This disclosure is directed to pyrido[4,3-b]indoles having rigid moieties. The compounds in one embodiment are pyrido[4,3-b]indoles having an unsaturated hydrocarbon moiety. The compounds in another embodiment are pyrido[4,3-b]indoles having a cycloalkyl, cycloalkenyl or heterocyclyl moiety. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

Description

215 parts

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 61/110,519 filed Oct. 31, 2008, U.S. Provisional Patent Application No. 61/173,960 filed Apr. 29, 2009 and U.S. Provisional Patent Application No. 61/245,150 filed Sep. 23, 2009, the disclosures of each of which are hereby incorporated herein by reference in their entireties.

›STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH

Not applicable.

›BACKGROUND OF THE INVENTION

Neurotransmitters such as histamine, serotonin, dopamine and norepinephrine mediate a large number of processes in the central nervous system (CNS) as well as outside the CNS. Abnormal neurotransmitter levels are associated with a wide variety of diseases and conditions including, but not limited to, Alzheimer's disease, Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitive impairment, schizophrenia (such as cognitive impairment associated with schizophrenia (CIAS), positive symptoms, disorganized symptoms, and negative symptoms of schizophrenia), anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis, depression, attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD) and a variety of allergic diseases. Compounds that modulate these neurotransmitters may be useful therapeutics.

Histamine receptors belong to the superfamily of G protein-coupled seven transmembrane proteins. G protein-coupled receptors constitute one of the major signal transduction systems in eukaryotic cells. Coding sequences for these receptors, in those regions believed to contribute to the agonist-antagonist binding site, are strongly conserved across mammalian species. Histamine receptors are found in most peripheral tissue and within the central nervous system. Compounds capable of modulating a histamine receptor may find use in therapy, e.g., histamine antagonists may find use as antihistamines.

Dimebon is a known anti-histamine drug that has also been characterized as a neuroprotective agent useful to treat, inter alia, neurodegenerative diseases. Dimebon has been shown to inhibit the death of brain cells (neurons) in preclinical models of Alzheimer's disease and Huntington's disease, making it a novel potential treatment for these and other neurodegenerative diseases. In addition, dimebon has been shown to improve the mitochondrial function of cells in the setting of cellular stress with very high potency. For example, dimebon treatment improved mitochondrial function and increased the number of surviving cells after treatment with the cell toxin ionomycin in a dose dependent fashion. Dimebon has also been shown to promote neurite outgrowth and neurogenesis, processes important in the formation of new and/or enhanced neuronal cell connections, and evidence of dimebon's potential for use in additional diseases or conditions. See, e.g., U.S. Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos. PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077, PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645, PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626, PCT/US2008/009357, PCT/US2007/024623 and PCT/US2008/008121. Hydrogenated pyrido[4,3-b]indoles and uses thereof have been disclosed in PCT Patent Application Nos. PCT/US2008/081390, PCT/US2009/032065 and PCT/US2009/038142. Hydrogenated pyrido[3,4-b]indoles and uses thereof have been described in PCT/US2009/038138. All references disclosed herein and throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.

Although dimebon holds great promise as a drug for the treatment of neurodegenerative diseases and/or diseases in which neurite outgrowth and/or neurogenesis may be implicated in therapy, there remains a need for new and alternative therapies for the treatment of such diseases or conditions. In addition, there remains a need for new and alternative antihistamine drugs, preferably ones in which side-effects such as drowsiness are reduced or eliminated. Compounds that exhibit enhanced and/or more desirable properties than dimebon (e.g., superior safety and efficacy) may find particular use in the treatment of at least those indications for which dimebon is believed to be advantageous. Further, compounds that exhibit a different therapeutic profile than dimebon as determined, e.g. by in vitro and/or in vivo assays, may find use in additional diseases and conditions.

›BRIEF SUMMARY OF THE INVENTION · 1 of 6

Numerous compounds have been synthesized and tested in biochemical and cell-based assays as well as in in vivo studies.

Tetrahydropyrido[4,3-b]indoles are provided. Compositions and kits comprising the compounds are also provided, as are methods of using and making the compounds. The compounds provided herein may find use as new histamine receptor modulators, as well as modulators of other neurotransmitters. Compounds provided may also find use in treating neurodegenerative diseases. Compounds provided may also find use in treating diseases and/or conditions in which modulation of aminergic G protein-coupled receptors and/or neurite outgrowth may be implicated in therapy. Compounds disclosed herein may find use in the methods disclosed herein, including use in treating, preventing, delaying the onset and/or delaying the development of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder in an individual in need thereof, such as humans.

In one aspect, the invention embraces compounds of the formula (V):

or a salt or solvate thereof;

wherein:

R 1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

each R 8a , R 8b , R 8c and R 8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with a geminal R 8 to form a moiety of the formula —OCH 2 CH 2 O—, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety;

each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;

each R 11 and R 12 is independently is H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carboxy, or carbonylalkoxy and the bond indicates the presence of either an E or Z double bond configuration; or R 11 and R 12 are taken together to form a bond; and

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, alkoxy, acyloxy, substituted or unsubstituted amino, aminoacyl, aminocarbonylalkoxy, cyano, alkynyl, carboxy, carbonylalkoxy or acylamino.

›BRIEF SUMMARY OF THE INVENTION · 2 of 6

In another aspect, the invention embraces compounds of the formula (II):

or a salt or solvate thereof;

wherein:

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

each R 8a , R 8b , R 8c and R 8d is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with a geminal R 8 to form a moiety of the formula —OCH 2 CH 2 O—, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety;

each R 11a and R 12a is independently H, hydroxyl, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carboxy, or carbonylalkoxy; or R 11a and R 12a may be taken together to represent a bond;

R 11b and R 12b are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety; and

In one variation, the compound is of the formula (VII) where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, q, m, R 8a , R 8b , R 8c , R 8d , R 11a , R 11b , R 12a and R 12b are as defined for formula (VII). In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (VII), including 2-(1,2,3,4-tetrahydro-2,8-dimethyl-5H-pyrido[4,3-b]indol-5-yl)cyclohexanol.

In one variation, compounds of the formula (VII) are provided, where X 7 , X 8 , X 9 , X 10 , R 1 , R 11b , R 12b , q, m, and Q are as defined for formula (VII), each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety; each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety; each R 8a , R 8b , R 8c and R 8d is independently H, hydroxyl, C 1 -C 8 alkyl, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety; each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl moiety; and each R 11a and R 12a is independently H, hydroxyl, or C 1 -C 8 alkyl; or R 11a and R 12a are taken together to represent a bond.

The invention also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms and geometric isomers of the compounds described, or mixtures thereof. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers, including geometric isomers, of a compound depicted. Unless olefin geometry is explicitly indicated, substituted olefinic bonds may be present as cis or trans or (Z) or (E) isomeric forms, or as mixtures thereof. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. For example, where only a Z form of a compound is specifically listed, it is understood that the E form of the compound is also embraced. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form, including a specific geometric isomer, thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantio-enriched and scalemic mixtures of a compound are embraced, or mixtures thereof.

›BRIEF SUMMARY OF THE INVENTION · 3 of 6

The invention is also directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. Kits comprising a compound of the invention and instructions for use are also embraced by this invention.

In one aspect, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of any one or more of the following: cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders in individuals in need thereof, such as humans. In one variation, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of diseases or conditions for which the modulation of an aminergic G protein-coupled receptor is believed to be or is beneficial. In one variation, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of any one or more of diseases or conditions for which neurite outgrowth and/or neurogenesis and/or neurotrophic effects are believed to be or are beneficial. In another variation, compounds of the invention are used to treat, prevent, delay the onset and/or delay the development of diseases or conditions for which the modulation of an aminergic G protein-coupled receptor and neurite outgrowth and/or neurogenesis and/or neurotrophic effects are believed to be or are beneficial. In one variation, the disease or condition is a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

In another aspect, compounds of the invention are used to improve cognitive function and/or reduce psychotic effects in an individual, comprising administering to an individual in need thereof an amount of a compound described herein or a pharmaceutically acceptable salt thereof effective to improve cognitive function and/or reduce psychotic effects.

In a further aspect, compounds of the invention are used to stimulate neurite outgrowth and/or promote neurogenesis and/or enhance neurotrophic effects in an individual comprising administering to an individual in need thereof an amount of a compound described herein or a pharmaceutically acceptable salt thereof effective to stimulate neurite outgrowth and/or to promote neurogenesis and/or to enhance neurotrophic effects. Synapse loss is associated with a variety of neurodegenerative diseases and conditions including Alzheimer's disease, schizophrenia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, head trauma and spinal cord injury. Compounds of the invention that stimulate neurite outgrowth may have a benefit in these settings.

In another aspect, compounds described herein are used to modulate an aminergic G protein-coupled receptor comprising administering to an individual in need thereof an amount of a compound described herein or a pharmaceutically acceptable salt thereof effective to modulate an aminergic G protein-coupled receptor. In one variation, a compound of the invention modulates at least one of the following receptors: adrenergic receptor (e.g., α 1D , α 2A and/or α 2B ), serotonin receptor (e.g., 5-HT 2A , 5-HT 2C , 5-HT 6 and/or 5-HT 7 ), dopamine receptor (e.g., D 2L ) and histamine receptor (e.g., H 1 , H 2 and/or H 3 ). In another variation, at least two of the following receptors are modulated: adrenergic receptor (e.g., α 1D , α 2A and/or α 2B ), serotonin receptor (e.g., 5-HT 2A , 5-HT 2C , 5-HT 6 and/or 5-HT 7 ), dopamine receptor (e.g., D 2L ) and histamine receptor (e.g., H 1 , H 2 and/or H 3 ). In another variation, at least three of the following receptors are modulated: adrenergic receptor (e.g., α 1D , α 2A and/or α 2B ), serotonin receptor (e.g., 5-HT 2A , 5-HT 2C , 5-HT 6 and/or 5-HT 7 ), dopamine receptor (e.g., D 2L ) and histamine receptor (e.g., H 1 , H 2 and/or H 3 ). In another variation, each of the following receptors is modulated: adrenergic receptor (e.g., α 1D , α 2A and/or α 2B ), serotonin receptor (e.g., 5-HT 2A , 5-HT 2C , 5-HT 6 and/or 5-HT 7 ), dopamine receptor (e.g., D 2L ) and histamine receptor (e.g., H 1 , H 2 and/or H 3 ). In another variation, at least one of the following receptors is modulated: α 1D , α 2A and/or α 2B , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 , D 2L , H 1 , H 2 and H 3 . In another variation, at least one of the following receptors is modulated: α 1D , α 2A and/or α 2B , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 , D 2 , H 1 , H 2 and H 3 . In another variation, at least two or three or four or five or six or seven or eight or nine or ten or eleven of the following receptors are modulated: α 1D , α 2A and/or α 2B , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 , D 2L , H 1 , H 2 and H 3 . In another variation, at least two or three or four or five or six or seven or eight or nine or ten or eleven of the following receptors are modulated: α 1D , α 2A and/or α 2B , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 , D 2 , H 1 , H 2 and H 3 . In a particular variation, at least dopamine receptor D 2 is modulated. In still another variation, at least dopamine receptor D 2L is modulated. In another particular variation, at least dopamine receptor D 2 and serotonin receptor 5-HT 2A are modulated. In another particular variation, at least dopamine receptor D 2L and serotonin receptor 5-HT 2A are modulated. In a further particular variation, at least adrenergic receptors α 1D , α 2A , α 2B and serotonin receptor 5-HT 6 are modulated. In another particular variation, at least adrenergic receptors α 1D , α 2A , α 2B , serotonin receptor 5-HT 6 and one or more of serotonin receptor 5-HT 7 , 5-HT 2A , 5-HT 2C and histamine receptor H 1 and H 2 are modulated. In a further particular variation, histamine receptor H 1 is modulated. In another variation, compounds of the invention exhibit any receptor modulation activity detailed herein and further stimulate neurite outgrowth and/or neurogenesis and/or enhance neurotrophic effects. In one variation, compounds detailed herein inhibit binding of a ligand to histamine receptor H 1 and/or H 2 by less than about 80% as determined by a suitable assay known in the art such as the assays described herein. In another variation, binding of a ligand to histamine receptor H 1 and/or H 2 is inhibited by less than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined by a suitable assay known in the art such as the assays described herein. In a further variation, compounds detailed herein: (a) inhibit binding of a ligand to histamine receptor H 1 and/or H 2 by less than about 80% (which can in different variations be less than about any of 75%, 70%, 65%, 60%, 55%, or 50%) as determined by a suitable assay known in the art such as the assays described herein and (b) inhibit binding of a ligand to dopamine receptor D 2L by greater than about any of 80%, 85%, 90%, 95%, 100% or between about 85% and about 95% or between about 90% and about 100%, as determined in a suitable assay known in the art such as the assays described herein. In a further variation, compounds detailed herein: (a) inhibit binding of a ligand to histamine receptor H 1 and/or H 2 by less than about 80% (which can in different variations be less than about any of 75%, 70%, 65%, 60%, 55%, or 50%) as determined by a suitable assay known in the art such as the assays described herein and (b) inhibit binding of a ligand to a dopamine receptor D 2 by greater than about any of 80%, 85%, 90%, 95%, 100% or between about 85% and about 95% or between about 90% and about 100%, as determined in a suitable assay known in the art such as the assays described herein.

›BRIEF SUMMARY OF THE INVENTION · 4 of 6

A compound of the formula (V) is provided:

or a salt or solvate thereof;

wherein:

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

each R 11 and R 12 is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carboxy, or carbonylalkoxy and the bond indicates the presence of either an E or Z double bond configuration, or R 11 and R 12 are taken together to form a bond; and

provided that when X 7 , X 8 and X 10 are each CH and each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is hydrogen, at least one of R 11 and R 12 is other than hydrogen and R 11 and R 12 are not taken together to form a bond. In one aspect, m is 0 and q is 0. In another aspect, X 7 , X 8 , X 9 and X 10 are CH or CR 4 . In a further aspect, at least one of X 7 , X 8 , X 9 and X 10 is N. In one variation, two of X 7 , X 8 , X 9 and X 10 are N. In another variation, at least one of X 7 , X 8 , X 9 and X 10 is CR 4 , such as when each R 4 is independently halo, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted aryl. Q in one aspect is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In another aspect, R 11 is H or C 1 -C 4 alkyl and R 12 is independently H, C 1 -C 4 alkyl or C 1 -C 4 perhaloalkyl.

Compound of formulae (1-b1) and (1-b2) are also provided:

or a salt or solvate thereof.

Compounds of the formula (VII) are also provided:

or a salt or solvate thereof;

wherein:

›BRIEF SUMMARY OF THE INVENTION · 5 of 6

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

each R 11a and R 12a is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxy, or carbonylalkoxy; or R 11a and R 12a are taken together to represent a bond;

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, alkoxy, acyloxy, substituted or unsubstituted amino, aminoacyl, aminocarbonylalkoxy, cyano, alkynyl, carboxy, carbonylalkoxy or acylamino.

Where applicable, in one aspect compounds of the formulae are provided where any one or more of the following apply: (i) m is 0 and q is 0; (ii) X 7 , X 8 , X 9 and X 10 are CH or CR 4 ; (iii) at least one of X 7 , X 8 , X 9 and X 10 is N; (iv) two of X 7 , X 8 , X 9 and X 10 are N; (v) at least one of X 7 , X 8 , X 9 and X 10 is CR 4 ; (vi) each R 4 is independently halo, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted aryl; (vii) Q is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group; (viii) each R 11a and R 12a is independently H, C 1 -C 4 alkyl, or C 1 -C 4 perhaloalkyl; (ix) R 11b and R 12b are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring; (x) R 11b and R 12b are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl ring; (xi) R 11b and R 12b are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl ring; (xi) R 11a and R 12a are taken together to form a bond.

Compounds of the formula (I-E) are also provided:

wherein:

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each R 4 is independently hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, aryloxy, carboxyl, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino or a salt or solvate thereof. In one aspect, X 7 , X 8 and X 10 are each CH and X 9 is CR 4 . In another aspect, X 7 , X 8 and X 10 are each CH and X 9 is CR 4 where R 4 is unsubstituted C 1 -C 8 alkyl, halo, C 1 -C 8 perhaloalkyl, or substituted or unsubstituted amino. In a further aspect, R 4 is CF 3 , CH 3 , F or Cl. In an additional aspect, R 1 is substituted or unsubstituted C 1 -C 8 alkyl, or perhaloalkyl. In one variation, R 1 is methyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or 3-hydroxy-3-methyl-but-1-yl. In another variation, Q is substituted aryl or substituted or unsubstituted heteroaryl. In one aspect, Q is substituted phenyl, or substituted or unsubstituted pyridyl, or pyrimidyl. In another aspect, Q is 4-fluorophenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methylcarbamoyl, 4-dimethylcarbamoyl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin-3-yl, 6-trifluoromethylpyridin-3-yl, or pyrimidin-4-yl. In a further aspect, the bond indicates the presence of an E double bond. In one variation, the bond indicates the presence of an Z double bond.

›BRIEF SUMMARY OF THE INVENTION · 6 of 6

Compounds of the formula (J-1) are provided:

wherein; R 1 is methyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or 3-hydroxy-3-methyl-but-1-yl; R 4 is CF 3 , CH 3 , F or Cl; R 12 is halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy; and Q is 4-fluorophenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methylcarbamoyl, 4-dimethylcarbamoyl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin-3-yl, 6-trifluoromethylpyridin-3-yl, or pyrimidin-4-yl; or a salt or solvate thereof. Method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual are provided, comprising administering to an individual in need thereof an effective amount of compound as detailed herein, or a pharmaceutically acceptable salt thereof. Methods of modulating a histamine receptor in an individual are also provided comprising administering to an individual in need thereof a compound as detailed herein, or a pharmaceutically acceptable salt thereof. Use of a compound as detailed herein in the manufacture of a medicament for the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder are also provided. A kit comprising a compound as detailed herein, or a pharmaceutically acceptable salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder are provided. Methods of treating a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition are provided, comprising administering to an individual in need thereof a low dose of a compound as detailed herein, or a pharmaceutically acceptable salt thereof. Method of treating (i) a psychotic disorder, (ii) a psychotic disorder in an individual who is also in need of improved cognition or (iii) a disorder characterized by causing at least one psychotic symptom and at least one symptom associated with impaired cognition are also embraced, comprising administering to an individual in need thereof a high dose of a compound as here detailed, or a pharmaceutically acceptable salt thereof. Use of a low dose of a compound as provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition is detailed herein. Also provided is use of a high dose of a compound as detailed herein, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a (i) psychotic disorder, (ii) a psychotic disorder in an individual who is also in need of improved cognition or (iii) a disorder characterized by causing at least one psychotic symptom and at least one symptom associated with impaired cognition. A kit comprising a low dose of a compound as provided herein, or a pharmaceutically acceptable salt thereof, and instructions for achieving a procognitive effect in the treatment of a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition are also provided. A kit comprising a high dose of a compound as detailed herein, or a pharmaceutically acceptable salt thereof, and instructions for achieving (i) a procognitive effect in the treatment of a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition and (ii) an antipsychotic effect in the treatment of a psychotic disorder; a psychotic disorder in an individual who is also in need of improved cognition or a disorder characterized by causing at least one psychotic symptom and at least one symptom associated with impaired cognition is also embraced.

›BRIEF DESCRIPTION OF THE FIGURES · 1 of 2

FIG. 1 is a graph of Total Distance Traveled (cm/5 min) vurses Time (min) pre- and post-injection, showing the results of Compound 88 (0.03, 0.1, 0.3, 1, 3, 10 and 30 mg/kg) and clozapine in a PCP Hyperactivity Mouse Model of Schizophrenia. Total distance traveled in the OF during the 90 minute test period are shown, with data presented as mean±SEM

FIG. 2 is a graph of Total Distance Traveled (cm/5 min) vurses Time (min) pre- and post-injection, showing the results of Compound 90 (0.03, 0.1, 0.3, 1, 3, 10 and 30 mg/kg) and clozapine in a PCP Hyperactivity Mouse Model of Schizophrenia. Total distance traveled in the OF during the 90 minute test period are shown, with data presented as mean±SEM

FIGS. 3A and 3B are graphs of time (in seconds) of object exploration during T2 for single administion of vehicle (p.o.), Compound 88 (0.03, 0.1, 0.3, 1, 3 and 10 mg/kg, p.o) or donepezil (1 mg/kg, i.p.) in a situation of natural forgetting in the rat object recognition model. All treatments were administered 30 minutes before T1. Time spent by rats exploring the novel and familiar objects during T2 is expressed as mean±SEM. In the figure, n is the number of rats per group; # is p<0.05; ## is p<0.01 and ### is p<0.001 versus novel object and ** is p<0.01 and *** is p<0.001 versus vehicle group.

FIGS. 4A and 4B are graphs of time (in seconds) of object exploration during T2 for single administion of vehicle (p.o.), Compound 90, or donepezil (1 mg/kg, i.p.) in a situation of natural forgetting in the rat object recognition model. FIG. 4A contains data for Compound 90 at doses 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg, p.o. FIG. 4B contains data for Compound 90 at doses 0.03, 0.1, 0.3, 1 and 3 mg/kg, p.o. All treatments were administered 30 minutes before T1. Time spent by rats exploring the novel and familiar objects during T2 is expressed as mean±SEM. In the figure, n is the number of rats per group; # is p<0.05; ## is p<0.01 and ### is p<0.001 versus novel object and * is p<0.01 and ** is p<0.001 versus vehicle group.

FIG. 5 is a graph of interaction time (seconds) for vehicle, clozapine and Compound 88 in a subchronic PCP-induced Social Interaction Deficit model, showing the effect of Compound 88 on PCP-induced disruption of social interaction. Data represent mean±SEM. In the figure, * is significantly different from PCP-vehicle, p<0.05.

FIG. 6 is a graph of interaction time (seconds) for vehicle, clozapine and Compound 90 in a subchronic PCP-induced Social Interaction Deficit model, showing the effect of Compound 90 on PCP-induced disruption of social interaction. Data represent mean±SEM. In the figure, * is significantly different from PCP-vehicle, p<0.05.

FIG. 7 is a graph of time spent holding the bar (seconds) at three time points (30 minutes, 1 hour and 3 hours) after administration of vehicle, haloperidol or Compound 88 (0.03, 0.1, 0.3, 1, 3, 10 and 30 mg/kg) in an extrapyramidal Syndrome (EPS) model catalepsy Test. The time the mice spent holding bar was averaged over the 3 trials at each time point. Data represent mean±SEM.

FIG. 8 is a graph of time spent holding the bar (seconds) at three time points (30 minutes, 1 hour and 3 hours) after administration of vehicle, haloperidol or Compound 90 (0.03, 0.1, 0.3, 1, 3, 10 and 30 mg/kg) in an extrapyramidal Syndrome (EPS) model catalepsy Test. The time the mice spent holding bar was averaged over the 3 trials at each time point. Data represent mean±SEM.

FIG. 9 is a graph depicting avoidance (% versus pretest) versus dose (mg/kg, p.o.) for compounds 83, 90 and 88 in a conditioned avoidance response model.

FIGS. 10A and 10B are graphs of Total Distance Traveled (cm/5 min) vurses Time (min) pre- and post-injection, showing the results of Compound 83 and clozapine in a PCP Hyperactivity Mouse Model of Schizophrenia. FIG. 10A depicts data for Compound 83 at doses 0.1, 0.3, 1, 3 and 10 mg/kg. FIG. 10B depicts data for Compound 83 at doses 0.1, 0.3, 1, 2 and 3 mg/kg. Total distance traveled in the OF during the 90 minute test period are shown, with data presented as mean±SEM.

FIGS. 11A , 11 B, 11 C and 11 D are graphs of total rearing pre- and post-injection versus treatment, showing the results of Compound 83 in a PCP Hyperactivity Mouse Model of Schizophrenia. Figure A depicts baseline rearing (prior to PCP) and Figure B depicts rearing post-PCP for Compound 83 at doses 0.1, 0.3, 1, 3 and 10 mg/kg. Figure C depicts baseline rearing (prior to PCP) and Figure D depicts rearing post-PCP for Compound 83 at doses 0.1, 0.3, 1, 2 and 3 mg/kg.

FIG. 12 is a graph of Total Distance Traveled (cm/5 min) vurses Time (min), showing the effect of Compound 83 (0.1, 0.3, 1, 3 and 10 mg/kg) in an amphetamine hyperactivity mouse model of schizophrenia.

FIGS. 13A and 13B are graphs of total rearing pre- and post-injection versus treatment, showing the results of Compound 83 in an amphetamine hyperactivity mouse model of schizophrenia. Figure A depicts baseline rearing (prior to amphetamine) and Figure B depicts rearing post-amphetamine for Compound 83 at doses 0.1, 0.3, 1, 3 and 10 mg/kg.

FIG. 14 is a graph of number of processes against treatment, showing the effect of Compound 83 (0.5, 5 and 50 nM), BDNF (50 ng/mL) and NGF (75 ng/mL) on neurite outgrowth in mixed cortical cultures. Results are depicted as mean+SD. In the figure, * is p<0.05, ** is p<0.01 and *** is p<0.001.

FIG. 15 is a graph of time spent holding the bar (seconds) at three time points (30 minutes, 1 hour and 3 hours) after administration of vehicle, haloperidol or Compound 83 (0.03, 0.1, 0.3, 1, 3, 10 and 30 mg/kg) in an extrapyramidal Syndrome (EPS) model catalepsy Test. The time the mice spent holding bar was averaged over the 3 trials at each time point. Data represent mean±SEM.

FIG. 16 is a graph of number of avoidance responses pre- and post-treatment, showing the number of avoidance responses observed before and after administration of vehicle (p.o.), Compound 83 (0.1, 0.3, 1, 3, 10 and 20 mg/kg, p.o.) or risperidone (0.3 mg/kg, s.c.) in a conditioned avoidance response test in the rat. Results are presented as mean±SEM with 12 animals per group. In the figure, ** is p<0.01 and *** is p<0.001 versus pre-treatment.

›BRIEF DESCRIPTION OF THE FIGURES · 2 of 2

FIG. 17 is a graph of number of avoidance responses pre- and post-treatment, showing the number of avoidance responses observed before and after administration of vehicle (p.o.), Compound 88 (0.3, 1, 3, 6 and 10 mg/kg, p.o.) or risperidone (0.3 mg/kg, s.c.) in a conditioned avoidance response test in the rat. Results are presented as mean±SEM with 12 animals per group. In the figure, * is p<0.05, ** is p<0.01 and *** is p<0.001 versus pre-treatment.

FIG. 18 is a graph of number of avoidance responses pre- and post-treatment, showing the number of avoidance responses observed before and after administration of vehicle (p.o.), Compound 90 (0.3, 1, 2, 3 and 10 mg/kg, p.o.) or risperidone (0.3 mg/kg, s.c.) in a conditioned avoidance response test in the rat. Results are presented as mean±SEM with 11 animals per group. In the figure, ** is p<0.01 versus pre-treatment.

DETAILED DESCRIPTION OF THE INVENTION

›Definitions · 1 of 48

For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.

As used herein, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

As used herein, the term “aminergic G protein-coupled receptors” refers to a family of transmembrane proteins involved in cellular communication. Aminergic G protein coupled receptors are activated by biogenic amines and represent a subclass of the superfamily of G protein coupled receptors, which are structurally characterized by seven transmembrane helices. Aminergic G protein-coupled receptors include but are not limited to adrenergic receptors, serotonin receptors, dopamine receptors, histamine receptors and imidazoline receptors.

As used herein, the term “adrenergic receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to an adrenergic receptor or reduces or eliminates or increases or enhances or mimics an activity of an adrenergic receptor. As such, an “adrenergic receptor modulator” encompasses both an adrenergic receptor antagonist and an adrenergic receptor agonist. In some aspects, the adrenergic receptor modulator binds to or inhibits binding to a ligand to an α1-adrenergic receptor (e.g., α 1A , α 1B and/or α 1D ) and/or a α 2 -adrenergic receptor (e.g., α 2A , α 2B and/or α 2C ) and/or reduces or eliminates or increases or enhances or mimics an activity of a α 1 -adrenergic receptor (e.g., α 1A , α 1B and/or α 1D ) and/or a α 2 -adrenergic receptor (e.g., α 2A , α 2B and/or α 2C ) in a reversible or irreversible manner. In some aspects, the adrenergic receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some aspects, the adrenergic receptor modulator reduces an activity of an adrenergic receptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the adrenergic receptor modulator or compared to the corresponding activity in other subjects not receiving the adrenergic receptor modulator. In some aspects, the adrenergic receptor modulator enhances an activity of an adrenergic receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the adrenergic receptor modulator or compared to the corresponding activity in other subjects not receiving the adrenergic receptor modulator. In some aspects, the adrenergic receptor modulator is capable of binding to the active site of an adrenergic receptor (e.g., a binding site for a ligand). In some embodiments, the adrenergic receptor modulator is capable of binding to an allosteric site of an adrenergic receptor.

As used herein, the term “dopamine receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a dopamine receptor or reduces or eliminates or increases or enhances or mimics an activity of a dopamine receptor. As such, a “dopamine receptor modulator” encompasses both a dopamine receptor antagonist and a dopamine receptor agonist. In some aspects, the dopamine receptor modulator binds to or inhibits binding of a ligand to a dopamine-1 (D 1 ) and/or a dopamine-2 (D 2 ) receptor or reduces or eliminates or increases or enhances or mimics an activity of a dopamine-1 (D 1 ) and/or a dopamine-2 (D 2 ) receptor in a reversible or irreversible manner. Dopamine D 2 receptors are divided into two categories, D 2L and D 2S , which are formed from a single gene by differential splicing. D 2L receptors have a longer intracellular domain than D 2S . In some embodiments, the dopamine receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the dopamine receptor modulator reduces an activity of a dopamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the dopamine receptor modulator or compared to the corresponding activity in other subjects not receiving the dopamine receptor modulator. In some embodiments, the dopamine receptor modulator enhances an activity of a dopamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the dopamine receptor modulator or compared to the corresponding activity in other subjects not receiving the dopamine receptor modulator. In some embodiments, the dopamine receptor modulator is capable of binding to the active site of a dopamine receptor (e.g., a binding site for a ligand). In some embodiments, the dopamine receptor modulator is capable of binding to an allosteric site of a dopamine receptor.

As used herein, the term “serotonin receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a serotonin receptor or reduces or eliminates or increases or enhances or mimics an activity of a serotonin receptor. As such, a “serotonin receptor modulator” encompasses both a serotonin receptor antagonist and a serotonin receptor agonist. In some embodiments, the serotonin receptor modulator binds to or inhibits binding of a ligand to a 5-HT 1A and/or a 5-HT 1B and/or a 5-HT 2A and/or a 5-HT 2B and/or a 5-HT 2C and/or a 5-HT 3 and/or a 5-HT 4 and/or a 5-HT 6 and/or a 5-HT 7 receptor or reduces or eliminates or increases or enhances or mimics an activity of a 5-HT 1A and/or a 5-HT 1B and/or a 5-HT 2A and/or a 5-HT 2B and/or a 5-HT 2C and/or a 5-HT 3 and/or a 5-HT 4 and/or a 5-HT 6 and/or a 5-HT 7 receptor in a reversible or irreversible manner. In some embodiments, the serotonin receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the serotonin receptor modulator reduces an activity of a serotonin receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the serotonin receptor modulator or compared to the corresponding activity in other subjects not receiving the serotonin receptor modulator. In some embodiments, the serotonin receptor modulator enhances an activity of a serotonin receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the serotonin receptor modulator or compared to the corresponding activity in other subjects not receiving the serotonin receptor modulator. In some embodiments, the serotonin receptor modulator is capable of binding to the active site of a serotonin receptor (e.g., a binding site for a ligand). In some embodiments, the serotonin receptor modulator is capable of binding to an allosteric site of a serotonin receptor.

›Definitions · 2 of 48

As used herein, the term “histamine receptor modulator” intends and encompasses a compound that binds to or inhibits binding of a ligand to a histamine receptor or reduces or eliminates or increases or enhances or mimics an activity of a histamine receptor. As such, a “histamine receptor modulator” encompasses both a histamine receptor antagonist and a histamine receptor agonist. In some embodiments, the histamine receptor modulator binds to or inhibits binding of a ligand to a histamine H 1 and/or H 2 and/or H 3 receptor or reduces or eliminates or increases or enhances or mimics an activity of a histamine H 1 and/or H 2 and/or H 3 receptor in a reversible or irreversible manner. In some embodiments, the histamine receptor modulator inhibits binding of a ligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assays described herein. In some embodiments, the histamine receptor modulator reduces an activity of a histamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to the corresponding activity in the same subject prior to treatment with the histamine receptor modulator or compared to the corresponding activity in other subjects not receiving the histamine receptor modulator. In some embodiments, the histamine receptor modulator enhances an activity of a histamine receptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more as compared to the corresponding activity in the same subject prior to treatment with the histamine receptor modulator or compared to the corresponding activity in other subjects not receiving the histamine receptor modulator. In some embodiments, the histamine receptor modulator is capable of binding to the active site of a histamine receptor (e.g., a binding site for a ligand). In some embodiments, the histamine receptor modulator is capable of binding to an allosteric site of a histamine receptor.

Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a human, bovine, primate, equine, canine, feline, porcine, and ovine animals. Thus, the invention finds use in both human medicine and in the veterinary context, including use in agricultural animals and domestic pets. The individual may be a human who has been diagnosed with or is suspected of having a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. The individual may be a human who exhibits one or more symptoms associated with a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. The individual may be a human who has a mutated or abnormal gene associated with a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. The individual may be a human who is genetically or otherwise predisposed to developing a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder.

As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, such as a clinical result. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In one variation, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. Preferably, treatment of a disease or condition with a compound of the invention or a pharmaceutically acceptable salt thereof is accompanied by no or fewer side effects than are associated with currently available therapies for the disease or condition and/or improves the quality of life of the individual.

As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. For example, a method that “delays” development of Alzheimer's disease is a method that reduces probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. For example, Alzheimer's disease development can be detected using standard clinical techniques, such as routine neurological examination, patient interview, neuroimaging, detecting alterations of levels of specific proteins in the serum or cerebrospinal fluid (e.g., amyloid peptides and Tau), computerized tomography (CT) or magnetic resonance imaging (MRI). Similar techniques are known in the art for other diseases and conditions. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at risk of developing a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder that can be treated with a compound of the invention. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s). These risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (i.e., hereditary) considerations, and environmental exposure. For example, individuals at risk for Alzheimer's disease include, e.g., those having relatives who have experienced this disease and those whose risk is determined by analysis of genetic or biochemical markers. Genetic markers of risk for Alzheimer's disease include mutations in the APP gene, particularly mutations at position 717 and positions 670 and 671 referred to as the Hardy and Swedish mutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Other markers of risk are mutations in the presenilin genes (e.g., PS1 or PS2), ApoE4 alleles, a family history of Alzheimer's disease, hypercholesterolemia and/or atherosclerosis. Other such factors are known in the art for other diseases and conditions.

›Definitions · 3 of 48

As used herein, the term “pro-cognitive” includes but is not limited to an improvement of one or more mental processes such as memory, attention, perception and/or thinking, which may be assessed by methods known in the art.

As used herein, the term “neurotrophic” effects includes but is not limited to effects that enhance neuron function such as growth, survival and/or neurotransmitter synthesis.

As used herein, the term “cognitive disorders” refers to and intends diseases and conditions that are believed to involve or be associated with or do involve or are associated with progressive loss of structure and/or function of neurons, including death of neurons, and where a central feature of the disorder may be the impairment of cognition (e.g., memory, attention, perception and/or thinking). These disorders include pathogen-induced cognitive dysfunction, e.g. HIV associated cognitive dysfunction and Lyme disease associated cognitive dysfunction. Examples of cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age-associated memory impairment (AAMI).

As used herein, the term “psychotic disorders” refers to and intends mental diseases or conditions that are believed to cause or do cause abnormal thinking and perceptions. Psychotic disorders are characterized by a loss of reality which may be accompanied by delusions, hallucinations (perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space), personality changes and/or disorganized thinking. Other common symptoms include unusual or bizarre behavior, as well as difficulty with social interaction and impairment in carrying out the activities of daily living. Exemplary psychotic disorders are schizophrenia, bipolar disorders, psychosis, anxiety and depression.

As used herein, the term “neurotransmitter-mediated disorders” refers to and intends diseases or conditions that are believed to involve or be associated with or do involve or are associated with abnormal levels of neurotransmitters such as histamine, serotonin, dopamine, norepinephrine or impaired function of aminergic G protein-coupled receptors. Exemplary neurotransmitter-mediated disorders include spinal cord injury, diabetic neuropathy, allergic diseases and diseases involving geroprotective activity such as age-associated hair loss (alopecia), age-associated weight loss and age-associated vision disturbances (cataracts). Abnormal neurotransmitter levels are associated with a wide variety of diseases and conditions including, but not limited, to Alzheimer's disease, Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitive impairment, schizophrenia, anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis, depression and a variety of allergic diseases.

As used herein, the term “neuronal disorders” refers to and intends diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with neuronal cell death and/or impaired neuronal function or decreased neuronal function. Exemplary neuronal indications include neurodegenerative diseases and disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), post-concussion syndrome, post-traumatic stress disorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration, autism, including autism spectrum disorder, Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy, fibromyalgia, neuropathy associated with spinal cord injury, schizophrenia, bipolar disorder, psychosis, anxiety or depression.

As used herein, the term “neuron” represents a cell of ectodermal embryonic origin derived from any part of the nervous system of an animal. Neurons express well-characterized neuron-specific markers, including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2, and class III tubulin. Included as neurons are, for example, hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory, sympathetic, septal cholinergic, and cerebellar neurons.

As used herein, the term “neurite outgrowth” or “neurite activation” refers to the extension of existing neuronal processes (e.g., axons and dendrites) and the growth or sprouting of new neuronal processes (e.g., axons and dendrites). Neurite outgrowth or neurite activation may alter neural connectivity, resulting in the establishment of new synapses or the remodeling of existing synapses.

As used herein, the term “neurogenesis” refers to the generation of new nerve cells from undifferentiated neuronal progenitor cells, also known as multipotential neuronal stem cells. Neurogenesis actively produces new neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/or other neural lineages. Much neurogenesis occurs early in human development, though it continues later in life, particularly in certain localized regions of the adult brain.

As used herein, the term “neural connectivity” refers to the number, type, and quality of connections (“synapses”) between neurons in an organism. Synapses form between neurons, between neurons and muscles (a “neuromuscular junction”), and between neurons and other biological structures, including internal organs, endocrine glands, and the like. Synapses are specialized structures by which neurons transmit chemical or electrical signals to each other and to non-neuronal cells, muscles, tissues, and organs. Compounds that affect neural connectivity may do so by establishing new synapses (e.g., by neurite outgrowth or neurite activation) or by altering or remodeling existing synapses. Synaptic remodeling refers to changes in the quality, intensity or type of signal transmitted at particular synapses.

›Definitions · 4 of 48

As used herein, the term “neuropathy” refers to a disorder characterized by altered function and/or structure of motor, sensory, and autonomic neurons of the nervous system, initiated or caused by a primary lesion or other dysfunction of the nervous system. Patterns of peripheral neuropathy include polyneuropathy, mononeuropathy, mononeuritis multiplex and autonomic neuropathy. The most common form is (symmetrical) peripheral polyneuropathy, which mainly affects the feet and legs. A radiculopathy involves spinal nerve roots, but if peripheral nerves are also involved the term radiculoneuropathy is used. The form of neuropathy may be further broken down by cause, or the size of predominant fiber involvement, e.g. large fiber or small fiber peripheral neuropathy. Central neuropathic pain can occur in spinal cord injury, multiple sclerosis, and some strokes, as well as fibromyalgia. Neuropathy may be associated with varying combinations of weakness, autonomic changes and sensory changes. Loss of muscle bulk or fasciculations, a particular fine twitching of muscle may also be seen. Sensory symptoms encompass loss of sensation and “positive” phenomena including pain. Neuropathies are associated with a variety of disorders, including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiple sclerosis, and herpes zoster infection, as well as with spinal cord injury and other types of nerve damage.

As used herein, the term “Alzheimer's disease” refers to a degenerative brain disorder characterized clinically by progressive memory deficits, confusion, behavioral problems, inability to care for oneself, gradual physical deterioration and, ultimately, death. Histologically, the disease is characterized by neuritic plaques, found primarily in the association cortex, limbic system and basal ganglia. The major constituent of these plaques is amyloid beta peptide (Aβ), which is the cleavage product of beta amyloid precursor protein (βAPP or APP). APP is a type I transmembrane glycoprotein that contains a large ectopic N-terminal domain, a transmembrane domain and a small cytoplasmic C-terminal tail. Alternative splicing of the transcript of the single APP gene on chromosome 21 results in several isoforms that differ in the number of amino acids. Aβ appears to have a central role in the neuropathology of Alzheimer's disease. Familial forms of the disease have been linked to mutations in APP and the presenilin genes (Tanzi et al., 1996, Neurobiol. Dis., 3:159-168; Hardy, 1996, Ann. Med., 28:255-258). Diseased-linked mutations in these genes result in increased production of the 42-amino acid form of Aβ, the predominant form found in amyloid plaques. Mitochondrial dysfunction has also been reported to be an important component of Alzheimer's disease (Bubber et al., Mitochondrial abnormalities in Alzheimer brain: Mechanistic Implications, Ann Neurol., 2005, 57(5), 695-703; Wang et al, Insights into amyloid-β-induced mitochondrial dysfunction in Alzheimer disease, Free Radical Biology & Medicine, 2007, 43, 1569-1573; Swerdlow et al., Mitochondria in Alzheimer's disease, Int. Rev. Neurobiol., 2002, 53, 341-385; and Reddy et al., Are mitochondria critical in the pathogenesis of Alzheimer's disease?, Brain Res Rev. 2005, 49(3), 618-32). It has been proposed that mitochondrial dysfunction has a causal relationship with neuronal function (including neurotransmitter synthesis and secretion) and viability. Compounds which stabilize mitochondria may therefore have a beneficial impact on Alzheimer's patients.

As used herein, the term “Huntington's disease” refers to a fatal neurological disorder characterized clinically by symptoms such as involuntary movements, cognition impairment or loss of cognitive function and a wide spectrum of behavioral disorders. Common motor symptoms associated with Huntington's disease include chorea (involuntary writhing and spasming), clumsiness, and progressive loss of the abilities to walk, speak (e.g., exhibiting slurred speech) and swallow. Other symptoms of Huntington's disease can include cognitive symptoms such as loss of intellectual speed, attention and short-term memory and/or behavioral symptoms that can span the range of changes in personality, depression, irritability, emotional outbursts and apathy. Clinical symptoms typically appear in the fourth or fifth decade of life. Huntington's disease is a devastating and often protracted illness, with death usually occurring approximately 10-20 years after the onset of symptoms. Huntington's disease is inherited through a mutated or abnormal gene encoding an abnormal protein called the mutant huntingtin protein; the mutated huntingtin protein produces neuronal degeneration in many different regions of the brain. The degeneration focuses on neurons located in the basal ganglia, structures deep within the brain that control many important functions including coordinating movement, and on neurons on the outer surface of the brain or cortex, which controls thought, perception and memory.

“Amyotrophic lateral sclerosis” or “ALS” is used herein to denote a progressive neurodegenerative disease that affects upper motor neurons (motor neurons in the brain) and/or lower motor neurons (motor neurons in the spinal cord) and results in motor neuron death. As used herein, the term “ALS” includes all of the classifications of ALS known in the art, including, but not limited to classical ALS (typically affecting both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, typically affecting only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking), Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons) and familial ALS (a genetic version of ALS).

The term “Parkinson's disease” as used herein refers to any medical condition wherein an individual experiences one or more symptoms associated with Parkinson's disease, such as without limitation one or more of the following symptoms: rest tremor, cogwheel rigidity, bradykinesia, postural reflex impairment, symptoms having good response to 1-dopa treatment, the absence of prominent oculomotor palsy, cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia. In a specific embodiment, the present invention is utilized for the treatment of a dopaminergic dysfunction-related disorder. In a specific embodiment, the individual with Parkinson's disease has a mutation or polymorphism in a synuclein, parkin or NURR1 nucleic acid that is associated with Parkinson's disease. In one embodiment, the individual with Parkinson's disease has defective or decreased expression of a nucleic acid or a mutation in a nucleic acid that regulates the development and/or survival of dopaminergic neurons.

›Definitions · 5 of 48

As used herein, the term “canine cognitive dysfunction syndrome,” or “CCDS” refers to an age-related deterioration of mental function typified by multiple cognitive impairments that affect an afflicted canine's ability to function normally. The decline in cognitive ability that is associated with CCDS cannot be completely attributed to a general medical condition such as neoplasia, infection, sensory impairment, or organ failure. Diagnosis of CCDS in canines, such as dogs, is generally a diagnosis of exclusion, based on thorough behavior and medical histories and the presence of clinical symptoms of CCDS that are unrelated to other disease processes. Owner observation of age-related changes in behavior is a practical means used to detect the possible onset of CCDS in aging domestic dogs. A number of laboratory cognitive tasks may be used to help diagnose CCDS, while blood counts, chemistry panels and urinalysis can be used to rule out other underlying diseases that could mimic the clinical symptoms of CCDS. Symptoms of CCDS include memory loss, which in domestic dogs may be manifested by disorientation and/or confusion, decreased or altered interaction with family members and/or greeting behavior, changes in sleep-wake cycle, decreased activity level, and loss of house training or frequent, inappropriate elimination. A canine suffering from CCDS may exhibit one or more of the following clinical or behavioral symptoms: decreased appetite, decreased awareness of surroundings, decreased ability to recognize familiar places, people or other animals, decreased hearing, decreased ability to climb up and down stairs, decreased tolerance to being alone, development of compulsive behavior or repetitive behaviors or habits, circling, tremors or shaking, disorientation, decreased activity level, abnormal sleep wake cycles, loss of house training, decreased or altered responsiveness to family members, and decreased or altered greeting behavior. CCDS can dramatically affect the health and well-being of an afflicted canine. Moreover, the companionship offered by a pet with CCDS can become less rewarding as the severity of the disease increases and its symptoms become more severe.

As used herein, the term “age-associated memory impairment” or “AAMI” refers to a condition that may be identified as GDS stage 2 on the global deterioration scale (GDS) (Reisberg, et al. (1982) Am. J. Psychiatry 139: 1136-1139) which differentiates the aging process and progressive degenerative dementia in seven major stages. The first stage of the GDS is one in which individuals at any age have neither subjective complaints of cognitive impairment nor objective evidence of impairment. These GDS stage 1 individuals are considered normal. The second stage of the GDS applies to those generally elderly persons who complain of memory and cognitive functioning difficulties such as not recalling names as well as they could five or ten years previously or not recalling where they have placed things as well as they could five or ten years previously. These subjective complaints appear to be very common in otherwise normal elderly individuals. AAMI refers to persons in GDS stage 2, who may differ neurophysiologically from elderly persons who are normal and free of subjective complaints, i.e., GDS stage 1. For example, AAMI subjects have been found to have more electrophysiologic slowing on a computer analyzed EEG than GDS stage 1 elderly persons (Prichep, John, Ferris, Reisberg, et al. (1994) Neurobiol. Aging 15: 85-90).

As used herein, the term “mild cognitive impairment” or “MCI” refers to a type of cognitive disorder characterized by a more pronounced deterioration in cognitive functions than is typical for normal age-related decline. As a result, elderly or aged patients with MCI have greater than normal difficulty performing complex daily tasks and learning, but without the inability to perform normal social, everyday, and/or professional functions typical of patients with Alzheimer's disease, or other similar neurodegenerative disorders eventually resulting in dementia. MCI is characterized by subtle, clinically manifest deficits in cognition, memory, and functioning, amongst other impairments, which are not of sufficient magnitude to fulfill criteria for diagnosis of Alzheimer's disease or other dementia. MCI also encompasses injury-related MCI, defined herein as cognitive impairment resulting from certain types of injury, such as nerve injury (i.e., battlefield injuries, including post-concussion syndrome, and the like), neurotoxic treatment (i.e., adjuvant chemotherapy resulting in “chemo brain” and the like), and tissue damage resulting from physical injury or other neurodegeneration, which is separate and distinct from mild cognitive impairment resulting from stroke, ischemia, hemorrhagic insult, blunt force trauma, and the like.

As used herein, the term “traumatic brain injury” or “TBI” refers to a brain injury caused by a sudden trauma, such as a blow or jolt or a penetrating head injury, which disrupts the function or damages the brain. Symptoms of TBI can range from mild, moderate to severe and can significantly affect many cognitive (deficits of language and communication, information processing, memory, and perceptual skills), physical (ambulation, balance, coordination, fine motor skills, strength, and endurance), and psychological skills.

“Neuronal death mediated ocular disease” intends an ocular disease in which death of the neuron is implicated in whole or in part. The disease may involve death of photoreceptors. The disease may involve retinal cell death. The disease may involve ocular nerve death by apoptosis. Particular neuronal death mediated ocular diseases include but are not limited to macular degeneration, glaucoma, retinitis pigmentosa, congenital stationary night blindness (Oguchi disease), childhood onset severe retinal dystrophy, Leber congenital amaurosis, Bardet-Biedle syndrome, Usher syndrome, blindness from an optic neuropathy, Leber's hereditary optic neuropathy, color blindness and Hansen-Larson-Berg syndrome.

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As used herein, the term “macular degeneration” includes all forms and classifications of macular degeneration known in the art, including, but not limited to diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane, the choroid, the neural retina and/or the retinal pigment epithelium. The term thus encompasses disorders such as age-related macular degeneration (ARMD) as well as rarer, earlier-onset dystrophies that in some cases can be detected in the first decade of life. Other maculopathies include North Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt's disease, pattern dystrophy, Best disease, and Malattia Leventinese.

As used herein, the term “autism” refers to a brain development disorder that impairs social interaction and communication and causes restricted and repetitive behavior, typically appearing during infancy or early childhood. The cognitive and behavioral defects are thought to result in part from altered neural connectivity. Autism encompasses related disorders sometimes referred to as “autism spectrum disorder,” as well as Asperger syndrome and Rett syndrome.

As used herein, the term “nerve injury” or “nerve damage” refers to physical damage to nerves, such as avulsion injury (i.e., where a nerve or nerves have been torn or ripped) or spinal cord injury (i.e., damage to white matter or myelinated fiber tracts that carry sensation and motor signals to and from the brain). Spinal cord injury can occur from many causes, including physical trauma (i.e., car accidents, sports injuries, and the like), tumors impinging on the spinal column, developmental disorders, such as spina bifida, and the like.

As used herein, the term “myasthenia gravis” or “MG” refers to a non-cognitive neuromuscular disorder caused by immune-mediated loss of acetylcholine receptors at neuromuscular junctions of skeletal muscle. Clinically, MG typically appears first as occasional muscle weakness in approximately two-thirds of patients, most commonly in the extraocular muscles. These initial symptoms eventually worsen, producing drooping eyelids (ptosis) and/or double vision (diplopia), often causing the patient to seek medical attention. Eventually, many patients develop general muscular weakness that may fluctuate weekly, daily, or even more frequently. Generalized MG often affects muscles that control facial expression, chewing, talking, swallowing, and breathing; before recent advances in treatment, respiratory failure was the most common cause of death.

As used herein, the term “Guillain-Barré syndrome” refers to a non-cognitive disorder in which the body's immune system attacks part of the peripheral nervous system. The first symptoms of this disorder include varying degrees of weakness or tingling sensations in the legs. In many instances the weakness and abnormal sensations spread to the arms and upper body. These symptoms can increase in intensity until certain muscles cannot be used at all and, when severe, the patient is almost totally paralyzed. In these cases the disorder is life threatening—potentially interfering with breathing and, at times, with blood pressure or heart rate—and is considered a medical emergency. Most patients, however, recover from even the most severe cases of Guillain-Barré syndrome, although some continue to have a certain degree of weakness.

As used herein, the term “multiple sclerosis” or “MS” refers to an autoimmune condition in which the immune system attacks the central nervous system (CNS), leading to demyelination of neurons. It may cause numerous symptoms, many of which are non-cognitive, and often progresses to physical disability. MS affects the areas of the brain and spinal cord known as the white matter. White matter cells carry signals between the grey matter areas, where the processing is done, and the rest of the body. More specifically, MS destroys oligodendrocytes which are the cells responsible for creating and maintaining a fatty layer, known as the myelin sheath, which helps the neurons carry electrical signals. MS results in a thinning or complete loss of myelin and, less frequently, the cutting (transection) of the neuron's extensions or axons. When the myelin is lost, the neurons can no longer effectively conduct their electrical signals. Almost any neurological symptom can accompany the disease. MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Most people are first diagnosed with relapsing-remitting MS but develop secondary-progressive MS (SPMS) after a number of years. Between attacks, symptoms may go away completely, but permanent neurological problems often persist, especially as the disease advances.

As used herein, the term “schizophrenia” refers to a chronic, mental disorder characterized by one or more positive symptoms (e.g., delusions and hallucinations) and/or negative symptoms (e.g., blunted emotions and lack of interest) and/or disorganized symptoms (e.g., disorganized thinking and speech or disorganized perception and behavior). Schizophrenia as used herein includes all forms and classifications of schizophrenia known in the art, including, but not limited to catatonic type, hebephrenic type, disorganized type, paranoid type, residual type or undifferentiated type schizophrenia and deficit syndrome and/or those described in American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Washington D.C., 2000 or in International Statistical Classification of Diseases and Related Health Problems, or otherwise known to those of skill in the art.

“Cognitive impairment associated with schizophrenia” or “CIAS” includes neuropsychological deficits in attention, working memory, verbal learning, and problem solving. These deficits are believed to be linked to impairment in functional status (e.g., social behavior, work performance, and activities of daily living).

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As used herein “geroprotective activity” or “geroprotector” means a biological activity that slows down ageing and/or prolongs life and/or increases or improves the quality of life via a decrease in the amount and/or the level of intensity of pathologies or conditions that are not life-threatening but are associated with the aging process and which are typical for elderly people. Pathologies or conditions that are not life-threatening but are associated with the aging process include such pathologies or conditions as loss of sight (cataract), deterioration of the dermatohairy integument (alopecia), and an age-associated decrease in weight due to the death of muscular and/or fatty cells.

As used herein, attention-deficit hyperactivity disorder (ADHD) is the most common child neuropsychiatric condition present in school-aged children, affecting about 5-8% of this population. ADHD refers to a chronic disorder that initially manifests in childhood and is characterized by hyperactivity, impulsivity, and/or inattention. ADHD is characterized by persistent patterns of inattention and/or impulsivity-hyperactivity that are much more extreme than is observed in individuals at the same developmental level or stage. There is considerable evidence, from family and twin studies, that ADHD has a significant genetic component. This disorder is thought to be due to an interaction of environmental and genetic factors. ADHD includes all known types of ADHD. For example, Diagnostic & Statistical Manual for Mental Disorders (DSM-IV) identifies three subtypes of ADHD: (1) ADHD, Combined Type which is characterized by both inattention and hyperactivity-impulsivity symptoms; 2. ADHD, Predominantly Inattentive Type which is characterized by inattention but not hyperactivity-impulsivity symptoms; and 3. ADHD, Predominantly Hyperactive-Impulsive Type which is characterized by Hyperactivity-impulsivity but not inattention symptoms.

As used herein, attention-deficit disorder (ADD) refers to a disorder in processing neural stimuli that is characterized by distractibility and impulsivity that can result in inability to control behavior and can impair an individual's social, academic, or occupational function and development. ADD may be diagnosed by known methods, which may include observing behavior and diagnostic interview techniques.

As used herein “allergic disease” refers to a disorder of the immune system which is characterized by excessive activation of mast cells and basophils and production of IgE immunoglobulins, resulting in an extreme inflammatory response. It represents a form of hypersensitivity to an environmental substance known as allergen and is an acquired disease. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees. Allergic reactions are accompanied by an excessive release of histamines, and can thus be treated with antihistaminic agents.

As used herein, by “combination therapy” is meant a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy comprising a compound detailed herein and anther compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances. In various embodiments, treatment with a combination therapy may result in an additive or even synergistic (e.g., greater than additive) result compared to administration of a single compound of the invention alone. In some embodiments, a lower amount of each compound is used as part of a combination therapy compared to the amount generally used for individual therapy. Preferably, the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone. In some embodiments, the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a compound in a combination therapy than the amount generally used for individual compound or therapy. Preferably, the use of a small amount of compound results in a reduction in the number, severity, frequency, and/or duration of one or more side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of a compound of the invention which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH—dependent or non-pH—dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

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As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. A pharmaceutically acceptable salt intends ionic interactions and not a covalent bond. As such, an N-oxide is not considered a salt. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclic univalent hydrocarbon structures and combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C 1 -C 8 alkyl”). When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C 3 -C 8 cycloalkyl”). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

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“Alkylene” refers to the same residues as alkyl, but having bivalency. Examples of alkylene include methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), butylene (—CH 2 CH 2 CH 2 CH 2 —) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms. Examples of alkenyl include but are not limited to —CH 2 —CH═CH—CH 3 and —CH 2 —CH 2 -cyclohexenyl, where the ethyl group of the latter example can be attached to the cyclohexenyl moiety at any available position on the ring. Cycloalkenyl is a subset of alkenyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as norbornenyl. A more preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C 3 -C 8 cycloalkenyl”). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the rings can be aryl or heteroaryl. A heterocycle having more than one ring where at least one ring is aromatic may be connected to the parent structure at either a non-aromatic ring position or at an aromatic ring position. In one variation, a heterocycle having more than one ring where at least one ring is aromatic is connected to the parent structure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. In one variation, a substituted heterocycle is a heterocycle substituted with an additional ring, wherein the additional ring may be aromatic or non-aromatic.

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“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclic group having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. Preferably, an aralkyl is connected to the parent structure via the alkyl moiety. In one variation, an aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety. A “substituted aralkyl” refers to a residue in which an aryl moiety is attached to a substituted alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. When an aralkyl is connected to the parent structure via the alkyl moiety, it may also be referred to as an “alkaryl”. More particular alkaryl groups are those having 1 to 3 carbon atoms in the alkyl moiety (a “C 1 -C 3 alkaryl”).

“Alkoxy” refers to the group alkyl-O—, which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxy refers to the group “alkynyl-O—”. “Substituted alkoxy” refers to the group substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH 2 .

“Substituted amino” refers to the group —NR a R b , where either (a) each R a and R b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, provided that both R a and R b groups are not H; or (b) R a and R b are joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR a R b where R a and R b are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic or R a and R b groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.

“Aminoacyl” refers to the group —NR a C(O)R b where each R a and R b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. Preferably, R a is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO 2 -alkyl, —NRSO 2 substituted alkyl, —NRSO 2 -alkenyl, —NRSO 2 -substituted alkenyl, —NRSO 2 -alkynyl, —NRSO 2 -substituted alkynyl, —NRSO 2 -cycloalkyl, —NRSO 2 -substituted cycloalkyl, —NRSO 2 -aryl, —NRSO 2 -substituted aryl, —NRSO 2 -heteroaryl, —NRSO 2 -substituted heteroaryl, —NRSO 2 -heterocyclic, and —NRSO 2 -substituted heterocyclic, where R is H or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

›Definitions · 11 of 48

“Sulfonylamino” refers to the groups —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , where the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic.

“Aminocarbonylalkoxy” refers to the group —NR a C(O)OR b where each R a and R b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH 2 ) a —OR where R is a substituted or unsubstituted alkyl and n is an integer from 1 to 100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each H is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl (—CF 3 ). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (—OCF 3 ).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO 2 .

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R 1 SO 2 NR a R b where R a and R b are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or the R a and R b groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring and R 1 is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that are attached to the same atom. For example, in the residue —CH 2 —CHR 1 R 2 , R 1 and R 2 are geminal and R 1 may be referred to as a geminal R group to R 2 .

“Vicinal” refers to the relationship between two moieties that are attached to adjacent atoms. For example, in the residue —CHR 1 —CH 2 R 2 , R 1 and R 2 are vicinal and R 1 may be referred to as a vicinal R group to R 2 .

A composition of “substantially pure” compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.

Compounds of the Invention

Compounds according to the invention are detailed herein, including in the Brief Summary of the Invention and the appended claims. The invention includes the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis/trans) or E/Z isomers, salts and solvates of the compounds described herein, as well as methods of making such compounds.

The invention embraces compounds of the formula (I):

or a salt or solvate thereof;

wherein:

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together to form a carbonyl moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 3a and R 3b are taken together to form a carbonyl moiety;

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

›Definitions · 12 of 48

each R 8a , R 8b , R 8c and R 8d is independently H, hydroxyl, C 1 -C 8 alkyl, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety;

each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 10a and R 10b are taken together to form a carbonyl moiety;

R 11 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl and the bond indicates the presence of either an E or Z double bond configuration;

R 12 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino;

provided that when X 7 , X 8 and X 10 are each CH and each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is hydrogen, then the compound is other than a compound in Table A. The compounds in Table A have the structure of formula (I) where each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H, each X 7 , X 8 and X 10 is CH, R 1 , m, q and Q are as listed in Table A, and X 9 is CR 4 where R 4 is as listed in Table A. When R 4 is listed as H, X 9 is CH.

Also provided are methods of using compounds described herein, such as compounds of formula (I), in various therapeutic applications. Method of using compounds of Table A are also encompassed. Thus, provided are methods of using a compound of Formula (I-1):

or a salt or solvate thereof;

wherein:

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together to form a carbonyl moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 3a and R 3b are taken together to form a carbonyl moiety;

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 10a and R 10b are taken together to form a carbonyl moiety;

R 11 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl and the bond indicates the presence of either an E or Z double bond configuration;

R 12 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

In one variation, compounds of the formula (V) are provided, where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, q, m, R 8a , R 8b , R 8c , R 8d are as defined for formula (I) and R 11 and R 12 are independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, substituted or unsubstituted heterocyclyl or C 1 -C 8 perhaloalkyl and the bond indicates the presence of either an E or Z double bond configuration. In one such variation, R 11 and R 12 are other than H. In another variation, R 12 is other than H, such as when R 12 is a substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

In one variation, the compound is of the formula (I), where at least one of R 11 and R 12 is other than H. In one such variation, the compound is of the formula (I) where R 11 is C 1 -C 8 alkyl. For example, the compound in one aspect is of the formula (I) where R 11 is methyl. In another such variation, the compound is of the formula (I) where R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. For example, the compound in one aspect is of the formula (I) where R 12 is methyl, ethyl, cyclopropyl or trifluoromethyl. In one aspect, the compound is of the formula (I) where R 12 is C 1 -C 8 alkyl (e.g., methyl and ethyl). In another aspect, the compound is of the formula (I) where R 12 is C 3 -C 8 cycloalkyl (e.g., cyclopropyl). In still another aspect, the compound is of the formula (I) where R 12 is C 1 -C 8 perhaloalkyl (e.g., trifluoromethyl). In another such variation, R 11 and R 12 are independently C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In yet another such variation, R 11 is C 1 -C 8 alkyl and R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. For example, a compound in one aspect is of the formula (I) where both R 11 and R 12 are methyl and in another aspect where R 11 is methyl and R 12 is methyl, ethyl, cyclopropyl or trifluoromethyl. Where applicable, including but not limited to the variations of this paragraph, in a one variation the compound of formula (I) is further defined by Q being a substituted or unsubstituted heteroaryl.

›Definitions · 13 of 48

When Q is an unsubstituted or substituted heteroaryl, in one variation it is a heteroaryl containing an annular nitrogen atom. In one aspect, when Q is an unsubstituted or substituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation, Q is an unsubstituted pyridyl that may be bound to the parent structure at any available ring position. For example, in one variation of formula (I), Q is 4-pyridyl, 3-pyridyl or 2-pyridyl. When Q is a substituted heteroaryl in one aspect it is a substituted pyridyl. When Q is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (I), Q is a monosubstituted pyridyl where the substituent is a C 1 -C 8 unsubstituted alkyl (e.g., methyl).

In a particular variation, the compound is of the formula (I) where both q and m are 0 and where at least one of R 11 and R 12 is other than H. For example, in one variation, both q and m are 0 and R 11 and R 12 are as provided in any of the variations detailed in the preceding paragraph. In a particular such variation, both q and m are 0 and R 12 is methyl. In still another variation, the compound is of the formula (I) where both q and m are 0, R 12 is methyl and at least one of (i)-(iii) applies: (i) X 9 is CR 4 where R 4 is halo (e.g., chloro); (ii) Q is a substituted phenyl; and (iii) X 7 , X 8 and X 10 are each CH. In yet another variation, the compound is of the formula (I) where both q and m are 0, R 12 is methyl and at least one of (i)-(iii) applies: (i) X 9 is CR 4 where R 4 is halo (e.g., chloro) or unsubstituted C 1 -C 8 alkyl; (ii) Q is a substituted or unsubstituted pyridyl; and (iii) X 7 , X 8 and X 10 are each CH.

In one variation of formula (I), both q and m are 0, R 12 is C 1 -C 8 alkyl (e.g., methyl) and at least one of X 7 -X 10 is CR 4 where R 4 is halo. In one such variation, both q and m are 0, R 12 is C 1 -C 8 alkyl (e.g., methyl), at least one of X 7 -X 10 is CR 4 where R 4 is halo, and the compound further has one or more of the following structural features: (i) Q is a substituted aryl; (ii) X 7 , X 8 and X 10 are each CH; (iii) R 11 is H; (iv) R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are each H; and (v) R 1 is alkyl. In a particular such variation, both q and m are 0, R 12 is methyl, X 9 is CR 4 where R 4 is chloro. In a more particular such variation, both q and m are 0, R 12 is methyl, X 9 is CR 4 where R 4 is chloro, and at least one of (i)-(v) applies: (i) Q is a substituted phenyl; (ii) X 7 , X 8 and X 10 are each CH; (iii) R 11 is H; (iv) R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are each H; and (v) R 1 is methyl.

In one variation, the compound is of the formula (I) where q is 0 and m is 1. In one such variation, the compound is of the formula (I) where q is 0, m is 1 and R 11 and R 12 are both H. In another aspect, the compound is of the formula (I) where q is 0, m is 1 and Q is an unsubstituted aryl or heteroaryl.

In another variation, the compound is of the formula (I) where Q is a di- or tri-substituted aryl, substituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl. In one aspect, the compound is of the formula (I) where Q is a di- or tri-substituted aryl. When Q is a di- or tri-substituted aryl, the substituents may be the same or different and may be located at any available position on the aryl ring. In one aspect, Q is a di- or tri-substituted phenyl (e.g., 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl and 2,4,6-trifluorophenyl). In another aspect, Q is a phenyl substituted with at least one chloro or methyl group (e.g., 4-chlorophenyl and 4-methylphenyl). In yet another aspect, the compound is of the formula (I) where Q is a substituted heteroaryl (e.g., where Q is 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl or pyrimidinyl). In one aspect, Q is a substituted pyridyl such as 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl. In another variation, compounds of formula (I) are provided where Q is an unsubstituted heteroaryl and R 12 is an unsubstituted C 1 -C 8 alkyl such as methyl. In one such variation, Q is pyridyl (e.g., 4-pyridyl) and R 12 is methyl.

In one variation, the compound is of the formula (I) where at least one of X 7 -X 10 is CR 4 where R 4 is chloro. In such variation, X 9 is CR 4 where R 4 is chloro. In another variation, X 9 is CR 4 where R 4 is chloro and X 7 , X 8 and X 10 are CH. In one aspect, the compound is of the formula (I) where at least one of X 7 -X 10 is CR 4 where R 4 is chloro. (e.g., when X 9 is CR 4 where R 4 is chloro) and Q is an unsubstituted aryl (e.g., phenyl), a substituted aryl (e.g., 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl and 2,4-dichlorophenyl), an unsubstituted heteroaryl (e.g., 3-pyridyl and 4-pyridyl) or a substituted heteroaryl (e.g., 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl). In a particular variation, X 9 is CR 4 where R 4 is chloro, X 7 , X 8 and X 10 are each CH, R 1 is methyl or cyclopropyl and Q is an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl or a substituted heteroaryl.

In any variation or aspect of formula (I) detailed herein, in one embodiment, the compound of formula (I) is in the E configuration. Similarly, in any variation or aspect of formula (I) detailed herein, in another embodiment, the compound of formula (I) is in the Z configuration.

In certain embodiments, the compound of formula (I) has the structure:

or a salt or solvate thereof;

›Definitions · 14 of 48

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , q, Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (I) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I) detailed throughout, where applicable, apply to formula (I-A) the same as if each and every variation were specifically and individually listed for formula (I-A). In one variation, compounds of formula (I-A) are detailed herein, provided the compound is other than a compound of Table A. In another variation, compounds of formula (I-A), including those of Table A, and methods of using and administering such compounds are encompassed. In one aspect of formula (I-A), q is 1. In another variation of formula (I-A), q is 0 and R 12 is other than H (e.g., where R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl). In another particular variation of formula (I-A), q is 0 and R 12 is C 1 -C 8 alkyl (e.g., methyl). In one such variation, R 12 is an unsubstituted C 1 -C 8 alkyl and Q is a substituted or unsubstituted heteroaryl. In one variation of formula (I-A), R 12 is an unsubstituted C 1 -C 8 alkyl and Q is other than a halo-substituted phenyl. In a more particular variation of formula (I-A), q is 0, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo and each X 7 , X 8 and X 10 is CH. In an even more particular variation of formula (I-A), q is 0, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo, each X 7 , X 8 and X 10 is CH, R 1 is alkyl (e.g., methyl) and each R 2a , R 2b , R 3a , R 3b , R 10a , R 10b is H. In any variation or aspect of formula (I-A) detailed herein, in one embodiment, the compound of formula (I-A) is in the E configuration. Similarly, in any variation or aspect of formula (I-A) detailed herein, in another embodiment, the compound of formula (I-A) is in the Z configuration.

In other embodiments, the compound of formula (I) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (I) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I) detailed throughout, where applicable, apply to formula (I-B) the same as if each and every variation were specifically and individually listed for formula (I-B). In one variation, compounds of formula (I-B) are detailed herein, provided the compound is other than a compound of Table A. In another variation, compounds of formula (I-B), including those of Table A, and methods of using and administering such compounds are encompassed. In one aspect of formula (I-B), at least one of R 11 and R 12 is other than H. In one such variation of formula (I-B), R 11 is H and R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In one aspect of formula (I-B), R 11 is H and R 12 is C 1 -C 8 alkyl. In another variation of formula (I-B) at least one of R 11 and R 12 is other than H and R 1 is C 1 -C 8 alkyl. In one such variation, R 12 is an unsubstituted C 1 -C 8 alkyl and Q is a substituted or unsubstituted heteroaryl. In one variation of formula (I-B), R 12 is an unsubstituted C 1 -C 8 alkyl and Q is other than a halo-substituted phenyl. In a more particular variation of formula (I-B), R 11 is H, R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl and R 1 is C 1 -C 8 alkyl. In an even more particular variation of formula (I-B), R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo and each X 7 , X 8 and X 10 is CH. In another variation of formula (I-B), R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo, each X 7 , X 8 and X 10 is CH, R 1 is alkyl and each R 2a , R 2b , R 3a , R 3b , R 10a , R 10b is H. In any variation or aspect of formula (I-B) detailed herein, in one embodiment, the compound of formula (I-B) is in the E configuration. Similarly, in any variation or aspect of formula (I-B) detailed herein, in another embodiment, the compound of formula (I-B) is in the Z configuration. For example, provided are compounds of formula (I-B) where R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo, each X 7 , X 8 and X 10 is CH and the compound is in the E configuration. Likewise, also provided are compounds of formula (I-B) where R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo, each X 7 , X 8 and X 10 is CH and the compound is in the Z configuration.

In specific embodiments, the compound having formula (I-B) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (I-B) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I-B) and formula (I) detailed throughout, where applicable, apply to formulae (I-b1) and (I-b2) the same as if each and every variation were specifically and individually listed for formulae (I-b1) and (I-b2). In one variation, compounds of formula (I-b1) and (I-b2) are detailed herein, provided the compound is other than a compound of Table A. In another variation, compounds of formula (I-b1) and (I-b2) are provided, including those of Table A, and methods of using and administering such compounds are encompassed. In one variation of formulae (I-b1) and (I-b2), at least one of R 11 and R 12 is other than H. In one such variation of formulae (I-b1) and (I-b2), R 11 is H and R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In one such variation, R 12 is an unsubstituted C 1 -C 8 alkyl and Q is a substituted or unsubstituted heteroaryl. In another variation, R 12 is an unsubstituted C 1 -C 8 alkyl and Q is other than a halo-substituted phenyl. In one variation, the compound is of the formula (I-b1) where R 12 is C 1 -C 8 alkyl (e.g., methyl). In another variation, the compound is of the formula (I-b1) where R 11 is H and R 12 is C 1 -C 8 alkyl (e.g., methyl). In a particular variation of formula (I-b1), R 11 is H, R 12 is C 1 -C 8 alkyl (e.g., methyl) and X 9 is CR 4 where R 4 is halo (e.g., chloro). In a more particular variation of formula (I-b1), R 11 is H, R 12 is C 1 -C 8 alkyl (e.g., methyl), X 9 is CR 4 where R 4 is halo (e.g., chloro) and at least of of (i)-(iv) applies: (i) X 7 , X 8 and X 10 are each CH; (ii) Q is an unsubstituted aryl (e.g., phenyl), a substituted aryl (e.g., 4-fluorophenyl, 4-chlorophenyl, 4-methyoxyphenyl, 3-fluoro-4-methoxyphenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4,5-trifluorophenyl and 2,4-dichlorophenyl), an unsubstituted heteroaryl (e.g., 3-pyridyl and 4-pyridyl) or a substituted heteroaryl (e.g., 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl); (iii) R 1 is C 1 -C 8 alkyl (e.g., methyl and cyclopropyl) and (iv) each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H. In a further variation of formula (I-b1), R 11 is H, R 12 is an unsubstituted C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is an unsubstituted C 1 -C 8 alkyl and Q is a substituted or unsubstituted heteroaryl. Such variations are also applicable to formula (I-b2).

›Definitions · 15 of 48

In other embodiments, the compound of formula (I) has the structure:

or a salt or solvate thereof;

In specific embodiments, the compound of formula (I-C) has the formula:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (I-C) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I-C) and formula (I) detailed throughout, where applicable, apply to formulae (I-c1) and (I-c2) the same as if each and every variation were specifically and individually listed for formulae (I-c1) and (I-c2).

In further embodiments, the compound of formula (I) has the structure:

or a salt or solvate thereof;

In specific embodiments, the compound of formula (I-D) has the formula:

or a salt or solvate thereof;

R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (I-D) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I-D) and formula (I) detailed throughout, where applicable, apply to formulae (I-d1) and (I-d2) the same as if each and every variation were specifically and individually listed for formulae (I-d1) and (I-d2).

In further embodiments, the compound of formula (I) has the structure:

or a salt or solvate thereof;

wherein R 1 , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (I) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I) detailed throughout, where applicable, apply to formula (I-E) the same as if each and every variation were specifically and individually listed for formula (I-E). In a particular variation of formula (I-E), X 9 is CR 4 where R 4 is halo. In further variations of formula (I-E), X 9 is CR 4 where R 4 is halo and each X 7 , X 8 and X 10 is CH. In still further variations of formula (I-E), X 9 is CR 4 where R 4 is halo and Q is a substituted aryl. In other variations of formula (I-E), X 9 is CR 4 where R 4 is halo and Q is a substituted or unsubstituted heteroaryl. In one aspect of formula (I-E), R 1 is a C 1 -C 8 alkyl (e.g., methyl) and X 9 is CR 4 where R 4 is halo. In another aspect of formula (I-E), R 1 is a C 1 -C 8 alkyl (e.g., methyl), X 9 is CR 4 where R 4 is halo (e.g., chloro) and Q is a substituted aryl (e.g., a substituted phenyl). In a further aspect of formula (I-E), R 1 is methyl, R 9 is CR 4 where R 4 is chloro, X 7 , X 8 and X 10 are each CH and Q is a substituted aryl or a substituted or unsubstituted heteroaryl. In another variation of formula (I-E), Q is a substituted or unsubstituted heteroaryl. When Q is an unsubstituted or substituted heteroaryl, in one variation it is a heteroaryl containing an annular nitrogen atom. In one aspect, when Q is an unsubstituted or substituted heteroaryl the heteroaryl contains only nitrogen and carbon annular atoms. In a particular variation, Q is an unsubstituted pyridyl that may be bound to the parent structure at any available ring position. For example, in one variation of formula (I), Q is 4-pyridyl, 3-pyridyl or 2-pyridyl. When Q is a substituted heteroaryl in one aspect it is a substituted pyridyl. When Q is a substituted pyridyl, the pyridyl may be substituted with one or more than one substituent and the substituted pyridyl may be bound to the parent structure at any available ring position. For example, in one variation of formula (I-E), Q is a monosubstituted pyridyl where the substituent is a C 1 -C 8 unsubstituted alkyl (e.g., methyl). In a particular variation of formula (I-E), X 9 is CR 4 where R 4 is an unsubstituted C 1 -C 8 alkyl and Q is a substituted or unsubstituted heteroaryl. In a further variation of formula (I-E), Q is a substituted or unsubstituted pyridyl and at least one of (i)-(iii) applies: (i) X 9 is CR 4 where R 4 is an unsubstituted C 1 -C 8 alkyl; (ii) R 1 is an unsubstituted C 1 -C 8 alkyl and (iii) X 7 , X 8 and X 10 are each CH.

›Definitions · 16 of 48

In specific embodiments, the compound of formula (I-E) has the formula:

or a salt or solvate thereof;

wherein R 1 , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (I-E) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I-E) and formula (I) detailed throughout, where applicable, apply to formulae (I-e1) and (I-e2) the same as if each and every variation were specifically and individually listed for formulae (I-e1) and (I-e2). In a particular variation of compounds (1-e1) and (1-e2), Q is a substituted or unsubstituted heteroaryl.

In further embodiments, the compound of formula (I) has the structure:

or a salt or solvate thereof;

wherein X 9 is CH or CR 4 and R 4 and Q are defined as for formula (I) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I) detailed throughout, where applicable, apply to formula (I-F) the same as if each and every variation were specifically and individually listed for formula (I-F). In one variation of formula (I-F), X 9 is CH or CR 4 where R 4 is -halo or substituted or unsubstituted C 1 -C 8 alkyl. In a particular variation of formula (I-F), X 9 is CR 4 where R 4 is halo (e.g. chloro). In another particular variation of formula (I-F), X 9 is CR 4 where R 4 is unsubstituted C 1 -C 8 alkyl (e.g. methyl). In a particular variation of formula (I-F), X 9 is CH. In further variations of formula (I-F), Q is a substituted or unsubstituted heteroaryl. In one variation, Q is an unsubstituted heteroaryl (e.g. 4-pyridyl or 4-pyrimidyl). In still further variations of formula (I-F), X 9 is CH or CR 4 where R 4 is halo or substituted or unsubstituted C 1 -C 8 alkyl and Q is a substituted or unsubstituted heteroaryl. In one aspect of formula (I-F), X 9 is CR 4 where R 4 is a C 1 -C 8 alkyl (e.g., methyl) and Q is a substituted or unsubstituted heteroaryl. In another aspect of formula (I-F), X 9 is CR 4 where R 4 is halo (e.g., chloro) and Q is a substituted or unsubstituted heteroaryl. In another aspect of formula (I-F), X 9 is CH and Q is a substituted or unsubstituted heteroaryl. In a further aspect of formula (I-F), X 9 is CH or CR 4 where R 4 is methyl or chloro and Q is 4-pyridyl.

In specific embodiments, the compound of formula (I-F) has the formula:

or a salt or solvate thereof;

wherein X 9 is CH or CR 4 and R 4 and Q are defined as for formula (I-F) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I-F) and formula (I) detailed throughout, where applicable, apply to formulae (I-f1) and (I-f2) the same as if each and every variation were specifically and individually listed for formulae (I-f1) and (I-f2). In one particular aspect of formula (I-f1), X 9 is CH or CR 4 where R 4 is methyl or chloro and Q is 4-pyridyl. In one particular aspect of formula (I-f2), X 9 is CH or CR 4 where R 4 is methyl or chloro and Q is 4-pyridyl.

In one variation, compounds of the formula (J-1) are provided:

or a salt or solvate thereof, where R 1 , R 4 , R 12 and Q are defined as for formula (I) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I) detailed throughout, where applicable, apply to formula (J-1) the same as if each and every variation were specifically and individually listed for formula (J-1).

In one variation, compounds of the formula (J-1) are provided, or a salt or solvate thereof, where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl; R 4 is H, halo, trifluoromethyl, a C 1 -C 8 unsubstituted alkyl or a substituted amino; R 12 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted aryl, halo and alkoxy; Q is substituted aryl or a substituted or unsubstituted heteroaryl and the bond indicates the presence of either an E or Z double bond configuration. In one variation of formula (J-1), R 1 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo or hydroxyl group. In one such variation, R 1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (J-1), R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH. In another variation of formula (J-1), R 4 is H, halo, methyl, trifluoromethyl, or a substituted amino of the formula —N(H)(C 1 -C 8 unsubstituted alkyl). When R 4 is a halo (e.g., fluoro or chloro), in one aspect R 4 is chloro. In one variation of formula (J-1), R 4 is H, methyl or chloro. In one variation of formula (J-1), R 4 is methyl or chloro. When R 4 is a substituted amino of the formula —N(H)(C 1 -C 8 unsubstituted alkyl), in one aspect C 1 -C 8 unsubstituted alkyl is a linear C 1 -C 8 unsubstituted alkyl such as methyl or ethyl. In a particular variation of formula (J-1), R 4 is —N(H)(CH 3 ). It is understood that any R 1 for formula (J-1) may be combined with any R 4 of formula (J-1) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (J-1) are provided where R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH and R 4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH 3 ). Likewise, compounds of the formula (J-1) are provided where R 1 is methyl and R 4 is H, halo, methyl or a substituted amino of the formula —N(H)(C 1 -C 8 unsubstituted alkyl). In one such aspect, compounds of the formula (J-1) are provided where R 1 is methyl and R 4 is H, halo or methyl. In one such aspect, compounds of the formula (J-1) are provided where R 1 is methyl and R 4 is halo (e.g., fluoro or chloro), trifluoromethyl, or methyl. In one variation of formula (J-1), R 12 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one such variation, R 12 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or an amido-substituted methyl group. In a particular variation, R 12 is methyl. When Q of formula (J-1) is a substituted aryl, in one aspect Q is a substituted phenyl. In one aspect, Q is a mono-substituted phenyl. In a particular aspect, Q of formula (J-1) is a halo-substituted phenyl, alkoxy-substituted phenyl or an acylamino-substituted phenyl. Thus, compounds of the formula (J-1) are provided where Q in one variation is a phenyl mono-substituted with a fluoro, C 1 -C 8 alkoxy (e.g., methoxy), an acylamino moiety of the formula —C(O)NH(C 1 -C 8 unsubstituted alkyl) or an acylamino moiety of the formula —C(O)N(C 1 -C 8 unsubstituted alkyl) 2 , such as 2-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-(C(O)NH(CH 3 ) and 4-(C(O)N(CH 3 ) 2 )-phenyl. In one aspect, Q is a di-substituted phenyl. In one aspect, Q of formula (J-1) is a di-halo substituted phenyl group such as 3,4-difluoro-phenyl. In a particular aspect, Q of formula (I-G) is a phenyl group substituted with one halo group and one C 1 -C 8 alkoxy group (e.g., methoxy). Thus, compounds of the formula (J-1) are provided where Q in one variation is a phenyl substituted with a fluoro and a C 1 -C 8 alkoxy group, such as 3-fluoro-4-methoxy-phenyl. When Q of formula (J-1) is a substituted or unsubstituted heteroaryl, in one variation the substituted or unsubstituted heteroaryl is a pyridyl or pyrimidyl moiety. Thus, in one aspect of formula (J-1), Q is an unsubstituted pyridyl or pyrimidyl, such as 3-pyridyl, 4-pyridyl and 4-pyrimidyl. In another aspect of formula (J-1), Q is a substituted pyridyl, such as 6-methyl-3-pyridyl. It is understood that any Q for formula (J-1) may be combined with any R 1 and/or R 4 of formula (J-1) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (J-1) are provided where R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH; R 4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH 3 ) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. Likewise, compounds of the formula (J-1) are provided where R 1 is methyl; R 4 is H, halo or methyl and Q is an unsubstituted pyridyl. In any variation of formula (J-1), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (J-1), in one aspect, the bond indicates the presence of a Z double bond configuration.

›Definitions · 17 of 48

In specific variations, compounds of the formula (J-1) have the formula:

or a salt or solvate thereof; wherein R 1 , R 4 , R 12 and Q are defined as for formula (J-1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (J-1) detailed throughout, where applicable, apply to formulae (J-1a) and (J-1b) the same as if each and every variation were specifically and individually listed for formulae (J-1a) and (J-1b). In one particular aspect of formula (J-1a), R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH; R 4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH 3 )R 12 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one such variation, R 1 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. In another aspect of formula (J-1a), R 1 is methyl, R 4 is H, chloro or methyl, R 12 is methyl and Q is a substituted or unsubstituted pyridyl. In one particular aspect of formula (J-1b), R 1 is methyl, R 4 is methyl, R 12 is methyl and Q is a substituted or unsubstituted pyridyl. Pharmaceutically acceptable salts of compounds of the formula (J-1), (J-1a) and (J-1b) are also provided.

In one variation, compounds of the formula (J-2) are provided:

or a salt or solvate thereof, where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl; R 4 is H, halo or a C 1 -C 8 unsubstituted alkyl, R 12 is substituted or unsubstituted C 1 - 8 alkyl, substituted or unsubstituted aryl, halo and alkoxy and the bond indicates the presence of either an E or Z double bond configuration and where R 4 and the pyridyl moiety may be connected to the parent structure at any available position. In one variation of formula (J-2), R 1 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo or hydroxyl group. In one such variation, R 1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (J-2), R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH. In another variation of formula (J-2), R 4 is H, halo, trifluoromethyl, or methyl. When R 4 is a halo (e.g., fluoro or chloro), in one aspect R 4 is chloro. In one variation of formula (J-2), R 4 is H, methyl or chloro. In one variation of formula (J-2), R 4 is methyl or chloro. In one variation of formula (J-1), R 12 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one such variation, R 1 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or an amido-substituted methyl group. In a particular variation, R 12 is methyl. It is understood that any R 1 for formula (J-2) may be combined with any R 4 of formula (J-2) the same as if each and every combination were specifically and individually listed. For example, compounds of the formula (J-2) are provided where R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH and R 4 is H, chloro, fluoro, trifluoromethyl, or methyl. Likewise, compounds of the formula (J-2) are provided where R 1 is methyl and R 4 is H, halo or methyl. In one such aspect, compounds of the formula (J-2) are provided where R 1 is methyl and R 4 is halo (e.g., fluoro or chloro), trifluoromethyl, or methyl. In any variation of formula (J-2), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (J-2), in one aspect, the bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (J-2) have the formula:

or a salt or solvate thereof; wherein R 1 , R 4 and R 12 are defined as for formula (J-2). That is, variations of formula (J-2) detailed throughout, where applicable, apply to formulae (J-2a) and (J-2b) the same as if each and every variation were specifically and individually listed for formulae (J-2a) and (J-2b). Pharmaceutically acceptable salts of compounds of the formula (J-2), (J-2a) and (J-2b) are also provided.

Compounds of the formula (J-3) and (J-4) are also provided:

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH), —CH 2 CF 3 , or —CH 2 CH 2 F; R 4a is H or F; R 4c is H, CH 3 , Cl, F, CF 3 , or —NHCH 3 ; R 9b is H or F; R 9c is F, OCH 3 , —CONH(CH 3 ) or —CON(CH 3 ) 2 and R 12 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo, hydroxyl, carboxyl or acylamino group. In one embodiment of formula (J-3) and (J-4), R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F or —NHCH 3 ; R 9b is H or F; R 9c is F, OCH 3 , —CONH(CH 3 ) or —CON(CH 3 ) 2 ; and R 12 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group. In a further embodiment, R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F or —NHCH 3 ; R 9b is H; R 9c is F, OCH 3 ; and R 12 is methyl

Compounds of the formula (J-5) and (J-6) are also embraced,

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH), —CH 2 CF 3 , or —CH 2 CH 2 F; R 4a is H or F; R 4c is H, CH 3 , Cl, F, CF 3 , or —NHCH 3 ; and R 12 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group. In one embodiment of formula (J-5) and (J-6) R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F or —NHCH 3 ; and R 12 is CH 3 . In yet another variation, R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl or F; and R 12 is CH 3 .

In one variation, compounds of the formula (J-7) or (J-8) are provided

›Definitions · 18 of 48

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH), —CH 2 CF 3 , or —CH 2 CH 2 F; R 4a is H or F; R 4c is H, CH 3 , Cl, F, CF 3 , or —NHCH 3 ; R 9c is H, F, CH 3 , CF 3 , OCH 3 , —CONH(CH 3 ) or —CON(CH 3 ) 2 ; and R 12 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group. In one variation of formula (J-7) and (J-8) R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F, CF 3 , or —NHCH 3 ; and R 9c is H, F, CF 3 , or CH 3 ; and R 12 is methyl. In a particular variation, R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , CF 3 , Cl or F; and R 9c is H, CF 3 , or CH 3 .

In another variation, compounds of the formula (J-9) and (J-10) are provided:

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH), —CH 2 CF 3 , or —CH 2 CH 2 F; R 4a is H or F; and R 4c is H, CH 3 , Cl, F, —CF 3 , or —NHCH 3 . R 12 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, halo (e.g., fluoro), a carboxyl-substituted methyl group or a amido-substituted methyl group In one embodiment of formula (J-9) and (J-10), R 1 is CH 3 ; R 4a is H; and R 4c is CH 3 , Cl, F, CF 3 , or —NHCH 3 . In one embodiment R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , CF 3 , Cl or F; and R 12 is methyl.

In one variation, compounds of the formula (I-G) are provided:

or a salt or solvate thereof, where R 1 , R 4 and Q are defined as for formula (I) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I) detailed throughout, where applicable, apply to formula (I-G) the same as if each and every variation were specifically and individually listed for formula (I-G).

In one variation, compounds of the formula (I-G) are provided, or a salt or solvate thereof, where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl; R 4 is H, halo, trifluoromethyl, a C 1 -C 8 unsubstituted alkyl or a substituted amino; Q is substituted aryl or a substituted or unsubstituted heteroaryl and the bond indicates the presence of either an E or Z double bond configuration. In one variation of formula (I-G), R 1 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo or hydroxyl group. In one such variation, R 1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (I-G), R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH. In another variation of formula (I-G), R 4 is H, halo, methyl, trifluoromethyl, or a substituted amino of the formula —N(H)(C 1 -C 8 unsubstituted alkyl). When R 4 is a halo (e.g., fluoro or chloro), in one aspect R 4 is chloro. In one variation of formula (I-G), R 4 is H, methyl or chloro. In one variation of formula (I-G), R 4 is methyl or chloro. When R 4 is a substituted amino of the formula —N(H)(C 1 -C 8 unsubstituted alkyl), in one aspect C 1 -C 8 unsubstituted alkyl is a linear C 1 -C 8 unsubstituted alkyl such as methyl or ethyl. In a particular variation of formula (I-G), R 4 is —N(H)(CH 3 ). It is understood that any R 1 for formula (I-G) may be combined with any R 4 of formula (I-G) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (I-G) are provided where R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH and R 4 is H, chloro, fluoro, methyl, trifluoromethyl, or —N(H)(CH 3 ). Likewise, compounds of the formula (I-G) are provided where R 1 is methyl and R 4 is H, halo, methyl or a substituted amino of the formula —N(H)(C 1 -C 8 unsubstituted alkyl). In one such aspect, compounds of the formula (I-G) are provided where R 1 is methyl and R 4 is H, halo, trifluoromethyl, or methyl. In one such aspect, compounds of the formula (I-G) are provided where R 1 is methyl and R 4 is halo (e.g., fluoro or chloro) or methyl. When Q of formula (I-G) is a substituted aryl, in one aspect Q is a substituted phenyl. In one aspect, Q is a mono-substituted phenyl. In a particular aspect, Q of formula (I-G) is a halo-substituted phenyl, alkoxy-substituted phenyl or a acylamino-substituted phenyl. Thus, compounds of the formula (I-G) are provided where Q in one variation is a phenyl mono-substituted with a fluoro, C 1 -C 8 alkoxy (e.g., methoxy), an acylamino moiety of the formula —C(O)NH(C 1 -C 8 unsubstituted alkyl) or an acylamino moiety of the formula —C(O)N(C 1 -C 8 unsubstituted alkyl) 2 , such as 2-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-(C(O)NH(CH 3 ) and 4-(C(O)N(CH 3 ) 2 )-phenyl. In one aspect, Q is a di-substituted phenyl. In one aspect, Q of formula (I-G) is a di-halo substituted phenyl group such as 3,4-difluoro-phenyl. In a particular aspect, Q of formula (I-G) is a phenyl group substituted with one halo group and one C 1 -C 8 alkoxy group (e.g., methoxy). Thus, compounds of the formula (I-G) are provided where Q in one variation is a phenyl substituted with a fluoro and a C 1 -C 8 alkoxy group, such as 3-fluoro-4-methoxy-phenyl. When Q of formula (I-G) is a substituted or unsubstituted heteroaryl, in one variation the substituted or unsubstituted heteroaryl is a pyridyl or pyrimidyl moiety. Thus, in one aspect of formula (I-G), Q is an unsubstituted pyridyl or pyrimidyl, such as 3-pyridyl, 4-pyridyl and 4-pyrimidyl. In another aspect of formula (I-G), Q is a substituted pyridyl, such as 6-methyl-3-pyridyl. It is understood that any Q for formula (I-G) may be combined with any R 1 and/or R 4 of formula (I-G) the same as if each and every combination where specifically and individually listed. For example, compounds of the formula (I-G) are provided where R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH; R 4 is H, chloro, fluoro, trifluoromethyl, methyl or —N(H)(CH 3 ) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. Likewise, compounds of the formula (I-G) are provided where R 1 is methyl; R 4 is H, halo or methyl and Q is an unsubstituted pyridyl. In any variation of formula (I-G), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (I-G), in one aspect, the bond indicates the presence of a Z double bond configuration.

›Definitions · 19 of 48

In specific variations, compounds of the formula (I-G) have the formula:

or a salt or solvate thereof; wherein R 1 , R 4 and Q are defined as for formula (I-G) and, where applicable, any variation thereof detailed herein. That is, variations of formula (I-G) detailed throughout, where applicable, apply to formulae (I-g1) and (I-g2) the same as if each and every variation were specifically and individually listed for formulae (I-g1) and (I-g2). In one particular aspect of formula (I-g1), R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH; R 4 is H, chloro, fluoro, methyl trifluoromethyl, or —N(H)(CH 3 ) and Q is 4-pyridyl, 3-pyridyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or 4-dimethylcarbamoyl-phenyl. In another aspect of formula (I-g1), R 1 is methyl, R 4 is H, chloro or methyl and Q is a substituted or unsubstituted pyridyl. In one particular aspect of formula (I-g2), R 1 is methyl, R 4 is methyl and Q is a substituted or unsubstituted pyridyl. Pharmaceutically acceptable salts of compounds of the formula (I-G), (I-g1) and (I-g2) are also provided.

In one variation, compounds of the formula (I-H) are provided:

or a salt or solvate thereof, where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl; R 4 is H, halo or a C 1 -C 8 unsubstituted alkyl and the bond indicates the presence of either an E or Z double bond configuration and where R 4 and the pyridyl moiety may be connected to the parent structure at any available position. In one variation of formula (I-H), R 1 is an unsubstituted C 1 - 8 alkyl or a C 1 -C 8 alkyl substituted with a halo or hydroxyl group. In one such variation, R 1 is methyl, 2-haloethyl (e.g., 2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentyl group. In a particular variation of formula (I-H), R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH. In another variation of formula (I-H), R 4 is H, halo, trifluoromethyl, or methyl. When R 4 is a halo (e.g., fluoro or chloro), in one aspect R 4 is chloro. In one variation of formula (I-H), R 4 is H, methyl or chloro. In one variation of formula (I-H), R 4 is methyl or chloro. It is understood that any R 1 for formula (I-H) may be combined with any R 4 of formula (I-H) the same as if each and every combination were specifically and individually listed. For example, compounds of the formula (I-H) are provided where R 1 is —CH 3 , —CH 2 CH 2 F, —CH 2 CF 3 , or —CH 2 CH 2 C(CH 3 ) 2 OH and R 4 is H, chloro, fluoro, trifluoromethyl, or methyl. Likewise, compounds of the formula (I-H) are provided where R 1 is methyl and R 4 is H, halo or methyl. In one such aspect, compounds of the formula (I-H) are provided where R 1 is methyl and R 4 is halo (e.g., fluoro or chloro) or methyl. In any variation of formula (I-H), in one aspect, the bond indicates the presence of an E double bond configuration. In any variation of formula (I-H), in one aspect, the bond indicates the presence of a Z double bond configuration.

In specific variations, compounds of the formula (I-H) have the formula:

or a salt or solvate thereof; wherein R 1 and R 4 are defined as for formula (I-H). That is, variations of formula (I-H) detailed throughout, where applicable, apply to formulae (I-h1) and (I-h2) the same as if each and every variation were specifically and individually listed for formulae (I-h1) and (I-h2). Pharmaceutically acceptable salts of compounds of the formula (I-H), (I-h1) and (I-h2) are also provided.

Compounds of the formula (H-1) and (H-2) are also provided:

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH), —CH 2 CF 3 , or —CH 2 CH 2 F; R 4a is H or F; R 4c is H, CH 3 , CF 3 , Cl, F or —NHCH 3 ; R 9b is H or F; and R 9c is F, OCH 3 , —CONH(CH 3 ) or —CON(CH 3 ) 2 . In one embodiment of formula (H-1) and (H-2), R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F, CF 3 , or —NHCH 3 ; R 9b is H or F; and R 9c is F, OCH 3 , —CONH(CH 3 ) or —CON(CH 3 ) 2 . In a further embodiment, R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F or —NHCH 3 ; R 9b is H; and R 9c is F, OCH 3 .

Compounds of the formula (H-3) and (H-4) are also embraced,

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH) or —CH 2 CH 2 F; R 4a is H or F; and R 4c is H, CH 3 , Cl, F or —NHCH 3 . In one embodiment of formula (H-3) and (H-4), R 1 is CH 3 ; R 4a is H and R 4c is CH 3 , Cl, F, CF 3 , or —NHCH 3 . In yet another variation, R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , CF 3 , Cl or F.

In one variation, compounds of the formula (H-5) or (H-6) are provided

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH), —CH 2 CF 3 , or —CH 2 CH 2 F; R 4a is H or F; R 4c is H, CH 3 , Cl, F, CF 3 , or —NHCH 3 ; and R 9c is H, F, CH 3 , CF 3 , OCH 3 , —CONH(CH 3 ) or —CON(CH 3 ) 2 . In one variation of formula (H-5) and (H-6) R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl, F, CF 3 , or —NHCH 3 ; and R 9 is H, F, CF 3 , or CH 3 . In a particular variation, R 1 is CH 3 ; R 4a is H; R 4c is CH 3 , Cl or F; and R 9 is H, CF 3 , or CH 3 .

In another variation, compounds of the formula (H-7) and (H-8) are provided:

or a salt or solvate thereof, wherein R 1 is CH 3 , —CH 2 CH 2 —C(CH 3 ) 2 (OH), —CH 2 CF 3 or —CH 2 CH 2 F; R 4a is H or F; and R 4c is H, CH 3 , CF 3 , Cl, F or —NHCH 3 . In one embodiment of formula (H-7) and (H-8), R 1 is CH 3 ; R 4a is H; and R 4c is CH 3 , Cl, F, CF 3 , or —NHCH 3 . In one embodiment R 1 is CH 3 ; R 4a is H; and R 4c is CH 3 , CF 3 , Cl or F

The substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 8c , R 8d , R 10a , R 10b , R 11 , R 12 , m, q, Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formula (I) are also suitable for compounds of formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-b1), (I-b2), (I-c1), (I-c2), (I-d1), (I-d2), (I-e1), (I-e2), (I-f1) and (I-f2) when applicable. Likewise, substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , q, Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formula (I) are also suitable for compounds of formulae (I-G), (I-g1), (I-g2), (I-H), (I-h1) and (I-h2) when applicable.

›Definitions · 20 of 48

The invention also embraces compounds of the formula (III):

or a salt or solvate thereof;

wherein:

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

R 11 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl and the bond indicates the presence of either an E or Z double bond configuration;

R 12 is H, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, C 2 -C 8 alkenyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino;

provided that (i) when X 7 , X 8 and X 10 are each CH and each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is hydrogen, the compound is other than a compound in Table A, and (ii) the compound is other than Compound 87. In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (III), including Compound 87. In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (III), including those listed in Table A. In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (III), including Compound 87 and those listed in Table A. The substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 8c , R 8d , R 10a , R 10b , R 11 , R 12 , m, q, Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formula (I) are also suitable for compounds of formulae (III). Variations of formula (I) detailed throughout, where applicable, apply to formula (III) the same as if each and every variation were specifically and individually listed for formula (III).

In one variation, the compound is of the formula (III) where R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In another variation, the compound is of the formula (III) where each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, hydroxyl, alkoxy or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety and each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, hydroxyl, alkoxy or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety. In some variations, the compound is of the formula (III) where R 1 is an unsubstituted C 1 -C 8 alkyl (e.g. methyl) and each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H.

In one variation, the compound is of the formula (III), where at least one of R 11 and R 12 is other than H. In one such variation, the compound is of the formula (I) where R 11 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. For example, the compound in one aspect is of the formula (III) where R 11 is a substituted aryl (e.g. 4-fluorophenyl). In another aspect, the compound is of the formula (III) where R 11 is an unsubstituted aryl (e.g. phenyl). In another such variation, the compound is of the formula (III) where R 12 is halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, C 2 -C 8 alkenyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. For example, the compound in one aspect is of the formula (III) where R 12 is halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or C 2 -C 8 alkenyl. In one aspect, the compound is of the formula (III) where R 12 is halo (e.g., fluoro). In another aspect, the compound is of the formula (III) where R 12 is a substituted aryl (e.g., 4-fluorophenyl) or unsubstituted aryl (e.g. phenyl). In another aspect, the compound is of the formula (III) where R 12 is a C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety (e.g., ethoxycarbonylmethyl, carboxymethyl or methylaminocarbonylmethyl). In still another aspect, the compound is of the formula (III) where R 12 is C 2 -C 8 alkenyl (e.g., propen-1-yl). In another such variation, R 11 is substituted or unsubstituted aryl and R 12 is H. In yet another such variation, R 11 is H and R 12 is halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or C 2 -C 8 alkenyl. In one particular variation, the compound is of the formula (III) where R 11 is substituted or unsubstituted aryl, R 12 is H, m is 0, q is 1, each R 8a and R 8b is H, and Q is carboxy or carbonylalkoxy. In another particular variation, the compound is of the formula (III) where R 11 is H, R 12 is halo, m and q are 0 and Q is a heteroaryl (e.g. a pyridyl such as 4-pyridyl). In another particular variation, the compound is of the formula (III) where R 11 is H, R 12 is substituted or unsubstituted aryl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or C 2 -C 8 alkenyl, m and q are 0 and Q is a substituted aryl (e.g., 4-fluorophenyl) or unsubstituted aryl (e.g. phenyl).

›Definitions · 21 of 48

The invention also embraces compounds of the formula (V):

or a salt or solvate thereof;

wherein:

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

In one variation, the compound is of the formula (V) where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, q, m, R 8a , R 8b , R 8c , R 8d , R 11 and R 12 are as defined for formula (V), provided that (i) when X 7 , X 8 and X 10 are each CH and each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is hydrogen, at least one of R 11 and R 12 is other than hydrogen and R 11 and R 12 are not taken together to form a bond; and (ii) the compound is other than Compound 87. In one aspect, compounds of the formula (V) are provided where q and m are both 0 and at least one of R 11 and R 12 is a substituted or unsubstituted alkyl, such as methyl. In another aspect, compounds of the formula (V) are provided where q and m are both 0 and at least one of R 11 and R 12 is a substituted or unsubstituted alkyl, such as methyl, and Q is a substituted or unsubstituted aryl, such as phenyl, or a substituted or unsubstituted heteroaryl, such as pyridyl. In another aspect, compounds of the formula (V) are provided where q and m are both 0, R 11 is H, R 12 is methyl and Q is a substituted or unsubstituted heteroaryl, such as pyridyl. In a more particular variation of formula (V), q and m are both 0, R 11 is H, R 12 is methyl and Q is a substituted or unsubstituted heteroaryl, such as pyridyl and one or more of the following structural features applies: (i) X 7 , X 8 and X 10 are each CH; (ii) X 9 is CH or CR 4 where R 4 is halo or an unsubstituted C 1 -C 8 alkyl; (iii) R 2a and R 2b are both H; (iv) R 1 is methyl; (v) R 3a and R 3b are both H and (vi) R 10a and R 10b are both H. In one such variation, at least two or three or four or five or all of (i)-(vi) apply. When more than one of (i)-(vi) applies, the provisions may be combined in any manner. In another variation, the compounds provided herein, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (V), including Compound 87. The substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , m, q, Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formulae (I) and (III) are also suitable for compounds of formula (V). Variations of formulae (I) and (III) detailed throughout, where applicable, apply to formula (V) the same as if each and every variation were specifically and individually listed for formula (V).

›Definitions · 22 of 48

In one variation, compounds of the formula (V) are provided, where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , q, m, and Q are as defined for formula (V), each R 8a , R 8b , R 8c and R 8d is independently H, hydroxyl, C 1 -C 8 alkyl, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety; R 11 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl and the bond indicates the presence of either an E or Z double bond configuration; and R 12 is H, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, C 2 -C 8 alkenyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In another variation, the compound is of the formula (V), where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, q, m, R 8a , R 8b , R 8c and R 8d are as defined for formula (V), R 11 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl and R 12 is H, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl or C 1 -C 8 perhaloalkyl. In another variation, the compound is of the formula (V), where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, q, m, R 8a , R 8b , R 8c , R 8d and R 11 are as defined for formula (V) and R 12 is C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety.

In one embodiment, provided is a compound of formula (V) where at least one R 3a and R 3b is aryl. In a particular variation of formula (V), at least one of R 3a and R 3b is phenyl.

In some embodiments, the compound of formula (V) has the formula (V-B):

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , R 11a , R 12 , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (V) and, where applicable, any variation thereof detailed herein. That is, variations of formula (V) detailed throughout, where applicable, apply to formula (V-B) the same as if each and every variation were specifically and individually listed for formula (V-B). In one variation, compounds of formula (V-B) are detailed herein, provided that (i) when X 7 , X 8 and X 10 are each CH and each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is hydrogen, at least one of R 11 and R 12 is other than hydrogen and R 11 and R 12 are not taken together to form a bond; and (ii) the compound is other than Compound 87. In another variation, compounds of formula (V-B), including Compound 87, and methods of using and administering such compounds are encompassed. In one aspect of formula (V-B), at least one of R 11 and R 12 is other than H. In one such variation of formula (V-B), R 11 is H and R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In one aspect of formula (V-B), R 11 is H and R 1 is C 1 -C 8 alkyl. In another variation of formula (V-B) at least one of R 11 and R 12 is other than H and R 1 is C 1 -C 8 alkyl. In one such variation, R 12 is an unsubstituted C 1 -C 8 alkyl and Q is a substituted or unsubstituted heteroaryl. In one variation of formula (V-B), R 12 is an unsubstituted C 1 -C 8 alkyl and Q is other than a halo-substituted phenyl. In a more particular variation of formula (V-B), R 11 is H, R 12 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl and R 1 is C 1 -C 8 alkyl. In an even more particular variation of formula (V-B), R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo and each X 7 , X 8 and X 10 is CH. In another variation of formula (V-B), R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo, each X 7 , X 8 and X 10 is CH, R 1 is alkyl and each R 2a , R 2b , R 3a , R 3b , R 10a , R 10b is H. In any variation or aspect of formula (V-B) detailed herein, in one embodiment, the compound of formula (V-B) is in the E configuration. Similarly, in any variation or aspect of formula (V-B) detailed herein, in another embodiment, the compound of formula (V-B) is in the Z configuration. For example, provided are compounds of formula (V-B) where R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo, each X 7 , X 8 and X 10 is CH and the compound is in the E configuration. Likewise, also provided are compounds of formula (V-B) where R 11 is H, R 12 is C 1 -C 8 alkyl, X 9 is CR 4 where R 4 is halo, each X 7 , X 8 and X 10 is CH and the compound is in the Z configuration.

In one embodiment, the compound is of the formula (V-B), where R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, X 7 , X 8 , X 9 , and X 10 are defined for formula (V); R 11 is H, hydroxyl, alkoxy, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and R 12 and Q are independently a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In one variation, R 12 and Q are the same substituted or unsubstituted aryl or heteroaryl moiety, such as when both R 12 and Q are phenyl.

In some embodiments, the compound of formula (V) has the formula (V-G):

or a salt or solvate thereof; where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 8c , R 8d , R 10a , R 10b q, m and Q are as defined for formula (V). In one variation, the compound is of the formula (V-G), provided that (i) when q and m are 0, each R 2a , R 2b , R 3a , R 3b , R 10a , and R 10b is H, each X 7 , X 8 , X 9 and X 10 is independently CH or CR 4 where R 4 is methyl, fluoro or CF 3 , and Q is phenyl, substituted phenyl, pyridyl or pyrimidyl, the compound is other than a compound specifically described in WO 2008/123796 A2, and (ii) the compound is other than Compound 478, Compound 490 and Compound 495. In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (V-G), including Compound 478, Compound 490 and Compound 495. In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (V-G), including compounds specifically described in WO 2008/123796 A2.

›Definitions · 23 of 48

In some embodiments, the compound of formula (V) has the formula (V-H):

or a salt or solvate thereof; where R 1 and Q are as defined for formula (V). In one variation, Q of formula (V-H) is a substituted or unsubstituted aryl, such as phenyl. In one aspect, Q of formula (V-H) is a mono-substituted phenyl, such as a mono-halo substituted phenyl, for example 4-fluoro-phenyl. In another variation Q of formula (V-H) is a mono-substituted phenyl and R 1 is an unsubstituted C 1 -C 8 alkyl such as methyl.

The invention further embraces compounds of the formula (IV):

or a salt or solvate thereof;

wherein:

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each R 13a and R 13b is independently H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl;

each R 14a and R 14b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carbonylalkoxy, carboxyl, acylamino or R 14a and R 14b are taken together with the carbon to which they are attached to form a cycloalkyl moiety, and;

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino and the bond indicates the presence of either an E or Z double bond configuration.

In one variation, compounds of the formula (IV) are provided, where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, R 13a , R 13b are as defined for formula (IV) and R 14a and R 14b are independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, substituted or unsubstituted heterocyclyl or C 1 -C 8 perhaloalkyl.

The substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formula (I) or formula (III) are also suitable for compounds of formulae (IV). Variations of formula (I) and formula (III) with regard to substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, X 7 , X 8 , X 9 , and X 10 detailed throughout, where applicable, apply to formula (IV) the same as if each and every variation were specifically and individually listed for formula (IV).

In some embodiments, the compound is of the formula (IV) where at least one of R 13a and R 13b is H. In one such variation, each R 13a and R 13b is H. In another variation, one of R 13a and R 13b is H and the other one of R 13a and R 13b is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In a particular variation, the compound is of the formula (IV) where each R 13a and R 13b is H and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl.

In some embodiments, the compound is of the formula (IV) where at least one of R 14a and R 14b is H. In one such variation, each R 14a and R 14b is H. In another such variation, one of R 14a and R 14b is H and the other one of R 14a and R 14b is substituted or unsubstituted C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carbonylalkoxy, carboxyl or acylamino. For example, the one of R 14a and R 14b that is not H is a an unsubstituted C 1 -C 8 alkyl (e.g. methyl, ethyl or propyl), a C 1 -C 8 alkyl substituted with hydroxy (e.g. 2-hydroxyethyl), a carbonylalkoxy, a carboxyl or an acylamino group. In one particular variation, the compound is of the formula (IV) where each R 13a and R 13b is H and each R 14a and R 14b is H. In a further variation, the compound is of the formula (IV) where each R 13a and R 13b is H, each R 14a and R 14b is H and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl.

›Definitions · 24 of 48

In some embodiments, the compound is of the formula (IV) where each R 14a and R 14b is independently substituted or unsubstituted C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carbonylalkoxy, carboxyl, acylamino or R 14a and R 14b are taken together with the carbon to which they are attached to form a cycloalkyl moiety. In one such variation, each R 14a and R 14b is independently substituted or unsubstituted C 1 -C 8 alkyl. For example, each R 14a and R 14b is methyl or one of R 14a and R 14b is methyl and the other is a substituted or unsubstituted C 1 -C 8 alkyl other than methyl. In another such variation, R 14a and R 14b are taken together with the carbon to which they are attached to form a cycloalkyl moiety. For example, R 14a and R 14b are taken together with the carbon to which they are attached to form a cyclopropyl moiety. In some variations, the compound is of the formula (IV) where each R 14a and R 14b is independently substituted or unsubstituted C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carbonylalkoxy, carboxyl, acylamino or R 14a and R 14b are taken together with the carbon to which they are attached to form a cycloalkyl moiety, each R 13a and R 13b is H and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl.

The invention also embraces compounds of the formula (VI):

or a salt or solvate thereof;

wherein:

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each R 13a and R 13b is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carboxy, or carbonylalkoxy;

each R 14a and R 14b is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carbonylalkoxy, carboxyl, acylamino or R 14a and R 14b are taken together with the carbon to which they are attached to form a cycloalkyl moiety; and

In one variation, the compound is of the formula (VI) where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, R 13a , R 13b , R 14a and R 14b are as defined for formula (VI), provided that the compound is other than Compound 132. In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (VI), including Compound 132. The substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , R 13a , R 13b , R 14a , R 14b , Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formula (IV) are also suitable for compounds of formula (VI). Variations of formula (IV) detailed throughout, where applicable, apply to formula (VI) the same as if each and every variation were specifically and individually listed for formula (VI).

In one variation, compounds of the formula (VI) are provided, where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, R 13a and R 13b are as defined for formula (VI) and each R 14a and R 14b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 perhaloalkyl, carbonylalkoxy, carboxyl, acylamino or R 14a and R 14b are taken together with the carbon to which they are attached to form a cycloalkyl moiety.

›Definitions · 25 of 48

In one embodiment, provided is a compound of formula (VI) where at least one R 3a and R 3b is aryl. In a particular variation of formula (VI), at least one of R 3a and R 3b is phenyl.

In one variation, compounds of the formula (VIA) are provided:

or a salt or solvate thereof; where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, R 13a , R 13b , R 14a , R 14b are as defined for formula (VI), or a variation thereof, and q is 0 or 1.

In another aspect, the invention embraces compounds of the formula (II):

or a salt or solvate thereof;

wherein:

each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together to form a carbonyl moiety;

each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 3a and R 3b are taken together to form a carbonyl moiety;

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 10a and R 10b are taken together to form a carbonyl moiety;

each R 11a and R 12a is independently H, hydroxyl, or C 1 -C 8 alkyl; or R 11a and R 12a may betaken together to represent a bond;

Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino.

In one variation of formula (II), q is 0 and m are both 0 and R 11a and R 12a are each H. In another variation of formula (II), q and m are both 0, R 11a and R 12a are each H and R 11b and R 12b are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted cycloalkyl moiety. In yet another variation of formula (II), q and m are both 0, R 11a and R 12a are each H, R 11b and R 12b are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted cycloalkyl moiety and at least one of (i)-(iv) applies: (i) X 9 is CR 4 where R 4 is a C 1 -C 8 alkyl (e.g., methyl) or halo (e.g., chloro); (ii) R 1 is a C 1 -C 8 alkyl (e.g., methyl); (iii) each X 7 , X 8 and X 10 is CH; and (iv) each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b , is H. Preferably, when Q is a cycloalkyl moiety, it is an unsubstituted C 3 -C 8 cycloalkyl moiety (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).

In one variation of formula (II), R 11a and R 12a are taken together to form a bond. In a particular variation of formula (II), R 11a and R 12a are taken together to form a double bond (such that the bond between the carbon bearing R 11a and R 11b and the carbon bearing R 12a and R 12b is a double bond) and together with R 11b and R 12b are taken to form a cycloalkenyl moiety (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl). In a further variation of formula (II), R 11a and R 12a are taken together to form a double bond and together with R 11b and R 12b are taken to form a cycloalkenyl moiety and at least of of (i)-(v) applies: (i) at least one of X 7 -X 10 is CR 4 where R 4 is halo (e.g., when X 9 is CR 4 where R 4 is chloro); (ii) R 1 is C 1 -C 8 alkyl (e.g., methyl); (iii) Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl; (iv) q and m are both 0; and (v) each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H.

In any variation or aspect of formula (II) detailed herein where R 11a and R 12a are taken together to form a double bond such that R 11a and R 12a are taken together with R 11b and R 12b to form a cycloalkenyl moiety. In one embodiment, the compound of formula (II) is in the E configuration. Similarly, in any variation or aspect of formula (II) detailed herein, in another embodiment, the compound of formula (II) is in the Z configuration.

In certain embodiments, the compound of formula (II) has the structure:

or a salt or solvate thereof;

›Definitions · 26 of 48

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , q, Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II) detailed throughout, where applicable, apply to formula (II-A) the same as if each and every variation were specifically and individually listed for formula (II-A).

In some such embodiments, R 11a and R 12a are taken together to form a bond and the compound of formula (II-A) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11 , R 12 , q, Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II-A) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II-A) and formula (II) detailed throughout, where applicable, apply to formula (II-a1) the same as if each and every variation were specifically and individually listed for formula (II-a1).

In other embodiments, the compound of formula (II) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , R 11a , R 11b , R 12a , R 12b , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II) detailed throughout, where applicable, apply to formula (II-B) the same as if each and every variation were specifically and individually listed for formula (II-B).

In some such embodiments, R 11a and R 12a are taken together to form a bond and the compound of formula (II-B) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , R 11a , R 12b , q, Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II-B) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II-B) and formula (II) detailed throughout, where applicable, apply to formula (II-b1) the same as if each and every variation were specifically and individually listed for formula (II-b1).

In other embodiments, the compound of formula (II) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11a , R 11b , R 12a , R 12b , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II) detailed throughout, where applicable, apply to formula (II-C) the same as if each and every variation were specifically and individually listed for formula (II-C).

In some such embodiments, R 11a and R 12a are taken together to form a bond and the compound of formula (II-C) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 10a , R 10b , R 11b , R 12b , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II-C) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II-C) and formula (II) detailed throughout, where applicable, apply to formula (II-c1) the same as if each and every variation were specifically and individually listed for formula (II-c1).

In further embodiments, the compound of formula (II) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8c , R 8d , R 10a , R 11a , R 11b , R 12a , R 12b , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II) detailed throughout, where applicable, apply to formula (II-D) the same as if each and every variation were specifically and individually listed for formula (II-D).

In some such embodiments, R 11a and R 12a are taken together to form a bond and the compound of formula (II-D) has the structure:

or a salt or solvate thereof;

wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 8c , R 8d , R 10a , R 10b , R 11b , R 12b , Q, X 7 , X 8 , X 9 , and X 10 are defined as for formula (II-D) and, where applicable, any variation thereof detailed herein. That is, variations of formula (II) detailed throughout, where applicable, apply to formula (II-d1) the same as if each and every variation were specifically and individually listed for formula (II-d1).

The substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 8c , R 8d , R 10a , R 10b , R 11a , R 11b , R 12a , R 12b , m, q, Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formula (II) are also suitable for compounds of formulae (II-A), (II-B), (II-C), (II-D), (II-a1), (II-b1), (II-c1) and (II-d1).

The invention also embraces compounds of the formula (VII):

or a salt or solvate thereof;

wherein:

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

›Definitions · 27 of 48

each m and q is independently 0 or 1;

In one variation, the compound is of the formula (VII) where X 7 , X 8 , X 9 , X 10 , R 1 , R 2a , R 2b , R 3a , R 3b , R 10a , R 10b , Q, q, m, R 8a , R 8b , R 8c , R 8d , R 11a , R 11b , R 12a and R 12b are as defined for formula (VII), provided that the compound is other than 2-(1,2,3,4-tetrahydro-2,8-dimethyl-5H-pyrido[4,3-b]indol-5-yl)cyclohexanol. In another variation, the compounds of the invention, and methods of using the compounds and administering the compounds as detailed herein, encompass any of the compounds of the formula (VII), including 2-(1,2,3,4-tetrahydro-2,8-dimethyl-5H-pyrido[4,3-b]indol-5-yl)cyclohexanol. The substituent groups R 1 , R 2a , R 2b , R 3a , R 3b , R 8a , R 8b , R 8c , R 8d , R 10a , R 10b , R 11a , R 11b , R 12a , R 12b , m, q, Q, X 7 , X 8 , X 9 , and X 10 described herein as suitable for compounds of formula (II) are also suitable for compounds of formula (VII). Variations of formula (II) detailed throughout, where applicable, apply to formula (VII) the same as if each and every variation were specifically and individually listed for formula (VII).

In one embodiment, provided is a compound of formula (VII) where at least one R 3a and R 3b is aryl. In a particular variation of formula (VII), at least one of R 3a and R 3b is phenyl.

The invention also embraces compounds of the formula (VIII):

or a salt or solvate thereof;

wherein:

›Definitions · 28 of 48

each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 ;

each m and q is independently 0 or 1;

each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R 8(a-f) to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R 8(a-f) to form a moiety of the formula —OCH 2 CH 2 O—, a methylene or a substituted methylene, is taken together with a vicinal R 8(a-f) and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(a-f) to form a bond, provided that (i) at least one of R 8c and R 8d is taken together with a vicinal R 8(a-f) and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(a-f) to form a bond, and (ii) when an R 8(a-f) is taken together with a vicinal R 8 to form a bond, the geminal R 8(a-f) is other than hydroxyl;

In another variation, compounds of the Formulae or pharmaceutically acceptable salts thereof are embraced, provided that the compounds are other than compounds in Table B or a pharmaceutically acceptable salt thereof. In a particular variation, compounds of the formula (I) are embraced, provided the compounds are other than any of compounds 1x-99x. In one variation, compounds of the formula (III) are embraced, provided the compounds are other than any of compounds 1x-99x. In another variation, compounds of the formula (V) are embraced, provided the compounds are other than any of compounds 1x-129x. In still another variation, compounds of the formula (VIII) are embraced, provided the compounds are other than any of compounds 1x-129x. In yet another variation, compounds of the formula (IV) are embraced, provided the compounds are other than compound 130x. In another variation, compounds of the formula (VI) are embraced, provided the compounds are other than compound 130x. In still a further variation, compounds of the formulae detailed herein are provided, wherein the compounds include a compound of Table B or a pharmaceutically acceptable salt thereof. In addition, methods provided herein, including methods of treatment as detailed herein, in one variation employ compounds according to the formulae detailed herein, including compounds of Table B.

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), R 1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In specific embodiments, R 1 is a substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In more specific embodiments, R 1 is an unsubstituted C 1 -C 8 alkyl such as methyl and cyclopropyl.

In certain embodiments, compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) are provided where R 1 is selected from the following moieties:

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), the ring comprising N, R 2a , R 2b , R 10a , R 10b , R 3a and R 3b K is sometimes referred to herein as the C-ring.

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together to form a carbonyl moiety. In specific embodiments, each R 2a and R 2b is independently H, methyl, fluoro or R 2a and R 2b are taken together to form a carbonyl moiety. In a specific embodiment, R 2a and R 2b are both H.

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together to form a carbonyl moiety. In specific embodiments, each R 3a and R 3b is independently H or fluoro. In another specific embodiment, R 3a and R 3b are both H. In a further specific embodiment, R 3a and R 3b are both H and R 2a and R 2b are both H.

›Definitions · 29 of 48

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 10a and R 10b are taken together to form a carbonyl moiety. In specific embodiments, each R 10a and R 10b is independently H, halo, hydroxyl or methyl or R 10a and R 10b are taken together to form a carbonyl moiety. In another specific embodiment, R 10a and R 10b are both H. In a further specific embodiment, R 10a and R 10b are both H and R 2a , R 2b , R 3a and R 3b are each H.

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), the ring comprising X 7 , X 8 , X 9 and X 10 is sometimes referred to herein as the A-ring. In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), each X 7 , X 8 , X 9 and X 10 is independently N, CH or CR 4 . In certain embodiments, each X 7 , X 8 , X 9 and X 10 is CH or CR 4 , such that the A-ring is an optionally substituted phenyl ring. In specific embodiments, X 9 is CR 4 where R 4 is halo or alkyl and X 7 , X 8 and X 10 are each CH. In other embodiments, one of X 7 , X 8 , X 9 and X 10 is N, and the others are CH or CR 4 , such that the A-ring is an optionally substituted pyridine ring. In further embodiments, two of X 7 , X 8 , X 9 and X 10 are N, and the others are CH or CR 4 , such that the A-ring is an optionally substituted pyrimidine or pyrazine ring. In one variation of formula (I), X 9 is CR 4 where R 4 is halo or alkyl, X 7 , X 8 and X 10 are each CH and R 12 is other than H. In one variation of formula (II), X 9 is CR 4 where R 4 is halo or alkyl, X 7 , X 8 and X 10 are each CH and either (a) R 11a and R 12a are both H and R 11b and R 12b are taken together to form a substituted or unsubstituted cycloalkyl; or (b) R 11a and R 12a are taken together to form a double bond and together with R 11b and R 12b form a cycloalkenyl moiety.

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), each R 4 , where present, is independently hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, aryloxy, carboxyl, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl. In one variation, at least one of X 7 -X 10 is CR 4 where R 4 is halo. In a particular variation, one of X 7 -X 10 is CR 4 where R 4 is chloro and the others are CH. In a specific variation, X 7 , X 8 and X 10 are each CH and X 9 is CR 4 where R 4 is chloro.

In certain embodiments of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), each R 4 , where present, is independently hydroxyl, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino or acyl. In further embodiments, each R 4 is independently hydroxyl, halo, C 1 -C 4 perhaloalkyl, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C 1 -C 4 alkoxy; or in still a further variation, each R 4 is independently halo, unsubstituted C 1 -C 4 alkyl or C 1 -C 4 perhaloalkyl.

In specific embodiments, the A-ring is a phenyl, pyridyl, pyrimidinyl or pyrazinyl ring, optionally substituted with 0-2 R 4 groups (i.e., (R 4 ) n ) where n is 0, 1 or 2. In some such embodiments, n is 1 or 2 and each R 4 is independently halo, methyl or CF 3 .

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), each R 8a , R 8b , R 8c and R 8d , where present, is independently H, hydroxyl, C 1 -C 8 alkyl or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety. In specific embodiments, each R 8a , R 8b , R 8c and R 8d , where present, is independently H, hydroxyl, methyl or is taken together with the carbon to which it is attached and a geminal R 8 to form a carbonyl moiety. In another specific embodiment, each R 8a , R 8b , R 8c and R 8d , where present, is H.

In specific embodiments of formulae (I), (II) and (III), q is 0 and m is 0. In other embodiments, q is 1 and m is 0. In compounds of formula (I), when m is 0, the group Q is directly bonded to the carbon atom bearing R 12 , and R 8c and R 8d and the carbon to which they are attached are absent. In compounds of formula (II), when m is 0, the group Q is directly bonded to the carbon atom bearing R 12a and R 12b , and R 8c and R 8d and the carbon to which they are attached are absent.

In further embodiments of formulae (I), (II) and (III), q is 0 and m is 1. When q is 0, R 8a and R 8b and the carbon to which they are attached are absent.

In certain preferred embodiments of formulae (I), (II) and (III), q is 0, and m is 0. In other embodiments, q is 1, and m is 0. In other embodiments, q is 0, and m is 1.

In compounds of formula (I), R 11 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl, and R 12 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In one variation, compounds are of the formula (I) where R 11 is H or C 1 -C 8 alkyl, and R 12 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. In some embodiments, each R 11 and R 12 is independently H or optionally substituted C 1 -C 8 alkyl. In certain embodiments, each R 11 and R 12 is independently H or C 1 -C 4 alkyl. In specific embodiments, each R 11 and R 12 is independently H or methyl. In other embodiments, R 11 is H or C 1 -C 4 alkyl and R 12 is C 1 -C 4 perhaloalkyl, preferably trifluoromethyl. In further embodiments, R 11 is H or Me, and R 12 is Me, Et, cyclopropyl or CF 3 . In some embodiments, the olefin bearing substituents R 11 and R 12 has the trans-orientation; in other embodiments, the olefin has the cis-orientation.

›Definitions · 30 of 48

In some embodiments of formula (II), each R 11a and R 12a is independently H, hydroxyl, or C 1 -C 8 alkyl. In certain embodiments, each R 11a and R 12a is independently H or C 1 -C 4 alkyl. In specific embodiments, each R 11a and R 12a is independently H or methyl. In other embodiments, R 11a and R 12a may be taken together to represent a bond, such that the bond between the carbon atoms to which R 11a and R 12a are attached is a double bond, and the ring formed between R 11b and R 12b is an unsaturated carbocyclic or heterocyclic ring.

In compounds of formula (II), R 11b and R 12b are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety. In some embodiments, when R 11b and R 12b are taken together to form a cycloalkenyl ring, R 11a and R 12a are taken together to represent a bond.

In certain embodiment of formula (II), R 11b and R 12b are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. In some such embodiments, the cycloalkyl ring is substituted with hydroxyl, C 1 -C 4 alkyl, or oxo (═O). In other embodiments, the cycloalkyl ring is unsubstituted.

In other embodiment of formula (II), R 11b and R 12b are taken together with the carbon atoms to which they are attached to form an optionally substituted cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl ring. In some such embodiments, R 11a and R 12a are taken together to represent a bond between the carbon atoms to which they are attached. In some embodiments, the cycloalkenyl ring is optionally substituted with hydroxyl, C 1 -C 4 alkyl, or oxo (═O). In other embodiments, the cycloalkenyl ring is unsubstituted.

In further embodiments, R 11b and R 12b are taken together with the carbon atoms to which they are attached to form an optionally substituted heterocyclic ring containing one or more heteroatoms selected from the group consisting of N, O and S, which heterocyclic ring may be saturated or unsaturated.

In certain variations of formula (II), R 11b and R 12b are taken together with the carbon atoms to which they are attached to form a cycloalkyl or cycloalkenyl ring selected from the following structures, each of which may be optionally substituted:

In compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino. In one variation, compounds are of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or a unsubstituted heterocyclyl. In certain embodiments, Q is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl. In some such embodiments, Q is a substituted or unsubstituted phenyl, pyridyl or pyrimidinyl ring. When Q is substituted, it is frequently substituted with from 1-3 substituents selected from group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 perhaloalkyl, and C 1 -C 4 alkoxy.

In a particular variation of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), Q is a substituted heteroaryl, a monosubstituted aryl group substituted with a chloro or alkyl group or a di- or tri-substituted aryl moiety. For instance, Q in one variation is selected from the group consisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl and pyrimidinyl. In one aspect, Q is a substituted pyridyl such as 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl.

In some embodiments of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), R 1 is a substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl; each R 2a and R 2b is independently H, methyl, fluoro or R 2a and R 2b are taken together to form a carbonyl moiety; each R 3a and R 3b is independently H or fluoro; and each R 10a and R 10b is independently H, halo, hydroxyl or methyl or R 10a and R 10b are taken together to form a carbonyl moiety. In particular variations of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), R 1 is an unsubstituted C 1 -C 8 alkyl and R 2a , R 2b , R 3a , R 3b , R 10a and R 10b , are each H. In still a further variation of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), R 1 is an unsubstituted C 1 -C 8 alkyl, R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are each H and Q is selected from the group consisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl and pyrimidinyl. In still a further variation of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), R 1 is an unsubstituted C 1 -C 8 alkyl, R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are each H and X 9 is CR 4 where R 4 is chloro. In yet a further variation of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII), R 1 is an unsubstituted C 1 -C 8 alkyl, R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are each H, X 9 is CR 4 where R 4 is chloro and Q is a substituted or unsubstituted aryl or a substituted or substituted heteroaryl. In one such variation, Q is a substituted phenyl.

›Definitions · 31 of 48

In particular embodiments of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), each X 7 , X 8 , X 9 and X 10 is CH or CR 4 . In other embodiments, the compound is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where at least one of X 7 , X 8 , X 9 and X 10 is N. Another variation provides a compound of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where at least two of X 7 , X 8 , X 9 and X 10 are N. A further variation provides a compound of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where two of X 7 , X 8 , X 9 and X 10 are N and two of X 7 , X 8 , X 9 and X 10 are CH or CR 4 . Compounds of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where one of X 7 , X 8 , X 9 and X 10 is N and three of X 7 , X 8 , X 9 and X 10 are CH or CR 4 are also embraced by this invention.

In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) wherein the A-ring is an aromatic moiety selected from the following structures:

where each R 4 is as defined for formula (I). In a particular variation, each R 4 is independently hydroxyl, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or acyl. In a further variation, each R 4 is independently halo, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 perhaloalkyl, or C 1 -C 4 alkoxy.

In still a further variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein the A-ring is an aromatic moiety selected from the following structures:

wherein R 4 is as defined in formula (I); or in a particular variation, where R 4 is hydroxyl, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or acyl; or in still a further variation, where each R 4 is independently halo, unsubstituted C 1 -C 4 alkyl, C 1 -C 4 perhaloalkyl, or C 1 -C 4 alkoxy.

In a further variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein the A-ring is an aromatic moiety selected from the following structures:

Any formula detailed herein, where applicable, may in one variation have X 7 , X 8 , X 9 and X 10 taken together to provide an aromatic moiety detailed herein above. It is understood that by “where applicable” it is intended that in one variation such X 7 , X 8 , X 9 and X 10 groups are taken together to provide a moiety hereinabove if the formula encompasses such a structure. For example, if a given formula does not encompass structures wherein X 7 , X 8 , X 9 and X 10 groups are taken together provide a pyridyl moiety, then a pyridyl moiety as detailed hereinabove is not applicable to that particular formula, but remains applicable to formulae that do encompass structures where X 7 , X 8 , X 9 and X 10 groups are taken together provide a pyridyl moiety.

In another embodiment, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 7 -X 10 are as defined in formula (I) or as detailed in any variation herein, where R 1 is H, substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl. In a further embodiment, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), wherein X 7 -X 10 are as defined in formula (I) or as detailed in any variation herein, where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In a particular variation, a compound of the invention is of the formula (I), wherein X 7 -X 10 are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where R 1 is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In another variation, the compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 and R 1 are as defined in formula (I) or as detailed in any variation herein, where R 2a and R 2b are independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro or R 2a and R 2b are taken together to form a carbonyl moiety and each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano or nitro. In another variation, the compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 and R 1 are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where each R 2a and R 2b is independently H, unsubstituted C 1 -C 8 alkyl, halo or R 2a and R 2b are taken together to form a carbonyl moiety and each R 3a and R 3b is independently H, unsubstituted C 1 -C 8 alkyl, halo or R 3a and R 3b are taken together to form a carbonyl moiety. In still a further variation, the compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 and R 1 are as defined in formula (I) or as detailed in any variation herein, where each R 2a and R 2b is independently H, unsubstituted C 1 -C 8 alkyl, halo or R 2a and R 2b are taken together to form a carbonyl moiety; and each R 3a and R 3b is independently H, unsubstituted C 1 -C 8 alkyl, halo or R 3a and R 3b are taken together to form a carbonyl moiety. The invention also embraces compounds of the invention according to formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 and R 1 are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where each R 2a and R 2b is independently H, methyl, halo or R 2a and R 2b are taken together to form a carbonyl moiety and each R 3a and R 3b is independently H, methyl, halo or R 3a and R 3b are taken together to form a carbonyl moiety.

›Definitions · 32 of 48

The invention further embraces compounds of the invention according to formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 and R 1 are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where each R 2a , R 2b , R 3a and R 3b is H. In one variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where X 7 -X 10 and R 1 are as defined in formula (I) or as detailed in any variation herein, where at least one of R 2a , R 2b , R 3a and R 3b is a substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro or is taken together with a geminal R 2 or R 3 to form a carbonyl moiety.

In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where X 7 -X 10 and R 1 are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where at least two of R 2a , R 2b , R 3a and R 3b is a substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro or is taken together with a geminal R 2 or R 3 to form a carbonyl moiety. In yet another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where X 7 -X 10 and R 1 are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where at least one of R 2a , R 2b , R 3a and R 3b is fluoro or methyl or is taken together with a geminal R 2 or R 3 to form a carbonyl moiety.

In still another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where X 7 -X 10 and R 1 are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where either R 2a and R 2b or R 3a and R 3b are each methyl or fluoro (e.g., both R 2a and R 2b are methyl or one is fluoro and one is methyl) or are taken together to form a carbonyl moiety. In one variation, R 2a and R 2b are taken together to form a carbonyl moiety. In another variation, at least one of R 2a and R 2b is hydroxyl or alkoxy. In a particular variation, each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro or R 2a and R 2b are taken together to form a carbonyl moiety. In another variation, each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro or R 2a and R 2b are taken together to form a carbonyl moiety.

The invention also embraces compounds according to formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where each R 10a and R 10b is independently H, halo, an unsubstituted C 1 -C 8 alkyl, hydroxyl or R 10a and R 10b are taken together to form a carbonyl moiety. Also embraced are compounds according to formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where each R 10a and R 10b is independently H, halo, an unsubstituted C 1 -C 4 alkyl, hydroxyl or R 10a and R 10b are taken together to form a carbonyl moiety. In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where each R 10a and R 10b is independently H, bromo, methyl, hydroxyl or R 10a and R 10b are taken together to form a carbonyl moiety.

In yet another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where at least one of R 10a and R 10b is an unsubstituted C 1 -C 8 alkyl, hydroxyl, halo or R 10a and R 10b are taken together to form a carbonyl moiety. In still a further variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where at least one of R 10a and R 10b is methyl, bromo, hydroxyl or R 10a and R 10b are taken together to form a carbonyl moiety.

In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where R 10a and R 10b are methyl. In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where R 10a and R 10b are taken together to form a carbonyl moiety. In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or as detailed in any variation herein, where R 10a is H and R 10b is methyl. In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), where X 7 -X 10 , R 1 , R 2a , R 2b , R 3a and R 3b are as defined in formula (I) or as detailed in any variation herein, where R 10a is H and R 10b is bromo. When the carbon of formula (I) bearing R 10a and R 10b is optically active, it may be in the (S)- or (R)-configuration and compositions comprising substantially pure (R) or (S) compound or mixtures thereof in any amount are embraced by this invention.

›Definitions · 33 of 48

In compounds of formula (I), (II), (III) or (IV), the ring comprising N, R 2a , R 2b , R 10a , R 10b , R 3a , and R 3b is sometimes referred to herein as the C-ring. In some embodiments, the C-ring is a ring selected from the structures:

where R 1 in the structures above is as defined for formula (I) or any particular variation detailed herein. In some embodiments, the C-ring is a ring of the structure:

where R 1 is as defined for formula (I) or any particular variation detailed herein. Any formula detailed herein, where applicable, may in one variation have a C-ring according to the structures above.

In compounds of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, which may be but is not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In one variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted phenyl or pyridyl group. In a particular variation, Q is a phenyl or pyridyl group substituted with at least one methyl, trifluoromethyl, methoxy or halo substituent. In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or C 1 -C 4 perhaloalkyl moiety.

In still another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted C 3 -C 8 cycloalkyl or a substituted or unsubstituted heterocyclyl. In another variation, Q is a substituted or unsubstituted C 3 -C 8 cycloalkyl or a substituted or unsubstituted heterocyclyl. In yet another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In a particular variation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl, CF 3 , methoxy or halo group.

In one variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is an unsubstituted cycloalkyl or an unsubstituted heterocyclyl. In another variation, Q is an unsubstituted C 3 -C 8 cycloalkyl or an unsubstituted heterocyclyl. In another variation, a compound of the invention is of the formula (I) or any variation of the foregoing detailed herein, where Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. In yet another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is a substituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group. Q groups may be attached to the parent structure at any available position on the Q moiety. Thus, although specific attachment points for certain Q moieties are depicted herein, it is understood that such Q moieties, may also be connected to the parent structure at any available position. For example, if a 2-fluoro-phenyl is depicted herein, it is understood that other mono-fluoro-phenyls are intended, e.g., 3-fluoro-phenyl and 4-fluoro-phenyl. It is also understood that any formula detailed herein, where applicable, may in one variation have a Q moiety as detailed herein and below.

In another variation, a compound of the invention is of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:

wherein each R 9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R 9 group. In another variation, Q is substituted with only one R 9 group. In one variation, Q is substituted with two R 9 groups. In a further variation, Q is selected from the aromatic structures detailed where the residue has the moiety (R 9 ) 0 such that Q either contains no R 9 functionality or a moiety of the formula N—R 9 .

wherein each R 9 is independently a halo, cyano, nitro, perhaloalkyl (C 1 -C 8 ), perhaloalkoxy (C 1 -C 8 ), substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R 9 group. In another variation, Q is substituted with only one R 9 group. In one variation, Q is substituted with two R 9 groups. In a further variation, Q is selected from the aromatic structures detailed where the residue has the moiety (R 9 ) 0 such that Q either contains no R 9 functionality or a moiety of the formula N—R 9 .

›Definitions · 34 of 48

In one variation, Q is substituted with no more than one R 9 group. In another variation, Q is substituted with only one R 9 group. In one variation, Q is substituted with two R 9 groups. In a further variation, Q is selected from the aromatic structures detailed where the residue has the moiety (R 9 ) 0 such that Q either contains no R 9 functionality or a moiety of the formula N—R 9 .

and wherein R 9 is connected to Q ortho or para to the position at which Q is connected to the carbon bearing R 8c and R 8d when m is 1, or the carbon bearing R 12 when m is 0. In a particular variation, Q is a structure of the formula:

and R 9 is connected to Q para to the position at which Q is connected to the carbon bearing R 8c and R 8d when m is 1, or the carbon bearing R 12 when m is 0.

In another variation, a compound of the invention is of the formula (II) or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:

and wherein R 9 is connected to Q ortho or para to the position at which Q is connected to the carbon bearing R 8c and R 8d when m is 1, or the carbon bearing R 12a and R 12b when m is 0. In a particular variation, Q is a structure of the formula:

and R 9 is connected to Q para to the position at which Q is connected to the carbon bearing R 8c and R 8d when m is 1, or the carbon bearing R 12a and R 12b when m is 0. In another particular variation, Q is a structure of the formula

where each R 9 is independently alkyl, perhaloalkyl or halo.

wherein each R 9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, Q is substituted with no more than one R 9 group. In another variation, Q is substituted with only one R 9 group. In yet another variation, Q is substituted with two R 9 groups. In a particular variation, Q is selected from the carbocyclic and heterocyclic structures detailed where the residue has the moiety (R 9 ) 0 such that Q either contains no R 9 functionality or a moiety of the formula N—R 9 .

In any structure or variation detailed herein containing an R 9 group, in one variation, each R 9 is independently a substituted or unsubstituted C 1 -C 4 alkyl, halo, trifluoromethyl or hydroxyl. In another variation, each R 9 is independently methyl, —CH 2 OH, isopropyl, halo, trifluoromethyl or hydroxyl.

In yet another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is a moiety selected from the structures:

In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is an substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino moiety. In a particular variation, Q is an unsubstituted amino. In another variation, Q is substituted amino of the formula —N(C 1 -C 8 alkyl) 2 such as the moiety —N(Me) 2 or —N(CH 3 )(CH 2 CH 3 ). In another variation, Q is a substituted amino of the formula —N(H)(cycloalkyl or substituted cycloalkyl), such as a moiety of the formula:

In another variation, Q is a substituted amino of the formula —N(H)(aryl or substituted aryl), such as a moiety of the formula:

In a particular variation, Q is an amino or substituted amino, m is 1 and R 8c and R 8d are taken together to form a carbonyl moiety. In yet another variation, Q is an acylamino moiety. In still another variation, Q is an acylamino moiety, and either (1) m is 1 and R 8c and R 8d are both hydrogen or (2) m is 0.

In another variation, Q is an alkoxy group of the formula —O—C 1 -C 8 alkyl, such as the moiety —O—CH 2 CH 3 . In yet another variation, Q is an alkoxy group, m is 1 and R 8c and R 8d are taken together to form a carbonyl moiety. In still a further variation, Q is a carbonylalkoxy moiety. In yet another variation, Q is a carbonylalkoxy moiety and either (1) m is 1 and R 8c and R 8d are both hydrogen or (2) m is 0.

In still another variation, Q is an acyloxy, aminocarbonylalkoxy or acylamino moiety. In one variation, Q is an acyloxy, aminocarbonylalkoxy or acylamino moiety and either (1) m is 1 and R 8c and R 8d are both hydrogen or (2) m is 0.

The invention also embraces compounds of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is an aminoacyl moiety. In one variation, Q is an aminoacyl group where at least one of R a and R b is H, such as when Q is of the formula —NHC(O)R b . In one variation, Q is an aminoacyl moiety selected from the group consisting of: —NHC(O)-heterocyclyl, —NHC(O)-substituted heterocyclyl, —NHC(O)-alkyl, —NHC(O)-cycloalkyl, —NHC(O)-aralkyl and —NHC(O)-substituted aryl. In another variation, Q is an aminoacyl moiety selected from the group consisting of: —NHC(O)—C 5 -C 7 heterocyclyl, —NHC(O)—C 1 -C 6 alkyl, —NHC(O)—C 3 -C 7 cycloalkyl, —NHC(O)—C 1 -C 3 aralkyl and —NHC(O)-substituted phenyl.

›Definitions · 35 of 48

In a particular variation, Q is a moiety of the formula:

In one variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is acyloxy.

In one variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is a carbonylalkoxy moiety. In one variation, Q is a carbonylalkoxy moiety of the formula —C(O)—O—R where R is H, alkyl, substituted alkyl or alkaryl. In one variation, Q is carbonylalkoxy moiety of the formula —C(O)—O—C 1 -C 6 alkyl. In a particular variation, Q is a carbonylalkoxy moiety of the formula —C(O)—O—C 2 H 5 . In one variation, Q is a carbonylalkoxy moiety selected from the group consisting of: —C(O)—O—C 1 -C 10 alkyl, —C(O)—O—C 1 -C 3 alkaryl, —C(O)—O—C 1 -C 3 substituted alkyl and —C(O)—OH. In another variation, Q is —C(O)—O—C 1 -C 6 alkyl. In a particular variation, Q is a moiety of the formula:

In another variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is an aminocarbonylalkoxy moiety. In one variation, Q is an aminocarbonylalkoxy moiety of the formula —NHC(O)—O—R b . In another variation, Q is an aminocarbonylalkoxy moiety of the formula —NHC(O)—O—R b where R b is a substituted alkyl group. In a particular variation, Q is a moiety of the formula —NH—C(O)—O—CH 2 —CCl 3 .

The invention also embraces compounds of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or any variation of the foregoing detailed herein, where Q is an acylamino moiety. In one variation, Q is an acylamino group where at least one of R a and R b is H, such as when Q is of the formula —C(O)N(H)(R b ). In another variation, Q is an acylamino group where both R a and R b are alkyl. In one variation, Q is an acylamino moiety selected from the group consisting of: —C(O)—N(H)(alkyl), —C(O)—N(alkyl) 2 , —C(O)—N(H)(aralkyl) and —C(O)—N(H)(aryl). In another variation, Q is an acylamino moiety selected from the group consisting of: —C(O)—N(H) 2 , —C(O)—N(H)(C 1 -C 8 alkyl), —C(O)—N(C 1 -C 6 alkyl) 2 and —C(O)—N(H)(C 1 -C 3 aralkyl). In a particular variation, Q is a moiety of the formula:

In a further variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where R 1 is an unsubstituted alkyl, R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are each H, each X 7 , X 8 , X 9 and X 10 is independently N or CH, each R 8a , R 8b , R 8c , and R 8d is independently H or hydroxyl, and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted phenyl or pyridyl group. Where Q is a substituted phenyl or pyridyl group, in one variation it is substituted with at least one methyl or halo group.

In yet a further variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl; each R 2a and R 2b is independently H, unsubstituted C 1 -C 8 alkyl or halo; each R 3a and R 3b is independently H or halo; each X 7 , X 8 , X 9 and X 10 is CH or CR 4 , where R 4 is as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or in a particular variation, R 4 is halo, pyridyl, methyl or trifluoromethyl; R 10a and R 10b are both H, and Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In a particular variation, Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C 1 -C 8 alkyl, halo or perhaloalkyl moiety. In one variation, a compound of the variation detailed herein is provided wherein R 1 is propylate, methyl, ethyl, cyclopropyl, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In still a further variation, a compound of the invention is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl; each R 2a , R 2b , R 3a and R 3b is independently H or halo; each R 4 is independently halo, C 1 -C 8 perhaloalkyl, substituted or a unsubstituted C 1 -C 8 alkyl; each R 8a , R 8b , R 8c and R 8d is H; and Q is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. The invention also embraces a compound of the formula (I) where R 1 is a methyl; at least one of X 7 , X 8 , X 9 and X 10 is CR 4 , and each R 4 is independently halo, methyl or trifluoromethyl. The invention embraces compounds where Q in any variation detailed is substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group, to the extent such substituent makes chemical sense.

In a particular variation, the compound is of the formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) where R 1 is a substituted or unsubstituted C 1 -C 8 alkyl; each R 2a and R 2b is independently H, a substituted or unsubstituted C 1 -C 8 alkyl or R 2a and R 2b are taken together to form a carbonyl moiety; R 3a and R 3b are both H; each R 4 is independently halo or a substituted or unsubstituted C 1 -C 8 alkyl; each is R 8a , R 8b , R 8c , and R 8d is H; each R 10a and R 10b is independently H, halo, a substituted or unsubstituted C 1 -C 8 alkyl, hydroxyl, alkoxy or R 10a and R 10b are taken together to form a carbonyl moiety, provided that at least one of R 10a and R 10b is other than H. In one aspect of this variation, Q may be a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In another aspect of this variation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl or halo group. In yet another aspect of this variation, X 7 , X 8 , X 9 and X 10 are CH or CR 4 and each R 4 is independently halo or methyl.

›Definitions · 36 of 48

In another variation, a compound of the invention is of a formula detailed herein, e.g., formula (I), (II) or (III) or any variation of the foregoing detailed herein, or a compound according to any one of the formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) (I-b1), (I-b2), (I-c1), (I-c2), (I-d1), (I-d2), (I-e1), (I-e2), (I-f1), (I-f2), (I-g1) and (I-g2) where Q is a substituted or unsubstituted cycloalkyl or heterocyclyl selected from the structures:

In another variation, a compound of the invention is of a formula detailed herein, e.g., formula (I), (II) or (III) or any variation of the foregoing detailed herein, or a compound according to any one of the formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-b1), (I-b2), (I-c1), (I-c2), (I-d1), (I-d2), (I-e1), (I-e2), (I-f1), (I-f2), (I-g1) and (I-g2) where Q is a substituted or unsubstituted heteroaryl selected from the structures:

In another variation, a compound of the invention is of a formula detailed herein, e.g., formula (I), (II) or (III) or any variation of the foregoing detailed herein, or a compound according to any one of the formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-b1), (I-b2), (I-c1), (I-c2), (I-d1), (I-d2), (I-e1), (I-e2), (I-f1), (I-f2), (I-g1) and (I-g2) where Q is a substituted or unsubstituted phenyl selected from the structures:

In another variation, a compound of the invention is of a formula detailed herein, e.g., formula (I), (II) or (III) or any variation of the foregoing detailed herein, or a compound according to any one of the formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-b1), (I-b2), (I-c1), (I-c2), (I-d1), (I-d2), (I-e1), (I-e2), (I-f1), (I-f2), (I-g1) and (I-g2) where Q is a substituted or unsubstituted heteroaryl selected from the structures:

The embodiments and variations described herein for Formula (I) are also suitable for compounds of formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-b1), (I-b2), (I-c1), (I-c2), (I-d1), (I-d2), (I-e1), (I-e2), (I-f1), (I-f2), (I-g1) and (I-g2). The embodiments and variations described herein for Formula (II) are also suitable for compounds of formulae (II-A), (II-B), (II-C), (II-D), (II-a1), (II-b1), (II-c1) and (II-d1). Where appropriate, substituents described herein for formula (I) and variations thereof are also suitable for compounds of formulae (II), (III), (IV), (V), (VI) and (VII), and variations thereof.

Strikingly, it has been discovered that compounds included in the invention that contain a substituted vinyl moiety, such as methylvinyl, exhibit a lower binding affinity to H 1 as compared to their unsubstituted vinyl counterparts. To illustrate, compound 106 (which contains a methylvinyl moiety) exhibits a lower binding affinity to H 1 as compared to its unsubstituted vinyl counterpart, compound 415. Likewise, compound 85 (which contains a methylvinyl moiety) exhibits a lower binding affinity to H 1 as compared to its unsubstituted vinyl counterpart, compound 95. The structures of compounds 106, 415, 85 and 95 are shown below, with the methylvinyl moieties of compounds 106 and 85 encircled by dotted lines.

Thus, it is believed that substituted vinyl moieties, such as methylvinyl, may be responsible for reduced H 1 affinity.

Compounds that exhibit affinity for the histamine receptor H 1 may induce undesirable side effects, such as metabolic syndrome, diabetes type 2, weight gain, hyperlipidemia, hyperglycemia, hypertension and drowsiness (Kroeze et al., Neuropsychopharmacology (2003) 28, 519-526). The number and extent of undesireable side effects increases with increasing affinity for the H 1 receptor Thus, in one aspect, compounds of the formulae herein display reduced, low or no affinity to histamine receptor H 1 . Compounds with low affinity to H 1 are those compounds which display less than about 80% inhibition of binding of a ligand to H 1 . Inhibition of binding of a ligand to H 1 for all variations detailed herein is determined by a suitable assay known in the art such as the assay described herein. In some variations, compounds of the formulae herein inhibit binding of a ligand to H 1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% and 50%. In one variation, compounds of the formulae herein inhibit binding of a ligand to H 1 by between about 50% to about 80%. In aspect, compounds of the formulae herein inhibit binding of a ligand to H 1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% and 50% at any concentration, such as those detailed herein, e.g., 0.1 μM and 1 μM. In one variation, compounds of the formulae herein inhibit binding of Pyrilamine to H 1 as determined in the assay described herein. In a further variation, percent inhibition of binding to H 1 is measured by assays detailed herein.

Compounds containing a substituted vinyl moiety, such as methylvinyl moiety, are detailed herein wherein the compounds exhibit reduced H 1 affinity as compared to their unsubstituted vinyl counterparts. In one aspect, compounds that contain a substituted vinyl moiety, such as a methylvinyl moiety, exhibit low or no H 1 affinity and thus provide compounds with fewer or lesser undesirable side effects than compounds containing an unsubstituted vinyl moiety. In one variation, compounds as detailed herein containing a substituted vinyl moiety, such as methylvinyl, inhibit binding of a ligand to H 1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% and 50%. In another variation, compounds as detailed herein containing a substituted vinyl moiety, such as methylvinyl, inhibit binding of a ligand to H 1 by less than about any of 50%, 40%, 30%, 20%, 10% and 5%.

Representative examples of compounds detailed herein, including intermediates and final compounds according to the invention are depicted in the tables below. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.

›Definitions · 37 of 48

The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds of the invention are pharmaceutically acceptable salts.

Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. Taking compound 1 as an example, a composition of substantially pure compound 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound 1 or a salt thereof. In one variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity.

In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

General Description of Biological Assays

The binding properties of compounds disclosed herein to a panel of aminergic G protein-coupled receptors including adrenergic receptors, dopamine receptors, serotonin receptors, histamine receptors and an imidazoline receptor may be determined. Binding properties may be assessed by methods known in the art, such as competitive binding assays. In one variation, compounds are assessed by the binding assays detailed herein. Compounds disclosed herein may also be tested in cell-based assays or in in vivo models for further characterization. In one aspect, compounds disclosed herein are of any formula detailed herein and further display one or more of the following characteristics: inhibition of binding of a ligand to an adrenergic receptor (e.g., α 1D , α 2A and α 2B ), inhibition of binding of a ligand to a serotonin receptor (e.g., 5-HT 2A , 5-HT 2C , 5-HT 6 and 5-HT 7 ), inhibition of binding of a ligand to a dopamine receptor (e.g., D 2L ), and inhibition of binding of a ligand to a histamine receptor (e.g., H 1 , H 2 and H 3 ); agonist/antagonist activity to a serotonin receptor (e.g., 5-HT 2A , 5-HT 6 ); agonist/antagonist activity to a dopamine receptor (e.g., D 2L , D 2S ); agonist/antagonist activity to a histamine receptor (e.g., H 1 ); activity in a neurite outgrowth assay; efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction; efficacy in a preclinical model of attention impulsivity and executive function, and efficacy in a preclinical model of schizophrenia.

In one variation, inhibition of binding of a ligand to a receptor is measured in the assays described herein. In another variation, inhibition of binding of a ligand is measured in an assay known in the art. In one variation, binding of a ligand to a receptor is inhibited by at least about 80% as determined in a suitable assay known in the art such as the assays described herein. In one variation, binding of a ligand to a receptor is inhibited by greater than about any one of 80%, 85%, 90%, 95%, 100%, or between about 85% and about 95% or between about 90 and about 100% as determined in a suitable assay known in the art such as the assays described herein. In one variation, binding of a ligand to a receptor is inhibited by at least about 80%±20% as determined in an assay known in the art.

›Definitions · 38 of 48

In one variation, a compound of the invention inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein (e.g. α 1D , α 2A , α 2B , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 , D 2L , H 1 , H 2 , H 3 ). In one variation, a compound of the invention inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein (e.g. α 1D , α 2A , α 2B , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 , D 2 , H 1 , H 2 , H 3 ). In one variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors detailed herein and further displays agonist or antagonist activity to one or more receptors detailed herein (e.g., serotonin receptor 5-HT 2A , serotonin receptor 5-HT 6 , dopamine receptor D 2L , dopamine receptor D 2S and histamine receptor H 1 ) as measured in the assays described herein. In one variation, agonist response of serotonin receptor 5-HT 2A is inhibited by compounds of the invention by at least about any one of 50%, 50%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% as determined in a suitable assay such as the assay described herein.

In one variation, a compound of the invention displays the above described neurotransmitter receptor binding profile i.e. inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein and further stimulates neurite outgrowth, e.g. as measured by the assays described herein. Certain compounds of the invention showed activity in neurite outgrowth assays using primary neurons in culture. Data is presented indicating that a compound of the invention has activity comparable in magnitude to that of naturally occurring prototypical neurotrophic proteins such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Notably, neurite outgrowth plays a critical part of new synaptogenesis, which is beneficial for the treatment of neuronal disorders. In one variation, neuronal disorders include ADHD. In one variation, neurite outgrowth is observed with a potency of about 1 μM as measured in a suitable assay known in the art such as the assays described herein. In another variation, neurite outgrowth is observed with a potency of about 500 nM. In a further variation, neurite outgrowth is observed with a potency of about 50 nM. In another variation, neurite outgrowth is observed with a potency of about 5 nM.

In another variation, a compound of the invention inhibits binding of a ligand to at least one receptor and as many as eleven as detailed herein, further displays agonist or antagonist activity to one or more receptors detailed herein and further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors as detailed herein and/or display the above described neurotransmitter receptor binding profile and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction, and in preclinical models of attention/impulsivity and executive function, i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction. Compounds of the invention have been shown to be effective in a preclinical model of memory dysfunction associated with cholinergic hypofunction (see relevant Examples). As H 1 antagonism may contribute to sedation, weight gain and reduced cognition, low affinity (less than about 80% inhibition of binding of Pyrilamine at 1 μM in the assay described herein) for this receptor may be associated with pro-cognitive effects and a more desirable side effect profile. Furthermore, compounds of the invention with increased potency as a 5-HT 6 antagonist may have cognition-enhancing effects as serotonin acting through this receptor may impair memory.

In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors as detailed herein, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction, in preclinical models of attention/impulsivity and executive function, and further displays agonist or antagonist activity to one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors as detailed herein, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction, and in preclinical models of attention/impulsivity and executive function, and further stimulates neurite outgrowth.

In another variation, a compound of the invention inhibits at least one and as many as eleven receptors as detailed herein, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects in a preclinical model of memory dysfunction, in preclinical models of attention/impulsivity and executive function, further displays agonist or antagonist activity to one or more receptor detailed herein and further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors and further possesses anti-psychotic effects as measured in a preclinical model of schizophrenia, i.e., shows efficacy in a preclinical model of schizophrenia.

In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia and further stimulates neurite outgrowth.

›Definitions · 39 of 48

In a further variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention/impulsivity and executive function, and further shows efficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia, further displays agonist or antagonist activity to one or more receptors detailed herein and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention/impulsivity and executive function.

In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention/impulsivity and executive function.

In a further variation, a compound of the invention inhibits binding of a lignad to at least one and as many as eleven receptors detailed herein, further displays agonist or antagonist activity to one or more receptors detailed herein, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of a ligand to at least one and as many as eleven receptors, further shows efficacy in a preclinical model of schizophrenia, further displays agonist or antagonist activity to one or more receptors detailed herein, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention/impulsivity and executive function.

In another variation, a compound of the invention stimulates neurite outgrowth. In another variation, a compound of the invention shows efficacy in a preclinical model of schizophrenia and further stimulates neurite outgrowth. In another variation, a compound of the invention stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention/impulsivity and executive function. In another variation, a compound of the invention shows efficacy in a preclinical model of schizophrenia, further stimulates neurite outgrowth and further shows efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction such as enhancement of memory retention and reduction of memory impairment, and in preclinical models of attention/impulsivity and executive function.

In one aspect, compounds of the invention inhibit binding of a ligand to adrenergic receptors α 1D , α 2A , α 2B and inhibit binding of a ligand to serotonin receptor 5-HT 6 . In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors α 1D , α 2A , α 2B , to serotonin receptor 5-HT 6 and to any one or more of the following receptors: serotonin receptor 5-HT 7 , 5-HT 2A and 5-HT 2C . In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors α 1D , α 2A , α 2B , to serotonin receptor 5-HT 6 and to any one or more of the following receptors: serotonin receptor 5-HT 7 , 5-HT 2A and 5-HT 2C and further show weak inhibition of binding of a ligand to histamine receptor H 1 and/or H 2 . In one variation, compounds of the invention that also display strong inhibition of binding of a ligand to the serotonin receptor 5-HT 7 are particularly desired. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors α 1D , α 2A , α 2B , to serotonin receptor 5-HT 6 and further show weak inhibition of binding of a ligand to histamine receptor H 1 and/or H 2 . Weak inhibition of binding of a ligand to the histamine H 1 receptor is permitted as agonists of this receptor have been implicated in stimulating memory as well as weight gain. In one variation, binding to histamine receptor H 1 is inhibited by less than about 80%. In another variation, binding of a ligand to histamine receptor H 1 is inhibited by less than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined by a suitable assay known in the art such as the assays described herein.

In another variation, compounds of the invention inhibit binding of a ligand to a dopamine receptor D 2 . In another variation, compounds of the invention inhibit binding of a ligand to dopamine receptor D 2L . In another variation, compounds of the invention inhibit binding of a ligand to dopamine receptor D 2 and to serotonin receptor 5-HT 2A . In another variation, compounds of the invention inhibit binding of a ligand to dopamine receptor D 2L and to serotonin receptor 5-HT 2A . In another variation, compounds of the invention inhibit binding of a ligand to histamine receptor H 1 . In certain aspects, compounds of the invention further show one or more of the following properties: strong inhibition of binding of a ligand to the serotonin 5-HT 7 receptor, strong inhibition of binding of a ligand to the serotonin 5-HT 2A receptor, strong inhibition of binding of a ligand to the serotonin 5-HT 2C receptor, weak inhibition of binding of a ligand to the histamine H 1 receptor, weak inhibition of binding of ligands to the histamine H 2 receptor, and antagonist activity to serotonin receptor 5-HT 2A .

›Definitions · 40 of 48

In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further display agonist/antagonist activity to one or more of the following receptors: serotonin receptor 5-HT 2A , serotonin receptor 5-HT 6 , dopamine receptor D 2L , dopamine receptor D 2S and histamine receptor H 1 . In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further stimulate neurite outgrowth. In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further show efficacy in a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction, such as enhancement of memory retention and reduction of memory impairment and in preclinical models of attention/impulsivity and executive function. In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further show efficacy in a preclinical model of schizophrenia. In one variation, compounds of the invention show any of the receptor binding aspects detailed herein and further show efficacy in any one or more of agonist/antagonist assays (e.g., to serotonin receptor 5-HT 2A , 5-HT 6 , dopamine receptor D 2L , dopamine receptor D 2S and histamine receptor H 1 ), neurite outgrowth, a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction and a preclinical model of schizophrenia.

In some aspects, compounds of the invention inhibit binding of a ligand to adrenergic receptors α 1D , α 2A , α 2B , serotonin receptor 5-HT 6 and a dopamine receptor D 2 by at least about 80% as determined in a suitable assay known in the art such as the assays described herein. In one variation binding is inhibited by at least about 80% as measured in a suitable assay such as the assays described herein. In some aspects, compounds of the invention inhibit binding of a ligand to adrenergic receptors α 1D , α 2A , α 2B , serotonin receptor 5-HT 6 and dopamine receptor D 2L by at least about 80% as determined in a suitable assay known in the art such as the assays described herein. In one variation binding is inhibited by at least about 80% as measured in a suitable assay such as the assays described herein. In one variation, binding of a ligand to a receptor is inhibited by greater than about any one of 80%, 85%, 90%, 95%, 100%, or between about 85 and about 95% or between about 90 and about 100% as determined in a suitable assay known in the art such as the assays described herein.

In some aspects, compounds of the invention display the above described neurotransmitter receptor binding profile and further show antipsychotic effects. It is recognized that compounds of the invention have binding profiles similar to compounds with antipsychotic activity and several compounds of the invention have been shown to be effective in a preclinical model of schizophrenia (see relevant Examples). In addition, compounds of the invention might possess the cognitive enhancing properties of dimebon and thus add to the beneficial pharmacology profile of these antipsychotic molecules. In one variation, compounds of the invention display the above described neurotransmitter receptor binding profile and further show pro-cognitive effects in a preclinical model of memory dysfunction such as enhancement of memory retention and reduction of memory impairment. In another variation, compounds of the invention display the above described neurotransmitter receptor binding profile and do not show pro-cognitive effects in a preclinical model of memory dysfunction, learning and memory.

In one variation, compounds of the invention demonstrate pro-cognitive effects in a preclinical model of memory dysfunction, learning and memory. In a further variation, compounds of the invention possess anti-psychotic effects in a preclinical model of schizophrenia. In a further variation, compounds of the invention demonstrate pro-cognitive effects in a preclinical model of memory dysfunction, learning and memory and further possess anti-psychotic effects in a preclinical model of schizophrenia.

Overview of the Methods

The compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders in individuals, such as humans. In one aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a cognitive disorder. In one variation, cognitive disorder as used herein includes and intends disorders that contain a cognitive component, such as psychotic disorders (e.g., schizophrenia) containing a cognitive component (e.g., CIAS). In one variation, cognitive disorder includes ADHD. In another aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a psychotic disorder. In one variation, psychotic disorder as used herein includes and intends disorders that contain a psychotic component, for example cognitive disorders (e.g., Alzheimer's disease) that contain a psychotic component (e.g., psychosis of Alzheimer's Disease or dementia). In one variation, methods of improving at least one cognitive and/or psychotic symptom associated with schizophrenia are provided. In one aspect, methods of improving cognition in an individual who has or is suspected of having CIAS are provided. In a particular aspect, methods of treating schizophrenia are provided wherein the treatment provides for an improvement in one or more negative symptom and/or one or more positive symptom and/or one or more disorganized symptom of schizophrenia. In yet another aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a neurotransmitter-mediated disorders disorder. In one aspect, a neurotransmitter-mediated disorder includes ADHD. In one embodiment, the neurotransmitter-mediated disorder includes spinal cord injury, diabetic neuropathy, allergic diseases (including food allergies) and diseases involving geroprotective activity such as age-associated hair loss (alopecia), age-associated weight loss and age-associated vision disturbances (cataracts). In another variation, the neurotransmitter-mediated disorder includes spinal cord injury, diabetic neuropathy, fibromyalgia and allergic diseases (including food allergies). In still another embodiment, the neurotransmitter-mediated disorder includes Alzheimer's disease, Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitive impairment, multiple sclerosis, stroke and traumatic brain injury. In yet another embodiment, the neurotransmitter-mediated disorder includes schizophrenia, anxiety, bipolar disorders, psychosis, depression and ADHD. In one variation, depression as used herein includes and intends treatment-resistant depression, depression related to a psychotic disorder, or depression related to a bipolar disorder. In another aspect, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of a neuronal disorder. In one aspect, the compounds described herein may also be used to treat, prevent, delay the onset and/or delay the development of cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders for which the modulation of an aminergic G protein-coupled receptor is believed to be or is beneficial.

›Definitions · 41 of 48

The invention also provides methods of improving cognitive functions and/or reducing psychotic effects comprising administering to an individual in need thereof an amount of a compound of the invention or a pharmaceutically acceptable salt thereof effective to improve cognitive functions and/or reduce psychotic effects. In a particular variation, a method of treating schizophrenia is provided, wherein the treatment provides an improvement in at least one cognitive function, such as an improvement in a cognitive function in an individual who has or is suspected of having CIAS. In a further variation, a method of treating schizophrenia is provided wherein the method reduces psychotic effects associated with schizophrenia. In one embodiment, a method of treating schizophrenia is provided wherein the method improves the negative symptoms of schizophrenia in an individual in need thereof. In one embodiment, a method of treating schizophrenia is provided wherein the method improves the positive symptoms of schizophrenia in an individual in need thereof. In a further variation, a method of treating schizophrenia is provided wherein the method both improves cognitive function and reduces psychotic effects in an individual in need thereof. A method of improving one or more negative, positive and disorganized symptoms of schizophrenia is also provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In one variation, a method of improving at least one negative symptom of schizophrenia is provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In another variation, a method of improving at least one negative and at least one positive symptom of schizophrenia is provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In yet another variation, a method of improving at least one negative and at least one disorganized symptom of schizophrenia is also provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In still another variation, a method of improving at least one positive and at least one disorganized symptom of schizophrenia is also provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement. In still a further variation, a method of improving at least one negative, at least one positive and at least one disorganized symptom of schizophrenia is provided, where the method entails administering a compound as detailed herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such improvement.

The invention also provides methods of stimulating neurite outgrowth and/or promoting neurogenesis and/or enhancing neurotrophic effects in an individual comprising administering to an individual in need thereof an amount of a compound of the invention or a pharmaceutically acceptable salt thereof effective to stimulate neurite outgrowth and/or to promote neurogenesis and/or to enhance neurotrophic effects.

The invention further encompasses methods of modulating an aminergic G protein-coupled receptor comprising administering to an individual in need thereof an amount of a compound of the invention or a pharmaceutically acceptable salt thereof effective to modulate an aminergic G protein-coupled receptor.

It is to be understood that methods described herein also encompass methods of administering compositions comprising the compounds of the invention.

Methods for Treating, Preventing, Delaying the Onset, and/or Delaying the Development Cognitive Disorders, Psychotic Disorders, Neurotransmitter-Mediated Disorders and/or Neuronal Disorders

In one aspect, the invention provides methods for treating, preventing, delaying the onset, and/or delaying the development of cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders for which the modulation of an aminergic G protein-coupled receptor is believed to be or is beneficial, the method comprising administering to an individual in need thereof a compound of the invention. In some variations, modulation of adrenergic receptor α 1D , α 2A , α 2B , serotonin receptor 5-HT 2A , 5-HT 6 , 5-HT 7 , histamine receptor H 1 and/or H 2 is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of adrenergic receptor α 1D , α 2A , α 2B and a serotonin receptor 5-HT 6 receptor is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of adrenergic receptor α 1D , α 2A , α 2B , and a serotonin receptor 5-HT 6 receptor and modulation of one or more of the following receptors serotonin 5-HT 7 , 5-HT 2A , 5-HT 2C and histamine H 1 and H 2 is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of a dopamine receptor D 2 is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of dopamine receptor D 2L is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, modulation of a dopamine receptor D 2 is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In certain variations, modulation of a dopamine D 2L receptor and serotonin receptor 5-HT 2A is expected to be or is beneficial for the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders. In some variations, the cognitive disorders, psychotic disorders, neurotransmitter-mediated disorders and/or neuronal disorders are treated, prevented and/or their onset or development is delayed by administering a compound of the invention.

›Definitions · 42 of 48

Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects

The invention provides methods for improving cognitive functions by administering a compound of the invention to an individual in need thereof. In some variations, modulation of one or more of adrenergic receptor α 1D , α 2A , α 2B , serotonin receptor 5-HT 2A , 5-HT 6 , 5-HT 7 , histamine receptor H 1 and/or H 2 is desirable or expected to be desirable to improve cognitive functions. In some variations modulation of α 1D , α 2A , α 2B adrenergic receptors and a serotonin 5-HT 6 receptor is desirable or expected to be desirable to improve cognitive functions. In some variations, modulation of α 1D , α 2A , α 2B adrenergic receptors and serotonin receptor 5-HT 6 and modulation of one or more of the following receptors: serotonin receptor 5-HT 7 , 5-HT 2A , 5-HT 2C and histamine receptor H 1 and H 2 , is desirable or expected to be desirable to improve cognitive functions. In another aspect, the invention encompasses methods to reduce psychotic effects by administering a compound of the invention to an individual in need thereof. In some embodiments, modulation of a dopamine D 2 receptor is expected to be or is desirable to reduce psychotic effects. In some embodiments, modulation of a dopamine D 2L receptor is expected to be or is desirable to reduce psychotic effects. In some embodiments, modulation of a dopamine D 2 receptor and a serotonin 5-HT 2A receptor is expected to be or is desirable to reduce psychotic effects. In some embodiments, modulation of a dopamine D 2L receptor and a serotonin 5-HT 2A receptor is expected to be or is desirable to reduce psychotic effects. In some variations, a compound of the invention is administered to an individual in need thereof.

Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/or Enhance Neurotrophic Effects

In a further aspect, the invention provides methods of stimulating neurite outgrowth and/or enhancing neurogenesis and/or enhancing neurotrophic effects comprising administering a compound of the invention or pharmaceutically acceptable salt thereof under conditions sufficient to stimulate neurite outgrowth and/or to enhance neurogenesis and/or enhance neurotrophic effects to an individual in need thereof. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 1 μM as measured in a suitable assay such as the assays described herein. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 500 nM as measured in a suitable assay such as the assays described herein. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 50 nM as measured in a suitable assay such as the assays described herein. In some variations, a compound of the invention stimulates neurite outgrowth at a potency of about 5 nM as measured in a suitable assay such as the assays described herein.

Methods to Modulate an Aminergic G Protein-Coupled Receptor

The invention further contemplates methods for modulating the activity of an aminergic G-protein-coupled receptor comprising administering a compound of the invention or pharmaceutically acceptable salt thereof under conditions sufficient to modulate the activity of an aminergic G protein-coupled receptor. In some variations, the aminergic G protein-coupled receptor is a α 1D , α 2A , α 2B adrenergic receptor and a serotonin 5-HT 6 receptor. In some variations, the aminergic G protein-coupled receptor is a α 1D , α 2A , α 2B adrenergic receptor and a serotonin 5-HT 6 and 5-HT 7 receptor. In some variations, the aminergic G protein-coupled receptor is a α 1D , α 2A , α 2B , adrenergic receptor, a serotonin 5-HT 6 and one or more of the following receptors: serotonin 5-HT 7 , 5-HT 2A and 5-HT 2C and histamine H 1 and H 2 receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D 2 receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D 2L receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D 2 receptor and a serotonin 5-HT 2A receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D 2L receptor and a serotonin 5-HT 2A receptor. In some variations, the aminergic G protein-coupled receptor is a histamine H 1 receptor.

Dose-Dependent Therapy (DDT)

Dose dependent therapy refers to the concept that a single molecule may be used for different indications depending on the dose at which it is administered. It has been shown that compounds included in the invention exert pro-cognitive effects (where in one aspect pro-cognitive effects are achieved by reducing one or more symptoms associated with impaired cognition) when administered at low dose, whereas at high dose, these compounds induce both pro-cognitive and anti-psychotic effects (where in one aspect anti-psychotic effects are achieved by reducing one or more symptoms associated with a psychotic disorder). These compounds are further referred to as Dose-Dependent Therapy compounds (DDT compounds). When administered at high dose, DDT compounds in one aspect show fewer and/or lesser side-effects such as, e.g., extrapyramidal syndrome (EPS), as compared to other anti-psychotics, such as anti-psychotics which are not 5-HT 2A receptor modulators. It is believed that EPS is caused, at least in part, by high D 2 receptor occupancy, the effect of which can be counteracted by compounds displaying a high affinity to the serotonin receptor 5-HT 2A . EPS can be determined using various scales known in the art such as the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Simpson-Angus Rating Scale (SARS), Extrapyramidal Symptoms Rating Scale (ESRS) and the Extrapyramidal Symptoms Rating Scale-Abbreviated (ESRS-A). DDT compounds in one aspect are 5-HT 2A modulators, and preferably are antagonists of 5-HT 2A . In one variation, DDT compounds have low or no affinity for the histamine receptor H 1 , which is also implicated in undesirable side effects such as metabolic syndrome, diabetes type 2, weight gain, hyperlipidemia, hyperglycemia, hypertension and drowsiness (Kroeze et al., Neuropsychopharmacology (2003) 28, 519-526).

›Definitions · 43 of 48

DDT Compounds

DDT compounds modulate at least serotonin receptor 5-HT 2A and/or serotonin receptor 5-HT 6 and modulate dopamine receptor D 2 , such as D 2L . In one aspect, DDT compounds inhibit binding of a ligand to at least 5-HT 2A and/or 5-HT 6 and binding of a ligand to D 2 . Inhibition of binding for all variations detailed herein is determined in a suitable assay known in the art, such as the assays described herein. In one aspect, DDT compounds act as antagonists of 5-HT 2A and/or 5-HT 6 and act as antagonists of D 2 . In another aspect, DDT compounds act as antagonists of 5-HT 2A and D 2 . In another aspect, DDT compounds act as antagonists of 5-HT 2A , 5-HT 6 and D 2 . In one variation, DDT compounds inhibit binding of a ligand to 5-HT 2A and/or 5-HT 6 by at least about 50% at a DDT concentration of about 0.1 μM and inhibit binding of a ligand to D 2 by at least about 90% at a DDT concentration of about 1 μM. In another variation, DDT compounds inhibit binding of a ligand to 5-HT 2A and/or 5-HT 6 by greater than about any of 50%, 60%, 70% and 80% at a DDT concentration of at least about 0.1 μM. In a further variation, DDT compounds inhibit binding of a ligand to 5-HT 2A and/or 5-HT 6 by greater than about any of 50%, 60%, 70% and 80% at a DDT concentration of less than about 0.1 μM (e.g., greater than about 0.01 μM and less than about 0.1 μM). In a further variation, DDT compounds inhibit binding of a ligand to 5-HT 2A and/or 5-HT 6 by at least about 80% at a DDT concentration of about 0.1 μM. In one variation, DDT compounds inhibit binding to of a ligand to D 2 by at least about 90% at a DDT concentration of greater than about 1 μM. In another variation, DDT compounds inhibit binding of a ligand to D 2 by at least about 90% at a DDT concentration of between about 1 μM to about 3 μM. In one variation, DDT compounds inhibit binding of Ketanserin, LSD and Spiperone to 5-HT 2A , 5-HT 6 and D 2 , respectively, as determined in the assays described herein. In another variation, binding of a ligand to 5-HT 2A and/or 5-HT 6 is inhibited by greater than about any of 80%, 85%, 90% and 95%, or by about 100% at a DDT concentration of about 0.1 μM. In a further variation, binding of a ligand to 5-HT 2A and/or 5-HT 6 is inhibited between about 85% to about 95% or between about 90% to about 100% at a DDT concentration of about 0.1 μM. In another variation, binding of a ligand to D 2 is inhibited by greater than about any of 90% and 95%, or by about 100% at a DDT concentration of about 1 μM. In a further variation, binding of a ligand to D 2 is inhibited by between about 90% to about 100% at a concentration of about 1 μM. In another variation, inhibition of binding of a ligand to 5-HT 2A and/or 5-HT 6 is at least 80%±20% at a DDT concentration of about 0.1 μM and binding of a ligand to D 2 is inhibited by at least about 90% at a concentration of about 1 μM as determined in assays known in the art. In one aspect, DDT compounds inhibit binding of a ligand to 5-HT 2A and D 2 . In another aspect, DDT compounds inhibit binding of a ligand to 5-HT 6 and D 2 . In yet another aspect, DDT compounds inhibit binding of a ligand to 5-HT 2A , 5-HT 6 and D 2 . In one variation, percent inhibition of binding to 5-HT 2A , 5-HT 6 and D 2 is measured by assays detailed herein.

In one aspect, DDT compounds display low affinity to histamine receptor H 1 . Compounds with low affinity to H 1 are those compounds which display less than about 80% inhibition of binding of a ligand to H 1 . Inhibition of binding of a ligand to H 1 for all variations detailed herein is determined by a suitable assay known in the art such as the assay described herein. In some variations, DDT compounds inhibit binding of a ligand to H 1 by less than about any of 80%, 75%, 70%, 65%, 60% 55% and 50%. In one variation, DDT compounds inhibit binding of a ligand to H 1 by between about 50% to about 80%. In some variations, DDT compounds inhibit binding by less than about 80% at any DDT concentration, e.g., at about 0.1 μM to about 1 μM. In one variation, DDT compounds inhibit binding of Pyrilamine to H1 as determined in the assay described herein. In a further variation, percent inhibition of binding to H 1 is measured by assays detailed herein.

In some aspects, DDT compounds act as 5-HT 2A and D 2 antagonists. Antagonist activity for all variations is measured in suitable assays known in the art such as the assays described herein. In one variation, 5-HT 2A activity is inhibited by at least about 70% at a DDT concentration of about 0.1 μM. In another variation, 5-HT 2A activity is inhibited by greater than about any of 70%, 75%, 80%, 85%, 90%, 95%, or by about 100% at a DDT concentration of about 0.1 μM. In one variation, D 2 activity is inhibited by at least about 70% at a DDT concentration of about 1 μM. In another variation, D 2 activity is inhibited by greater than about any of 70%, 75%, 80%, 85%, 90%, 95%, or by about 100% at a DDT concentration of about 1 μM. In one variation, percent inhibition of activity is determined in the assays described herein. In one aspect, DDT compounds inhibit 5-HT 2A and D 2 activity. In another aspect, DDT compounds inhibit 5-HT 2A , 5-HT 6 and D 2 activity.

In one aspect, DDT compounds display any of the activities detailed herein for DDT compounds and further have a structure of the formulae provided herein. In one aspect, DDT compounds contain a substituted vinyl moiety, such as a methylvinyl moiety. Accordingly, in a particular aspect, DDT compounds are of the formula (I-C), or any variation thereof, including compounds of the formulae (I-c1) and (I-c2), where at least one of R 11 and R 12 is other than H, such as when at least one of R 11 and R 12 is a C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 perhaloalkyl. DDT compounds may also be of the formula (I-D), or any variation thereof, including compounds of the formulae (I-d1) and (I-d2), where at least one of R 11 and R 12 is other than H. In one variation, DDT compounds are of the formula (I-E), or any variation thereof, including compounds of the formulae (I-e1) and (I-e2). In another variation, DDT compounds are of the formula (I-F), or any variation thereof, including compounds of the formulae (I-f1) and (I-f2). In still another variation, DDT compounds are of the formula (J-1), or any variation thereof, including compounds of the formulae (J-1a) and (J-1b). In still another variation, DDT compounds are of the formula (J-2), or any variation thereof, including compounds of the formulae (J-1a) and (J-1b). DDT compounds may also be of the formula (J-1), (J-2), (J-3), (J-4), (J-5), (J-6), (J-7) or (J-8). In still another variation, DDT compounds are of the formula (I-G), or any variation thereof, including compounds of the formulae (I-g1) and (I-g2). In yet another variation, DDT compounds are of the formula (I-H), or any variation thereof, including compounds of the formulae (I-h1) and (I-h2). DDT compounds may also be of the formula (H-1), (H-2), (H-3), (H-4), (H-5), (H-6), (H-7) or (H-8). In another aspect, DDT compounds are of the formula (II-a1) or (II-b1) or (II-c1) or (II-d1) where at least one of R 11 and R 12 is other than H (e.g., methyl). In another aspect, DDT compounds are of the formula (III) or any variation thereof where at least one of R 11 and R 12 is other than H (e.g., methyl). In another aspect, DDT compounds are of the formula (V) or any variation thereof, such as formula (V-B), where at least one of R 11 and R 12 is other than H (e.g., methyl).

›Definitions · 44 of 48

DDT compounds may be present as pharmaceutically acceptable salts, or solvates thereof. Pharmaceutical compositions comprising a DDT compound and a pharmaceutically acceptable carrier are also embraced. These pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

High Dose

In one aspect, high dose of a DDT compound corresponds to an amount that results in at least 65% of receptor occupancy of dopamine receptor D 2 , which may be assessed by known methods, such as Positron Emission Tomography (PET) (Pani et al., European Psychiatry (2007) 22, 276-275). In some variations, a high dose provides D 2 occupancy that is greater than any one of 65%, 70%, 75%, 80%, 85% and 90%. In one variation, a high dose provides D 2 occupancy that is at least 65%. In another variation, a high dose provides a D 2 occupancy that is from at least 65% to 90%, or from at least 65% to 85%, or from at least 65% to 80%, or from at least 65% to 75%, or from at least 65% to 70%, or from at least 70% to 90%, or from at least 70% to 85%, or from at least 70% to 80%, or from at least 70% to 75%, or from at least 75% to 90%, or from at least 75% to 85%, or from at least 75% to 80%, or from at least 80% to 90%. In one variation, a high dose provides D 2 occupancy that is less than 80% and greater than 65%.

In another aspect, high dose of a DDT compound corresponds to a daily dose of at least about 1 mg/kg. In another variation, high dose corresponds to a daily dose of about 1 mg/kg. In another variation, high dose corresponds to a daily dose of at least about 1 mg/kg to at least about 3 mg/kg. In yet another variation, high dose corresponds to a daily dose of at least about 1 mg/kg to about 5 mg/kg. In a further variation, high dose corresponds to a daily dose of greater than 1 mg/kg.

In a further aspect, high dose of a DDT compound corresponds to an amount that induces anti-psychotic effects as determined by the Positive and Negative Syndrome Scale (PANSS). In another variation, anti-psychotic effects are measured by one or more of the following: PANSS, Brief Psychiatric Rating Scale (BPRS), Positive symptom sub-scale of PANSS, Young Mania Rating Scale (Y-MRS), Mania Rating Scale (MRS). In a further variation, anti-psychotic effects are measured by another scale and/or test known in the art.

In another aspect of the invention, high dose of a DDT compound corresponds to at least about 100 times the amount that induces pro-cognitive effects but does not induce anti-psychotic effects. In one variation, pro-cognitive effects are determined by cognition scales known in the art such as the Measurement and Treatment Research to Improve Cognition in Schizophrenia MATRICS. In another variation, pro-cognitive effects are determined by measuring the cognitive components of one or more of the following scales and/or tests: MATRICS, Negative Symptoms Assessment scale (NSA), Scale for the Assessment of Negative Symptoms (SANS), Schedule for the Deficit Syndrome (GDS), Negative symptom sub-scale of PANSS, MATRICS Consensus Cognition Battery (MCCB), CNSVitalSigns, CogState battery, Cognitive Drug Research battery (CDR), Brief Assessment of Cognition in Schizophrenia (BACS), Schizophrenia Cognition Rating Scale (SCoRS), Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Test of Adaptive Behavior in Schizophrenia (TABS), Independent Living Skills Inventory (ILS), UCSD Performance-Based Skills Assessment (UPSA), Cognitive Assessment Interview (CAI), Global Assessment of Function from CAI (GAF), Quality of Life Scale (QLS), Maryland Assessment of Social Competence (MASC), Calgary Depression Scale (CDS), and Montgomery-Asberg Depression Rating Scale (MADRS). In a further variation, pro-cognitive effects are determined by another scale and/or test known in the art.

Low Dose

In one aspect, low dose of a DDT compound corresponds to an amount that results in less than 65% receptor occupancy of dopamine receptor D 2 . In some variations, a low dose provides D 2 occupancy that is less than any one of 65%, 60%, 55% and 50%.

In another aspect, low dose of a DDT compound corresponds to a daily dose of about 0.03 mg/kg. In another variation, low dose corresponds to a daily dose of about 0.03 to about 0.3 mg/kg. In another variation, low dose corresponds to a daily dose of about 0.3 mg/kg. In yet another variation, low dose corresponds to a daily dose of about 0.03 to about 1 mg/kg. In a further variation, low dose corresponds to a daily dose of about 0.01 mg/kg. In yet another variation, low dose corresponds to a daily dose of 0.01 to about 1 mg/kg. In a further variation, low dose corresponds to a daily dose of about 0.5 mg/kg. In yet another variation, low dose corresponds to a daily dose of less than about 0.5 mg/kg. In another variation, low dose corresponds to a daily dose of less than 1 mg/kg.

In a further aspect, low dose of a DDT compound corresponds to an amount that induces pro-cognitive effects as determined by cognition scales such as MATRICS but does not induce anti-psychotic effects. In another variation, pro-cognitive effects are determined by measuring the cognitive components of one or more of the following scales and/or tests: MATRICS, Negative Symptoms Assessment scale (NSA), Scale for the Assessment of Negative Symptoms (SANS), Schedule for the Deficit Syndrome (GDS), Negative symptom sub-scale of PANSS, MATRICS Consensus Cognition Battery (MCCB), CNSVitalSigns, CogState battery, Cognitive Drug Research battery (CDR), Brief Assessment of Cognition in Schizophrenia (BACS), Schizophrenia Cognition Rating Scale (SCoRS), Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Test of Adaptive Behavior in Schizophrenia (TABS), Independent Living Skills Inventory (ILS), UCSD Performance-Based Skills Assessment (UPSA), Cognitive Assessment Interview (CAI), Global Assessment of Function from CAI (GAF), Quality of Life Scale (QLS), Maryland Assessment of Social Competence (MASC), Calgary Depression Scale (CDS), and Montgomery-Asberg Depression Rating Scale (MADRS). In a further variation, pro-cognitive effects are determined by another scale and/or test known in the art.

›Definitions · 45 of 48

In another aspect of the invention, low dose of a DDT compound corresponds to at least about 1/100 the amount that induces anti-psychotic effects. In one variation, anti-psychotic effects are determined by assays such as PANSS. In another variation, anti-psychotic effects are measured by one or more of the following: PANSS, Brief Psychiatric Rating Scale (BPRS), Positive symptom sub-scale of PANSS, Young Mania Rating Scale (Y-MRS), Mania Rating Scale (MRS). In a further variation, anti-psychotic effects are measured by another scale and/or test known in the art.

Unit Dosage Forms

DDT compounds may be provided in various unit dosage forms. In one aspect, single therapy dosages are provided. In one variation, a unit dosage form comprises a low dose as described herein of a DDT compound. In another variation, a unit dosage form comprises a high dose as described herein of a DDT compound.

In another aspect, combination therapy dosage forms are provided. In one variation, combination dosage forms comprise a low dose as described herein of a DDT compound and a second drug suitable for anti-psychotic therapy. In another variation, combination dosage forms comprise a high dose as described herein of a DDT compound and a second drug suitable for anti-psychotic therapy.

Kits

The present invention further provides for kits comprising DDT compounds with instructions for achieving pro-cognitive effects at low dose as detailed herein or pro-cognitive effects and anti-psychotic effects at high dose as detailed herein. In one aspect, kits comprise a low dose of a DDT compound and instructions for achieving only pro-cognitive effects. In some variations, pro-cognitive effects include (i) improvement of CIAS such as improvement of any one or more of memory (e.g., short term memory, working memory, social memory), attention, impulsivity, verbal fluency and executive function and/or (ii) improvement of negative symptoms of schizophrenia such as improvement of any one or more of blunted affect, avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness, depression and low mood. Thus, kits for use to achieve pro-cognitive effects in one aspect comprise a low dose of a DDT compound as described herein. In another variation, kits for use to achieve pro-cognitive effects comprise a unit dosage form containing a low dose of a DDT compound as described herein.

In a further aspect, kits of the present invention comprise a high dose of a DDT compound and instructions for achieving both pro-cognitive and anti-psychotic effects. In some variations, anti-psychotic effects comprise improvement of any one or more of psychotic symptoms such as positive symptoms of schizophrenia (e.g., delusions, hallucinations, disorganized thought and agitation). Kits comprising a high dose of a DDT compound may be used to achieve one or more pro-cognitive effects and one or more anti-psychotic effects. Thus, kits for use to achieve pro-cognitive and anti-psychotic effects in one aspect comprise a high dose of a DDT compound as described herein. In another variation, kits for use to achieve pro-cognitive and anti-psychotic effects comprise a unit dosage form containing a high dose of a DDT compound as detailed herein. In a further variation, kits for use to achieve pro-cognitive and anti-psychotic effects comprise a low dose of a DDT compound and a second drug suitable for anti-psychotic therapy. In yet another variation, kits for use to achieve pro-cognitive and anti-psychotic effects comprise a high dose of a DDT compound and a second drug suitable for anti-psychotic therapy. In one aspect, kits for use to achieve pro-cognitive and anti-psychotic effects comprise DDT compounds in unit dosage forms as detailed herein.

Methods of Treatment

The invention provides methods of treating diseases or conditions in which cognition and/or psychosis are implicated. The present invention provides methods of treating cognitive disorders and/or psychotic disorders by administering a DDT compound at a pharmaceutically effective dose to a subject in need thereof. In one variation, cognitive disorder as used herein includes and intends disorders that contain a cognitive component, such as psychotic disorders (e.g., schizophrenia) containing a cognitive component (e.g., CIAS). In one variation, psychotic disorder as used herein includes and intends disorders that contain a psychotic component, for example cognitive disorders (e.g., Alzheimer's disease) that contain a psychotic component (e.g., psychosis of Alzheimer's Disease or dementia).

In one aspect, the present invention encompasses methods of improving cognition by administering a DDT compound at a pharmaceutically effective dose to a subject in need thereof. In one variation, improving cognition comprises reducing one or more symptoms associated with impaired cognition. In a further aspect, the present invention provides methods of (i) improving cognition and (ii) reducing symptoms associated with psychotic disorders in a subject in need thereof. In yet another aspect, the present invention encompasses methods of improving cognition and not reducing symptoms associated with psychotic disorders in a subject in need thereof. In yet a further aspect, the present invention provides methods of improving cognition and not significantly reducing symptoms associated with psychotic disorders in a subject in need thereof. In some variations, a subject in need thereof is an individual who is refractory to other pro-cognitive and/or anti-psychotic therapy.

In one aspect, the invention is directed to methods of improving cognition and/or reducing symptoms associated with impaired cognition by administering a DDT compound at either low or high dose. In one variation improving cognition comprises (i) improvement of CIAS such as improvement of any one or more of memory (e.g., short term memory, working memory, social memory), attention, impulsivity, verbal fluency and executive function and/or (ii) improvement of negative symptoms of schizophrenia such as improvement of any one or more of blunted affect, avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness, depression and low mood.

›Definitions · 46 of 48

In a further aspect, the invention provides methods of both (i) improving cognition (e.g., as set forth herein) and/or reducing symptoms associated with impaired cognition and (ii) reducing symptoms associated with psychotic disorders by administering a DDT compound at high dose. In one variation, reducing symptoms associated with psychotic disorders comprises improvement of any one or more of psychotic symptoms such as positive symptoms of schizophrenia (e.g., delusions, hallucinations, disorganized thought and agitation). In one variation, the invention is directed to methods of treating schizophrenia by administering a high dose of a DDT compound. In another variation, the invention provides methods of reducing one or more symptom of positive symptoms of schizophrenia by administering a high dose of a DDT compound. In a further variation, the invention encompasses methods of reducing one or more symptom of positive and/or one or more symptom of negative symptoms of schizophrenia by administering a high dose of a DDT compound. In yet another variation, the invention provides methods of reducing one or more symptom of positive symptoms and/or one or more symptom of CIAS by administering a high dose of a DDT compound. In yet another variation, the invention provides methods of reducing one or more symptom of positive symptoms and/or one or more symptom of negative symptoms and/or one or more of disorganized symptoms of schizophrenia by administering a high dose of a DDT compound.

In another aspect, the invention is directed to methods of improving cognition and/or reducing symptoms associated with impaired cognition and not reducing symptoms associated with psychotic disorders by administering a DDT compound at low dose. In one variation improving cognition comprises (i) improvement of CIAS such as improvement of any one or more of memory (e.g., short term memory, working memory, social memory), attention, impulsivity, verbal fluency and executive function and/or (ii) improvement of negative symptoms of schizophrenia such as improvement of any one or more of blunted affect, avolition, anhedonia, alogia, dysphoria, suicidality, hopelessness, depression and low mood.

In yet another aspect, the invention encompasses methods of improving cognition and/or reducing symptoms associated with impaired cognition without significantly improving symptoms associated with psychotic disorders by administering a DDT compound at low dose.

Methods of Manufacturing a Medicament

In a further aspect of the invention use of DDT compounds and compositions thereof in the manufacture of a medicament is provided. Particularly, the manufacture of a medicament for use in the treatment of diseases or conditions in which cognition and/or psychosis are implicated are described herein. Further, pharmaceutical compositions of DDT compounds are also intended for use in the manufacture of a medicament for use in treatment of diseases or conditions in which cognition and/or psychosis are implicated.

Method of Determining a Dose/Treatment

The present invention further encompasses methods of determining a suitable or optimal dose of a DDT compound to either (i) achieve pro-cognitive effects alone or (ii) achieve both pro-cognitive effects and anti-psychotic effects in an individual in need thereof. In one aspect, a suitable dose is determined by measuring the percentage of D 2 occupancy and adjusting an individual's dosage in response thereto. In one variation, dosage is increased to achieve anti-psychotic effects if D 2 occupancy is less than 65% as determined by methods known in the art such as PET. In another variation, dosage is increased to achieve anti-psychotic effects if D 2 occupancy is less than any one of 65%, 60%, 55%, and 50%. In a further variation, dosage is reduced to achieve pro-cognitive and not anti-psychotic effects if D 2 occupancy is at least 65%. In yet another variation, dosage is reduced to achieve pro-cognitive and not anti-psychotic effects if D 2 occupancy is at greater than any one of 65%, 70%, 75%, 80% and 90%. In a further variation, dosage is reduced to achieve pro-cognitive and no significant anti-psychotic effects if D 2 occupancy is greater than 65%. One indication of at least 65% D2 occupancy or greater than any one of 65%, 70%, 75%, 80% and 90% D2 occupancy is the reduction in the number or severity of one or more symptoms associated with a psychotic disorder.

In another aspect, a suitable dose is determined by assessing pro-cognitive and/or anti-psychotic effects in an individual and adjusting an individual's dosage in response thereto. For example, in one variation, an individual's dosage is increased from a first dosage to a higher, second dosage, in order to achieve anti-psychotic effects at the second dosage level, if it is determined that the first dosage does not induce anti-psychotic effects in the individual, as may be assessed by suitable test and/or scales known in the art. In another variation, dosage is reduced from a first dosage to a lower, second dosage wherein the second dosage still achieves anti-psychotic effects but reduces side effects as compared to the first dosage. Side effects may be determined by suitable tests and/or scales known in the art. In another variation, dosage is decreased from a first dosage to a lower, second dosage, in order to achieve pro-cognitive and not anti-psychotic effects. In another variation, dosage is decreased from a first dosage to a lower, second dosage, in order to achieve pro-cognitive and not anti-psychotic effects and wherein the dosage induces fewer or lesser side effects than the first dosage. Thus, in yet another variation, dosage is reduced to a minimum dosage which still achieves pro-cognitive effects but reduces side-effects as determined by suitable tests and/or scales.

In one aspect, an individual's therapy is monitored as set forth above for a period of time, such as one week, two weeks, three weeks, one month, two months, three months, four months, five months, 6 months or more (such as throughout the course of an individual's therapy), to adjust an individual's dosage level as needed. As such, individualized therapy as detailed herein provides for methods of measuring therapeutic parameters and adjusting dosage in response thereto in order to achieve an optimal dosage amount according to an individual's initial and continued response to therapy.

›Definitions · 47 of 48

General Synthetic Methods

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a variation thereof unless otherwise indicated.

Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

The following abbreviations are used herein: thin layer chromatography (TLC); hour (h); minute (min.); second (sec.); ethanol (EtOH); dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); tetrahydrofuran (THF); EtOAc (EtOAc); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane (DCM); RT (RT); Retention factor (Rf).

A method of synthesizing carboline intermediates used in the synthesis of compounds of the invention is shown as General Method 1. Although identifiers such as R 4 and R 1 are shown in the method below, it is understood that these moieties apply to the compounds detailed herein even if different identifiers or variations thereof are used elsewhere (e.g., it is understood that compounds may include more than one R 4 ).

General Method 1.

Compound A (1 equiv.) and compound B (0.76-1.4 equiv.) are mixed in a suitable solvent such as EtOH and heated at 80° C. for 16 h (overnight) after which the solvent is removed in vacuo. The remaining residue is basified, e.g., with saturated aq. NaHCO 3 . The aqueous layer is extracted with DCM and the combined organic layers are dried over sodium sulfate, concentrated in vacuo, and purified, e.g., by silica gel chromatography (230-400 mesh) using a suitable solvent gradient such as either a MeOH-DCM gradient or an EtOAc-hexane gradient.

Representative carboline compounds prepared according to General Method 1 are shown in Table 1.

A method of synthesizing epoxide intermediates used in the synthesis of compounds of the invention is shown as General Method 2. Although identifiers such as R 9 and R are shown in the method below, it is understood that these moieties apply to the compounds detailed herein even if different identifiers or variations thereof are used elsewhere. It is also understood that modifications to the specific materials shown are intended, e.g., where Compound L can be a heteroaryl group such as pyridyl.

General Method 2.

DMSO is added to NaH 60% dispersion in oil (1-1.8 equiv.) and heated to 65° C. for 1 h. THF (10 mL) is added to the solution at 65° C. and heating is continued for another 10 min. The reaction mixture is then cooled to 0° C. and Trimethylsulfonium iodide (1-1.2 equiv.) is added. The reaction mixture is stirred for another 10 min. after which appropriate aldehyde/ketone (1 equiv.) is added as a solution in THF. The reaction mixture is further stirred at RT until the reaction is complete (monitored by TLC and LCMS). The reaction mixture is then poured in ice water and the product is extracted in organic solvent (ether or EtOAc), dried over sodium sulfate and concentrated at 25° C. to obtain the product.

Representative oxirane compounds prepared according to General Method 2 are shown in Table 2.

A general method of synthesizing alcohol intermediates by epoxide ring opening using a carboline is shown as General Method 3. Although identifiers such as R 2 , R 3 , etc. are shown in the method below, it is understood that these moieties apply to the compounds detailed herein even if different identifiers or variations thereof are used elsewhere. For example, although compound C in the method below lists substituent identifier R 2 , it is understood that compound C is the same as that obtained from General Method 1 which utilizes identifier R 4 . It is also understood that modifications to the specific materials shown are intended, e.g., where Compound L can be a heteroaryl group such as pyridyl.

General Method 3.

Compound C (1 equiv.), compound L (2-7.5 equiv.) and NaH (1-3 equiv.) are heated in DMF at 120° C. for 16 h. The contents are quenched by MeOH and evaporated to dryness. The resulting crude product is purified by silica gel chromatography (230-400 mesh) using MeOH-DCM gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).

Representative pyrido[4,3b]indo-5-yl alcohol compounds prepared according to General Method 3 are shown in Table 3.

A method of synthesizing certain compounds by dehydration of alcohol intermediates is shown as General Method 4. Although identifiers such as R 2 , R 3 , etc. are shown in the method below, it is understood that these moieties apply to the compounds detailed herein even if different identifiers or variations thereof are used elsewhere. It is also understood that modifications to the specific materials shown are intended.

General Method 4.

Indol-5-yl alcohol derivative (1 equiv.) is refluxed with 25% sulfuric acid until the reaction is complete. The reaction mixture is then cooled to 5° C. and basified with KOH to pH 9-10. The product is extracted in EtOAc, extracts are washed with 10 mL of water followed by brine, dried over sodium sulfate and evaporated under vacuum to obtain the crude product that is purified by silica gel chromatography and/or HPLC.

›Definitions · 48 of 48

Certain compounds detailed herein are synthesized according to General Method 5.

General Method 5.

To a solution of appropriate 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 equiv.) in N-methyl-2-pyrrolidone is added KOH (7 equiv.). The reaction mixture is stirred at RT for 20 min. A solution of appropriate 2-bromoethanone (1 equiv.) in N-methyl-2-pyrrolidone is added dropwise and stirring is continued for additional 2-4 h. The reaction is monitored by LCMS and TLC. The reaction mixture is diluted by adding water and extracted with EtOAc. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography.

Appropriate 2-(3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanone (100 mg, 3 mmol) is dissolved in toluene and (carbethoxymethylene)triphenylphosphorane (200 mg, 0.56 mmol) is added. The reaction mixture is heated overnight at 100° C. Solvent is removed under reduced pressure and the residue is purified by silica gel chromatography.

Representative compounds prepared according to the General Methods described herein are shown in Table 4. Isomeric compounds obtained by the Methods are shown in Table 5.

Although certain compounds of Table 4 are explicitly listed as both the (Z) and the (E) form (e.g., Compound 83 is the (E) form and Compound 397 is the (Z) form), it is understood that all forms of compounds of Table 4 are intended. Thus, for compounds of Table 4 that are listed only as a single form, it is understood that all other forms are also embraced by the invention and are provided herein the same as if each and every stereochemical form were specifically and individually listed. In particular, where only the (Z) form of a compound is listed in Table 4, the (E) form of such compound is also provided herein the same as if the (E) form were specifically and individually listed in Table 4. Likewise, where only the (E) form of a compound is listed in Table 4, the (Z) form of such compound is also provided herein the same as if the (Z) form were specifically and individually listed in Table 4.

Compounds of formula (II) may be prepared by the reaction schemes shown below. Representative examples shown below may be prepared by the methods suggested in Table 6.

General Method 6. General Method of Synthesis using Scheme A

›Step 1: Synthesis of the Carbolines

The carbolines in Scheme A can be obtained by the reaction of a suitably substituted phenyl hydrazine with 1-methyl-4-piperidone, under standard conditions. Typically, 1-methyl-4-piperidone (1 equiv.) and appropriately substituted arylhydrazine hydrochloride (1 equiv.) are refluxed in a mixture of 7% sulfuric acid in 1,4-dioxane overnight under nitrogen. The mixture is poured on to ice and basified with 50% aq NaOH. The resulting precipitate is filtered, washed well with water, and dried in air to provide the substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivative.

›Step 2: Synthesis of 1-cycloalkenyl-4-halobenzenes

Compounds I through IV in Scheme A can be obtained, e.g., by the methods described in Barbero et al., Tet. Letters (1992), 33(39):5841-42.

›Step 3: The reaction of 1-cycloalkenyl-4-halobenzene with carbolines

Typically, a mixture appropriately substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 equiv.), 1-cycloalkenyl-4-halobenzene (3 equiv.) and KOH (7 equiv.) in NMP (0.5 mL/mmol) is stirred and heated at 100° C. for 3 h. The reaction mixture is cooled to RT and diluted by adding ice and satd. aqueous NaCl. The aqueous layer is extracted with EtOAc and organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the product.

In each of the cases shown in Scheme A the final compounds are mixtures of isomers illustrated below. While the route suggested in scheme A provides access to the chemically pure compounds, the separation of isomers is a secondary step that has to be carried out in order to complete the synthesis of the unique isomers, if required.

Synthesis of Intermediates I through IV in Scheme A

It is envisaged that intermediate I through IV would be synthesized using methodologies akin to, but not limited to those described in Barbero et al., Tet. Letters (1992), 33(39):5841-42, which describes the synthesis of a molecule such as intermediate IV, without the p-fluoro group on the phenyl ring.

General Method 7. General Method of Synthesis using Scheme B

›Step 1: Synthesis of the Carbolines

The carbolines in scheme B can be obtained by the reaction of a suitably substituted phenyl hydrazine with 1-methyl-4-piperidone, under standard conditions. Typically 1-methyl-4-piperidone (1 equiv.) and appropriately substituted arylhydrazine hydrochloride (1 equiv.) are refluxed in a mixture of 7% sulfuric acid in 1,4-dioxane overnight under nitrogen. The mixture is poured on to ice and basified with 50% aq NaOH. The resulting precipitate is filtered, washed well with water, and dried in air to provide substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivative.

›Step 2: Synthesis of 1-(4-halophenyl)-5-oxabicyclo[m.n.0]alkanes

Compounds V through VIII in Scheme B can be obtained by, e.g., the methods outlined in Yu & Corey, Org. Letters (2002), 4(16):2727-30.

›Step 3: Synthesis of 1-(4-halophenyl)-5-oxabicyclo[m.n.0]alkanes with carbolines

Typically, appropriately substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 equiv.) is dissolved in DMF (2 mL/mmol). To this solution sodium hydride (2.2 equiv.) is added in portions at RT and stirred for 10 min. Appropriate 1-(4-halophenyl)-5-oxabicyclo[m.n.0]alkanes (2 equiv.) in DMF (0.5 mL/mmol) is added dropwise for 10 min. and stirred overnight at RT. The reaction mixture is quenched with MeOH and concentrated to dryness. Water is added to the residue and product is extracted in EtOAc. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the product.

›Step 4: Dehydration Step

Typically, appropriately substituted 2-(3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanol (1 equiv.) is taken in 25% aqueous sulfuric acid, and stirred at 90° C. for 3 h. The reaction mixture is cooled and basified with aq. KOH solution and extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the product.

Synthesis of Intermediates V through VIII in Scheme B

It is envisaged that intermediate V through VIII would be synthesized using methodologies akin to, but not limited to those described in Yu & Corey, Org. Letters (2002), 4(16):2727-30, which describes the synthesis of a molecule such as intermediate VII, without the p-fluoro group on the phenyl ring.

The compounds depicted may be prepared as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.

A representative compound was prepared as shown in Scheme C.

General Method 8. General Method of Synthesis using Scheme C

›Step 1: Synthesis of the Carboline 1

Sulfuric acid (3.5 mL) is added to a solution of 4-chlorophenylhydrazine hydrochloride (1 equiv.) in dioxane (50 mL), and stirred for 5 min. at RT. N-methyl-4-piperidone (1 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion of reaction (as analyzed by TLC), reaction mixture is concentrated to approximately 20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired compound.

›Step 2: Synthesis of 4-cyclohexenylpyridine

Compounds IX can be obtained by methods outlined in, Barbero et al., Tet. Letters (1992), 33(39):5841-42.

›Step 3: The Reaction of Carboline Cl with 3-cyclohexenylpyridine

To a solution of 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.45 mmol) in N-methyl-2-pyrrolidone (1.0 mL) is added powdered KOH (0.140 g, 2.5 mmol) and stirred for 10 min. at RT. 3-Cyclohexenylpyridine (1.25 mmol) is added and the reaction mixture is stirred for additional 4 h at 100° C. After completion of reaction (as analyzed by TLC), reaction mixture is diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product.

Certain compounds detailed herein are synthesized according to General Method 9.

General Method 9.

A pyrido[4,3-b]indole compound such as ones listed in Table 1 is coupled with an appropriately substituted vinyl bromide under similar conditions as described in Examples 293 and 294 to give 5-vinyl-pyrido[4,3-b]indole compounds as shown in Scheme D.

General Method 10

Alkynes of the type shown in Scheme E can be prepared by coupling a carboline of the type in Table 1 with an appropriately substituted phenyl-acetylene, or similar acetylene-linked aromatic compound, using copper/phenanthroline coupling agents as described in Examples 475-498, or by treatment of the carboline with base followed by addition of a haloethynyl-benzene. Alternatively, the fluorinated alkene products can be synthesized from the intermediate alkyne compound by palladium-mediated coupling with a haloaromatic in the presence of fluoride ion, as described in Examples 353 or 379.

The methods detailed above may be adapted as known by those of skill in the art to make compounds detailed herein. Particular examples of each of the General Methods are provided in the Examples below.

The following Examples are provided to illustrate but not to limit the invention.

All references disclosed herein are incorporated by reference in their entireties.

EXAMPLES

›Examples144

›Example 1

Preparation of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 1)

Sulfuric acid (3.5 mL) was added to a solution of 4-chlorophenylhydrazine hydrochloride (2.0 g, 11.2 mmol) in dioxane (50 mL), and stirred for 5 min. at RT. N-methyl piperidone (0.76-1.4 equiv.) was added and the mixture was heated at 80° C. for 2 h. After reaction completion as determined by thin layer chromatography (TLC), the reaction mixture was concentrated to approximately 20 mL under reduced pressure and basified to pH 10 using a 10% aqueous KOH solution. The reaction product was extracted with EtOAc (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator to obtain the product (1.3 g) as a brown solid. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.40 (s, 1H), 7.20-7.10 (d, 1H), 7.10-7.00 (d, 1H), 3.60 (s, 2H), 2.90 (s, 4H), 2.60 (s, 3H).

›Example 1A

4-Chlorophenyl hydrazine hydrochloride (30 g, 167.59 mmol) was dissolved in dioxane (300 mL) and 1-methyl-4-piperidone (28 mL, 234.63 mmol) was added. Sulfuric acid (14.4 mL) was added dropwise and the mixture was heated at 80° C. for 3 h. After completion of reaction (monitored by TLC), the dioxane layer was decanted and the residue was basified with 10% aqueous KOH solution. The resulting solid was filtered and washed with water (2 L) and finally with hexane (500 mL). The product was dried under vacuum at RT. Yield: 30 g as a light brown solid.

›Example 2

Preparation of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 3)

Sulfuric acid (2 mL) was added to a solution of p-tolyl hydrazine hydrochloride (6.0 g, 37 mmol) in dioxane (60 mL), and stirred for 5 min. at RT. N-Methyl piperidone (5.03 g, 41 mmol) was added and the mixture was heated at 80° C. for 2 h. After reaction completion as determined by TLC), the reaction mixture was concentrated to approximately 20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction mixture was extracted with EtOAc (3×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator to provide the desired compound as a brown colored solid (4.0 g, 52% yield). 1 H NMR (DMSO-d 6 , di-HCl salt) δ (ppm): 7.30 (s, 1H), 7.20-7.10 (d, 1H), 7.10-7.00 (d, 1H), 3.80 (s, 2H), 2.90 (s, 4H), 2.60 (s, 3H), 2.40 (s, 3H).

›Example 2A

Water (26.25 kg) was charged to a 50-L glass cylindrical jacketed reactor followed by p-tolylhydrazine HCl 7 (1.75 kg). Dissolution occurred after 15 min of stirring at RT and N-methyl-4-piperidone (1.56 kg) was added over a period of 4 min. The batch was heated to a range of 45-55° C. and concentrated HCl was added (37%, 3.97 kg) over 50 min. The solution was held for 17 h before a sample was taken, at which point the HPLC IPC indicated 0.07A % p-tolylhydrazine remaining. The reaction was cooled to 30-45° C. and addition of approximately 4.5 L of 6.25 N NaOH brought the solution to pH 3.2. Slight precipitation that occurred at this pH did not re-dissolve after the addition was discontinued. MTBE (1.94 kg) was added and precipitation continued upon further addition of approximately 4 L of 6.25 N NaOH to bring the final pH to 12.4. The suspension was allowed to stir for 30 min at 30-45° C. and was cooled over 1.5 h to a range of 5-15° C. The batch was held for 30 min followed by a fast filtration. The cake was washed with water (8.75 kg) and cold MTBE (3.89 kg) and conditioned on the filter for 1 h before being transferred to drying trays. The batch was dried under reduced pressure at 70° C. for 68 h to reduce the water level to <1.0%. The carboline free base (1.99 kg) was isolated in 90% yield (>99.9A % by HPLC). 1 H NMR (DMSO-d 6 , free base) δ (ppm) 7.2 (d, 1H), 7.15 (s, 1H), 6.95 (d, 1H), 4.5 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 3.0 (m, 2H), 2.9 (s, 3H), 2.4 (s, 3H).

›Example 3

Preparation of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 5)

Phenyl hydrazine hydrochloride (1 equiv.) and 1-methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is dissolved in EtOH and stirred at 80-90° C. overnight. The reaction is monitored by TLC. Upon completion, the reaction mixture is cooled to RT and the solvent is evaporated to dryness. The residue is dissolved in EtOAc and washed with a saturated sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 3A

Phenyl hydrazine hydrochloride (5 g, 34.57 mmol) and 1-methylpiperidin-4-one hydrochloride (4.5 g, 30.1 mmol, 1 eq.) was dissolved in of ethanol (150 mL) and stirred at 80-90° C. for overnight. The reaction was monitored by TLC. The mixture was cooled to RT, solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated sodium bicarbonate solution. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3.0 g of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1 H NMR (CDCl 3 , free base) δ (ppm) 8.0 (bs, 1H), 7.4 (d, 1H), 7.35 (d, 1H), 7.20-7.0 (m, 2H), 3.7 (s, 2H), 2.9 (s, 4H), 2.6 (s, 3H).

›Example 4

Preparation of 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 7)

To a solution of phenylhydrazine hydrochloride (1 equiv.) in EtOH is added 1-ethylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) and the reaction mixture is heated at 80° C. for 16 h. After completion of the reaction, e.g., as monitored by liquid chromatography-mass spectrometry (LCMS), the reaction mixture is concentrated to dryness and basified with aq. saturated NaHCO 3 and extracted in EtOAc. The organic layer is separated, dried over sodium sulfate and concentrated to obtain 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 4A

To a solution of phenylhydrazine hydrochloride (1 equiv) in ethanol was added 1-ethylpiperidin-4-one hydrochloride (1 equiv) and heated at 80° C. for 16 h. After completion of the reaction (monitored by LCMS). The reaction mixture was concentrated under vacuum and basified with aq. saturated NaHCO 3 , extracted with EtOAc, the organic layer was separated dried over sodium sulfate and concentrated under reduced pressure to obtain 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1 H NMR (CDCl 3 , free base) δ (ppm) 7.8 (bs, 1H), 7.4 (d, 1H), 7.20-7.0 (m, 3H), 3.7 (s, 2H), 2.9 (s, 4H), 2.7-2.6 (q, 2H), 1.2 (t, 3H).

›Example 5

Preparation of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (Compound 9)

To a solution of p-tolylhydrazine hydrochloride (1 equiv.) in EtOH is added 1-ethylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) and the contents are heated at 80° C. for 16 h. After completion of the reaction, as monitored by LCMS, the reaction mixture is concentrated to dryness and basified with aq. saturated NaHCO 3 . The reaction product is extracted with EtOAc and the organic layer is separated, dried over sodium sulfate and concentrated to obtain 2-ethyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 5A

To a solution of p-tolylhydrazine hydrochloride (5.0 g, 31.5 mmol) in Ethanol (150 mL) was added 1-ethylpiperidin-4-one hydrochloride (4.0 g, 24.5 mmol) and heated at 80° C. for 16 h. After completion of the reaction (monitored by LCMS). The reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO 3 , extracted with EtOAc, the organic layer was separated dried over sodium sulfate and concentrated under vacuum to obtain 4.8 g (Yield 71.0%) of 2-ethyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1 H NMR (CDCl 3 , free base) δ (ppm) 7.7 (bs, 1H), 7.2-7.1 (m, 2H), 6.9 (d, 1H), 3.8 (s, 2H), 2.9 (s, 4H), 2.7 (q, 2H), 2.4 (s, 3H), 1.2 (t, 3H).

›Example 6

Preparation of 6,8-dichloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 11)

2,4-Dichlorophenyl hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxan. N-Methylpiperidine-4-one (0.76-1.4 equiv.) is added and the contents are stirred at RT for 15 min., followed by heating at 80° C. for 14 h. After completion of the reaction, as monitored by LCMS, the solvent is removed in vacuo, basified with saturated aq. NaHCO 3 and extracted with EtOAc. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated. The resulting crude product is purified by column chromatography to afford 6,8-dichloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 6A

2,4-Dichlorophenylhydrazine hydrochloride (1.0 g, 4.68 mmol) was dissolved in 7% H 2 SO 4 in 1,4-dioxan (50 mL) and N-methylpiperidine-4-one (0.76 g, 5.0 mmol) was added and stirred at RT for 15 min, heated at 80° C. for 14 h. After completion of the reaction (monitored by LCMS), solvent was removed in vacuum, basified with saturated aq. NaHCO 3 and extracted with EtOAc. Organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting product was purified by column chromatography to afford 0.58 g of 6,8-dichloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 7

Preparation of 8-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 13)

4-Chloro-2-fluorophenyl hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxan. N-Methylpiperidine-4-one (0.76-1.4 equiv.) is added and the contents are stirred at RT for 10 min. The reaction mixture is then stirred at 100° C. for 6 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated and then slowly quenched with aq. NaHCO 3 solution, followed by extraction with EtOAc. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography to afford 8-chloro-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 7A

4-Chloro-2-fluoro hydrazine hydrochloride (3 g, 15.3 mmol) was dissolved in 7% H 2 SO 4 in 1,4-dioxane (150 mL), N-methylpiperidine-4-one (2.28 g, 15.3 mmol) was added and stirred at RT for 10 min. Reaction mixture was stirred at 100° C. for 6 h. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated under vacuum and slowly quenched with aq. NaHCO 3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum and purified by column chromatography to afford 1.2 g of 8-chloro-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1 H NMR (CDCl 3 , freebase) δ (ppm) 8.1 (bs, 1H), 7.15 (s, 1H), 6.9-6.8 (d, 1H), 3.65 (s, 2H), 2.95-2.8 (dd, 4H), 2.6 (s, 3H).

›Example 8

Preparation of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 15)

Sulfuric acid is added to a solution of 4-ethyl phenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.

›Example 8A

Sulfuric acid (2 mL) was added to a solution of 4-Ethyl phenyl hydrazine hydrochloride (2.0 g, 11 mmol) in dioxane (30 mL), and allowed to stir for 5 min at RT. N-methylpiperidone (1.7 g, 13 mmol) was added and the mixture was heated at 80° C. for 3 h. After completion of reaction (monitored by TLC), reaction mixture was concentrated to ˜20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The mixture was extracted with EtOAc (3×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound as a brown colored solid (0.35 g, 82% yield).

›Example 9

Preparation of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 2)

Sulfuric acid is added to a solution of 4-isopropyl phenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.

›Example 9A

Sulfuric acid (14 mL) was added to a solution of 4-Isopropyl phenyl hydrazine hydrochloride (7.0 g, 37 mmol) in dioxane (186 mL) and allowed to stir for 5 min at RT. N-methyl piperidone (4.6 mL, 37 mmol) was added and the mixture was heated at 80° C. for 2 h. After completion of reaction (monitored by TLC), reaction mixture was concentrated to ˜20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The mixture was extracted with EtOAc (3×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound as yellow colored solid (7.0 g, 82% yield). 1 H NMR (DMSO-d 6 , free base) δ (ppm) 10.6 (s, 1H), 7.16 (s, 1H), 7.13 (d, 1H), 6.88 (d, 1H), 3.48 (s, 2H), 2.9 (m, 1H), 2.74 (m, 2H), 2.68 (m, 2H), 2.40 (s, 3H), 1.21 (d, 6H).

›Example 10

Preparation of 8-chloro-9-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 4)

Sulfuric acid is added to a solution of 4-chloro-3-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to give a mixture or regioisomeric products. For this Example, silica gel chromatography separates the title compound from the other regioisomer (Compound 6) obtained in Example 11.

›Example 10A

Sulfuric acid (1.0 mL) was added to a solution of 4-chloro-3-fluorophenylhydrazine hydrochloride (0.5 g, 2.1 mmol) in dioxane (15 mL), and allowed to stir for 5 min at RT. N-methylpiperidone (0.3 mL, 2.3 mmol) was added and the mixture was heated at 80° C. for 3 h. After completion of reaction (monitored by TLC), reaction mixture was concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The mixture was extracted with EtOAc (3×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to give the mixture of 6 (major) and 7 (minor) as a brown colored solid (0.17 g, 33% yield).

›Example 11

Preparation of 8-Chloro-7-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 6)

›Example 11A

Sulfuric acid (1.0 mL) was added to a solution of 4-chloro-3-fluoro phenyl hydrazine hydrochloride (0.5 g, 2.1 mmol) in dioxane (15 mL), and allowed to stir for 5 min at RT. N-methylpiperidone (0.3 mL, 2.3 mmol) was added and the mixture was heated at 80° C. for 3 h. After completion of reaction (monitored by TLC), reaction mixture was concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The mixture was extracted with EtOAc (3×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to give the mixture of 6 (major) and 7 (minor) as a brown colored solid (0.17 g, 33% yield). 1 H NMR (DMSO-d 6 , free base) δ (ppm) 11.1 (s, 1H), 7.48 (d, 1H), 7.27 (d, 1H), 3.5 (s, 2H), 2.76 (m, 2H), 2.70 (m, 2H), 2.41 (s, 3H).

›Example 12

Preparation of Methyl 2,3,4,5-tetrahydro-2-methyl-1H-pyrido(4,3-b)indole-8-carboxylate (Compound 8)

Methyl-4-hydrazinylbenzoate hydrochloride (1 equiv.) and 1-methylpiperidin-4-one HCl (0.76-1.4 equiv.) are taken aqueous HCl and heated at 100° C. overnight (the product was detected by LCMS). The reaction mixture is concentrated and refluxed (90° C.) in methanolic HCl overnight (product was detected by LCMS and TLC). The reaction mixture is concentrated and basified with aqueous NaHCO 3 solution and extracted with EtOAc. The crude product is crystallized in DCM and ether and hexane.

›Example 12A

Methyl-4-hydrazinylbenzoate hydrochloride (10 g, 50 mmol) and 1-methylpiperidin-4-one hydrochloride (7.3 g, 50 mmol) were dissolved in aqueous HCl and heated at 100° C. overnight (product was detected by LCMS). The reaction mixture was concentrated under vacuum and refluxed (90° C.) in methanolic HCl overnight (product was detected by LCMS & TLC). The reaction mixture was concentrated under vacuum and basified with aqueous NaHCO 3 solution and extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product. The product was crystallized in DCM and ether and hexane. Yield 5.1 g. 1 H NMR (DMSO-d 6 , free base) δ (ppm): 8.55 (s, 1H), 8.27 (s, 1H) 7.82-7.79 (d, 1H), 7.24-7.20 (d, 1H), 3.94 (s, 3H), 3.72 (s, 2H), 3.85 (s, 4H) 2.60 (s, 3H).

›Example 13

Preparation of 2,3,4,5-tetrahydro-2-methyl-8-(trifluoromethoxy)-1H-pyrido[4,3-b]indole (Compound 10)

(4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxane. 1-Methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is added and the mixture is stirred at 80° C. for 6 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated, then slowly quenched with aq. NaHCO 3 solution and extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate, evaporated to dryness and purified by column chromatography to afford 2-methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 13A

(4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (1 g, 4.37 mmol) was dissolved in 7% H 2 SO 4 in 1,4-dioxane (50 mL), 1-methylpiperidin-4-one hydrochloride (0.65 g, 4.37 mmol) was added and stirred at 80° C. for 6 h. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated under vacuum and slowly quenched with aq. NaHCO 3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography to afford 0.9 g of 2-methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1 H NMR (CDCl 3 , free base) δ (ppm) 7.9 (bs, 1H), 7.3-7.2 (m, 2H), 7.1-6.9 (d, 1H), 3.7 (s, 2H), 2.9-2.8 (m, 4H), 2.6 (s, 3H).

›Example 14

Preparation of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole (Compound 12)

O-Tolyl hydrazine hydrochloride (1 equiv.) is taken in EtOH. 1-Methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) and ethanolic HCl is added (pH acidic) and the contents are stirred at 80° C. for 5 h. The reaction is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated. The residue is dissolved in aq NaHCO 3 solution and extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 14A

O-Tolyl hydrazine hydrochloride (3.0 g, 18.9 mmol) was dissolved in of ethanol (10 mL), 1-methylpiperidin-4-one hydrochloride (2.8 g, 18.9 mmol) and ethanolic HCl (10 mL) was added (pH acidic) and stirred at 80° C. for 5 h. Reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under vacuum. Residue was dissolved in aq NaHCO 3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 2.5 g of 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1 H NMR (CDCl 3 , free base) δ (ppm) 7.65 (s, 1H), 7.01 (t, 1H), 6.9 (d, 1H), 3.61 (s, 2H), 2.89-2.80 (m, 4H), 2.58 (s, 3H), 2.41 (s, 3H).

›Example 15

Preparation of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 14)

(4-tert-Butylphenyl)hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxane. 1-Methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is added and the contents are stirred at 80° C. for 3 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated and then quenched with aq. NaHCO 3 solution, followed by extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate, evaporated to dryness and purified by column chromatography (5% MeOH-DCM) to afford 8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

›Example 15A

(4-tert-Butylphenyl)hydrazine hydrochloride (1 g, 4.98 mmol) was dissolved in 7% H 2 SO 4 in 1,4-dioxane (50 mL), 1-methylpiperidin-4-1 hydrochloride (0.742 g, 4.98 mmol) was added and stirred at 80° C. for 3 h. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated under vacuum and quenched with aq. NaHCO 3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum and purified by column chromatography (5% Methanol-DCM) to afford 0.51 g of 8-tert-butoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1 H NMR (DMSO-d 6 , free base) δ (ppm) 11.1 (bs, 1H), 10.6 (bs, 1H), 7.4 (s, 1H), 7.3-7.2 (d, 1H), 7.2-7.1 (d, 1H), 4.6-4.5 (m, 1H), 4.3 (bs, 1H), 3.7 (bs, 1H), 3.5 (bs, 1H), 3.2-3.3 (m, 2H), 2.9 (s, 3H), 1.3 (s, 9H).

›Example 16

Preparation of 2,3,4,5-tetrahydro-8-iodo-2-methyl-1H-pyrido[4,3-b]indole (Compound 16)

To a solution of compound 4-iodophenylhydrazine (1 equiv.) in 1,4-dioxane (50 mL) is added conc. sulfuric acid, followed by dropwise addition of 1-methyl-4-piperidone (1 equiv.) at RT. The reaction mixture is heated at 70° C. for 90 min., evaporated, diluted with water and the pH is adjusted to 12 with 40 mL of 15% aq. KOH solution. The reaction mixture is extracted with EtOAc, followed by brine wash, dried over sodium sulfate and evaporated under vacuum. The crude product is column purified over 230-400 silica gel using a gradient of 0-5% of MeOH in EtOAc. Note 1: The reaction temperature should be 70° C. Higher temperature results in the de-iodo carboline.

›Example 16A

To a suspension of 4-iodophenylhydrazine hydrochloride (2.0 g, 0.0074 mol) in dioxane (30 mL) at RT was added conc. H 2 SO 4 (0.7 mL, 0.0171 mol) dropwise and the reaction mixture was stirred for 5 min. To this was added N-methyl-4-piperidone (0.838 g, 0.0074 mol) and the reaction mixture was stirred at RT for 10 min and heated at 70° C. for 90 min. Reaction monitored by TLC. The solvent was evaporated and pH adjusted to 9-10 by 10% KOH Solution. The product was extracted with (3×50 mL) EtOAc. Combined organic layer washed with water and brine and dried over sodium sulfate, concentrated under vacuum and product purified by column chromatography (100-200 mesh silica) in solvent system (0-10%, DCM/MeOH). Obtained 1.8 g of brown solid. 1 H NMR (CDCl 3 , free base) δ (ppm) 7.70 (s, 1H), 7.38 (d, 1H), 7.05 (d, 1H), 3.60 (s, 2H), 2.90 (m, 4H), 2.58 (s, 3H).

›Example 17

Preparation of 8-chloro-2-cyclopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 17)

Sulfuric acid is added to a solution of 4-Chloro phenyl hydrazine hydrochloride (1 equiv.) in dioxane and stirred for 5 min. at RT. N-cyclopropyl piperidone (1 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction product is extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.

›Example 17A

Sulfuric acid (3.5 mL) was added to a solution of 4-chlorophenylhydrazine hydrochloride (1 eq.) in dioxane (50 mL), and allowed to stir for 5 min at RT. N-cyclopropylpiperidone (1 eq.) was added and the mixture was heated at 80° C. for 2 h. After completion of reaction (monitored by TLC), reaction mixture was concentrated to ˜20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The mixture was extracted with EtOAc (3×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound as a brown colored solid (1.3 g, 53% yield).

›Example 18

Preparation of 8-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 18)

Sulfuric acid is added to a solution of 4-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction mixture is extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.

›Example 18A

Sulfuric acid (3.5 mL) was added to a solution of 4-fluorophenylhydrazine hydrochloride (2.0 g, 12.3 mmol) in dioxane (50 mL), and allowed to stir for 5 min at RT. N-methylpiperidone (1.38 g, 12 mmol) was added and the mixture was heated at 80° C. for 2 h. After completion (TLC), reaction mixture was concentrated to ˜20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction mixture was extracted with EtOAc (3×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound as a brown colored solid (1.3 g, 53% yield). 1 H NMR (CDCl 3 , free base) δ (ppm) 7.90 (bs, 1H), 7.18 (m, 1H), 7.05 (d, 1H), 6.82 (t, 1H), 3.60 (s, 2H), 2.90 (m, 2H), 2.82 (m, 2H), 2.38 (s, 3H).

›Example 19

Preparation of 2-methyl-5-(oxiran-2-yl)pyridine (Compound 19)

DMSO is added to NaH 60% dispersion in oil (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added to the mixture at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. A solution of 6-methylnicotinaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h, and monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get crude product 2-methyl-5-(oxiran-2-yl)pyridine.

›Example 19A

DMSO (4 mL) was added to NaH 60% dispersion in oil (0.314 g, 7.8 mmol, 1.3 eq.) and heated it to 65° C. for 1 h. THF (10 mL) was added at the same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1.2 g, 5.9 mmol, 1 eq.) was added and stirred for 10 min and solution of 6-methylnicotinaldehyde (0.720 g, 5.9 mmol, 1 eqv) in THF was added dropwise. After complete of addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get product 2-methyl-5-(oxiran-2-yl)pyridine (1.1 g).

›Example 20

Preparation of 2-(4-fluorophenyl)-2-methyloxirane (Compound 21)

To a solution of trimethylsulfonium iodide (1-1.2 equiv.) in DMSO is added sodium hydride 50%-55% dispersion in oil (1-1.8 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 1-(4-fluorophenyl)ethanone (1 equiv.) in DMSO is added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The reaction is monitored by TLC and at completion the reaction mixture is poured in water (100 mL) and extracted with EtOAc. The combined organic extract is washed with water, followed by brine, dried over sodium sulfate and evaporated to dryness.

›Example 20A

To a solution of trimethylsulfonium iodide (3.5 g, 17.15 mmol, 1.2 eq.) in DMSO (30 mL) was added sodium hydride 50%-55% dispersion in oil (0.97 g, 22.2 mmol, 1.5 eq.) portionwise over 5 min. and stirred for an hour at RT. A solution of 1-(4-fluorophenyl)ethanone (2 g, 14.47 mmol, 1 eq.) in DMSO (10 mL) was added to the reaction mixture dropwise over 20 min. It was stirred at RT for 4 h. TLC was checked and the reaction mixture was poured in 100 mL water and extracted with EtOAc (3×100 mL). The combined organic extract was washed with water (2×150 mL), followed by brine. It was dried over sodium sulfate and concentrated under vacuum. Yield: 2.2 g brown oil. 1 H NMR (Acetone-d 6 , free base) δ (ppm) 7.43-7.39 (dd, 2H), 7.11 (t, 2H), 2.95 and 2.72 (dd, 2H), 1.65 (s, 3H).

›Example 21

Preparation of 2-p-tolyloxirane (Compound 23)

To a solution of Trimethylsulfonium iodide (1-1.2 equiv.) in DMSO is added sodium hydride 60% dispersion in oil (1-1.8 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 4-methylbenzaldehyde (1 equiv.) in DMSO is added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The reaction is monitored by TLC and the reaction mixture poured in water and extracted with EtOAc. The combined organic extract is washed with water, followed by brine, and dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-p-tolyloxirane as crude product.

›Example 21A

To a solution of trimethylsulfonium iodide (10.28 g, 50.37 mmol, 1.2 eq.) in DMSO (70 mL) was added sodium hydride 60% dispersion in oil (2.82 g, 70.5 mmol, 1.7 eq.) portionwise over 5 min. and stirred for an hour at RT. A solution of 4-methylbenzaldehyde (5.0 g, 42.0 mmol, 1 eq.) in DMSO (25 mL) was added to the reaction mixture dropwise over 20 min. It was stirred at RT for 4 h. TLC was checked and the reaction mixture was poured in 150 mL water and extracted with EtOAc. The combined organic extract was washed with water and brine. It was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5.2 g of 2-p-tolyloxirane as product. 1 H NMR (CDCl 3 , free base) δ (ppm) 7.2-7.1 (m, 4H), 3.81-3.8 (t, 1H), 3.2-3.1 (m, 1H), 2.6-2.5 (m, 1H), 2.4 (s, 3H).

›Example 22

Preparation of 3-(oxiran-2-yl)pyridine (Compound 25)

Sodium hydride 50% dispersion in oil (1-1.8 equiv.) is taken in DMSO and heated at 65° C. for 1 h. THF is added to at the mixture at the same temperature and heated for 10 min. The reaction mixture is cooled to 0° C. and Trimethylsulfonium iodide (1-1.2 equiv.) is added, followed by nicotinaldehyde (1 equiv.) and the contents are stirred at RT for 1 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is poured in ice and extracted with diethyl ether, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude product (3-(oxiran-2-yl)pyridine).

›Example 22A

Sodium hydride 50% dispersion in oil (1.64 g, 34.2 mmol, 1.8 eq.) was dissolved in DMSO (12 mL) and heated at 65° C. for 1 h. THF (36 mL) was added at the same temperature and heated for 10 min. Reaction mixture was cooled to 0° C. and trimethylsulfonium iodide (3.81 g, 18.6 mmol, 1 eq.) was added, followed by nicotinaldehyde (2 g, 18.6 mmol, 1 eq.) and stirred at RT for 1 h. Reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was poured in ice and extracted with diethyl ether, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 1 g of product (3-(oxiran-2-yl)pyridine). 1 H NMR (CDCl 3 , free base) δ (ppm) 8.6-8.5 (m, 2H), 7.5 (d, 1H), 7.3 (m, 1H), 3.9 (t, 1H), 3.2 (t, 1H), 2.9 (t, 1H).

›Example 23

Preparation of 2-(2,4,6-trifluorophenyl)-2-methyloxirane (Compound 27)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents were stirred for 10 min. after which the solution of 1-(2,4,6-trifluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored for completion. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 23A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(2,4,6-trifluorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 24

Preparation of 2-(2,4-dichlorophenyl)-2-methyloxirane (Compound 29)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for one h. THF is added at same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 24A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.40 (d, 1H), 7.23 (m, 2H), 3.01 (d, 1H), 2.79 (d, 1H), 1.62 (s, 3H).

›Example 25

Preparation of 2-(2,4-difluorophenyl)-2-methyloxirane (Compound 31)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(2,4-difluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 25A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(2,4-difluorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.41 (m, 1H), 6.81 (m, 2H), 2.98 (d, 1H), 2.79 (d, 1H), 1.59 (s, 3H).

›Example 26

Preparation of 2-(3,4-dichlorophenyl)-2-methyloxirane (Compound 33)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(3,4-dichlorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 26A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(3,4-dichlorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.42 (d, 1H), 7.39 (m, 1H), 7.18 (m, 1H), 2.98 (d, 1H), 2.76 (d, 1H), 1.65 (s, 3H).

›Example 27

Preparation of 2-(3,4-difluorophenyl)-2-methyloxirane (Compound 35)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(3,4-difluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 27A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(3,4-difluorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.17 (m, 3H), 2.99 (d, 1H), 2.79 (d, 1H), 1.71 (s, 3H).

›Example 28

Preparation of 2-(3-chloro-4-fluorophenyl)-2-methyloxirane (Compound 37)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents were stirred for 10 min. after which the solution of 1-(3-chloro-4-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 28A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(3-chloro-4-fluorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 29

Preparation of 2-(3-fluoro-4-methoxyphenyl)-2-methyloxirane (Compound 39)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(3-fluoro-4-methoxyphenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 29A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min. after which the solution of 1-(3-fluoro-4-methoxyphenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.12 (m, 2H), 6.87 (m, 1H), 3.84 (s, 3H), 2.91 (d, 1H), 2.78 (d, 1H), 1.68 (s, 3H).

›Example 30

Preparation of 2-(3-fluoro-4-methoxyphenyl)oxirane (Compound 41)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 3-fluoro-4-methoxybenzaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 30A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 3-fluoro-4-methoxybenzaldehyde (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 31

Preparation of 2-(4-chloro-3-fluorophenyl)-2-methyloxirane Compound 20)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(4-chloro-3-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 31A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(4-chloro-3-fluorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 32

Preparation of 2-(4-chlorophenyl)-2-methyloxirane (Compound 22)

DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and the contents were stirred for 10 min. after which the solution of 1-(4-chlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h; the reaction was monitored by LCMS. After completion, the reaction mixture was poured in ice water, extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the crude product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.38 (m, 4H), 2.97 (d, 1H), 2.78 (d, 1H), 1.69 (s, 3H).

›Example 33

Preparation of 2-(4-fluorophenyl)-2,3-dimethyloxirane (Compound 24)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(4-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture was poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 33A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Triethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(4-fluorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the product.

›Example 34

Preparation of 2-(4-methoxyphenyl)-2-methyloxirane (Compound 26)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(4-methoxyphenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 33A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(4-methoxyphenyl)ethanone (1 equiv) in THF was added drop wise. After complete addition, reaction mixture was stirred at room temperature for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.24 (d, 2H), 6.83 (d, 2H), 3.8 (s, 3H), 2.98 (d, 1H), 2.78 (d, 1H), 1.71 (s, 3H).

›Example 35

Preparation of 2-(trifluoromethyl)-2-(4-fluorophenyl)oxirane (Compound 28)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 35A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 36

Preparation of 2-(trifluoromethyl)-5-(2-methyloxiran-2-yl)pyridine (Compound 30)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 5-acetyl-2-(trifluoromethyl) pyridine (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 36A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 37

Preparation of 2-(trifluoromethyl)-5-(oxiran-2-yl)pyridine (Compound 32)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 6-(trifluoromethyl)pyridine-3-carbaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 37A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 6-(trifluoromethyl)pyridine-3-carbaldehyde (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 38

Preparation of 2-cyclopropyl-2-(4-fluorophenyl)oxirane (Compound 34)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of cyclopropyl(4-fluorophenyl)methanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 38A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of cyclopropyl(4-fluorophenyl)methanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.05 (m, 4H), 2.9 (d, 1H), 2.7 (d, 1H), 0.87 (m, 1H), 0.61 (m, 2H), 0.45 (m, 2H).

›Example 39

Preparation of 2-ethyl-2-(4-fluorophenyl)oxirane (Compound 36)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(4-fluorophenyl)propan-1-one (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 39A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(4-fluorophenyl)propan-1-one (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the product.

›Example 40

Preparation of 2-methyl-2-phenyloxirane (Compound 38)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of acetophenone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 40A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of acetophenone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.35 (m, 5H), 2.95 (d, 1H), 2.8 (d, 1H), 1.75 (s, 3H).

›Example 41

Preparation of 2-methyl-5-(2-methyloxiran-2-yl)pyridine (Compound 40)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(6-methylpyridin-3-yl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 41A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(6-methylpyridin-3-yl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 42

Preparation of 2-methyl-5-(2-methyloxiran-2-yl)pyrimidine (Compound 42)

DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(2-methylpyrimidin-5-yl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.

›Example 42A

DMSO was added to NaH (1 equiv) and heated to 65° C. for 1 h. THF was added at same temp. and heated for another 10 min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of 1-(2-methylpyrimidin-5-yl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get the product.

›Example 43

Preparation of racemic-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (Compound 43)

3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.2 g, 11 mmol, 1 equiv.), 4-methylstyrene oxide (5.8 g, 44 mmol, 4 equiv.) and NaH (1.3 g, 32.5 mmol, 2.95 eq) were heated in DMF (70 mL) at 120° C. for 16 h (overnight). The contents were quenched by MeOH and evaporated to dryness. The resulting crude product was purified by silica gel chromatography (230-400 mesh) using EtOAc-hexane gradient to obtain 1.3 g of racemic-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol. The free base was converted into its hydrochloride salt by treatment of ethanolic HCl. 1 H NMR (DMSO-d6, HCl salt) δ (ppm): 10.30 (s, 1H), 7.42-7.0 (m, 7H), 5.6 (m, 1H), 4.90-4.80 (m, 1H), 4.60-4.55 (d, 1H), 4.30-4.00 (m, 3H), 3.70 (s, 1H), 3.4 (m, 1H), 3.22-3.10 (d, 1H), 3.00-2.90 (m, 3H), 2.80-2.60 (d, 1H), 2.40 (s, 3H), 2.30 (s, 3H).

›Example 44

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol (Compound 45)

To a solution of carboline (290 mg, 1.314 mmol, 1.0 equiv.) in DMF (6 mL) was added 38 mg of sodium hydride 55-60% dispersion in oil, in one portion, and heated to 120° C. for 1 h under stirring. The reaction mixture was cooled to 0° C. and epoxide (400 mg, 2.628 mmol, 2 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. again and stirred at the same temperature for 2 h. The reaction mixture was brought to RT and partitioned between 60 mL of EtOAc and 15 mL of water. The organic layer was separated and the aqueous layer extracted with EtOAc (1×50 mL). The combined organic layer was washed with water and then with brine, dried over sodium sulfate and concentrated under vacuum to yield crude product (600 mg). The crude product was purified by column chromatography (flash) over 230-400 silica gel (deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc. 1 H NMR and LCMS were found to be consistent. Yield: 150 mg free base. The pure compound was converted to its oxalate salt with 1 equiv. of oxalic acid in THF. 1 H NMR (CD 3 OD, oxalate salt) δ (ppm): 7.4 (m, 3H), 7.18 (d, 1H), 6.98 (m, 3H), 4.45 (bs, 2H), 4.3 (d, 1H), 4.19 (d, 1H), 3.6-(bs, 2H), 3.0 (s, 3H), 3.1-2.9 (m, 2H), 1.60 (s, 3H).

›Example 45

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol (Compound 47)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg, 1.31 mmol, 1.0 equiv.) in DMF (6 mL), a heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 2-methyl-5-(2-methyloxiran-2-yl)pyridine (400 mg, 2.68 mmol, 2.0 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc (60 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (1×20 mL). The combined organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in 10 mL THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.50 (s, 1H), 7.70 (d, 1H), 7.47 (s, 1H), 7.42 (d, 1H), 7.15 (d, 1H), 7.03 (d, 1H), 4.40 (m, 2H), 4.30 (m, 1H), 4.10 (m, 1H), 3.50 (m, 1H), 3.10 (m, 3H), 2.90 (s, 3H), 2.45 (s, 3H), 1.60 (m, 3H).

›Example 46

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyrimidin-5-yl)propan-2-ol (Compound 49)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF (6 mL), and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 5-(2-methyloxiran-2-yl)pyrimidine (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc (60 mL) and water (15 mL). The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 46A

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg, 1.31 mmol, 1.0 equiv.) in DMF (6 ml), a heated to 120 deg C. for 1 hour with stirring. The reaction mixture was cooled to 0 deg C. and 5-(2-methyloxiran-2-yl)pyrimidine (400 mg, 2.9 mmol, 2.2 equiv) was added dropwise over 5 minutes. The temperature was raised to 120 deg C. and stirred for 2 hours. The reaction mixture was cooled to RT and partitioned between EtOAc (60 ml) and water (15 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (1×20 ml). The combined organic layer was washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, pretreated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the product.

›Example 47

Preparation of racemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (Compound 51)

2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (214 mg, 1 mmol), 4-methylstyrene oxide (1 mL, 7.5 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 mL) at 120° C. for 16 h (overnight) to obtain 50 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1 H NMR (CDCl 3 , TFA salt) δ (ppm): 13.20 (bs, 1H), 7.4-7.0 (m, 7H), 5.05-4.97 (m, 1H), 4.70 (t, 1H), 4.25-4.10 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.10 (m, 5H), 2.5 (s, 3H), 2.38 (s, 3H), 1.41 (t, 3H).

›Example 48

Preparation of racemic-2-(1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (Compound 53)

2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (400 mg, 2.1 mmol), 4-methylstyrene oxide (2.1 g, 15.7 mmol) and NaH (252 mg, 6.3 mmol) were heated in DMF (5 mL) at 120° C. for 16 h to obtain 75 mg of racemic-2-(1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., inject ion vol. 5 mL). 1 H NMR (CDCl 3 , TFA salt) δ (ppm): 13.45-13.20 (bs, 1H), 7.40-7.05 (m, 8H), 5.0-4.9 (t, 1H), 4.8-4.6 (t, 1H), 4.25-4.05 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.30 (m, 2H), 3.05 (m, 1H), 3.00-2.91 (m, 3H), 2.3 (s, 3H).

›Example 49

Preparation of racemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (Compound 44)

2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 2.0 mmol), 4-methylstyrene oxide (2.01 g, 15 mmol) and NaH (240 mg, 6 mmol) were heated in DMF (6 mL) at 120° C. for 16 h to obtain 120 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolyethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1 H NMR (CDCl 3 , TFA salt) δ (ppm): 13.40-13.10 (bs, 1H), 7.40-7.30 (t, 2H), 7.29-7.10 (m, 6H), 5.07-4.95 (m, 1H), 4.75-4.60 (t, 1H), 4.25-4.02 (m, 3H), 3.75-3.65 (m, 1H), 3.40-3.0 (m, 5H), 2.35 (S, 3H), 1.47-1.40 (t, 3H).

›Example 50

Preparation of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-phenylpropan-2-ol (Compound 46)

Sodium hydride (1-3 equiv.) is added to a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF, and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-methyl-2-phenyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 51

Preparation of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(6-methylpyridin-3-yl)ethanol (Compound 48)

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.35 g, 6.65 mmol) was taken in DMF (10 mL). NaH (0.9 g, 19.5 mmol) was added portionwise at RT and the contents were stirred for 15 min. 2-Methyl-5-(oxiran-2-yl)pyridine (0.9 g, 6.65 mmol) was added to the reaction mixture dropwise at RT. After complete addition, the reaction mixture was stirred at RT for 2 h, the reaction was monitored by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. Water (20 mL) was added and the reaction mixture was extracted in EtOAc (2×100 mL), dried over sodium sulfate and concentrated to provide a dark brown crude oil. This product was purified by HPLC to obtain pure 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(6-methylpyridin-3-yl)ethanol as the TFA salt (310 mg). 1 H NMR (CD 3 OD, TFA salt) δ (ppm): 8.5 (s, 1H), 8.4 (s, 1H), 7.8 (d, 1H), 7.2 (s, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 5.2 (bs, 1H), 4.7 (d, 1H), 4.4 (m, 3H), 3.9 (bs, 1H), 3.5 (m, 1H), 3.3 (s, 2H), 3.1 (s, 3H), 2.7 (s, 3H),

›Example 52

Preparation of 2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (Compound 50)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF, and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 5-acetyl-2-(trifluoromethyl)pyridine (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 53

Preparation of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol (Compound 52)

A mixture of compound 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.5 g, 7.5 mmol, 1 equiv.) and NaH (252 mg, 10.5 mmol, 1.4 equiv.) in DMF (30 mL) were heated to 120° C. for 1 h. The reaction mixture was cooled to RT and 2-methyl-5-(2-methyloxiran-2-yl)pyridine (2.46 g, 16.5 mmol, 2.2 equiv.) in DMF (17 mL) was added dropwise over 12 min. The temperature was again raised to 120° C. and stirred for 3 h. The reaction mixture was cooled to RT and water (5 mL) was added, diluted with EtOAc (700 mL) and the organic layer was washed with water (3×100 mL) and then with brine, dried over sodium sulfate and concentrated under vacuum. The compound was purified by column chromatography over 230-400 silica gel using a gradient of 10-20% MeOH in EtOAc. Yield: 2.3 g (87%). 1 H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.52 (bs, 1H), 7.73-7.71 (d, 1H), 7.31-7.29 (d, 1H), 7.17-7.15 (m, 2H), 6.88-6.86 (d, 1H), 4.34 (bs, 2H), 4.24-4.40 (dd, 2H), 3.47 (bs, 2H), 2.98 (bs, 2H), 2.91 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H), 1.48 (s, 3H).

›Example 54

Preparation of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-3-yl)ethanol (Compound 54)

Carboline (500 mg, 2.5 mmol) was dissolved in DMF (5 mL). To this solution was added NaH (60%, 180 mg, 4.5 mmol) at RT and the reaction mixture was stirred for 10-15 min. after which 3-(oxiran-2-yl)pyridine (450 mg, 3.7 mmol) was added. The reaction mixture was stirred at RT for 4 h and the reaction was monitored by LCMS. After completion, the reaction mixture was poured on ice water and extracted with EtOAc. The organic layer was dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to obtain 420 mg of product as a white solid (TFA salt). TLC (silica gel) 5:95 MeOH:DCM, Rf 0.1 was observed. 1 H NMR (CD 3 OD, TFA salt) δ (ppm): 8.60 (d, 2H), 8.20 (bs, 1H), 7.85 (bs, 1H), 7.20 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 5.2 (bs, 1H), 4.8 (d, 2H), 4.4 (m, 4H), 3.9 (bs, 1H), 3.60-(bs, 2H), 3.10-(s, 3H), 2.40 (s, 3H).

›Example 55

Preparation of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-3-yl)ethanol (Compound 56)

Chloro carboline (500 mg, 2.27 mmol) was taken in DMF. NaH (180 mg, 4.5 mmol) was added at RT and stirred for 10-15 min. Neat epoxide (450 mg, 3.7 mmol) was added dropwise at RT. The reaction was stirred at RT for 4 h and the reaction was monitored by LCMS. After completion, the reaction mixture was poured on ice water and extracted with EtOAc, dried and concentrated. The residue was purified by HPLC. 465 mg of product as a white solid (TFA salt). TLC: 5% MeOH-DCM, Rf 0.1 was observed. 1 H NMR (CD 3 OD, TFA salt) δ (ppm): 8.80 (s, 2H), 8.40 (s, 1H), 7.9 (t, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 7.0 (d, 1H), 5.25 (bs, 1H), 4.7 (d, 1H), 4.4 (m, 2H), 4.3 (d, 1H), 3.9 (bs, 1H), 3.5 (bs, 1H), 3.3 (m, 2H), 3.10 (s, 3H).

›Example 56

Preparation of 2-(4-fluorophenyl)-1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-2-ol (Compound 55)

A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.6 g, 13.1 mmol, 1 equiv.) and NaH (55%, 750 mg, 17.2 mmol, 1.3 equiv.) in 60 mL of THF was heated to 120° C. for 1 h. The reaction mixture was cooled to RT and compound 2-(4-fluorophenyl)-2-methyloxirane (4 g, 26 mmol, 2 equiv.) in DMF (25 mL) was added dropwise for 5 min. at RT followed by heating at 120° C. for 2 h. The reaction mixture was cooled to RT and water (10 mL) was added followed by dilution with EtOAc (800 mL), which was washed with water (3×150 mL) and then brine, dried over sodium sulfate and concentrated under vacuum. The product was purified using column chromatography over 230-400 Silica gel (flash) using 15% MeOH in EtOAc as eluent. Yield: 3 g (66%). 1 H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.5 (m, 2H), 7.3 (d, 1H), 7.12 (m, 3H), 6.8 (d, 1H), 4.3 (bs, 1H), 4.2 (m, 2H), 4.0 (m, 3H), 3.4 (bs, 1H), 3.0 (m, 1H), 2.9 (s, 3H), 2.3 (s, 3H), 1.5 (m, 3H).

›Example 57

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol (Compound 57)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg, 1.31 mmol, 1.0 equiv.) in DMF (6 mL), a heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 2-(4-methoxyphenyl)-2-methyloxirane (400 mg, 2.43 mmol, 1.85 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc (60 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layer was washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF (10 mL) and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.45 (m, 2H), 7.38 (d, 2H), 7.04 (d, 1H), 6.86 (d, 2H), 4.20 (m, 2H), 4.08 (m, 2H), 3.72 (s, 3H), 3.60 (m, 2H), 3.0 (m, 2H), 2.84 (m, 3H), 1.50 (s, 3H).

›Example 58

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-fluoro-4-methoxyphenyl)propan-2-ol (Compound 59)

Sodium hydride (38 mg, 1.6 mmol, 1.2 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg, 1.31 mmol, 1.0 equiv.) in DMF (6 mL), a heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 2-(3-fluoro-4-methoxyphenyl)-2-methyloxirane (400 mg, 2.2 mmol, 1.7 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc (60 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in 10 mL THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.45 (m, 2H), 7.24 (m, 2H), 7.07 (m, 2H), 4.24 (m, 2H), 4.11 (m, 2H), 3.88 (s, 3H), 2.97 (m, 4H), 2.84 (s, 3H), 1.45 (s, 3H).

›Example 59

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ol (Compound 58)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF, and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(trifluoromethyl)-5-(2-methyloxiran-2-yl)pyridine (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer was extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 60

Preparation of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-ol (Compound 60)

Sodium hydride (1-3 equiv.) was added to a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF, and heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 3-(2-methyloxiran-2-yl)pyridine (2-7.5 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (CD 3 OD, TFA salt) δ (ppm): 8.51 (m, 2H), 8.36 (m, 1H), 7.69 (m, 1H), 7.15 (s, 1H), 6.76 (m, 2H), 4.67 (m, 1H), 4.34 (m, 3H), 3.84 (m, 1H), 3.47 (m, 2H), 3.24 (m, 1H), 3.11 (s, 3H), 2.40 (s, 3H), 1.80 (s, 3H).

›Example 61

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol (Compound 61)

Sodium hydride (1-3 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF, and heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 3-(2-methyloxiran-2-yl)pyridine (2-7.5 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (CD 3 OD, oxalate salt) δ (ppm): 8.43 (s, 1H), 8.34 (d, 1H), 7.87 (d, 1H), 7.37 (s, 1H), 7.30 (m, 1H), 6.97 (m, 1H), 6.93 (d, 1H), 4.48 (m, 2H), 4.32 (m, 2H), 3.71 (m, 2H), 3.12 (s, 3H), 2.81 (m, 2H), 1.70 (s, 3H).

›Example 62

Preparation of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (Compound 62)

Sodium hydride (1-3 equiv.) was added to a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF, and heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 4-(2-methyloxiran-2-yl)pyridine (2-7.5 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (CD 3 OD, oxalate salt) δ (ppm): 8.38 (d, 2H), 7.50 (d, 2H), 7.15 (s, 1H), 7.06 (d, 1H), 6.86 (d, 1H), 4.45 (m, 2H), 4.31 (m, 1H), 4.22 (m, 1H), 3.61 (m, 2H), 3.19 (m, 1H), 3.06 (s, 3H), 2.78 (m, 2H), 2.35 (s, 3H), 1.60 (s, 3H).

›Example 63

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (Compound 63)

Sodium hydride (1-3 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 4-(2-methyloxiran-2-yl)pyridine (2-7.5 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (CDCl 3 , oxalate salt) δ (ppm): d 8.42 (d, 2H), 7.35-7.20 (m, 3H), 7.00-6.90 (m, 2H), 4.10 (q, 2H), 3.50 (q, 2H), 2.95-2.68 (m, 4H), 2.42 (s, 3H), 1.55 (s, 3H).

›Example 64

Preparation of 1-(5-(trifluoromethyl)pyridin-3-yl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanol (Compound 65)

Sodium hydride (1-3 equiv.) is added to a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 3-(trifluoromethyl)-5-(oxiran-2-yl)pyridine (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 65

Preparation of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)ethanol (Compound 67)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 3-(trifluoromethyl)-5-(oxiran-2-yl)pyridine (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 66

Preparation of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol (Compound 69)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(3-fluoro-4-methoxyphenyl)oxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 67

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-propylpyridin-3-yl)propan-2-ol (Compound 71)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 5-(2-methyloxiran-2-yl)-2-propylpyridine (2-7.5 equiv.) added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 68

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3,4-difluorophenyl)propan-2-ol (Compound 73)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(3,4-difluorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 69

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chlorophenyl)propan-2-ol (Compound 64)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(4-chlorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 70

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chloro-3-fluorophenyl)propan-2-ol (Compound 66)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(4-chloro-3-fluorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 71

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3,4-dichlorophenyl)propan-2-ol (Compound 68)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(3,4-dichlorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 72

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-chloro-4-fluorophenyl)propan-2-ol (Compound 70)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(3-chloro-4-fluorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer was extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 73

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4-difluorophenyl)propan-2-ol (Compound 72)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(2,4-difluorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 74

Preparation of 1-(8-fluoro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol (Compound 75)

Sodium hydride (1-3 equiv.) is added to a solution of 8-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(4-fluorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer was extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 75

Preparation of 1-(8-chloro-2-cyclopropyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol (Compound 77)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2-cyclopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(4-fluorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 76

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-phenylpropan-2-ol (Compound 79)

Sodium hydride (1-3 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 2-methyl-2-phenyloxirane (2-7.5 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (CDCl 3 , freebase) δ (ppm): 7.38 (d, 1H), 7.21 (m, 5H), 6.93 (m, 2H), 4.15 (m, 2H), 3.4 (m, 2H), 2.78 (m, 2H), 2.61 (m, 2H), 2.4 (s, 3H), 1.59 (s, 3H).

›Example 77

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4,6-trifluorophenyl)propan-2-ol (Compound 81)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(2,4,6-trifluorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 78

Preparation of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)butan-2-ol (Compound 74)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(4-fluorophenyl)-2,3-dimethyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 79

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,4-dichlorophenyl)propan-2-ol (Compound 76)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(2,4-dichlorophenyl)-2-methyloxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 80

Preparation of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)butan-2-ol (Compound 78)

Sodium hydride (1-3 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 2-ethyl-2-(4-fluorophenyl)oxirane (2-7.5 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (CDCl 3 , oxalate salt) δ (ppm): 7.38 (m, 3H), 7.10 (d, 1H), 7.0 (m, 3H), 4.20 (m, 1H), 4.10 (m, 1H), 3.80 (m, 2H), 2.80 (m, 3H), 2.61 (m, 1H), 2.50 (s, 3H), 2.15 (m, 2H), 1.80 (m, 1H), 0.7 (t, 3H).

›Example 81

Preparation of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-ol (Compound 80)

Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture is cooled to 0° C. and 2-(trifluoromethyl)-2-(4-fluorophenyl)oxirane (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120° C. and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

›Example 82

Preparation of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-cyclopropyl-1-(4-fluorophenyl)ethanol (Compound 82)

Sodium hydride (1-3 equiv.) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.) in DMF and heated to 120° C. for 1 h with stirring. The reaction mixture was cooled to 0° C. and 2-cyclopropyl-2-(4-fluorophenyl)oxirane (2-7.5 equiv.) was added dropwise over 5 min. The temperature was raised to 120° C. and stirred for 2 h. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product was purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound was converted to its oxalate salt. The analytical sample was prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate. 1 H NMR (CD 3 OD, oxalate salt) δ (ppm): 7.40 (m, 3H), 7.20 (m, 1H), 7.0 (m, 3H), 4.42 (m, 1H), 4.38 (m, 1H), 4.15 (m, 1H), 3.60 (m, 2H), 3.45 (m, 1H), 3.0 (m, 4H), 1.50 (m, 1H), 1.1 (m, 1H), 0.5 (m, 4H).

›Example 83

Preparation of 8-chloro-5-((E)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compounds 83 and 128)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol (1 g, 2.68 mmol, 1 equiv.) was refluxed with 7 mL of 25% sulfuric acid for 2 h. It was brought to RT and then cooled to 5° C. with an ice-water bath. 15% aq. solution of KOH was dropwise added to the reaction mixture to attain pH 9-10. It was then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with 10 mL of water followed by brine, dried over sodium sulfate and evaporated under vacuum. It was then column purified using 100-200 silica gel, using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers (150 mg), which was separated by HPLC. Yield: 15 mg of 8-chloro-5-((E)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 25 mg of 8-chloro-5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (as a TFA salt). The isomers can alternatively be separated by silica gel chromatography using an EtOAc:hexane (80:20) eluent. TLC: three runs in EtOAc:hexane (80:20).

8-Chloro-5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole: 1 H NMR (DMSO-d6, TFA salt) δ (ppm): 10.1 (bs, 1H), 7.64 (m, 2H), 7.59 (d, 2H), 7.24 (m, 2H), 7.19 (d, 1H), 5.35 (s, 1H), 5.21 (m, 2H), 4.65 (d, 1H), 4.3 (s, 2H), 3.76 (s, 1H), 3.5 (bs, 1H), 3.0 (s, 2H), 2.97 (s, 3H).

›Example 84

Preparation of 2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(6-methylpyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole (Compounds 85 and 130)

1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(6-methylpyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 85

Preparation of 5-((E)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and 5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (Compounds 87 and 132)

2-(4-Fluorophenyl)-1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-2-ol (4.6 g, 13.05 mmol, 1 equiv.) was heated to reflux with 14 mL of 25% aq. sulfuric acid for 2 h. The reaction mixture was cooled to 0-5° C. and made alkaline with 15% aq. KOH solution and extracted with THF:EtOAc (1:1 mixture, 2×30 mL). The combined organic layer was washed with water (15 mL) and then brine, dried over sodium sulfate and evaporated under vacuum. 4.1 g of crude product was obtained which contained 5-((Z)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole as the minor isomer. This isomer was isolated by repeated flash chromatography using 230-400 mesh silica gel using EtOAc as eluent. Yield: 500 mg of 5-((E)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and 1 g of 5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole were isolated as pure products.

5-(2-(4-Fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole: 1 H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.70-7.50 (m, 2H), 7.40-7.30 (d, 1H), 7.30-7.18 (m, 3H), 7.00-6.85 (d, 1H), 5.30 (s, 1H), 5.17 (s, 2H), 4.40 (bs, 2H), 4.28 (s, 2H), 3.50 (bs, 1H), 3.10-3.00 (t, 2H), 2.90 (s, 3H), 2.30 (s, 3H).

›Example 86

Preparation of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(6-methylpyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole (Compounds 89 and 136)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol (1 equiv.) was refluxed with 25% sulfuric acid for 2 h. The reaction mixture was cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(6-methylpyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole, which were separated by HPLC.

8-Chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole: 1 H NMR (DMSO-d6, TFA salt) δ (ppm): 8.74 (m, 1H), 8.16 (m, 1H), 7.59 (m, 2H), 7.52 d, 1H), 7.19 (d, 1H), 5.54 (d, 1H), 5.28 (m, 2H), 4.65 (m, 1H), 4.45 (m, 1H), 4.29 (m, 1H), 3.76 (m, 1H), 3.49 (m, 1H), 3.08 (m, 2H), 2.98 (s, 3H), 2.55 (s, 3H).

›Example 87

Preparation of 8-chloro-5-((E)-2-(6-(trifluoromethyl)pyridin-3-yl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compounds 84 and 129)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-5-((E)-2-(6-(trifluoromethyl)pyridin-3-yl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 88

Preparation of 2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(pyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole (Compounds 91 and 131)

1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(pyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 89

Preparation of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(pyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole (Compounds 86 and 133)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol (1 equiv.) was refluxed with 25% sulfuric acid for 2 h. The reaction mixture was cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(pyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole, which were separated by HPLC.

8-Chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole: 1 H NMR (CD 3 OD, TFA salt) δ (ppm): 8.80 (m, 1H), 8.63 (m, 1H), 8.34 (m, 1H), 7.75 (m, 1H), 7.51 (s, 1H), 7.44 (d, 1H), 7.19 (d, 1H), 5.61 (m, 1H), 5.27 (m, 2H), 4.73 (m, 2H), 4.36 (m, 1H), 3.86 (m, 1H), 3.59 (m, 1H), 3.2 (m, 2H), 3.11 (s, 3H).

›Example 90

Preparation of 2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)allyl)-1H-pyrido[4,3-b]indole (Compounds 88 and 135)

1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)allyl)-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 91

Preparation of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-4-yl)allyl)-1H-pyrido[4,3-b]indole (Compounds 90 and 137)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-4-yl)allyl)-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 92

Preparation of 8-chloro-2,3,4,5-tetrahydro-5-((E)-2-(4-methoxyphenyl)prop-1-enyl)-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-5-(2-(4-methoxyphenyl)allyl)-2-methyl-1H-pyrido[4,3-b]indole (Compounds 92 and 138)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol (1 equiv.) is heated to 55° C. with sulfuric acid in water for 2.5 h. The reaction mixture is cooled to 5-10° C. and neutralized by dropwise addition of satd. aq. sodium hydrogen carbonate solution followed by extraction with EtOAc. The combined organic extract is washed with water, then brine, dried over sodium sulfate and evaporated under vacuum to obtain 8-chloro-2,3,4,5-tetrahydro-5-((E)-2-(4-methoxyphenyl)prop-1-enyl)-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-5-(2-(4-methoxyphenyl)allyl)-2-methyl-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 93

Preparation of 8-chloro-5-((E)-2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(3-fluoro-4-methoxyphenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compounds 93 and 140)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-fluoro-4-methoxyphenyl)propan-2-ol (1 equiv.) was refluxed with 25% sulfuric acid for 2 h. The reaction mixture was cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain 8-chloro-5-((E)-2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(3-fluoro-4-methoxyphenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, which were separated by HPLC.

8-Chloro-5-(2-(3-fluoro-4-methoxyphenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole: 1 H NMR (DMSO-d6, TFA salt) δ (ppm): 7.57 (m, 2H), 7.51 (d, 1H), 7.36 (d, 1H), 7.16 (m, 2H), 5.36 (s, 1H), 5.25 (m, 2H), 4.65 (m, 1H), 4.29 (m, 2H), 3.38 (s, 3H), 3.76 (m, 1H), 3.50 (m, 1H), 3.07 (m, 2H), 2.98 (s, 3H).

›Example 94

Preparation of 2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(6-methylpyridin-3-yl)vinyl)-1H-pyrido[4,3-b]indole (Compound 95)

2-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(6-methylpyridin-3-yl)ethanol (1 equiv.) was refluxed with 25% sulfuric acid for 2 h. The reaction mixture was cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).

›Example 95

Preparation of 5-((E)-2-(5-(trifluoromethyl)pyridin-3-yl)vinyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (Compound 97)

1-(5-(Trifluoromethyl)pyridin-3-yl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).

›Example 96

Preparation of 8-chloro-5-((E)-2-(5-(trifluoromethyl)pyridin-3-yl)vinyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 99)

2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).

›Example 97

Preparation of 5-(3-fluoro-4-methoxystyryl)-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compound 94)

2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(3-fluoro-4-methoxyphenyl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).

›Example 98

Preparation of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(6-propylpyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-propylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole (Compounds 96 and 134)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-propylpyridin-3-yl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(6-propylpyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-propylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 99

Preparation of 8-chloro-5-((E)-2-(3,4-difluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(3,4-difluorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compounds 98 and 142)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3,4-difluorophenyl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-5-((E)-2-(3,4-difluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(3,4-difluorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 100

Preparation of 8-chloro-5-((E)-2-(4-chlorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(4-chlorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compounds 100 and 144)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chlorophenyl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-5-((E)-2-(4-chlorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(4-chlorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 101

Preparation of 8-chloro-5-((E)-2-(4-chloro-3-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(4-chloro-3-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compounds 101 and 139)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chloro-3-fluorophenyl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-5-((E)-2-(4-chloro-3-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(4-chloro-3-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, which are separated by HPLC.

›Example 102

Preparation of 8-chloro-5-((E)-2-(3,4-dichlorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(3,4-dichlorophenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (Compounds 103 and 141)

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3,4-dichlorophenyl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of 8-chloro-5-((E)-2-(3,4-dichlorophenyl)prop-1-enyl)-2,3,4

›Tables in the description — 15

TABLE A Com-

pound							E/
No.	R 4	R 1	q	m	R 11	R 12	Z	Q
1x	H	CH 3	0	0	H	H	Z	Phenyl
2x	H	CH 3	0	0	H	H	E	Phenyl
3x	H	CH 3	0	0	H	H	E	4-Pyridyl
4x	H	CH 3	0	0	H	H	Z	3-Pyridyl
5x	H	CH 3	0	0	H	H	E	2-Pyridyl
6x	H	t-butyl	0	0	H	H	Z	3-Pyridyl
7x	F	CH 3	0	0	H	H	Z	Phenyl
8x	F	CH 3	0	0	H	H	E	Phenyl
9x	F	CH 3	0	0	H	H	E	4-Pyridyl
10x	F	CH 3	0	0	H	H	Z	3-Pyridyl
11x	F	CH 3	0	0	H	H	E	2-Pyridyl
12x	CH 3	CH 3	0	0	H	H	Z	Phenyl
13x	CH 3	CH 3	0	0	H	H	E	Phenyl
14x	CH 3	CH 3	0	0	H	H	Z	3-Pyridyl
15x	CH 3	CH 3	0	0	H	H	E	4-Pyridyl
16x	CH 3	Benzyl	0	0	H	H	Z	3-Pyridyl
17x	F	CH 3	0	0	H	H	E	4-Fluorophenyl
18x	F	CH 3	0	0	H	H	Z	3-Fluorophenyl
19x	CH 3	CH 3	0	0	H	H	E	4-CF 3 -Phenyl
20x	CH 3	CH 3	0	0	H	H	Z	3-CF 3 -Phenyl
21x	F	CH 3	0	0	H	H	E	4-CF 3 -Phenyl
22x	F	CH 3	0	0	H	H	Z	4-OCH 3 -Phenyl
23x	F	CH 3	0	0	H	H	Z	4-N(Me) 2 -Phenyl
24x	CH 3	CH 3	0	0	H	H	E	4-Fluorophenyl

TABLE B

No.	Compound Name
1x	2,3,4,5-tetrahydro-2-methyl-5-[(1Z)-2-phenylethenyl]-1H-Pyrido[4,3-b]indole
2x	2,3,4,5-tetrahydro-2-methyl-5-[(1E)-2-phenylethenyl]-1H-Pyrido[4,3-b]indole
3x	2,3,4,5-tetrahydro-2-methyl-5-[(1E)-2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
4x	2,3,4,5-tetrahydro-2-methyl-5-[(1Z)-2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
5x	2,3,4,5-tetrahydro-2-methyl-5-[(1E)-2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
6x	2-(1,1-dimethylethyl)-2,3,4,5-tetrahydro-5-[(1Z)-2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-
	b]indole
7x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(1Z)-2-phenylethenyl]-1H-Pyrido[4,3-b]indole
8x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(1E)-2-phenylethenyl]-1H-Pyrido[4,3-b]indole
9x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(1E)-2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
10x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(1Z)-2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
11x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(1E)-2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
12x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(1Z)-2-phenylethenyl]-1H-Pyrido[4,3-b]indole
13x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(1E)-2-phenylethenyl]-1H-Pyrido[4,3-b]indole
14x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(1Z)-2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
15x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(1E)-2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
16x	2,3,4,5-tetrahydro-8-methyl-2-(phenylmethyl)-5-[(1Z)-2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-
	b]indole
17x	8-fluoro-5-[(1E)-2-(4-fluorophenyl)ethenyl]-2,3,4,5-tetrahydro-2-methyl-1H-Pyrido[4,3-
	b]indole
18x	8-fluoro-5-[(1Z)-2-(3-fluorophenyl)ethenyl]-2,3,4,5-tetrahydro-2-methyl-1H-Pyrido[4,3-
	b]indole
19x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(1E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1H-Pyrido[4,3-
	b]indole
20x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(1Z)-2-[3-(trifluoromethyl)phenyl]ethenyl]-1H-Pyrido[4,3-
	b]indole
21x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(1E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1H-
	Pyrido[4,3-b]indole
22x	8-fluoro-2,3,4,5-tetrahydro-5-[(1Z)-2-(4-methoxyphenyl)ethenyl]-2-methyl-1H-Pyrido[4,3-
	b]indole
23x	4-[(1Z)-2-(8-fluoro-1,2,3,4-tetrahydro-2-methyl-5H-pyrido[4,3-b]indol-5-yl)ethenyl]-N,N-
	dimethyl-Benzenamine
24x	5-[(1E)-2-(4-fluorophenyl)ethenyl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole
25x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
26x	2,3,4,5-tetrahydro-8-methyl-5-[2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
27x	8-fluoro-2,3,4,5-tetrahydro-5-[2-(4-methoxyphenyl)ethenyl]-2-methyl-1H-Pyrido[4,3-b]indole
28x	2,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2-(3-pyridinylmethyl)-1H-Pyrido[4,3-b]indole
29x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
30x	2,3,4,5-tetrahydro-2-methyl-5-(2-phenylethenyl)-8-(trifluoromethyl)-1H-Pyrido[4,3-b]indole
31x	2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
32x	2,3,4,5-tetrahydro-8-methyl-2-[1-[(4-methylphenyl)sulfonyl]-4-piperidinyl]-5-[2-(2-
	pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
33x	2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
34x	2,3,4,5-tetrahydro-8-methyl-2-(4-piperidinyl)-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-
	b]indole
35x	8-fluoro-5-[2-(4-fluorophenyl)ethenyl]-2,3,4,5-tetrahydro-2-methyl-1H-Pyrido[4,3-b]indole
36x	9-hydroxy-2-methyl-3-[2-[1,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2H-pyrido[4,3-
	b]indol-2-yl]ethyl]-4H-Pyrido[1,2-a]pyrimidin-4-one
37x	2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
38x	N,N-dimethyl-4-[2-(1,2,3,4-tetrahydro-2,8-dimethyl-5H-pyrido[4,3-b]indol-5-yl)ethenyl]-
	Benzenamine
39x	2,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-1H-Pyrido[4,3-b]indole
40x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
41x	2,3,4,5-tetrahydro-8-methyl-2-[1-[(4-methylphenyl)sulfonyl]-4-piperidinyl]-5-[2-(4-
	pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
42x	8-bromo-2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
43x	2,3,4,5-tetrahydro-8-methyl-2-(4-piperidinyl)-5-[2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-
	b]indole
44x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-[4-(trifluoromethyl)phenyl]ethenyl]-1H-Pyrido[4,3-
	b]indole
45x	2,9-dimethyl-3-[2-[1,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2H-pyrido[4,3-b]indol-2-
	yl]ethyl]-4H-Pyrido[1,2-a]pyrimidin-4-one
46x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
47x	2,3,4,5-tetrahydro-5-[2-(4-methoxyphenyl)ethenyl]-2,8-dimethyl-1H-Pyrido[4,3-b]indole
48x	1,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2H-Pyrido[4,3-b]indole-2-carboxylic acid
	ethyl ester
49x	2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
50x	2,3,4,5-tetrahydro-2-methyl-5-[2-(4-methylphenyl)ethenyl]-1H-Pyrido[4,3-b]indole
51x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
52x	2,3,4,5-tetrahydro-8-methyl-2-(4-piperidinyl)-5-[2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-
	b]indole
53x	5-[2-(4-ethylphenyl)ethenyl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole
54x	6,7,8,9-tetrahydro-2-methyl-3-[2-[1,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2H-
	pyrido[4,3-b]indol-2-yl]ethyl]-4H-Pyrido[1,2-a]pyrimidin-4-one
55x	2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethenyl]-8-(trifluoromethyl)-1H-Pyrido[4,3-
	b]indole
56x	5-[2-(4-fluorophenyl)ethenyl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole
57x	2,3,4,5-tetrahydro-8-methyl-2-[(4-methylphenyl)sulfonyl]-5-(2-phenylethenyl)-1H-Pyrido[4,3-
	b]indole
58x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
59x	2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-phenylethenyl)-1H-Pyrido[4,3-b]indole
60x	2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethenyl]-8-(trifluoromethyl)-1H-Pyrido[4,3-
	b]indole
61x	2,3,4,5-tetrahydro-8-methyl-2-(1-methyl-4-piperidinyl)-5-[2-(2-pyridinyl)ethenyl]-1H-
	Pyrido[4,3-b]indole
62x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-[4-(1-methylethyl)phenyl]ethenyl]-1H-Pyrido[4,3-b]indole
63x	1-[2-[1,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-2-
	Imidazolidinone
64x	2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole-8-carboxylic
	acid
65x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-[4-(trifluoromethyl)phenyl]ethenyl]-1H-Pyrido[4,3-
	b]indole
66x	2,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2-[2-(2-pyridinyl)ethyl]-1H-Pyrido[4,3-
	b]indole
67x	2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethenyl]-8-(trifluoromethyl)-1H-Pyrido[4,3-
	b]indole
68x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(4-methylphenyl)ethenyl]-1H-Pyrido[4,3-b]indole
69x	2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole-8-carbonitrile
70x	2,3,4,5-tetrahydro-8-methyl-2-(1-methyl-4-piperidinyl)-5-[2-(3-pyridinyl)ethenyl]-1H-
	Pyrido[4,3-b]indole
71x	5-[2-[4-(1,1-dimethylethyl)phenyl]ethenyl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-
	b]indole
72x	2,3,4,5-tetrahydro-8-methyl-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
73x	2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
74x	2,3,4,5-tetrahydro-2-methyl-5-[2-(4-methylphenyl)ethenyl]-8-(trifluoromethyl)-1H-Pyrido[4,3-
	b]indole
75x	2,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2-[2-(4-pyridinyl)ethyl]-1H-Pyrido[4,3-
	b]indole
76x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
77x	2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-(2-phenylethenyl)-1H-Pyrido[4,3-b]indole
78x	2,3,4,5-tetrahydro-2-methyl-8-(3-pyridinyl)-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
79x	2,3,4,5-tetrahydro-8-methyl-2-(1-methyl-4-piperidinyl)-5-[2-(4-pyridinyl)ethenyl]-1H-
	Pyrido[4,3-b]indole
80x	2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
81x	2,3,4,5-tetrahydro-8-methyl-5-[2-(3-pyridinyl)ethenyl]-1H-Pyrido[4,3-b]indole
82x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(2-pyrazinyl)ethenyl]-1H-Pyrido[4,3-b]indole
83x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(4-methylphenyl)ethenyl]-1H-Pyrido[4,3-b]indole
84x	5-hydroxy-6-methyl-4-[[1,3,4,5-tetrahydro-8-methyl-5-(2-phenylethenyl)-2H-pyrido[4,3-
	b]indol-2-yl]methyl]-3-Pyridinemethanol
85x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3-pyridinyl)ethenyl]-1H-Pyrido[4,3-
	b]indole
86x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-(2-phenylethenyl)-1H-Pyrido[4,3-b]indole
87x	2,3,4,5-tetrahydro-2-methyl-8-(phenylsulfonyl)-5-[2-(2-pyridinyl)ethenyl]-1H-Pyrido[4,3-
	b]indole
88x	2,3,4,5-tetrahydro-8-methyl-2-[(4-methylphenyl)sulfonyl]-5-[2-(2-pyridinyl)ethenyl]-1H-
	Pyrido[4,3-b]indole
89x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[3-(4-methylphenyl)-2-propen-1-yl]-1H-Pyrido[4,3-b]indole
90x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(2E)-3-phenyl-2-propen-1-yl]-1H-Pyrido[4,3-b]indole
91x	2,3,4,5-tetrahydro-5-[3-(4-methoxyphenyl)-2-propen-1-yl]-2,8-dimethyl-1H-Pyrido[4,3-
	b]indole
92x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(2Z)-3-phenyl-2-propen-1-yl]-1H-Pyrido[4,3-b]indole
93x	5-[3-(4-fluorophenyl)-2-propen-1-yl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole
94x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[(2Z)-3-phenyl-2-propen-1-yl]-1H-Pyrido[4,3-b]indole
95x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-(3-phenyl-2-propen-1-yl)-1H-Pyrido[4,3-b]indole
96x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[3-(4-methylphenyl)-2-propen-1-yl]-1H-Pyrido[4,3-
	b]indole
97x	2,3,4,5-tetrahydro-8-methoxy-2-methyl-5-[3-(4-methylphenyl)-2-propen-1-yl]-1H-Pyrido[4,3-
	b]indole
98x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[(2E)-3-phenyl-2-propen-1-yl]-1H-Pyrido[4,3-b]indole
99x	5-[(1Z)-2-(4-fluorophenyl)-1-propen-1-yl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-
	b]indole
100x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[3-(2-pyridinyl)-2-propyn-1-yl]-1H-Pyrido[4,3-b]indole
101x	2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-phenylethynyl)-1H-Pyrido[4,3-b]indole
102x	5-[2-(4-fluorophenyl)ethynyl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole
103x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
104x	2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
105x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(3-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
106x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-[2-(trifluoromethyl)phenyl]ethynyl]-1H-Pyrido[4,3-
	b]indole
107x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-(2-phenylethynyl)-1H-Pyrido[4,3-b]indole
108x	8-fluoro-5-[2-(4-fluorophenyl)ethynyl]-2,3,4,5-tetrahydro-2-methyl-1H-Pyrido[4,3-b]indole
109x	2,3,4,5-tetrahydro-5-[2-(3-methoxyphenyl)ethynyl]-2,8-dimethyl-1H-Pyrido[4,3-b]indole
110x	6-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
111x	5-[2-(3-fluorophenyl)ethynyl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole
112x	2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
113x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(4-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
114x	5-[2-(2-fluorophenyl)ethynyl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole
115x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(2-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
116x	8-fluoro-5-[2-(3-fluorophenyl)ethynyl]-2,3,4,5-tetrahydro-2-methyl-1H-Pyrido[4,3-b]indole
117x	2,3,4,5-tetrahydro-5-[2-(2-methoxyphenyl)ethynyl]-2,8-dimethyl-1H-Pyrido[4,3-b]indole
118x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-[4-(trifluoromethyl)phenyl]ethynyl]-1H-Pyrido[4,3-
	b]indole
119x	2,3,4,5-tetrahydro-2-methyl-5-[2-(4-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
120x	2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethynyl]-8-(trifluoromethyl)-1H-Pyrido[4,3-
	b]indole
121x	2,3,4,5-tetrahydro-5-[2-(4-methoxyphenyl)ethynyl]-2,8-dimethyl-1H-Pyrido[4,3-b]indole
122x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-(3-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
123x	8-fluoro-2,3,4,5-tetrahydro-2-methyl-5-[2-[4-(trifluoromethyl)phenyl]ethynyl]-1H-Pyrido[4,3-
	b]indole
124x	2,3,4,5-tetrahydro-2-methyl-5-(2-phenylethynyl)-1H-Pyrido[4,3-b]indole
125x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-(2-pyridinyl)ethynyl]-1H-Pyrido[4,3-b]indole
126x	2,3,4,5-tetrahydro-2,8-dimethyl-5-[2-[3-(trifluoromethyl)phenyl]ethynyl]-1H-Pyrido[4,3-
	b]indole
127x	2,3,4,5-tetrahydro-2-methyl-5-[2-(5-pyrimidinyl)ethynyl]-1H-Pyrido[4,3-b]indole
128x	8-fluoro-2,3,4,5-tetrahydro-5-[2-(4-methoxyphenyl)ethynyl]-2-methyl-1H-Pyrido[4,3-b]indole
129x	N,N-dimethyl-4-[2-(1,2,3,4-tetrahydro-2,8-dimethyl-5H-pyrido[4,3-b]indol-5-yl)ethynyl]-
	Benzenamine
130x	5-[2-(4-fluorophenyl)-2-propen-1-yl]-2,3,4,5-tetrahydro-2,8-dimethyl-1H-Pyrido[4,3-b]indole

TABLE 7 — Representative Characterization Data

Ex.			NMR		MS	HPLC	HPLC Rt
No.	Salt	MW	Solvent	NMR Data	observed	Method 1	(min.)
1.	Oxalate	462.86	CD 3 OD	7.4 (m, 3H), 7.18 (d,	373	1	3.66
				1H), 6.98 (m, 3H),
				4.45 (bs, 2H), 4.3 (d, 1H),
				4.19 (d, 1H), 3.6- (bs,
				2H), 3.0 (s, 3H),
				3.1-2.9 (m, 2H), 1.60 (s, 3H)
2.	TFA	468.85	CD 3 OD	7.68 (t, 2H), 7.54 (s,	355	1	3.93
				1H), 7.21 (s, 2H),
				7.16 (t, 2H), 6.97 (s, 1H),
				4.8 (bs, 1H), 4.39 (bs, 1H),
				3.85 (bs, 1H), 3.60 (bs,
				1H), 3.13 (bs, 5H),
				1.92 (s, 3H)
3.	TFA	448.43	DMSO	10.0 (bs, 1H), 7.7 (m,	NONE	1	6.22
				2H), 7.2 (m, 3H),
				7.10 (d, 2H), 7.0 (d, 1H),
				4.6 (d, 1H), 4.3 (d, 1H),
				3.7 (bs, 1H), 3.49 (bs, 1H),
				3.0 (bs, 2H), 3.0 (s, 3H),
				2.4 (s, 3H), 1.8 (s, 3H).
Method-1	Column: Zorbax SB C18 (50 × 4.6 mm) 1.8 micron
	Mobile Phase: Gradient of ACN and 0.05% TFA
	Flow rate: 1.0 mL/min.
	Wavelength 230 nm

TABLE 8 — Binding data Imidazoline

	Example	Compound	I 2 Central	Histamine Binding (1 μM)
No.	No.	(1 μM)	H 1	H 2
2	3	58	30	6
43	43	76/79	81/85	58/84
49	44	46	54	26
44	45	—	65/73	94
45	47	—	33	48
51	48	—	93	47
47	51	79	100	59
53	52	—	46	51
48	53	78	47	58
54	54	—	68	5
56	55	—	91	88
55	56	—	90	26
57	57	—	41	82
58	59	—	63	58
60	60	—	52	40
61	61	—	52	41
62	62	—	38	43
63	63	—	46	53
80	78	—	52/69	89
82	82	—	35/64	99
83	83	85	60/79/84	99
84	85	—	9/13	—
89	86	—	72	54
85	87	—	65/81	100
90	88	—	16/19/37/28	30
86	89	—	43	91
91	90	—	48/59	60
88	91	—	11	52
92	92	—	44	99
93	93	—	39	100
94	95	—	85	41
99	98	—	53	99
100	100	—	65/67	100
105	102	—	60	98
102	103	—	81	101
107	106	—	84	99
104	107	—	88	—
113	110	—	77/83	102
110	111	—	73/74	91
125	125	—	96	48
126	126	—	103	85
127	127	—	100	22
83	128	—	98	100
85	132	—	96	96
89	133	—	101	60
86	136	—	99	85
93	140	—	98	99
429	166	—	14	56
259	171	—	13/22	85
260	172	—	95	65
261	173	—	91	78
262	174	—	34/43	80
263	175	—	71	91
428	176	—	21	74
264	177	—	83	101
265	178	—	30	89
266	180	—	84	24
267	181	—	0	25
268	182	—	26	53
269	183	—	91	47
270	184	—	23	57
271	185	—	8	29
272	186	—	1	22
273	187	—	36	57
274	188	—	8	13
275	189	—	77	85
276	190	—	−11	9
277	191	—	23	—
278	192	—	61	—
279	193	—	−7	—
280	194	—	9	—
281	195	—	20	—
282	196	—	19	—
283	197	—	61	—
284	198	—	64	—
285	199	—	61	—
286	200	—	45	—
152	202	—	100	97
155	203	—	64/72	99
156	204	—	55	101
157	205	—	31/39	95
158	206	—	76	102
159	207	—	15	46
160	208	—	64	102
161	209	—	9	20
163	210	—	53	96
165	211	—	53/54	100
166	212	—	70	84
167	213	—	69	99
168	214	—	23	100
169	215	—	89	98
170	216	—	47/49	61
171	217	—	12/38	50
172	218	—	78/79	98
173	219	—	60/66	82
174	220	—	91	99
175	221	—	90	98
176	222	—	25	91
179	223	—	6/11	44
180	224	—	24/26	58
181	225	—	81	98
182	226	—	71	100
185	227	—	52	101
186	228	—	66	102
187	229	—	54	96
189	230	—	35	96
190	231	—	58	97
191	232	—	71	95
192	233	—	85	99
193	234	—	69	94
194	235	—	73	96
195	236	—	20	99
196	237	—	88	95
197	238	—	58	93
199	239	—	14	28
200	240	—	95	99
201	241	—	89	98
202	242	—	88	97
203	243	—	95	90
204	244	—	87	88
205	245	—	60	71
206	246	—	7	29
207	247	—	75	99
209	248	—	90	—
210	249	—	48	—
211	250	—	12	—
212	251	—	15	—
213	252	—	22	—
214	253	—	20	—
215	254	—	7	—
216	255	—	11	—
217	256	—	92	—
218	257	—	18	—
219	258	—	59	—
220	259	—	10	—
221	260	—	−19	—
222	261	—	11	—
223	262	—	66	—
224	263	—	8	—
225	264	—	24	—
226	265	—	22	—
227	266	—	−1	—
228	267	—	6	—
229	268	—	53	—
231	269	—	−2	—
232	270	—	19	—
233	271	—	−16	—
234	272	—	48	—
235	273	—	41	—
236	274	—	72	—
237	275	—	39	—
238	276	—	63	—
239	277	—	95	—
240	278	—	24	—
241	279	—	21	—
242	280	—	12	—
243	281	—	42	—
244	282	—	31	—
245	283	—	23	—
246	284	—	40	—
247	285	—	21	—
430	286	—	19	—
248	287	—	33	—
249	288	—	25	—
250	289	—	34	—
255	291	—	−4	—
256	292	—	11	—
257	293	—	9	—
258	294	—	83	—
293	320	—	65	—
294	332	—	23	—
295	333	—	29	—
296	334	—	18	—
297	338	—	83	—
287	341	—	11	—
288	342	—	48	—
289	343	—	22	—
290	344	—	7	—
291	345	—	56	—
292	346	—	17	—
433	347	—	42/56	87
434	348	—	32/38	73
435	349	—	53/65	84
436	350	—	27/37	93
437	351	—	78/80	100
438	352	—	4	15
439	353	—	100	93
440	354	—	86	97
441	355	—	116	93
442	356	—	70	17
443	357	—	61	—
444	358	—	47	—
445	359	—	38	—
446	360	—	47	—
447	361	—	96	—
448	362	—	98	—
449	363	—	62	—
450	364	—	95	—
301	365	—	92	—
298	367	—	64	—
299	368	—	82	—
300	369	—	29	—
302	370	—	72	—
303	375	—	65	—
304	376	—	23	—
305	377	—	29	—
306	378	—	18	—
307	379	—	83	—
308	380	—	64	—
309	381	—	82	—
310	382	—	29	—
311	383	—	72	—
312	384	—	66	—
313	385	—	68	—
314	386	—	8	—
315	387	—	84	—
316	388	—	100	—
317	389	—	39	—
318	390	—	49	—
319	391	—	84	—
320	392	—	84	—
321	393	—	69	—
322	394	—	75	—
323	395	—	102	—
324	396	—	15	—
325	397	—	89	—
326	398	—	95	—
327	399	—	13	—
328	400	—	22	—
329	401	—	8	—
330	402	—	15	—
331	403	—	37	—
332	404	—	37	—
333	405	—	67	—
334	406	—	74	—
335	407	—	10	—
336	408	—	98	—
337	409	—	18	—
338	410	—	36	—
339	411	—	0	—
340	412	—	27	—
341	413	—	16	—
342	414	—	61	—
343	415	—	97	—
344	416	—	91	—
345	417	—	48	—
346	418	—	33	—
347	419	—	52	—
348	420	—	13	—
349	421	—	93	—
350	422	—	8	—
351	423	—	31	—
352	424	—	43	—
353	425	—	4	—
354	426	—	50	—
355	427	—	1	—
356	428	—	97	—
357	429	—	101	—
358	430	—	72	—
359	431	—	33	—
360	432	—	46	—
361	433	—	13	—
363	435	—	11	—
364	436	—	12	—
365	437	—	44	—
366	438	—	92	—
367	439	—	9	—
368	440	—	4	—
369	441	—	91	—
370	442	—	29	—
371	443	—	−5	—
372	444	—	−13	—
373	445	—	1	—
374	446	—	−4	—
375	447	—	−1	—
376	448	—	−10	—
377	449	—	−7	—
378	450	—	43	—
379	451	—	99	—
380	452	—	18	—
381	453	—	26	—
382	454	—	21	—
383	455	—	13	—
384	456	—	17	—
385	457	—	37	—
386	458	—	56	—
387	459	—	53	—
388	460	—	17	—
389	461	—	31	—
390	462	—	32	—
392	464	—	66	—
393	465	—	−14	—
394	466	—	10	—
395	467	—	54	—
396	468	—	82	—
397	469	—	14	—
398	470	—	17	—
400	471	—	2	—
401	472	—	21	—
402	473	—	35	—
403	474	—	98	—
404	475	—	34	91
405	476	—	27	88
406	477	—	17	97
407	478	—	28	94
408	479	—	11	51
409	480	—	40	93
410	481	—	12	97
411	482	—	13	−3
412	483	—	−1	10
413	484	—	6	77
414	485	—	−6	97
415	486	—	22	—
416	487	—	75	—
417	488	—	9	—
418	489	—	13	—
419	490	—	18	—
420	491	—	52	—
421	492	—	68	—
422	493	—	69	—
423	494	—	2	—
424	495	—	52	—
425	496	—	15	—
426	497	—	17	—
427	498	—	65	—
430	499	—	26	—
432	500	54	70	30

TABLE 9 — Inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention: Dopamine

Example		Adrenergic (1 μM)	(1 μM)
No.	Compound No.	α 1A	α 1B	α 1D	α 2A	α 2B	α 2C	D 2L
2	3	—	—	42	58	91	—	14
43	43	90/96	97/96	87/89	98/100	108/102	100/94	65
49	44	39	38	35	65	94	35	—
44	45	—	—	61	89	109	—	34/35
45	47	—	—	82	81	106	—	7
51	48	—	—	45	83	100	—	8
47	51	86	95	89	91	118	92	—
53	52	—	—	39	84	104		12
48	53	74	66	55	93	114	82	—
54	54	—	—	15	39	103	—	−4
56	55	—	—	64	85	108	—	34
55	56	—	—	43	65	112	—	4
57	57	—	—	84	70	108	—	22
58	59	—	—	81	83	95	—	17
60	60	—	—	33	81	96	—	6
61	61	—	—	87	76	107	—	19
62	62	—	—	82	57	103	—	7
63	63	—	—	84	74	101	—	17
80	78	—	—	49	91	87	—	27/33
82	82	—	—	62	96	99	—	39/45
83	83	90	96	96	98	121	99	98
84	85	—	—	—	—	—	—	43/57
89	86	—	—	—	—	—	—	40
85	87	—	—	99	95	121	—	97
90	88	—	—	78	65	107	—	41/66/93
86	89	—	—	87	97	108	—	68
91	90	—	—	93	95	104	—	93/98
88	91	—	—	—	—	—	—	27
92	92	—	—	99	89	103	—	83/97
93	93	—	—	96	94	108	—	85/97
94	95	—	—	89	95	103	—	17
99	98	—	—	—	—	—	—	78
100	100	—	—	87	101	97	—	67/68
105	102	—	—	—	—	—	—	99
102	103	—	—	—	—	—	—	49
107	106	—	—	92	93	114	—	90
104	107	—	—	—	—	—	—	72
113	110	—	—	86	99	92	—	96/98
110	111	—	—	47	101	90	—	27/29
125	125	—	—	51	76	110	—	20
126	126	—	—	50	87	116	—	84
127	127	—	—	46	60	68	—	10
83	128	—	—	91	99	120	—	97
85	132	—	—	93	97	118	—	91
89	133	—	—	55	89	103	—	29
86	136	—	—	70	95	90	—	54
93	140	—	—	84	86	106	—	57
429	166	—	—	28	44	63	—	−2
259	171	—	—	49	83	86	—	12/13
260	172	—	—	88	98	104	—	36
261	173	—	—	58	94	98	—	32
262	174	—	—	57	93	88	—	34/34
263	175	—	—	75	94	96	—	24
428	176	—	—	42	94	95	—	6
264	177	—	—	70	96	94	—	33
265	178	—	—	46	88	79	—	30
266	180	—	—	60	84	105	—	10
267	181	—	—	—	—	—	—	8
268	182	—	—	—	—	—	—	8
269	183	—	—	—	—	—	—	15
270	184	—	—	—	—	—	—	1
271	185	—	—	—	—	—	—	−1
272	186	—	—	—	—	—	—	3
273	187	—	—	—	—	—	—	35
274	188	—	—	—	—	—	—	−5
275	189	—	—	—	—	—	—	2
276	190	—	—	—	—	—	—	−15
277	191	—	—	—	—	—	—	15
278	192	—	—	—	—	—	—	34
279	193	—	—	—	—	—	—	14
280	194	—	—	—	—	—	—	12
281	195	—	—	—	—	—	—	17
282	196	—	—	—	—	—	—	9
283	197	—	—	—	—	—	—	14
284	198	—	—	—	—	—	—	5
285	199	—	—	—	—	—	—	16
286	200	—	—	—	—	—	—	6
152	202	—	—	98	98	98	—	83
155	203	—	—	89	100	108	—	72/78
156	204	—	—	67	99	86	—	87
157	205	—	—	90	99	101	—	98/99
158	206	—	—	102	96	89	—	76
159	207	—	—	100	86	80	—	12
160	208	—	—	89	99	103	—	78
161	209	—	—	21	30	59	—	7
163	210	—	—	17	79	102	—	52
165	211	—	—	96	97	114	—	39/49
166	212	—	—	78	88	105	—	32
167	213	—	—	76	88	103	—	76
168	214	—	—	—	—	—	—	83
169	215	—	—	—	—	—	—	36
170	216	—	—	—	—	—	—	97/98
171	217	—	—	—	—	—	—	86/88
172	218	—	—	—	—	—	—	40/43
173	219	—	—	—	—	—	—	96/97
174	220	—	—	—	—	—	—	32
175	221	—	—	—	—	—	—	34
176	222	—	—	—	—	—	—	82
179	223	—	—	—	—	—	—	96/97
180	224	—	—	—	—	—	—	65/80
181	225	—	—	—	—	—	—	43
182	226	—	—	—	—	—	—	46
185	227	—	—	—	—	—	—	97
186	228	—	—	—	—	—	—	98
187	229	—	—	—	—	—	—	100
189	230	—	—	—	—	—	—	44
190	231	—	—	—	—	—	—	40
191	232	—	—	—	—	—	—	91
192	233	—	—	—	—	—	—	48
193	234	—	—	—	—	—	—	73
194	235	—	—	—	—	—	—	80
195	236	—	—	—	—	—	—	76
196	237	—	—	—	—	—	—	45
197	238	—	—	—	—	—	—	81
199	239	—	—	—	—	—	—	39
200	240	—	—	—	—	—	—	34
201	241	—	—	—	—	—	—	47
202	242	—	—	—	—	—	—	55
203	243	—	—	—	—	—	—	96
204	244	—	—	—	—	—	—	86
205	245	—	—	—	—	—	—	92
206	246	—	—	—	—	—	—	57
207	247	—	—	—	—	—	—	28
209	248	—	—	—	—	—	—	95
210	249	—	—	—	—	—	—	93
211	250	—	—	—	—	—	—	18
212	251	—	—	—	—	—	—	25
213	252	—	—	—	—	—	—	13
214	253	—	—	—	—	—	—	22
215	254	—	—	—	—	—	—	11
216	255	—	—	—	—	—	—	29
217	256	—	—	—	—	—	—	34
218	257	—	—	—	—	—	—	72
219	258	—	—	—	—	—	—	81
220	259	—	—	—	—	—	—	−12
221	260	—	—	—	—	—	—	9
222	261	—	—	—	—	—	—	28
223	262	—	—	—	—	—	—	97
224	263	—	—	—	—	—	—	89
225	264	—	—	—	—	—	—	49
226	265	—	—	—	—	—	—	73
227	266	—	—	—	—	—	—	94
228	267	—	—	—	—	—	—	85
229	268	—	—	—	—	—	—	98
231	269	—	—	—	—	—	—	91
232	270	—	—	—	—	—	—	88
233	271	—	—	—	—	—	—	63
234	272	—	—	—	—	—	—	85
235	273	—	—	—	—	—	—	12
236	274	—	—	—	—	—	—	56
237	275	—	—	—	—	—	—	92
238	276	—	—	—	—	—	—	82
239	277	—	—	—	—	—	—	98
240	278	—	—	—	—	—	—	51
241	279	—	—	—	—	—	—	69
242	280	—	—	—	—	—	—	52
243	281	—	—	—	—	—	—	51
244	282	—	—	—	—	—	—	57
245	283	—	—	—	—	—	—	66
246	284	—	—	—	—	—	—	84
247	285	—	—	—	—	—	—	53
248	287	—	—	—	—	—	—	72
430	286	—	—	—	—	—	—	23
249	288	—	—	—	—	—	—	92
250	289	—	—	—	—	—	—	90
255	291	—	—	—	—	—	—	0
256	292	—	—	—	—	—	—	71
257	293	—	—	—	—	—	—	31
258	294	—	—	—	—	—	—	83
293	320	—	—	—	—	—	—	61
294	332	—	—	—	—	—	—	79
295	333	—	—	—	—	—	—	51
296	334	—	—	—	—	—	—	90
297	338	—	—	—	—	—	—	97
287	341	—	—	—	—	—	—	2
288	342	—	—	—	—	—	—	11
289	343	—	—	—	—	—	—	9
290	344	—	—	—	—	—	—	10
291	345	—	—	—	—	—	—	15
292	346	—	—	—	—	—	—	26
433	347	—	—	90	96	111	—	27/30
434	348	—	—	35	92	105	—	18/29
435	349	—	—	60	97	102	—	34/46
436	350	—	—	85	95	107	—	12/21
437	351	—	—	45	84	99	—	70/80
438	352	—	—	11	34	47	—	0
439	353	—	—	—	—	—	—	92
440	354	—	—	—	—	—	—	98
441	355	—	—	—	—	—	—	81
442	356	—	—	—	—	—	—	37
443	357	—	—	—	—	—	—	14
444	358	—	—	—	—	—	—	14
445	359	—	—	—	—	—	—	27
446	360	—	—	—	—	—	—	36
447	361	—	—	—	—	—	—	51
448	362	—	—	—	—	—	—	79
449	363	—	—	—	—	—	—	53
450	364	—	—	—	—	—	—	27
301	365	—	—	—	—	—	—	49
298	367	—	—	—	—	—	—	48
299	368	—	—	—	—	—	—	74
300	369	—	—	—	—	—	—	64
302	370	—	—	—	—	—	—	63
312	384	—	—	—	—	—	—	91
313	385	—	—	—	—	—	—	51
314	386	—	—	—	—	—	—	25
315	387	—	—	—	—	—	—	99
316	388	—	—	—	—	—	—	99
317	389	—	—	—	—	—	—	49
318	390	—	—	—	—	—	—	97
319	391	—	—	—	—	—	—	72
320	392	—	—	—	—	—	—	99
321	393	—	—	—	—	—	—	99
322	394	—	—	—	—	—	—	99
323	395	—	—	—	—	—	—	99
324	396	—	—	—	—	—	—	7
325	397	—	—	—	—	—	—	80
326	398	—	—	—	—	—	—	97
327	399	—	—	—	—	—	—	73
328	400	—	—	—	—	—	—	94
329	401	—	—	—	—	—	—	57
330	402	—	—	—	—	—	—	87
331	403	—	—	—	—	—	—	66
332	404	—	—	—	—	—	—	92/97
333	405	—	—	—	—	—	—	88
334	406	—	—	—	—	—	—	96
335	407	—	—	—	—	—	—	74
336	408	—	—	—	—	—	—	44
337	409	—	—	—	—	—	—	54
338	410	—	—	—	—	—	—	47
339	411	—	—	—	—	—	—	55
340	412	—	—	—	—	—	—	94
341	413	—	—	—	—	—	—	60
342	414	—	—	—	—	—	—	100
343	415	—	—	—	—	—	—	95
344	416	—	—	—	—	—	—	20
345	417	—	—	—	—	—	—	87
346	418	—	—	—	—	—	—	14
347	419	—	—	—	—	—	—	20
348	420	—	—	—	—	—	—	29
349	421	—	—	—	—	—	—	79
350	422	—	—	—	—	—	—	68
351	423	—	—	—	—	—	—	−10
352	424	—	—	—	—	—	—	20
353	425	—	—	—	—	—	—	6
354	426	—	—	—	—	—	—	32
355	427	—	—	—	—	—	—	17
356	428	—	—	—	—	—	—	57
357	429	—	—	—	—	—	—	30
358	430	—	—	—	—	—	—	25
359	431	—	—	—	—	—	—	80
360	432	—	—	—	—	—	—	79
361	433	—	—	—	—	—	—	61
363	435	—	—	—	—	—	—	71
364	436	—	—	—	—	—	—	69
365	437	—	—	—	—	—	—	15
366	438	—	—	—	—	—	—	17
367	439	—	—	—	—	—	—	16
368	440	—	—	—	—	—	—	16
369	441	—	—	—	—	—	—	64
370	442	—	—	—	—	—	—	77
371	443	—	—	—	—	—	—	92
372	444	—	—	—	—	—	—	36
373	445	—	—	—	—	—	—	20
374	446	—	—	—	—	—	—	42
375	447	—	—	—	—	—	—	59
376	448	—	—	—	—	—	—	79
377	449	—	—	—	—	—	—	59
378	450	—	—	—	—	—	—	35
379	451	—	—	—	—	—	—	70
380	452	—	—	—	—	—	—	71
381	453	—	—	—	—	—	—	51
382	454	—	—	—	—	—	—	80
383	455	—	—	—	—	—	—	56
384	456	—	—	—	—	—	—	80
385	457	—	—	—	—	—	—	53
386	458	—	—	—	—	—	—	15
387	459	—	—	—	—	—	—	71
388	460	—	—	—	—	—	—	67
389	461	—	—	—	—	—	—	78
390	462	—	—	—	—	—	—	76
392	464	—	—	—	—	—	—	93
393	465	—	—	—	—	—	—	21
394	466	—	—	—	—	—	—	54
395	467	—	—	—	—	—	—	7
396	468	—	—	—	—	—	—	12
397	469	—	—	—	—	—	—	12
398	470	—	—	—	—	—	—	1
400	471	—	—	—	—	—	—	2
401	472	—	—	—	—	—	—	53
402	473	—	—	—	—	—	—	59
403	474	—	—	—	—	—	—	53
404	475	—	—	91	93	106	—	95
405	476	—	—	95	96	87	—	19
406	477	—	—	79	97	107	—	25
407	478	—	—	92	96	106	—	89
408	479	—	—	55	83	37	—	72
409	480	—	—	68	94	100	—	18
410	481	—	—	77	99	98	—	24
411	482	—	—	21	8	6	—	−2
412	483	—	—	59	77	14	—	37
413	484	—	—	—	—	—	—	−4
414	485	—	—	—	—	—	—	14
415	486	—	—	—	—	—	—	14
416	487	—	—	—	—	—	—	17
417	488	—	—	—	—	—	—	19
418	489	—	—	—	—	—	—	9
419	490	—	—	—	—	—	—	74
420	491	—	—	—	—	—	—	82
421	492	—	—	—	—	—	—	60
422	493	—	—	—	—	—	—	56
423	494	—	—	—	—	—	—	13
424	495	—	—	—	—	—	—	58
425	496	—	—	—	—	—	—	25
426	497	—	—	—	—	—	—	14
427	498	—	—	—	—	—	—	9
430	499	—	—	—	—	—	—	18
432	500	27	27	11	72	23	43	—

TABLE 10 — Inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention: Ex- am-

ple	Comp
No.	No.	5-HT 2A	5-HT 2B	5-HT 2C	5-HT 5A	5-HT 6	5-HT 7
	Serotonin (1 μM)
2	3	—	—	96	—	58	—
43	43	100	70/77	96/100	61/73	95/99	98
49	44	80	11	36	0	9	42
44	45	99	—	95	—	94	92
45	47	84	—	81	—	39	—
51	48	73	—	67	—	59	—
47	51	102	32	84	27	83	91
53	52	83	—	87	—	37	—
48	53	100	23	82	26	49	87
54	54	42	—	22	—	31	—
56	55	100	—	93	—	90	—
55	56	68	—	38	—	62	—
57	57	95	—	86	—	68	—
58	59	96	—	99	—	54	—
60	60	78	—	86	—	50	—
61	61	77	—	90	—	65	—
62	62	88	—	89	—	43	—
63	63	95	—	95	—	73	—
80	78	97	—	103	—	101	97
82	82	100	—	105	—	103	93
83	83	99	88	98	97	102	93
84	85	—	—	—	—	68	—
89	86	95	—	94	—	77	93
85	87	99	—	100	—	101	100
90	88	98/101	—	99/100	—	102/103	93
86	89	101	—	98	—	67	—
91	90	100	—	97	—	103	—
88	91	98	—	100	—	76	95
92	92	100	—	91	—	97	—
93	93	100	—	99	—	93	—
94	95	91	—	91	—	71	—
99	98	95	—	100	—	100	94
100	100	101	—	97	—	95	99
105	102	100	—	95	—	105	93
102	103	101	—	98	—	89	90
107	106	98	—	98	—	104	98
113	110	98	—	101	—	104	92
110	111	99	—	100	—	94	102
125	125	97	—	77	—	62	—
126	126	102	—	84	—	95	—
127	127	84	—	72	—	41	—
83	128	100	—	100	—	101	98
85	132	100	—	96	—	100	103
89	133	96	—	96	—	80	—
86	136	100	—	93	—	73	—
93	140	98	—	98	—	75	—
429	166	46	—	46	—	6	—
259	171	97	—	98	—	93	42
260	172	91	—	97	—	93	100
261	173	99	—	98	—	85	103
262	174	97/100	—	95/98	—	82/87	95/98
263	175	102	—	95	—	100	79
428	176	97	—	99	—	82	65
264	177	97	—	95	—	100	42
265	178	98	—	95	—	95	48
266	180	86	—	74	—	72	77
267	181	77	—	80	—	32	30
268	182	91	—	93	—	47	54
269	183	82	—	78	—	72	74
270	184	82	—	65	—	31	48
271	185	82	—	83	—	26	41
272	186	74	—	72	—	12	37
273	187	102	—	99	—	98	94
274	188	50	—	66	—	9	45
275	189	96	—	91	—	87	82
276	190	71	—	52	—	31	47
152	202	101	—	101	—	105	91
155	203	100	—	98	—	103	95
156	204	101	—	102	—	102	93
157	205	97	—	100	—	103	102
158	206	98	—	98	—	102	93
159	207	97	—	97	—	58	92
160	208	102	—	102	—	103	100
161	209	93	—	95	—	41	36
163	210	98	—	99	—	76	65
165	211	99	—	107	—	98	101
166	212	91	—	104	—	97	98
167	213	98	—	102	—	100	100
168	214	93	—	95	—	94	97
169	215	97	—	96	—	97	90
170	216	99	—	94	—	104	79
171	217	98	—	87/92	—	102	73/91
172	218	99	—	96	—	99	93
173	219	101	—	98	—	102	94
174	220	99	—	98	—	99	104
175	221	97	—	99	—	95	93
176	222	100	—	99	—	102	69
179	223	95	—	93	—	103	91
180	224	99	—	97	—	102	91
181	225	99	—	100	—	103	94
182	226	98	—	100	—	101	100
185	227	103	—	103	—	107	90
186	228	101	—	97	—	106	97
187	229	100	—	100	—	107	89
189	230	98	—	100	—	97	93
190	231	101	—	98	—	97	94
191	232	99	—	98	—	103	84
192	233	97	—	101	—	102	95
193	234	100	—	102	—	101	99
194	235	98	—	101	—	99	96
195	236	99	—	102	—	98	93
196	237	101	—	98	—	101	100
197	238	101	—	99	—	99	98
199	239	93	—	93	—	104	98
200	240	99	—	99	—	104	99
201	241	93	—	100	—	101	96
202	242	98	—	99	—	107	100
203	243	100	—	99	—	107	97
204	244	103	—	99	—	106	99
205	245	102	—	96	—	103	74
206	246	97	—	94	—	104	88
207	247	101	—	100	—	103	101
433	347	100	—	104	—	101	101
434	348	99/100	—	91/95	—	94/98	93/93
435	349	97/100	—	96/98	—	102/103	93/100
436	350	100	—	87	—	103	71
437	351	100	—	101	—	103	90
438	352	84	—	93	—	32	52
439	353	98	—	97	—	100	87
440	354	100	—	101	—	103	75
441	355	92	—	99	—	101	92
442	356	81	—	83	—	90	60
332	404	—	—	90	—	—	95
397	469	87	—	—	—	—	—
398	470	89	—	—	—	—	—
404	475	99	—	96	—	99	—
405	476	100	—	95	—	64/86	90/92
406	477	95	—	99	—	89	65
407	478	99	—	110	—	97	96
408	479	78	—	69	—	91	17
409	480	98	—	102	—	67	84
410	481	101	—	104	—	87	84
411	482	−8	—	−12	—	4	22
412	483	34	—	35	—	53	16
413	484	98	—	95	—	34	83
414	485	96	—	102	—	89	77
432	500	40	34	77	23	18	48
	Serotonin (0.1 μM)
43	43	—	−2	81	19	62	—
44	45	86	—	88	—	48	—
47	51	—	12	43	—	29	—
80	78	76	—	69	—	78	—
82	82	92	—	94	—	90	86/95
83	83	98	—	100	—	96	82/96
84	85	88/98	—	92	—	22/19	—
85	87	100	—	101	—	97	—
90	88	87/95	—	74/96	—	82/102	75/97
91	90	97	—	85	—	102	82
100	100	97	—	104	—	62	—
104	107	96	—	95	—	97	95
113	110	102	—	99	—	102	—
110	111	86	—	95	—	71	—
83	128	99	—	—	—	94	—
259	171	60	—	51	—	35	—
262	174	96	—	96	—	40	68
277	191	98	—	94	—	45	69
278	192	91	—	81	—	38	78
279	193	69	—	44	—	3	40
280	194	71	—	47	—	7	16
281	195	62	—	43	—	32	18
282	196	36	—	8	—	10	12
283	197	17	—	16	—	4	10
284	198	23	—	−1	—	11	4
285	199	40	—	33	—	25	30
286	200	30	—	17	—	20	31
155	203	98	—	101	—	97	—
157	205	104	—	96	—	99	—
165	211	97	—	98	—	60	—
170	216	98	—	83	—	100	66
171	217	96	—	62	—	97	58
172	218	94	—	92	—	85	—
173	219	100	—	94	—	96	—
179	223	97	—	81	—	104	67
180	224	92	—	95	—	96	88
209	248	108	—	92	—	101	57
210	249	90	—	60	—	98	70
211	250	36	—	31	—	13	33
212	251	85	—	77	—	8	74
213	252	67	—	50	—	9	23
214	253	85	—	49	—	9	54
215	254	65	—	52	—	15	63
216	255	81	—	69	—	4	54
217	256	100	—	90	—	96	85
218	257	94	—	94	—	71	75
219	258	98	—	98	—	81	84
220	259	96	—	92	—	21	81
221	260	34	—	29	—	−7	5
222	261	74	—	31	—	4	47
223	262	99	—	100	—	99	94
224	263	64	—	18	—	99	15
225	264	99	—	94	—	89	51
226	265	96	—	89	—	97	52
227	266	67	—	12	—	81	18
228	267	66	—	54	—	87	85
229	268	98	—	86	—	97	87
231	269	87	—	55	—	102	51
232	270	92	—	84	—	97	79
233	271	41	—	19	—	90	10
234	272	62	—	40	—	98	−1
235	273	94	—	100	—	46	85
236	274	98	—	99	—	97	94
237	275	93	—	98	—	101	72
238	276	99	—	96	—	81	86
239	277	100	—	98	—	98	103
240	278	88	—	91	—	69	79
241	279	75	—	70	—	90	53
242	280	83	—	86	—	56	20
243	281	103	—	96	—	78	93
244	282	100	—	94	—	102	91
245	283	101	—	90	—	88	71
246	284	103	—	93	—	101	75
247	285	52	—	45	—	67	44
430	286	79	—	74	—	56	10
248	287	50	—	74	—	25	48
249	288	82	—	72	—	99	56
250	289	85	—	64	—	100	41
255	291	1	—	1	—	7	0
256	292	45	—	12	—	60	27
257	293	30	—	32	—	6	50
258	294	102	—	98	—	97	84
293	320	94	—	107	—	92	91
294	332	80	—	53	—	92	48
295	333	55	—	73	—	32	39
296	334	103	—	109	—	76	14
297	338	104	—	112	—	103	94
287	341	11	—	3	—	2	2
288	342	14	—	4	—	1	6
289	343	8	—	5	—	−7	−1
290	344	−6	—	−6	—	−1	31
291	345	43	—	56	—	−1	40
292	346	26	—	26	—	5	57
433	347	90	—	99	—	70	—
434	348	96	—	88	—	62	62
435	349	100	—	99	—	92	72
436	350	94	—	101	—	84	—
437	351	98	—	100	—	100	—
443	357	45	—	53	—	18	11
444	358	49	—	67	—	0	6
445	359	56	—	74	—	22	12
446	360	64	—	52	—	13	22
447	361	89	—	81	—	80	78
448	362	88	—	92	—	100	92
449	363	79	—	47	—	49	26
450	364	38	—	45	—	24	44
301	365	99	—	102	—	50	72
298	367	91	—	106	—	75	85
299	368	92	—	96	—	76	71
300	369	72	—	105	—	52	63
302	370	79	—	99	—	79	78
312	384	96	—	92	—	107	98
313	385	67	—	69	—	19	69
314	386	62	—	64	—	13	58
315	387	98	—	98	—	105	89
316	388	99	—	98	—	106	83
317	389	78	—	78	—	25	79
318	390	92	—	93	—	76	70
319	391	84	—	86	—	35	87
320	392	94	—	94	—	98	80
321	393	95	—	69	—	13	75
322	394	94	—	79	—	36	81
323	395	95	—	32	—	105	60
324	396	−12	—	3	—	10	−15
325	397	102	—	95	—	100	95
326	398	97	—	31	—	97	52
327	399	100	—	57	—	16	70
328	400	89	—	19	—	96	61
329	401	66	—	47	—	89	69
330	402	79	—	44	—	101	69
331	403	25	—	16	—	59	2
332	404	85/99	—	50/65	—	101/105	55/67
333	405	91	—	78	—	99	74
334	406	93	—	75	—	103	73
335	407	96	—	92	—	57	47
336	408	7272	—	6969	—	49	93
337	409	97	—	97	—	64	69
338	410	92	—	92	—	54	72
339	411	61	—	17	—	63	28
340	412	92	—	50	—	101	82
341	413	94	—	87	—	37	73
342	414	80	—	30	—	103	75
343	415	97	—	99	—	105	98
344	416	101	—	99	—	16	71
345	417	94	—	95	—	57	64
346	418	33	—	29	—	20	15
347	419	73	—	45	—	15	70
348	420	90	—	76	—	17	39
349	421	74	—	81	—	61	17
350	422	67	—	40	—	93	56
351	423	52	—	31	—	2	20
352	424	84	—	93	—	16	54
353	425	59	—	43	—	15	38
354	426	87	—	60	—	59	74
355	427	18	—	4	—	64	12
356	428	94	—	81	—	82	79
357	429	41	—	48	—	50	91
358	430	96	—	80	—	3	59
359	431	78	—	82	—	75	60
360	432	84	—	68	—	77	33
361	433	21	—	8	—	55	23
363	435	93	—	94	—	3	76
364	436	70	—	66	—	12	81
365	437	8	—	6	—	10	−14
366	438	72	—	64	—	16	20
367	439	−5	—	2	—	14	11
368	440	−3	—	3	—	23	−3
369	441	97	—	87	—	28	98
370	442	50	—	33	—	82	34
371	443	10	—	14	—	59	13
372	444	17	—	19	—	72	3
373	445	8	—	6	—	56	−3
374	446	5	—	−2	—	60	14
375	447	14	—	1	—	41	15
376	448	8	—	14	—	57	14
377	449	44	—	11	—	73	21
378	450	19	—	−6	—	62	14
379	451	88	—	89	—	47	78
380	452	98	—	100	—	79	84
381	453	90	—	98	—	67	64
382	454	95	—	98	—	35	89
383	455	94	—	97	—	65	42
384	456	96	—	93	—	84	97
385	457	33	—	24	—	12	43
386	458	39	—	8	—	16	68
387	459	98	—	101	—	69	91
388	460	86	—	89	—	38	24
389	461	91	—	96	—	68	41
390	462	99	—	99	—	23	88
392	464	89	—	36	—	49	38
393	465	97	—	83	—	38	29
394	466	93	—	86	—	33	34
395	467	55	—	20	—	15	19
396	468	28	—	3	—	6	11
397	469	44	—	57	—	4	31
398	470	49	—	1	—	16	18
400	471	−2	—	3	—	5	1
401	472	82	—	75	—	53	68
402	473	96	—	55	—	38	45
403	474	103	—	98	—	81	98
404	475	98	—	100	—	54	—
405	476	97	—	—	—	27	67
407	478	99	—	104	—	56	—
415	486	98	—	103	—	33	10
416	487	100	—	101	—	21	28
417	488	94	—	97	—	44	7
418	489	96	—	85	—	37	40
419	490	99	—	95	—	66	55
420	491	99	—	103	—	94	92
421	492	98	—	100	—	89	77
422	493	97	—	96	—	49	69
423	494	99	—	97	—	26	36
424	495	91	—	77	—	65	45
425	496	103	—	100	—	25	13
426	497	34	—	10	—	−9	25
427	498	79	—	69	—	22	41
430	499	79	—	66	—	30	0

TABLE 11 — 5-HT 2A agonist/antagonist activity of compounds of the invention 5-HT 2A

	Agonist	Antagonist
Compound No.	EC 50 (μM)	IC 50 (μM)
83	3.1	0.97, >1.0
	5-HT 7
	Antagonist IC 50 (μM)
83	0.46, 0.77

TABLE 12 — Dopamine D 2L antagonist activity of compounds of the invention D 2L GTPgS Compound 83 conc.

(nM)	% Inhibition
1	16
3	28
10	49
30	55
100	77

TABLE 13 — Dopamine D 2S antagonist activity of compounds of the invention D 2S GTPgS Compound 83 conc.

(nM)	% Inhibition
1	15
3	45
10	56
30	74
100	91

TABLE 14 — 5-HT 1B radioligand binding activity of compounds of the invention 5-HT 1B (5 μM) % Binding relative to

Compound No.	bound radioligand
91	9
174	16
182	3
217	10
223	4
224	10
259	25
274	6
359	68

TABLE 15 — 5-HT 1B radioligand competition binding assay

Compound No. 91	% Binding relative
Conc. (nM)	to bound radioligand	IC 50
0.08	120	365 nM
0.31	138
1.2	132
5	129
20	113
78	103
313	66
1250	31
20000	1
50000	−5

TABLE 16 — Agonist/antagonist activity at the D 2L receptor.

Agonist	% Activation
Concentration (nM)	Compound No. 83	Compound No. 90
10	2.43	0.95
30	0.68	0.25
100	1.26	−0.23
300	0.92	−0.24
1000	−0.12	−0.48
3000	0.00	−1.20
10000	6.32	−0.78
30000	84.25	−0.92
Antagonist	% Inhibition
Concentration (nM)	Compound No. 83	Compound No. 90
5	93.51	95.45
15	96.42	97.28
50	96.75	93.46
150	96.83	96.83
500	96.84	97.86
1500	95.95	97.19
5000	95.95	97.41
15000	92.35	96.07

TABLE 17 — Agonist/antagonist activity at the 5-HT 2A receptor.

Agonist	% Activation
Concentration (nM)	Compound No. 83	Compound No. 90
10	0.70	0.62
30	0.55	0.26
100	0.85	0.27
300	0.58	0.18
1000	0.62	0.11
3000	0.31	0.04
10000	0.34	0.02
30000	1.24	0.49
Antagonist	% Inhibition
Concentration (nM)	Compound No. 83	Compound No. 90
5	85.40	73.03
15	96.57	95.03
50	98.47	98.52
150	98.70	98.32
500	98.82	98.44
1500	98.89	98.43
5000	97.83	98.52
15000	97.05	97.61

TABLE 18 — Antagonist activity at the D 2L receptor.

Antagonist	% Inhibition
Concentration (nM)	Compound No. 83	Compound No. 90
5	75.50	84.10
15	97.82	91.69
50	98.15	94.68
150	103.93	93.97
500	106.41	93.68
1500	106.91	100.03
5000	106.46	100.06
15000	110.66	102.18

TABLE 19 — Antagonist activity at the D 2L receptor.

Antagonist	% Inhibition
Concentration (nM)	Compound No. 83	Compound No. 90
5	51.76	58.98
15	89.96	101.12
50	103.73	106.43
150	109.48	109.15
500	117.78	109.33
1500	113.47	116.02
5000	110.56	112.00
15000	104.55	116.26

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Claims as granted

48 claims

Classifications

6 codes

IPC · International Patent Classification

Section A — Human necessities

A61K31/445

Section C — Chemistry; metallurgy

C07D401/14
C07D471/04
C07D401/00

USPC · US Patent Classification

546/201514/323

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