RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 61/108.808. filed October 27, 2008. which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION [0002] The present invention relates to the fields of chemistry and medicine.

BACKGROUND OF THE INVENTION

[0003] Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems, gastrointestinal system, heart, endocrine glands, lungs, and other tissues. Muscarinic receptors play a central role in the central nervous system for higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Five distinct muscarinic receptor subtypes, referred to as subtypes M ₁ -M ₅ . have been identified. The M ₁ subtype is the predominant subtype found in the cerebral cortex in hippocampus and and is believed to be involved in the control of cognitive functions; the M ₂ subtype is the predominant subtype found in heart and is believed to be involved in the control of heart rate; the M ₂ subtype is also found in brain regions such as cortex and hippocampus where it is predominantly located presynaptically; the M ₃ subtype is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation: the M ₄ subtype is present in the brain and may be involved in locomotion; the M ₅ , receptor is present in the brain. Mi and M ₄ have been particularly associated with the dopaminergic system.

[0004] Conditions associated with cognitive impairment are frequently accompanied by loss of acetylcholine in the brain and dysfunction of the muscarinic cholinergic nervous system. This is believed to be the result of degeneration of cholinergic neurons in the basal forebrain, which widely innervate multiple areas of the brain, including the association cortices and hippocampus, which are critically involved in higher processes.

[0005] Efforts to increase acetylcholine levels have focused on increasing levels of choline, the precursor for acetylcholine synthesis, and on blocking acetylcholineesterase (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.

[0006] Accordingly, there is a need for compounds, such as muscarinic agonists, that increase acetylcholine signaling and/or effect the brain via activity at specific muscarinic receptor subtypes in the central and peripheral nervous system, both as pharmacological tools and as therapeutic agents.

SUMMARY OF THE INVENTION

[0007] Some embodiments relates to compounds covered by the general formula

(1):

or a pharmaceutically acceptable salt thereof, wherein Z is selected from NR\ oxygen, sulfur, and CH ₂ ; R ¹ and R ² are separately selected from hydrogen, optionally substituted C _{1 -6} alky], optionally substituted C ₁ _ ₆ alkenyl. optionally substituted C _{1 -6} alkynyl, optionally substituted C ₁ _ ₆ alkoxy. optionally substituted C _{1 -6} heteroalkyl. optionally substituted C _3-6 cycloalkyl, optionally substituted C _5-6 aryl, optionally substituted C _5-6 aryl-C ₁ _ ₆ alkyl. optionally substituted C ₅ _ ₆ heteroaryl. and optionally substituted C _5-6 heteroaryl-C _{1 -6} alkyl; wherein at least one of R ¹ and R ² is not hydrogen.

[0008] Some embodiments disclosed herein include compounds having the following structures:

or a pharmaceutically acceptable salt thereof.

[0009] Some embodiments provide a pharmaceutical composition comprising an effective amount of a compound discloased herein or a pharmaceutically acceptable salt thereof.

[0010] Some embodiments provide a method of increasing an activity of a muscarinic receptor, comprising contacting the muscarinic receptor or a system containing the muscarinic receptor with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

[0011] Some embodiments proλ'ide a method of treating a disease condition associated with reduced levels of acetylcholine or a method of treating a disease condition associated with a muscarinic receptor, comprising administering to a subject in need of such treatment an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or a pharmaceutical composition disclosed herein thereof.

[0012] Some embodiments provide a method of treating a disease condition comprising administering to a subject in need of such treatment an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein, wherein the disease condition is selected from the group consisting of cognitive dysfunctions such as cognitive impairment, forgetfulness, confusion, memory loss, depression, attentional deficits, deficits in visual perception, and cognitive dysfunctions associated with mental disorders such as neuropsychiatric disorders, neurodegenerative disorders, dementia, age-related cognitive decline, and Down's syndrome; neuropsychiatric disorders such as sleep disorders, depression, psychosis, hallucinations. aggressiveness, paranoia, schizophrenia, attention deficit disorders, and Gilles de Ia Tourette ^' s syndrome: eating disorders such as anorexia nervosa and bulimia; anxiety disorders such as obsessive compulsive disorders, panic disorders, phobic disorders, general anxiety disorders, and posttraumatic stress disorders; mood disorders, such as clinical depression, bipolar disorder, and major depressive disorder: neurodegenerative disorders and conditions such as alcoholism. Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration. Huniington's disease. HlV-associated dementia, Lewy body dementia, multiple sclerosis, Parkinson's disease, Pick ^' s disease, and progressive supranuclear palsy; and other diseases and disorders such as pain, such as neuropathic pain; and glaucoma.

[0013] Some embodiments provide a use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein for the preparation of a medicament for increasing an activity of a muscarinic receptor, treating a disease condition associated with a muscarinic receptor, treating a disease condition associated with reduced levels of acetylcholine, or treating a disease condition listed above.

[0014] Some embodiments provide a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein for use in increasing an activity of a muscarinic receptor, treating a disease condition associated with a muscarinic receptor, treating a disease condition associated with reduced levels of acetylcholine, or treating a disease condition listed above.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Definitions

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there are plurality of definitions for a term herein, those in this section prevail unless stated otherwise

[0016] As used herein. "EC ₅₀ ^" refers to an amount, concentration, or dosage of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response such as but not limited to R-SAT^ assay described herein.

[0017] When a substituent is deemed to be "optionally subsituted." or ''substituted ^" it is meant that one or more hydrogen atoms on the referenced group may be replaced with a group(s) individually and independently selected from alkyl. alkenyl. alkynyl, cycloalkyl. cycloalkenyl. hydroxy, alkoxy. mercapto. alkylthio. cyano. halogen, nitro. and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protecth e derivatives of the above substituents are known to those of skill in the art and may be found in references Greene and Wuts. Protective Groups in Organic Synthesis. 3 ^rd Ed.. John Wiley & Sons, New York. NY. 1999, which is hereby incorporated by reference in its entirety.

[0018] As used herein, "C ₁₁₁ to C _n " or "C _m-n " in which ''m ^" and "n ^" are integers refers to the number of carbon atoms in the relevant group. That is. the group can contain from "m ^" to "n", inclusive, carbon atoms. Thus, for example, a "C] to C4 alkyl ^" group refers to all alkyl groups having from 1 to 4 carbons, that is. CH ₃ -. CH ₃ CH ₂ -. CH ₃ CH ₂ CH ₂ -. (CH ₃ ) ₂ CH-. CH ₃ CH ₂ CH ₂ CH ₂ -. CH ₃ CH ₂ CH(CH ₃ )- and (CH ₃ ) ₃ C-. If no "m ^" and "n ^" are designated with regard to a group, the broadest range described in these definitions is to be assumed.

[0019] As used herein, "alkyl-' refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenexer it appears herein, a numerical range such as "1 to 20 ^" refers to each integer in the given range: e g . "1 to 20 carbon atoms" means that the alkyl group ma\ consist of 1 carbon atom. 2 carbon atoms, 3 carbon atoms, etc . up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl ^" where no numerical range is designated). The alkyl group may also be a medium size alkyl ha\ ing 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having ] to 5 carbon atoms. The alkyl group of the compounds may be designated as "C ₁ -C ₄ alkyl ^" or similar designations. By way of example only. " C _{1 -4} alkyl ^" indicates that there are one to four carbon atoms in the alkyl chain, i.e.. the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl. n-butyl, iso-butyl. sec-butyl- and t-butyl. Typical alk\l groups include, but are in no way limited to. methyl, ethyl, propyl, isopropyl. butyl, isobutyl. tertiary butyl, pentyl. hexyi. ethenyl. propenyl. butenyl. and the like.

[0020] The alkyl group may be substituted or unsubstitυted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl. alkynyl, cycloalkyl, cycloalkenyl, hydroxy, alkoxy, mercapto, alkylthio. cyano. halogen, nitro. and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.

[0021] As used herein, "alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.

[0022] As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstitυted or substituted. When substituted, the sυbstituent(s) may be selected from the same groups disclosed above with regard to alk>l group substitution.

[0023] As used herein, "heteroalkyl ^" refers to an alkyl group where one or more carbon atoms has been replaced with a heteroatom selected from nitrogen, oxygen and sulfur.

[0024] herever "hetero" is used it is intended to mean a group as specified where one or more carbon atoms has been replaced with a heteroatom selected from nitrogen, oxygen and sulfur.

[0025] As used herein, "aryl ^" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to. benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl. alkenyl. alkynyl. cycloalkyl, cycloalkenyl. hydroxy, alkoxy. mercapto. alkylthio, cyano. halogen, nitro. and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.. When substituted, substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl. cycloalkenyl, cycloalkynyl, and heterocyclyl. [0026] As used herein, "heteroaryl ^" refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is. an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. Examples of heteroaryl rings include, but are not limited to, furan. thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole. isoxazole, isothiazole. triazole, thiadiazole, pyridine, pyridazine, pyrimidine. pyrazine and triazine. A heteroaryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl. cycloalkenyl, hydroxy , alkoxy. mercapto, alkylthio. cyano. halogen, nitro, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. When substituted, substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl. cycloalkenyl, cycloalkynyl. and heterocyclyl.

[0027] An "aralkyl ^" or "arylalkyl ^" is an aryl group connected, as a substituent, via an alkylene group. The alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl. 2- phenylethy], 3-phenylpropyl. and naphtylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0028] A "heteroaralkyl"' or "heteroarylalkyl" is heteroaryl group connected, as a substituent. via an alkylene group. The alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl. furylmethyl. thienylethyl. pyrrolylalkyl, pyridylalkyl. isoxazollylalkyl, and imidazolylalky], and their substituted as well as benzo-fused analogs. In some cases, the alkylene group is a lower alkylene group.

[0029] As used herein, "alkoxy ^" refers to the formula -OR wherein R is an alkyl is defined as above, e.g. methoxy. ethoxy, n-propoxy. 1 -methylethoxy (isopropoxy). n- butoxy. iso-butoxy. sec-butoxy. tert-butoxy. amoxy. tert-amoxy and the like. An alkoxy may be substituted or unsubstituted.

[0030] As used herein, "cycloalkyl ^" refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups may range from C ₃ to C ₁₀ . in other embodiments it may range from C ₃ to C ₆ . A cycloalkyl group may be unsubstituted or substituted. Typical c\cloalkyl groups include, but are in no way limited to. cyclopropyl. cyclobut>l. cxclopentyl. c\clohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.

[0031] As employed herein, the following terms have their accepted meaning in the chemical literature.

[0032] It is understood that, in any compound disclosed herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enatiomerically pure or be stereoisomeric mixtures. In addition, it is understood that in any compound having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z a mixture thereof. Likewise, all tautomeric forms are also intended to be included.

[0033] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt ( CNH ₄ ⁺ ): alkali metal, such as. without limitation, sodium or potassium, salts: alkaline earth, such as, without limitation, calcium or magnesium, salts: salts of organic bases such as. without limitation, dicyclohexylamine. N-methyl-D-glucamine. tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as. without limitation, arginine and lysine. Useful acid- based salts include, without limitation, hydrochlorides, hydrobromides. sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates. p-toluenesulfonates and salicylates.

[0034] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100. or 1 to about 10. or one to about 2. 3 or 4. solvent or water molecules.

[0035] As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may. for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. An example, without limitation, of a prodrug would be a compound disclosed herein, which is administered as an ester (the "prodrug ^" ) to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see. e.g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach. Oxford University Press. New York, pages 388-392)

[0036] An "agonist ^" is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor). [0037] As used herein, "partial agonist ^" refers to a compound that has an affinity for a receptor but. unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with -the receptor even if a large number of receptors are occupied by the compound.

[0038] An "inverse agonist" is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.

[0039] As used herein, "antagonist" refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor was unoccupied. An antagonist attenuates the action of an agonist on a receptor. An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.

[0040] As used herein, a "subject ^-- refers to an animal that is the object of treatment, observation or experiment. "Animal ^-' includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice: rats: rabbits; guinea pigs; dogs: cats; sheep; goats: cows; horses: primates, such as monkeys, chimpanzees, and apes. and. in particular, humans.

[0041] As used herein, a "patient" refers to a subject that is being treated by a medical professional such as an M. D. or a D. V. M. to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.

[0042] As used herein, a "carrier- refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0043] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as. without limitation, phosphate buffered saline that mimics the composition of human blood.

[0044] The term "physiologically acceptable ^" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0045] As used herein, an "excipient ^" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc.. to the composition. A "diluent ^" is a type of excipient.

[0046] A "receptor" is intended to include any molecule present inside or on the surface of a cell that may affect cellular physiology when it is inhibited or stimulated by a ligand. Typically, a receptor comprises an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding ("signal transduction"). A receptor also includes any molecule having the characteristic structure of a receptor, but with no identifiable ligand. In addition, a receptor includes a truncated, modified, mutated receptor, or any molecule comprising partial or all of the sequences of a receptor.

"Ligand" is intended to include any substance that interacts with a receptor.

[0047] The "M] receptor". "M ₂ receptor". "M ₃ receptor". "M ₄ receptor" and "M ₅ receptor" is defined as a receptor having an activity corresponding to the activity of the M|. M ₂ . M ₃ . M ₄ and/or M ₅ muscarinic receptor subtype characterized through molecular cloning and pharmacology.

"Selective" or "selectivity" is defined as a compound's ability to generate a desired response from a particular receptor type, subtype, class or subclass while generating less or little response from other receptor types. "Selective" or "selectivity" of one or more particular subtypes of a muscarinic agonist compound means a compound's ability to increase the activity of the subtypes while causing little or no increase in the activity of other subtypes.

[0048] The term "pharmaceutical composition ^" refers to a mixture of a compound disclosed herein or derived therefrom with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to. oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0049] As used herein, "coadministration" of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration means the simultaneous delivery of separate agents: the simultaneous delivery of a mixture of agents; as well as the delivery of one agent followed by delivery of a second agent or additional agents. Agents that are coadministered are typically intended to work in conjunction with each other.

[0050] The term "an effective amount" as used herein means an amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or palliation of the symptoms of the disease being treated. Compounds

[0051] Disclosed herein are compounds that modulate cholinergic receptors, including muscarinic receptors, are prodrugs of cholinergic receptor modulators, or are intermediates in the synthesis of cholinergic receptor modulators or prodrugs thereof. In one embodiment, the compounds disclosed herein or derived therefrom have therapeutic effects and can be used to treat disease conditions associated with cholinergic receptors, such as muscarinic receptors, such as the preferred M ₁ - M ₂ and/or M ₄ muscarinic receptors, e.g. cognitive impairment in Alzheimer's disease, glaucoma, pain, or schizophrenia: and used to treat other disease conditions disclosed herein.

[0052] In some embodiments, the compounds are compounds covered by the genera] formula (1) or a pharmaceutically acceptable salt thereof, wherein:

[0053] Z is selected from NR ⁵ _, oxygen, sulfur, and CH ₂ :

[0054] R ¹ and R ² are separately selected from hydrogen, optionally substituted C _{1- 6} alkyl, optionally substituted C _{1 -6} alkenyl. optionally substituted C ₁ _ ₆ alkynyl. optionally substituted C _{1 -6} alkoxy. optionally substituted C ₁ _ ₆ heteroalkyl. optionally substituted C _3-6 cycloalkyl. optionally substituted C ₅ . ₆ aryl. optionally substituted C _5-6 aryl-C] _-( , alkyl. optionally substituted C _5-6 heteroaryl. and optionally substituted C _5-6 heteroaryl-C ₁ _ ₆ alkyl: wherein at least one of R ¹ and R ² is not hydrogen.

[0055] In some embodiments. R ¹ is selected from the group consisting of optionally substituted C _{1 -6} alky], optionally substituted C _{1 -6} alkenyl. optionally substituted C1- ₆ alkynyl, optionally substituted C _{1 -6} alkoxy. optionally substituted cycloalkyl. and optionally substituted C _{1 -6} heteroalkyl .

[0056] In some embodiments, R is selected from the group consisting of hydrogen, optionally substituted C ₁ _ ₆ alkyl. optionally substituted C ₁ _ ₆ alkenyl. optionally substituted C _{1 -6} alkynyl. optionally substituted C _{1 -6} alkoxy. and optionally substituted C ₁ _ ₆ heteroalkyl.

[0057] In some embodiments. R ² is hydrogen or C ₁ _ ₆ alkyl. and R ¹ is selected from the group consisting of optionally substituted C ₁ _ ₆ alkyl. optionally substituted C ₁ _ ₆ alkenyl, optionally substituted C _{1 -6} alkynyl. optionally substituted C ₁ _ ₆ alkoxy. optionally- substituted cycloalkyl. and optionally substituted C ₁ _ ₆ heteroalkyl. In some embodiments, the C i _-6 alkyl is methyl.

[0058] In some embodiments. R ¹ is optionally substituted C _{1 -6} alkoxy. and R ² is hydrogen or optionally substituted C _{1 -6} alkyl; or R ^! is optionally substituted C _{1 -6} alky], and R ² is hydrogen or optionally substituted C _{1 -6} alkyl.

[0059] Some embodiments disclosed herein include compounds having the following structures:

[0060] In some embodiments the compounds of the invention are muscarinic agonists, such as M ₁ , M ₂ and/or M ₄ agonists.

[0061] In some embodiments the compounds of the invention are selective for one or more muscarinic receptor(s). the compound may be selective for M]. Mi and/or M ₄ receptors. Methods of Preparation

[0062] The compounds disclosed herein may be synthesized by methods described herein or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc.. and will be obvious to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J. F. W. McOmie. Plenum Press. 1973): and Greene & Wuts. Protective Groups in Organic Synthesis. John Wiley & Sons. 1991. which are both hereby incorporated herein by reference in their entirety. The protecting groups be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock. Comprehensive Organic Transformations. VCH Publishers. 1989. or L. Paquette. ed.. Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons. 1995, which are both hereby incorporated herein by reference in their entirety.

[0063] During any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups. Methods of Use

[0064] In general, compounds disclosed herein are active at cholinergic, and specifically muscarinic receptors, or ma\ be used as prodrugs of such active compounds or synthetic intermediates in the preparation of such active compounds or prodrugs thereof. In some embodiments, the active compounds are selective for one or more muscarinic receptor subtypes (e.g.. M]. M ₂ . M ₃ . M ₄ . and/or M ₅ ). The compounds may be active at several of the subtypes simultanously. It is often preferred that the compounds ha\e low or no M ₃ activity.

[0065] The active compounds typically have therapeutic effects and can be used to treat or alleviate symptoms of disease conditions associated with cholinergic receptors, such as muscarinic receptors. The disease condition may result from dysfunction, decreased activity , modification, mutation, truncation, or loss of cholinergic receptors, especially muscarinic receptors, as well as from reduced levels of acetylcholine. Sy mptoms of disease conditions associated with cholinergic receptors may be one or more of the following: cognitive dysfunctions such as cognitive impairment, forgetfulness. confusion, memory loss, depression, attentional deficits, deficits in visual perception, and cognitive dysfunctions associated with mental disorders such as neuropsychiatric disorders, neurodegenerative disorders, dementia, age-related cognitive decline, and Down ^' s syndrome: neuropsychiatric disorders such as sleep disorders, depression, psychosis, hallucinations, aggressiveness, paranoia, schizophrenia, attention deficit disorders, and Gilles de Ia Tourette ^' s syndrome; eating disorders such as anorexia nervosa and bulimia; anxiet\ disorders such as obsessive compulsive disorders, panic disorders, phobic disorders, general anxiety disorders, and posttraumatic stress disorders: mood disorders, such as clinical depression, bipolar disorder, and major depressive disorder: neurodegenerative disorders and conditions such as alcoholism, Alzheimer ^' s disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Huntington ^' s disease, HIV-associated dementia. Lewy body dementia, multiple sclerosis, Parkinson's disease. Pick's disease, and progressi\e supranuclear palsy; and other diseases and disorders such as pain, such as neuropathic pain; and glaucoma.

[0066] The acti\e compounds may be used to treat diseases, such as cognitive dysfunctions such as cognitive impairment, forgetfulness. confusion, memon loss, depression, attentional deficits, deficits in visual perception, and cognitive dysfunctions associated with mental disorders such as neuropsychiatric disorders, neurodegenerative disorders, dementia, age-related cognitive decline, and Down's syndrome: neuropsychiatric disorders such as sleep disorders, depression, psychosis, hallucinations, aggressiveness, paranoia, schizophrenia, attention deficit disorders, and Gilles de Ia Tourette ^' s syndrome: eating disorders such as anorexia nervosa and bulimia; anxiet} disorders such as obsessive compulsive disorders, panic disorders, phobic disorders, general anxiety disorders, and posttraumatic stress disorders: mood disorders, such as clinical depression, bipolar disorder, and major depressive disorder: neurodegenerative disorders and conditions such as alcoholism, Alzheimer ^' s disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Huntington ^' s disease. HIV-associated dementia. Lewy body dementia, multiple sclerosis, Parkinson's disease. Pick ^' s disease, and progressive supranuclear palsy; and other diseases and disorders such as pain, such as neuropathic pain: and glaucoma.

[0067] The acthe compounds have the abilit} to increase cholinergic receptor activity or activate cholinergic receptors. Cholinergic receptor activity includes signaling activity or any other activity that is directly or indirectly related to cholinergic signaling or activation. The cholinergic receptors include muscarinic receptors. The muscarinic receptor can be. for example, in the central nervous system, peripheral nervous system, gastrointestinal system, heart, endocrine glands, or lungs. The muscarinic receptor can be a wild-type, truncated, mutated, or modified cholinergic receptor. Kits comprising the compounds disclosed herein or compounds derived therefrom for increasing cholinergic receptor activity or activating cholinergic receptors are also contemplated.

[0068] The system containing the cholinergic receptor may. for example, be a subject such as a mammal, 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 that expresses a cholinergic receptor, a cell-free extract thereof that contains a cholinergic receptor, or a purified receptor. Non-limiting examples of such systems are tissue culture cells expressing the receptor, or extracts or lysates thereof. Cells that may be used in the present method include any cells capable of mediating signal transduction via cholinergic receptors, especially the Mi. M ₂ and/or M ₄ muscarinic receptor, either via endogenous expression of this receptor (certain types of neuronal cells lines, for example, natively express the Mi receptor), or such as following introduction of the an exogenous gene into the cell, for example, by transfection of cells with plasmids containing the receptor gene. Such cells are typically mammalian cells (or other eukaryotic cells, such as insect cells or Xenopus oocytes), because cells of lower life forms generally lack the appropriate signal transduction pathways for the present purpose. Examples of suitable cells include: the mouse fibroblast cell line N1H 3T3 (ATCC CRL 1658), which responds to transfected M, receptors by increased growth; RAT 1 cells (Pace et a!.. Proc. Natl. Acad. Sci. USA 88:7031 -35 (1991 )): and pituitary cells (Vallar et a!.. Nature 330:556-58 (1987)). Other useful mammalian cells for the present method include but are not limited to HEK 293 cells, CHO cells and COS cells.

[0069] The active compounds also have the ability to reduce intraocular pressure and therefore can be used in the treatment of such diseases as glaucoma. Glaucoma is a disease in which an abnormality is observed in the circulation-control mechanism of the aqueous humor filling up the anterior chamber, i.e.. the space formed between the cornea and the lens. This leads to an increase in the volume of the aqueous humor and an increase in intraocular pressure, consequently leading to visual field defects and even to loss of eyesight due to the compulsion and contraction of the papillae of the optic nerve.

[0070] The pharmacological properties and the selectivity of the active compounds for specific muscarinic receptor subtypes may be demonstrated by a number of different assay methods using, for example, recombinant receptor subtypes, preferably of the human receptors as available, e.g.. conventional second messenger or binding assays. A particularly convenient functional assay system is the receptor selection and amplification assay disclosed in U.S. Pat. No. 5.707.798, which describes a method of screening for bioactive compounds by utilizing the ability of cells transfected with receptor DNA, e.g.. coding for the different muscarinic subtypes, to amplify in the presence of a ligand of the receptor. Cell amplification is detected as increased levels of a marker also expressed by the cells.

[0071] One embodiment includes a method of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound of Formulas 1 as defined supra or a compound derived therefrom. In some embodiments the cholinergic receptor is a muscarinic receptor.

[0072] Disorders suitable for treatment by active compounds include, but are not limited to. cognitive dysfunctions such as cognitive impairment, forgetfulness, confusion, memory loss, depression, attentional deficits, deficits in visual perception, and cognitive dysfunctions associated with mental disorders such as neuropsychiatric disorders, neurodegenerative disorders, dementia, age-related cognitive decline, and Down ^' s syndrome; neuropsychiatric disorders such as sleep disorders, depression, psychosis, hallucinations, aggressiveness, paranoia, schizophrenia, attention deficit disorders, and Gilles de Ia Tourette ^' s syndrome: eating disorders such as anorexia nervosa and bulimia: anxiety disorders such as obsessive compulsive disorders, panic disorders, phobic disorders, general anxiety disorders, and posttraumatic stress disorders; mood disorders, such as clinical depression, bipolar disorder, and major depressive disorder; neurodegenerative disorders and conditions such as alcoholism, Alzheimer ^' s disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Huntington ^' s disease, HlV-associated dementia, Lewy body dementia, multiple sclerosis, Parkinson ^' s disease, Pick's disease, and progressive supranuclear palsy; and other diseases and disorders such as pain, such as neuropathic pain; and glaucoma. Pharmaceutical Compositions

[0073] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a physiologically acceptable surface active agent, carrier, diluent, excipient, smoothing agent, suspension agent, film forming substance, and a coating assistant, or a combination thereof: and a compound disclosed herein or a compound derived therefrom. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art. and are described, for example, in Remington's Pharmaceutical Sciences,, 18th Ed., Mack Publishing Co.. Easton. PA (1990). which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may be used.

[0074] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in ''Remington s Pharmaceutical Sciences. ^" Mack Publishing Co.. Easton. PA. 18th edition. 1990.

[0075] Suitable routes of administration may. for example, include oral, rectal, transmucosal. topical, or intestinal administration: parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.

[0076] The pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0077] Pharmaceutical compositions for use as described herein may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. [0078] Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical compositions. Alternatively or additionally, pharmaceutical compositions may be combined with other compositions that contain other therapeutic or diagnostic agents. Methods of Administration

[0079] The compounds or pharmaceutical compositions may be administered to the patient by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular. which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously. intraperitoneally. intravenously, intramuscularh . intradermal!} ⁷ , intraorbitally. intracapsularly, intraspinally. intrasternally. or the like, including infusion pump delivery: (d) administration locally such as by injection directly in the renal or cardiac area. e.g.. by depot implantation; as well as (e) administration topically: as deemed appropriate by those of skill in the art for bringing the compound disclosed herein into contact with living tissue.

[0080] Phaπnaceutical compositions suitable for administration include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0081] As will be readily apparent to one skilled in the art. the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age: weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.

[0082] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be between about 10 microgram/kg and 100 mg/kg body weight, preferably between about 100 microgram/kg and 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood b\ those of skill in the art.

[0083] The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient ^' s condition. (See e.g., Fingl el al. 1975. in "The Pharmacological Basis of Therapeutics ^" , which is hereby incorporated herein b\ reference in its entirety, with particular reference to Ch. 1 p. 1 ). Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED ₅₀ or ID ₅₀ values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0084] Further details are provided in the follow ing examples, which are not in any way intended to limit the scope of the invention as claimed.

EXAMPLES Examples 1 (Compounds 9-12)

[0085] Compounds 9-12 of the invention were synthesized according to the following methods.

[0086] A mixture of methyl 2-hydrox>benzoate (about 1 eq.), a ethyl 4-fluoro-3- nitrobenzoate (about ] eq.) and CS ₂ CO ₃ (about 1 eq.) in acetonitrile was heated to 70 °C for 1 hour, and then allowed to obtain room temperature. The mixture was diluted with EtOAc and washed with I M NaOH-solution and dried over sodium sulfate and filtered. The filtrate was concentrated and the obtained crude material (1) v\as dissolved in THF (400 ml) followed by addition of I M lithium hydroxide (200 ml). The two phase system was stirred at 60 °C over night. The reaction mixture was allowed to cool to room temperature and the aqueous phase treated with 2M HCl solution until a pH of about 2 was obtained. The mixture was stirred for about an hour and a formed precipitate was filtered, washed with water and dried under reduced pressure. The crude product (2) (about 1 g) was was taken up in MeOH (66 ml). The mixture was flushed with argon and Pd/C (5%. wet) was added. Hydrogen was added and the mixture was hydrogenated for 4 h. then flushed with argon, filtered through celite and concentrated to give crude 3-amino-4-(2-carboxyphenoxy)benzoic acid (3) that was used in the next step without any further purification. To a mixture of 3-amino-4-(2- carboxyphenoxy)benzoic acid (890 mg) in THF (20 ml) was added I J '-carbonyldiimidazole (1.32 g) and the mixture stirred at room temperature for 5h. 2M HCl solution was added followed by water. THF was distilled off under reduced pressure and the product ( 1 1 -oxo- 10.1 l -dihydrodibenzo[b.fJ[1.4]oxazepine-8-carboxylic acid) (4) was filtered off. 1 1 -oxo- 10.1 ] -dihydrodibenzo[b.fJ[1.4]oxazepine-8-carboxylic acid (1.6 g) was dissolved in DMF (60 ml) and cesium carbonate (slight excess) was added and the mixture stirred 5 min at room temperature. Methyl iodide (slight excess) was added and the resulting mixture stirred 4 h at room temperature. The mixture was diluted with aqueous NaOH solution and EtOAc. The aqueous phase was extracted twice with EtOAc and the combined organics were dried and concentrated to give methyl 1 l -oxo-10,1 l-dihydrodibenzo[b.f][1.4]oxazepine-8- carbox\late (5). Methyl 1 l -oxo-10,1 l -dihydrodibenzo[b,f][1,4]oxazepine-8-carboxylate was added to 30 ml toluene and SOCl ₂ (thionyl chloride, 20 ml) was added dropwise followed by 0.5 ml DMF. The mixture was stirred at 70 °C overnight and thereafter 2h at 90 °C. The mixture was cooled to room temperature and the mixture concentrated and thereafter diluted with EtOAc. washed with 0.5 M NaOH solution, dried, concentrated and chromatographically purified (SiO ₂ , heptanerEtOAc, 4:1) to give methyl 1 l -chloro-10,1 1 - dihydrodibenzo[b.f][L4]oxazepine-8-carboxy]ate (6). The residue (210 mg) λ\as taken up in dioxane ( 10 mL) and triethylamine (210 μl. 1.86 mmol) and /-butyl- 1-piperazinecarboxylate (204 mg. 1.09 mmol) were added and the resulting mixture was stirred at 85°C for 2 days then allowed to cool to room temperature. The mixture was diluted with EtOAc. washed with saturated aqueous NH^Cl-solution, dried (Na ₂ SO ₄ ). concentrated and chromatographically purified (SiO ₂ . heptanerEtOAc. 7:1 -3:1) to give methyl 1 l-(4-(tert-butoxycarbonyl)piperazin- l -y])dibenzo[b,f][1 ,4]oxazepine-8-carboxylate (287 mg) (7).

[0087] 1 ] -(4-(tert-butoxycarbonyl)piperazin-l -y])dibenzo[b,fj[1.4joxazepine-8- carboxylate (7) was dissolved in THF and 5 eq lithium hydroxide was added and the resulting mixture stirred at 70 °C overnight and thereafter diluted with EtOAc and water. The mixture acidified with 0.25 M HCl solution. The aqueous phase was extracted with EtOAc and the combined organics combined, dried and concentrated to give l l -(4-(tert- butoxycarbonyl)piperazin-l -yl)dibenzo[b,fJ[1.4]oxazepine-8-carboxylic acid (8).

[0088] 1 l -(4-(tert-butoxycarbonyl)piperazin-1-yl)dibenzo[b.f][1.4]oxa zepine-8- carboxylic acid (8) was used to prepare compounds 9-12.

[0089] Compounds 9-12 was prepared by adding 1 1 -(4-(tert- butoxycarbonyl)piperazin-l -yl)dibenzo[b,fj[1.4]oxazepine-8-carboxylic acid (8) (1 eq) to dichloromethane (2.5 ml) and adding DMF (0.25 ml). Two equivalents of the appropriate hydroxylamine hydrochloride (O-methylhydroxylamine hydrochloride, compound 1 : N.O- dimethylhydroxylamine hydrochloride. compound 2;: O-tert-but\ lhydroxylamine hydrochloride, compound 3: and O-ethylhydroxvlamine hydrochloride, compound 4). 2 equivalents of benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and 3 equivalents of N.N-diisopropylethylamine (DiPEA) were added and the mixture stirred at room temperature overnight. The mixture was concentrated to about 1 ml and the remaining mixture dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1.1 eq) was added and the mixture stirred overnight and thereafter diluted with EtOAc. washed with NaOH-solution (until basic aqueous phase), dried and concentrated. The residue was purified by chromatography to give one of the desired compounds 9-12. Compounds 9-12 may also be prepared using piperazine in analogy with the procedure described in Example 2. Examples 2 (Compounds 18-20)

[0090] Compounds 18-20 of the invention were synthesized according to the following methods.

[0091] To Ethyl 4-fluoro-3-nitrobenzoate (about 1 eq.) and Cs:Cθ ₃ (about 1 eq.) in DMF (10.1 ml) methyl 2-mercaptobenzoate (about I eq.) dissolved in DMF (10.1 ml) was added at 40 °C during 40 min.. The mixture was diluted with EtOAc and water. The water phase was extracted with EtOAc and the combined organics were dried and concentrated. The obtained crude was recrystallized from EtOAc/Heptane to give ( 13) was dissolved in THF (60 ml) followed by addition of IM lithium hydroxide (20 ml). The two phase system was stirred at 60 °C for 24h. The reaction mixture was allowed to cool to room temperature and the aqueous phase treated with 2M HCl and a formed precipitate was filtered, washed with water and dried under reduced pressure. The crude product (14) was was taken up in MeOH (10 ml) and Pd/C (5%. wet) and platinum oxide was added. Hydrogen was added the reaction chamber evacuated and refilled with hydrogen several times. The mixture was stirred for 16h at room temperature under argon atmosphere. The mixture was filtered through celite and washed with MeOH and concentrated to give crude 3-amino-4-(2- carboxyphenylthio)benzoic acid ( 15) that was used in the next step without any further purification. To a mixture of 3-amino-4-(2-carboxypheny]thio)benzoic acid in THF 1 ,1 '- carbonyldiimidazole (10 eq) was added and the mixture stirred at room temperature for 18h. 2M HCl solution was added until pH 2 was obtained. A white precipitate was filtered off and washed with water to give ] l -oxo-10.1 l -dihydrodibenzo[b,fj[1.4]thiazepine-8-carboxylic acid (16). 1 l -oxo-10.1 l -dihydrodibenzo[b.fJ[l ,4]thiazepine-8-carboxylic acid (54 mg) was dissolved in toluene and SOCl ₂ (thionyl chloride, excess) was added dropwise followed by 2 drops of DMF. The mixture was stirred at 90 °C for 6h. The mixture was cooled to room temperature and the mixture concentrated and thereafter diluted with toluene and concentrated. The crude product (1 7) ( 1.0 mmol) dissolved in DCM (4 ml) was added to the appropriate hydroxylamine hydrochloride (O-methylhydroxylamine hydrochloride, compound 18; O-ethylhydroxylamine hydrochloride, compound 19; and N, O- dimethylhydroxylamine. compound 20:) (2.5 mmol) in DCM (2 ml) at 0° C. Shaken for 4 h at room temperature. The reaction mixture was filtered through AI2O ₃ (acidic), eluating with DCM/EtOAc. The filtrate was concentrated at reduce pressure and the obtained imidoylchloride used in the next step without any further purification.

[0092] Piperazine (100 ul) in toluene (1 ml) was added to the imidoylchloride (0.03 mmol) and the mixture was shaken for Ih at 100° C. The volatile material was removed at reduced pressure and the crude product was purified by preparative HPLC-MS to give one of the desired compound 18. 19. or 20. Example 3 (Compounds 21 -31)

[0093] The crude product (17) (1.0 mmol) was dissolved in DCM (5 ml) and the appropriate amine (propylamine, compound 21 ; isopentylamine. compound 22; isobυtylamine. compound 23: N-methylbutan-1 -amine, compound 24; butylamine. compound 25: cyclopentaneamine. compound 26; 4-(aminomethyl)benzenesulfonamide. compound 27; pyridin-3-yhnethanamine, compound 28; pyridin-2-ylmethanamine. compound 29; pyridin-4-ylmethanamine. compound 30: 2-ethoxyethanamine; compound 31) (2.5 mmol) was added and stirred 24 h at room temperature. The reaction mixture was filtered through silica. The filtrate was concentrated at reduce pressure and the obtained imidoylchloride used in the next step without any further purification.

[0094] Piperazine (100 ul) in toluene (I ml) was added to the imidoylchloride (0.03 mmol) and the mixture was shaken for I h at 100° C. The volatile material was removed at reduced pressure and the crude product was purified by preparative HPLC-MS to give compounds 21 -31. Example 4 (Compounds 32-37)

[0095] 1 ] -(4-(tert-butoxycarbonyl)piperazin-l -y])dibenzo[b.fj[l .4]oxazepine-8- carboxylic acid (8) was used to prepare compounds 32-37.

[0096] Compounds 32-37 was prepared by adding l l -(4-(tert- butoxycarbonyl)piperazin-l -yl)dibenzo[b.l][L4]oxazepine-8-carboxylic acid (8) ( 1 eq) to dichloromethane (2.5 ml) and adding DMF (0.25 ml). Two equivalents of the appropriate amine (ethylamine. compound 32; 2-methylpropan-2-amine. compound 33: 2-methylpropan- 1 -amine, compound 34: 2-ethoxyethanamine. compound 35: cyclopentaneamine. compound 36; phenylmethanamine. compound 37). 2 equivalents of benzotriazol-1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and 3 equivalents of N .N- diisopropylethylamine (DiPEA) were added and the mixture stirred at room temperature overnight. The mixture was concentrated to about 1 ml and the remaining mixture dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1.1 eq) was added and the mixture stirred overnight and thereafter diluted with EtOAc. washed with NaOH-solution (until basic aqueous phase), dreied and concentrated. The residue was purified by chromatography to give compounds one of the desired 32-37. Compounds 32-37 may also be prepared using piperazine in analogy with the procedure described in Example 2.

Example 4 - Biological Activity

[0097] Some of the compounds disclosed herein were evaluated for activity at muscarinic receptors using Receptor Selection and Amplification Technology (R-SAT) as described in U.S. Patent No. 5.707.798. the disclosure of which is incorported herein by reference in its entirety. The efficacy (eff) and potency (expressed as pEC _? o) of these compounds at M ₁ -M ₄ receptors are presented in Table 1.

[0098] Although the invention has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.