹H NMR(CDCl₃)δ6.90(d，J＝8.4Hz，1H)，6.73(d，J＝2.8Hz，1H)，6.50(dd，J＝8.4Hz，J＝2.8Hz，1H)，5.11(t，J＝7.6Hz，1H)，4.54(q，J＝14.4Hz，2H)，3.97-3.94(d，J＝6.8Hz，2H)，3.78(s，3H)，2.48-2.41(m，2H)，2.33-2.23(m，5H)，2.20-2.13(m，4H)，1.96(q，J＝7.4Hz，2H)，1.40-1.29(m，2H)，0.91-0.86(m，6H)；¹³C NMR(CHCl₃) δ 165.3, 155.5, 139.8, 136.5, 129.8, 122.5, 117.2, 107.0, 103.4, 68.1, 63.8, 56.5, 56.0, 55.7, 45.5, 36.2, 29.3, 29.2, 28.4, 23.3, 16.9, 13.9; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝373.3。

(R) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-6-methoxy-4H-benzene And [1, 4]]Oxazin-3-one (111MF40)

[0292]Mixing the compound (S) -4- (3-iodo-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF36) (0.239g, 0.66mmol) and 3-butyl-8-aza-bicyclo [3.2.1]Octane (0.100g, 0.60 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF40) (0.163g, 61%).¹H NMR(CDCl₃)δ6.88(d，J＝8.8Hz，1H)，6.85(d，J＝2.8Hz，1H)，6.49(dd，J＝8.8Hz，J＝2.8Hz，1H)，4.61-4.47(m，2H)，4.01-3.99(m，2H)，3.77(s，3H)，3.17-3.04(m，2H)，2.35-2.29(m，1H)，2.14-1.79(m，3H)，1.57-1.13(m，6H)，0.88(m，3H)；¹³C NMR(CDCl₃) δ 165.4, 155.6, 139.8, 129.8, 117.1, 107.0, 103.8, 68.0, 61.6, 60.2, 58.1, 56.0, 45.4, 38.5, 38.4, 36.9, 31.6, 29.4, 28.2, 27.3, 26.5, 23.9, 14.3; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝401.3。

(R) -6-methoxy-4- [ 2-methyl-3- (3-pentyl-8-aza-bicyclo [3.2.1]]Octyl-8-) propyl]-4H-benzene And [1, 4]]Oxazin-3-one (111MF41)

[0293]Mixing the compound (S) -4- (3-iodo-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF36) (0.226g, 0.63mmol) and 3-pentyl-8-azabicyclo [3.2.1]Octane (0.101g, 0.56 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) and preparative HPLC purification gave the title compound (111MF41) (0.101g, 39%).¹H NMR(CHCl₃)δ6.89(d，J＝8.8Hz，1H)，6.81(d，J＝2.8Hz，1H)，6.49(dd，J＝8.8Hz，J＝2.8Hz，1H)，4.60-4.46(m，2H)，4.01(d，J＝6.8Hz，2H)，3.77(s，3H)，3.15-3.02(m，2H)，2.32-2.26(m，1H)，2.20-1.79(m；7H)，1.68-1.51(m，3H)，1.42-1.16(m，10H)，0.89-0.85(m，6H)；¹³C NMR(CDCl₃)δ168.4，155.6，139.8，129.8，117.0，106.9，103.8，68.0，60.6，59.1，58.1，56.0，45.3，39.4，36.6，36.4，32.2，31.5，28.4，28.4，28.0，27.3，22.8，16.8，14.2；HPLC-MS (ammonium acetate) [ M + H ]]⁺＝415.3。

(R) -6-methoxy-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Oxazine-3- Ketones (111MF42)

[0294]Mixing the compound (S) -4- (3-iodo-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] according to GP16]Oxazin-3-one (111MF36) (0.556g, 1.5mmol) and 4-propoxypiperidine (0.20g, 1.4 mmol). CC (SiO)₂(ii) a heptane/EtOAc 4: 1-4) to give the title compound (111MF42) (0.30g, 53%).¹H NMR(CDCl₃)δ6.89(d，J＝8.8Hz，1H)，6.85(d，2.8Hz，1H)，6.49(dd，J＝8.8Hz，J＝2.8Hz，1H)，4.53(q，J＝14.6Hz，2H)，3.93(d，J＝6.6Hz，2H)，3.77(s，3H)，3.38(t，J＝6.8Hz，2H)，3.29-3.22(m，1H)，2.80-2.77(t，6.4Hz，1H)，2.65-2.61(t，J＝6.0Hz，1H)，2.29-2.00(m，5H)，1.88-1.84(m，2H)，1.65-1.53(m，4H)，0.94-0.87(m，6H)；¹³C NMR(CDCl₃) δ 165.4, 155.5, 139.8, 129.8, 117.2, 107.1, 103.3, 75.1, 69.7, 68.0, 63.7, 56.0, 52.5, 51.9, 45.4, 31.6, 31.5, 29.2, 23.5, 16.9, 10.8; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝377.3。

General method 17(GP17)

[0295]To a 7mL vial was added 4- (3-iodo-2-methylpropyl) -6-methyl-4H-benzo [1, 4]]Crude product of oxazin-3-one (1 eq), Et₃N (0.5mL) and secondary amine (1.2-1.5 equiv). The mixture was shaken at 60 ℃ for 72h, then diluted with MeOH (10mL) and basic Al₂O₃(2g) Concentrating, and purifying by flash chromatography.

(R) -6-methyl-4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl]-4H-benzo [1, 4]]Oxazin-3-ones (101IS69)

[0296](S) -4- (3-iodo-2-methylpropyl) -6-methyl-4H-benzo [1, 4] according to GP17]Crude oxazin-3-one (0.23g), 4-propoxypiperidine (0.12g, 81mmol) and Et₃N (0.5 mL). Rapid CC (SiO)₂；CH₂Cl₂acetone/MeOH 90: 5) to give the title compound (0.20g, 83%).¹H NMR(CD₃OD)δ6.97(brs，1H)，6.79(d，J＝8.0Hz，1H)，6.75(dm，J＝8.0Hz，1H)，4.47(brs，2H)，3.97(dd，J＝6.4，14.4Hz，1H)，8.82(dd，J＝7.2，14.4Hz，1H)，3.44(brs，1H)，3.33(t，J＝6.8Hz，2H)，3.10-2.90(m，2H)，2.90-2.6(m，3H)，2.29(m，1H)，2.24(s，3H)，1.98-1.86(m，2H)，1.78-1.64(m，2H)，1.47(tq，J＝14.4，7.2Hz，2H)，0.92(d，J＝6.4Hz)，0.83(t，J＝7.2Hz)；¹³CNMR(CD₃OD)δ166.4，143.8，132.8，128.3，124.7，116.7，116.1，69.9，67.4，61.5，50.7，50.5，44.1，28.9，28.6，23.0，20.0 15.6，9.8。

[0297]The product was dissolved in diethyl ether and oxalic acid (1.1 eq) dissolved in diethyl ether was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.204 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

(R) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-6-methyl-4H-benzo [1, 4]]Oxazin-3-ones (101IS71-A)

[0298](S) -4- (3-iodo-2-methylpropyl) -6-methyl-4H-benzo [1, 4] according to GP17]Crude product of oxazin-3-one (0.34g), Et₃N (0.5mL) was reacted with 4-butylidenepiperidine (0.17g, 1.2 mmol). Rapid CC (SiO)₂；CH₂Cl₂acetone/MeOH 90: 7: 3) to give the title compound (0.22g, 58%).¹H NMR(CD₃OD)δ7.01(s，1H)，6.86(d，J＝8.0Hz，1H)，6.82(dm，J＝8.0Hz，1H)，5.12(t，J＝7.2Hz，1H)，4.52(ABq，J＝14.8，20.8Hz，2H)，4.03(dd，J＝5.6，14.4Hz，1H)，3.91(dd，J＝8.0，14.4Hz，1H)，2.48-2.34(m，2H)，2.33-2.11(m，8H)，2.31(s，3H)，1.96(q，J＝7.2Hz，2H)，1.34(m，2H)，0.91-0.86(m，6H)；¹³C NMR(CD₃OD)δ165.9，143.9，136.0，132.4，128.3，124.3，122.4，116.6，116.2，67.4，63.6，56.3，55.4，45.0，28.92，28.85，28.0，23.0，20.0，15.9，12.8。

[0299]The product was dissolved in diethyl ether and oxalic acid (1.1 eq) dissolved in diethyl ether was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.236 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝367.3。

(R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl]-6-methyl-4H-benzo [1, 4]]Oxazin-3-ones (101IS71-D)

[0300](S) -4- (3-iodo-2-methylpropyl) -6-methyl-4H-benzo [1, 4] according to GP17]Crude product of oxazin-3-one (0.30g), Et₃N (0.5mL) was reacted with 4-butylpiperidine (0.15g, 1.0 mmol). Rapid CC (SiO)₂；CH₂Cl₂acetone/MeOH 90: 7: 3) to give the title compound (0.26g, 84%).¹H NMR(CD₃OD)δ7.00(s，1H)，6.86(d，J＝8.0Hz，1H)，6.81(dm，J＝8.0Hz，1H)，4.52(ABq，J＝14.4，20.8Hz，2H)，3.99(dd，J＝6.0，14.4Hz，1H)，3.90(dd，J＝8.4，14.4Hz，1H)，2.97(brd，J＝11.2Hz，1H)，2.82(brd，J＝8.4Hz，1H)，2.39-2.10(m，2H)，2.31(s，3H)，2.07-1.88(m，2H)，1.73-1.62(m，2H)，1.35-1.18(m，9H)，0.94-0.08(m，6H)；¹³C NMR(CD₃OD)δ166.0，143.8，132.4，128.3，124.3，116.6，116.2，67.4，63.6，55.0，54.2，44.8，36.2，35.6，32.1(br)，28.9，28.8，22.8，20.0，15.9，13.2。

[0301]The product was dissolved in diethyl ether and oxalic acid (1.1 eq) dissolved in diethyl ether was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.253 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝359.3。

(R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one (101IS71-B3)

[0302](S) -4- (3-iodo-2-methylpropyl) -6-methyl-4H-benzo [1, 4] according to GP17]OxazinesCrude product of (e) -3-one (0.19g, 0.54mmol), Et₃N (0.5mL) and 3-butyl-8-azabicyclo [3.2.1]Octane (0.10g, 0.61 mmol). Rapid CC (SiO)₂；CH₂Cl₂/i-PrOH 92: 8) to give the title compound (0.13g, 62%).¹H NMR(CD₃OD)δ7.05(s，1H)，6.86(d，J＝8.4Hz，1H)，6.81(dm，J＝8.4Hz，1H)，4.52(ABq J＝14.8，24.8Hz，2H)，4.05(dd，J＝5.6，14.0Hz，1H)，3.94(dd，J＝8.8，14.0Hz，1H)，3.05-3.16(m，2H)，2.35-2.14(m，2H)，2.31(s，3H)，2.05-1.78(m，3H)，1.63-1.40(m，5H)，1.36-1.12(m，5H)，0.99(d，J＝6.4Hz，3H)，0.90(t，J＝6.8Hz，3H)；¹³CNMR(CD₃OD)δ167.4，144.9，133.7，129.2，125.6，117.7，117.3，68.5，63.2(br)，62.5(br)，56.0(br)，43.3，37.8(br)，31.3，30.5，30.0，28.3，26.7，26.4，23.7，21.0，16.8，14.2。

[0303]The product was dissolved in diethyl ether and oxalic acid (1.1 eq) dissolved in diethyl ether was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.104 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.3。

(R) -4- [3- (3-pentyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-6-methyl-4H-benzo [1，4]Oxazin-3-one (101IS71-C3)

[0304](S) -4- (3-iodo-2-methylpropyl) -6-methyl-4H-benzo [1, 4] according to GP17]Crude product of oxazin-3-one (0.15g), Et₃N (0.5mL) and 3-pentyl-8-azabicyclo [3.2.1]Octane (95mg, 5.2 mmol). Rapid CC (SiO)₂；CH₂Cl₂/i-PrOH 92: 8) to give the title compound (0.12g, 68%).¹H NMR(CD₃OD)δ7.06(s，1H)，6.86(d，J＝8.0Hz，1H)，6.81(brd，J＝8.0Hz，1H)，4.52(ABq，J＝14.8，27.2Hz，2H)，4.06(dd，J＝5.6，14.2Hz，1H)，4.96(dd，J＝8.8，14.2Hz，1H)，3.16-3.02(m，2H)，2.34-2.07(m，7H)，2.31(s，3H)，2.04-1.81(m，3H)，1.70-1.55(m，3H)，1.46-1.21(m，10H)，0.92-0.85(m，6H)；¹³C NMR(CD₃OD)δ167.2，145.1，133.6，129.4，125.5，117.7，117.5，68.7，61.6，60.2，58.6，46.1，39.6，37.2，36.9，33.1，32.4，29.6，29.5，28.5，27.8，23.7，21.18，17.0，14.4。

[0305]The product was dissolved in diethyl ether and oxalic acid (1.1 eq) dissolved in diethyl ether was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.128 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝399.3。

1- [3- (4-propoxypiperidinyl-1-) propyl]-3, 4-dihydro-1H-quinolin-2-one (85LM32)

[0306]A4 mL vial was charged with the crude product of 1- (3-chloro-propyl) -3, 4-dihydro-1H-quinolin-2-one (85LM31) (0.200g), 4-propoxy-piperidine (79KS-66) (0.130g, 0.897mmol), potassium carbonate (0.247g, 1.79mmol), and sodium iodide (0.269g, 1.79mmol) dissolved in MeCN (2mL) and shaken for 20H at 50 ℃. The reaction mixture was quenched with water (1mL) and the product was extracted with EtOAc (3X 1 mL). The organic layers were combined and washed with Na₂SO₄Drying, evaporating, and purifying with quick CC (SiO)₂(ii) a MeOH/DCM 0: 1 → 3: 7) to give the title compound (85LM32) (0.012g, 3% overall yield).¹H NMR(CDCl₃)δ7.25(t，J＝7.4Hz，1H)，7.18-7.08(m，2H)，6.98(t，J＝7.4Hz，1H)，3.98(t，J＝7.6Hz，CH₂)，3.38(t，J＝6.8Hz，CH₂)，3.35-3.25(m，1H)，2.87(t，J＝7.6Hz，CH₂)，2.80-2.70(m，2H)，2.65-2.60(m，2H)，2.45-2.35(m，2H)，2.20-2.10(m，2H)，1.95-1.80(m，4H)，1.65-1.50(m，4H)，0.95(t，J＝7.6Hz，CH₃)；¹³C NMR(CDCl₃) δ 170.2, 140.0, 128.2, 127.5, 126.6, 122.8, 115.3, 70.0, 56.0, 51.8, 40.5, 32.0, 31.5, 25.8, 25.2, 22.8, 10.7; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝331.3。

1- [3- (4-Butylpiperidinyl-1-) propyl-6-fluoro-3, 4-dihydro-1H-quinolin-2-one (92LH81)

[0307]To a 4mL vial was added 1- (3-chloropropyl) -6-fluoro-3, 4-dihydro-1H-quinolin-2-one (92LH79) (0.090g, 0.37mmol), 4-butylpiperidine (0.078g, 0.55mmol), KI (0.091g, 0.55mmol) and K dissolved in MeCN₂CO₃(0.076g, 0.55mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc) to afford the title compound (92LH81) (0.090g, 70%).¹H NMR(CD₃OD)δ7.19-7.15(m，1H)，6.99-6.97(m，2H)，3.97(t，J＝6.4Hz，CH₂)，2.90-2.87(m，4H)，2.59(t，J＝7.6Hz，CH₂)，2.38(t，J＝7.6Hz，CH₂)；1.96-1.78(m，4H)，1.67(d，J＝9.6Hz，2H)，1.29-1.22(m，9H)，0.90-0.88(m，3H)；¹³C NMR(CD₃OD) δ 172.1, 160.0(d, J ═ 241.8Hz), 136.7(d, J ═ 2.3Hz), 130.6(d, J ═ 7.7Hz), 117.8(d, J ═ 8.1Hz), 115.9(d, J ═ 23.1Hz), 114.6(d, J ═ 22.7Hz), 57.0, 55.0, 41.6, 37.4, 36.9, 33.1, 32.4, 30.1, 26.2, 25.5, 23.9, 14.4; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝347.33。

6-fluoro-1- [3- (4-propoxypiperidinyl-1-) propyl]-3, 4-dihydro-1H-quinolin-2-one (107LH70)

[0308]To a 4mL vial was added 1- (3-chloropropyl) -6-fluoro-3, 4-dihydro-1H-quinolin-2-one (92LH79) (0.242g, 1.00mmol), 4-propoxypiperidine (0.143g, 1.00mmol), KI (0.250g, 1.50mmol) and K dissolved in MeCN (2mL)₂CO₃(0.207g, 1.50mmol) and shaken at 40 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc, MeOH/EtOAc 1: 4) to yield the title compound (107LH70) (0.165g, 47%).¹HNMR(CD₃OD)δ7.19-7.15(m，1H)，7.01-6.97(m，2H)，3.96(t，J＝7.4Hz，CH₂)，3.40(t，J＝6.6Hz，CH₂)，3.35-3.30(m，3H)，2.88(t，J＝6.8Hz，2H)，2.76(m，2H)，2.60-2.57(m，2H)，2.43-2.39(m，2H)，2.22-2.17(m，2H)，1.90-1.78(m，4H)，1.61-1.50(m，4H)，0.91(t，J＝7.4Hz，CH₃)；¹³C NMR(CD₃OD) δ 172.2, 160.0(d, J-242.2 Hz), 136.7(d, J-2.3 Hz), 130.6(d, J-7.7 Hz), 117.8(d, J-8.5 Hz), 115.9(d, J-23.1 Hz), 114.64(d, J-22.3 Hz), 75.6, 70.7, 56.5, 52.0, 41.6, 32.4, 31.8, 26.1, 25.5, 24.2, 11.0; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.30。

(R, S) -1- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-6-fluoro-3, 4-dihydro-1H-quinolin-2-one (107LH71-1)

[0309]To a 4mL vial was added the crude product of (R, S) -1- (3-chloro-2-methylpropyl) -6-fluoro-3, 4-dihydro-1H-quinolin-2-one (107LH68) (0.154g), 4-butylpiperidine (0.141g, 1.0mmol), KI (0.250g, 1.5mmol) and K in DMF (2mL)₂CO₃(0.207g, 1.5mmol) and shaken at 100 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Cation exchange CC and fast CC (SiO) for crude product₂(ii) a EtOAc) to afford the title compound (107LH77-1) (0.069g, total yield 13%).¹HNMR(CD₃OD)δ7.22-7.18(m，1H)，7.00-6.93(m，1H)，3.94(d，J＝6.8Hz，2H)，2.91-2.86(m，3H)，2.74(d，J＝10.2Hz，1H)，2.62-2.158(m，2H)，2.24-2.02(m，3)，1.90-1.81(m，2H)，1.66-1.61(m，2H)，1.30-1.19(m，9H)，0.89(t，J＝6.6Hz，CH₃)，0.86(d，J＝6.7Hz，CH₃)；¹³C NMR(CD₃OD)δ172.7，160.0(d，J＝241.8Hz)，136.7(d，J＝2.7Hz)，130.9(d，J＝8.1Hz)，118.4(d，J＝8.1Hz)，115.9(d，J＝23.5Hz)，114.4(d，J＝22.7Hz)，65.0，56.1，55.6，46.9，37.5，37.0，33.5，33.4，32.6，30.1，30.1，26.2，24.0，17.2，14.4。

[0310]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the titleThe oxalate salt of the compound (0.076 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.32。

(R, S) -6-fluoro-1- [3- (4-propoxypiperidinyl-1) -2-methylpropyl]-3, 4-dihydro-1H-quinolin-2-one (107LH71-2)

[0311]To a 4mL vial was added the crude product of (R, S) -1- (3-chloro-2-methylpropyl) -6-fluoro-3, 4-dihydro-1H-quinolin-2-one (107LH68) (0.154g), 4-propoxypiperidine (0.143g, 1.0mmol), KI (0.250g, 1.5mmol) and K in DMF (2mL)₂CO₃(0.207g, 1.5mmol) and shaken at 100 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Cation exchange CC and fast CC (SiO) for crude product₂(ii) a EtOAc) to afford the title compound (107LH77-2) (0.053g, 10% overall yield).¹H NMR(CD₃OD)δ7.23-7.19(m，1H)，7.00-6.95(m，1H)，3.95(d，J＝7.0Hz，2H)，3.41(t，J＝6.6Hz，CH₂)，3.31-3.27(m，1H)，2.90(t，J＝6.6Hz，2H)，2.74-2.71(m，1H)，2.64-2.58(m，3H)，2.26-2.00(m，5H)，1.89-1.85(m，2H)，1.60-1.49(m，4H)，0.91(t，J＝7.4Hz，CH₃)，0.86(d，J＝6.7Hz，CH₃)；¹³CNMR(CD₃OD)δ172.7，160.0(d，J＝242.2Hz)，136.7(d，J＝2.7Hz)，130.9(d，J＝7.7Hz)，118.3(d，J＝8.1Hz)，115.9(d，J23.1Hz)，114.5(d，J＝22.7Hz)，76.4，70.7，64.4，53.2，52.8，46.9，32.5，32.4，32.3，30.3，26.17，26.15，24.2，17.1，11.0。

[0312]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.048 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.30。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6-chloro-3, 4-dihydro-1H-quinolin-2-one (107LH36)

[0313]The reaction flask was charged under argon6-chloro-3, 4-dihydro-1H-quinolin-2-one (107LH30) (0.100g, 0.55mmol) in dry DMF (2 mL). NaH (60% in oil, 0.024g, 0.60mmol) was added and the mixture was stirred at room temperature for 0.5 h. 1-bromo-3-chloropropane (0.087g, 0.55mmol) was then added and the mixture was stirred at 30 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in MeCN (3mL) and 4-butylpiperidine (0.078g, 0.055mmol), KI (0.166g, 1.00mmol) and K were added₂CO₃(0.138g, 1.00mmol) and shaken at 50 ℃ for 2 days. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The product was purified by preparative RP-HPLC to give the title compound (107LH36) (0.047g, 24%).¹H NMR(CD₃OD)δ7.25-7.13(m，3H)，3.96(t，J＝7.2Hz，CH₂)，2.95-2.86(m，4H)，2.61-2.57(m，2H)，2.45-2.41(m，2H)，2.04-1.98(m，2H)，1.87-1.79(m，2H)，1.28-1.18(m，9H)，0.90(t，J＝7.0Hz，CH₃)；¹³CNMR(CD₃OD) delta 172.3, 139.2, 130.2, 129.3, 128.9, 128.4, 117.8, 56.8, 54.9, 41.4, 37.2, 36.6, 32.9, 32.4, 30.0, 26.0, 25.3, 23.9, 14.4; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.28。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH18-1)

[0314]To a 4mL vial was added the crude product of 1- (3-chloropropyl) -6-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH14) (0.128g), 4-butylpiperidine (0.076g, 0.54mmol), KI (0.166g, 1.00mmol) and K dissolved in MeCN (2mL)₂CO₃(0.138g, 1.00mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc, MeOH/EtOAc 1: 4) to yield the title compound (107LH18-1) (0.088g, 41% overall yield).¹HNMR(CD₃OD)δ7.07-7.01(m，3H)，3.94(t，J＝7.4Hz，CH₂)，2.90-2.80(m，4H)，2.57-2.53(m，2H)，2.39-2.33(m，2H)，2.27(s，3H，CH₃)，1.95-1.90(m，2H)，1.85-1.79(m，2H)，1.66(d，J＝9.8Hz，2H)，1.30-1.17(m，9H)，0.89(t，J＝6.8Hz，CH₃)；¹³C NMR(CD₃OD) delta 172.4, 137.9, 134.1, 129.8, 129.0, 128.0, 116.3, 57.1, 55.0, 41.3, 37.4, 36.8, 33.1, 32.8, 30.1, 26.2, 25.5, 23.9, 20.7, 14.4; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.33。

6-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl-3, 4-dihydro-1H-quinolin-2-one (107LH18-2)

[0315]To a 4mL vial was added 1- (3-chloropropyl) -6-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH14) (0.128g), 4-propoxypiperidine (0.079g, 0.54mmol), KI (0.166g, 1.0mmol) and K dissolved in MeCN (2mL)₂CO₃(0.138g, 1.0mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc, MeOH/EtOAc 1: 4) to yield the title compound (107LH18-2) (0.108g, 50% overall yield).¹HNMR(CD₃OD)δ7.05-7.00(m，3H)，3.95(t，J＝7.2，CH₂)，3.41-3.30(m，3H)，2.84-2.76(m，4H)，2.57-2.53(m，2H)，2.47-2.43(m，2H)，2.27(s，3H，CH₃)，2.27-2.22(m，2H)，1.90-1.81(m，4H)，1.63-1.52(m，4H)，0.91(t，J＝7.4Hz，CH₃)；¹³C NMR(CD₃OD) delta 172.4, 137.8, 134.0, 129.8, 129.0, 128.0, 116.2, 75.3, 70.7, 56.5, 51.9, 41.2, 32.8, 31.7, 26.2, 25.5, 24.3, 20.7, 11.0; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.30。

1- [3- (4-Butylpiperidinyl-1-) propyl]-7-fluoro-3, 4-dihydro-1H-quinolin-2-one (107LH21)

[0316]To the reaction flask was added 7-fluoro-3, 4-bis dissolved in dry DMF (2mL) under argonhydro-1H-quinolin-2-one (97LH36) (0.080g, 0.48 mmol). NaH (60% in oil, 0.021g, 0.53mmol) was added and the mixture was stirred at room temperature for 0.5 h. 1-bromo-3-chloropropane (0.075g, 0.48mmol) was then added and the mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in MeCN (3mL) and 4-butylpiperidine (0.071g, 0.50mmol), KI (0.166g, 1.00mmol) and K were added₂CO₃(0.138g, 1.00mmol) and shaken at 50 ℃ for 4 days. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc) to afford the title compound (107LH21) (0.062g, 37%).¹HNMR(CD₃OD)δ7.20-7.17(m，1H)，7.01-6.98(m，1H)，6.76-6.72(m，1H)，3.95(t，J＝7.4Hz，CH₂)，2.93-2.84(m，4H)，2.61-2.57(m，2H)，2.42-2.38(m，2H)，2.00-1.94(m，2H)，1.84-1.80(m，2H)，1.68(d，J＝10.0Hz，2H)，1.30-1.22(m，9H)，0.89(t，J＝6.8Hz，CH₃) (ii) a HPLC-MS (ammonium acetate) [ M + H ]]⁺＝347.31。

1- [3- (4-Butylpiperidinyl-1-) propyl]-5-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH28)

[0317]To a 4mL vial was added 1- (3-chloropropyl) -5-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH27-11, 3) (0.057g, 0.24mmol), 4-butylpiperidine (0.042g, 0.30mmol), KI (0.083g, 0.50mmol) and K dissolved in MeCN₂CO₃(0.069g, 0.50mmol) and shaken at 50 ℃. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc, MeOH/EtOAc 1: 4) to yield the title compound (107LH28) (0.060g, 74%).¹H NMR(CD₃OD)δ7.15(t，J＝8.0Hz，1H)，7.03(d，J＝8.2Hz，1H)，6.92(d，J＝7.4Hz)，4.00(t，J＝7.2Hz，CH₂)，3.10(d，J＝12.1Hz，2H)，2.87-2.83(m，2H)，2.66-2.62(m，2H)2.59-2.55(m，2H)，2.31-2.25(m，2H)，2.29(s，CH₃)，1.93-1.87(m，2H)，1.76(d，J＝11.7Hz，2H)，1.31-1.24(m，9H)，0.90(t，J＝6.8Hz，CH₃)；¹³C NMR(CD₃OD) delta 172.7, 140.2, 137.0, 128.1, 126.6, 126.5, 114.5, 56.5, 54.6, 41.2, 37.0, 36.0, 32.2, 32.2, 30.0, 25.0, 23.9, 22.4, 19.7, 14.4; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.36。

1- [3- (4-Butylpiperidinyl-1-) propyl]7-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH29)

[0318]To a 4mL vial was added 1- (3-chloropropyl) -7-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH27-13, 1) (0.117g, 0.49mmol), 4-butylpiperidine (0.071g, 0.50mmol), KI (0.166g, 1.00mmol) and K in MeCN₂CO₃(0.138g, 1.00mmol) and shaken at 50 ℃. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc, MeOH/EtOAc 1: 4) to yield the title compound (107LH28) (0.060g, 74%).¹H NMR δ7.06(d，J＝7.4Hz，1H)，6.97(s，1H)，6.84(d.J＝7.6Hz，1H)，3.97(t，J＝7.4Hz，CH₂)，2.91(d，J＝11.2Hz，2H)，2.82(t，J＝6.8Hz，CH₂)，2.57-2.54(m，2H)，2.41-2.37(m，2H)，2.33(s，CH₃)，1.98-1.92(m，2H)，1.87-1.79(m，2H)，1.68(d，J＝9.6Hz，2H)，1.30-1.17(m，9H)，0.89(t，J＝6.8Hz，CH₃)；¹³C NMR(CD₃OD) delta 172.7, 140.1, 138.5, 128.9, 125.1, 124.9, 117.0, 57.0, 55.0, 41.3, 37.3, 36.8, 33.1, 30.1, 25.8, 25.6, 23.9, 21.6, 14.4; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.37。

1- [3- (4-Butylpiperidinyl-1-) propyl]-7-fluoro-6-methyl-3, 4-dihydro-1H-quinolin-2-one (112KK06)

[0319]Add solution to 4mL vial1- (3-chloropropyl) -7-fluoro-6-methyl-3, 4-dihydro-1H-quinolin-2-one (112KK01) (0.047g, 0.18mmol), 4-butylpiperidine (0.039g, 0.28mmol), NaI (0.100g, 0.67mmol) and K in MeCN (2mL)₂CO₃(0.075g, 0.54mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined, purified using cation exchange CC, then rapid CC (SiO)₂(ii) a MeOH/DCM 1: 10) to afford the title compound (112KK06) (0.022g, 34%).¹H NMR(CD₃OD)δ7.05(d，J＝8.4Hz，1H)，6.93(d，J＝11.7Hz，1H)，3.93(t，J＝7.2Hz，CH₂)，2.93(d，J＝11.1Hz，2H)，2.83(t，J＝6.9Hz，CH₂)，2.60-2.56(m，2H)，2.44-2.40(m，2H)，2.19(d，J＝1.8Hz，CH₃)2.03-1.98(m，2H)，1.86-1.79(m，2H)，1.69(d，J＝11.0Hz，2H)，1.31-1.19(m，9H)，0.89(t，J＝6.6Hz，CH₃)；¹³C NMR(CD₃OD)δ172.4，161.7(d，J＝241.0Hz)，139.5(d，J＝10.0Hz)，131.7(d，J＝6.1Hz)，123.5(d，J＝3.6Hz)，119.9(d，J＝17.4Hz)，104.0(d，J＝28.1Hz)，56.8，55.0，41.5，37.3，36.7，33.0，32.8，30.1，25.5，25.3，23.9，14.4，13.7。

[0320]The product was dissolved in MeOH/Et₂O, adding dissolved Et₂Oxalic acid in O. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.018 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.35。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (112KK07)

[0321]To a 4mL vial was added 1- (3-chloropropyl) -6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (112KK03) (0.123g, 0.47mmol), 4-butylpiperidine (0.074g, 0.52mmol), NaI (0.100g, 0.67mmol) and K dissolved in MeCN (2mL)₂CO₃(0.075g, 0.54mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined, purified using cation exchange CC, then rapid CC (SiO)₂(ii) a MeOH/DCM 1: 10) to afford the title compound (112KK07) (0.097g, 57%).¹H NMR(CD₃OD)δ7.20-7.09(m，2H)，3.91(t，J＝7.2Hz，CH₂)，2.90-2.82(m，4H)，2.59-2.55(m，2H)，2.38-2.34(m，2H)，1.97-1.91(m，2H)，1.82-1.75(m，2H)，1.66(d，J＝9.8Hz，2H)，1.28-1.16(m，9H)，0.87(t，J＝6.7Hz，CH₃)；¹³C NMR(CD₃OD)δ172.1，150.4(q，J＝243.2Hz，J＝13.2Hz)，146.9(q，J＝243.2Hz，J＝12.6Hz)，137.3(q，J＝8.1Hz，J＝2.9Hz)，124.9(q，J＝5.8Hz，J＝3.9Hz)，117.6(d，J＝18.7Hz)，106.4(d，J＝22.6Hz)，56.8，55.0，41.8，37.4，36.8，33.1，32.4，30.1，25.5，25.3，23.9，14.4。

[0322]The product was dissolved in MeOH/Et₂O, adding dissolved Et₂Oxalic acid in O. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.046 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝365.32。

6, 7-difluoro-1- [3- (4-propoxypiperidinyl-1-) propyl]-3, 4-dihydro-1H-quinolin-2-one (122LH7)

[0323]To a 4mL vial was added 1- (3-chloropropyl) -6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (112KK03) (0.286g, 1.1mmol), 4-propoxypiperidine (0.160g, 1.1mmol), KI (0.250g, 1.5mmol) and K dissolved in MeCN (2.5mL)₂CO₃(0.207g, 1.54mmol) and shaken at 40 ℃ for 2 days. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Cation exchange CC, fast CC (SiO) for crude product₂(ii) a EtOAc) and preparative RP-HPLC gave the title compound (122LH07) (0.165g, 41%).¹H NMR(CD₃OD)δ7.22-7.11(m，2H)，3.94(t，J＝7.2Hz，CH₂)，3.42-3.35(m，3H)，2.89-2.83(m，4H)，2.62-2.51(m，4H)，2.40-2.36(m，2H)，1.95-1.82(m，4H)，1.69-1.51(m，4H)，0.91(t，J＝7.2Hz，CH₃)；¹³CNMR(CD₃OD)δ172.0，150.3(q，J＝243.3Hz，J＝13.5Hz)，146.9(q，J＝243.3Hz，J＝12.7Hz)，137.3(q，J＝8.1Hz，J＝2.7Hz)，124.9(q，J＝5.8Hz，J＝3.8Hz)，117.6(d，J＝18.8Hz)，106.3(d，J＝22.7Hz)，74.8，70.7，56.1，51.7，41.5，32.3，31.4，25.5，25.1，24.3，11.0。

[0324]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.154 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝367.25。

(R, S) -1- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (122LH11-1)

[0325]To the reaction flask was added 6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (97KK47) (0.183g, 1.0mmol) dissolved in dry DMF (1mL) under argon. NaH (60% in oil, 0.050g, 1.3mmol) was added and the mixture was stirred at room temperature for 0.5 h. Then (R, S) -1-bromo-3-chloro-2-methylpropane (0.172g, 1.0mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. By fast CC (SiO)₂(ii) a EtOAc/n-heptane 1: 1) purification, the crude product was dissolved in DMF (0.5mL) and 4-butylpiperidine (0.085g, 0.6mmol), NaI (0.113g, 0.075mmol) and K were added₂CO₃(0.104g, 0.075mmol), and then stirred at 50 ℃ for 3 days. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was purified by cation exchange CC and preparative RP-HPLC to give the title compound (122LH 11-1).¹H NMR(CD₃OD)δ7.25-7.20(m，1H)，7.16-7.12(m，1H)，3.97(dd，J＝14.3Hz，J＝8.4Hz，1H)，3.85(dd，J＝14.5Hz，J＝5.1Hz，1H)，2.94-2.85(m，3H)，2.78(d，J＝9.4Hz，1H)，2.66-2.57(m，2H)，2.27-2.13(m，2H)，2.03-1.85(m，3H)，1.67-1.65(m，2H)，1.31-1.22(m，9H)，0.90(t，J＝6.6Hz，CH₃)，0.87(d，J＝6.7Hz，CH₃)。

[0326]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.025g, 7%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝379.27。

(R, S) -6, 7-difluoro-1- [3- (4-propoxypiperidinyl-1) -2-methylpropyl]-3, 4-dihydro-1H-quinoline-2- Ketones (122LH11-2)

[0327]To the reaction flask was added 6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one (97KK47) (0.183g, 1.0mmol) dissolved in dry DMF (1mL) under argon. NaH (60% in oil, 0.050g, 1.3mmol) was added and the mixture was stirred at room temperature for 0.5 h. Then (R, S) -1-bromo-3-chloro-2-methylpropane (0.172g, 1.0mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. By fast CC (SiO)₂(ii) a EtOAc/n-heptane 1: 1) purification, the crude product was dissolved in DMF (0.5mL) and 4-butylpiperidine (0.085g, 0.6mmol), NaI (0.113g, 0.075mmol) and K were added₂CO₃(0.104g, 0.075mmol), and then stirred at 50 ℃ for 3 days. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was purified using cation exchange CC and preparative RP-HPLC to give the crude title compound (122LH 11-2).¹H NMR(CD₃OD)δ7.24-7.12(m，2H)，3.97(dd，J＝14.5Hz，J＝8.6Hz，1H)，3.87(dd，J＝14.3Hz，J＝5.1Hz，1H)，3.41(t，J＝6.7Hz，CH₂)，3.35-3.28(m，1H)，2.89-2.85(m，2H)，2.78-2.75(m，1H)，2.66-2.59(m，3H)，2.26-2.21(m，1H)，2.17-2.11(m，2H)，2.07-1.97(m，2H)，1.90-1.86(m，2H)，1.61-1.51(m，4H)，0.92(t，J＝7.4Hz，CH₃)，0.86(d，J＝6.6Hz，CH₃)；¹³CNMR(CD₃OD)δ172.5，150.3(q，J＝242.9Hz，J＝13.1Hz)，146.8(q，J＝243.3Hz，J＝13.1Hz)，137.3(q，J＝8.1Hz，J＝2.7Hz)，125.1(q，J＝5.8Hz，J＝3.8Hz)，117.6(d，J＝18.8Hz)，106.7(d，J＝22.7Hz)，76.3，70.9，64.5，53.4，52.8，47.1，32.5，32.4，30.5，25.5，24.3，17.2，11.0。

[0328]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.030g, 8%). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝381.27。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH93-1)

[0329]In N₂Next, 6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (0.150g, 0.84mmol) dissolved in dry DMF (1mL) was added to the reaction flask. NaH (60% in oil, 0.038g, 0.92mmol) was added and stirred at room temperature for 30 min. Then 3-chloro-1-iodopropane (0.131g, 0.84mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in MeCN (2mL) and 4-butylpiperidine (0.085g, 0.6mmol), NaI (0.150g, 1.0mmol) and K were added₂CO₃(0.138g, 1.0mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The residue was purified by cation exchange CC followed by fast CC (SiO)₂(ii) a EtOAc) to afford the title compound (107LH93-1) (0.166g, 55% overall yield).¹H NMR(CH₃OD)δ7.00(d，J＝6.4Hz，1H)，6.88(d，J＝9.2Hz，1H)，3.98-3.91(m，2H)，2.93-2.86(m，2H)，2.85-2.78(m，2H)，2.58-2.52(m，2H)，2.40-2.43(m，2H)，2.25(d，J＝2.0Hz，3H)，1.98-1.76(m，4H)，1.70-1.62(m，2H)，1.35-1.22(m，9H)，0.88(t，J＝7.0Hz，3H)；¹³CNMR(CH₃OD)δ171.1，157.2(d，J＝241Hz)，135.1(d，J＝3Hz)，126.5(d，J＝8Hz)，123.2(d，J＝18Hz)，118.1(d，J＝5Hz)，114.3(d，J＝24Hz)，55.8，43.9，40.4，36.2，35.7，32.0，31.5，29.0，24.6，24.3，22.8，13.4(br)。

[0330]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.172 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.4。

6-fluoro-7-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl]-3, 4-dihydro-1H-quinolin-2-one (107LH93-2)

[0331]In N₂Next, 6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (0.150g, 0.84mmol) dissolved in dry DMF (1mL) was added to the reaction flask. NaH (60% in oil, 0.038g, 0.92mmol) was added and stirred at room temperature for 30 min. Then 3-chloro-1-iodopropane (0.131g, 0.84mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in MeCN (2mL) and 4-propoxypiperidine (0.086g, 0.6mmol), NaI (0.150g, 1.0mmol) and K were added₂CO₃(0.138g, 1.0mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The residue was purified by cation exchange CC followed by fast CC (SiO)₂(ii) a EtOAc) to afford the title compound (107LH93-2) (0.171g, 56% overall yield).¹H NMR(CH₃OD)δ7.00(d，J＝6.4Hz，1H)，6.87(d，J＝9.2Hz，1H)，3.94(brt，J＝7.2Hz，2H)，3.39(t，J＝6.6Hz，2H)，3.35-3.26(m，1H)，2.85-2.70(m，4H)，2.58-2.51(m，2H)，2.39(brt，7.4Hz，2H)，2.24(d，J＝1.6Hz，3H)，2.21-2.12(m，2H)，1.92-1.75(m，4H)，1.62-1.48(m，4H)，0.91(t，J＝7.4Hz)；¹³C NMR(CH₃OD)δ171.0，157.1(d，J＝241)，135.2(d，J＝3Hz)，126.5(d，J＝8Hz)，123.2(d，J＝18Hz)，118.1(d，J＝5Hz)，114.3(d，J＝24Hz)，74.6，69.5，55.4，51.0，40.4，31.5，30.9，24.7，24.5，23.2，13.5(br)，10.0。

[0332]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.172 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝364.3。

(R, S) -1- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-6-fluoro-7-methyl-3, 4-dihydro-1H-quinoline -2-one (107LH94-1)

[0333]In N₂Next, 6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (0.150g, 0.84mmol) dissolved in dry DMF (1mL) was added to the reaction flask. NaH (60% in oil, 0.038g, 0.92mmol) was added and stirred at room temperature for 30 min. Then (R, S) -1-bromo-3-chloro-2-methylpropane (0.144g, 0.84mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in dry DMF (2mL) and 4-butylpiperidine (0.085g, 0.6mmol), NaI (0.150g, 1.0mmol) and K were added₂CO₃(0.138g, 1.0mmol) and shaken at 100 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The residue was purified by cation exchange CC followed by fast CC (SiO)₂(ii) a EtOAc) to afford the title compound (107LH94-1) (0.045g, overall yield 14%).¹H NMR(CH₃OD)δ7.01(d，J＝6.4Hz，1H)，6.90(d，J＝9.2Hz)，4.03-3.88(m，2H)，2.90(brd，J＝10.8Hz，2H)，2.83(brt，J＝7.0Hz，2H)，2.75(brd，J＝10.2Hz)，2.64-2.50(m，2H)，2.26-1.98(m，6H)，1.93-1.78(m，2H)，1.68-1.58(m，2H)，1.35-1.148(m，9H)，0.89(t，J＝6.8Hz，3H)，0.84(d，J＝6.8Hz，3H)；¹³C NMR(CH₃OD)δ171.6，156.1(d，J＝241Hz)，135.1(d，J＝3Hz)，126.9(d，J＝8Hz)，123.0，(d，J＝19Hz)，118.6(d，J＝5Hz)，114.3(d，J＝24Hz)，63.9，55.1，54.4，45.5，36.3，35.9，32.4(br)，31.6，29.0，28.8，24.6，22.8，16.0，13.5(br)。

[0334]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.037 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝375.3。

(R, S) -6-fluoro-7-methyl-1- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl-3, 4-dihydro-1H-quina-zine Lin-2-one (107LH94-2)

[0335]In N₂Next, 6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one (0.150g, 0.84mmol) dissolved in dry DMF (1mL) was added to the reaction flask. NaH (60% in oil, 0.038g, 0.92mmol) was added and stirred at room temperature for 30 min. Then (R, S) -1-bromo-3-chloro-2-methylpropane (0.144g, 0.84mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in dry DMF (2mL) and 4-propoxypiperidine (0.086g, 0.6mmol), NaI (0.150g, 1.0mmol) and K were added₂CO₃(0.138g, 1.0mmol) and shaken at 100 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The residue was purified with cation-exchanged CC followed by flash CC (SiO 2; EtOAc) to give the title compound (107LH94-2) (0.033g, 10% overall yield).¹H NMR(CH₃OD)δ7.02(d，J＝6.8Hz，1H)，6.91(d，J＝9.6Hz，1H)，3.95(d，J＝7.2Hz，2H)，3.41(t，J＝6.6Hz，2H)，3.33-3.25(m，1H)，2.84(brt，J＝7.4Hz)，2.79-2.71(m，1H)，2.67-2.51(m，3H)，2.28-1.98(m，8H)，1.92-1.83(m，2H)，1.60-1.48(m，4H)，0.91(t，J＝7.6Hz，3H)，0.85(d，J＝6.4Hz，3H)；¹³C NMR(CH₃OD)δ171.7，157.2(d，J＝241Hz)，135.1(d，J＝3Hz)，126.9(d，J＝8Hz)，123.1(d，J＝18Hz)，114.3(d，J＝24Hz)，75.2，69.5，52.1，51.7，45.5，31.6，31.3，29.0，24.6，23.1，15.9，13.5，13.3，9.8。

[0336]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.036 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝377.3。

1- [3- (4-butyl-piperidinyl-1-) propyl]-6-fluoro-5-methyl-3, 4-dihydro-1H-quinolin-2-one (107LH95-1)

[0337]In N₂Next, 6-fluoro-5-methyl-3, 4-dihydro-1H-quinolin-2-one (0.090g, 0.50mmol) dissolved in dry DMF (0.5mL) was added to the reaction flask. NaH (60% in oil, 0.023g, 0.55mmol) was added and stirred at room temperature for 30 min. Then 3-chloro-1-iodopropane (0.079g, 0.50mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in MeCN (2mL) and 4-butylpiperidine (0.085g, 0.6mmol), NaI (0.150g, 1.0mmol) and K were added₂CO₃(0.138g, 1.0mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The residue was purified by cation exchange CC followed by fast CC (SiO)₂(ii) a EtOAc) to afford the title compound (107LH95-1) (0.059g, 33% overall yield).¹H NMR(CH₃OD)δ7.02(dd，J＝4.8，9.2Hz，1H)，6.98-6.92(m，1H)，3.95(brt，J＝7.4Hz，2H)，2.92-2.82(m，4H)，2.59-2.52(m，2H)，2.39-2.32(m，2H)，2.00(d，J＝1.6Hz，3H)，1.97-1.75(m，4H)，1.66(brd，10.8Hz，2H)，1.35-1.12(m，9H)，0.89(t，J＝6.4Hz)；¹³C NMR(CH₃OD)δ170.9，157.6(d，J＝240Hz)，135.4(d，J＝3Hz)，128.1(d，J＝4Hz)，122.7(d，J＝18Hz)，114.2(d，J＝8Hz)，112.9，(d，J＝25Hz)，55.9，53.9，40.6，36.2，35.7，31.9，30.9，28.9，24.4，22.8，21.4(br)，13.2，9.7(br)。

[0338]Dissolving the product in acetone, adding acetone-soluble grassAcid (1.1 eq). The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.058 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

6-fluoro-5-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl]-3, 4-dihydro-1H-quinolin-2-one (107LH95-2)

[0339]In N₂Next, 6-fluoro-5-methyl-3, 4-dihydro-1H-quinolin-2-one (0.090g, 0.50mmol) dissolved in dry DMF (0.5mL) was added to the reaction flask. NaH (60% in oil, 0.023g, 0.55mmol) was added and stirred at room temperature for 30 min. Then 3-chloro-1-iodopropane (0.079g, 0.50mmol) was added, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The crude product was dissolved in MeCN (2mL) and 4-propoxypiperidine (0.086g, 0.6mmol), NaI (0.150g, 1.0mmol) and K were added₂CO₃(0.138g, 1.0mmol) and shaken at 50 ℃ for 20 h. The reaction mixture was quenched with water and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. The residue was purified by cation exchange CC followed by fast CC (SiO)₂(ii) a EtOAc) to afford the title compound (107LH95-2) (0.074g, 41% overall yield).¹H NMR(CH₃OD)δ7.03(dd，J＝4.8，9.2Hz，1H)，6.99-6.92(m，1H)，3.98(brt，J＝7.4Hz，2H)，3.46-3.38(m，3H)，2.95-2.84(m，4H)，2.64-2.42(m，6H)，2.20(d，J＝2.0Hz，3H)，1.98-1.83(m，4H)，1.72-1.30(m，4H)，0.92(t，J＝7.4Hz，3H)；¹³C NMR(CH₃OD)δ171.1，157.7(d，J＝240Hz)，135.4(d，J＝3Hz)，128.1(d，J＝4Hz)，122.8(d，J＝18Hz)，114.1(d，J＝9Hz)，113.0(d，J＝25Hz)，73.1，69.7，55.0，50.3，40.3，30.8，29.9，23.9，23.1，22.7，21.4，9.8(br)。

[0340]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.067 g). HPLC-MS (ammonium acetate))[M+H]⁺＝363.3。

(R) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl-3, 4-dihydro-1H-quinolin-2-one (107LH47-A)

[0341]A4 mL vial was charged with (S) -1- (3-iodo-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (122LH18) (0.329g, 1.0mmol) and 4-butylpiperidine (0.283g, 2.0mmol) dissolved in MeCN (2mL) and shaken for 20H at 60 ℃. The reaction mixture was concentrated and the product was purified using fast CC (SiO)₂(ii) a EtOAc, EtOAc/MeOH 4: 1) to yield the title compound (107LH47-A) (0.186g, 54%).¹H NMR(CD₃OD)δ7.26-7.19(m，3H)，7.04-7.00(m，1H)，2.93-2.88(m，3H)，2.77(d，J＝10.4Hz，2H)，2.62-2.58(m，2H)，2.29-2.06(m，3H)，1.93-1.86(m，2H)，1.68-1.62(m，2H)，1.31-1.22(m，9H)，0.91-0.86(m，2CH₃)；¹³C NMR(CD₃OD)δ173.2，140.3，129.1，128.5，128.4，124.4，166.9，64.9，56.0，55.6，37.5，36.9，33.4，33.3，32.9，30.1，30.1，26.2，24.0，17.2，14.4。

[0342]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.222 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.33。

(R) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-3, 4-dihydro-1H-quinolin-2-one (107LH48)

[0343]A4 mL vial was charged with (S) -1- (3-iodo-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (122LH18) (0.493g, 1.5mmol) and 4-propoxypiperidine (0.430g, 3.0mmol) dissolved in MeCN (2mL) and shaken for 20H at 60 ℃. The reaction mixture was quenched with water, basified with ammonium hydroxide and the product extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc, EtOAc/MeOH 4: 1) to yield the title compound (107LH48) (0.197g, 38%).¹H NMR(CD₃OD)δ7.26-7.19(m，3H)，7.03-6.98(m，1H)，3.96(d，J＝7.0Hz，2H)，3.40(t，J＝6.7Hz，2H)，2.90-2.86(m，2H)，2.74-2.71(m，1H)，2.65-2.54(m，3H)，2.26-1.99(m，6H)，1.87-1.84(m，2H)，1.59-1.49(m，4H)，0.91(t，J＝7.4Hz，CH₃)，0.85(d，J＝6.6Hz，CH₃)；¹³CNMR(CD₃OD)δ173.0，140.3，129.1，128.4，128.4，124.3，116.8，76.3，70.7，64.5，53.2，52.8，32.9，32.4，32.4，30.3，26.2，24.3，17.1，11.0。

[0344]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.189 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.31。

(R) -1- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-3, 4-dihydro-1H-quinolin-2-one (107LH53)

[0345]A4 mL vial was charged with (S) -1- (3-iodo-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (122LH18) (0.169g, 0.51mmol) and 4-butylidenepiperidine (0.200g, 1.4mmol) dissolved in MeCN (2mL) and shaken for 20H at 40 ℃. The reaction mixture was quenched with water, basified with ammonium hydroxide and the product extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a n-heptane/EtOAc 4: 1) to yield the title compound (107LH53) (0.116g, 67%).¹H NMR(CD₃OD)δ7.23-7.18(m，3H)，7.02-6.98(m，1H)，5.11(t，J＝7.4Hz，1H)，3.98(d，J＝6.8Hz，2H)，2.89-2.85(m，2H)，2.61-2.56(m，2H)，2.40-2.35(m，2H)，3.32-2.04(m，11H)，1.98-1.92(m，2H)，1.36-1.29(m，2H)，0.90-0.85(m，2CH3)；¹³C NMR(CD₃OD)δ173.0，140.3，137.1，129.1，128.4，128.4，124.3，123.7，116.9，64.6，57.4，56.6，46.5，37.0，32.9，30.2，30.1，29.1，26.3，24.2，17.2，14.1。

[0346]Dissolving the product in acetone, adding the solutionOxalic acid. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.130 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝341.33。

(R) -1- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-3, 4-dihydro-1H-quinoline -2-ketones (107LH54)

[0347]To a 4mL vial were added (S) -1- (3-iodo-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (122LH18) (0.185g, 0.56mmol) and 3-butyl-8-azabicyclo [3.2.1] dissolved in MeCN (0.5mL)]Octane (0.100g, 0.60mmol) and shaken at 40 ℃ for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide and the product extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a n-heptane/EtOAc 4: 1) to yield the title compound (107LH54) (0.063g, 30%).¹H NMR(CD₃OD)δ7.29-7.19(m，3H)，7.03-6.99(m，1H)，4.03-4.00(m，2H)，3.14-3.13(m，1H)，3.07-3.05(m，1H)，2.90-2.86(m，2H)，2.62-2.57(m，2H)，2.28-2.19(m，2H)，1.97-1.82(m，3)，1.58-1.42(m，5H)，1.34-1.15(m，8H)，0.90-0.87(m，6H)；¹³C NMR(CD₃OD)δ173.1，140.3，129.1，128.4，128.3，124.3，117.2，62.2，61.2，58.2，46.5，39.0，38.0，32.9，32.1，30.3，29.1，27.8，27.3，26.3，24.0，17.1，14.5。

[0348]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.064 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝369.34。

(R) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1]]Octyl-8-) propyl-3, 4-dihydro-1H-quinoline -2-ketones (107LH55)

[0349]To a 4mL vial were added (S) -1- (3-iodo-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (122LH18) (0.185g, 0.56mmol) and 3-pentyl-8-azabicyclo [ in MeCN (0.5mL) ]3.2.1]Octane (0.112g, 0.62mmol) and shaken at 40 ℃ for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide and the product extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a n-heptane/EtOAc 4: 1) to yield the title compound (107LH55) (0.075g, 35%).¹H NMR(CD₃OD)δ7.28-7.18(m，3H)，7.01(t，J＝7.2Hz，1H)，4.03(d，J＝7.0Hz，2H)，3.11-3.04(m，2H)，2.90-2.85(m，2)，2.64-2.56(m 2H)，2.28-2.11(m，4H)，1.97-1.84(m，3H)，1.66-1.54(m，3H)，1.42-1.21(m，10H)，0.90-0.85(m，2CH₃)；¹³C NMR(CD₃OD)δ173.1，140.3，129.1，128.4，128.3，124.3，117.1，61.4，60.2，58.3，46.4，39.5，37.1，37.0，33.1，32.9，32.2，29.5，29.4，28.5，27.9，26.3，23.7，17.1，14.4。

[0350]The product is dissolved in acetone and oxalic acid dissolved in acetone is added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.054 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝383.35。

1- [3- (4-Butylpiperidinyl-1-) propyl]-1H-quinolin-2-one (092LH70-A)

[0351]To a 7mL vial was added 1- (3-chloropropyl) -1H-quinolin-2-one (0.450g, 2.0mmol), K₂CO₃(0.34g, 2.5mmol), KI (0.42g, 2.5mmol), 4-butylpiperidine (0.30g, 2.1mmol) and dry CH₃CN (3 mL). The mixture was shaken at 50 ℃ for 60h, then diluted with EtOAc (50mL) and washed with water (50 mL). The aqueous phase was extracted with EtOAc (2X 50 mL). The organic phases were combined with Na₂SO₄Drying, filtering, and concentrating under reduced pressure. Rapid CC (SiO) for residue₂(ii) a EtOAc/MeOH 4: 1) followed by preparative RP-HPLC gave the title compound (0.32g, 49%).¹H NMR(CD₃OD)δ7.88(d，J＝9.6Hz)，7.68(brd，J＝8.0Hz)，7.65-7.61(m，2H)，7.33-7.25(m，1H)，6.64(d，9.6Hz)，4.39-4.32(m，2H)，2.95-2.86(m，2H)，2.50-2.43(m，2H)，2.01-1.86(m，4H)，1.71-1.62(m，2H)，1.35-1.12(m，9H)，0.89(t，J＝6.6Hz)；¹³C NMR(CD₃OD)δ163.1，140.4，139.0，131.1，129.2，122.6，121.4，120.3，114.7，55.8，53.9，40.6，36.2，35.7，32.0，28.9，24.7，22.8，13.2。

[0352]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.356 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝327.3。

1- [3- (4-propoxypiperidinyl-1-) propyl]-1H-quinolin-2-one (092LH69)

[0353]To a 4mL vial was added 1- (3-chloropropyl) -1H-quinolin-2-one (0.069g, 0.31mmol), K₂CO₃(0.069g, 0.50mmol), KI (0.083g, 0.50mmol), 4-propoxypiperidine (0.050g, 0.35mmol) and dry CH₃CN (2 mL). The mixture was shaken at 50 ℃ for 24h, then diluted with water (25mL) and EtOAc (25 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2X 50 mL). The organic phases were combined with Na₂SO₄Drying, filtering, and concentrating under reduced pressure. Rapid CC (SiO) for residue₂(ii) a EtOAc/MeOH 4: 1) followed by preparative RP-HPLC gave the title compound (0.060g, 59%).¹H NMR(CD₃OD)δ7.85(d，J＝9.4Hz，1H)，7.65(brd，J＝7.2Hz，1H)，7.63(m，2H)，7.29-7.22(m，1H)，6.62，(d，J＝9.4Hz)，4.36-4.29(m，1H)，3.38(t，J＝6.6Hz，2H)，3.34-3.24(m，1H)，2.78-2.69(m，2H)，2.48-2.41(m，2H)，2.18-2.09(m，2H)，1.94-1.82(m，4H)，1.59-1.47(m，4H)，0.90(t，J＝7.4Hz)；¹³CNMR(CD₃OD) δ 162.0, 140.3, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 74.7, 69.5, 55.4, 51.0, 40.6, 31.0, 24.9, 32.1, 9.9; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝329.3。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6-fluoro-1H-quinolin-2-one (107LH22)

[0354]To a 4mL vial was added6-fluoro-1H-quinolin-2-one (00.56g, 0.34mmol), dry DMF (2mL), and NaH (60% in oil, 0.015g, 0.34mmol) were added. In N₂The mixture was stirred at room temperature for 1h, followed by addition of 1-bromo-3-chloropropane (34. mu.l, 0.34mmol), and then shaking the mixture at room temperature for 20 h. The reaction was diluted with ether (25mL) and washed with water (15 mL). The organic phase was washed with water (15mL) and brine (15mL), Na₂SO₄Drying, and concentrating under reduced pressure. By CH₃CN (2mL) diluted the oily residue, KI (0.083g, 0.50mmol) and K were added₂CO₃(0.069g, 0.50mmol) and 4-butylpiperidine (0.048g, 0.34 mmol). The mixture was shaken at 50 ℃ for 72h, then diluted with EtOAc (25mL) and washed with water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by cation exchange CC followed by fast CC (SiO)₂(ii) a EtOAc/MeOH 4: 1) to yield the title compound (0.034g, 29%).¹H NMR(CD₃OD)δ7.90(d，J＝9.2Hz，1H)，7.69(dd，J＝4.0，8.8Hz，1H)，7.50-7.41(m，2H)，6.72(d，J＝8.8Hz，1H)，4.41(t，J＝6.8Hz，2H)，3.02-2.95(m，2H)，2.65-2.60(m，2H)，2.19-2.08(m，2H)，1.91-1.82(m，4H)，1.53-1.21(m，9H)，0.90(t，J＝7.0Hz)；¹³C NMR(CD₃OD) δ 169.9, 158.4(d, J-242 Hz), 139.8(d, J-3 Hz), 134.4(d, J-2 Hz), 122.5(d, J-9 Hz), 121.6, 119.9(d, J-24 Hz), 116.8(d, J-8 Hz), 113.9 (d-23 Hz), 54.4, 53.0, 40.1, 34.5, 34.1, 30.1, 28.7, 23.3, 22.6, 13.2; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.3。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6-methyl-1H-quinolin-2-one (107LH32-A)

[0355]A4 mL vial was charged with 6-methyl-1H-quinolin-2-one (0.110g, 0.71mmol), dry DMF (2mL), and NaH (60% in oil, 0.031g, 0.78 mmol). In N₂The mixture was shaken for 1h, followed by the addition of 1-bromo-3-chloropropane (70. mu.l, 0.71 mmol). The reaction was shaken at room temperature for 20h, then poured into ether (25mL) and washed with water (15 mL). The ether phase was washed with water (15mL) and brine (15 mL). Organic phaseWith Na₂SO₄Drying, and concentrating under reduced pressure. By CH₃CN (2mL) diluted the residue, to which KI (0.160g, 1.0mmol) and K were added₂CO₃(0.140g, 1.0mmol) and 4-butylpiperidine (0.100g, 0.71 mmol). The mixture was shaken at 50 ℃ for 72h, then poured into EtOAc (25mL) and water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. Rapid CC (SiO) for residue₂(ii) a EtOAc/MeOH 4: 1) followed by preparative RP-HPLC gave the title compound (0.058g, 23%).¹H NMR(CD₃OD)δ7.78(d，J＝9.2Hz，1H)，7.52-7.40(m，3H)，6.60(d，J＝9.2Hz，1H)，4.3(t，J＝7.6Hz，2H)，2.92-2.2.85(m，2H)，2.50-2.39(m，2H)，2.39(s，3H)，1.99-1.84(m，4H)，1.69-1.61(m，2H)，1.35-1.11(m，9H)，0.88(t，J＝6.8Hz)；¹³C NMR(CD₃OD) δ 162.9, 140.1, 137.0, 132.5, 132.3, 128.8, 121.4, 120.2, 114.6, 55.8, 53.9, 40.6, 36.2, 35.7, 32.0, 28.9, 24.8, 22.8, 19.4, 13.3; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝341.3。

1- [3- (4-Butylpiperidinyl-1) propyl group]-7-fluoro-1H-quinolin-2-one (107LH33-A)

[0356]A4 mL vial was charged with 7-fluoro-1H-quinolin-2-one (0.032g, 0.19mmol), NaH (60% in oil, 8.7mg, 0.21mmol), and dry DMF (2.5 mL). The mixture was shaken at room temperature for 1h, then 1-bromo-3-chloropropane (20. mu.l, 0.19mmol) was added and the reaction was shaken at room temperature overnight. The mixture was diluted with ether (25mL), washed with water (15mL), and the ether phase was washed with water (15mL) and brine (15 mL). Na for organic phase₂SO₄Drying, and concentrating under reduced pressure. By CH₃CN (2mL) diluted the oily residue and to the resulting solution was added: KI (0.050g, 0.30mmol), K₂CO₃(0.041g, 0.30mmol) and 4-butylpiperidine (0.028g, 0.20 mmol). The mixture was shaken at 50 ℃ for 72h, then poured into EtOAc (25mL) and water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. Rapid CC (SiO) for residue₂；EtOAc/MeOH 4∶1) Purification, followed by preparative RP-HPLC, gave the title compound (7.0mg, 11%).¹HNMR(CD₃OD)δ7.89(d，J＝9.6Hz，1H)，7.73(dd，J＝6.2，8.6Hz，1H)，7.47(dd，J＝2.4，11.6Hz，1H)，7.08(dt，J＝2.4，8.6Hz，1H)，6.60(dJ＝9.6Hz，1H)，4.33(t，J＝7.6Hz，2H)，2.98-2.00(m，2H)，2.50-2.42(m，2H)，2.05-1.86(m，4H)，1.55-1.64(m，2H)，1.36-1.15(m，9H)，0.90(t，J＝6.8Hz)；¹³C NMR(CD₃OD) δ 164.7(d, J ═ 248), 163.2, 140.9(br), 139.9, 131.4(d, J ═ 10Hz), 119.3(d, J ═ 3Hz), 118.1(br), 110.6(d, J ═ 23Hz), 101.6(d, J ═ 28Hz), 55.5, 53.9, 41.0, 36.8, 35.6, 31.9, 28.9, 24.5, 22.7, 13.2; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.3。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6-methoxy-1H-quinolin-2-one (107LH37-A)

[0357]A4 mL vial was charged with 6-methoxy-1H-quinolin-2-one (0.032g, 0.18mmol), dry DMF (2mL), and NaH (60% in oil, 8mg, 0.20mmol), followed by N₂The mixture was stirred at 45 ℃ for 45min, then 1-bromo-3-chloropropane (18 μ l, 0.18mmol) was added and the mixture was shaken at 30 ℃ overnight. The reaction was diluted with ether (25mL), washed with water (15mL), the ether phase washed with water (15mL) and brine (15mL), Na₂SO₄Drying, and concentrating under reduced pressure. By CH₃CN (3mL) diluted the oily residue, KI (0.080g, 0.50mmol) and K were added₂CO₃(0.070g, 0.50mmol) and 4-butylpiperidine (0.028g, 0.20 mmol). The mixture was shaken at 50 ℃ for 48h, then diluted with EtOAc (25mL) and washed with water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by preparative RP-HPLC to give the title compound (0.028g, 44%).¹H NMR(CD₃OD)δ7.85(d，J＝9.6Hz，1H)，7.56(d，J＝9.2Hz，1H)，7.26(dd，J＝2.8，9.6Hz，1H)，7.19(d，J＝2.8Hz，1H)，6.65(d，J＝9.6Hz，1H)，4.34(t，J＝7.2Hz，2H)，3.85(s，3H)，3.07-2.98(m，2H)，2.64-2.58(m，2H)，2.19-2.10(m，2H)，2.04-1.94(m，2H)，1.76-1.66(m，2H)，1.35-0.96(m，9H)，0.89(t，J＝6.8Hz)；¹³C NMR(CD₃OD) δ 162.7, 155.5, 140.1, 133.3, 122.3, 120.6, 120.1, 116.1, 110.5, 55.3, 55.0, 53.6, 40.5, 36.0, 35.2, 31.4, 28.8, 24.4, 22.7, 13.2; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝357.3。

1- [3- (4-Butylpiperidinyl-1-) propyl]-6-chloro-1H-quinolin-2-one (107LH38-A)

[0358]To a 4mL vial was added 6-chloro-1H-quinolin-2-one (107LH35) (0.085g, 0.47mmol), dry DMF (3mL), and NaH (60% in oil, 0.023g, 0.56mmol) in N₂The mixture was stirred at room temperature for 45 min. 1-bromo-3-chloropropane (18. mu.l, 0.18mmol) was then added, the mixture was shaken overnight at room temperature, the reaction was diluted with ether (25mL) and washed with water (15 mL). The ether phase was washed with brine (15mL) and Na₂SO₄Drying, and concentrating under reduced pressure. By dry CH₃CN (2mL) diluted the oily residue, KI (0.170g, 1.0mmol) and K were added₂CO₃(0.140g, 1.0mmol) and 4-butylpiperidine (0.071g, 0.50 mmol). The mixture was shaken at 50 ℃ for 24h, then diluted with EtOAc (25mL) and washed with water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by preparative RP-HPLC to give the title compound (32mg, 89. mu. mol, 19%).¹H NMR(CD₃OD)δ7.80(d，J＝9.2Hz，1H)，7.66(brs，1H)，7.60-7.51(m，2H)，6.65(d，J＝9.6Hz，1H)，5.30(t，J＝7.6Hz，2H)，3.09-2.95(m，2H)，2.68-2.57(m，2H)，2.24-2.06(m，2H)，2.00-1.90(m，2H)，1.75-1.64(m，2H)，1.32-1.12(m，9H)，0.84(t，6.4Hz，3H)；¹³C NMR(CD₃OD) δ 162.6, 139.2, 137.4, 130.8, 128.0, 127.8, 122.4, 121.5, 116.3, 55.0, 53.3, 40.3, 35.7, 34.8, 31.0, 28.6, 23.9, 22.5, 13.0; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.3。

1- [3- (4-Butylpiperidinyl-1-) propyl]-5-methyl-1H-quinolin-2-one (107LH45)

[0359]To a 4mL vial was added the solution in CH₃1- (3-chloropropyl) -5-methyl-1H-quinolin-2-one (0.053g, 0.23mmol), KI (0.083g, 0.5mmol) in CN (2mL), K₂CO₃(0.069g, 0.50mmol) and 4-butylpiperidine (50. mu.l, 0.30 mmol). The mixture was shaken at 50 ℃ for 72h, then diluted with EtOAc (25mL) and washed with water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. Rapid CC (SiO) for residue₂(ii) a EtOAc/MeOH 1: 4) to yield the title compound (0.058g, 74%).¹H NMR(CD₃OD)δ8.13(d，J＝9.8Hz，1H)，7.56-7.46(m，2H)，7.15(brd，6.8Hz，2H)，6.67(d，J＝9.8Hz，1H)，4.38(t，J＝7.2Hz，2H)，3.10-3.03(m，2H)，2.68-2.61(m，2H)，2.57(s，3H)，2.25-2.15(m，2H)，2.04-1.95(m，2H)，1.78-1.69(m，2H)，1.36-1.16(m，9H)，0.89(t，J＝7.0Hz，3H)；¹³C NMR(CD₃OD) δ 162.3, 138.7, 136.6, 136.2, 130.4, 123.6, 119.4, 118.9, 112.4, 54.7, 52.9, 39.9, 35.3, 34.5, 30.7, 28.2, 23.7, 22.1, 17.3, 12.6; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝341.3。

1- [3- (4-butyl-piperidinyl-1-) propyl]-7-methyl-1H-quinolin-2-one (107LH46-A)

[0360]To a 4mL vial was added the solution in CH₃1- (3-chloro-propyl) -7-methyl-1H-quinolin-2-one 107LH40(0.130g, 0.56mmol), KI (0.170g, 1.0mmol), K in CN (2mL)₂CO₃(0.140g, 1.0mmol) and 4-butylpiperidine (100. mu.l, 0.60 mmol). The mixture was shaken at 50 ℃ for 72h, then poured into EtOAc (25mL) and water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified using flash CC (SiO 2; EtOAc/MeOH 1: 4) to give the title compound (0.017g, 6%).¹H NMR(CD₃OD)δ7.84(d，J＝9.4Hz)，7.56(d，J＝8.0Hz，1H)，7.43(brs，1H)，7.14(brd，J＝8Hz，1H)，6.58(d，J＝9.4Hz)，4.36(d，J＝7.2Hz，2H)，3.02-2.95(m，2H)，2.57-2.48(m，2H)，2.51(s，3H)，2.09-1.91(m，4H)，1.75-1.65(m，2H)，1.36-1.16(m，9H)，0.89(t，J＝6.8Hz，3H)；¹³C NMR(CD₃OD) δ 163.3, 142.2, 140.3, 139.1, 129.1, 124.1, 119.3, 119.0, 114.7, 55.6, 53.8, 40.4, 36.1, 35.5, 31.8, 28.9, 24.6, 22.7, 21.1, 13.2; HPLC-MS (ammonium acetate) [ M + H ]]⁺＝341.3。

(R) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl]-1H-quinolin-2-one (107LH52)

[0361]To a 4mL vial was added the crude product of (S) -1- (3-iodo-2-methyl-propyl) -1H-quinolin-2-one (0.66g), 4-butylpiperidine (0.43g, 3.0mmol), and dry CH₃CN (1 mL). The mixture was shaken at 50 ℃ for 72h, then poured into EtOAc (50mL) and water (25 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. Rapid CC (SiO) for residue₂(ii) a EtOAc/MeOH 1: 4) and then cation exchange CC to afford the title compound (0.300g, 44%).¹H NMR(CD₃OD)δ7.88(d，J＝9.2Hz，1H)，7.73-7.66(m，2H)，7.61(t，J＝8.0Hz，1H)，7.29(t，J＝7.4Hz，1H)，6.65(d，J＝9.2Hz，1H)，4.42-4.26(m，2H)，2.90(brd，J＝11.4Hz，1H)，2.74(brd，J＝11.4Hz，1H)，2.40-2.16(m，3H)，1.94-1.78(m，2H)，1.64-1.54(m，2H)，1.35-1.00(m，9H)，0.96-0.85(m，6H)；¹³C NMR(CD₃OD)δ163.7，140.2，139.5，130.8，129.1，122.5，121.4，120.4，115.3，64.0，55.1，54.2，46.8，36.3，35.8，32.4，32.3，29.8，28.9，22.8，16.1，13.2。

[0362]The product was dissolved in acetone and tartronic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.277 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝341.3。

(R) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl]-1H-quinolin-2-one (107LH65)

[0363]To a 4mL vial was added the crude product of (S) -1- (3-iodo-2-methylpropyl) -1H-quinolin-2-one (0.190g), 4-propoxypiperidine (0.137g, 0.96mmol) and dry CH₃CN (2.5 mL). The mixture was shaken at 50 ℃ for 24h, then purified using cation exchange CC followed by flash CC (SiO)₂(ii) a EtOAc/MeOH 1: 4) to yield the title compound (0.051g, 17%).¹H NMR(CD₃OD)δ7.85(d，J＝9.6Hz)，7.70-7.63(m，2H)，7.60(brt，J＝7.8Hz，1H)，7.26(brt，7.6Hz)，6.63(d，J＝9.6Hz，1H)，4.39-4.23(m，2H)，3.37(t，J＝6.6Hz)，3.28-3.18(m，1H)，2.77-2.69(m，1H)，2.64-2.58(m，1H)，2.35(dd，J＝8.4，12.0Hz)，2.51-2.21(m，1H)，2.18(dd，J＝4.8，12.0Hz)，2.13-2.04(m，1H)，2.00-1.92(m，1H)，1.84-1.75(m，2H)，1.58-1.32(m，4H)，0.95-0.85(m，6H)；¹³C NMR(CD₃OD)δ163.7，140.2，139.5，130.8，129.2，12.5，121.4，120.4，115.2，75.3，69.5，63.6，52.3，51.5，46.8，31.4，31.3，30.0，23.1，16.1，9.8。

[0364]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.032 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.3。

1- [3- (4-allyloxypiperidinyl-1-) propyl]-1H-quinolin-2-one (107LH85)

[0365]To a 4mL vial was added 1- (3-chloropropyl) -1H-quinolin-2-one (0.130g, 0.6mmol), NaI (0.225g, 1.5mmol), K₂CO₃(0.210g, 1.5mmol), 4-allyloxypiperidine (0.085g, 0.60mmol) and dry CH₃CN (1 mL). The mixture was shaken at 40 ℃ for 72h, then poured into EtOAc (25mL) and water (15 mL). The aqueous phase was extracted (2X 25mL), the organic phases combined and washed with Na₂SO₄Drying, and concentrating under reduced pressure. Rapid CC (SiO) for residue₂(ii) a EtOAc/MeOH 4: 1) followed by cation exchange CC gave the title compound (0.140g, 70%).¹HNMR(CD₃OD)δ7.81(d，J＝9.6Hz，1H)，7.64-7.55(m，3H)，7.27-7.21(m，1H)，6.61(d，J＝9.6Hz，1H)，5.93-5.82(m，1H)，5.27-5.20(m，1H)，5.13-5.07(m，1H)，4.33-4.26(m，2H)，3.40-3.28(m，2H)，2.76-2.67(m，2H)，2.47-2.39(m，2H)，2.18-2.08(m，1H)，1.93-1.80(m，4H)，1.61-1.50(m，2H)；¹³C NMR(CD₃OD)δ162.9，140.3，139.0，135.5，131.1，129.2，122.6，121.3，120.4，115.5，114.7，74.2，68.7，55.3，51.0，40.6，30.9，24.9。

[0366]The product was dissolved in acetone and oxalic acid (1.1 eq) dissolved in acetone was added. The crystals formed were filtered and washed with acetone to give the oxalate salt of the title compound (0.140 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝327.3。

General method 18(GP18)

[0367]To a 7mL vial were added the heterocyclic compound (1 equivalent), (R, S) -1-bromo-3-chloro-2-methylpropane (1.2 equivalents) and Cs dissolved in MeCN (4mL)₂CO₃(2 eq.) and stirred at 50 ℃ for 20 h. Water was added to the reaction mixture and the product was extracted with EtOAc. The combined organic layers were filtered through a PTFF filter and concentrated. The product was used in the next reaction without further purification.

(R, S) -4- (3-chloro-2-methylpropyl) -6-methyl-4H-benzo [1, 4-]Oxazin-3-one (112KK19-a)

[0368]6-methyl-4H-benzo [1, 4] in MeCN (4mL) according to GP18]Oxazin-3-one (0.512g, 3.14mmol), (R, S) -1-bromo-3-chloro-2-methylpropane (0.646g, 3.77mmol) and Cs₂CO₃(2.036g, 6.25mmol) to give the title compound (112KK19-a) as a crude product (0.692 g).

(R, S) -4- (3-chloro-2-methylpropyl) -6-fluoro-4H-benzo [1, 4]Oxazin-3-ones (112KK19-b)

[0369]6-fluoro-4H-benzo [1, 4] dissolved in MeCN (4mL) according to GP18]Oxazin-3-one (0.502g, 3.00mmol), (R, S) -1-bromo-3-chloro-2-methylpropane (0.617g, 3.60mmol) and Cs₂CO₃(1.983g, 6.09mmol) to give the title compound (112KK19-b) as a crude product (0.768 g).

(R, S) -4- (3-chloro-2-methylpropyl) -7-fluoro-4H-benzo [1, 4%]Oxazin-3-one (112KK19-c)

[0370]7-fluoro-4H-benzo [1, 4] dissolved in MeCN (4mL) according to GP18]Oxazin-3-one (0.498g, 2.98mmol), (R, S) -1-bromo-3-chloro-2-methylpropane (0.613g, 3.58mmol) and Cs₂CO₃(1.985g, 6.09mmol) to give the title compound (112KK19-c) as a crude product (0.694 g).

(R, S) -3- (3-chloro-2-methylpropyl) -3H-benzothiazol-2-one (112KK19-d)

[0371]Benzothiazol-2-ol (0.476g, 3.15mmol), (R, S) -1-bromo-3-chloro-2-methylpropane (0.648g, 3.78mmol) and Cs dissolved in MeCN (4mL) according to GP18₂CO₃(2.024g, 6.21mmol) to give the title compound (112KK19-d) as a crude product (0.804 g).

General method 19(GP19)

[0372]To a 7mL vial were added the heterocyclic compound (1 equivalent), (R, S) -1-bromo-3-chloro-2-methylpropane (1 equivalent), and Cs dissolved in MeCN (3mL)₂CO₃(1.5 eq.) and stirred at 50 ℃ for 20 h. Water was added to the reaction mixture and the product was extracted with EtOAc. The organic layers were combined and washed with Na₂SO₄Drying, filtering and concentrating. Fast CC (SiO) for product₂(ii) a EtOAc/n-heptane 1: 1).

(R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1.4]Oxazin-3-one (107LH61-1)

[0373]4H-benzo [1.4] in MeCN (3mL) according to GP19]Oxazin-2-one (0.447g, 3.0mmol), (R, S) -1-bromo-3-chloro-2-methylpropane (0.514g, 3.0mmol) and Cs₂CO₃(1.466g, 4.5mmol) was reacted and purified to give the title compound (107LH61-1) as a crude product (0.595 g).

(R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [4.4]Thiazine-3-one (107LH61-2)

[0374]4H-benzo [1.4] in MeCN (3mL) according to GP19]Thiazin-3-one (0.496g, 3.0mmol), (R, S) -1-bromo-3-chloro-2-methylpropane (0.514g, 3.0mmol), and Cs₂CO₃(1.466g, 4.5mmol) was reacted and purified to give the title compound (107LH61-2) as a crude product (0.593 g).

(R, S) -4- (3-chloro-2-methylpropyl) -6-methoxy-4H-benzo [1, 4-]Oxazin-3-one (107LH69)

[0375]6-methoxy-4H-benzo [1, 4] dissolved in MeCN (3mL) according to GP19]Oxazin-3-one (111MF24) (0.538g, 3.0mmol), (R, S) -1-bromo-3-chloro-2-methylpropane (0.514g, 3.0mmol) and Cs₂CO₃(1.466g, 4.5mmol) was reacted and purified to give the crude product (0.658g) of the title compound (107LH 69).

(R, S) -1- (3-chloro-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (107LH63)

[0376]To the reaction flask was added 3, 4-dihydro-1H-quinolin-2-one (1.00g, 6.8mmol) dissolved in dry DMF (10 mL). NaH 60% (0.300g, 7.5mmol) was added and the mixture was stirred at room temperature under argon for 1 h. Then (R, S) -1-bromo-3-chloro-2-methylpropane (1.165g, 6.8mmol) was added, followed by stirring at room temperature for 20 h. The crude product was concentrated with fast CC (SiO)₂(ii) a EtOAc/n-heptane 1: 1) to yield the crude product (0.753g) of the title compound (107LH 63).

General method 20(GP20)

[0377]A4 mL vial was charged with the crude heterocyclic compound dissolved in DMF, amine, NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) and stirred at 100 ℃ for 5 days. Water was added to the reaction mixture and the product was extracted with EtOAc. The crude product was purified by cation exchange CC followed by preparative RP-HPLC to give the titleThe title compound.

(R, S) -4- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-6-methyl-4H-benzo [1, 4]]Oxazin-3-ones (112KK20-a1)

[0378](R, S) -4- (3-chloro-2-methylpropyl) -6-methyl-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Crude product of oxazin-3-one (112KK19-a) (0.046g), 4-butylpiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-a1) (0.007 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝359.32。

(R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-6-methyl-4H-benzo [1.4]Oxazine-3- Ketones (112KK20-a2)

[0379](R, S) -4- (3-chloro-2-methylpropyl) -6-methyl-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Crude product of oxazin-3-one (112KK19-a) (0.046g), 4-propoxypiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-a2) (0.010 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.29。

(R, S) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-6-methyl-4H-benzo [1.4]Oxazine-3- Ketones (112KK20-a3)

[0380](R, S) -4- (3-chloro-2-methylpropyl) -6-methyl-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Crude product of oxazin-3-one (112KK19-a) (0.046g), 4-butylidenepiperidine (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-a3) (0.008 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝357.30。

(R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-6-methyl-4H-benzo [1.4]Oxazin-3-ones (112KK20-a4)

[0381](R, S) -4- (3-chloro-2-methylpropyl) -6-methyl-4H-benzo [1, 4] dissolved in DMF (1.2mL) according to GP20]Crude product of oxazin-3-one (112KK19-a) (0.023g), 3-butyl-8-azabicyclo [3.2.1] and]octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-a4) (0.007 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝385.32。

(R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1]]Octyl-8-) propyl]-6-methyl-4H-benzene And [1.4]]Oxazin-3-ones (112KK20-a5)

[0382](R, S) -4- (3-chloro-2-methylpropyl) -6-methyl-4H-benzo [1, 4] dissolved in DMF (1.2mL) according to GP20]Crude product of oxazin-3-one (112KK19-a) (0.023g), 3-pentyl-8-azabicyclo [3.2.1] and]octane (0.024g, 0.13mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-a5) (0.002 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝399.35。

(R, S) -4- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-6-fluoro-4H-benzo [1.4]Oxazin-3-ones (112KK20-b1)

[0383](R, S) -4- (3-chloro-2-methylpropyl) -6-fluoro-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Crude product of oxazin-3-one (112KK19-b) (0.051g), 4-butylpiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-b1) (0.011 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.28。

(R, S) -6-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-4H-benzo [1.4]Oxazin-3-ones (112KK20-b2)

[0384](R,s) -4- (3-chloro-2-methylpropyl) -6-fluoro-4H-benzo [1, 4]Crude product of oxazin-3-one (112KK19-b) (0.051g), 4-propoxypiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-b2) (0.010 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝365.26。

(R, S) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl-6-fluoro-4H-benzo [1, 4]]Oxazin-3-ones (112KK20-b3)

[0385](R, S) -4- (3-chloro-2-methylpropyl) -6-fluoro-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Oxazin-3-one (112KK19-b) (0.051g), 4-butylidenepiperidine (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-b3) (0.011 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.27。

(R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-6-fluoro-4H-benzo [1.4]Oxazin-3-ones (112KK20-b4)

[0386](R, S) -4- (3-chloro-2-methylpropyl) -6-fluoro-4H-benzo [1, 4] dissolved in DMF (1.2mL) according to GP20]Crude product of oxazin-3-one (112KK19-b) (0.026g), 3-butyl-8-azabicyclo [3.2.1]Octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-b4) (0.009 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝389.30。

(R, S) -6-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] S]Octyl-8-) propyl]-4H-benzo [1，4]Oxazin-3-ones (112KK20-b5)

[0387](R, S) -4- (3-chloro-2-methylpropyl) -6-fluoro-4H-benzo [1, 4] dissolved in DMF (1.2mL) according to GP20]Crude product of oxazin-3-one (112KK19-b) (0.026g), 3-pentyl-8-azabicyclo [3.2.1]Octane (0.024g, 0.13mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-b5) (0.009 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝403.31。

(R, S) -4- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-7-fluoro-4H-benzo [1, 4]]Oxazin-3-ones (112KK20-c1)

[0388](R, S) -4- (3-chloro-2-methylpropyl) -7-fluoro-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Crude product of oxazin-3-one (112KK19-c) (0.046g), 4-butylpiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-c1) (0.002 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.29。

(R, S) -7-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Oxazin-3-ones (112KK20-c2)

[0389](R, S) -4- (3-chloro-2-methylpropyl) -7-fluoro-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Crude product of oxazin-3-one (112KK19-c) (0.046g), 4-propoxypiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-c2) (0.002 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝365.28。

(R, S) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-7-fluoro-4H-benzo [1.4]Oxazin-3-ones (112KK20-c3)

[0390](R, S) -4- (3-chloro-2-methylpropyl) -7-fluoro-4H-benzo [1, 4] dissolved in DMF (1.4mL) according to GP20]Crude product of oxazin-3-one (112KK19-c) (0.046g), 4-butylidenepiperidine (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-c3) (0.008 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.29。

(R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8-]-2-methylpropyl-7-fluoro-4H-benzo [1，4]Oxazin-3-ones (112KK20-c4)

[0391](R, S) -4- (3-chloro-2-methylpropyl) -7-fluoro-4H-benzo [1, 4] dissolved in DMF (1.2mL) according to GP20]Crude product of oxazin-3-one (112KK19-c) (0.023g), 3-butyl-8-azabicyclo [3.2.1] and]octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-c4) (0.004 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝389.31。

(R, S) -7-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] S]Octyl-8-) propyl]-4H-benzo [1，4]Oxazin-3-ones (112KK20-c5)

[0392](R, S) -4- (3-chloro-2-methylpropyl) -7-fluoro-4H-benzo [1, 4] dissolved in DMF (1.2mL) according to GP20]Crude product of oxazin-3-one (112KK19-c) (0.023g), 3-pentyl-8-azabicyclo [3.2.1] and]octane (0.024g, 0.13mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-c5) (0.002 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝403.32。

(R, S) -3- [3- (4-butylpiperidinyl-1) -2-methylpropyl-3H-benzothiazol-2-one (112KK20-d1)

[0393]The crude product of (R, S) -3- (3-chloro-2-methylpropyl) -3H-benzothiazol-2-one (112KK19-d) (0.054g), 4-butylpiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K dissolved in DMF (1.4mL) was reacted according to GP20₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-d1) (0.012 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝347.28。

(R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-3H-benzothiazol-2-ones (112KK20-d2)

[0394]The crude product of (R, S) -3- (3-chloro-2-methylpropyl) -3H-benzothiazol-2-one (112KK19-d) (0.054g), 4-propoxypiperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K dissolved in DMF (1.4mL) was reacted according to GP20₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-d2) (0.011 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝349.25。

(R, S) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-3H-benzothia-2-one (112KK20-d3)

[0395]The crude product of (R, S) -3- (3-chloro-2-methylpropyl) -3-benzothiazol-2-one (112KK19-d) (0.054g), 4-butylidenepiperidine (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K dissolved in DMF (1.4mL) was reacted according to GP20₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-d3) (0.011 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.27。

(R, S) -3- [ - (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-3H-benzothiazole-2- Ketones (112KK20-d4)

[0396]The crude product of (R, S) -3- (3-chloro-2-methylpropyl) -3H-benzothiazol-2-one (112KK19-d) (0.027g), 3-butyl-8-azabicyclo [3.2.1] in DMF (1.2mL) was dissolved according to GP20]Octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-d4) (0.011 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝373.30。

(R, S) -3- [ 2-methyl-3- (3-pentyl-8-azabicyclo [ 3.2.1)]Octyl-8-) propyl]-3H-benzothiazole -2-one (112KK20-d5)

[0397]The crude product of (R, S) -3- (3-chloro-2-methylpropyl) -3H-benzothiazol-2-one (112KK19-d) (0.027g), 3-pentyl-8-azabicyclo [3.2.1] in DMF (1.2mL) was dissolved according to GP20]Octane (0.024g, 0.13 mmo)l), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (112KK20-d5) (0.011 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝387.30。

(R, S) -4- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-4H-benzo [1, 4]]Oxazin-3-ones (107LH74-a1)

[0398](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH61-1) (0.149g), 4-butylpiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-a1) (0.092 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.30。

(R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Oxazin-3-ones (107LH74-a2)

[0399](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH61-1) (0.149g), 4-propoxypiperidine (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-a2) (0.077 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝347.30。

(R, S) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-4H-benzo [1, 4]]Oxazin-3-ones (107LH74-a3)

[0400](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH61-1) (0.149g), 4-butylidenepiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-a3) (0.083 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.30。

(R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-4H-benzo [1, 4]]Oxazole (oxazole) (I) Oxazin-3-ones (107LH74-a4)

[0401](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH61-1) (0.074g), 3-butyl-8-azabicyclo [3.2.1]Octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-a4) (0.046 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝371.33。

(R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1]]Octyl-8-) propyl]-4H-benzo [1, 4]]Oxazole (oxazole) (I) Oxazin-3-ones (107LH74-a5)

[0402](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH61-1) (0.074g), 3-pentyl-8-azabicyclo [3.2.1]Octane (0.027g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-a5) (0.053 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝385.34。

(R, S) -4- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-4H-benzo [1, 4]]Thiazin-3-ones (107LH74-b1)

[0403](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Thiazin-3-one (107LH61-2) crude (0.148g), 4-butylpiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-b1) (0.083 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝361.29。

(R, S) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-4H-benzo [1, 4]]Thiazin-3-ones (107LH74-b2)

[0404](R, S) -1- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Thiazin-3-one (107LH61-2) crude (0.148g), 4-propoxypiperidine (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-b2) (0.071 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝363.27。

(R, S) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-4H-benzo [1, 4]]Thiazin-3-ones (107LH74-b3)

[0405](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Thiazin-3-one (107LH61-2) crude (0.148g), 4-butylidenepiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-b3) (0.064 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝359.27。

(R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-4H-benzo [1, 4]]Thia-methyl Oxazin-3-ones (107LH74-b4)

[0406](R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Thiazin-3-one (107LH61-2) crude product (0.074g), 3-butyl-8-azabicyclo [ 3.2.1%]Octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-b4) (0.040 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝387.30。

(R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1]]Octyl-8-) propyl]-4H-benzo [1, 4]]Thia-methyl Oxazin-3-ones (107LH74-b5)

[0407]Crude (R, S) -4- (3-chloro-2-methylpropyl) -4H-benzo [1, 4] in DMF (1mL) according to GP20]Thiazin-3-one (107LH61-2) (0.074g), 3-pentyl-8-azabicyclo [3.2.1]Octane (0)027g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) in DMF (1mL) was reacted and purified to give the title compound (107LH74-b5) (0.040 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝401.30。

(R, S) -1- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-3, 4-dihydro-1H-quinolin-2-one (107LH74-c1)

[0408]The crude product of (R, S) -1- (3-chloro-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (107LH63) (0.188g), 4-butylpiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K dissolved in DMF (1mL) is reacted according to GP20₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-c1) (0.047 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝343.32。

(R, S) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl]-3, 4-dihydro-1H-quinolin-2-one (107LH74-c2)

[0409]The crude product of (R, S) -1- (3-chloro-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (107LH63) (0.188g), 4-propoxypiperidine (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K dissolved in DMF (1mL) was reacted as GP20₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-c2) (0.040 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝345.32。

(R, S) -1- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl-3, 4-dihydro-1H-quinolin-2-one (107LH74-c3)

[0410]The crude product of (R, S) -1- (3-chloro-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (107LH63) (0.188g), 4-butylidenepiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K dissolved in DMF (1mL) is reacted according to GP20₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-c3) (0.038 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝341.31。

(R, S) -1- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-3, 4-dihydro-1H-quine Lin-2-ones (107LH74-c4)

[0411]The crude product of (R, S) -1- (3-chloro-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (107LH63) (0.094g), 3-butyl-8-azabicyclo [3.2.1] in DMF (1mL) was dissolved according to GP20]Octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-c4) (0.025 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝369.33。

(R, S) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [ 3.2.1)]Octyl-8-) propyl]-3, 4-dihydro-1H-quine Lin-2-ones (107LH74-c5)

[0412]The crude product of (R, S) -1- (3-chloro-2-methylpropyl) -3, 4-dihydro-1H-quinolin-2-one (107LH63) (0.094g), 3-pentyl-8-azabicyclo [3.2.1] in DMF (1mL) was dissolved according to GP20]Octane (0.027g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-c5) (0.023 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝383.34。

(R, S) -4- [3- (4-Butylpiperidinyl-1) -2-methylpropyl]-6-methoxy-4H-benzo [1, 4]]Oxazine-3- Ketones (107LH74-d1)

[0413](R, S) -4- (3-chloro-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH69) (0.165g), 4-butylpiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-d1) (0.094 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝375.31。

(R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -6-methoxy]-4H-benzo [1, 4]]Oxazin-3-ones (107LH74-d2)

[0414](R, S) -4- (3-chloro-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH69) (0.165g), 4-propoxypiperidine (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-d2) (0.086 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝377.29。

(R, S) -4- [3- (4-Butylidenepiperidinyl-1) -2-methylpropyl]-6-methoxy-4H-benzo [1, 4]]Oxazines -3-one (107LH74-d3)

[0415](R, S) -4- (3-chloro-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH69) (0.165g), 4-butylidenepiperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-d3) (0.086 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝373.29。

(R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1]]Octyl-8) -2-methylpropyl]-6-methoxy-4H-benzene And [1, 4]]Oxazin-3-one (107LH74-d4)

[0416](R, S) -4- (3-chloro-2-methylpropyl) -6-methoxy-4H-benzo [1, 4] dissolved in DMF (1mL) according to GP20]Crude product of oxazin-3-one (107LH69) (0.082g), 3-butyl-8-azabicyclo [3.2.1]Octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-d4) (0.044 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝401.32。

(R, S) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [ 3.2.1)]Octyl-8-) propyl]-6-methoxy-4H- Benzo [1, 4] s]Oxazin-3-one (107LH74-d5)

[0417](R, S) -4- (3-chloro-2-methyl) dissolved in DMF (1mL) according to GP20Cyclopropyl) -6-methoxy-4H-benzo [1, 4]]Crude product of oxazin-3-one (107LH69) (0.082g), 3-pentyl-8-azabicyclo [3.2.1]Octane (0.027g, 0.15mm0l), NaI (0.100g, 0.67mmol) and K₂CO₃(0.075g, 0.54mmol) was reacted and purified to give the title compound (107LH74-d5) (0.051 g). HPLC-MS (ammonium acetate) [ M + H ]]⁺＝415.34。

1- [3- (4-butyl-piperidinyl-1) -propyl]-1, 2, 3, 4-tetrahydro-quinoline (55-LH-12-2)

[0418]A solution of n-butyllithium in hexane (1.5M, 7.3mL, 11mmol) was added dropwise to a solution of 1, 2, 3, 4-tetrahydro-quinoline (1.256mL, 10mmol) in tetrahydrofuran (10mL) at-78 deg.C under argon. The reaction mixture was stirred for 1/2h, then 1-chloro-3-iodopropane (1.0mL, 9.5mmol) was added. The reaction mixture was stirred at-78 ℃ for 1/2h, then at room temperature for a further 16 h. Tetrahydrofuran was evaporated and dissolved in acetonitrile (10 mL). KI (1.83g, 11mmol) and K were added₂CO₃(2.76g, 20mmol) and 4-butylpiperidine (1.66mL, 10 mmol). The slurry was stirred at 50 ℃ for 48h, then water (10mL) was added and the product extracted with ethyl acetate (2X 20 mL). Drying (Na)₂SO₄) The organic layer was concentrated in vacuo. The product was purified by column chromatography (eluent: ethyl acetate) to give the title compound (1.11g, 35%). The oxalate salt was prepared with oxalic acid (1.1 equivalents) dissolved in acetone. HPLC-MS: m +1⁺＝315.1(MS(％)＝95)。¹H NMR(400MHz，CHCl₃): δ is 0.89(3H, t), 1.18-1.34(9H, m), 1.64-1.70(2H, m), 1.79(2H, quinoline), 1.85-1.98(4H, m), 2.36(2H, t), 2.74(2H, t), 2.92(2H, broad d), 3.24-3.31(4H, m), 6.54(1H, ddd), 6.60(1H, dd), 6.93(1H, dd), 7.03(1H, ddd).¹³C NMR(CDCl₃)：δ14.3，22.5，23.1，24.2，28.4，29.3，32.7，36.0，36.5，49.6，49.8，54.4，56.7，110.9，115.5，122.5，127.3，129.3，145.6。

1- [3- (4-butyl-piperidinyl-1) -propyl]-2-methyl-1, 2, 3, 4-tetrahydro-quinoline (55-LH-28-8)

[0419]According to the synthesis 1- [3- (4-butyl-piperidinyl-1) -propyl]Method for 1, 2, 3, 4-tetrahydro-quinoline 2-methyl-1, 2, 3, 4-tetrahydro-quinoline (346mg, 2.35mmol) was converted into the title product. Yield: 88.6mg, 11%. HPLC-MS: m +1⁺＝329.5(UV/MS(％)＝100/99)。¹H NMR(400MHz，CHCl₃)：δ＝0.89(3H，t)，1.11(3H，d)，1.16-1.34(9H，m)，1.67(2H，broadd)，1.65-2.03(8H，m)，2.39(2H，t)，2.57-2.66(1H，m)，2.74-2.85(1H，m)，2.93(2H，broad d)，3.12-3.21(1H，m)，3.33-3.42(1H，m)，3.44-3.52(1H，m)，6.45(1H，t)，6.54(1H，d)，6.87(1H，d)，6.97(1H，t)。¹³C NMR(CD₃OD)：δ13.2，17.8，22.8，23.7，24.4，28.0，28.9，31.9，35.7，36.2，52.7，53.9，54.0，56.4，110.8，115.1，121.9，126.7，128.7，144.2。

1- [3- (4-butyl-piperidinyl-1) -propyl-6-methyl-1, 2, 3, 4-tetrahydro-quinoline (55-LH-44A)

[0420]According to the synthesis 1- [3- (4-butyl-piperidinyl-1) -propyl]Method for 1, 2, 3, 4-tetrahydro-quinoline 6-methyl-1, 2, 3, 4-tetrahydro-quinoline (346mg, 2.35mmol) was converted into the title product. Yield: 137mg, 18 percent. HPLC-MS: m +1⁺＝329.5(UV/MS(％)＝98/99)。¹H NMR(400MHz，CDCl₃): δ ═ 0.89(3H, t), 1.14-1.34(9H, m), 1.68(2H, broad d), 1.76(2H, quinoline), 1.85-1.99(4H, m), 2.14(3H, s), 2.34-2.39(2H, m), 2.66(2H, t), 2.92(2H, broad d), 3.18-3.26(4H, m), 6.49(1H, d), 6.58(1H, broad s), 6.76(1H, broad).¹³C NMR(CD₃OD)：δ13.2，19.2，22.5，22.8，23.2，28.0，28.9，31.9，35.7，36.2，49.4，49.6，53.9，56.5，111.3，122.7，124.7，127.2，129.6，143.2。

1- [3- (4-butyl-piperidinyl-1) -propyl]-8-methyl-1, 2, 3, 4-tetrahydro-quinoline (77-LH-1)

[0421]8-methyl-1, 2, 3 dissolved in acetonitrile (2mL) was shaken at 60 ℃,4-tetrahydroquinoline (125mg, 0.85mmol), 1-chloro-3-iodopropane (82. mu.l, 0.77mmol) and Cs₂CO₃(415mg, 1.27mmol) for 7 days. KI (140mg, 0.85mmol) and K were added₂CO₃(117mg, 0.85mmol) and 4-butylpiperidine (113. mu.l, 0.68mmol), the reaction mixture being shaken at 60 ℃ for 2 days. Water (5mL) was added and the product extracted with ethyl acetate (2X 10 mL). Drying (Na)₂SO₄) The organic layer was concentrated in vacuo. Purification of the product by column chromatography (eluent: ethyl acetate with 20% methanol) gave the title compound. Yield: 45.6mg (20.4%). HPLC-MS: m +1⁺＝329.5(UV/MS(％)＝99/97)。¹HNMR(400MHz，CDCl₃)：δ＝0.89(3H，t)，1.18-1.34(9H，m)，1.70(2H，broad d)，1.75-1.92(4H，m)，1.99(2H，broad t)，2.22(3H，s)，2.38(2H，dd)，2.70-2.81(4H，m)，2.96(2H，broad d)，3.04-3.10(2H，m)，6.76(1H，t)，6.80(1H，broad d)，6.91(1H，broad d)。¹³C NMR(CD₃OD)：δ13.2，17.2，18.0，18.1，22.8，25.7，27.7，28.9，31.9，35.7，36.2，52.7，53.9，56.3，121.5，127.1，128.7，128.9，131.0，148.0。

1- [3- (4-butyl-piperidinyl-1) -propyl]-7-fluoro-2-methyl-1, 2, 3, 4-tetrahydro-quinoline (77-LH-2)

[0422]According to the synthesis 1- [3- (4-butyl-piperidinyl-1) -propyl]Method for 8-methyl-1, 2, 3, 4-tetrahydro-quinoline 7-fluoro-2-methyl-1, 2, 3, 4-tetrahydro-quinoline (165mg, 1.0mmol) is converted into the title product. Yield: 43.2mg, 16%. HPLC-MS: m +1⁺＝347.5(UV/MS(％)＝95/92)。¹H NMR(400MHz，CDCl₃)：δ＝0.89(3H，t)，1.10(3H，d)，1.18-1.36(9H，m)，1.66-1.91(6H，m)，2.00-2.10(2H，m)，2.44(2H，t)，2.62(1H，dt)，2.74-2.85(1H，m)，2.99(2H，broad d)，3.16(1H，q)，3.30-3.40(1H，m)，3.41-3.49(1H，m)，6.63-6.74(1H，m)，6.63-6.74(2H，m)。¹³C NMR(CD₃OD)：δ13.2，17.6，22.7，23.7，23.8，24.3，29.9，28.9，31.7，35.5，36.1，52.6，53.8，56.2，112.7(d)，114.8(d)，123.7，140.8，153.5，155.8。

1- [3- (4-butyl-piperidinyl-1) -propyl]-7-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinoline (55-LH-54)

[0423]According to the synthesis 1- [3- (4-butyl-piperidinyl-1) -propyl]Method for 1, 2, 3, 4-tetrahydro-quinoline 7-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinoline (0.50g, 2.5mmol) is converted into the title product. Yield: 1.71mg, 18%. HPLC-MS: m +1⁺＝347.5(UV/MS(％)＝99/91)。¹HNMR(400MHz，CDCl₃): δ is 0.89(3H, t), 1.14-1.36(9H, m), 1.68(2H, broad d), 1.79(2H, quinoline), 1.86-2.03(4H, m), 2.38(2H, dd), 2.75(2H, dd), 2.94(2H, broad d), 3.32(4H, m), 6.71(1H, d), 6.75(1H, s), 6.99(1H, d).

1- [3- (4-butyl-piperidinyl-1) -propyl]-3, 4-dihydro-1H-quinolin-2-one (77-LH-28-1)

[0424]NaH (55-60%) (712mg) suspended in mineral oil was added to a solution of 3, 4-dihydro-1H-quinolin-2-one (2.0g, 13.6mmol) in N, N-dimethylformamide (50mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1h, then 1-bromo-3-chloropropane (1.34mL, 13.6mmol) was added. The slurry was stirred at room temperature for a further 16h, then water (50mL) was added and the product extracted with diethyl ether (2X 50 mL). Drying (Na)₂SO₄) The organic layer was concentrated in vacuo. The product is purified by flash chromatography (eluent: dichloromethane) to give 1- [ 3-chloropropyl [ -chloropropyl ]]-3, 4-dihydro-1H-quinolin-2-one (2.41g, 10.8 mmol). KI (2.5g, 15mmol) and K₂CO₃(2.1g, 15mmol) and 4-butylpiperidine (1.8mL, 15mmol) were added to 1- [ 3-chloropropyl]-3, 4-dihydro-1H-quinolin-2-one (2.41g, 10.8mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 60 ℃ for 16 h. Acetonitrile was evaporated in vacuo, water (50mL) was added and the product extracted with ethyl acetate (2X 50 mL). Drying (Na)₂SO₄) The organic layer was filtered and concentrated in vacuo. Purification by flash chromatography (eluent: ethyl acetate) afforded the product. Yield: 2.06g, 58%. Preparation of grass from oxalic acid (1.1 equiv) dissolved in acetoneAn acid salt. HPLC-MS: m +1⁺＝329.5(UV/MS(％)＝100/100)。¹H NMR(400MHz，CD₃OD): δ ═ 0.89(3H, t), 1.12-1.36(9H, m), 1.67(2H, broad d), 1.83(2H, quinoline), 1.97(2H, broad t), 2.41(2H, t), 2.59(2H, t), 2.84-2.96(4H, m), 3.99(2H, t), 7.02(1H, broad t), 7.16(1H, broad d), 7.20(1H, broad d), 7.25(1H, broad t).¹³C NMR(CD₃OD)：δ13.2，22.8，24.3，25.0，28.9，31.6，31.9(2C)，35.6，36.2，40.1，53.8(2C)，55.9，115.2，123.2，127.0，127.4，127.9，139.1，171.5。

1- [3- (4-butyl-piperidinyl-1) -propyl]-6-methoxy-3, 4-dihydro-1H-quinolin-2-one (77-LH-22A)

[0425]6-methoxy-3, 4-dihydro-1H-quinolin-2-one (108mg, 0.61mmol), 1-chloro-3-iodopropane (64. mu.l, 0.6mmol) and Cs dissolved in acetonitrile (2mL) were shaken at 60 ℃₂CO₃(290mg, 0.9mmol) for 14h, then the reaction was cooled to room temperature. Water (5mL) was added and the product extracted with ethyl acetate (2X 10 mL). Drying (Na)₂SO₄) The organic layer was filtered and concentrated in vacuo. The slurry was dissolved in acetonitrile (4 mL). KI (83mg, 3.6mmol) and K were added₂CO₃(100mg, 0.6mmol) and 4-butylpiperidine (83. mu.l, 0.5mmol), the reaction mixture being shaken for 16h at 60 ℃. Water (5mL) was added and the product extracted with ethyl acetate (2X 10 mL). Drying (Na)₂SO₄) The organic layer was concentrated in vacuo. The product was purified by column chromatography (eluent: ethyl acetate containing 20% methanol) to give the title compound. Yield: 24.8mg, 11.3%. HPLC-MS: m +1⁺＝359.5(UV/MS(％)＝90/78)。¹H NMR(400MHz，CHCl₃): δ is 0.89(3H, t), 1.12-1.34(9H, m), 1.67(2H, broad d), 1.85(2H, quinoline), 1.93(2H, broad t), 2.39(2H, t), 2.59(2H, dd), 2.83(2H, t), 2.90(2H, broad d), 3.76(3H, s), 3.94(2H, t), 6.70(1H, d), 6.74(1H, dd), 7.01(1H, d).¹³CNMR(CDCl₃)：δ14.3，23.0，25.0，26.1，29.2，32.1，32.5(2C)，35.9，36.4，40.8，54.3(2C)，55.8，56.3，112.2，114.2，116.2，128.3，133.4，155.4，169.9。

4- [3- (4-butyl-piperidinyl-1) -propyl]-6-methyl-4H-benzo [1, 4]]Oxazin-3-ones (64-LHY-89-6)

[0426]6-methyl-4H-benzo [1, 4] benzo dissolved in acetonitrile (2mL) at 50 ℃ with shaking]Oxazin-3-one (82mg, 0.5mmol), 1-chloro-3-iodopropane (50 μ l, 0.5mmol) and Cs₂CO₃(163mg, 0.5mmol) for 24h, then the reaction mixture was concentrated in vacuo. The product (4- [ 3-chloropropyl) was purified on an Isco Combiflash Sq 16 × (4g silica column, eluted with 0-20% ethyl acetate in heptane)]-6-methyl-4H-benzo [1, 4]]-oxazin-3-one) and then dissolved in acetonitrile (2 mL). Adding K₂CO₃(85mg, 0.5mmol) and 4-butylpiperidine (80. mu.l, 0.5 mmol). The reaction mixture was shaken at 60 ℃ for 16h and then cooled to room temperature. Dichloromethane (2mL) and PS-isocyanate (1.47 mmol/g, 100mg charge) were added. After 5h the mixture was filtered and the organic layer was loaded onto a Varian SCX ion exchange column. The column was washed with methanol (2X 5mL) and the product was eluted from the column with 10% ammonium hydroxide in methanol (6 mL). The lysate was concentrated in vacuo to give the title product. Yield: 100mg, 58%. HPLC-MS: m +1⁺＝345.5(UV/MS(％)＝99/99)。¹H NMR(400MHz，CHCl₃)：δ＝0.89(3H，t)，1.15-1.30(9H，m)，1.65(2H，broad d)，1.81-1.89(4H，m)，2.30(3H，s)，2.36(2H，t)，2.86(2H，broad d)，3.94(2H，dd)，4.51(2H，s)，6.76(1H，dd)，6.84(1H，d)，6.86(1H，d)。¹³C NMR(CHCl₃)：δ14.3，21.3，23.1，25.1，29.2，32.8(2C)，36.0，36.5，39.8，54.4(2C)，56.1，67.9，115.8，116.9，124.3，128.6，132.5，143.4，164.6。

6-acetyl-4- [3- (4-butyl-piperidinyl-1) -propyl]-4H-benzo [1, 4]]Oxazin-3-ones (64-LHY-89-5)

[0427]According to the synthesis 4- [3- (4-butyl-piperidinyl-1) -propyl]-6-methyl-4H-benzo [1, 4]]-oxazin-3-one process, 6-acetyl-4H-benzeneAnd [1, 4]]Oxazin-3-one (96mg, 0.5mmol) was converted to the title product. Yield: 120mg, 64%. HPLC-MS: m +1⁺＝373.5(UV/MS(％)＝99/100)。¹H NMR(400MHz，CDCl₃)：δ＝0.89(3H，t)，1.13-1.27(9H，m)，1.63(2H，broad d)，1.81-1.88(4H，m)，2.37(2H，t)，2.55(3H，s)，2.84(2H，broad d)，4.02(2H，dd)，4.65(2H，s)，6.99(1H，d)，7.58(1H，dd)，7.66(1H，d)。¹³C NMR(CDCl₃)：δ14.3，23.1，24.7，26.5，29.2，32.7(2C)，36.0，36.5，39.9，54.4(2C)，56.3，67.6，114.9，117.0，125.3，128.8，132.4，149.5，163.5，196.3。

4- [3- (4-butyl-piperidinyl-1) -propyl]-6-methyl-3, 4-dihydro-2H-benzo [1, 4]]Oxazines (64-LHY-91-6)

[0428]A solution of borane in THF (1M, 0.5mL, 0.5mmol) was added to 4- [3- (4-butyl-piperidinyl-1) -propyl]-6-methyl-4H-benzo [1, 4]]Oxazin-3-one (50mg, 0.15mmol) in THF (6 mL). The reaction mixture was stirred at 40 ℃ for 16h, then aqueous HCl (4M, 10mL) was added dropwise at room temperature. The reaction mixture was stirred for 16h, then concentrated in vacuo. Adding K₂CO₃(0.5g) was dissolved in water (5mL) and the product was extracted with dichloromethane (2X 10 mL). Drying (Na)₂SO₄) The organic layer was concentrated in vacuo. In an Isco Combiflash Sq 16 × (4g silica column, in 0-20% ethyl acetate in heptane + 1% Et)₃N elution) to purify the product. Yield: 29.2mg, 56%. HPLC-MS: m +1⁺＝373.5(UV/MS(％)＝95/90)。¹H NMR(400MHz，CDCl₃): δ is 0.90(3H, t), 1.18-1.35(9H, m), 1.68(2H, broad d), 1.78(2H, quinoline), 1.89(2H, broad t), 2.24(3H, s), 2.35(2H, t), 2.89(2H, broad d), 3.27(2H, t), 3.31(2H, t), 4.19(2H, t), 6.39(1H, broad d), 6.52(1H, broad s), 6.66(1H, d).¹³C NMR(CHCl₃)：δ14.3，21.4，23.1，24.2，29.3，32.8(2C)，36.1，36.6，47.4，49.3，54.5(2C)，56.5，64.7，113.0，116.2，117.7，131.1，135.3，142.0。

4- [3- (4-butyl-piperidinyl-1) -propyl]-6-ethyl-3, 4-dihydro-2H-benzo [1, 4]]Oxazines (64-LHY-91-5)

[0429]According to the synthesis 4- [3- (4-butyl-piperidinyl-1) -propyl]-6-methyl-3, 4-dihydro-2H-benzo [1, 4]]Method for oxazine, 6-acetyl-4- [3- (4-butyl-piperidinyl-1) -propyl]-4H-benzo [1, 4]]Oxazin-3-one (60mg, 0.161mmol) was converted to the title product. Yield: 22mg, 40%. HPLC-MS: m +1⁺＝373.5(UV/MS(％)＝98/97)。¹H NMR(400MHz，CDCl₃): δ is 0.89(3H, t), 1.18-1.35(12H, m), 1.68(2H, broad d), 1.75(2H, quinoline), 1.89(2H, broad t), 2.35(2H, t), 2.53(2H, qv), 2.89(2H, broad d), 3.26-3.33(4H, m), 4.20(2H, t), 6.43(1H, dd), 6.53(1H, d), 6.69(1H, d).¹³C NMR(CHCl₃)：δ14.3，16.2，23.1，24.2，28.9，29.3，32.8(2C)，36.1，36.6，47.4，49.4，54.5(2C)，56.5，64.7，112.0，116.2，116.5，135.3，137.7，142.2。

4- (3-chloropropyl) -4H-benzo [1, 4]]Thiazine-3-one (81MF07)

[0430]2H-1, 4-benzothiazin-3 (4H) -one (1.0g, 6.05mmol) and Cs were placed under nitrogen₂CO₃(2.96g, 9.08mmol) was dissolved in dry acetonitrile (20mL) and stirred at room temperature for 30 min. 3-chloro-1-iodopropane (1.37g, 6.66mmol) dissolved in acetonitrile (4mL) was added by injection. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. Water (150mL) was added and the reaction mixture was extracted with ethyl acetate (3X 150 mL). The combined organic phases were dried (MgSO)₄) And (4) concentrating in vacuum. This gave 1.45g of crude product. The crude product was passed through CC [ eluent: EtOAc (4: 1)]The pure title compound was obtained as a pale yellow oil. Yield: 1.37g, 90.2%. R_f0.24[ heptane: EtOAc (4: 1)]，¹HNMR(CHCl₃)：δ2.14(m，2H)，3.38(s，2H)，3.36(t，2H)，4.17(t，2H)，7.03(t，1H)，7.18(d，1H)，7.26(t，1H)，7.37(d，1H)。¹³C NMR(CDCl₃)：δ30.61，31.81，42.48，42.66，117.87，123.78，124.29，127.52，127.52，128.78，139.40，165.51。

4- [3- (4-butyl-piperidinyl-1) -propyl]-4H-benzo [1, 4]]Thiazine-3-one (81MF09)

[0431]NaI (1.24g, 8.27mmol), K were stirred in acetonitrile (10mL) at room temperature₂CO₃(1.14g, 8.27mmol) and 4-butylpiperidine (0.62g, 4.34 mmol). 4- (3-chloropropyl) -4H-benzo [1, 4] benzo dissolved in acetonitrile (15mL) was added by injection]Thiazin-3-one (1.0g, 4.14 mmol). The reaction was stirred at 60 ℃ for 13 h under nitrogen, then at 80 ℃ for a further 25 h and concentrated in vacuo. Water (150mL) was added and the reaction mixture was extracted with ethyl acetate (3X 150 mL). The organic phases are combined and dried (Na)₂SO₄) And (4) concentrating in vacuum. This gave 1.63g of crude product. The crude product was passed through CC [ eluent: EtOAc: MeOH (100: 1-5%)]To yield the title compound. Yield: 1.06g, 74.2% HPLC-MS: [ M + H ]]⁺347(UV/MS(％)＝100/99。¹HNMR(CHCl₃)：δ0.88(t，3H)，1.23(m，9H)，1.64(d，2H)，1.85(m，4H)，2.34(t，2H)，2.83(d，2H)，3.36(s，1H)，4.03(t，2H)，6.99(m，1H)，7.22(d，2H)，7.34(d，1H)，¹³C NMR(CHCl₃)：δ14.21，23.03，25.23，29.15，31.80，32.63，35.90，36.44，43.28，54.26，55.91，118.18，123.45，124.17，127.27，128.56，139.63，165.19。

[0432]To a solution of 4- [3- (4-butyl-piperidinyl-1) -propyl group in 30ml of diethyl ether]-4H-benzo [1, 4]]To thiazin-3-one (1.06g, mmol) was added oxalic acid (0.28g, 3.1mmol) in diethyl ether (5 mL). The crystals formed were filtered, washed with diethyl ether (5X 10mL) and dried to give 1.21g of the oxalate salt. HPLC-MS [ M + H ]]⁺347(UV/MS(％)＝100/99。

4- (3-chloropropyl) -4H-benzo [1, 4]]Oxazin-3-one (81MF08)

[0433]2H-1, 4-Benzoxazin-3 (4H) -one (1.0g, 6.70mmol) and Cs were mixed under nitrogen₂CO₃(3.28g, 10.1mmol) was dissolved in dry acetonitrile (20mL) and stirred at room temperature for 30 min. 3-chloro-1-iodopropane (1.58g, 7.38mmol) dissolved in acetonitrile (4mL) was added by injection. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. Water (150mL) was added and the reaction mixture was extracted with ethyl acetate (3X 150 mL). The combined organic phases were dried (MgSO)₄) And concentrated in vacuo to give 1.65g of crude product. The crude product was passed through CC [ eluent: EtOAc (4: 1)]The title compound was obtained as a colorless oil. Yield: 1.36g, 89.2%. R_f0.24[ heptane: EtOAc (4: 1)]，¹HNMR(CHCl₃)：δ2.16(m，2H)，3.62(t，2H)，4.10(t，2H)，4.59(s，2H)，7.00(m，2H)，7.05(m，2H)，¹³C NMR(CHCl₃)：δ30.16，39.04，42.45，67.72，114.80，117.38，123.07，124.14，128.49，145.47，164.58。

4- [3- (4-butyl-piperidinyl-1) -propyl]-4H-benzo [1, 4]]Oxazin-3-one (81MF10)

[0434]NaI (1.33g, 8.87mmol), K were stirred in acetonitrile (10mL) at room temperature₂CO₃(1.23g, 8.90mmol) and 4-butylpiperidine (0.66g, 4.71 mmol). 4- (3-chloropropyl) -4H-benzo [1, 4] benzo dissolved in acetonitrile (15mL) was added by injection]Oxazin-3-one (1.0g, 4.43 mmol). The reaction was stirred at 60 ℃ for 13 hours under nitrogen, then at 80 ℃ for another 5 hours and concentrated in vacuo. Water (150mL) was added and the reaction mixture was extracted with ethyl acetate (3X 150 mL). The organic phases are combined and dried (Na)₂SO₄) And concentrated in vacuo to give 1.58g of crude product. The crude product was passed through CC [ eluent: EtOAc: MeOH (100: 1-5%)]The title compound was obtained in pure form. Yield: 0.82g, 56.0% HPLC-MS [ M + H ]]⁺331(UV/MS(％)＝100/99。¹HNMR(CHCl₃)：δ0.88(t，3H)，1.21(m，6H)，1.26(m，3H)，1.66(d，2H)，1.86(m，4H)，2.37(t，2H)，2.86，(d，2H)，3.97(t，2H)，4.58(s，2H)，6.99(m，3H)，7.11(d，1H)，¹³C NMR(CHCl₃)：δ14.22，23.04，24.90，29.17，32.68，35.95，36.46，39.74，54.31，56.02，67.77，115.26，117.15，122.83，123.83，128.78，145.50，164.34。

[0435]To a solution of 4- [3- (4-butyl-piperidinyl-1) -propyl group in 30ml of diethyl ether]-4H-benzo [1, 4]]To oxazin-3-one (0.82g, mmol) was added oxalic acid (0.25g, 2.8mmol) in diethyl ether (5 mL). The crystals formed were filtered, washed with diethyl ether (5X 10mL) and dried to give 0.75g of the oxalate salt. HPLC-MS [ M + H ]]⁺331(UV/MS(％)＝100/99。

Example 2

Pharmacological data

[0436] Receptor selection and amplification (R-SAT) assays were performed using the cloned M1-M5 receptor and were essentially disclosed in the following references: Brauner-Osborne H, Brann MR. Pharmacology of muconic acetyl choline receptors subunit (m1-m 5): highgroughput assays in mammalian cells eur J Pharmacol 1996 Jan 4; 295(1): 93-102, and Spalding TA, Trotter C, Skjaerbaek N, Messier TL, CurrierEA, Burstein ES, Li D, Hacksel U, Brann MR.discovery of an anatomical site on the M (1) M usacarinic receiver. mol Pharmacol.2002 Jun; 61(6): 1297-302.

Number of Compounds	m1 efficacy% pEC	m2 efficacy% pEC	m3 efficacy% pEC	m4 efficacy% pEC	m3 efficacy% pEC
Number of Compounds	m1 efficacy% pEC	m2 efficacy% pEC	m3 efficacy% pEC	m4 efficacy% pEC	m3 efficacy% pEC	55-LH-28-1(1549)	87 7.5	41 5.8	Unreacted	66 6.2	Unreacted
77-LH-1(1606)	Unreacted	Unreacted	Unreacted	Unreacted	Unreacted	55-LH-28-1(1549)	87 7.5	41 5.8	Unreacted	66 6.2	Unreacted
77-LH-1(1606)	Unreacted	Unreacted	Unreacted	Unreacted	Unreacted	55-LH-28-8(1598)	45 6.7	67 ＜5.5	Unreacted	64 ＜5.5	Not tested
55-LH-12-2	72 7.3	35 6.2	Unreacted	68 6.0	Unreacted	55-LH-28-8(1598)	45 6.7	67 ＜5.5	Unreacted	64 ＜5.5	Not tested
55-LH-12-2	72 7.3	35 6.2	Unreacted	68 6.0	Unreacted	55LH44-A	54 6.5	Unreacted	Unreacted	28 ＜5.5	Not tested
55LH54	57 6.4	Unreacted	Unreacted	Unreacted	Unreacted	55LH44-A	54 6.5	Unreacted	Unreacted	28 ＜5.5	Not tested
55LH54	57 6.4	Unreacted	Unreacted	Unreacted	Unreacted	73MF01	90 7.7	55 6.3	Unreacted	65 6.8	49 6.2
73MF02	90 7.6	50 6.0	Unreacted	75 6.6	30 6.3	73MF01	90 7.7	55 6.3	Unreacted	65 6.8	49 6.2
73MF02	90 7.6	50 6.0	Unreacted	75 6.6	30 6.3	77LH02-1917	55 6.7	Unreacted	Unreacted	37 ＜5.5	Unreacted
64LHY89-5	45 5.6	Unreacted	Unreacted	Unreacted	Not tested	77LH02-1917	55 6.7	Unreacted	Unreacted	37 ＜5.5	Unreacted
64LHY89-5	45 5.6	Unreacted	Unreacted	Unreacted	Not tested	64LHY89-6	80 7.4	35 6.2	Unreacted	50 6.5	48 6.2
64LHY91-5	69 6.8	Unreacted	Unreacted	51 5.7	38 6.2	64LHY89-6	80 7.4	35 6.2	Unreacted	50 6.5	48 6.2
64LHY91-5	69 6.8	Unreacted	Unreacted	51 5.7	38 6.2	64LHY91-6	86 7.2	31 6.9	Unreacted	52 6.6	Unreacted
77LH22-A	76 7.1	Unreacted	Unreacted	Unreacted	37 ＜5.5	64LHY91-6	86 7.2	31 6.9	Unreacted	52 6.6	Unreacted
77LH22-A	76 7.1	Unreacted	Unreacted	Unreacted	37 ＜5.5	82LHY19	81 7.7	39 6.3	Unreacted	46 6.8	Not tested
77LH61-A	79 7.5	28 ＜5.5	Unreacted	33 5.8	51 ＜5.5	82LHY19	81 7.7	39 6.3	Unreacted	46 6.8	Not tested
77LH61-A	79 7.5	28 ＜5.5	Unreacted	33 5.8	51 ＜5.5	81MF24	96 7.8	70 7.0	Unreacted	Not tested	Not tested
81MF763	92 7.5	47 6.6	Unreacted	57 6.4	50 5.9	81MF24	96 7.8	70 7.0	Unreacted	Not tested	Not tested
81MF763	92 7.5	47 6.6	Unreacted	57 6.4	50 5.9	85LM47A	122 7.9	74 6.0	Unreacted	91 6.1	35 ＜5.5
85LM96-86R	106 7.6	97 6.2	305.9	94 5.8	90 5.6	85LM47A	122 7.9	74 6.0	Unreacted	91 6.1	35 ＜5.5
85LM96-86R	106 7.6	97 6.2	305.9	94 5.8	90 5.6	85LM96-87R	101 7.7	116 5.9	366.0	140 6.1	62 6.0
107LH55	103 8.9	28 7.5	Unreacted	54 7.3	Unreacted	85LM96-87R	101 7.7	116 5.9	366.0	140 6.1	62 6.0
107LH55	103 8.9	28 7.5	Unreacted	54 7.3	Unreacted	108LM39-36	106 8.8	37 8.1	Unreacted	71 7.7	Unreacted
107LH74-3D	97 8.0	Unreacted	Not tested	Not tested	Not tested	108LM39-36	106 8.8	37 8.1	Unreacted	71 7.7	Unreacted
107LH74-3D	97 8.0	Unreacted	Not tested	Not tested	Not tested	112KK20-c5	117 8.3	Unreacted	Unreacted	Not tested	Not tested
107LH95-1	103 7.6	Unreacted	Not tested	Not tested	Not tested	112KK20-c5	117 8.3	Unreacted	Unreacted	Not tested	Not tested

Claims

1. A compound of formula I and its salts and isomers

Wherein R is¹Is a monovalent radical selected from optionally substituted C_1-6-alkyl, optionally substituted C_2-6Alkylene, optionally substituted C_2-6-alkenyl, optionally substituted C_2-6-alkynyl, optionally substitutedO-C of_1-6-alkyl, optionally substituted O-C_2-6-alkenyl, optionally substituted O-C_2-6-alkynyl, optionally substituted S-C_1-6-alkyl, optionally substituted S-C_2-6-alkenyl, and optionally substituted S-C_2-6-an alkynyl group;

m is0, 1 or 2;

C₃-C₄is CH₂-CH or CH ═ C, or C₄Is CH and C₃Is absent;

R²and R³Independently selected from hydrogen, optionally substituted C_1-6Alkyl, optionally substituted O-C_1-6Alkyl, halogen, hydroxy, or alternatively R²、R³M and C₃-C₄So that

Is selected from

And

wherein R is⁸Is present 0, 1 or 2 times and is independently selected from optionally substituted C_1-6Alkyl, optionally substituted O-C_1-6Alkyl, halogen and hydroxy;

L¹and L²Is a divalent group independently selected from-C (R)⁶)＝C(R⁷)、-C(R⁶)＝N-、-N＝C(R⁶)-、-S-、-NH-and-O-; wherein L is¹And L²Only one of which may be selected from-S-, -NH-, and-O-;

y is selected from O, S and H₂；

X is a divalent group selected from-C (R)⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁷)-O-、-S-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-S-、-N(R^N)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-N(R^N)-、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、-O-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、S-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、N(R^N)-C(R⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-O、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-S、-C(R⁶)(R⁷)-C(R⁶)(R⁷)-N(R^N)-、-C(R⁶)(R⁷)-C(R⁶)＝C(R⁷) -and-C (R)⁶)＝C(R⁷)-C(R⁶)(R⁷) Wherein R is⁶And R⁷Independently selected from hydrogen, halogen, hydroxy, nitro, cyano, NR^NR^N、N(R^N)-C(O)N(R^N) Optionally substituted C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, optionally substituted O-C_1-6-alkyl, optionally substituted O-aryl, optionally substituted O-C_2-6-alkenyl and optionally substituted O-C_2-6-an alkynyl group,

wherein R is^NSelected from hydrogen and optionally substituted C_1-6-an alkyl group,

with the proviso that the following compounds are excluded:

1- [3- (4-butyl-piperidinyl-1) -propyl ] -8-alkyl-1, 2, 3, 4-tetrahydro-quinoline.

2. The compound of claim 1, wherein R1 is selected from optionally substituted C_1-6-alkyl, optionally substituted C_1-6Alkylene and optionally substituted O-C_1-6-an alkyl group.

3. The compound of claim 1, wherein R²And R³Is hydrogen, or alternatively C₃-C₄、m、R²And R³So that

Is selected from

And

4. the compound of claim 1, wherein R²And R³Independently selected from hydrogen, optionally substituted C_1-6Alkyl, optionally substituted O-C_1-6Alkyl, halogen and hydroxyl.

5. The compound of claim 1, wherein m is 1.

6. The compound of claim 1, wherein m is0, C₃Is absent, C₄Is CH, thereby

Is that

7. The compound of claim 1, wherein X is selected from-C (R)⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁷)-O-、-S-C(R⁶)(R⁷)-、-C(R⁶)(R⁷)-S-、-N(R^N)-C(R⁶)(R⁷) -and-C (R)⁶)(R⁷)-N(R^N)-。

8. The compound of claim 1, wherein Y is selected from O and H₂。

9. The compound of claim 1, wherein L¹And L²Independently selected from-C (R)⁶)＝C(R⁷)-、-C(R⁶) N-and-N ═ C (R)⁷)-。

10. A compound of formula Ia according to claim 1

Wherein R is¹Selected from optionally substituted C_1-6-alkyl, optionally substituted C_1-6Alkylene, optionally substituted C_2-6-alkenyl, optionally substituted C_2-6-alkynyl, optionally substituted O-C_1-6Alkyl and optionally substituted O-C_2-6-an alkenyl group; and R²、R³、R⁴、X、Y、R⁶And R⁷As defined in claim 1.

11. As claimed in claim 10The compound of (1), wherein C is optionally substituted_1-6-alkyl is selected from unsubstituted C_1-6-alkyl and C_1-6Alkoxyalkyl radical, Y being selected from O and H₂X is selected from-C (R)⁶)(R⁷)-C(R⁶)(R⁷)-、-C(R⁶)＝C(R⁷)-、-O-C(R⁶)(R⁷)-、C(R⁶)(R⁷)-O-、-S-C(R⁶)(R⁷) -and-C (R)⁶)(R⁷)-S-，L¹And L²Independently selected from-C (R)⁶)＝C(R⁷)-、-C(R⁶) N-and-N ═ C (R)⁷) -, and R⁴Selected from hydrogen, halogen, hydroxy, optionally substituted C_1-6-alkyl and optionally substituted O-C_1-6An alkyl group.

12. A compound according to claim 1 selected from 1- [3- (4-butyl-piperidinyl-1) -propyl ] -1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -2-methyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -7-fluoro-2-methyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -7-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinoline; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methoxy-3, 4-dihydro-1H-quinolin-2-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; 6-acetyl-4- [3- (4-butyl-piperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -6-methyl-3, 4-dihydro-2H-benzo [1, 4] oxazine; 4- [3- (4-butyl-piperidinyl-1) -propyl ] -6-ethyl-3, 4-dihydro-2H-benzo [1, 4] oxazine; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [3- (4-butylidene-piperidinyl-1) -2-methyl-propyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [3- (3-butyl-8-aza-bicyclo [3.2.1] octyl-8) -2-methyl-propyl ] -4H-benzo [1, 4] thiazin-3-one; (R) -4- [ 2-methyl-3- (3-pentyl-8-aza-bicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6, 8-dichloro-7-methyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butyl-piperidinyl-1-) propyl ] -6, 8-dimethyl-4H-benzo [1, 4] oxazin-3-one (81MF 2237F); 6-tert-butyl-4- [3- (4-butyl-piperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -5-methyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7-methyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6-chloro-7-nitro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7-chloro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7, 8-difluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -4H-pyrido [4, 3-b ] [1, 4] thiazin-3-one; 4- [3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylidenepiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; 4- [3- (4-butylidenepiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (3-butylidene-8-aza-bicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -6, 8-dichloro-7-ethyl-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -8-fluoro-4H-benzo [1, 4] oxazin-3-one; 6-bromo-4- [3- (4-butylpiperidinyl-1-) propyl ] -8-fluoro-4H-benzo [1, 4] oxazin-3-one; 4- [3- (4-butylpiperidinyl-1-) propyl ] -8-isopropyl-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl ] -4H-benzo [1, 4] oxazin-3-one; (-) -4- [3- (4-butylpiperidinyl-1) -2-hydroxypropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidine) -2-methoxypropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-hydroxy-3- (3-pentylbicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; 4- [2- (4-butylpiperidinyl-1-methyl) allyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-fluoropropyl ] -4H-benzo [1, 4] oxazin-3-one; (S) -4- [3- (4-butyl-piperidinyl-1) -2-methyl-propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-aza-bicyclo [3.2.1] octyl-8) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -6-fluoro-4- [ 2-methyl-3- (4-propoxy-piperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methyl-propyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -6-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1-) 2-methylpropyl ] -7-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -7-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -7-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -7-fluoro-4H-benzo [1, 4] oxazin-3-one; (R) -7-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methyl-propyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R) -6-methoxy-4- [ 2-methyl-3- (3-pentyl-8-aza-bicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -6-methoxy-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -6-methyl-4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; (R) -4- [3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methyl-4H-benzo [1, 4] oxazin-3-one; 1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-3, 4-dihydro-1H-quinolin-2-one; 6-fluoro-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-3, 4-dihydro-1H-quinolin-2-one; (R, S) -6-fluoro-1- [3- (4-propoxypiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-chloro-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-methyl-3, 4-dihydro-1H-quinolin-2-one; 6-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -5-methyl-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-methyl-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-6-methyl-3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one; 6, 7-difluoro-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6, 7-difluoro-3, 4-dihydro-1H-quinolin-2-one; (R, S) -6, 7-difluoro-1- [3- (4-propoxypiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one; 6-fluoro-7-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-7-methyl-3, 4-dihydro-1H-quinolin-2-one; (R, S) -6-fluoro-7-methyl-1- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butyl-piperidinyl-1-) propyl ] -6-fluoro-5-methyl-3, 4-dihydro-1H-quinolin-2-one; 6-fluoro-5-methyl-1- [3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -1H-quinolin-2-one; 1- [3- (4-propoxypiperidinyl-1-) propyl ] -1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-fluoro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-methyl-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -7-fluoro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-methoxy-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -6-chloro-1H-quinolin-2-one; 1- [3- (4-butylpiperidinyl-1-) propyl ] -5-methyl-1H-quinolin-2-one; 1- [3- (4-butyl-piperidinyl-1-) propyl ] -7-methyl-1H-quinolin-2-one; (R) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -1H-quinolin-2-one; (R) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1) -propyl ] -1H-quinolin-2-one; 1- [3- (4-allyloxypiperidin-1-) propyl ] -1H-quinolin-2-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1) -2-methylpropyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -6-methyl-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -6-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -6-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -7-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -7-fluoro-4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1-) -2-methylpropyl ] -7-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -7-fluoro-4H-benzo [1.4] oxazin-3-one; (R, S) -7-fluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1.4] oxazin-3-one; (R, S) -3- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -3H-benzothiazol-2-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -3H-benzothiazol-2-one; (R, S) -4- [3- (4-butylidenpiperidinyl-1) -2-methylpropyl ] -3H-benzothiazol-2-one; (R, S) -3- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -3H-benzothiazol-2-one; (R, S) -3- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -3H-benzothiazol-2-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -4- [3- (4-butylidenepiperidinyl-1) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] thiazin-3-one; (R, S) -1- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [ 2-methyl-3- (4-propoxypiperidinyl-1-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (4-butylidenepiperidin-1-y 1) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -3, 4-dihydro-1H-quinolin-2-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [ 2-methyl-3- (4-propoxypiperidinyl-1) -6-methoxy ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylidenpiperidyl-1) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butyl-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -1- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -6-methoxy-4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (4-butylpiperidinyl-1) -2-methylpropyl ] -6, 7-difluoro-4H-benzo [1, 4] oxazin-3-one; (R, S) -6, 7-difluoro-4- [ 2-methyl-3- (3-pentyl-8-azabicyclo [3.2.1] octyl-8-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butoxy-8-azabicyclo [3.2.1] octyl-8) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R, S) -6-fluoro-4- {3- [3- (2-methoxyethyl) -8-azabicyclo [3.2.1] octyl-8- ] -2-methylpropyl } -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butylazetidin-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; (R, S) -6-fluoro-4- [ 2-methyl-3- (3-propoxyazetidin-1-) propyl ] -4H-benzo [1, 4] oxazin-3-one; (R, S) -4- [3- (3-butylazetidin-1) -2-methoxypropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one; and 4- [3- (4-butyl-3-fluoropiperidinyl-1) -2-methylpropyl ] -6-fluoro-4H-benzo [1, 4] oxazin-3-one.

13. A composition comprising

i) One or more compounds of the general formula I as claimed in claim 1, and

ii) at least one pharmaceutically acceptable excipient or carrier.

14. Use of a compound of general formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing, as claimed in any one of claims 1 to 12, in the manufacture of a medicament for the treatment of a disease in a mammal, wherein modulation of the activity of cholinergic receptors is associated with a physiologically beneficial response in the disease in the mammal.

15. The use according to claim 14, wherein the cholinergic receptor is a muscarinic receptor.

16. The use according to claim 14, wherein the cholinergic receptor is muscarinic M₁-receptor subtype.

17. The use according to claim 14, wherein the cholinergic receptor is muscarinic M₄-receptor subtype.

18. The use according to claim 14, wherein the physiologically beneficial response is associated with muscarinic M₁Receptor subtype vs. muscarinic M₂-or M₃Selective modulation of receptor subtypes.

19. The use according to claim 14, wherein the compound is a muscarinic agonist.

20. The use of claim 14, wherein the disease or disorder is a mental disorder, wherein the physiologically beneficial response is due to a response to M₁Agonism, M₁And M₄Agonism, M₁Agonism and D₂Antagonism, or M₁And M₄Agonism and D₂Modulation of antagonism.

21. Use of a compound of general formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing, as claimed in any one of claims 1 to 12, for the manufacture of a medicament for use in the enhancement of cholinergic receptor activity.

22. Use of a compound of general formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing as claimed in any one of claims 1 to 12, for the manufacture of a medicament for the treatment or prevention or alleviation of symptoms associated with an aberration in a mammal associated with M₁Muscarinic receptor subtypes are related.

23. The use of claim 22, wherein the disorder is selected from cognitive impairment, amnesia, confusion, memory loss, attention deficit, vision loss, depression, pain, sleep disorders, psychosis and increased intraocular pressure.

24. The use of claim 22, wherein the disorder is selected from the group consisting of neurodegenerative disorders, alzheimer's disease, parkinson's disease, schizophrenia, huntington's chorea, friedreich's ataxia, gilles de la tourette's syndrome, down syndrome, niemann pick disease, dementia, clinical depression, age-related cognitive decline, attention deficit, sudden infant death syndrome and glaucoma.

25. Use of a compound of general formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing, as claimed in any one of claims 1 to 12, for the manufacture of a medicament for the treatment of a disease or disorder associated with a cholinergic receptor or a ligand thereof.

26. Use of a compound of general formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising any of the foregoing, as claimed in any one of claims 1 to 12, in the manufacture of a medicament for the treatment of a disease or disorder selected from: alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, Friedreich's ataxia, Gilles de la Tourette's syndrome, Down's syndrome, Niemann pick's disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, amnesia, confusion, memory loss, attention deficit, vision loss, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.