The present invention relates to tetrahydroquinoline compounds as muscarinic receptor agonists; compositions comprising the same; methods of inhibiting an activity of a muscarinic receptor with said compounds; methods of treating a disease condition associated with a muscarinic receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

Description

67 parts

›CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No. 11/019,556, filed Dec. 21, 2004 which is a continuation-in-part of application Ser. No. 10/329,455, filed Dec. 23, 2002, now U.S. Pat. No. 7,307,075, which in turn claims priority to U.S. Provisional Application No. 60/344,722, filed Dec. 28, 2001, all of which are incorporated by reference herein in their entirety, including any drawings.

›BACKGROUND OF THE INVENTION · 1 of 2

1. Field of the Invention

The present invention relates to compounds that affect cholinergic receptors, especially muscarinic receptors. The present invention provides compounds that are agonists of cholinergic receptors including muscarinic receptors, especially the M 1 and M 4 subtype of muscarinic receptors. The invention also provides methods of using the provided compounds for modulating conditions associated with cholinergic receptors, especially for treating or alleviating disease conditions associated with muscarinic receptors, such as the M 1 and/or M 4 receptor subtypes.

2. Description of the Related Art

Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems. Muscarinic receptors play a critical role in the central nervous system mediating higher cognitive functions, as well as in the peripheral parasympathetic nervous system where they mediate cardiac, respiratory, digestive, and endocrine and exocrine responses. Five distinct muscarinic receptor subtypes have been identified, M 1 -M 5 . The muscarinic M 1 receptor subtype is predominantly expressed in the cerebral cortex and is believed to be involved in the control of higher cognitive functions; the M 2 receptor is the predominant subtype found in heart and is involved in the control of heart rate; the M 3 receptor is widely expressed in many peripheral tissues and is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; the M 4 receptor is present in brain and may be involved in locomotion; the M 5 , receptor is present in the brain where its role is at present poorly defined. M 1 and M 4 have been particularly associated with the dopaminergic system.

Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a reduction of acetylcholine content in the brain. This is believed to be the result of degeneration of cholinergic neurons of the basal forebrain, which widely innervate multiple areas of the brain, including the association cortices and hippocampus, that are critically involved in higher processes.

Efforts to increase acetylcholine levels have focused on increasing levels of choline, the precursor for acetylcholine synthesis, and on blocking acetylcholinesterase (AChE), the enzyme that metabolizes acetylcholine. Attempts to augment central cholinergic function through the administration of choline or phosphatidylcholine have not been successful. AChE inhibitors have shown therapeutic efficacy, but have been found to have frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, and diarrhea. These gastrointestinal side effects have been observed in about a third of the patients treated. In addition, some AChE inhibitors, such as tacrine, have also been found to cause significant hepatotoxicity with elevated liver transaminases observed in about 30% of patients. The adverse effects of AChE inhibitors have severely limited their clinical utility.

The dopamine hypothesis of schizophrenia suggests that increased dopamine neurotransmission underlies the positive symptoms of the disease and is supported by the evidence that dopamine receptor blockade is effective in ameliorating such psychotic symptoms. Further, drugs that enhance dopamine neurotransmission in the brain cause psychotic-like episodes in man and exacerbate psychotic symptoms in schizophrenic patients. In animal studies, drugs that increase dopamine neurotransmission cause behavioural effects such as increased locomotion, climbing and deficits in prepulse inhibition. Known antipsychotics and dopamine receptor antagonists can block these behavioural effects. Unfortunately, dopamine receptor antagonists also cause severe extrapyramidal side effects in patients as predicted by induction of catalepsy in animal models. These extrapyramidal side effects include tremor, bradykinesia, akithesias, and tardive dyskinesias.

Due in part to these observations, the discovery of agents with M 1 receptor agonist activity has been sought after for the treatment of dementia. However, existing agents lack specificity in their actions at the various muscarinic receptor subtypes. Known M 1 muscarinic agonists such as arecoline have also been found to be weak agonists of M 2 as well as M 3 receptor subtypes and are ineffective in the treatment of cognitive impairment, due in large part to their dose-limiting M 2 and M 3 receptor mediated side effects.

Xanomeline (Shannon et al., J. Pharmacol. Exp. Ther. 1994, 269, 271; Shannon et al., Schizophrenia Res. 2000, 42, 249) is an M 1 /M 4 preferring muscarinic receptor agonist with little or no affinity for dopamine receptors despite inhibiting A10 but not A9 dopamine cells. The thiadiazole derivative PTAC has been reported (Shannon et al., European Journal of Pharmacology, 1998, 356, 109) to have partial agonist effect at muscarinic M 2 and M 4 receptors and antagonist effect at muscarinic M 1 , M 3 , and M 5 receptors as well as exhibiting functional dopamine antagonism.

Recently, muscarinic agonists including xanomeline have been shown to be active in animal models with similar profiles to known antipsychotic drugs, 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., Schizophrenia Res. 2000, 42, 249). Further, xanomeline was shown to reduce psychotic behavioural symptoms such as delusions, suspiciousness, vocal outbursts, and hallucinations in Alzheimer's disease patients (Bodick et al., Arch. Neurol. 1997, 54, 465), however treatment induced side effects that severely limit the clinical utility of this compound.

Analogues of 1,2,5-thiadiazole have been reported (Sauerberg et al., J. Med. Chem. 1998, 41, 4378) to have high affinity and selectivity for central muscarinic receptors as well as exhibiting functional dopamine antagonism despite lack of affinity for dopamine receptors.

›BACKGROUND OF THE INVENTION · 2 of 2

The present investigators have, in part, focussed their efforts on the development of molecules that simultaneously reduced the positive symptoms and improved the negative symptoms and the cognitive impairments associated with schizophrenia as a novel treatment of mental disorders. It is the intent of the present investigators to demonstrate that muscarinic M 1 and/or M 4 agonists with combined D 2 antagonist activity may possess superior antipsychotic efficacy without the side effects associated with high dose D 2 antagonism alone. The D 2 antagonist properties of some of the compounds of the present invention may contribute to a reduction in the positive symptoms of this disease.

Based on distribution of M 1 and M 4 receptors in the cerebral cortex and hippocampus (the areas involved in higher order cognitive functions), the M 1 and/or M 4 agonist properties of these compounds may reduce the cognitive dulling and perhaps ameliorate other negative symptoms associated with schizophrenia. (Friedman, Biol. Psychiatry, 1999, 45, 1; Rowley, J. Med. Chem. 2001, 44, 477; Felder, J. Med. Chem. 2000, 43, 4333). This unique combination of central nervous system activities in one molecule is unprecedented and may lead to the development of an entirely new class of antipsychotic drugs, ones with the superior clinical properties without the limiting side-effect profile.

U.S. Pat. No. 3,324,137 and U.S. Pat. No. 3,365,457 describe N-[indolyl-lower-alkanoyl]-1,5-iminocycloalkanes and iminocycloalkanes not encompassed by the invention.

EP 0 584 487 describes 4,5-dihydro-4-oxo-pyrroles with linked to piperazine rings not encompassed by the invention.

Mokrosz et al ( Pharmazie, 52, 1997, 6, p 423) describes 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 invention.

›SUMMARY OF THE INVENTION

The invention provides novel compounds of formula I, as well as salts and isomers thereof

wherein R 1 is a monoradical selected from the group consisting of optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkylidene, 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 -alkynyl;

m is 0, 1 or 2;

C 3 -C 4 is CH 2 —CH or CH═C or C 4 is CH and C 3 is absent;

R 2 and R 3 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted O—C 1-6 alkyl, halogen, hydroxy or selected such that R 2 and R 3 together form a ring system;

each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1-6 -alkyl, optionally substituted O—C 1-6 alkyl, optionally substituted aryl-C 1-6 alkyl, and optionally substituted arylheteroalkyl;

L 1 and L 2 are biradicals independently selected from the group consisting of —C(R 6 )═C(R 7 ), —C(R 6 )═N—, —N═C(R 6 )—, —S—, —NH— and —O—; wherein only one of L 1 and L 2 may be selected from the group consisting of —S—, —NH— and —O—;

Y is selected from the group consisting of O, S, and H 2 ;

X is a biradical selected from the group consisting of —C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )═C(R 7 )—, —O—C(R 6 )(R 7 )—, C(R 6 )(R 7 )—O—, —S—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—S—, —N(R N )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—N(R N ), —C(R 6 )(R 7 )—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —O—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, S—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, N(R N )—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—O, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—S, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—N(R N )—, —C(R 6 )(R 7 )—C(R 6 )═C(R 7 )—, and —C(R 6 )═C(R 7 )—C(R 6 )(R 7 ), wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NR N R N , N(R N )—C(O)N(R N ), optionally substituted C 1-6 -alkyl, 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

wherein R N is selected from the group consisting of hydrogen, and optionally substituted C 1-6 -alkyl.

The invention further provides compositions comprising

i) one or more compounds of formula I, and;

ii) at least one pharmaceutically acceptable excipient or carrier.

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

Thus, the invention provides methods of treating or preventing or alleviating one or more symptoms associated with a disorder in a mammal, such as a human, said disorder associated with a muscarinic receptor, for example, the M 1 muscarinic receptor subtype. In one embodiment, a method includes the administration of an effective amount of the compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity. Particular disorders treatable by a method of the invention include, for example, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.

The invention additionally provides a method of treating a mental disorder wherein the physiologically beneficial response is due to modulation in terms of M 1 agonism; M 1 and M 4 agonism; both M 1 agonism and D 2 antagonism; or M 1 and M 4 agonism and D 2 antagonism.

The invention additionally provides the use of a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity, for the preparation of a medicament for the treatment of diseases or disorders associated with a cholinergic receptor or ligand thereof.

The invention therefore provides methods for the preparation of a medicament for the treatment of diseases or disorders selected from the group consisting of Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.

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

The invention provides kits including one or more compounds of the invention, and instructions for practicing a method of the invention. In one embodiment, instructions are for treating or preventing or alleviating one or more symptoms associated with a disorder in a mammal, such as a human, said disorder associated with a muscarinic receptor, for example, the M 1 muscarinic receptor subtype. In another embodiment, instructions are for increasing cholinergic receptor activity or activating cholinergic receptors.

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 1 of 10

For the purpose of the current disclosure, the following definitions shall in their entireties be used to define technical terms.

The term “agonist” is defined as a compound that increases the activity of a receptor when it contacts the receptor.

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 action of an agonist or inverse agonist on the receptor. However, an antagonist (also known as a “neutral” antagonist) has no effect on constitutive receptor activity.

The term “inverse agonist” is defined as a compound that decreases the basal activity of a receptor (i.e., signaling mediated by the receptor). Such compounds are also known as negative antagonists. An inverse agonist is a ligand for a receptor that causes the receptor to adopt an inactive state relative to a basal state occurring in the absence of any ligand. Thus, while an antagonist can inhibit the activity of an agonist, an inverse agonist is a ligand that can alter the conformation of the receptor in the absence of an agonist. The concept of an inverse agonist has been explored by Bond et al. in Nature 374:272 (1995). More specifically, Bond et al. have proposed that unliganded β 2 -adrenoceptor exists in an equilibrium between an inactive conformation and a spontaneously active conformation. Agonists are proposed to stabilize the receptor in an active conformation. Conversely, inverse agonists are believed to stabilize an inactive receptor conformation. Thus, while an antagonist manifests its activity by virtue of inhibiting an agonist, an inverse agonist can additionally manifest its activity in the absence of an agonist by inhibiting the spontaneous conversion of an unliganded receptor to an active conformation.

The “M 1 -receptor” is defined as a receptor having an activity corresponding to the activity of the m1 muscarinic receptor subtype characterized through molecular cloning and pharmacology.

The term “subject” refers to an animal, for example a mammal, such as a human, who is the object of treatment, observation or experiment.

The term “selective” is defined as a property of a compound whereby an amount of the compound sufficient to effect a desired response from a particular receptor type, subtype, class or subclass causes a substantially smaller or no effect upon the activity of other receptor types.

The EC 50 for an agonist is intended to denote the concentration of a compound needed to achieve 50% of a maximal response seen in an in vitro assay such as R-SAT. For inverse agonists, EC50 is intended to denote the concentration of a compound needed to achieve 50% inhibition of an R-SAT response from basal, no compound, levels.

As used herein, the term “coadministration” of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration refers to the simultaneous delivery of separate agents; to the simultaneous delivery of a mixture of agents; as well as to the delivery of one agent followed by delivery of a second agent or additional agents. In all cases, agents that are coadministered are intended to work in conjunction with each other.

In the present context, the term “C 1-6 -alkyl” means a linear or branched saturated hydrocarbon chain wherein the longest chain has from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.

In the present context, the term “C 2-8 -alkenyl” means a linear or branched hydrocarbon group having from two to eight carbon atoms and containing one or more double bonds. Illustrative examples of C 2-8 -alkenyl groups include allyl, homo-allyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. Illustrative examples of C 2-8 -alkenyl groups with more than one double bond include butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl and octatrienyl groups as well as branched forms of these. The position of the unsaturation (the double bond) may be at any position along the carbon chain.

In the present context the term “C 2-8 -alkynyl” means a linear or branched hydrocarbon group containing from two to eight carbon atoms and containing one or more triple bonds. Illustrative examples of C 2-8 -alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl groups as well as branched forms of these. The position of unsaturation (the triple bond) may be at any position along the carbon chain. More than one bond may be unsaturated such that the “C 2-8 -alkynyl” is a di-yne or enedi-yne as is known to the person skilled in the art.

In the present context, the term “C 3-8 -cycloalkyl” includes three-, four-, five-, six-, seven-, and eight-membered rings comprising carbon atoms only, whereas the term “heterocyclyl” means three-, four-, five-, six- seven-, and eight-membered rings wherein carbon atoms together with from 1 to 3 heteroatoms constitute said ring. The heteroatoms of such heterocyclyl groups are independently selected from oxygen, sulphur, and nitrogen.

The term “Heterocyclyl” groups may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.

C 3-8 -cycloalkyl and heterocyclyl rings may optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic π-electron system does not arise.

Heterocyclyl rings may optionally also be fused to aryl rings, such that the definition includes bicyclic structures. Examples of such fused heterocyclyl groups share one bond with an optionally substituted benzene ring. Examples of benzo-fused heterocyclyl groups include, but are not limited to, benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene ring structures.

Illustrative examples of “C 3-8 cycloalkyl” are the carbocycles 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.

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 2 of 10

Illustrative examples of “heterocyclyls” are the heterocycles tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, 1,3-oxathiolane. Binding to the heterocycle may be at the position of a heteroatom or via a carbon atom of the heterocycle, or, for benzo-fused derivatives, via a carbon of the benzenoid ring.

In the present context the term “aryl” means a carbocyclic aromatic ring or ring system. Moreover, the term “aryl” includes fused ring systems wherein at least two aryl rings, or at least one aryl and at least one C 3-8 -cycloalkyl share at least one chemical bond. Illustrative examples of “aryl” rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. An example of an aryl group is phenyl. The term “aryl” relates to aromatic, typically benzenoid groups connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. As stated, aryl groups may be phenyl, and, most suitably, substituted phenyl groups, carrying one or two, same or different, of the substituents listed above. One pattern of substitution is 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.

In the present context the term “aryl(C 1-6 -alkyl)” means a carbocyclic aromatic ring as defined above connected via a C 1-6 -alkyl group.

The term arylheteroalkyl should be interpreted as an aryl group, as defined above, connected, as a substituent, via a C 1-6 -alkyl tether which, additionally, contains, in the chain, at least one atom selected from the group consisting of oxygen, sulfur, and nitrogen.

In the present context, the term “heteroaryl” means a heterocyclic aromatic group where one or more carbon atoms in an aromatic ring have been replaced with one or more heteroatoms selected from the group comprising nitrogen, sulphur, phosphorous and oxygen.

Furthermore, the term “heteroaryl” comprises fused ring systems wherein at least one aryl ring and at least one heteroaryl ring, at least two heteroaryl rings, at least one heteroaryl ring and at least one heterocyclyl ring, or at least one heteroaryl ring and at least one C 3-8 -cycloalkyl ring share at least one chemical bond.

The term “heteroaryl” is understood to relate to aromatic, C 2-6 cyclic groups further containing one O or S atom or up to four N atoms, or a combination of one O or S atom with up to two N atoms, and their substituted as well as benzo- and pyrido-fused derivatives, typically connected via one of the ring-forming carbon atoms. Heteroaryl groups may carry one or more substituents, selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C 1-6 -alkoxy, C 1-6 -alkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 1-6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Particular heteroaryl groups are five- and six-membered aromatic heterocyclic systems carrying 0, 1, or 2 substituents, which may be the same as or different from one another, selected from the list above. Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, and tetrazole, as well as furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, quionoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, pteridine, pyrrole, phenoxazole, oxazole, isoxazole, oxadiazole, benzopyrazole, indazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. The most typical substituents are halo, hydroxy, cyano, O—C 1-6 -alkyl, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, amino-C 1-6 -alkyl.

When used herein, the term “O—C 1-6 -alkyl” means C 1-6 -alkyloxy, or alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy and hexyloxy

The term “halogen” includes fluorine, chlorine, bromine and iodine.

When used herein, the term “optionally substituted” means that the group in question 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 groups selected from C 1-6 -alkyl, C 1-6 -alkoxy, oxo (which may be represented in the tautomeric enol form), carboxyl, amino, hydroxy (which when present in an enol system may be represented in the tautomeric keto form), nitro, alkylsulfonyl, alkylsulfenyl, alkylsulfinyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, formyl, mono- and di(C 1-6 -alkyl)amino; carbamoyl, mono- and di(C 1-6 -alkyl)aminocarbonyl, amino-C 1-6 -alkyl-aminocarbonyl, mono- and di(C 1-6 -alkyl)amino-C 1-6 -alkyl-aminocarbonyl, C 1-6 -alkylcarbonylamino, cyano, guanidino, carbamido, C 1-6 -alkanoyloxy, C 1-6 -alkylsulphonyloxy, dihalogen-C 1-6 -alkyl, trihalogen-C 1-6 -alkyl, and halo. In general, the above substituents may be susceptible to further optional substitution

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 3 of 10

The term “salt” means pharmaceutically acceptable acid addition salts obtainable by treating the base form of a functional group, such as an amine, with appropriate acids such as inorganic acids, for example hydrohalic acids; typically hydrochloric, hydrobromic, hydrofluoric, or hydroiodic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic, propionic, hydroacetic, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic acid, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic, and other acids known to the skilled practitioner.

The method of the invention relates to the modulation of a cholinergic receptor. Typically, said cholinergic receptor is a muscarinic receptor; one example of a cholinergic receptor is a muscarinic receptor of M 1 -receptor subtype. As can be seen from the Examples, in suitable embodiments, the cholinergic receptor may be either or both the muscarinic M 1 -receptor and the muscarinic M 4 -receptor subtypes. The physiologically beneficial response in the method of the invention is typically associated with the specific activation of the M 1 -receptor subtype over the M 2 - or M 3 -receptor subtype, or the specific activation of the M 1 - and M 4 -receptor subtypes over the M 2 - or M 3 -receptor subtype. Moreover, a physiologically beneficial response in a method of the invention is typically associated with the agonistic activity of the compound of formula I or IA. Thus, in one embodiment, the compound of formula I or IA is a muscarinic agonist, such as an M 1 agonist or an M 1 and M 4 agonist.

A further aspect of the invention relates to a method of increasing the activity of a cholinergic receptor. In one embodiment, a method includes contacting a cholinergic receptor or a system containing a cholinergic receptor with an effective amount of at least one compound of formula I or IA, as defined supra.

A related aspect of the invention is directed to a method of treating or preventing or alleviating one or more symptoms associated with a disorder in a mammal, such as a human. In one embodiment, a method includes the administration of an effective amount of a compound of formula I or IA, said disorder associated with a muscarinic receptor, for example, M 1 muscarinic receptor subtype.

The disorders associated with the M 1 muscarinic receptor subtype are typically mental disorders. Suitable mental disorders which can be treated by the method of the invention may be selected from the group comprising of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, and increased intraocular pressure.

Disorders associated with the M 1 muscarinic receptor subtype need not be a mental disorder. For instance, increased intraocular pressure is associated with the M 1 muscarinic receptor subtype. Disorders to which the method of the invention are directed therefore include non-mental disorders.

Disorders to which the method of the invention are directed may be further selected from the group comprising neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, sudden infant death syndrome, and glaucoma.

As stated, the compounds of the invention have high selectivity and affinity for the muscarinic M 1 receptor subtypes. As can be seen from the Examples, the compounds also have high affinity for one or both of the M 1 and M 4 receptor subtypes, selectively over other receptors such as the M 2 , M 3 and M 5 receptor subtypes. The compounds of the invention typically act, at least in part, as an M 1 agonist or as M 1 and M 4 agonist.

The compounds of the invention also have an affinity for the dopamine D 2 receptor. As discussed supra in connection with the dopamine hypothesis in relation to schizophrenia, compounds which act as both muscarinic agonists and dopamine antagonists may be keys to adequately treat many mental disorders. Thus, the invention is also directed to methods of treating mental disorders, using compounds of the invention, said compounds acting as a D 2 antagonist or D 2 inverse agonist as well as a muscarinic agonist, particularly an M 1 agonist or as M 1 and M 4 agonist. Thus, the method of the invention may be such that the disease in a mental disorder and the physiologically beneficial response to due to modulation in terms of M 1 agonism; M 1 and M 4 agonism; both M 1 agonism and D 2 antagonism; or M 1 and M 4 agonism and D 2 antagonism.

In one aspect of the invention, the compounds of the invention are anti-psychotic agents, said anti-psychotic activity due to the compounds of the invention acting as M 1 agonist; or as M 1 and M 4 agonists; or acting as an both M 1 agonists and D 2 antagonist; or as M 1 and M 4 agonists and D 2 antagonists.

Another aspect of the invention relates to the use of a compound of formula IA, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising either entity, for the preparation of a medicament for the treatment of diseases or disorders associated with a cholinergic receptor or ligand thereof. The medicament may be for the treatment of diseases associated with the receptors as discussed supra and for disorders as discussed supra. A related aspect of the invention is directed to a pharmaceutical composition comprising an effective amount of a compound of formula I, as defined supra, or pharmaceutically acceptable salts thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity, together with pharmaceutically acceptable carriers or excipients.

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 4 of 10

The invention provides novel compounds of formula I, as well as salts and isomers thereof

m is 0, 1 or 2;

C 3 -C 4 is CH 2 —CH or CH═C or C 4 is CH and C 3 is absent;

each R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1-6 -alkyl, OC 1-6 alkyl, aryl-C 1-6 alkyl, and arylheteroalkyl;

Y is selected from the group consisting of O, S, and H 2 ;

X is a biradical selected from the group consisting of —C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )═C(R 7 )—, —O—C(R 6 )(R 7 )—, C(R 6 )(R 7 )—O—, —S—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—S—, —N(R N )—C(R 6 )(R 7 ), —C(R 6 )(R 7 )—N(R N )—, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —O—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, S—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, N(R N )—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—O, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—S, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—N(R N )—, —C(R 6 )(R 7 )—C(R 6 )═C(R 7 )—, and —C(R 6 )═C(R 7 )—C(R 6 )(R 7 ), wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NR N R N , N(R N )—C(O)N(R N ), optionally substituted C 1-6 -alkyl, 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

wherein R N is selected from the group consisting of hydrogen, and optionally substituted C 1-6 -alkyl.

The present investigators have found that the compounds of the invention have a high affinity and specificity for the M 1 muscarinic receptor. The compounds of the invention may be of use in an array of conditions associated with the modulation of the M 1 muscarinic receptor subtype.

Typically, the compounds of formula I are such that R 1 is selected from the group consisting of optionally substituted C 1-6 -alkyl, optionally substituted C 1-6 -alkylidene, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, optionally substituted O—C 1-6 -alkyl, and optionally substituted O—C 2-6 -alkenyl. R 1 can be selected from the group consisting of optionally substituted C 1-6 -alkyl, optionally substituted C 1-6 -alkylidene, optionally substituted C 2-6 -alkenyl, optionally substituted O—C 1-6 -alkyl. R 1 can typically be selected from the group consisting of optionally substituted C 1-6 -alkyl, optionally substituted C 1-6 -alkylidene, and optionally substituted O—C 1-6 -alkyl. Most typically, R 1 is selected from the group consisting of optionally substituted C 4 -alkyl, optionally substituted C 5 -alkyl, optionally substituted C 4 -alkylidene, and optionally substituted O—C 1-6 -alkyl. In a preferred embodiment, R 1 may be unsubstituted C 4 -alkyl, unsubstituted C 5 -alkyl, or unsubstituted O—C 3 -alkyl, e.g. n-butyl, n-pentyl, or n-propyloxy.

In a particular embodiment of the invention, the compounds of formula I are such that R 1 is an optionally substituted C 1-6 -alkyl, selected from the group consisting of unsubstituted C 1-6 -alkyl, and C 1-6 -alkoxyalkyl. The C 1-6 -alkoxyalkyl may be C 1-3 -alkoxyC 1-3 alkyl. Typically, the C 1-6 -alkoxyalkyl is selected from methoxypropyl, ethoxyethyl, propyloxymethyl, and methoxyethyl.

In one embodiment of the invention, the compounds of formula I are piperidines, bicyclic piperidines, 3-4-unsaturated piperidines or bicyclic 3-4-unsaturated piperidines. Within this embodiment, the C 3 -C 4 bond may be a single bond to form either a piperidine ring or a bicyclic piperidine. Alternatively, piperidine may be 3-4 unsaturated. That is to say that C 3 -C 4 may be a double bond (C 3 ═C 4 ) so as to form either a 3-4-unsaturated piperidine or bicyclic 3-4-unsaturated piperidine.

In another embodiment of the invention, m is 0 and C 3 is absent while C 4 is CH, so as to result in an azetidine ring. Bicyclic analogues of azetidine are also included.

In an alternative embodiment, m is 0 so as to result in a pyrrolidine ring or a 3-pyrroline, when C3-C4 is a single bond or a double bond, respectively. Bicyclic analogues of pyrrolidine ring or a 3-pyrroline are further included. In a further suitable embodiment, m is 2 so as to form a 7-membered ring. In a particular embodiment, m is 1.

In one embodiment, R 2 and R 3 together form a bicyclic ring system such that

is selected from the group consisting of

wherein R 8 is present 0, 1, or 2 times and is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted O—C 1-6 alkyl, halogen, hydroxy.

Within such an embodiment, R 2 and R 3 may preferably be selected such that R 2 and R 3 together form a ring system such that

is selected from the group comprising

In a more preferred embodiment, the substituents R 2 and R 3 are selected so that the bicyclic ring is 3-substituted 8-azabicyclo[3.2.1]octane.

However, in a particular embodiment, R 2 and R 3 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted O—C 1-6 alkyl, halogen and hydroxy.

Thus, in a combination of embodiments of compounds of formula I, C 3 -C 4 is a single bond, R 2 and R 3 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted O—C 1-6 alkyl, halogen and hydroxy, and m is 1. Suitably, R 2 and R 3 are hydrogen.

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 5 of 10

In a further combination, m can be 0, C 3 can be absent, and C 4 can be CH such that

In a further combination of embodiments, C 3 -C 4 and m are so as to form a piperidine ring, for example, wherein R 2 and R 3 are hydrogen. In additional embodiments, C 3 -C 4 and m are so as to form a piperidine ring, R 2 and R 3 are hydrogen, and R 1 an unsubstituted C 4 -alkyl, an unsubstituted C 5 -alkyl, or an O—C 3 -alkyl, such as butyl, pentyl, or propyloxy.

Thus, in one embodiment

is a 4-butyl piperidine.

In another embodiment

is 4-butyl piperidine.

In one embodiment of the invention, C 3 -C 4 and m are such as to form an azetidine ring,

R 2 and R 3 are hydrogen, and R 1 is selected from unsubstituted C 4 -alkyl, unsubstituted C 5 -alkyl, and O—C 3 -alkyl. Thus, in one embodiment

is a 4-butylazetidine.

In one aspect of the invention a 3-carbon tether is linking the two nitrogen atoms of the two ring systems of the compounds of formula I. The present investigators have found that this optionally substituted propylene spacer unit provides for compounds with highly efficacious binding capacity to the cholinergic receptors. More specifically, the compounds of the invention show agonistic properties at cholinergic receptors, especially muscarinic receptors.

In one embodiment, the tether

is unsubstituted, meaning that all of R 4 and R 5 are hydrogen.

In another embodiment one of the substituents R 4 is selected from the group consisting of C 1-6 -alkyl, O—C 1-6 -alkyl, and halogen, while the other two of the substituents R 4 are hydrogen.

In a combination of embodiments one of the substituents R 4 is selected from the group consisting of C 1-6 -alkyl, O—C 1-6 -alkyl, and halogen, while the other two of the substituents R 4 are hydrogen, and all of R 5 are hydrogen.

In a preferred embodiment one of the substituents R 4 is selected from the group consisting of methyl, methoxy, ethyl, and fluoro while the remaining R 4 and R 5 are all hydrogen.

Typically, when one of the substituents R 4 is C 1-6 -alkyl, O—C 1-6 -alkyl, or halogen, the tether is a 2-substituted-1,3-propylene group.

In a further suitable embodiment, the tether is a 2,2-disubstituted-1,3-propylene group, in which one of R 4 and one of R 5 are typically C 1-6 -alkyl or fluoro.

Certain embodiments of the invention, wherein the propylene tether carries one or more substituents possess a stereogenic atom in the propylene tether. As set forth in the Examples, such chiral compounds may be preferred either in racemic or enantiomerically enriched form. Pure enantiomers and racemates are both included in the invention.

X may be a 1-, 2-, or 3-atom linear unit such that, together with the atoms in the ring comprising X, a 5-, 6- or 7-membered ring is formed. As stated, X, within the ring, is a biradical selected from the group consisting of —C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )═C(R 7 )—, —C(R 6 )(R 7 ), C(R 6 )(R 7 )—O, —S—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—S—, —N(R N )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—N(R N )—, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —O—C(R 6 )(R 7 )—C(R 6 )(R 7 ), S—C(R 6 )(R 7 )C(R 6 )(R 7 )—, N(R N )—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )(R 8 )—C(R 6 )(R 7 )—O, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—S, —C(R 6 )(R 6 )—C(R 6 )(R 7 )—N(R N )—, —C(R 6 )(R 7 )—CH═CH— and —CH═CH—C(R 6 )(R 7 ).

In a preferred embodiment X is selected from the group consisting of —C(R 6 )(R 7 )C(R 6 )(R 7 )—, —C(R 6 )═C(R 7 )—, —O—C(R 6 )(R 7 )—, C(R 6 )(R 8 )—O—, —S—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—S—, —N(R N )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—N(R N )—.

In a more preferred embodiment X is selected from the group consisting of —C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —O—C(R 6 )(R 7 )—, C(R 6 )(R 8 )—O—, and —C(R 6 )═C(R 7 )—.

R 6 and R 7 are optional substituents of the ring system. An array of substituents is anticipated by the present investigators and are known to the person skilled in the art. The substituents R 6 and R 7 may independently be selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NR N R N , N(R N )—C(O)N(R N ), optionally substituted C 1-6 -alkyl, 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.

Suitably, when the substituents R 6 and R 7 occur within the definition of X, they are typically selected from hydrogen, halogen, hydroxy and C 1-6 -alkyl. More typically, R 6 and R 7 , when constituting part of the definition of X, are both hydrogen.

In one embodiment, Y is selected from the group consisting of O, S and H 2 .

In a preferred embodiment, Y is O.

As stated, L 1 and L 2 are biradicals independently selected from the group consisting of —C(R 7 )═C(R 8 ), —C(R 7 )═N—, —N═C(R 7 )—, —S—, —NH— and —O—; wherein only one of L 1 and L 2 may be selected from the group consisting of —S— and —O—. Typically, L 1 and L 2 are such that

is an aromatic or heteroaromatic ring. In one embodiment, L 1 and L 2 are independently selected from the group consisting of —C(R 6 )═C(R 7 )—, —C(R 6 )═N—, —N═C(R 7 )—, and —S—; wherein only one of L 1 and L 2 is —S—. In another embodiment, at least one of L 1 and L 2 is C(R 6 )═C(R 7 ). In yet another embodiment, L 1 and L 2 are so as to form a 6-membered ring. In still another embodiment, both of L 1 and L 2 are —C(R 6 )═C(R 7 )—.

Suitably, when the substituents R 6 and R 7 occur within the definition of

they are typically selected from hydrogen, halogen, hydroxy, C 1-6 -alkyl and O—C 1-6 -alkyl.

Preferably, when the substituents R 6 and R 7 occur within the definition of

they are selected from hydrogen, fluoro, chloro, methyl, and methoxy.

Thus, in a combination of embodiments, the compounds of the invention are of formula Ia

wherein R 1 is selected from the group consisting of optionally substituted C 1-6 -alkyl, optionally substituted C 1-6 -alkylidene, 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; and R 2 , R 3 , R 4 , X, Y, R 6 , and R 7 are as defined supra.

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 6 of 10

In another combination of embodiments, the compounds of the invention are of formula Ia, wherein X is selected from the group consisting of —C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )═C(R 7 )—, —O—C(R 6 )(R 7 )—, C(R 6 )(R 8 )—O—, —S—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—S—, —N(R N )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—N(R N )—,

wherein R 6 and R 7 are suitably hydrogen.

In a further combination of embodiments, the compounds of the invention are of formula Ia, wherein Y is O.

In yet another combination of embodiments, the compounds of the invention are of formula Ia, wherein R 4 is selected from hydrogen, C 1-6 -alkyl, O—C 1-6 -alkyl, and halogen.

In a further combination of embodiments, the compounds of the invention are of formula Ia, wherein R 6 and R 7 are selected from hydrogen, halogen, hydroxy, C 1-6 -alkyl and O—C 1-6 -alkyl.

In another combination of embodiments, the compounds of the invention are of formula Ia, wherein the optionally substituted C 1-6 -alkyl is selected from the list comprising unsubstituted C 1-6 -alkyl, and C 1-6 -alkoxyalkyl, and wherein Y is selected from the group consisting of 0 and H 2 , and wherein X is selected from the group consisting of —C(R 6 )(R 7 )—C(R 6 )(R 7 ), —C(R 6 )═C(R 7 )—, —O—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—O—, —S—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—S—, and wherein L 1 and L 2 are independently selected from the group consisting of —C(R 6 )═C(R 7 )—, —C(R 6 )═N—, and —N═C(R 7 )—, and wherein R 4 selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1-6 -alkyl, and optionally substituted O—C 1-6 alkyl.

In a further combination of embodiments, the compounds of the invention are optionally substituted 1-[3-(4-alkylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolines, optionally substituted 1-[3-(4-alkylpiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-ones, optionally substituted 1-[3-(4-alkylpiperidin-1-yl)propyl]-1H-quinolin-2-ones, optionally substituted 4-[3-(4-alkylpiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-ones, optionally substituted 4-[3-(4-alkylpiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-ones; optionally substituted 1-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-1,2,3,4-tetrahydroquinolines; optionally substituted 1-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-ones, optionally substituted 1-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-1H-quinolin-2-ones optionally substituted 4-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-ones; optionally substituted 4-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-ones; optionally substituted 1-[3-(3-alkylazetidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-ones, optionally substituted 1-[3-(3-alkylazetidin-1-yl)propyl]-1H-quinolin-2-ones, optionally substituted 1-[3-(3-alkylazetidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolines; optionally substituted 4-[3-(3-alkylazetidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-ones; optionally substituted 4-[3-(3-alkylazetidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-ones.

Suitable embodiments of the compounds of the invention may be selected from the group consisting of 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline; 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-methyl-1,2,3,4-tetrahydro-quinoline; 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-1,2,3,4-tetrahydro-quinoline; 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-8-methyl-1,2,3,4-tetrahydro-quinoline; 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline; 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline; 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-3,4-dihydro-1H-quinolin-2-one; 4-[3-(4-Butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]thiazin-3-one; 4-[3-(4-Butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; 6-Acetyl-4-[3-(4-butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine; and 4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine; (R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one; (R)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one; (R)-4-[3-(4-Butylidene-piperidin-1-yl)-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one; (R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one; (R)-4-[2-Methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-6,8-dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butyl-piperidin-1-yl)propyl]-6,8-dimethyl-4H-benzo[1,4]oxazin-3-one (81MF2237F); 6-tert-Butyl-4-[3-(4-butyl-piperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-7-nitro-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-7-chloro-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-7,8-difluoro-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-4H-pyrido[4,3-b][1,4]thiazin-3-one; 4-[3-(4-Propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one; 4-[3-(4-Propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one; 4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; 4-[3-(3-Butylidene-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-6,8-dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one; 6-Bromo-4-[3-(4-butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1-yl)propyl]-8-isopropyl-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxy-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one; (−)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin)-2-methoxypropyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[2-Hydroxy-3-(3-pentylbicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; 4-[2-(4-Butylpiperidin-1-ylmethyl)allyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-fluoropropyl]-4H-benzo[1,4]oxazin-3-one; (S)-4-[3-(4-Butyl-piperidin-1-yl)-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R)-6-Fluoro-4-[2-methyl-3-(4-propoxy-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methyl-propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-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]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-7-Fluoro-4H-benzo[1,4]oxazin-3-one; (R)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-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]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-1-yl)-2-methyl-propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-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]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R)-6-Methoxy-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R)-6-Methyl-4-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R)-4-[3-(3-Pentyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; 1-[3-(4-Propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one; 6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; (R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one; (R,S)-6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-3,4-dihydro-1H-quinolin-2-one; 6-Methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one; 6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; (R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one; (R,S)-6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one; 6-Fluoro-7-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; (R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one; (R,S)-6-Fluoro-7-methyl-1-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butyl-piperidin-1-yl)propyl]-6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one; 6-Fluoro-5-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; (R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; (R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; (R)-1-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; (R)-1-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; (R)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-1H-quinolin-2-one; 1-[3-(4-Propoxypiperidin-1-yl)propyl]-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-1H-quinolin-2-one; 1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-1H-quinolin-2-one; 1-[3-(4-Butyl-piperidin-1-yl)propyl]-7-methyl-1H-quinolin-2-one; (R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-1H-quinolin-2-one; (R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-1H-quinolin-2-one; 1-[3-(4-Allyloxypiperidin-1-yl)propyl]-1H-quinolin-2-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methyl-4H-benzo[1.4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1.4]oxazin-3-one; (R,S)-6-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1.4]oxazin-3-one; (R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-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]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one; (R,S)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-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]oct-8-yl)propyl]-4H-benzo[1.4]oxazin-3-one; (R,S)-3-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3H-benzothiazol-2-one; (R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3H-benzothiazol-2-one; (R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3H-benzothiazol-2-one; (R,S)-3-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3H-benzothiazol-2-one; (R,S)-3-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3H-benzothiazol-2-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one; (R,S)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one; (R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one; (R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; (R,S)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)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]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one; (R,S)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)-6-methoxy]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one; (R,S)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-1-yl)-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]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(3-Butoxy-8-azabicyclo[3.2.1]oct-8-yl)-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]oct-8-yl]-2-methylpropyl}-4H-benzo[1,4]oxazin-3-one, (R,S)-4-[3-(3-Butylazetidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one; (R,S)-6-Fluoro-4-[2-methyl-3-(3-propoxyazetidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one; (R,S)-4-[3-(3-Butylazetidin-1-yl)-2-methoxypropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one; 4-[3-(4-Butyl-3-fluoropiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one.

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 7 of 10

In another aspect, disclosed herein is a compound of formula (I), and salts and isomers thereof

wherein:

m is 0, 1 or 2;

C 3 -C 4 is CH 2 —CR 1 R 9 or CH═CR 1 or C 4 is CR 1 R 9 and C 3 is absent;

each R 1 and each R 9 is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C 1-6 alkyl, straight- or branched-chain optionally substituted C 2-6 alkenyl, straight- or branched-chain optionally substituted C 2-6 alkynyl, straight- or branched-chain optionally substituted C 1-6 alkylidene, straight- or branched-chain optionally substituted C 1-6 alkoxy, straight- or branched-chain optionally substituted C 1-6 heteroalkyl, straight- or branched-chain optionally substituted C 1-6 aminoalkyl, straight- or branched-chain optionally substituted C 1-6 haloalkyl, straight- or branched-chain optionally substituted C 1-6 alkoxycarbonyl, straight- or branched-chain optionally substituted C 1-6 hydroxyalkoxy, straight- or branched-chain optionally substituted C 1-6 hydroxyalkyl, straight- or branched-chain optionally substituted C 1-6 alkylthio, straight- or branched-chain optionally substituted —O—C 2-6 alkenyl, straight- or branched-chain optionally substituted —O—C 2-6 alkynyl, straight- or branched-chain optionally substituted C 3-6 alkenylalkoxy, straight- or branched-chain optionally substituted C 1-6 alkyloxyimino, straight- or branched-chain optionally substituted C 1-6 alkyloxyamino, optionally substituted —O—CH 2 —C 5-6 aryl, —C(O)NR 10 R 11 , —CR 10 R 11 R 12 , —OC(O)R 10 , straight- or branched-chain optionally substituted —(O)(CH 2 ) s NR 11 R 12 , straight- or branched-chain optionally substituted —(CH 2 ) s NR 11 R 12 , straight- or branched-chain optionally substituted —OC(O)O(CH 2 ) s CH 3 , straight- or branched-chain optionally substituted —S—C 1-6 -alkyl, straight- or branched-chain optionally substituted —S—C 2-6 -alkenyl, and straight- or branched-chain optionally substituted —S—C 2-6 -alkynyl, each of which may be optionally substituted with one or more substituents R x ;

each R 10 is separately selected from the group consisting of hydrogen, straight- or branched-chain C 1-6 alkyl, straight- or branched-chain C 2-6 alkenyl, straight- or branched-chain C 2-6 alkynyl, straight- or branched-chain C 2-6 heteroalkyl, straight- or branched-chain C 2-6 aminoalkyl, straight- or branched-chain C 2-6 haloalkyl, straight- or branched-chain C 1-6 alkoxycarbonyl, straight- or branched-chain C 2-6 hydroxyalkyl, C 3-8 cycloalkyl, —C(O)—C 5-6 aryl substituted with C 1-3 alkyl or halo, C 5-6 aryl, C 5-6 heteroaryl, C 5-6 cycloalkyl, C 5-6 heterocycloalkyl, —C(O)NR 11 R 12 , —CR 11 R 12 R 13 , and straight- or branched-chain —(CH 2 ) s NR 11 R 12 ;

each s is separately selected to be an integer from 1 to 8;

each R 11 and each R 12 is separately selected from the group consisting of hydrogen, straight- or branched-chain C 1-6 alkyl, C 3-6 cycloalkyl, and C 5-6 heteroaryl, or each R 11 and R 12 together form a C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;

R 13 is selected from the group consisting of hydrogen, halogen, straight- or branched-chain C 1-6 alkyl, formyl, and C 3-6 cycloalkyl;

each R x is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C 1-6 alkyl, straight- or branched-chain optionally substituted C 1-6 alkoxy, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 heterocyclyl, and straight- or branched-chain optionally substituted C 1-6 alkylidene;

R 2 and R 3 are separately selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted O—C 1-6 alkyl, halogen, hydroxy or selected such that R 2 and R 3 are covalently linked together to form a ring system;

each R 4 and each R 5 are separately selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1-6 -alkyl, optionally substituted O—C 1-6 alkyl, optionally substituted aryl-C 1-6 alkyl, and optionally substituted arylheteroalkyl;

L 1 and L 2 are biradicals separately selected from the group consisting of —C(R 6 )═C(R 7 ), —C(R 6 )═N—, —N═C(R 6 )—, —S—, —NH— and —O—; wherein only one of L 1 and L 2 may be selected from the group consisting of —S—, —NH— and —O—;

Y is selected from the group consisting of O, S, and H 2 ; and

X is a biradical selected from the group consisting of —C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 (R 7 )—, —O—C(R 6 )(R 7 )—, C(R 6 )(R 7 )—O—, —S—C(R 6 )(R 7 )—C(R 6 )(R 7 )—S—, N(R N )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—N(R N )—, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —O—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, S—C(R 6 )(R 7 )—C(R 6 )(R 7 )—, N(R N )C(R 6 )(R 7 )—C(R 6 )(R 7 )—, —C(R 6 )(R 7 ) C(R 6 )(R 7 )—O, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—S, —C(R 6 )(R 7 )—C(R 6 )(R 7 )—N(R N )—, —C(R 6 )(R 7 )—C(R 6 )═C(R 7 )—, and —C(R 6 )═C(R 7 )—C(R 6 )(R 7 ), wherein R 6 and R 7 are separately selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NR N R N , N(R N )—C(O)N(R N ), optionally substituted C 1-6 -alkyl, 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,

wherein R N is selected from the group consisting of hydrogen, and optionally substituted C 1-6 -alkyl.

Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound of formula (I), as disclosed above, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

In some embodiments, disclosed herein is a compound of formula (I), wherein:

at least one of R 1 or R 9 is selected from the group consisting of hydroxy, straight- or branched-chain optionally substituted C 1-6 alkoxy, straight- or branched-chain optionally substituted C 1-6 alkyl, straight- or branched-chain optionally substituted C 2-6 alkenyl, straight- or branched-chain optionally substituted C 3-6 alkenylalkoxy, straight- or branched-chain optionally substituted C 1-6 alkyloxyimino, and straight- or branched-chain optionally substituted —OC(O)O(CH 2 ) s CH 3 ; and

›DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT · 8 of 10

R x is selected from the group consisting of halogen, optionally substituted C 3-8 cycloalkyl, optionally substituted straight- or branched-chain C 1-6 alkyl, optionally substituted C 1-6 alkoxy and optionally substituted straight- or branched-chain C 2-6 alkenyl