WO2011025748A1 - Amino substituted diaryl [a, d] cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders - Google Patents

Abstract

Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.

Description

AMINO SUBSTITUTED DIARYL[M]CYCLOHEPTENE ANALOGS AS

MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF

NEUROPSYCHIATRIC DISORDERS

RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/237,220, filed August 26, 2009 which is incorporated herein by reference in its entirety.

BACKGROUND QF THE INVENTION

Field of the Invention

[0002] The present invention relates to the fields of chemistry and medicine. More particularly, disclose herein are compounds that modulate the activity of muscarinic receptors and methods for making such compounds.

Description of the Related Art

[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 have been identified, ml-m5. The ml subtype is the predominant subtype found in the cerebral cortex and is believed to be involved in the control of cognitive functions; m2 is the predominant subtype found in heart and is believed to be involved in the control of heart rate; m3 is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; m4 is present in brain and may be involved in locomotion; and m5, present in brain, may be involved in certain functions of the central nervous system associated with the dopaminergic system.

[0004] Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by loss of acetylcholine in the brain. This is believed to be the result of degeneration of cholinergic neurons in the basal forebrain, which innervate areas of the association cortex, and hippocampus, which is 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 acetylcholine esterase (AChE), the enzyme that metabolizes acetylcholine. Administration of choline or phosphatidylcholine has not been very successful. AChE inhibitors have shown some therapeutic efficacy, but may cause cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. 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 limited their clinical utility.

[0006] Known ml muscarinic agonists such as arecoline have also been found to be weak agonists of m2 as well as m3 subtype and are not very effective in treating cognitive impairment, most likely because of dose- limiting side effects.

[0007] There is a need for compounds that increase acetylcholine signaling or effect in the brain. Specifically there is a need for muscarinic agonists that are active at various muscarinic receptor subtypes in the central and peripheral nervous system. Furthermore, there is a need for more highly selective muscarinic agonists, such as ml- or m4-selective agents, both as pharmacological tools and as therapeutic agents.

SUMMARY QF THE INVENTION

[0008] Some embodiments disclosed herein relate to a method of chemical synthesis that includes: (a) performing a metal catalyzed coupling reaction between a compound of Formula 2-C, and a compound of Formula 2-D, to provide a compound of Formula 2-E;

-?-

(b) reducing a compound of Formula 2-E to provide a compound of Formula 2-F;

(c) converting a compound of formula 2-F to form a fused ring compound of Formula 2- G;

(d) converting the lactam of Formula 2-G to a compound of Formula 2-H;

(e) performing a nucleophilic substitution reaction on the compound of Formula 2- H with a compound of Formula 1-G, to obtain a compound of Formula 2-J;

(f) deprotecting a compound of Formula 2-J to provide a compound of Formula 2- K;

[0009] wherein: X_b can be a halogen; n_a can be 0, 1, or 2; PG_a can be protecting group; and R₂b, R3b, Rib, Rsb, Rβb, R7b, Rsb, and R_9b, can be each independently selected from hydrogen, halogen, optionally substituted Ci_₆ alkyl, optionally substituted C₂_₆ alkenyl, optionally substituted C₂_₆ alkynyl, perhaloalkyl, and CN. In some embodiments, the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base. In some embodiments, the palladium catalyst can be derived from a Pd(II) source; and the inorganic base can be selected from the group consisting of Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, KHCO₃, and CsHCO₃. In some embodiments, the reducing of step (b) can comprise reduction with hydrogen gas in the presence of a catalyst selected from the group consisting of platinum catalyst, palladium catalyst, and Raney nickel catalyst; or reduction using sodium hydrosulfite (Na₂S₂O₄); or reduction using SnCl₂; or reduction using iron; or reduction using sodium sulfide; or reduction using hydrogen sulfide; or reduction using titanium(III) chloride; or reduction using zinc. In some embodiments, the reduction using iron can include iron in the presence of an acid. In some embodiments, the the acid can be acetic acid. In some embodiments, the converting of step (c) can include using phosgene or a phosgene equivalent. In some embodiments, the phosgene equivalent can be selected from the group consisting of trichloromethyl chloroformate and triphosgene. In some embodiments, the converting of step (c) can include using a Lewis acid. In some embodiments, the Lewis acid can be selected from the group consisting of TiCl₄, AICI₃, AlBr₃, BF₃, ZnCl₂, GaCl₃, FeCl₃, SbCl₅, ZrCl₄, SnCl₄, SmI₃, ytterbium triflate, Samarium triflate, and BCl₃. In some embodiments, the converting of step (d) can include using a halogenating agent. In some embodiments, the halogenating agent can be selected from the group consisting of P(O)Cl₃, PCl₃, PCI₅, TiCl₄, and thionyl chloride. In some embodiments, the deprotecting of step (f) includes using an acid. In some embodiments, the acid can be selected from the group consisting of trifluoracetic acid and hydrochloric acid.

[0010] In an embodiment of the chemical synthesis of a compound of Formula (2-H), R_7b and R_8b can be each independently selected from the group consisting of hydrogen and halogen and R_5b can be an optionally substituted Ci_-6 alkyl or halogen. In some embodiments of the chemical synthesis of a compound of Formula (2- J) or (2-K), R2b, R3b, R4b, Rβb, and Rt>b can each be hydrogen. In an embodiment of the chemical synthesis of a compound of Formula (2-J), PG_a can be tert-butoxycarbonyl (Boc).

[0011] In an embodiment of the chemical synthesis of a compound of Formula (2-J) or (2-K), R_7b and R_8b can be each independently selected from the group consisting of hydrogen and halogen and R_5b can be an optionally substituted Ci_-6 alkyl or halogen. In some embodiments of the chemical synthesis of a compound of Formula (2-J), R_2b, R^_b, R_4b, R_όb, and R_9b can each be hydrogen. In an embodiment of the chemical synthesis of a compound of Formula (2-J), PG_a can be tert-butoxycarbonyl (Boc).

[0012] In some embodiments disclosed herein (1-G) in step (e) above is replaced by

followed by performing a nucleophilic substitution reaction on the compound of Formula 2-H with a compound of Formula 3-A, to obtain a compound of Formula 3-B

[0013] wherein: n_a, R₂b, R3b, R4b, Rsb, Rβb, R7b, Rsb, and R_9b are defined as above; and Rn_b can be hydrogen.

[0014] Some embodiments disclosed herein relate to a method of chemical synthesis that includes: protecting compound of formula 4- A to obtain a compound of Formula 4-B and performing a coupling reaction between a compound of Formula 4-B and a compound of Formula 4-C to provide a compound of Formula (4-D). The compound of Formula (4-D) is converted to a compound fo Formula (2-F), which is cyclized to give a compound of Formula (2-G) (above), which by following the above mentioned steps result in a compound of Formula (2-K) or (3-B).

[0015] wherein: Xc and X_D independently can be halogen; n_a, R₂b, R3b, R₄b, Rsb, Rβb, R7b, Rβb, and R(>b are defined as above; and Rub can be hydrogen. In some embodiments, the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base. In some embodiments, the palladium catalyst can be derived from a Pd(II) source; and the inorganic base can be selected from the group consisting of Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, KHCO₃, and CsHCO₃. In some embodiments, the converting of step (d) includes using phosgene or a phosgene equivalent, preferably the phosgene equivalent is selected from the group consisting of trichloromethyl chloroformate and triphosgene. In some embodiments, the converting of step (d) can include using a Lewis acid. In some embodiments, the Lewis acid can be selected from the group consisting of TiCl₄, AlCl₃, AlBr₃, BF₃, ZnCl₂, GaCl₃, FeCl₃, SbCl₅, ZrCl₄, SnCl₄, SmI₃, ytterbium triflate, Samarium triflate, and BCl₃. In some embodiments, the converting of step (e) can include using a chlorinating agent. In some embodiments, the chlorinating agent can be selected from the group consisting of P(O)Cl₃, PCl₃, PCl₅, TiCl₄, and thionyl chloride.

[0016] In some embodiments of the chemical synthesis of a compound of Formula (2-K) or (3-B), R_7b, and Rs_b can be each independently selected from the group consisting of hydrogen and halogen and R_5b can be an optionally substituted Ci_₆ alkyl or halogen. In some embodiments of the chemical synthesis of a compound of Formula (2- K) or (3-B), R₂b, R3b, R₄b, Rβb, and R_9b can each be hydrogen. In some embodiments of the chemical synthesis of a compound of Formula (2- J) or (3-B), Rn_b is hydrogen.

[0017] Some embodiments disclosed herein relate to a compound having the Formula I:

[0018] wherein Rs_b and R_7b are independently selected from the group consisting of Ci_-6 alkyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, both Rs_b and R_7b are halogens or Ci_ ₆ alkyl;. In one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, R_5b and R_7b are independently selected from the group consisting of methyl and halogen. In one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, R_5b is methyl and R_7b is halogen. In one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, R_5b is selected from the group consisting of methyl and halogen and R_7b is chloro. In one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, R_7b is chloro. In one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, Rs_b is methyl. In one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, R_7b is chloro and R_5b is selected methyl.

[0019] Some embodiments disclosed herein relate to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I.

[0020] In one embodiment the compound of Formula I is 3-Chloro-10-methyl- 6-(piperazin-l-yl)-llH-dibenzo[&,e]azepine or 3,10-dichloro-6-(piperazin-l-yl)-l lH- dibenzo [b ,e] azepine.

[0021] In one embodiment the compound of Formula I is 3-Chloro-10-methyl- 6-(piperazin-l-yl)-llH-dibenzo[&,e]azepine hydrochloride or 3,10-dichloro-6-(piperazin- l-yl)-l lH-dibenzo[b,e]azepine hydrochloride.

[0022] Some embodiments disclosed herein relate to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof; and a compound of Formula I.

[0023] Some embodiments disclosed herein relate to a method of treating a neuropsychiatric disorder comprising administering to the patient a therapeutically effective amount of a compound of Formula I. In one embodiment the neuropsychiatric disorder is selected from the group consisting of schizophrenia, schizophrenia related idiopathic psychosis, cognitive enhancement in schizophrenia, anxiety, sleep disorders, appetite disorders, affective disorders, drug-induced psychosis, cognitive impairment, and psychosis secondary to neurodegenerative disorders. In one embodiment the affective disorders are selected from the list consisting of major depression, bipolar disorder, depression with psychotic features, and Tourette's Syndrome; and the psychosis secondary to neurodegenerative disorders are selected from the list consisting of Alzheimer's disease and Huntington's Disease.

[0024] Some embodiments disclosed herein relate to a method of treating a neuropsychiatric disorder comprising contacting a therapeutically effective amount of a compound of Formula I with the patient. In one embodiment the neuropsychiatric disorder is selected from the group consisting of schizophrenia, schizophrenia related idiopathic psychosis, cognitive enhancement in schizophrenia, anxiety, sleep disorders, appetite disorders, affective disorders, drug-induced psychosis, cognitive impairment, and psychosis secondary to neurodegenerative disorders. In one embodiment the affective disorders are selected from the list consisting of major depression, bipolar disorder, depression with psychotic features, and Tourette's Syndrome; and the psychosis secondary to neurodegenerative disorders are selected from the list consisting of Alzheimer's disease and Huntington's Disease.

[0025] Some embodiments disclosed herein relate to a compound having the Formula I:

I

[0026] or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I,

[0027] wherein Rs_b and R_7b are independently selected from the group consisting of Ci_₆ alkyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof for treating a neuropsychiatric disorder. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where both Rs_b and R_7b are halogens or Ci_₆ alkyl. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R_5b and R_7b are independently selected from the group consisting of methyl and halogen. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R_5b is methyl and R_7b is halogen. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R_5b is selected from the group consisting of methyl and halogen and R_7b is chloro. In one embodiment, R_7b is chloro. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where Rs_b is methyl. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R_7b is chloro and Rs_b is methyl.

DETAILED DESCRIPTION QF THE PREFERRED EMBODIMENT

Definitions

[0028] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic 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. Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.

[0029] As used herein, "EC₅₀" 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.

[0030] The term "ester" refers to a chemical moiety with formula -(R)_n- COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.

[0031] An "amide" is a chemical moiety with formula -(R)_n-C(O)NHR' or - (R)_n-NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.

[0032] Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified or amidified. The procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.

[0033] The terms "protecting group" and "protecting groups" as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference. The protecting group moiety may be chosen in such a way, that they are stable to the reaction conditions applied and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls (e.g., t-butoxycarbonyl (BOC)); arylalkylcarbonyls (e.g., benzyloxycarbonyl, benzoyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t- butyldimethylsilyl, or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate, mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane or 1,3-dioxolanes); acyclic acetal; cyclic acetal; acyclic hemiacetal; cyclic hemiacetal; and cyclic dithioketals (e.g., 1,3-dithiane or 1,3- dithiolane).

[0034] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the 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 to reveal the active moiety.

[0035] Whenever a group is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the indicated substituents. When the group is substituted, the group may be mono-substituted or poly-substituted. When the group is described as being "mono-substituted," the group is only substituted with one substitutent. When the group is described as being "poly-substituted," the group may have two or more substitutents, and each substitutent may be independently selected from any of the indicated substituents. Likewise, when a group is described as being "unsubstituted or substituted," if substituted, the substituent(s) may be independently selected from one or mmore of the indicated substituents.

[0036] Unless otherwise indicated, when a substituent is deemed to be "optionally subsituted," the substitutent itself may be unsubstituted or substituted with one ore more of the indicated substitutents. When the referenced substituent is substituted, it is meant that one or more hydrogen atoms on the referenced substituent is replaced with a group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective 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.

[0037] As used herein, "C_1n to C_n," "C_1n-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 "Ci to C₄ alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, (CHs)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-. If no "m" and "n" are designated with regard to a group, the broadest range described in these definitions is to be assumed.

[0038] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, which means that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched or straight chain.

[0039] The alkyl group may have 1 to 20 carbon atoms (whenever 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 may 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 having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group of the compounds of the invention may be designated as "Ci-C₄ alkyl" or similar designations. By way of example only, "Ci-C₄ 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.

[0040] The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Wherever a substituent is described as being "optionally substituted" that substitutent may be substituted with one of the above substituents.

[0041] 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.

[0042] 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 unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.

[0043] As used herein, "hetero" may be attached to a group and refers to one or more carbon atom(s) and the associated hydrogen atom(s) in the attached group have been independently replace with the same or different heteroatoms selected from nitrogen, oxygen and sulfur. When C_m__n or C_1n-C_n is also indicated, it means that one or more carbon atom(s) and the associated hydrogen atom(s) in the C_m__n or C_1n-C_n group have been independently replace with the same or different heteroatoms selected from nitrogen, oxygen and sulfur.

[0044] The term "perhaloalkyl" refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[0045] 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 C₃ to C₁₀, in other embodiments it may range from C₃ to Ce. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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.

[0046] As used herein, "heteroalicyclic" or "heteroalicyclyl" refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The "heteroalicyclic" or "heteroalicyclyl" may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic" or "heteroalicyclyl" may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi- electron system throughout all the rings. Heteroalicyclyl groups may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Examples of such "heteroalicyclic" or "heteroalicyclyl" include but are not limited to, azepinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4- piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. When substituted, substituents on a heteroalicyclyl group may form an aromatic ring fused to the heteroalicyclyl group, including an aryl and a heteroaryl.

[0047] A heteroalicyclyl can 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.

[0048] Some examples of "heteroalicyclyls" include, but are not limited to, 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-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5- triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3- dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. The attachment point of a heterocycle radical can be at the position of a nitrogen heteroatom or via a carbon atom of the heterocycle.

[0049] 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 optionally substituted. 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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthiocyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, 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.

[0050] 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 optionally substituted. 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, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, 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.

[0051] As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl as defined 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 optionally substituted.

[0052] As used herein, "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).

Methods of synthesis

[0053] One embodiment includes a method of synthesizing a compound of Formula 2-K comprising.

[0054] (a) performing a metal catalyzed coupling reaction between a compound of Formula 2-C,

and a compound of Formula 2-D,

to provide a compound of Formula 2-E;

[0055] (b) reducing a compound of Formula 2-E to provide a compound of

Formula 2-F;

[0056] (c) converting a compound of formula 2-F to form a fused ring compound of Formula 2-G;

[0057] (d) converting the the lactam of Formula 2-G to a compound of Formula 2-H;

[0058] (e) performing a nucleophilic substitution reaction on the compound of Formula 2-H with a compound of Formula 1-G,

to obtain a compound of Formula 2- J;

[0059] (f) deprotecting a compound of Formula 2-J to provide a compound of

Formula 2-K;

[0060] wherein:

[0061] Xb is a halogen;

[0062] n_a is 0, 1, or 2;

[0063] PG_a is protecting group; and

[0064] R₂b, R3b, R4b, Rsb, Rβb, R7b, Rsb, and R_9b, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci_₆ alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C₂-₆ alkynyl, perhaloalkyl, and CN.

[0065] In a typical embodiment, the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base. For example, the palladium catalyst can be derived from a Pd(II) source, such as Pd(II)C^ and the like, and the inorganic base can be selected from the group consisting of Na₂CO₃, K₂CO₃, CS₂CO₃, NaHCO₃, KHCO₃, CsHCO₃ and the like.

[0066] In some embodiments, R_7b and Rs_b can be each independently selected from the group consisting of hydrogen and halogen; and Rs_b can be an optionally substituted Ci_-6 alkyl or halogen. In some embodiments, R₂b, R3b, R4b, Rβb, and R_9b can be each hydrogen. In a typical embodiment, PG_a can be tert-butoxycarbonyl (Boc).

[0067] In some embodiments disclosed herein (1-G) in step (e) above is replaced by

followed by performing a nucleophilic substitution reaction on the compound of Formula 2-H with a compound of Formula 3-A, to obtain a compound of Formula 3-B

[0068] In a typical embodiment, the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base. For example, the palladium catalyst can be derived from a Pd(II) source, such as Pd(II)Cl₂ and the like, and the inorganic base can be selected from the group consisting of Na₂CO₃, K^CO₃, Cs₂CO₃, NaHCO₃, KHCO₃, CsHCO₃ and the like.

[0069] In some embodiments, R_7b and Rs_b can be each independently selected from the group consisting of hydrogen and halogen; and Rs_b can be selected from the goup consisting of an optionally substituted Ci_-6 alkyl and halogen. In some embodiments, R₂b, R3b, R₄b, Rβb, and R_9b can be each hydrogen. [0070] Another embodiment includes a method of synthesizing a compound of Formula (3-B) comprising;

[0071] (a) protecting compound of formula 4-A

to obtain a compound of formula 4-B

[0072] (b) performing a coupling reaction between a compound of formula 4- B and a compound of formula 4-C

to provide a compound of formula (4-D)

[0073] (c) deprotecting the compound of formula (4-D) to provide a compound of formula (2-F)

[0074] (d) converting a compound of formula (2-F) to form a fused ring compound of Formula 2-G

[0075] (e) converting the lactam of Formula 2-G to a compound of Formula

2-H;

[0076] (f) performing a nucleophilic substitution reaction on the compound of Formula 2-F with a compound of Formula 3-A,

to obtain a compound of Formula (3-B);

[0077] wherein:

[0078] Xc and X_D independently are halogen;

[0079] n_a is 0, 1, or 2;

[0080] R₂b, R3b, R4b, Rsb, Rβb, R7b, Rsb, and R_9b, are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci_₆ alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C₂-₆ alkynyl, perhaloalkyl, and CN; and

[0081] Rub is hydrogen.

[0082] In some embodiments, R_7b and R_8b independently is selected from the group consisting of hydrogen and halogen; and R_5b can be selected from the goup consisting of an optionally substituted Ci_-6 alkyl and halogen. In some embodiments, R_2b, R3b, R4b, Rβb, and R_9b can be hydrogen.

[0083] In one embodiment Rsb and R₇b is halogen or Ci_6 alkyl; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment Rs_b and R_7b are independently selected from the group consisting of methyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment Rs_b is methyl and R_7b is halogen; or a pharmaceutically acceptable salt or a solvate thereof

[0084] In one embodiment R_5b and R_7b are independently selected from the group consisting of methyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment Rs_b is methyl and R_7b is halogen; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment the compound is 3-Chloro-10- methyl-6-(piperazin- 1 -yl)- 1 lH-dibenzo[&, e]azepine hydrochloride, 3 , 10-dichloro-6- (piperazin-l-yl)-HH-dibenzo[b,e]azepine hydrochloride, 3-Chloro-10-methyl-6- (piperazin- 1 -yl)- 11 Η-dibenzo[&, e] azepine, or 3,10-dichloro-6-(piperazin- 1 -yl)- 1 IH- dibenzo [b ,e] azepine. [0085] Formula 2-K may be made according to Scheme 4.

Scheme 4

[0086] In step (a) of Scheme 4, the carboxylic acid moiety of a compound of formula (2-A) can be reduced to provide an benzyl alcohol of formula (2-B); R₂b, R3b, R4b, Rsb, Rβb, R7b, Rβb, and Rt>b, can be each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci_₆ alkyl, optionally substituted C₂-₆ alkenyl, optionally substituted C₂-₆ alkynyl, perhaloalkyl, and CN; R_m can be hydrogen or a protecting group (PG_a); and n_a can be 0, 1, or 2. In some embodiments, a compound of formula (2-A) in an organic solvent, such as diethyl ether, dioxane, dimethoxy ethane or THF, can be treated with a reducing agent, such as AlH₃, BH₃, DiBaIH, NaBH₄ and AlCl₃, LiAlH(OMe)₃, LiAlH₄, and NaAlEt₂H₂ to provide a compound of formula (2-B). For example, a compound of formula (2-A) in THF can be treated with BH₃-SMe₂ to provide a compound of formula (2-B). [0087] In step (b) of Scheme 4, a compound of formula (2-B) can be transformed to a benzyl halide of formula (2-C). In some embodiments, an alcohol of formula (2-B) can be converted to benzyl halide of formula (2-C) using a halogenating agent. In a typical embodiment, an alcohol of formula (2-B) can be treated with a halogenating agent, such as P(O)Cl₃, PCI₃, PCI₅, thionyl chloride, p-toluenesulfonyl chloride, P(O)Br₃, PBr₃, PBr₅, thionyl bromide or p-toluenesulfonyl bromide, to provide a benzyl halide of formula (2-C). For example, a benzyl bromide of formula (2-C) can be formed by treating an alcohol of formula (2-B) in toluene with PBr₃.

[0088] In step (c) of Scheme 4, a compound of formula (2-E) can be formed by reaction of a benzyl halide of formula (2-C) with a boronic acid of formula (2-D) under metal catalyzed conditions. In some embodiments, a benzyl bromide of formula (2- C) can be reacted with a boronic acid of formula (2-D) in the presence of palladium to provide a compound of formula (2-E). For example, a mixture of a benzyl bromide of formula (2-C) and a boronic acid of formula (2-D) in an organic solvent, such as butyl alcohol, DMF, NMP, or acetone, and water can be treated with Pd(II) and an inorganic base, such as Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, KHCO₃, or CsHCO₃, to provide a compound of formula (2-E). In a typical embodiment, a mixture of a benzyl bromide of formula (2-C) and a boronic acid of formula (2-D) in an acetone and water can be treated with PdCl₂ and K₂CO₃ to provide a compound of formula (2-E).

[0089] In step (d) of Scheme 4, a compound of formula (2-F) can be formed by reduction of the nitro group of a compound of formula (2-E). In some embodiments, the nitro group of a compound of formula (2-E) can be reduced by hydrogenation, with sodium hydrosulfite (Na₂S₂O₄), with SnCl₂, or with iron to provide a compound of formula (2-F). In a typical embodiment, a compound of formula (2-E) can be reduced with iron in the presence of acid. For example, a mixture of a compound of formula (2-E) in ethyl alcohol, and acetic acid can be treated with iron powder to provide a compound of formula (2-F).

[0090] In step (e) of Scheme 4, a compound of formula (2-F) can be converted to a lactam of formula (2-G). In some embodiments, a compound of formula (2-F) can be converted to a lactam of formula (2-G) using a phosgene equivalent. For example, a compound of formula (2-F) can be converted to a lactam of formula (2-G) using a trichloromethyl chloroformate, to provide a lactam of formula (2-G). In one embodiment, the lactam of formula (2-G) can be formed using chloroformate as the phosgene equivalent and a Lewis acid. For example, a compound of formula (2-F) can be treated with trichloromethyl chloroformate in an organic solvent, such as diethyl ether, dimethoxyethane, THF and dioxane, then after reacting for an appropriate amount of time the organic solvent can be removed and replaced with a solvent, such as methylene chloride, carbon tetrachloride, dichloroethane, nitrobenzene, carbon disulfide or 1,2- dichlorobenzene, the mixture can then be combined with a Lewis acid, such as TiCl₄, AlCl₃, AlBr₃, BF₃, ZnCl₂, GaCl₃, FeCl₃, SbCl₅, ZrCl₄, SnCl₄, SmI₃, ytterbium triflate, Samarium triflate, or BCl₃, to provide a lactam of formula (2-G). In a typical embodiment, a compound of formula (2-F) can be treated with trichloromethyl chloroformate in dioxane, then after reacting for an appropriate amount of time the dioxane can be removed and replaced with 1,2-dichlorobenzene, and the mixture can be added to a suspension of AlCl₃ in 1 ,2-dichlorobenzene to provide a lactam of formula (2- G). Compound (2-F) is converted to compound (2-G) by the use of a phosgene equivalent, such as those mentioned above, via the formation of an isocyanate of formula (2-Fb)

which may or may not be isolated before conversion to compound (2-G).

[0091] In step (f) of Scheme 4, a compound of formula (2-G) can be transformed to a compound of formula (2-H). In some embodiments, a lactam of formula (2-G) can be converted to an imidoylhalide using a halogenating agent. For example, a lactam of formula (2-G) can be treated with a halogenating agent, such as P(O)Cl₃, PCl₃, PCI₅, TiCl₄, thionyl chloride, or thionyl chloride with DMF, to provide a imidoylchloride of formula (2-H). In one embodiment, the imidoylchloride of formula (2-H) can be formed using P(O)Cl₃ as the chlorinating reagent and the solvent. In another embodiment, the imidoylchloride of formula (2-H) can be formed using thionyl chloride with catalytic DMF and toluene as the solvent.

[0092] In step (g) of Scheme 4, a compound of formula (2-H) can be transformed to a compound of formula (2- J) by a nucleophilic substitution reaction. In some embodiments, a compound of formula (2- J) can be formed by reacting a compound of formula (2-H) with a compound of formula (2-1) under suitable nucleophilic substitution conditions. For example, an imidoylchloride of formula (2-H) can be reacted with a compound of formula (2-1) optionally in the presence of a base, such as triethylamine, diisopropylethylamine or N-methyl piperidine, in an organice solvent, such as methylene chloride, DMF, NMP, dimethoxyethane, THF, ethyl ether, or dioxane, to provide a compound of formula (2- J). In some embodiments, Ru_b of a compound of formula (2-1) can be Boc. In a typical embodiment, Ru_b of a compound of formula (2-1) can be hydrogen and the compound of formula (2-K) can be formed directly without the deprotection step (h). For example, an imidoylchloride of formula (2-H) can be reacted with a piperizine in dioxane, to provide a compound of formula (2-K which is equivalent to 2-J where Rm, is hydrogen). In some embodiments, Rm, of a compound of formula (2-1) can be a protecting group PG_a.

[0093] In step (h) of Scheme 4, a compound of formula (2-J, where Ru_b is a protecting group PG_a) can be deprotected to a provide a compound of formula (2-K). In a typical embodiment, R_llb can be a Boc protecting group. For example, compound of formula (2-J), wherein Rπ_b is a Boc group can be deprotected using an acid, such as trifluoracetic acid or hydrochloric acid, to provide a compound of formula (2-K). The compound of formula (2-K) can be isolated as a free base or a salt following procedures know by those of skill in the art

[0094] In an exemplary embodiment, for the compounds depicted in Scheme 4, X_b can be chlorine; R₂b, R3b, Rib, Rβb, Rsb, and R_9b can be hydrogen; R_5b can be optionally substituted Ci_-6 alkyl or halogen; R_7b can be halogen or optionally substituted Ci_₆ alkyl; and n_a can be 1. For example, in a typical embodiment, Rs_b can be methyl and R_7b can be chlorine.

Compounds

[0095] One embodiment includes a compound of Formula I:

[0096] wherein R_5b and R_7b are independently selected from the group consisting of Ci_-6 alkyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment R_5b and R_7b are independently selected from the group consisting of methyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment R_5b is methyl and R_7b is halogen; or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment, the compound of Formula I is 3- Chloro- 10-methyl-6-(piperazin- 1 -yl)- 1 lH-dibenzo[&, ejazepine, 3 , 10-dichloro-6-

(piperazin-l-yl)-HH-dibenzo[b,e]azepine, 3-Chloro-10-methyl-6-(piperazin-l-yl)-l lH- dibenzo[&,e]azepine hydrochloride or 3,10-dichloro-6-(piperazin-l-yl)-l lH- dibenzo[b,e]azepine hydrochloride.

[0097] In some embodiments, compounds of Formula I, may be used to modulate the activity of a muscarinic receptor.

[0098] The term "modulate" refers to the ability of a compound disclosed herein to alter the function of a muscarinic receptor. A modulator may activate the activity of a muscarinic receptor, may activate or inhibit the activity of a muscarinic receptor depending on the concentration of the compound exposed to the muscarinic receptor, or may inhibit the activity of a muscarinic receptor. The term "modulate" also refers to altering the function of a muscarinic receptor by increasing or decreasing the probability that a complex forms between a muscarinic receptor and a natural binding partner. A modulator may increase the probability that such a complex forms between the muscarinic receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the muscarinic receptor and the natural binding partner depending on the concentration of the compound exposed to the muscarinic receptor, and or may decrease the probability that a complex forms between the muscarinic receptor and the natural binding partner. In some embodiments, modulation of the muscarinic receptor may be assessed 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.

[0099] The term "activate" refers to increasing the cellular function of a muscarinic receptor. The term "inhibit" refers to decreasing the cellular function of a muscarinic receptor. The muscarinic receptor function may be the interaction with a natural binding partner or catalytic activity.

[0100] The term "contacting" as used herein refers to bringing a compound disclosed herein and a target muscarinic receptor together in such a manner that the compound can affect the activity of the muscarinic receptor, either directly; i.e., by interacting with the muscarinic receptor itself, or indirectly; i.e., by interacting with another molecule on which the activity of the muscarinic receptor is dependent. Such "contacting" can be accomplished in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a muscarinic receptor of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a muscarinic receptor related disorder; i.e., the IC₅₀ of the compound can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the muscarinic receptors in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques. The term "contacting" can also refer to bringing a compound disclosed herein to contact with a target muscarinic receptor in vivo. Thus, if a compound disclosed herein, or a prodrug thereof, is administered to an organism and the compound is brought together with a muscarinic receptor within the organism, such contacting is within the scope of the present disclosure.

[0101] In some embodiments, the compound of Formula I may be an agonist of said receptor, such as a muscarinic receptor, while in other embodiments, the compound may be an antagonist of said receptor. In yet other embodiments, the compound may be a partial agonist of said receptor. A compound that is a partial agonists may in some cases be a partial activator of a receptor, while in other cases may be a partial repressor of a receptor. In yet other circumstances, the compound may be a tissue- specific modulator, while in other circumstances, the compound may be a gene-specific modulator.

[0102] Certain of the compounds disclosed herein may exist as stereoisomers including optical isomers. The scope of the present disclosure includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.

[0103] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and a compound of Formula I.

[0104] The term "pharmaceutical composition" refers to a mixture of a compound of the invention 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.

[0105] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

[0106] The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0107] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0108] 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.

[0109] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.

[0110] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly in the renal or cardiac area, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue- specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

[0111] The pharmaceutical compositions of the present invention 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.

[0112] Pharmaceutical compositions for use in accordance with the present invention thus 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. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.

[0113] For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0114] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0115] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0116] Pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0117] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0118] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0119] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0120] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0121] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0122] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0123] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0124] A pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[0125] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0126] Many of the compounds used in the pharmaceutical combinations of the invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.

[0127] Pharmaceutical compositions suitable for use in the present invention include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. 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. [0128] The exact formulation, route of administration and dosage for the pharmaceutical compositions of the present invention can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics," Ch. 1 p. 1). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Note that for almost all of the specific compounds mentioned in the present disclosure, human dosages for treatment of at least some condition have been established. Thus, in most instances, the present invention will use those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED₅₀ or ID₅₀ values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0129] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions of the present invention or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day. Alternatively the compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0130] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0131] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0132] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0133] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0134] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0135] In another aspect, the present disclosure is related to a method of treating a neuropsychiatric disorder comprising administering to said patient a therapeutically effective amount of a compound of Formula I. In some embodiments, the neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychosis, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome, drug-induced psychosis, psychosis secondary to neurodegenerative disorders such Alzheimer's or Huntington's Disease. [0136] In yet another aspect, the present disclosure is related to a method of treating a neuropsychiatric disorder comprising contacting a therapeutically effective amount of a compound of Formula I with said patient .

[0137] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of Formula I and a neuropsychiatric agent. As used herein, a "neuropsychiatric agent" refers to a compound, or a combination of compounds, that affects the neurons in the brain either directly or indirectly, or affects the signal transmitted to the neurons in the brain. Neuropsychiatric agents, therefore, may affect a person's psyche, such as the person's mood, perception, nociception, cognition, alertness, memory, etc. In certain embodiments, the neuropsychiatric agent may be selected from the group consisting of a selective serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine agonist, antipsychotic agent, serotonin 2A antagonists, and inverse serotonin 2A agonists.

[0138] In some embodiments, the antipsychotic agent may be selected from the group consisting of a phenothiazine, phenylbutylpiperadine, dibenzapine, benzisoxidil, and salt of lithium. The phenothiazine group of compounds may be selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®). The phenylbutylpiperadine group of compounds may be selected from the group consisting of haloperidol (Haldol®), and pimozide (Orap®). The dibenzapine group of compounds may be selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®). The benzisoxidil group of compounds may be selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®). The salt of lithium may be lithium carbonate. In some embodiments, the antipsychotic agent may be selected from the group consisting of Aripiprazole (Abilify), Clozapine, Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Olanzapine (Zyprexa), Orap, Permitil, Prolixin, Phenergan, Quetiapine (Seroquel), Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon, and Zyprexa, or pharmaceutically acceptable salts thereof.

[0139] In certain embodiments, the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.

[0140] In other embodiments, the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.

[0141] In further embodiments, the dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.

[0142] In another aspect, the present disclosure is directed to a method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I and a neuropsychiatric agent. In yet another aspect, the present disclosure is directed to a method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I and a therapeutically effective amount of a neuropsychiatric agent.

[0143] In certain embodiments, the patient may be a mammal. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans. In some embodiments, the patient is a human.

[0144] In some embodiments, the administering step in the above methods comprises administering said compound of Formula I and said neuropsychiatric agent nearly simultaneously. These embodiments include those in which the compound of Formula I and the neuropsychiatric agent are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, contains both compounds. The embodiments also include those in which each compound is in a separate administrable composition, but the patient is directed to take the separate compositions nearly simultaneously, i.e., one pill is taken right after the other or that one injection of one compound is made right after the injection of another compound, etc.

[0145] In other embodiments the administering step comprises administering one of the compound of Formula I and the neuropsychiatric agent first and then administering the other one of the compound of Formula I and the neuropsychiatric agent. In these embodiments, the patient may be administered a composition comprising one of the compounds and then at some time, a few minutes or a few hours, later be administered another composition comprising the other one of the compounds. Also included in these embodiments are those in which the patient is administered a composition comprising one of the compounds on a routine or continuous basis while receiving a composition comprising the other compound occasionally.

[0146] In certain embodiments, the neuropsychiatric disorder to be treated by the methods and the compounds of the present disclosure is selected from the group consisting of schizophrenia and related idiopathic psychosis, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome, drug-induced psychosis, psychosis secondary to neurodegenerative disorders such Alzheimer's or Huntington's Disease.

EXAMPLES

Example 1 3-Chloro-10-methyl-6-(piperazin-l-yl)-l lH-dibenzor£,elazepine hydrochloride (24)

Scheme 4- A

(4-Chloro-2-nitrophenyl)methanol (18)

18

[0147] To a mixture of 4-chloro-2-nitrobenzoic acid (30 g, 150 mmol) in dry THF (200 niL) at 0⁰C under argon was added BH₃-Me₂S (28 niL, 300 mmol) dropwise. The mixture was allowed to reaqh room temperature over night then raised to 50⁰C and stirred at that temp for 1.5 h then the temperature was raised to 60⁰C and stirred at that temperature for another 2h. The mixture was cooled to 0⁰C and ice was added carefully until the gas evolution ceased, then ice-cold water (100 mL) and 2 M aqueous NaOH- solution (100 mL) were added. The mixture was diluted with water and extracted with EtOAc (3 x 300 mL). The combined organic phases were washed with saturated aqueous NaHCθ₃-solution and brine, dried (Na₂SO₄) and concentrated to give crude (4-Chloro-2- nitrophenyl)methanol (18) (32 g) that was used in the next step without any further purification. l-(Bromomethyl)-4-chloro-2-nitrobenzene (19)

19

[0148] To a mixture of crude (4-Chloro-2-nitrophenyl)methanol (18) (32 g) in toluene (225 mL) was added PBr₃ (4.9 mL, 53 mmol) and the resulting mixture was heated to 100⁰C and stirred at that temperature for 15 minutes, then allowed to cool to room temperature. Et₂O was added and the mixture was decanted into a separation funnel. The mixture was washed with water (2x) and brine (Ix), dried (Na₂SO₄) and concentrated to give l-(Bromomethyl)-4-chloro-2-nitrobenzene (19) (37 g, 98%). ¹H NMR (CDCl₃) δ ppm 8.04 (d, / = 2.1 Hz, IH), 7.61-7.50 (m, 2H), 4.79 (s, 2H).

4-Chloro- 1 -(2-methylbenzyl)-2-nitrobenzene (21)

[0149] Argon was bubbled through a mixture of l-(Bromomethyl)-4-chloro-2- nitrobenzene (19) (12.6 g, 50 mmol) and o-tolyl boronic acid (20) (10.2 g, 75 mmol) in acetone (360 mL) and water (120 mL) for 10 minutes, then kept under argon. K₂CO₃ (17.3 g, 125 mmol) and PdCl₂ (445 mg, 5 mol-%) were added and the resulting mixture was stirred at room temperature for 1 h, then diluted with Et₂O and washed with water. The aqueous phase was re-extracted with Et₂O and the combined organic phases were dried (Na₂SO₄) concentrated and flash chromatographed (SiO₂, heptane: EtOAc 25:1-15:1) to give 4-Chloro-l-(2-methylbenzyl)-2-nitrobenzene (21) (7.1 g of impure product) which was used in the next step without further purification.

5-Chloro-2-(2-methylbenzyl)aniline (22)

[0150] To a mixture of crude 4-Chloro-l-(2-methylbenzyl)-2-nitrobenzene (21) (7.1 g, approx. 27 mmol) in EtOH (100 mL) and AcOH (100 mL) was added iron powder (4.6 g, 81 mmol) and the resulting mixture was stirred vigorously at 90⁰C for 50 minutes then allowed to cool to room temperature. The mixture was concentrated to approximately 50 mL then diluted with EtOAc, washed with water, saturated aqueous NaHCO₃-solution and brine, dried (Na₂SO₄), concentrated and flash chromatographed (SiO₂, heptane:EtOAc 25: 1-15:1) to give 5-Chloro-2-(2-methylbenzyl)aniline (22) (4.9 g, 42%, 2 steps). ¹H NMR (CDCl₃) δ ppm 7.23-7.08 (m, 3H), 7.00-6.92 (m, IH), 6.81-6.67 (m, 3H), 4.09 (bs, IH), 3.79 (s, 2H), 2.28 (s, 3H), 1.56 (bs, IH).

3-Chloro-10-methyl-5H-dibenzorb.elazepin-6(l lHVone (23)

[0151] To a mixture of 5-chloro-2-(2-methylbenzyl)aniline (22) (4.9 g, 21 mmol) in dioxane (100 mL) at room temeperaure was added trichloromethyl chloroformate, the mixture was stirred at 55⁰C for 45 min and then concentrated. The residue was taken up in 1 ,2-dichlorobenzene (16 mL) and added to a suspension of AICI₃ (2.8 g, 21 mmol) in 1 ,2-dichlorobenzene (16 mL) at 70⁰C. The mixture was stirred at 120⁰C over night and then allowed to reach room temperature. 2 M aqueous NaOH- solution (7 mL) was added followed by Na₂SO₄. The mixture was filtered and the filter- cake was extracted with EtOAc. The combined filtrates were concentrated to give 3- chloro-10-methyl-5H-dibenzo[&,e]azepin-6(llH)-one (23) (6.1 g, impure product) which was used in the next step without any further purification. GCMS m/z 257 [M]⁺.

3-Chloro- 10-methyl-6-(piperazin- 1 -yl)- 11 H-dibenzo \b, el azepine hydrochloride (24)

[0152] To a mixture of 3-Chloro-10-methyl-5H-dibenzo[&,e]azepin-6(l lH)- one (23) (6.1 g, approx. 20 mmol) was added POCI₃ (200 mL) and the resulting mixture was heated to 90⁰C over night then concentrated. The residue was taken up in EtOAc, washed with water, saturated aqueous NaHCθ₃-solution and brine, dried (Na₂SO₄) and chromatographed through a short column (SiO₂, 5Og, heptane: EtOAc, 50:1-15:1) to give 3.8 g of the intermediate imidoyl chloride.

[0153] The residue was taken up in dioxane (100 mL) and added to a solution of piperazine (17.2 g, 200 mmol) in dioxane (100 mL) at 8O⁰C. The mixture was stirred at 8O⁰C over night, then cooled to room temperature, diluted with EtOAc and washed with 0.2 M aqueous NaOH-solution (2 x 200 mL). The organic phase was extracted with 0.5 M aqueous HCl-solution (3 x 100 mL). The acidic aqueous phases were combined and adjusted to pH 10-12 with 2 M aqueous NaOH-solution, then extracted with EtOAc (3x). The combined organic phases (from the last extraction) were dried (Na₂SO₄) and concentrated to give the free base (3.81 g, 58%, 3 steps)

[0154] The free base was dissolved in acetone and HCl (2.9 mL, 4 M in dioxane) was added. The mixture was concentrated to give 4.24 g off 3-Chloro-10- methyl-6-(piperazin-l-yl)-HH-dibenzo[&,e]azepine hydrochloride (24). Purity LCMS (UV/MS) 100/98. LCMS m/z 326.1 [M+H]⁺. [0155] NMR of free base ¹H NMR (CD₃OD) δ ppm 7.16 (s, IH), 7.11-6.99 (m, 3H), 6.89-6.87 (m, IH), 6.78 (dd, / = 8.1, 2.2 Hz, IH), 3.84 (d, J_AB = 13.2 Hz, IH), 3.45-3.34 (m, 4H), 3.07 (d, J_AB = 13.2 Hz, IH), 2.90-2.80 (m, 2H), 2.77-2.68 (m, 2H), 2.37 (s, 3H). ¹³C NMR (CD₃OD) δ ppm 162.2, 147.2, 140.9, 133.5, 132.2, 131.6, 131.5, 127.5, 127.0, 125.9, 125.8, 123.7, 122.3, 44.9, 32.4, 18.5.

Example 2 - 3,10-dichloro-6-(piperazin-l-yl)-llH-dibenzorb,elazepine hydrochloride

(37)

Scheme 4-B

AICI₃

CI₂-benzene

N-benzylidene-5-chloro-2-iodoaniline (33)

[0156] 5-chloro-2-iodoaniline (10.0 g, 39.45 mmol) and benzaldehyde (4.19 g, 39.45 mmol) were dissolved in benzene (100 mL) in the presence of a catalytic amount of 4-toluene sulfonic acid (5 mg). The reaction was refluxed in a Dean-Stark apparatus for 2h. The reaction was quenched with sodium bicarbonate (100 mg), filtered and evaporated to give the title compound (10.1 g) which was used in the next step without any further purification. GC/MS m/z 341 [M]⁺.

N-benzylidene-5-chloro-2-(2-chlorobenzyl)aniline (34)

[0157] N-benzylidene-S-chloro^-iodoaniline (33) (1.0 g, 2.93 mmol) was dissolved in THF and cooled to -15 ⁰C. Isopropyl magnesium chloride (1.8 M in THF, 3.22 mmol, 1.79 mL) was added and the reaction was stirred at -15 ⁰C for Ih. Freshly prepared CuCN-2LiCl solution (1 M in THF, 2.93 mmol, 2.9 mL) was added and the reaction was stirred for 30 min at -15 ⁰C. l-(bromomethyl)-2-chlorobenzene (1.20 g, 5.86 mmol) was added and reaction was allowed to warm-up to room temperature. The reaction was quenched with saturated ammonium chloride (20 mL) then extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and evaporated to give a crude product (1.4 g) that was used in the next step without any further purification. GC/MS m/z 339 [M]⁺.

5-chloro-2-(2-chlorobenzyl)aniline (35)

[0158] N-benzylidene-5-chloro-2-(2-chlorobenzyl)aniline (34) (crude oil, 1.4 g) was dissolved in THF (50 mL) and aqueous hydrochloric acid (4 N, 50 mL) was added. The reaction was stirred at room temperature for 15h then was basified by slow addition of potassium carbonate. The reaction was diluted with ethyl acetate (100 mL) and washed with aqueous sodium hydroxide (2 N, 100 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give a crude product which was purified by silica gel chromatography (gradient : 0-4% ethyl acetate :n-heptane) to give the title compound (0.5 g). ¹H NMR (CDCl₃) δ ppm 7.39-7.41 (m, IH), 7.16-7.22 (m, 2H), 6.99-7.02 (m, IH), 6.87-6.89 (m, IH), 6.71-6.74 (m, 2H), 3.92 (s, 2H), 3.76 (bs, 2H). ¹³C NMR (CDCl₃) δ ppm 145.5, 136.2, 134.3, 133.2, 131.7, 129.9, 129.5, 128.0, 127.5, 121.9, 118.7, 115.5, 34.4. GCMS m/z 251 [M]⁺ 3J0-dichloro-5H-dibenzorb,e1azepin-6(llH)-one (36)

[0159] To a mixture of 5-chloro-2-(2-chlorobenzyl)aniline (35) (0.4 g, 1.59 mmol) in dioxane (20 mL) at room temperature was added trichloromethyl chloroformate (0.10 mL, 0.79 mmol) and the resulting mixture was stirred at 55 ⁰C for 45 min and then concentrated. The residue was taken up in 1 ,2-dichlorobenzene (12 mL), AICI₃ (0.21 g, 1.59 mmol) was added and the reaction was stirred at 120 ⁰C over night and then allowed to reach room temperature. Aqueous sodium hydroxide (2M, 7 mL) was added followed by sodium sulfate. The mixture was filtered and the precipitate was washed with ethyl acetate (20 mL). The combined filtrates were concentrated to give the title compound (0.18 g) which was used in the next step without any further purification.

[0160] ¹H NMR (DMSO-d₆) δ ppm 10.69 (bs, IH), 7.64-7.66 (m, 2H), 7.32- 7.37 (m, 2H), 7.14-7.18 (m, 2H), 4.07 (bs, 2H).

3, 10-dichloro-6-(piperazin-l-yl)-llH-dibenzorb,elazepine hydrochloride (37)

[0161] 3,10-dichloro-5H-dibenzo[b,e]azepin-6(llH)-one (36) (0.18 g, 0.65 mmol) was suspended in POCI₃ (20 mL) and the resulting mixture was heated to 90 ⁰C over night then concentrated. The residue was taken up in EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate and evaporated to give the intermediate imidoyl chloride that was used without any further purification. [0162] The residue was dissolved in dioxane (20 mL) and piperazine (0.56 g, 6.50 mmol) was added. The reaction was stirred at 100 ⁰C for 15 h then cooled to room temperature and concentrated. The reaction was diluted with ethyl acetate (50 mL) and washed with aqueous sodium hydroxide (2 N, 50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by silica gel chromatography (gradient: 0-10% methanol :dichloromethane) to give the title compound (0.14 g) as the free base. The free base was dissolved in acetone (5 mL) and HCl (0.1 mL, 4 N in dioxane) was added. The solid was filtered off and washed with diethyl ether to give the mono hydrochloride salt of the title compound (0.14 g). Purity LC/MS (UV/MS) 100/100. LC/MS m/z 346.0 [M+H]⁺.

[0163] NMR of free base ¹H NMR (CDCl₃) δ ppm 7.41-7.44 (m, IH), 7.24- 7.27 (m, IH), 7.15-7.17 (d, 2H), 7.07-7.08 (d, IH), 6.90-6.93 (m, IH), 4.25-4.28 (d, IH), 3.47-3.53 (m, 5H), 3.23-3.26 (d, IH), 2.88-3.05 (m, 4H). ¹³C NMR (CDCl₃) δ ppm 160.0, 147.0, 139.5, 132.6, 131.8, 131.3, 129.7, 129.4, 127.9, 127.1, 127.0, 124.5, 123.0, 50.8, 46.0, 33.6.

Example 3 - Functional Screen

[0164] 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 pECso) of these compounds are presented in Table 1 at Ml, M2, and M3 receptors.

Table 1.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:

I

wherein Rs_b and R_7b are independently selected from the group consisting of Ci_₆ alkyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound of Claim 1, wherein both Rs_b and R_7b are methyl or halogen, or a pharmaceutically acceptable salt or a solvate thereof.

3. The compound of Claim 1, wherein Rs_b is selected from the group consisting of methyl and halogen, or a pharmaceutically acceptable salt or a solvate thereof.

4. The compound of Claim 1, wherein Rs_b is selected from the group consisting of methyl and halogen and R_7b is chloro, or a pharmaceutically acceptable salt or a solvate thereof.

5. The compound of Claim 1 wherein the compound is 3-Chloro-10-methyl-6- (piperazin-l-yl)-l lH-dibenzo[Z?,e]azepine or 3,10-dichloro-6-(piperazin-l-yl)-l IH- dibenzo[b,e]azepine; or a pharmaceutically acceptable salt or a solvate thereof.

6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of Claims 1 - 5.

7. A method of chemical synthesis comprising;

(a) performing a metal catalyzed coupling reaction between a compound of Formula 2-C,

and a compound of Formula 2-D,

to provide a compound of Formula 2-E;

(b) reducing a compound of Formula 2-E to provide a compound of

Formula 2-F;

(c) converting a compound of formula 2-F to form a fused ring compound of Formula 2-G;

(d) converting the the lactam of Formula 2-G to chloroimine of Formula 2-

H;

(e) performing a nucleophilic substitution reaction on the compound of Formula 2-H with a compound of Formula 1-G or of Formula 2-1,

b

to obtain a compound of Formula 2-H or 2-J;

(f) deprotecting a compound of Formula 2-H to provide a compound of

Formula 2-K;

wherein:

X_b is a halogen;

n_a is 0, 1, or 2;

PG₃ is protecting group;

Rub is hydrogen; and

R_2b, R3b, R4b, Rsb, Rόb, R7b, Rsb, and R_9b, are each independently selected from the group consisting of hydrogen, halogen, CN, perhaloalkyl, optionally substituted C_1-6 alkyl, optionally substituted C₂_₆ alkenyl, and optionally substituted C₂_₆ alkynyl.

8. The method of Claim 7, wherein the metal catalyzed coupling reaction of step (a) is performed using a palladium catalyst and an inorganic base.

9. The method of Claim 8, wherein

the palladium catalyst is derived from a Pd(II) source; and the inorganic base is selected from the group consisting of Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, KHCO₃, and CsHCO₃.

10. The method of any one of Claims 7 to 9, wherein R₇b and Rsb are each independently selected from the group consisting of hydrogen and halogen; and Rs_b is an optionally substituted C_1-6 alkyl or halogen.

11. The method of any one of Claims 7 to 10, wherein R₂b, R₃b, R-ib, Rόb, and R% are each hydrogen.

12. The method of any one of Claims 7 to 11, wherein PG₃ is tert-butoxycarbonyl (Boc)

13. A method of chemical synthesis comprising; (a) protecting compound of formula 4-A

to obtain a compound of formula 4-B

(b) performing a coupling reaction between a compound of formula 4-B and a compound of formula 4- C

to provide a compounc of formula (4-D)

(c) deprotecting the compound of formula (4-D) to provide a compound of formula (2-F)

(d) converting a compound of formula (2-F) to form a fused ring compound of Formula 2- G

(e) converting the lactam of Formula 2-E to a compound of Formula 2-H;

(g) performing a nucleophilic substitution reaction on the compound of Formula 2-H with a compound of Formula 2-1,

to obtain a compound of Formula 2- J;

wherein:

Xc and X_D independently are halogen;

n_a is 0, 1, or 2;

R2b, R3b, R4b, Rδb, Rόb, R7b, Rβb, and R_9b, are each independently selected from the group consisting of hydrogen, halogen, CN, perhaloalkyl, optionally substituted Ci_₆ alkyl, optionally substituted C₂-6 alkenyl, and optionally substituted C2-6 alkynyl; and

Rub is hydrogen.

14. The method of Claim 13, wherein the metal catalyzed coupling reaction of step (a) is performed using a palladium catalyst and an inorganic base.

15. The method of Claim 13, wherein

the palladium catalyst is derived from a Pd(II) source; and the inorganic base is selected from the group consisting of Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, KHCO₃, and CsHCO₃.

16. The method of Claim 13, wherein R_7b, and Rg_b are each independently selected from the group consisting of hydrogen and halogen; and Rs_b is selected from the group consisting of an optionally substituted C_1-6 alkyl and halogen.

17. The method of any of Claims 13 to 16, wherein R₂b, R₃b, R4b, Rόb, and R% are each hydrogen.

18. A method of treating a neuropsychiatric disorder comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1 - 5 or a composition of claim 6.

19. The method of Claim 18, wherein the neuropsychiatry disorder is selected from the group consisting of schizophrenia, schizophrenia related idiopathic psychosis, cognitive enhancement in schizophrenia, anxiety, sleep disorders, appetite disorders, affective disorders, drug-induced psychosis, cognitive impairment, and psychosis secondary to neurodegenerative disorders.

20. The method of Claim 19,

wherein:

the affective disorders are selected from the list consisting of major depression, bipolar disorder, depression with psychotic features, and Tourette's Syndrome; and

the psychosis secondary to neurodegenerative disorders are selected from the list consisting of Alzheimer' s disease and Huntington's Disease.

21. The compound of any one of claims 1 - 5 or a composition of claim 6 for treating a neuropsychiatric disorder.

22. The compound of any one of claims 1 - 5 or a composition of claim 6, wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, schizophrenia related idiopathic psychosis, cognitive enhancement in schizophrenia, anxiety, sleep disorders, appetite disorders, affective disorders, drug-induced psychosis, cognitive impairment, and psychosis secondary to neurodegenerative disorders.

23. The compound of any one of claims 1 - 5 or a composition of claim 6,

wherein:

the affective disorders are selected from the list consisting of major depression, bipolar disorder, depression with psychotic features, and Tourette's Syndrome; and

the psychosis secondary to neurodegenerative disorders are selected from the list consisting of Alzheimer' s disease and Huntington's Disease..