WO2014031170A1

WO2014031170A1 - Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use

Info

Publication number: WO2014031170A1
Application number: PCT/US2013/032401
Authority: WO
Inventors: Sarvajit Chakravarty; Andrew Asher Protter; Rajendra Parasmal Jain; Michael John Green
Original assignee: Medivation Technologies, Inc.
Priority date: 2012-08-22
Filing date: 2013-03-15
Publication date: 2014-02-27

Abstract

This disclosure is directed to pyrido[4,3-b]indole and pyrido [3, 4-b] indole derivatives and heterocyclic analogs thereof. 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

PYRIDO[4,3-b]INDOLE AND PYRIDO[3,4-b]INDOLE DERIVATIVES AND

METHODS OF USE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.

61/692,183 filed August 22, 2012, the disclosure of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 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-Barre 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.

[0003] 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.

[0004] 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. Patent 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.

Azepino[4,5-b]indoles and uses thereof have been described in PCT/US2009/062872. All references disclosed herein and throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.

[0005] Despite the potential uses of dimebon 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

[0006] Hydrogenated pyrido[4,3-b]indoles and pyrido [3, 4-b] indoles and heterocyclic analogs thereof are described. 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. 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.

[0007] In one aspect, the compounds of invention are the compounds described in Tables 1, 2, 3, and 4, such as a compound selected from the group consisting of Compound Nos. 1 to 179, II I to 11-352, III-l to III-139, and IV-1 to IV-371; or a salt (e.g., a pharmaceutically acceptable salt), solvate, or N-oxide thereof .

[0008] In another aspect, the compounds of invention are the compounds described in Table 5 (e.g., a compound selected from the group consisting of Compound Nos. V-l to V-378, or a compound selected from the group consisting of Compound Nos. V-l to V-335), or a salt (e.g., a pharmaceutically acceptable salt), solvate, or N-oxide thereof.

[0009] Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention. For example, in some embodiments, provided is a compound selected from a group consisting of any one or more of Compound Nos. 1 to 179, II I to 11-352, III-l to III-139, IV-1 to IV-371, and V-l to V-378, such as a group consisting of any one or any two or any three or more of Compound Nos. 1 to 179, IT1 to 11-352, III-l to III-139, IV-1 to IV-371, and V-l to V-378, or a salt (e.g., a

pharmaceutically acceptable salt), solvate or N-oxide thereof. A selection of any

combination of Compound Nos. 1 to 179, II I to 11-352, III-l to III-139, IV-1 to IV-371, and V-l to V-378, or salt, solvate or N-oxide thereof, is intended the same as if each and every combination were specifically and individually listed.

[0010] It is understood that compounds as detailed herein include all stereoisomeric forms. For example, reference to Compound Nos. 1-179 includes and intends all "a," "b," etc. forms of Compound Nos. 1-179 per se; reference to Compound Nos. V-l to V-378 includes and intends all "a," "b," etc. forms of Compound Nos. V-l to V-378 per se. Provided herein is a compound selected from the group consisting of Compound Nos. 1 to 179, II- 1 to 11-352, III- 1 to III-139, IV-1 to IV-371, and V-l to V-378; or a salt, solvate or N-oxide thereof. In some of these embodiments, the compound is selected from the group consisting of Compound Nos. 1 to 179, II I to 11-352, III-l to III-139, IV-1 to IV-371, and V-1 to V-335; or a salt, solvate or N-oxide thereof. In a particular variation, provided herein is a compound selected from the group consisting of Compound Nos. 1 to 179, II I to 11-352, III-l to III-139, IV-1 to

IV- 371, and V-1 to V-378; or a pharmaceutically acceptable salt thereof. In some of these embodiments, the compound is selected from the group consisting of Compound Nos. V-1 to

V- 378. In some of these embodiments, the compound is selected from the group consisting of Compound Nos. V-1 to V-335.

[0011] The invention also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes N-oxides of the tertiary amines where one or more tertiary amine moieties are present in the compounds described. 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 tautomers are intended, whether the tautomer specifically depicted is the predominant tautomer or not. 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, which in some embodiments is a specific stereochemical form, including a specific geometric isomer. 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.

[0012] 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. Compounds as detailed herein or a pharmaceutically acceptable salt thereof are also provided for the manufacture of a medicament for the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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^, ₂Α and/or α₂β), serotonin receptor (e.g. , 5-HT₂A, 5-HT₂c, 5-HT₆ and/or 5-HT₇), dopamine receptor (e.g., D₂L) and histamine receptor (e.g., Hi, H₂ and/or H₃). In another variation, at least two of the following receptors are modulated: adrenergic receptor (e.g. , am, a₂A and/or α₂β), serotonin receptor (e.g. , 5-HT₂A, 5-HT₂c, 5-HT₆ and/or 5-HT₇), dopamine receptor (e.g., D₂L) and histamine receptor (e.g., Hi, H₂ and/or H₃). In another variation, at least three of the following receptors are modulated: adrenergic receptor (e.g. , am, a₂A and/or α₂β), serotonin receptor (e.g. , 5-HT₂A, 5-HT₂c, 5-HT6 and/or 5-HT₇), dopamine receptor (e.g., D₂L) and histamine receptor (e.g., Hi, H₂ and/or H ). In another variation, each of the following receptors is modulated: adrenergic receptor (e.g. , am, (¾A and/or α₂β), serotonin receptor (e.g. , 5-HT₂A, 5-HT₂c, 5-HT6 and/or 5-HT₇), dopamine receptor (e.g., D₂L) and histamine receptor (e.g., Hi, H₂ and/or H₃). In another variation, at least one of the following receptors is modulated: am, (¾A, (¾B, 5-HT₂A, 5-HT₂c, 5-HT₆, 5-HT₇, D₂L, ¾, H₂ and H . In another variation, at least one of the following receptors is modulated: am, (¾A, (¾B, 5-HT₂A, 5-HT₂c, 5-HT₆, 5-HT₇, D₂, Hi, H₂ and H₃. 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: am, (¾A, (¾B, 5-HT₂A, 5-HT₂c, 5-HT₆, 5-HT₇, D₂L, HI, H₂ and H . 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: am, ct₂A, ct₂B, 5-HT₂A, 5-HT₂c, 5-HT6, 5-HT₇, D₂, Hi, H₂ and H₃. In a particular variation, at least dopamine receptor D₂ is modulated. In still another variation, at least dopamine receptor D₂L is modulated. In another particular variation, at least dopamine receptor D₂ and serotonin receptor 5-HT₂A are modulated. In another particular variation, at least dopamine receptor D₂L and serotonin receptor 5-HT₂A are modulated. In a further particular variation, at least adrenergic receptors am, ct₂A, ct₂B and serotonin receptor 5-HT₆ are modulated. In another particular variation, at least adrenergic receptors am, ¾A, a₂B, serotonin receptor 5-HT₆ and one or more of serotonin receptor 5-HT₇, 5-HT₂A, 5-HT₂c and histamine receptor Hi and H₂ are modulated. In a further particular variation, histamine receptor Hi 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 Hi and/or H₂ 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 Hi and/or H₂ 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 Hi and/or H₂ 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 Hi and/or H₂ 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 D₂ 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.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0017] For use herein, unless clearly indicated otherwise, use of the terms "a", "an" and the like refers to one or more.

[0018] 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".

[0019] 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.

[0020] 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 ccl-adrenergic receptor (e.g. , <¾Α, and/or am) and/or a <¾-adrenergic receptor (e.g. , <¾A, <¾B and/or <¾c) and/or reduces or eliminates or increases or enhances or mimics an activity of a (^-adrenergic receptor (e.g. , <¾A, <¾B and/or am) and/or a a₂-adrenergic receptor (e.g. , α₂Α, a₂B and/or a₂c) 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.

[0021] 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 and/or a dopamine-2 (D₂) receptor or reduces or eliminates or increases or enhances or mimics an activity of a dopamine- 1 (D and/or a dopamine-2 (D₂) receptor in a reversible or irreversible manner. Dopamine D₂ receptors are divided into two categories, D₂L and D₂s, 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.

[0022] 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-HTiA and/or a 5-HTi_B and/or a 5-HT₂A and/or a 5-HT₂B and/or a 5-HT_2C and/or a 5-HT₃ and/or a 5-HT₄ and/or a 5-HT₆ and/or a 5-HT₇ receptor or reduces or eliminates or increases or enhances or mimics an activity of a 5-HT_1A and/or a 5- HTi_B and/or a 5-HT₂A and/or a 5-HT₂B and/or a 5-HT₂c and/or a 5-HT₃ and/or a 5-HT₄ and/or a 5-ΗΤ₆ and/or a 5-HT₇ 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.

[0023] 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 Hi and/or H₂ and/or H₃ receptor or reduces or eliminates or increases or enhances or mimics an activity of a histamine Hi and/or H₂ and/or H₃ 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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. , PS 1 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.

[0028] 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.

[0029] 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.

[0030] 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).

[0031] 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.

[0032] 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-Barre 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.

[0033] 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-Barre syndrome, multiple sclerosis, diabetic neuropathy, fibromyalgia, neuropathy associated with spinal cord injury, schizophrenia, bipolar disorder, psychosis, anxiety or depression.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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 (Αβ), which is the cleavage product of beta amyloid precursor protein (βΑΡΡ 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. Αβ 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, Neurobiol. Dis. 3: 159-168, 1996; Hardy, Ann. Med. 28:255-258, 1996). Diseased-linked mutations in these genes result in increased production of the 42-amino acid form of Αβ, 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. 57(5):695-703, 2005; Wang et al, Insights into amyloid- β-induced mitochondrial dysfunction in Alzheimer disease, Free Radical Biology & Medicine 43: 1569-1573, 2007; Swerdlow et al, Mitochondria in Alzheimer's disease, Int. Rev. Neurobiol. 53:341-385, 2002; and Reddy et al, Are mitochondria critical in the pathogenesis of Alzheimer's disease?, Brain Res Rev. 49(3):618-32, 2005). 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.

[0040] 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.

[0041] "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).

[0042] 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.

[0043] 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. [0044] 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, Am. J. Psychiatry 139: 1136-1139, 1982) 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 et al, Neurobiol. Aging 15:85-90, 1994).

[0045] 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 {e.g., battlefield injuries, including post- concussion syndrome, and the like), neurotoxic treatment {e.g., 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.

[0046] 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.

[0047] "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.

[0048] 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.

[0049] 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.

[0050] As used herein, the term "nerve injury" or "nerve damage" refers to physical damage to nerves, such as avulsion injury (e.g. , where a nerve or nerves have been torn or ripped) or spinal cord injury (e.g. , 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 (e.g. , car accidents, sports injuries, and the like), tumors impinging on the spinal column, developmental disorders, such as spina bifida, and the like.

[0051] 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.

[0052] As used herein, the term "Guillain-Barre 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-Barre syndrome, although some continue to have a certain degree of weakness.

[0053] 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 relap sing-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. [0054] 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.

[0055] "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).

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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. [0061] 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, e.g. , 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.

[0062] 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.

[0063] 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, e.g. , 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).

[0064] 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.

[0065] "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 metal 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.

66(1): 1-19, 1977. 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.

[0066] The term "excipient" as used herein includes an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound detailed herein, or a pharmaceutically acceptable salt thereof, 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.

[0067] 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

[0068] Compounds according to the invention are detailed herein, including in the Brief Summary of the Invention and elsewhere. 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), tautomers, salts and solvates of the compounds described herein, as well as methods of making such compounds.

[0069] In one aspect, the invention relates to Compounds described in Tables 1, 2, 3, and 4, such as a compound selected from the group consisting of Compound Nos. 1 to 179, IT1 to IT352, III- 1 to III- 139, and IV- 1 to IV-371; or a salt (e.g., a pharmaceutically acceptable salt), solvate, or N-oxide thereof; and uses thereof.

[0070] In another aspect, the invention relates to Compounds described in Table 5 (e.g., a compound selected from the group consisting of Compound Nos. V-l to V-335, or a compound selected from the group consisting of Compound Nos. V-l to V-378); or a salt (e.g., a pharmaceutically acceptable salt), solvate, or N-oxide thereof; and uses thereof. [0071] In one particular aspect, the invention relates to Compound Nos. 6, 9, 10-12, 14, 16- 21, 23-28, 39-40, 44-59, 63-72, 75-82, 108-131, 133-171, 173-179, 11-57, III-7 to III-l l, III- 14, 111-80 to 111-82, 111-84 to 111-98, III-101 to III- 138, IV-115 to IV-125, IV-132 to IV-312,

IV- 314 to IV-371, and V-l to V-335, and related stereoisomers thereof; or a salt (e.g., a pharmaceutically acceptable salt), solvate, or N-oxide thereof; and uses thereof.

[0072] In another particular aspect, the invention relates to Compound Nos. 6, 9, 10-12, 14, 16-21, 23-28, 39-40, 42, 44-45, 47-49, 51-59, 63-72, 75-82, 108-116, 118-122, 124-131, 133- 142, 144-163, 165-171, 173-178, 11-57, III-7 to III-l l, 111-14, 111-80 to 111-82, 111-84 to 111-98, III-101 to III-117, III-119 to III-129, III-131 to III-138, IV-132 to IV-312, IV-314 to IV-371,

V- l to V-15, V-17 to V-82, V-84 to V-102, V-104 to V-255, V-257 to V-378, and related stereoisomers thereof; or a salt (e.g., a pharmaceutically acceptable salt), solvate, or N-oxide thereof; and uses thereof.

[0073] 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.

[0074] 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. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.

[0075] Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. For example, when a 2-hydroxypyridyl moiety is depicted, the corresponding 2-pyridone tautomer is also intended. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.

[0076] The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described. The structure or name is intended to embrace all possible stereoisomers of a compound depicted, and each unique stereoisomer has a compound number bearing a suffix "a", "b", etc. 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 thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.

[0077] For compounds bearing one or more chiral centers, each unique stereoisomer has a compound number bearing a suffix "a", "b", etc. As examples, racemic compound V-221, bearing one chiral center, can be resolved into its individual enantiomers V-221a and V-221b.

Enantiomers V-221 a and V-221b

* = chiral center

2

Similarly, racemic compound V-239, bearing two chiral centers, can be resolved into its individual diastereomers V-239a, V-239b, V-239c and V-239d.

Diastereomers V-239a, V-239b, V-239c and V-239d

iral center

[0078] It is known that pure enantiomers and pure diastereomers can sometimes be susceptible to epimerization, depending upon a number of factors such as the nature of the chemical structure, and the environmental conditions under which it is stored. In the case of diastereomers, one chiral center may be more susceptible than another to epimerization.

Once a stereoisomer is isolated in its pure chiral form, it is preferable to minimize any later epimerization either by modifying storage conditions or use of certain salt forms or other formulation techniques known to those in the art. Alternatively, the chemical structure itself is modified by addition or removal of substituents, such that epimerization is disfavored, typically through a combination of steric and electronic effects. [0079] Certain compounds of the invention, such as for example Compound No. 129d, suggest a tendency to epimerize at the chiral center indicated:

# = chiral center susceptible to epimerization

[0080] It is presented herein that particular substitution on the aromatic ring comprising X⁷- X¹⁰ tends to minimize or eliminate epimerization. Addition of electron withdrawing groups, such as in one example the modification of molecule A below, to analogs B, C, or D, results in compounds with more epimerization-resistant characteristics, such as Compound No. V-

B C D

[0081] 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.

[0082] 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.

[0083] 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.

[0084] Kits comprising a compound of the invention, or a salt or solvate thereof, and suitable packaging are provided. In one embodiment, a kit further comprises instructions for use. In one aspect, a kit comprises a compound of the invention, or a salt or solvate thereof, and instructions for use of the compounds in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

[0085] Articles of manufacture comprising a compound of the invention, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule and the like.

[0086] Representative compounds of the invention are shown in Tables 1, 2, 3, 4 and 5. Table 1. Representative Compounds of the Invention

40

43

44

Table 2. Representative Compounds of the Invention

54



80

81

82

83

85

86

87

88



90

91

92

Table 3. Representative Compounds of the Invention.

99

101

105

107

Table 4. Representative Compounds of the Invention.

114

115

116

118

119

120













130

ı33













140

141

ı42











150

151

ı53







160

161

ı62

ı63

ı64

ı65

ı66







170

171

ı73

Table 5. Representative Compounds of the Invention

General Description of Biological Assays

[0087] 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., am, <¾A and <¾B), inhibition of binding of a ligand to a serotonin receptor (e.g., 5-HT₂A, 5-HT₂C, 5-HT₆ and 5-HT₇), inhibition of binding of a ligand to a dopamine receptor (e.g., D₂L), and inhibition of binding of a ligand to a histamine receptor (e.g., H_{1 ;} H₂ and H₃); agonist/antagonist activity to a serotonin receptor (e.g. , 5- HT_2A, 5-HT₆); agonist/antagonist activity to a dopamine receptor (e.g. , D_2L, D_2S);

agonist/antagonist activity to a histamine receptor (e.g., HO; 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.

[0088] 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.

[0089] 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., am, a₂A, a₂B, 5-HT₂A, 5-HT₂C, 5- HT₆, 5-HT₇, D_2L, Η_{1 ;} H₂, H ). 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., m, a₂A, a₂B, 5-HT₂A, 5-HT₂C, 5-HT₆, 5-HT₇, D₂, H_{1 ;} H₂, H₃). 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-HT₆, dopamine receptor D_2L, dopamine receptor D₂s and histamine receptor H as measured in the assays described herein. In one variation, agonist response of serotonin receptor 5-HT₂A is inhibited by compounds of the invention by at least about any one of 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% as determined in a suitable assay such as the assay described herein. [0090] In one variation, a compound of the invention displays the above described neurotransmitter receptor binding profile, e.g. 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 μΜ 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.

[0091] 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.

[0092] 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, e.g. 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 Hi antagonism may contribute to sedation, weight gain and reduced cognition, low affinity (less than about 80% inhibition of binding of Pyrilamine at 1 μΜ 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-HT₆ antagonist may have cognition-enhancing effects as serotonin acting through this receptor may impair memory.

[0093] 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, e.g. 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.

[0094] 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, e.g. 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.

[0095] 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, e.g. 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.

[0096] 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, e.g., shows efficacy in a preclinical model of schizophrenia.

[0097] 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 and further displays agonist or antagonist activity to one or more receptors detailed herein.

[0098] 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.

[0099] 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. [0100] 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.

[0101] 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.

[0102] In a further variation, a compound of the invention inhibits binding of a ligand 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.

[0103] 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.

[0104] 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.

[0105] In one aspect, compounds of the invention inhibit binding of a ligand to adrenergic receptors <¾_D, <¾_A, <¾_B ^and inhibit binding of a ligand to serotonin receptor 5-HT₆. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors <¾_D, <¾_A, <¾_B, ^t0 serotonin receptor 5-HT₆ and to any one or more of the following receptors: serotonin receptor 5ΉΤ₇, 5-HT_2A and 5-HT₂c. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors am, <¾_A, <¾_B, ^t0 serotonin receptor 5-HT₆ and to any one or more of the following receptors: serotonin receptor 5-HT₇, 5-HT_2A and 5-HT_2C and further show weak inhibition of binding of a ligand to histamine receptor Hi and/or H₂. In one variation, compounds of the invention that also display strong inhibition of binding of a ligand to the serotonin receptor 5-HT₇ are particularly desired. In another variation, compounds of the invention inhibit binding of a ligand to adrenergic receptors am, <¾_A, <¾_B, ^t0 serotonin receptor 5-HT₆ and further show weak inhibition of binding of a ligand to histamine receptor Hi and/or H₂. Weak inhibition of binding of a ligand to the histamine Hi 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 Hi is inhibited by less than about 80%. In another variation, binding of a ligand to histamine receptor Hi 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.

[0106] In another variation, compounds of the invention inhibit binding of a ligand to a dopamine receptor D₂. 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 D₂ 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 Hi. 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-HT₇ 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-HT₂c receptor, weak inhibition of binding of a ligand to the histamine Hi receptor, weak inhibition of binding of ligands to the histamine H₂ receptor, and antagonist activity to serotonin receptor 5-HT_2A. [0107] 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-HT₂A, serotonin receptor 5-HT₆, dopamine receptor D₂L, dopamine receptor D₂s and histamine receptor ¾. 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-HT₂A, 5-HT₆, dopamine receptor D₂L, dopamine receptor D₂s and histamine receptor HO, neurite outgrowth, a preclinical model of memory dysfunction associated with cholinergic dysfunction/hypofunction and a preclinical model of schizophrenia.

[0108] In some aspects, compounds of the invention inhibit binding of a ligand to adrenergic receptors m, a₂A, ct₂B, serotonin receptor 5-HT₆ and a dopamine receptor D₂ 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 am, ct₂A, ct₂B, serotonin receptor 5-HT₆ and dopamine receptor D₂L 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.

[0109] 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.

[0110] 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

[0111] 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 neuro transmitter-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-Barre 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.

[0112] Parkinson's disease (PD) is characterized by the selective degeneration of

dopaminergic neurons in the substantia nigra region of the brain. PD is associated with one or more of the following symptoms: bradykinesia, gait disorders, muscle rigidity, postural reflex impairment, symptoms having good response to L-3,4-dihydroxyphenylalanine (L- DOPA) treatment, the absence of prominent oculomotor palsy, cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia. At a molecular level, PD is accompanied by the accumulation within neurons of protein aggregates termed Lewy bodies. These insoluble inclusions are comprised of several proteins including a-synuclein (a-syn).

[0113] Several genetic determinants are associated with disease incidence, both in familial PD and in spontaneous instances of the disease. Genetic studies of diseased families have revealed several disease-associated autosomal dominant single gene mutations, as well as recessive inheritance of mutations in certain genes. Spontaneous cases of PD have been linked to polymorphisms in genes associated with the disease or in a genetic susceptibility factor that increases risk for the disease. For example, mutations in factors important for the regulation of development or survival of dopaminergic neurons would increase risk for PD. Mutations in the SNCA gene give rise to misregulated expression of a-syn that results in the misfolding and accumulation of this protein in oligomers, fibrils or inclusions found in typical and atypical PD. The exact mechanisms of toxicity and the identity of toxic species in a-syn-mediated neurodegeneration remain unclear. However, evidence strongly suggests that the formation of nonfibrillar a-syn oligomers, induced by an increase in the concentration of a-syn from either impared degradation and/or upregulated expression, results in synapse dysfunction and neuron degeneration. Controlling the concentration of a-syn by preventing or inhibiting its expression or enhancing its degradation has been proposed as a possible neuroprotective therapeutic strategy that could have an important impact on disease progression. The exact route of a-syn degradation has been shown to be dependent on a variety factors. Recently, it was demonstrated that chaperone mediated autophagy (CMA) is one of the main contributors to a-syn degradation when the protein is overexpressed, particularly in neurons. CMA involves the recognition, targeting and translocation of selected proteins to lysosomes for degradation. Because CMA plays a critical role in a-syn degradation and proteasomal activity may be compromised in the substantia nigra of PD patients, small molecule activators of autophagic lysosomal pathways represent promising candidates to prevent a-syn accumulation.

[0114] There is evidence to suggest that progressive neurodegeneration of the main noradrenergic nucleus occurs early in the progression of PD, suggesting a causative role in the natural progression of PD. Adrenergic a2-receptor antagonists have been shown to increase spontaneous locomotion as well as the rotational behavior induced by direct and indirect stimulators of dopaminergic neurotransmission such as amphetamine, L-DOPA, apomorphine or dopamine-uptake inhibitors, suggesting that adrenergic a2-receptor antagonists increase extracellular dopamine availability.

[0115] L-DOPA remains the most effective agent to improve motor symptoms in PD, but chronic use is associated with the emergence of tremors, or dyskinesia. Dyskinesia is a movement disorder that is epitomized by involuntary movements similar to tics or choreia. These can include slight movements of the hand or uncontrollable movement of the upper or lower body. Uncoordinated movement can also occur internally, particularly with respiratory muscles, but it often goes unrecognized. Dyskinesia occurs in more than half of PD patients after 5 to 10 years of L-DOPA treatment, with the percentage of affected patients increasing over time. Patients with the young-onset PD are often hesitant to commence L-DOPA therapy until absolutely necessary for fear of suffering severe dyskinesia later on. The occurrence of dyskinesia limits the ability to optimize the treatment regimen, affects functional disability and impacts quality of life.

[0116] The reasons for the appearance of the dyskinesia are not entirely known, but it might be that the L-DOPA dose that is required to compensate for the lack of dopamine in striatum is above the tolerated threshold in other regions of the brain that are important for motor control. Several studies have reported that a2 adrenoceptor antagonists improve some neurochemical and behavioral abnormalities in PD, enhance the efficacy of anti-parkinsonian effects of L-DOPA and alleviate motor complications following repeated L-DOPA treatment in PD. The use of alpha-2-adrenergic receptor antagonists as an adjunct to levodopa has been shown to reduce the expression of established L-DOPA induced dyskinesia (LID). These findings suggest a potential role of abnormal a2 adrenoceptor transmission in PD and LID.

[0117] In some embodiments, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of Parkinson's Disease. In some embodiments, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of one of more of the symptoms of Parkinson's Disease, such as

bradykinesia, gait disorders, muscle rigidity, postural reflex impairment, symptoms having good response to L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the absence of prominent oculomotor palsy, cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia. In some embodiments, the compounds described herein may be used to treat, prevent, delay the onset and/or delay the development of one of more of the symptoms of Parkinson's Disease, including but without limitation to, 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 dysphasi.

[0118] 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.

[0119] 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.

[0120] 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. [0121] 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

[0122] 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 am, <¾A, <¾B, serotonin receptor 5-HT₂A, 5-HT₆, 5-HT₇, histamine receptor Hi and/or H₂ 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 am, <¾A, <¾B ^and a serotonin receptor 5-HT₆ 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 am, <¾A, <¾B, ^AN^ ^A

serotonin receptor 5-HT₆ receptor and modulation of one or more of the following receptors serotonin 5-HT₇, 5-HT₂A, 5-HT₂C and histamine Hi and H₂ 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 D₂ 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 D₂L 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 D₂ 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 D₂L 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.

Methods to improve cognitive functions and/or reduce psychotic effects

[0123] 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 am, <¾A, <¾B, serotonin receptor 5-HT₂A, 5-HT₆, 5- HT₇, histamine receptor Hi and/or H₂ is desirable or expected to be desirable to improve cognitive functions. In some variations modulation of <¾D, <¾A, <¾B adrenergic receptors and a serotonin 5-HT₆ receptor is desirable or expected to be desirable to improve cognitive functions. In some variations, modulation of <¾D, <¾A, <¾B adrenergic receptors and serotonin receptor 5-HT₆ and modulation of one or more of the following receptors: serotonin receptor 5-HT₇, 5-HT₂A, 5-HT₂C and histamine receptor Hi and H₂, 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 D₂ 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 D₂ 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 D₂L receptor and a serotonin 5-HT₂A 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

[0124] 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 μΜ 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

[0125] 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 am, <¾A, <¾B adrenergic receptor and a serotonin 5-HT6 receptor. In some variations, the aminergic G protein-coupled receptor is a <¾D, <¾A, <¾B adrenergic receptor and a serotonin 5-HT₆ and 5-HT₇ receptor. In some variations, the aminergic G protein-coupled receptor is a am, <¾A, <¾B adrenergic receptor, a serotonin 5- HT₆ and one or more of the following receptors: serotonin 5-HT₇, 5-HT₂A and 5-HT₂c and histamine Hi and H₂ receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D₂ receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D₂L receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D₂ receptor and a serotonin 5-HT₂A receptor. In some variations, the aminergic G protein-coupled receptor is a dopamine D₂L receptor and a serotonin 5-HT₂A receptor. In some variations, the aminergic G protein-coupled receptor is a histamine Hi receptor.

[0126] In one aspect, compounds are provided that do no bind to one or more of <¾- adrenergic receptors (e.g. , CCIA, OCIB and am) and a₂-adrenergic receptors (e.g. , a₂A, <¾B and a₂c)- In some embodiments, the compound is not an adrenergic receptor modulator. In any of the methods detailed herein, in one variation the individual does not have a disease or condition that involves impaired insulin secretion, or a disease or condition that is responsive to an increase in insulin secretion (e.g., type-2 diabetes, glucose intolerance, or metabolic syndrome). In another varioation, the individual does not have a disease or condition that is responsive to any one or more of: (i) a decrease in blood pressure; (ii) an increase in renal blood flow; and (iii) a decrease of sodium reabsorption. In one such variation, the individual does not have hypertension. In another varioation, the individual does not have one or more of diseases or conditions selected from hypertension, type-2 diabetes, glucose intolerance, and metabolic syndrome. General Synthetic Methods

[0127] 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 the formulae herein.

[0128] 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.

[0129] 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.

General Protocol for Chiral Preparative HPLC Separation ofRacemic Compounds

[0130] For chiral separations, samples were dissolved in MeOH and EtOH according to the solubility of sample and filtered through 0.22μ PTFE filters. The columns used were CHIRALPAK-AD; 20*250mm, 10μ and CHIRALCEL- ODH ; 20*250mm, 5μ. A flow rate of 12 mL/min -17 mL/min was used according to the resolution. Alkanes such as n-Pentane, Hexane and Heptane (40% - 95%) and alcohols such as EtOH, Isopropyl alcohol and t- Butanol (5% - 60%) were used as mobile phase. In some cases alcohol combinations i.e., (EtOH + MeOH), (EtOH + IP A), (IPA + MeOH), (t-Butanol + MeOH), (t-Butanol + EtOH) were used instead of a single alcohol. Diethyl amine (up to 0.3%) was used as modifier in the mobile phase.

Example HI: General method for the chiral HPLC separation and characterization of compounds that were synthesized initially as a mixture of enantiomers:

[0131] Crude or in some cases partially purified (normal or reverse phase HPLC) mixtures of enantiomers are analyzed by analytical chiral HPLC methods. Once adequate separation is achieved, larger quantities of the mixtures are separated using preparative scale columns.

Separation is followed by removal of solvents on a rotary evaporator to accomplish the isolation of the individual single enantiomers. In some cases where appropriate, after removal of solvent, the samples are lyophilized. After isolation, each individual enantiomer is further analyzed by analytical (reverse phase and chiral) HPLC, LCMS and NMR. When final products are converted to salts, final characterization of the compounds is carried out after conversion to the salt for each enantiomer.

[0132] Analytical Chiral HPLC of Compounds of the Invention.

Column: Chiralcel OD-H; Column ID: 4.6*250mm, 5μ. Mobile Phase:

Hexane:(EtOH:MeOH 80:20) - 93:7. Flow rate: 1 mL/min..

[0133] Chiral Preparative Data of Compounds of the Invention.

Column: Chiralcel OD-H. Column ID: 20*250mm, 5μ. Mobile Phase: Hexane:

(EtOH:MeOH 80:20) - 95:5. Flow rate: 15 mL/min.

Example H2: General method for the chiral HPLC separation and characterization of compounds that are synthesized initially as a mixture of diastereomers:

[0134] Crude or in some cases partially purified (normal or reverse phase HPLC) mixtures of diastereomers are analyzed by analytical chiral HPLC methods. Once adequate separation is achieved, larger quantities of the mixtures are separated using preparative scale columns.

Separation is followed by removal of solvents on a rotary evaporator to accomplish the isolation of the individual single diastereomers. In some cases where appropriate, after removal of solvent, the samples are lyophilized. Once each individual diastereomer is isolated they are further analyzed by analytical (reverse phase and chiral) HPLC, LCMS and

NMR. When final products are converted to salts, final characterization of the compounds is carried out after conversion to the salt for each diastereomer.

[0135] Analytical Chiral HPLC Data of Compounds of the Invention.

Column: Chiral Pak AD-H. Column ID: 4.6*250mm, 5μ. Mobile Phase: Hexane (0.2% diethylamine):Isopropanol - 93:7. Flow rate: 1 mL/min.

[0136] Chiral Preparative Data of Compounds of the Invention.

Column: Chiral PAK-AD-H. Column ID: 20*250mm, 5μ. Mobile Phase: Hexane (0.2% diethylamine):Isopropanol - 93:7. Flow rate: 15 mL/min.

Example H3: Epimerization method for studying chiral compounds in Simulated Gastric Fluid (SGF) and Stimulated Intestinal Fluid (SIF): Incubation:

[0137] A measured quantity of sample was dissolved in SGF or SIF at the concentration of 1 mg/mL in a volumetric flask and appropriate number of aliquots of this solution were transferred to incubation vials as per the given time points. For the sample of zero hour, the appropriate volume of saturated Bicarbonate solution was added immediately to the sample, and was stirred for 5-10 mins. The compound was extracted in a suitable solvent (e.g. Ethyl acetate), decanting the organic layer. The organic solvent was evaporated, and the residue was dissolved in an appropriate solvent (Methanol/Ethanol), filtered through a 0.22μιη membrane filter and analyzed by chiral HPLC. The remaining aliquots were incubated at different temperatures i.e. 25 °C and 37 °C in a water bath as per the given time points. The respective samples were retrieved from the incubator AVater bath at different time intervals as per the given time points: 90 mins, 4 h, 6 h, 12 h and 24 h, and the same procedure for sample preparation was followed for the zero hour sample.

Data compilation:

[0138] All the chromatograms were obtained at the specified wavelength, compiled and the curves between Time Vs %Area were plotted.

Results:

[0139] Compound No. 129d showed epimerization of up to 41.29% in SGF after 24h @ 25 °C, whereas Compound No. V-281a showed only 2 % epimerization under the same conditions. Running the same study at the higher temperature of 37 °C resulted in 50.13% epimerization of Compound No. 129d, and 21.39% epimerization of Compound No. V-281a.

[0140] 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); Normal(N); aqueous (aq.); methanol (MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor (Rf); room temperature (RT).

[0141] Compounds detailed herein may be prepared by those of skill in the art by referral to General Methods and Examples described in published PCT applications WO2009/055828 (see e.g., General Methods 1-24 and Examples 1-325), WO2010/127177 (General Methods 1-3 and Examples 1-58), WO2009/120720 (General Methods 1-15C and Examples 1-134), WO2009/120717 (General Methods 1-17 and Examples 1-134), WO2010/051501 (General Methods 1-10 and Examples 1-450) and WO2010/051503 (General Methods 1-15 and Examples 1-111), WO2011/019417 (General Methods 1-9 and Examples 1-10), WO2011/038164 (General Methods 1-19), WO2011/038162 (General Methods 1-21 and Examples 1-6), WO2011/038163 (General Methods 1-19 and Examples 1-49),

WO2011/038161 (General Methods 1-15B and Examples 1-22), WO2012/112966 (Examples 1-423) and WO2012/ 154261 (Examples 1-423). The PCT publications described above are incorporated herein by reference in their entireties.

[0142] Particular examples of each of the General Methods and Examples are provided in the Examples below.

General Method 1

[0143] In certain examples of formula (I) provided herein, and as similarly described in the publications presented above, alcohols of the type C can be prepared by treating

appropriately functionalized carboline A with functionalized epoxide B, in the presence of a base. A selection of bases effective for this reaction will be apparent to those skilled in the art, such as for example, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium ethoxide, sodium methoxide, and the like. In some instances, one or more of the bases may be used interchangeably; for example, other bases such as sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium ethoxide or sodium methoxide may be substituted where sodium hydride is specifically described. It is understood that modifications to the specific materials shown are intended, e.g., where Compound B can be a heteroaryl group such as pyridyl, and Compound A can comprise structures such as pyrido [3, 4-b] indoles, azepino[4,5-b]indoles, and indolizino[7,8-b]indoles, and the like.

[0144] The General Method detailed above may be adapted or combined as required by those of skill in the art to make compounds detailed herein.

[0145] The following Examples are provided to illustrate but not to limit the invention. [0146] The Examples below, where appropriate, describe the preparation of compounds bearing stereocenters. In those Examples, the procedure describes the preparation of the racemate, wherefrom individual stereoisomers can be isolated, as described above.

EXAMPLES

Example 1: Preparation of Compound Nos. V-55, V-55a and V-55b

[0147] To a suspension of l-(8-methyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2- (pyridin-3-yl)propan-2-ol (150 mg, 0.467 mmol) and potassium carbonate (198 mg, 1.42 mmol) in acetonitrile (1.5 mL) was added l,l-difluoro-2-iodo-ethane (107 mg, 0.557 mmol). The reaction mixture was allowed to stir at 80 °C for 1 h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT and diluted water (20 mL). The product was extracted with EtOAc (3x20 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by reverse phase HPLC to afford 20 mg of l-(2-(2,2- difluoroethyl)-8-methyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3- yl)propan-2-ol as the free base. Separation by chiral HPLC provides enantiomers V-55a and V-55b.

Example 2: Preparation of Compound Nos. V-94, V-94a, V-94b, V-94c and V-94d

[0148] To a solution of 7-fluoro-2,3,5,10,l l,l la-hexahydro-lH-indolizino[7,6-b]indole (100 mg, 0.4 mmol) in DMF (2 mL) was added NaH (48 mg, 1.2 mmol) at RT and the mixture was allowed to stir for 5 min. To this was added 3-(2-methyl-oxiranyl)-pyridine (98 mg, 0.6 mmol) and the reaction mixture was allowed to stir for 16 h. The reaction mixture was diluted with ice-cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was recrystallized in an ether- hexane system to obtain 90 mg of a diastereomeric mixture. Separation by chiral HPLC provided diastereomers V-94a, V-94b, V-94c and V-94d.

Example 3: Preparation of Compound Nos. V-95, V-95a and V-95b

[0149] A solution of 5-(2-(allyloxy)-2-(pyridin-4-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole (125 mg, 0.34 mmol) in MeOH (100 mL) was subjected to hydrogenation in H-cube at 60 psi pressure. Removal of solvent under reduced pressure gave crude product which was purified by reverse phase chromatography to obtain 65 mg of an enantiomeric mixture of (R) and (S)-2,8-dimethyl-5-(2-propoxy-2-(pyridin-4-yl)ethyl)- 2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole. The enantiomers were separated by chiral HPLC to afford 12 mg of (S)-2,8-dimethyl-5-(2-propoxy-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole. Separation by chiral HPLC provided enantiomers V-95a and V-95b.

Example 4: Preparation of Compound Nos. V-96, V-96a and V-96b

[0150] A solution of 5-(2-ethoxy-2-(pyridin-4-yl)vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (200 mg, 0.57 mmol) in MeOH (100 mL) was passed through H-cube (10 % Pd/C) at 60 psi pressure. MeOH was removed under reduced pressure and the crude was purified by reverse phase chromatography to obtain 60 mg of an enantiomeric mixture.

Separation by chiral HPLC provided enantiomers V-96a and V-96b.

Example 5: Preparation of Compound Nos. V-98, V-98a, V-98b, V-98c and V-98d

[0151] To a solution of 8,10-dimethyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.834 mmol) in DMF (3 mL) was added sodium hydride (167 mg, 4.17 mmol) at 0 °C. After 5 min of stirring, a solution of 3-(2-methyloxiran-2-yl)pyridine (250 mg, 1.67 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and it was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x100 mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded a crude product which was column chromatography on neutral alumina using 2-3% MeOH-DCM system as eluent to obtain 160 mg of a diastereomeric mixture. Separation by chiral HPLC provided diastereomers V-98a, V-98b, V-98c and V-98d.

Example 6: Preparation of Compound Nos. V-99, V-99a, V-99b, V-99c and V-99d

[0152] To a solution of 7-methyl-2,3,5, 10,11,1 la-hexahydro-lH-indolizino[7,6-b]indole (200 mg, 0.834 mmol) in DMF (3 mL) was added sodium hydride (106 mg, 2.654 mmol) at 0 °C. After 5 min of stirring, a solution of 2-(oxiran-2-yl)pyridine (160 mg, 1.327 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT overnight. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture to get a precipitate which was filtered to afford a diastereomeric mixture. Separation by chiral HPLC provided

diastereomers V-99a, V-99b, V-99c and V-99d.

Example 7: Preparation of Compound Nos. V-100, V-lOOa and V-lOOb

[0153] To a suspension of sodium hydride (240 mg, 6.00 mmol) in DMF (3 mL) was added 2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole (600 mg, 3 mmol) at 0 °C. After 15 min of stirring at the same temperature, to this was added a solution of 3-fluoro-5-(2- methyloxiran-2-yl)pyridine (550 mg, 3.59 mmol) in DMF (2 mL) and the reaction mixture was allowed to stir at RT for 16 h. The DMF was removed, the residue was diluted with water and the product was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by crystallization in diethyl ether to afford 350 mg of (S)-l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol- 5(2H)-yl)-2-(5-fluoropyridin-3-yl)propan-2-ol and (R)- l-(2,8-dimethyl-3,4-dihydro- 1H- pyrido[4,3-b]indol-5(2H)-yl)-2-(5-fluoropyridin-3-yl)propan-2-ol as racemate. Separation by chiral HPLC provided enantiomers V-lOOa and V-lOOb.

Example 8: Preparation of Compound Nos. V-10L V-lOla and V-lOlb

[0154] To a solution of 2-(6-bromopyridin-3-yl)-l-(2,8-dimethyl-3,4-dihydro-lH- pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol (200 mg, 0.483 mmol) in MeOH (2 mL) was added ammonium hydroxide (2 mL) and Cu(II)oxide (0.011 mg, 0.145 mmol) and the reaction mixture was heated on oil bath at 160 °C for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was concentrated and purified by preparative HPLC to afford 15 mg of 2-(6-aminopyridin-3-yl)-l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)- yl)propan-2-ol as the free base. Separation by chiral HPLC provides enantiomers V-lOla and V-lOlb.

Example 9: Preparation of Compound Nos. V-102, V-102a, V-102b, V-102c and V-102d

[0155] To a stirred solution of 2,3,5,6,7,1 lc-hexahydro-10-methyl-lH-indolizino[7, 8- b]indole (590 mg, 2.61 mmol) in dry DMF (6 mL) at 0 °C was added sodium hydride (0.26 g, 6.52 mmol, 60%) portionwise under nitrogen atmosphere. After 15 min was added solution of compound 2-fluoro-4-(2-methyloxiran-2-yl)pyridine (0.600 g, 3.91 m mol) in DMF (1 mL) drops wise at 0 °C. After complete addition, the reaction mixture stirred at RT for 1.5 h. The desired product was detected by NMR & LCMS. The reaction mixture was slowly poured into ice-cold water and extracted with EtOAc (5x75 mL). The combined organic layer was washed with water (5x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a diastereomeric mixture. Separation by chiral HPLC provided diastereomers V-102a, V-102b, V-102c and V-102d.

Example 10: Preparation of Compound Nos. V-103, V-103a and V-103b

[0156] To a solution of 5-(2-isopropoxy-2-(pyridin-4-yl)vinyl)-2,8-dimethyl-2,3,4,5- tetrahydro-lH-pyrido[4,3-b]indole (200 mg, 0.5 mmol) in MeOH (20 mL) was added 10% Pd/C and the reaction mixture was hydrogenated for 18 h. The reaction mixture was passed through a Celite bed and the filtrate was concentrated under vacuum to give crude product which was purified by reverse phase HPLC to afford 12 mg of 5-(2-isopropoxy-2-(pyridin-4- yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole. Separation by chiral HPLC provides enantiomers V-103a and V-103b.

Example 11: Preparation of Compound Nos. V-104, V-104a, V-104b, V-104c and V-104d

[0157] To a suspension of sodium hydride (69 mg, 1.7 mmol) in DMF (2 mL) was added 9- chloro-10-methyl-2,3, 5,6,7, l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.5 mmol) at 0 °C. After 5 min of stirring at the same temperature, to this was added a solution of 4- (2- methyl-oxiranyl)-pyridine (132mg, 0.9 mmol) in DMF (2 mL) and the reaction mixture was allowed to stir at RT for 18 h. The DMF was removed, the residue was diluted with water and the product was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by crystallization in diethyl ether to afford 250 mg of a diastereomeric mixture. Separation by chiral HPLC provided diastereomers V-104a, V-104b, V-104c and V-104d.

Example 12: Preparation of Compound Nos. V-105, V-105a, V-105b, V-105c and V-105d

[0158] To a suspension of sodium hydride (125 mg, 3.125 mmol) in DMF (3 mL) was added 10-fluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (240 mg, 1.043 mmol) at 0 °C. After 5 min of stirring at the same temperature, to this was added a solution of 4-(2- methyl-oxiranyl)-pyridine (225 mg, 1.66 mmol) in DMF (2 mL) and the reaction mixture was allowed to stir at RT for 5 h. The DMF was removed, the residue was diluted with water and the product was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by crystallization in diethyl ether to afford 240 mg of a diastereomeric mixture. Separation by chiral HPLC provided

diastereomers V-105a, V-105b, V-105c and V-105d.

Example 13: Preparation of Compound Nos. V-106, V-106a, V-106b, V-106c and V-106d

[0159] To a suspension of sodium hydride (90 mg, 2.2 mmol) in DMF (2.5 mL) was added 10-chloro-8-fluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.7 mmol) at 0 °C. After 5 min of stirring at the same temperature, to this was added a solution of 4-(2- methyl-oxiranyl)-pyridine (173 mg, 1.2 mmol) in DMF (2 mL) and the reaction mixture was allowed to stir at RT for 18 h. The DMF was removed, the residue was diluted with water and the product was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by crystallization in diethyl ether to afford 170 mg of a diastereomeric mixture. Separation by chiral HPLC provided diastereomers V-106a, V-106b, V-106c and V-106d.

Example 14: Preparation of Compound Nos. V-107, V-107a, V-107b, V-107c and V-107d

[0160] To a suspension of sodium hydride (90 mg, 2.2 mmol) in DMF (2.5 mL) was added 10-chloro-8-fluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.7 mmol) at 0 °C. After 5 min of stirring at the same temperature, to this was added a solution of 4-(2- methyl-oxiranyl)-pyridine (173 mg, 1.2 mmol) in DMF (2 mL) and the reaction mixture was allowed to stir at RT for 18 h. The DMF was removed, the residue was diluted with water and the product was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by crystallization in diethyl ether to afford 140 mg of a diastereomeric mixture. Separation by chiral HPLC provided diastereomers V-107a, V-107b, V-107c and V-107d.

Example 15: Preparation of Compound Nos. V-108, V-108a and V-108b

[0161] To a suspension of 5-(2-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)- l-hydroxyethyl)picolinic acid (100 mg, 0.273 mmol) and EDC.HC1 (75 mg, 0.391 mmol) DCM (5 mL) was added 2M dimethylamine solution in THF (0.3 mL). The reaction mixture was allowed to stir RT for 3 h. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (10 mL) and the product was extracted with EtOAc (3x20 mL). The combined organic layer was washed with water (3x10 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by reverse phase HPLC to afford 1 mg of 5-(2-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)-l-hydroxyethyl)-N,N-dimethylpicolinamide as the free base. Separation by chiral HPLC provides enantiomers V-108a and V-108b.

Example 16: Preparation of Compound Nos. V-109, V-109a and V-109b

[0162] To a suspension of 5-(2-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)- l-hydroxyethyl)picolinic acid (200 mg, 0.548 mmol) and EDC.HC1 (158 mg, 0.822 mmol) in DCM (5 mL) was added cyclopropyl amine (0.057 mL, 0.822 mmol). The reaction mixture was allowed to stir RT for 3 h. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (10 mL) and the product was extracted with EtOAc (3x20 mL). The combined organic layer was washed with water (3x10 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product which was purified by reverse phase HPLC to afford 8 mg of N-cyclopropyl-5-(2-(2,8- dimethyl-3,4-dihydro-lH-pyrido^ as the free base. Separation by chiral HPLC provides enantiomers V-109a and V-109b.

Example 17: Preparation of Compound Nos. V-l 10, V-l lOa and V-l lOb

[0163] To a solution of cyclopropylmethanol (52 mg, 0.726 mmol) in DMF (10 mL) was added sodium hydride (38 mg, 0.968 mmol) at RT. After 10 min of stirring was added slowly a solution of 2-(6-bromopyridin-3-yl)-l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3- b]indol-5(2H)-yl)propan-2-ol (200 mg, 0.484) in DMF (3 mL) and the reaction mixture was allowed to stir at 100 °C overnight. The progress of the reaction was monitored by NMR and LCMS. The reaction mixture was diluted with ice-cold water, the precipitate was filtered, washed with water and dried under vacuum to get crude product which was purified reverse phase HPLC to afford 2-(6-(cyclopropylmethoxy)pyridin-3-yl)-l-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol as the TFA salt. Separation by chiral HPLC provides enantiomers V-l 10a and V-l 10b.

Example 18: Preparation of Compound Nos. V-l 12, V-112a and V-112b

[0164] 2,8-Dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole (80 mg, 0.4 mmol) was charged in a reaction vessel with DMF (2 mL). To this was added NaH (48 mg, 1.2 mmol) and stirred for 5 min. Then 3-(2-methyloxiran-2-yl)quinoline (88 mg, 0.48 mmol) was added and the reaction was stirred at RT overnight. The reaction was monitored by LCMS. The reaction was quenched with ice cool water and extracted with EtOAc (4x50 mL). The organic layer was concentrated and the crude thus obtained was purified by preparative HPLC to get 13 mg of required product as the TFA salt.

Example 19: Preparation of Compound Nos. V-l 13, V-l 13a, V-l 13b, V-l 13c and V-l 13d

[0165] To a solution of 10-fluoro-2,3, 5,6,7, l lc-hexahydro-lH-indolizino[7,8-b]indole (230 mg, 1.0 mmol) in DMF (3 mL) was added sodium hydride (120 mg, 3.0 mmol) at 0 °C. After 5 min of stirring, a solution of 3-(2-methyloxiran-2-yl)pyridine (216 mg, 1.6 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (2x100 mL). The combined organic layer was washed with water (4x50 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure afforded a crude product which was purified by crystallization in EtOAc-hexane system to afford 270 mg of a diastereomeric mixture. Separation by chiral HPLC provided diastereomers V-l 13a, V-l 13b, V-l 13c and V-l 13d. Example 20: Preparation of Compound Nos. V-124, V-124a and V-124b

[0166] To a solution of 2-(6-bromopyridin-3-yl)-l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3- b]indol-5(2H)-yl)propan-2-ol(100 mg, 0.242 mmol) in ethanol (1.0 mL) was added diethylamine (1.0 mL) the reaction mixture was heated under microwave condition at 120 °C for 1 h. The progress of reaction was monitored by 1H NMR spectroscopy. The solvent was removed under reduced pressure to obtain crude product which was purified by reverse phase HPLC to afford 80 mg of l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2-(6- (dimethylamino)pyridin-3-yl)propan-2-ol as a TFA salt. Separation by chiral HPLC provided enantiomers V-124a and V-124b.

Example 21: Preparation of Compound Nos. V-205, V-205a and V-205b

[0167] To a solution of 2-(4-chloropyridin-3-yl)-l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3- b]indol-5(2H)-yl)propan-2-ol (1 g, 2.71 mmol) in DMF (50 mL) was added cesium fluoride (4.10 g, 27.1 mmol) and the reaction mixture was allowed to stir at 140 °C for 3 h. The progress of reaction mixture was monitored by LCMS. The reaction mixture was allowed to cool to RT and poured into ice-cold water (150 mL). The aqueous layer was extracted with EtOAc (3x200 mL). The combined organic layer was washed with water (5x100 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave crude product which was purified by reverse phase HPLC to afford 3 mg of l-(2,8-dimethyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluoropyridin-3-yl)propan-2-ol as a free base. Separation by chiral HPLC provides enantiomers V-205a and V-205b.

Example 22: Preparation of Compound No. V-209

[0168] To a solution of 2- (2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-l- (pyridin-3-yl)ethyl methanesulfonate (0.5 g, 1.25 mmol) in DMSO (5 mL) was added sodium methanesulfinate (1.02 g, 10 mmol) and the reaction mixture was allowed to stir at 80 °C for 24 h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was washed with water (6x50 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product (400 mg ) that was purified by reverse phase HPLC to afford 40 mg of pure 2,8-dimethyl-5- (2- (5- (methylsulfonyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole as a solid.

Example 23: Preparation of Compound Nos. V-212, V-212a, V-212b, V-212c and V-212d

[0169] To a solution of 7-methyl-2,3,5, 10,11,1 la-hexahydro-lH-indolizino[7,6-b]indole (200 mg, 0.877 mmol) in DMF (5 mL) was added NaH (105 mg, 2.631 mmol) at RT and the mixture was allowed to stir for 5 min. To this was added 4-(2-methyloxiran-2-yl)pyridine (153 mg, 1.140 mmol) and the reaction mixture was allowed to stir overnight. The reaction was quenched and diluted with water and the solid mass thus obtained was filtered to get 176 mg of a mixture of stereoisomers.

Example 24: Preparation of Compound Nos. V-213, V-213a, V-213b, V-213c and V-213d

[0170] To a solution of 7-methyl-2,3,5,10,l l,l la-hexahydro-lH-indolizino[7,6-b]indole (200 mg, 0.877 mmol) in DMF (5 mL) was added NaH (105 mg, 2.631 mmol) at RT and the mixture was allowed to stir for 5 min. To this was added 3-(2-methyloxiran-2-yl)pyridine (153 mg, 1.140 mmol) and the reaction mixture was allowed to stir overnight. The reaction was quenched and diluted with water and the solid mass thus obtained was filtered to get 176 mg of a mixture of stereoisomers. Separation by chiral HPLC provided diastereomers V- 213a, V-213b, V-213c and V-213d.

Example 25: Preparation of Compound Nos. V-220, V-220a, V-220b, V-220c and V-220d

[0171] To a stirred solution of Beta carboline (50 mg, 0.20 mmol) in dry DMF (2 mL) at 25 °C was added sodium hydride (5.53 g, 0.138 mol 60 %) portionwise under nitrogen atmosphere. After 5 min. was added a solution of 4-(2-methyloxiran-2-yl)pyridine (56 mg, 0.41 mmol) in DMF (0.5 mL) drops wise at 25 °C. After complete addition, the reaction mixture was stirred at 25 °C overnight. The reaction mixture was slowly poured in ice-cold water and extracted with EtOAc, organic layer washed with water (5 times). The organic layer dried over anhydrous sodium sulfate, concentrated under vacuum to obtain a crude product, which was purified by reverse phase HPLC to obtain the desired product as the TFA salt. The mixture was separated by chiral HPLC to afford 5 mg of desired product.

Example 26: Preparation of Compound Nos. V-22L V-221a and V-221b

[0172] To a solution of 2,3,5,6,7, l lc-hexahydro-lH-indolizino[7,8-b]indole (400 mg, 1.88 mmol) in 60 % aq. NaOH (5 mL) was added 3-vinyl pyridine (396 mg, 3.77 mmol) and tetrabutyl ammonium bromide (607 mg, 1.88 mmol). The reaction mixture was allowed to stir at 100 °C for 18 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x100 mL). The combined organic layer was washed with water (4x50 mL) and dried over sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 60 mg of 2,3,5,6,7,1 lc-hexahydro-7- (2- (pyridin-3-yl)ethyl)-lH- indolizino[7,8-b]indole. The stereoisomers were separated by chiral HPLC.

Example 27: Preparation of Compound Nos. V-222, V-222a and V-222b

[0173] To a solution of (E)-4- (2- (2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5 (2H)- yl)-l- (pyridin-4-yl)ethoxy)but-2-enoic acid (0.5 g, 1.7 mmol) in water (20 mL) was added Pd/C (0.2 g). Hydrogen gas was purged to the reaction mixture for 30 min. The progress of reaction was monitored by LCMS. The reaction mixture was filtered through a Celite bed and washed with water (10 mL). The filtrate was concentrated under reduced pressure to yield a crude product that was purified by reverse phase HPLC to afford 18 mg of 4- (2- (2,8- dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5 (2H)-yl)- 1 - (pyridin-4-yl)ethoxy)butanoic acid.

Example 28: Preparation of Compound Nos. V-223, V-223a and V-223b

[0174] To a solution of 2-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-l- (pyridin-4-yl)ethanol (500 mg, 1.5 mmol) in DMF (5 mL) at 0 °C was added sodium hydride (300 mg, 5.5 mmol) portionwise. After 5 min. of stirring, to this was added

bromocyclopentane (680 mg, 4.6 mmol) at the same temperature and the reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc (2x100 mL). The combined organic layer was washed with water (3x50 mL) and dried over sodium sulfate. Removal of water under reduced pressure gave crude product that was purified by column chromatography on silica gel (100-200 mesh) using 10% MeOH-DCM system as eluent to obtain 100 mg of 5-(2-(cyclopentyloxy)-2- (pyridin-4-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole as racemic mixture. The enantiomers were separated by chiral HPLC to afford 40 mg of (S)-5-(2- (cyclopentyloxy)-2-(pyridin-4-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- b]indole.

Example 29: Preparation of Compound Nos. V-224, V-224a and V-224b

[0175] To a solution of 2- (2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-l- (pyridin-4-yl)ethanol (200 mg, 0.62 mmol) in DMF (2 mL) was added NaH (60% dispersion in mineral oil, 74 mg, 1.8 mmol) at RT and the mixture was allowed to stir for 10 min. To this mixture was then added pyrrolidine- 1-carbonyl chloride (165 mg, 1.2 mmol) and the reaction mixture was allowed to stir for 1 h. The progress of the reaction was monitored by LCMS. The reaction was quenched with ice cooled water (200 mL). The aqueous layer was extracted with EtOAc (2x200 mL). The combined organic layer was washed with water (3x100 mL), dried over sodium sulfate and concentrated to get the crude product that was purified by column chromatography on silica gel (100-200 mesh) using 0-10% MeOH-DCM system as eluent to afford 43 mg of 2- (2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-l- (pyridin-4-yl)ethyl pyrrolidine- 1-carboxylate as a free base. Example 30: Preparation of Compound Nos. V-225, V-225a and V-225b

[0176] To a solution of 2- (2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-l- (pyridin-4-yl)ethanol (200 mg, 0.62 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil) (74.4mg, 1.86 mmol) at RT. The reaction mixture was stirred at the same temperature for 10 min. then 4-methylpiperazine-l-carbonyl chloride (162 mg, 1.2 mmol) was added and the reaction mixture further stirred for 1 h. The progress of the reaction was monitored by TLC and LCMS. The reaction was quenched with cold water (200 mL). The aqueous layer was extracted with EtOAc (3x200 mL). The combined organic layer was washed with water (3x100 mL), dried over sodium sulfate and concentrated to get the crude product which was purified by reverse phase HPLC to afford 44 mg of 2- (2,8-dimethyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-l- (pyridin-4-yl)ethyl 4-methylpiperazine-l- carboxylate as a free base.

Example 31: Preparation of Compound Nos. V-226, V-226a, V-226b, V-226c and V-226d

[0177] To a stirred solution of 10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8- b]indole (250 mg, 1.106 mmol) in dry DMF (7 mL) at 0 °C was added NaH (110 mg, 2.765 mmol) portionwise. After 5 min. of stirring, a solution of 2-fluoro-5- (2-methyloxiran-2-yl) pyridine (304 mg, 1.99 mmol) in DMF (3 mL) was added dropwise. The reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with ice water and extracted with EtOAc (2x150 mL). The combined organic layer was washed with water (5x40 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to obtain 200 mg of 2-(6- fluoropyridin-3-yl)-l-(10-methyl-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7 (l lcH)- yl)propan-2-ol.

Example 32: Preparation of Compound Nos. V-227, V-227a and V-227b

[0178] To a solution of 2- (10-methyl-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7 (l lcH)-yl)-l- (pyridin-4-yl)ethyl methanesulfonate (1.0 g, 2.88 mmol) in NMP (20 mL) was added KOH powder (806 mg, 14.3 mmol) at 0 °C. The reaction mixture was stirred for 15 min. at 0 °C then at RT for 90 min. The progress of reaction was monitored with LCMS. The reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (3x100 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by reverse phase HPLC to obtain 150 mg of (E)-10-methyl-7- (2- (pyridin-4- yl)vinyl)-2,3, 5,6,7, l lc-hexahydro-lH-indolizino[7,8-b]indole as a solid. Example 33: Preparation of Compound Nos. V-229, V-229a, V-229b, V-229c and V-229d

[0179] To a stirred solution of beta-BOC-carboline (50 mg, 0.20 mmol) in dry DMF (2 mL) at 25 °C was added sodium hydride (5.53 g, 0.138 mol 60%) portionwise under nitrogen atmosphere. After 5 min., to this was added a solution of 4-(oxiran-2-yl)pyridine (56 mg, 0.619 mmol) in DMF (0.5 mL) dropwise at 25 °C. After complete addition, the reaction mixture was stirred at 25 °C overnight. The desired product was detected by LCMS. The reaction mixture was slowly poured into ice-cold water and extracted with EtOAc, organic layer washed with water (5 times). The organic layer was dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product that was used in the next step without any purification. The crude BOC compound was dissolved in 2M HC1 solution (20 mL) and stirred at RT overnight. The reaction mixture was concentrated under vacuum to obtain crude product that purified by reverse phase HPLC to obtain 20 mg of mixture of desired products. The optical isomers were separated by chiral HPLC to obtain 5 mg of desired product.

Example 34: Preparation of Compound Nos. V-230, V-230a and V-230b

[0180] To a solution of 2- (2,8-dimethyl-l,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-l- pyridin-4-yl-ethanol (321 mg, 1.00 mmol) in THF (3 mL) was added dropwise trichloroacetyl isocyanate (375 mg, 2 mmol) at RT. The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was basified with 10% potassium carbonate solution and extracted with EtOAc (3x50 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 70 mg of 2- (2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol- 5 (2H)-yl)-l- (pyridin-4-yl)ethyl carbamate.

Example 35: Preparation of Compound Nos. V-23L V-231a and V-231b

[0181] To a solution of 2- (2,8-dimethyl-l,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-l- pyridin-4-yl-ethanol (2.0 g, 6.23 mmol) in DMSO (20 mL) was added methanesulfonic acid 2,2-dimethyl-propyl ester (2.01 g, 12.40 mmol) and potassium tertiary butoxide (2.09 g,18.66 mmol) at RT. The reaction mixture was heated at 120 °C for 24 h. The progress of reaction was monitored by LCMS. The reaction mixture was poured in to ice-cold water and extracted with EtOAc (3x100 mL). The combined organic layer was dried over sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to obtain 2- (2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5 (2H)- yl)-4,4-dimethyl-l- (pyridin-4-yl)pentan-l-one as TFA salt. Example 36: Preparation of Compound Nos. V-233, V-233a, V-233b, V-233c and V-233d

[0182] To a solution of 8-aza-2,3,5, 6,7,1 lc-hexahydro-lH-indolizino[7,8-b]indole (180 mg, 0.52 mmol) in DCM (5 mL) was added a solution of Diethylaminosulfur trifluoride (166 mg, 1.03 mmol) in DCM (1 mL) dropwise at -78 °C. The reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (2x100 mL). The combined organic layer was dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by reverse phase HPLC to afford 6 mg of 7- (2-fluoro-2- (6-methylpyridin-3-yl)ethyl)-8-aza-2,3,5,6,7,l lc- hexahydro- 1 H-indolizino [7,8 -b] indole .

Example 37: Preparation of Compound Nos. V-234, V-234a and V-234b

[0183] To a suspension of 1- (8-methyl-l,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2- pyridin-3-yl-propan-2-ol (750 mg, 2.33mmol) and potassium carbonate (967 mg, 7.0 mmol) in acetonitrile (10 mL) was added ethyl chloroformate (3.5 mg, 0.79 mmol) at RT and the reaction mixture was stirred for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was filtered, the filtrate was concentrated, and the residue obtained was diluted with water and extracted with EtOAc (3x50 mL). The combined organic layer was dried over sodium sulfate. Removal of solvent gave a crude product that was purified by column chromatography on silica gel (100-200 mesh) using 4% MeOH-DCM as eluent to obtain 600 mg of 5- (2-hydroxy- 2-pyridin-3-yl- propyl)-8-methyl- 1,3,4,5- tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester.

Example 38: Preparation of Compound Nos. V-236, V-236a and V-236b

[0184] A solution of methanesulfonic acid 2- (2-methyl-l,2,3,4-tetrahydro-pyrido[4,3- b]indol-5-yl)-l-pyridin-3-yl-ethylester (0.2 g, 0.519 mmol) in tertiary butyl amine (2 mL) was stirred at 100 °C for 18 h. The reaction was monitored by LCMS. After completion of reaction mixture it was concentrated to give crude product which was purified by reverse phase HPLC to obtain 5 mg of 2-methyl-N- (2- (2-methyl-3,4-dihydro-lH-pyrido[4,3- b]indol-5 (2H)-yl)-l- (pyridin-3-yl)ethyl)propan-2-amine.

Example 39: Preparation of Compound Nos. V-238, V-238a, V-238b, V-238c and V-238d

[0185] To a solution of 10-methyl-2,3, 5,6,7, l lc-hexahydro-lH-indolizino[7,8-b]indole (500 mg, 2.21 mmol) in DMF (5 mL) was added sodium hydride (159 mg, 6.63 mmol) at 0 °C. After 5 min. of stirring, a solution of 4- (2-methyl-oxiranyl) pyridine (590 mg, 4.37mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction ice-cold water was added to the reaction mixture and it was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x100 mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded a crude product which was recrystallized in ether-hexane to obtain 360 mg of 1- (lO-methyl-2,3,5,6- tetrahydro-lH-indolizino[7,8-b]indol-7 (l lcH)-yl)-2- (pyridin-4-yl)propan-2-ol. The optical isomers were separated by chiral HPLC.

Example 40: Preparation of Compound Nos. V-239, V-239a, V-239b, V-239c and V-239d

[0186] To a solution of 10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (400 mg, 1.76 mmol) in DMF (5ml) was added sodium hydride (212 mg, 5.3 mmol) portionwise at RT. After 10 min. of stirring, 3-fluoro-4- (oxiran-2-yl)pyridine (320 mg, 2.30 mmol) was added dropwise. The reaction mixture was stirred at RT for 12 h. The progress of reaction was monitored by TLC and LCMS. The reaction was quenched with Ice-cold water and the product was extracted with EtOAc (3x200 mL). The combined organic layer was washed with water (4x150 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 400 mg of 1- (3-fluoropyridin-4-yl)-2- (10-methyl-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7 (l lcH)-yl)ethanol as a freebase.

Example 41: Preparation of Compound Nos. V-240, V-240a, V-240b, V-240c and V-240d

[0187] To a solution of a mixture of (2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol- l-yl)methanol and (2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indol-3-yl)methanol (500 mg, 2.17 mmol) in DMF (6 mL) was added sodium hydride (260 mg, 6.51 mmol) portionwise at 0 °C. After stirring for 15 min. at 0 °C, a solution of 3- (2-methyloxiran-2-yl) pyridine (439 mg, 3.25 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was poured on crushed ice-cold water (50 mL). The product was extracted with EtOAc (2x70 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude mixture of regioisomers that were separated by reverse phase HPLC. These regioisomers were subjected to chiral HPLC to afford 20 mg of 1- (3- (hydroxymethyl)-2,8-dimethyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-2- (pyridin-3-yl)propan-2-ol.

Example 42: Preparation of Compound Nos. V-241, V-241a, V-241b, V-241c and V-241d

[0188] To a solution of a mixture of (2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol- l-yl)methanol and (2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indol-3-yl)methanol (500 mg, 2.17 mmol) in DMF (6 mL) was added sodium hydride (260 mg, 6.51 mmol) portionwise at 0 °C. After stirring for 15 min. at 0 °C, a solution of 3- (2-methyloxiran-2-yl) pyridine (439 mg, 3.25 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was poured on crushed ice-cold water (50 mL). The product was extracted with EtOAc (2x70 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude mixture of regioisomers that were separated by reverse phase HPLC. These regioisomers were subjected to chiral HPLC to afford 30 mg of 1- (1- (hydroxymethyl)-2,8-dimethyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-2- (pyridin-3-yl)propan-2-ol.

Example 43: Preparation of Compound Nos. V-242, V-242a and V-242b

[0189] To a suspension of NaH (283 mg, 11.8 mmol, 60% dispersion in mineral oil) in DMF (15 mL) was added 6,9-dichloro-2-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole (1 g, 3.9 mmol) slowly at 0 C and the mixture was allowed stir for 30 min. Then, a solution of 3- (oxiran-2-yl)pyridine (952 mg, 7.8 mmol) in DMF (1 mL) was added at 0 C. The ice bath was removed and the reaction mixture was allowed to stir at RT for 20 h. The reaction mixture was poured into ice-cold water (150 mL) and the product was extracted with DCM (2x40 mL). The combined organic layer was washed with water (8x30 mL) and dried over anhydrous sodium sulfate. Removal of DCM under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 140 mg of 2-(6,9-dichloro-2-methyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5 (2H)-yl)-l-(pyridin-3-yl)ethanol.

Example 44: Preparation of Compound Nos. V-243, V-243a, V-243b, V-243c and V-243d

[0190] To a solution of 10-fluoro-2,3, 5,6,7, l lc-hexahydro-lH-indolizino[7,8-b]indole (250 mg, 1.08 mmol) in DMF (5 mL) was added sodium hydride (129 mg, 3.2 mmol) at 0 °C. After 5 min. of stirring, 4-oxiranyl pyridine (210 mg, 1.7 mmol) was added and the reaction mixture was allowed to stir at RT for 3 h. The reaction mixture was poured in to ice-cold water and extracted with EtOAc (3x100 mL). The combined organic layer was washed with water (3x25ml) and dried over sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to obtain 47 mg of 2- (10- fluoro-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7 (l lcH)-yl)-l-(pyridin-4-yl)ethanol.

Example 45: Preparation of Compound Nos. V-244. V-244a. V-244b. V-244c and V-244d

[0191] To a suspension of NaH (500 mg, 20.8 mmol, 60% dispersion in mineral oil) in DMF (20 mL) was added 8,10-dimethyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (1 g, 4.0 mmol) slowly at 0 C and the mixture was allowed stir for 30 min. Then, a solution of 4- (2-methyloxiran-2-yl)pyridine (1.1 g, 90 mmol) in DMF (1 mL) was added at 0 C. The ice bath was removed and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was poured into ice-cold water (150 mL) and the product was extracted with EtOAc (2x40). The combined organic layer was washed with water (8x30 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was washed with hexane (2x30 mL) followed by ether. The solid was filtered to afford 200 mg of l-(8,10-dimethyl-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7-(l lcH)-yl)-2- (pyridin-4-yl)propan-2-ol as off white solid.

Example 46: Preparation of Compound Nos. V-245, V-245a and V-245b

[0192] To a suspension of NaH (327 mg, 13.6 mmol, 60% dispersion in mineral oil) in DMF (12 mL) was added 6-chloro-2-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole (1 g, 4.5 mmol) slowly at 0 C and the mixture was allowed stir for 30 min. Then, a solution of 3- (oxiran-2-yl)pyridine (1.1 g, 90 mmol) in DMF (1 mL) was added at 0 C. The ice bath was removed and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was poured into ice-cold water (150 mL) and the product was extracted with EtOAc (2x40 mL). The combined organic layer was washed with water (8x30 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 550 mg of 2-(6-chloro-2-methyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5-(2H)-yl)-l-(pyridin-3-yl)ethanol.

Example 47: Preparation of Compound Nos. V-246, V-246a and V-246b

[0193] To a solution of 5-(l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2- hydroxypropan-2-yl)picolinic acid (100 mg, 2.638 mmol) in DCM (5 mL) was added

EDC.HC1 (60 mg, 3.166 mmol) and 1-cyclopropyl-N-methylmethanamine (33 mg, 3.9577 mmol) at RT. The reaction mixture was allowed to stir at RT for 3 h. The DCM was removed under reduced pressure to obtain crude product that was purified by reverse phase HPLC to afford 16 mg of N-(cyclopropylmethyl)-5-(l-(2,8-dimethyl-3,4-dihydro-lH- pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)-N-methylpicolinamide as a TFA salt.

Example 48: Preparation of Compound Nos. V-247, V-247a, V-247b, V-247c and V-247d

[0194] To a solution of 9-chloro-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8- b]indole (200 mg, 0.76 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol) at 0 °C. After 5 min. of stirring, 4-oxiranyl-pyridine (186 mg, 1.53 mmol) was added and the reaction mixture was allowed to stir at RT for 5 h. The reaction mixture was poured in to ice- cold water and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to obtain 60 mg of 2-(8-chloro-9-methyl-l,2,3,4,5,10c-hexahydro-3a,6-diaza- cyclopenta[c]fluoren-6-yl)-l-pyridin-4-yl-ethanol. Example 49: Preparation of Compound Nos. V-248, V-248a, V-248b, V-248c and V-248d

[0195] To a solution of 10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (100 mg, 0.442 mmol) in DMF (1 mL) was added NaH (53 mg, 1.325 mmol) portionwise at 0 °C. After 5 min. of stirring, a solution of 4-4-(oxiran-2-yl)pyridine-l -oxide (121 mg, 0.883 mmol) in DMF (1 mL) was added dropwise at the same temperature. The reaction mixture was brought to RT and allowed to stir for 18 h. The reaction mixture was diluted with ice- cold water and concentrated and purified by reverse phase HPLC obtained 40 mg of 4- (1- hydroxy-2- (10-methyl-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7 (1 lcH)- yl)ethyl)pyridine 1 -oxide.

Example 50: Preparation of Compound Nos. V-249, V-249a, V-249b, V-249c and V-249d

[0196] To a solution of 2- (10-methyl-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7 (l lcH)-yl)-l- (pyridin-4-yl)ethanol (150 mg, 0.43 mmol) in dichloromethane (10 mL) was added meta-chloroperbenzoic acid (75 mg, 0.43 mmol) and the resulting mixture was allowed to stir 30 min. The progress of reaction was monitored by LCMS. To the reaction mixture was added a saturated sodium bicarbonate solution (10 mL) was added and the product was extracted with DCM (2x25 mL). The combined organic layer was dried over sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 100 mg of 7-(2-hydroxy-2-(pyridin-4-yl)ethyl)-10-methyl- 1,2,3,4,5,6,7,1 lc-octahydroindolizino[7,8-b]indole 4-oxide compound.

Example 51: Preparation of Compound Nos. V-250, V-250a, V-250b, V-250c and V-250d

[0197] A solution of 2- (3-{ [ (2,2-dimethoxy-ethyl)-methyl-amino] -methyl } -5-methyl-indol- l-yl)-l-pyridin-3-yl-ethanol (1.0 g, 2.61 mmol) in 6N HC1 (26ml) at 0 °C was stirred for 2 h. Then reaction mixture was brought to RT and the reaction mixture was allowed to stir for another 18 h. The progress of reaction was monitored by TLC. The reaction mixture was poured in to ice-cold water, basified with aq. ammonia and extracted with EtOAc (4x50 mL). The combined organic layer was dried over sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 5- (2-Hydroxy-2-pyridin-3-yl-ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-4- ol.

Example 52: Preparation of Compound Nos. V-25L V-251a and V-251b

[0198] To a 500 mL three-neck round bottle flask was added l-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol (10.0 g, 29.8 mmol) in DCM (120 mL) at RT. Triethylamine (6.34 mL, 45.4 mmol) was charged to the mixture, followed by addition of 4-dimethylaminopyridine (0.87 g, 7.1 mmol). After 10 min, propionic anhydride (7.11 mL, 55.5 mmol) was added in one portion. The mixture was stirred at RT for 36 h. The reaction was diluted with sat. sodium bicarbonate (150 mL) to adjust the pH to 9-10. The mixture was extracted with DCM (3x50 mL). The combined organic layers were washed with brine (2x100 mL). The organic layers were dried over anhydrous sodium sulfate. After evaporation, the mixture was purified on the silica gel column (DCM-MeOH- triethylamine, 95:5:0.2, v/v/v). The compound was dried under vacuum for 16h to afford 4.75 g (41% yield) of a light yellow solid.

Example 53: Preparation of Compound Nos. V-252, V-252a and V-252b

[0199] To a 500 mL three-neck round bottle flask was added l-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol (10.0 g, 29.8 mmol) in DCM (120 mL) at RT. Triethylamine (6.34 mL, 45.4 mmol) was charged to the mixture, followed by addition of 4-dimethylaminopyridine (0.87 g, 7.1 mmol). After 10 min, benzoic anhydride (12.54 g, 55.5 mmol) was added in one portion. The mixture was stirred at RT for 36h. The reaction was diluted with sat. sodium bicarbonate (150 mL) to adjust the pH to 9-10. The mixture was extracted with DCM (3x50 mL). The combined organic layers were washed with brine (2x100 mL). The organic layers were dried over anhydrous sodium sulfate. After evaporation, the mixture was purified on the silica gel column (DCM-MeOH-triehtylamine, 95:5:0.2, v/v/v). The compound was dried under vacuum for 16h to afford 3.20 g of a light yellow solid.

Example 54: Preparation of Compound Nos. V-253, V-253a, V-253b, V-253c and V-253d

[0200] To a solution of (R)-7-methyl-2,3,5, 10,11,1 la-hexahydro-lH-indolizino[7,6-b]indole (150 mg, 0.663 mmol) in DMF (10 mL) at 0 °C was added sodium hydride (79 mg, 1.989 mmol). After 5 min. of stirring, 3-(oxiran-2-yl)pyridine (96 mg, 0.796 mmol) was added and the reaction was allowed to stir at RT for 12 h. The reaction was quenched with ice-cold water and extracted with EtOAc (2x50 mL). The organic layer was washed with water (4x20 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product that was purified by reverse phase HPLC to afford 123 mg of 2-(R)-7- methyl-2,3-dihydro-lH-indolizino[7,6-b]indol-10(5H,l lH,l laH)-yl)-l-(pyridin-3-yl)ethanol as the TFA salt.

Example 55: Preparation of Compound Nos. V-254, V-254a and V-254b

[0201] To a solution of 4-(l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2- hydroxypropan-2-yl)benzoic acid (100 mg, 0.263 mmol) in DCM (20 mL) at RT was added EDC.HC1 (60 mg, 0.316 mmol). After 5 minute of stirring, was added a solution pyrrolidine (28 mg, 0.394 mmol) in DCM (1 mL) and the reaction mixture was allowed to stir at RT for 18 h. The reaction mixture was diluted with saturated solution of NaHC0₃ (50 mL) and extracted with DCM (2x100 mL). The organic layer was dried over sodium sulfate concentrated under vacuum to obtain crude product that was purified by column

chromatography on silica gel (100-200 mesh) using MeOH-DCM (0-50%) system as eluent to afford 30 mg of (4-(l-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2- hydroxypropan-2-yl)phenyl) (pyrrolidin- 1 -yl)methanone.

Example 56: Preparation of Compound Nos. V-257, V-257, V-257b, V-257c and V-257d

[0202] To a solution of ethyl 7-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2,3, 5,6,7, l lc-hexahydro- lH-indolizino[7,8-b]indole-10-carboxylate (200 mg, 0.49 mmol) in dry THF (8 mL) was added lithium aluminum hydride (56 mg,1.4 mmol) at RT under nitrogen and the reaction mixture was allowed to stir for 1 h. The reaction was quenched with ice at -78 °C and the product was extracted with EtOAc (3x20 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 140 mg of 2-(10- (hydroxymethyl)-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7(l lcH)-yl)-l-(pyridin-4- yl)ethanol.

Example 57: Preparation of Compound Nos. V-258, V-258a and V-258b

[0203] To a solution of 4,4-difluoro-2,3,4,5-tetrahydro-2,7-dimethyl-lH-pyrido[4,3-b]indole (10 mg, 0.0423 mmol) in DMF (2 mL) was added NaH (4 mg, 0.0847 mmol) at 0 °C. After 5 min. of stirring, 3-(oxiran-2-yl)pyridine (10 mg, 0.0847 mmol) in DMF (1 mL) was added dropwise and the reaction mixture was stirred at RT overnight. The reaction was monitored by LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice and the aqueous layer was extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product that was purified by preparative HPLC to afford 1.6 mg of 2-(4,4-difluoro-2,8-dimethyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-l-(pyridin-3-yl)ethanol.

Example 58: Preparation of Compound Nos. V-260, V-260a, V-260b, V-260c and V-260d

[0204] To a solution of (R)-10-fluoro-2,3, 5,6,7, l lc-hexahydro-lH-indolizino[7,8-b]indole (240mg, 1.043 mmol) in DMF (3 mL) at 0 °C was added sodium hydride(125 mg, 3.125 mmol). After 5 min. of stirring, to this was added a solution of 4-(2-methyl-oxiranyl)pyridine (225 mg, 1.66 mmol) in DMF (1 mL) and the reaction mixture was allowed to stir at RT for 5 h. The reaction mixture was poured into ice-cold water and extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (5x20 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gave crude product that was

recrystallized from ether-hexane to obtain 120 mg of diastereomeric mixture of l-(9-Fluoro- 1, 2,3,4,5, 10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-pyridin-4-yl-propan-2-ol. The mixture was subjected to chiral separation to afford 50 mg of (R)-l-((R)-10-fluoro- 2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7(l lcH)-yl)-2-(pyridin-4-yl)propan-2-ol.

Example 59: Preparation of Compound Nos. V-26 V-261a and V-261b

[0205] To a solution of 2-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-l- (pyridin-4-yl)ethanol (500 mg, 1.5 mmol) in DMF (4 mL) was added sodium hydride (180 mg, 4.5 mmol) at 0 °C. After 20 min of stirring, a solution of bromomethyl-cyclobutane (1.16 g, 7.7 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 2 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (3x100 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded a crude product that was purified by reverse phase HPLC to afford 280 mg of racemic mixture of (S)-5-(2-(cyclobutylmethoxy)-2-(pyridin-4-yl)ethyl)-2,8-dimethyl- 2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole and (R)-5-(2-(cyclobutylmethoxy)-2-(pyridin-4- yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole. Separation by chiral HPLC provided enantiomers V-261a, and V-261b.

Example 60: Preparation of Compound Nos. V-262, V-262a and V-262b

[0206] To a solution of 2-(2-methyl-8-(trifluoromethyl)-3,4-dihydro-lH-pyrido[4,3-b]indol- 5(2H)-yl)-l-(pyridin-4-yl)ethanol (400 mg, 1.06 mmol) in DMF (3 mL) was added sodium hydride (127 mg, 5.3 mmol) at 0 °C. After 20 min of stirring, a solution of

bromocyclopentane (790 mg, 5.3 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 5 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and extracted with EtOAc (3x100 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded a crude products that were purified by reverse phase HPLC to afford 30 mg of racemic mixture of (S)-5-(2-(cyclopentyloxy)-2-(pyridin-4-yl)ethyl)-2- methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole and (R)-5-(2- (cyclopentyloxy)-2-(pyridin-4-yl)ethyl)-2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole. Separation by chiral HPLC provided enantiomers V-262a and V-262b.

Example 61: Preparation of Compound Nos. V-263, V-263a, V-263b, V-263c and V-263d

[0207] To a solution of 9-fluoro-7-methyl-2,3,5, 10,11,1 la-hexahydro-lH-indolizino[7,6- b]indole (150 mg, 0.614 mmol) in DMF (2 mL) was added sodium hydride (73 mg, 1.82 mmol) at 0 °C. After 20 min of stirring, 3-(2-methyloxiran-2-yl)pyridine (165 mg, 1.22 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (6x10 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 20 mg of l-(9-fluoro-7- methyl-2,3-dihydro-lH-indolizino[7,6-b]indol-10(5H,l lH,l laH)-yl)-2-(pyridin-3-yl)propan- 2-ol. Separation by chiral HPLC provided diastereomers V-263a, V-263b, V-263c and V- 263d.

Example 62: Preparation of Compound Nos. V-264, V-264a, V-264b, V-264c and V-264d

[0208] To a solution of 9-fluoro-7-methyl-2,3,5, 10,11,1 la-hexahydro-lH-indolizino[7,6- b]indole (150 mg, 0.614 mmol) in DMF (2 mL) was added sodium hydride (73 mg, 1.82 mmol) at 0 °C. After 20 min of stirring, 4-(2-methyloxiran-2-yl)pyridine (165 mg, 1.22 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (6x10 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 20 mg of l-(9-fluoro-7- methyl-2,3-dihydro-lH-indolizino[7,6-b]indol-10(5H,HH,l laH)-yl)-2-(pyridin-4-yl)propan- 2-ol. Separation by chiral HPLC provided diastereomers V-264a, V-264b, V-264c and V- 264d.

Example 63: Preparation of Compound Nos. V-265, V-265a, V-265b, V-265c and V-265d

[0209] To a solution of 7-chloro-9-fluoro-2,3,5, 10,11,1 la-hexahydro-lH-indolizino[7,6- b]indole (150 mg, 0.56 mmol) in DMF (2 mL) was added sodium hydride (68 mg, 1.7 mmol) at 0 °C. After 5 min of stirring, 3-(2-methyloxiran-2-yl)pyridine (130 mg, 0.96 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (4x30 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude that was purified by reverse phase HPLC to afford 25 mg of l-(7-chloro-9-fluoro-2,3-dihydro-lH- indolizino[7,6-b]indol-10(5H,l 1H,1 laH)-yl)-2-(pyridin-3-yl)propan-2-ol. Separation by chiral HPLC provided diastereomers V-265a, V-265b, V-265c and V-265d.

Example 64: Preparation of Compound Nos. V-266, V-266a, V-266b, V-266c and V-266d

[0210] To a solution of 10-(trifluoromethyl)-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8- b]indole (150 mg, 0.53 mmol) in DMF (2 mL) was added sodium hydride (68 mg, 1.7 mmol) at 0 °C. After 5 min of stirring, 3-(2-methyloxiran-2-yl)pyridine (122 mg, 0.9 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (4x30 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 200 mg of compound V-266. Separation by chiral HPLC provided diastereomers V-266a, V-266b, V-266c and V-266d.

Example 65: Preparation of Compound Nos. V-277, V-277a, V-277b, V-277c and V-277d

[0211] (l lcS)-10-Fluoro-8-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.614 mmol) was dissolved in DMF (2 mL) and sodium hydride (73 mg, 1.82 mmol) was added at 0 °C and stirred for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (165 mg, 1.22 mmol) was dissolved in DMF (1 mL) and added dropwise into the reaction mixture. The reaction mixture was allowed to come to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (4x10 mL) and dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by reverse phase chromatography to obtain 1-[(1 lcS)-10-fluoro-8- methyl- 1,2,3,5, 6, l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(3-pyridyl)propan-2-ol (Cpd. No. 75) (34 mg). The mixture was separated by chiral chromatography to obtain (2S)-1- [(l lcS)-10-fluoro-8-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(3- pyridyl)propan-2-ol (14 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 66: Preparation of Compound Nos. V-278, V-278a, V-278b, V-278c and V-278d

[0212] (1 laR)-7-Fluoro-9-methyl-2,3,5,10,l 1,1 la-hexahydro-lH-indolizino[7,6-b]indole (150 mg, 0.614 mmol) was dissolved in DMF (3 mL) and sodium hydride (73 mg, 1.82 mmol) was added at 0 °C and stirred for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (165 mg, 1.22 mmol) was dissolved in 1 mL DMF and added dropwise into the reaction mixture, which was allowed to come to RT and was stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (4x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain (2R)-l-[(l laR)-7-fluoro-9-methyl-l,2,3,5, 11,11a- hexahydroindolizino[7,6-b]indol-10-yl]-2-(3-pyridyl)propan-2-ol (30 mg). Other

diastereomers can be prepared by using appropriate chiral starting materials.

Example 67: Preparation of Compound Nos. V-279, V-279a, V-279b, V-279c and V-279d

[0213] (1 lcS)-10-Fluoro-8-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.614 mmol)was dissolved in DMF (3 mL) and sodium hydride(73 mg , 1.82 mmol) was added at 0 °C and stirred for 5 min. 4-(2-Methyl-oxiranyl)-pyridine (165 mg, 1.22 mmol) was dissolved in 1 mL DMF and added dropwise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water(4xl0 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain l-[(l lcS)-10-fluoro-8-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(4- pyridyl)propan-2-ol(54mg). The racemic mixture was separated by chiral chromatography to obtain(2S)-l-[(l lcS)-10-fluoro-8-methyl- 1,2,3,5, 6,1 lc-hexahydroindolizino[7, 8-b]indol-7- yl]-2-(4-pyridyl)propan-2-ol(10 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 68: Preparation of Compound Nos. V-280, V-280a, V-280b, V-280c and V-280d

[0214] (1 laR)-7-Fluoro-9-methyl-2,3,5,10,l 1,1 la-hexahydro-lH-indolizino[7,6-b]indole (150 mg, 0.614 mmol) was dissolved in DMF (3 mL) and sodium hydride(73 mg, 1.82 mmol) was added at 0 °C and stirred for 5 min. 4-(2-Methyl-oxiranyl)-pyridine (165 mg, 1.22 mmol) was dissolved in DMF (1 mL) and added dropwise into the reaction mixture and was allowed to come to room and the reaction mixture was stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (4x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 1-[(1 laR)-7-fluoro-9-methyl- 1,2,3,5,11,1 la-hexahydroindolizino[7,6-b]indol-10-yl]-2-(4-pyridyl)propan-2-ol (58 mg). The racemic mixture was separated by chiral chromatography to obtain (2R)-1-[(1 laR)-7- fluoro-9-methyl- 1,2,3,5,11,11 a-hexahydroindolizino [7 ,6-b] indol- 10-yl] -2- (4-pyridyl)propan- 2-ol (18 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 69: Preparation of Compound Nos. V-281, V-281a, V-281b, V-281c and V-281d

[0215] (1 lcR)-8-Fluoro-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.614 mmol) was dissolved in DMF (2 mL) and sodium hydride (73mg,1.82 mmol) was added at 0 °C and stirred for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (165 mg, 1.22 mmol) was dissolved in DMF (1 mL) and added dropwise into the reaction mixture and was allowed to come to RT and the reaction mixture was stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (6x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 1-[(1 lcR)-8-fluoro-10-methyl- 1,2,3,5,6,1 lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(3-pyridyl)propan-2-ol (45 mg). The racemic mixture was separated by chiral chromatography to obtain (2S)-1-[(1 lcR)-8-fluoro- 10-methyl- 1,2,3, 5,6, l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(3-pyridyl)propan-2-ol (18 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 70: Preparation of Compound Nos. V-283, V-283a, V-283b, V-283c and V-283d

[0216] (1 lcR)-8-Fluoro-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150mg, 0.614mmol) was dissolved in DMF (3 mL) and sodium hydride (73 mg, 1.82 mmol) was added at 0 °C and stirred for 5 min. 4-(2-Methyl-oxiranyl)-pyridine (165 mg, 1.22 mmol) was dissolved in 1 mL DMF and added dropwise into the reaction mixture and was allowed to come to RT and the resultant solution was stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (4x10 mL) and dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by reverse phase chromatography to obtain 1-[(7R)-1 l-fluoro-7,9- dimethyl-2,3,4,5,6,7-hexahydro-lH-azonino[4,5-b]indol-12-yl]-2-(4-pyridyl)propan-2-ol (40mg). The racemic mixture was separated by chiral chromatography to obtain (2S)-1- [(l lcR)-8-fluoro-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(4- pyridyl)propan-2-ol (9 mg ). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 71: Preparation of Compound Nos. V-284, V-284a, V-284b, V-284c and V-284d

[0217] (lS)-2-[(l lcR)-10-Methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4- pyridyl)ethanol (400 mg, 1.1 mmol) was dissolved in DMF (4 mL), and cooled to 0 °C. Sodium hydride (138 mg, 3.4 mmol) was added portionwise and bromo-cyclopentane (850 mg, 5.7 mmol) was added at the same temperature, and the reaction mixture was allowed to come to RT and stirred for 4 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (3x100 mL). The combined organic layer was washed with water (4x50 mL) and the organic layer was dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain (l lcR)-7-[(2S)-2-(cyclopentoxy)-2-(4- pyridyl)ethyl]-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indole (20 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 72: Preparation of Compound Nos. V-287, V-287a, V-287b, V-287c and V-287d

[0218] (1 laR)-7-(Trifluoromethyl)-2,3,5,10,l 1,1 la-hexahydro- lH-indolizino [7, 6-b] indole (150 mg, 0.53 mmol) was dissolved in DMF (2 mL) and sodium hydride (64 mg, 1.6 mmol) was added at 0 °C and stirred for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (122 mg, 0.9 mmol) was added into the reaction mixture and was allowed to come to RT and the reaction mixture was stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase

chromatography to obtain l-[(l laR)-7-(trifluoromethyl)-l,2,3, 5, 11,11a- hexahydroindolizino[7,6-b]indol-10-yl]-2-(3-pyridyl)propan-2-ol (200 mg). The mixture was separated by chiral chromatography to obtain (2R)-l-[(l laR)-7-(trifluoromethyl)- 1,2,3,5,11,1 la-hexahydroindolizino[7,6-b]indol-10-yl]-2-(3-pyridyl)propan-2-ol (30 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 73: Preparation of Compound Nos. V-288, V-288a, V-288b, V-288c and V-288d

[0219] (l laS)-7-Chloro-9-fluoro-2,3,5,10,l l,l la-hexahydro-lH-indolizino[7,6-b]indole (150 mg, 0.56 mmol) was dissolved in DMF (2 mL) and sodium hydride (68 mg, 1.7 mmol) was added at 0 °C and stirred for 5 min. 4-(2-Methyl-oxiranyl)-pyridine (130 mg, 0.96 mmol) was added into the reaction mixture and was allowed to come to RT and the reaction mixture was stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (4x30 mL) and dried over sodium sulfate and concentrated to give a crude product, which was purified by reverse phase chromatography to obtain 1- [(l laS)-7-chloro-9-fluoro-l,2,3,5,l l,l la-hexahydroindolizino[7,6-b]indol-10-yl]-2-(4- pyridyl)propan-2-ol (25 mg ). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 74: Preparation of Compound Nos. V-289, V-289a, V-289b, V-289c and V-289d

[0220] (1 lcS)-l l-Fluoro-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.8 mmol) was dissolved in DMF (2 mL) and sodium hydride (96 mg, 2.4 mmol) was added at 0 °C and stirred for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (188 mg, 1.3 mmol) was added into the reaction mixture and was allowed to come to RT and the reaction mixture was stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water(4x30 mL) and dried over sodium sulfate and concentrated to give a crude product, which was purified by reverse phase chromatography to obtain (2R)-1- [(l lcS)-l l-fluoro-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(3- pyridyl)propan-2-ol (40 mg), and l-(10-fluoro-9-methyl-l,2,3,4,5,10c-hexahydro-3a,6-diaza- cyclopenta[c]fluoren-6-yl)-2-pyridin-3-yl-propan-2-(30 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 75: Preparation of Compound Nos. V-290, V-290a, V-290b, V-290c and V-290d

[0221] (HcR)-8-Chloro-10-fluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.56 mmol) was dissolved in DMF (4 mL), and sodium hydride (68 mg, 1.7 mmol) was added at 0 °C and stirred for 5 min. 4-(2-Methyl-oxiranyl)-pyridine (153 mg, 1.13 mmol) was added and the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (6x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 1-[(1 lcR)-8-chloro- 10-fluoro- 1,2,3,5, 6, l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(4-pyridyl)propan-2-ol (30 mg). The racemic mixture was separated by chiral chromatography to obtain (2S)-1-[(1 lcR)- 8-chloro- 10-fluoro- 1,2,3, 5,6, l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(4-pyridyl)propan- 2-ol (11 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 76: Preparation of Compound Nos. V-291, V-291a, V-291b, V-291c and V-291d

[0222] (1 lcS)-8-Chloro-10-fluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.56 mmol) was dissolved in DMF (2 mL) and sodium hydride (68 mg, 1.7 mmol) was added at 0 °C and stirred for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (153 mg, 1.13 mmol) and added dropwise into the reaction mixture and was allowed to come to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (6x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 1-[(1 lcS)-8- chloro- 10-fluoro-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(3-pyridyl)propan-2- ol (30 mg ). The racemic mixture was separated by chiral chromatography to obtain (2S)- 1- [(l lcS)-8-chloro- 10-fluoro- l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-2-(3- pyridyl)propan-2-ol (9 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 77: Preparation of Compound Nos. V-293, V-293a, V-293b, V-293c and V-293d

[0223] To a solution of (S)-8,10-dimethyl-2,3,5,6,7, l lc-hexahydro-lH-indolizino[7,8- b]indole (200 mg, 0.769 mmol) in DMF (5 mL) was added sodium hydride (120 mg, 3.08 mmol) at 0 °C. After 20 min of stirring, a solution of 3-(2-methyloxiran-2-yl)pyridine (207 mg, 1.54 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (3x30 mL). The combined organic layer was washed with water (6x40 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure afforded a crude product which was purified by column chromatography on neutral alumina, eluting a pure compound in 2-3% MeOF DCM as eluent to afford a diastereomeric mixture which was purified by chiral HPLC to afford 50 mg of (S)-l-((R)-8-chloro- 10-methyl- 2,3,5,6-tetrahydro- lH-indolizino[7,8-b]indol-7(l lcH)-yl)-2-(pyridin-4-yl)propan-2-ol as free base. Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 78: Preparation of Compound Nos. V-298, V-298a and V-298b

[0224] 5-[2-(2,8-Dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5-yl)-l-hydroxy- ethyl]pyridine-2-carboxylic acid (20 mg, 0.054 mmol) was dissolved in DCM (0.3 mL) then PyBOP (31 mg, 0.060 mmol) was added. To this reaction mixture, triethylamine (11 mg, 0.108 mmol) and pyrrolidine (5.7 mg, 0.081 mmol) were added. The resultant reaction mixture was allowed to stir at RT for 4 h. Progress of the reaction was monitored by LCMS. Water (2 mL) was added and the mixture was extracted with DCM (3x5 mL). The combined organic layer was washed with water (2x3 mL), dried over sodium sulfate, and evaporated to obtain the crude product, which was purified by preparative HPLC to obtain [5-[2-(2,8- dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5-yl)- l-hydroxy-ethyl]-2-pyridyl]-pyrrolidin- l- yl-methanone (4 mg). The other enantiomer can be prepared by using appropriate chiral starting materials.

Example 79: Preparation of Compound Nos. V-303, V-303a, V-303b, V-303c and V-303d

[0225] To the corresponding carboline (200 mg, 0.884 mmol) was added DMF (5 mL) and the mixture was stirred for 2 min. To this, sodium hydride (106 mg, 2.652 mmol) was added and the reaction mixture was stirred for 5 min. 3-(2-Methyloxiran-2-yl)pyridine (143 mg, 1.061 mmol) was added and the reaction was stirred overnight. Progress of the reaction was monitored by LCMS. Ice cold water was added to the reaction mixture, which was then filtered to get the desired product (270 mg). The racemic compound was separated by chiral HPLC to get Cpd. No. V-303a, (86 mg) & Cpd. No. V-303b (39 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 80: Preparation of Compound Nos. V-304, V-304a, V-304b, V-304c and V-304d

[0226] To the corresponding carboline (200 mg, 0.884mmol) was added DMF (5 mL) and the reaction was stirred for 2 min. To this, sodium hydride (106 mg, 2.652mmol) was added and the reaction mixture was allowed to stir for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (161 mg, 1.061 mmol) was added and the reaction was stirred overnight. Progress of the reaction was monitored by LCMS. Ice cold water was added to the reaction mixture and the mixture was filtered to get the desired product (260 mg). The racemic compound was separated by chiral HPLC to get Cpd. No. V-304a (82 mg) and Cpd. No. V-304 (72 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 81: Preparation of Compound Nos. V-336, V-336a, V-336b, V-336c and V-336d

[0227] (1 lcR)-10-Chloro-8-fluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.7 mmol) was dissolved in DMF (2.5 mL),and sodium hydride (90 mg, 2.2 mmol) was added at 0 °C and stirred for 5 min. 4-Oxiranyl-pyridine (155 mg, 1.2 mmol) was added and the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x75 mL). The combined organic layer was washed with water (4x50 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 2-[(l lcR)-10-chloro-8-fluoro-l,2,3,5,6,l lc- hexahydroindolizino[7,8-b]indol-7-yl]-l-(4-pyridyl)ethanol (120 mg) , the racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcR)-10-chloro-8-fluoro- 1,2,3,5,6,1 lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4-pyridyl)ethanol (26 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 82: Preparation of Compound Nos. V-337, V-337a, V-337b, V-337c and V-337d [0228] (1 lcR)-10-Fluoro-8-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.614 mmol) was dissolved in DMF (2 mL) and sodium hydride (73 mg, 1.82 mmol) was added at 0 °C and stirred for 5 min. 4-Oxiranyl-pyridine (148 mg, 1.22 mmol) was dissolved in DMF (1 mL) and added dropwise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (4x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 2- [(l lcR)-10-fluoro-8-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4- pyridyl)ethanol (62 mg). The racemic mixture was separated by chiral chromatography to obtain(lS)-2-[(l lcR)-10-fluoro-8-methyl- 1,2,3, 5,6,1 lc-hexahydroindolizino[7, 8-b]indol-7- yl]-l-(4-pyridyl)ethanol (19 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 83: Preparation of Compound Nos. V-338, V-338a, V-338b, V-338c and V-338d

[0229] (1 lcR)-8-Fluoro-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.614 mmol)was dissolved in DMF (2 mL)and sodium hydride (73 mg, 1.82 mmol) was added at 0 °C and stirred for 5 min. 4-Oxiranyl-pyridine (148 mg, 1.22 mmol) was dissolved in DMF (1 mL) and added dropwise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (6x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 2- [(l lcR)-8-fluoro-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4- pyridyl) ethanol (93 mg). The racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcR)-8-fluoro-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7- yl]-l-(4-pyridyl)ethanol (25 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 84: Preparation of Compound Nos. V-339, V-339a, V-339b, V-339c and V-339d

[0230] 2-[(l lcR)-10-Methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4- pyridyl)ethanol (200 mg, 0.576 mmol) was dissolved in DMF (2 mL), and cooled to 0 °C. Sodium hydride (69 mg, 1.725 mmol) was added portionwise and bromomethyl-cyclobutane (429 mg, 2.879 mmol) was added at the same temperature, and the reaction mixture was warmed to RT and stirred for 2 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (6x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain (l lcR)-7-[2-(cyclobutylmethoxy)-2-(4-pyridyl)ethyl]-10- methyl- 1,2,3,5, 6,l lc-hexahydroindolizino[7,8-b]indole (68 mg). The mixture was separated by chiral chromatography to obtain (l lcR)-7-[(2R)-2-(cyclobutylmethoxy)-2-(4- pyridyl)ethyl]-10-methyl- 1,2,3, 5,6,1 lc-hexahydroindolizino[7,8-b]indole (11 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 85: Preparation of Compound Nos. V-340, V-340a and V-340b

[0231] To a stirred solution of l-(8-(2-(tert-butyldimethylsilyloxy)ethyl)-2-methyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol (350 mg, 0.730 mmol) in THF (5 mL) at 0 °C was added TBAF in THF solution (1M, 2.2 mL, 2.192 mmol) dropwise. The reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was poured on ice- water and extracted with EtOAc (2x25 mL). The organic layer dried over anhydrous sodium sulfate, concentrated under vacuum to obtain a crude product, which was purified by column chromatography using neutral alumina (eluent system 5 % MeOF DCM ) to obtain the desired product, which was separated by chiral column to obtain (S)-l-(8-(2- hydroxyethyl)-2-methyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3- yl)propan-2-oland(R)-l-(8-(2-hydroxyethyl)-2-methyl-3,4-dihydro-lH-pyrido[4,3-b]indol- 5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol (18 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 86: Preparation of Compound Nos. V-34L V-341a and V-341b

[0232] To a stirred solution of 2-(8-(2-(tert-butyldimethylsilyloxy)ethyl)-2-methyl-3,4- dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-l-(pyridin-4-yl)ethanol (280 mg, 0.602 mmol) in THF (4 mL) at 0 °C was added TBAF in THF Solution (1M, 1.8 mL, 1.806 mmol) dropwise. The reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was poured into ice- water and extracted with EtOAc (2x20 mL). The organic layer dried over anhydrous sodium sulfate, concentrated under vacuum to obtain a crude product, which was purified by column chromatography using neutral alumina (eluent system 5 % MeOH:DCM ) to obtain the desired product, which was separated by chiral column to obtain (S)-2-(8-(2- hydroxyethyl)-2-methyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-l-(pyridin-4- yl)ethanoland(R)-2-(8-(2-hydroxyethyl)-2-methyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)- yl)-l-(pyridin-4-yl)ethanol (7 mg). The other enantiomer can be prepared by using appropriate chiral starting materials. Example 87: Preparation of Compound Nos. V-342, V-342a, V-342b, V-342c and V-342d

[0233] (R)-8,10-Dimethyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (100 mg ,0.416 mmol) was dissolved in DMF (2 mL). Sodium hydride (50 mg, 1.24 mmol) was added into the reaction mixture and stirred at RT for 10 min. 2-Cyclohexyloxirane (78 mg, 0.63 mmol) was added dropwise over 10 min and reaction mixture was stirred at RT for 12h. The progress of reaction was monitored by TLC and LCMS. Ice cold water was added into the reaction mixture and extracted with EtOAc (3x100 mL). The combined organic layer was washed with water (4x100 mL), dried over sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase chromatography to get the racemic compound. The racemic compound was separated by chiral HPLC to obtain (R)-l- cyclohexyl-2-((R)-8,10-dimethyl-2,3,5,6-tetrahydro-lH-indolizino[7,8-b]indol-7(l lcH)- yl)ethanol (30 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 88: Preparation of Compound Nos. V-343, V-343a, V-343b, V-343c and V-343d

[0234] To a solution of (R)-8-chloro-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8- b]indole (20 mg, 0.769 mmol) in DMF (4 mL) was added sodium hydride (123 mg, 3.076 mmol) at 0 °C. After 20 min of stirring, a solution of 4-(oxiran-2-yl)pyridine (186 mg, 1.538 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was allowed to stir at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (3x30 mL). The combined organic layer was washed with water (6x40 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure afforded a crude product that was purified by column chromatography on neutral alumina eluting pure compound in 2-3% MeOF DCM as eluent to afford a diastereomeric mixture, which was purified by chiral HPLC to afford 10 mg of (S)-2-((R)-8-chloro-10-methyl-2,3,5,6- tetrahydro-lH-indolizino[7,8-b]indol-7(l lcH)-yl)-l-(pyridin-4-yl)ethanol. Other

diastereomers can be prepared by using appropriate chiral starting materials.

Example 89: Preparation of Compound Nos. V-344, V-344a, V-344b, V-344c and V-344d

[0235] (HcR)-10-Chloro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.813 mmol) was dissolved in DMF (3 mL) and sodium hydride (49 mg, 2.0 mmol) was added at 0 °C and stirred for 5 min. 4-Oxiranyl-pyridine (148 mg, 1.2 mmol) was added and the reaction mixture was allowed to stir at RT for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc , dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was recrystallized from ether/hexane to obtain 2-[(l lcR)-10-chloro-l,2,3,5, 6,11c- hexahydroindolizino[7,8-b]indol-7-yl]-l-(4-pyridyl) ethanol (120 mg). The racemic mixture was separated by chiral chromatography to obtain (lR)-2-[(l lcR)-10-chloro-l,2,3,5,6,l lc- hexahydroindolizino[7,8-b]indol-7-yl]-l-(4-pyridyl)ethanol (35 mg). 1H NMR (CDC1₃, freebase) δ (ppm): 8.58 (d, 2H), 7.42 (s, 1H), 7.22 (m, 3H), 7.10 (d, 1H), 5.00 (t, 1H), 4.18 (m, 2H), 3.82 (t, 1H), 3.25 (m, 1H), 2.92 (m, 2H), 2.75 (m, 2H), 2.42 (m, 2H), 1.90 (m, 3H). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 90: Preparation of Compound Nos. V-345, V-345a, V-345b, V-345c and V-345d

[0236] (HcR)-8,10-Difluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.806 mmol) was dissolved in DMF (2 mL) and sodium hydride (48 mg, 2.0 mmol) was added at 0 °C and stirred for 5 min. 4-Oxiranyl-pyridine (146 mg, 1.2 mmol) was added and the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc , dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was recrystallized in ether hexane to obtain 2-[(l lcR)-8,10-difluoro-l,2,3, 5,6,1 lc- hexahydroindolizino[7,8-b]indol-7-yl]-l-(4-pyridyl)ethanol (110 mg). The racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcR)-8,10-difluoro- 1,2,3,5,6,1 lc-hexa hydro indolizino[7,8-b]indol-7-yl]-l-(4-pyridyl)ethanol (25 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 91: Preparation of Compound Nos. V-346, V-346a, V-346b, V-346c and V-346d

[0237] To a solution of 2-(2,6-dimethyl-3,4-dihydro-lH-pyrido[3,4-b]indol-9(2H)-yl)-l- (pyridin-4-yl)ethanol (250 mg, 0.77mmol) in THF/Water/ Acetic acid (24 mL, 1: 1: 1), and N- bromosuccinimide (138 mg, 0.77 mmol) was added. The reaction mixture was stirred in the dark at RT for 1 h. The reaction mixture was neutralized by adding to it a saturated solution of aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (2x150 mL). The combined organic extract was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude mixture was purified by reverse phase HPLC to obtain l-(2-hydroxy-2-(pyridin-4-yl)ethyl)-l',5-dimethylspiro[indoline-3,3'-pyrrolidin]-2-one (75 mg ) followed by chiral separation to obtain 145a (5 mg), 145b (5 mg), 145c (5 mg) and 145d (5 mg).

Example 92: Preparation of Compound Nos. V-347, V-347a, V-347b, V-347c and V-347d

[0238] (1 lcR)-10-(Trifluoromethyl)-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.714 mmol) was dissolved in DMF (2 mL) and sodium hydride (43 mg, 1.79 mmol) was added at RT and stirred for 10 min. 4-(Oxiran-2-yl)pyridine (173 mg, 1.43 mmol) was dissolved in DMF (1 mL) and added dropwise at RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (4x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 160 mg of desired compound . The racemic mixture was separated by chiral chromatography to obtain (lS)-2- [(l lcR)-10 trifluoromethyl)-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4- pyridyl)ethanol(40 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 93: Preparation of Compound Nos. V-348, V-348a, V-348b, V-348c and V-348d

[0239] (1 lcR)-10-(Trifluoromethyl)-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.714 mmol) was dissolved in DMF (2 mL) and sodium hydride (43 mg, 1.79 mmol) was added at RT and stirred for 10 min. 3-(Oxiran-2-yl)pyridine (173 mg, 1.43 mmol) was dissolved in DMF (1 mL) and added dropwise at RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (4x20 mL). The combined organic layer was washed with water (4x10 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 160 mg of desired compound . The racemic mixture was separated by chiral chromatography to obtain(lS)-2- [(l lcR)-10 trifluoromethyl)-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(3- pyridyl)ethanol(50 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 94: Preparation of Compound Nos. V-349, V-349a, V-349b, V-349c and V-349d

[0240] (1 lcR)-10-Chloro-8-fluoro-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.56 mmol) was dissolved in DMF (2 mL) and sodium hydride (67 mg, 1.16 mmol) was added at 0 °C and stirred for 5 min. 3-(oxiran-2-yl)pyridine (116 mg, 0.96 mmol) was dissolved in DMF (1 mL) and added dropwise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (3x40 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 130 mg of desired compound. The racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcR)-10-chloro-8-fluoro-l,2,3, 5,6,1 lc-hexahydroindolizino[7,8-b]indol- 7-yl]-l-(3-pyridyl)ethanol (15 mg). Other diastereomers can be prepared by using

appropriate chiral starting materials.

Example 95: Preparation of Compound Nos. V-350, V-350a, V-350b, V-350c and V-350d

[0241] (1 lcS)-10-chloro-8-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.56 mmol) was dissolved in DMF (2 mL) and sodium hydride (67 mg, 1.16 mmol) was added at 0 °C and stirred for 5 min. 4-(oxiran-2-yl)pyridine (116 mg, 0.96 mmol) was dissolved in DMF (1 mL) and added drop wise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (3x40 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 100 mg of desired compound. The racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcS)-10-chloro-8-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol- 7-yl]-l-(4-pyridyl)ethanol (25 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 96: Preparation of Compound Nos. V-351, V-351a, V-351b, V-351c and V-351d

[0242] (1 lcS)-10-Chloro-8-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.56 mmol) was dissolved in DMF (2 mL) and sodium hydride (67 mg, 1.16 mmol) was added at 0 °C and stirred for 5 min. 3-(Oxiran-2-yl)pyridine (116 mg, 0.96 mmol) was dissolved in DMF (1 mL) and added drop wise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (3x40 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain the desired compound. The racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcS)-10-chloro-8-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7- yl]-l-(3-pyridyl)ethanol (3 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 97: Preparation of Compound Nos. V-352. V-352a. V-352b. V-352c and V-352d

[0243] (lS)-2-[(l lcR)-9-Chloro-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7- yl]-l-(4-pyridyl)ethanol (150 mg, 0.56 mmol) was dissolved in DMF (2 mL) and sodium hydride (67 mg, 1.16 mmol) was added at 0 °C and stirred for 5 min. 3-(Oxiran-2-yl)pyridine (116 mg, 0.96 mmol) was dissolved in DMF (1 mL) and added drop wise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured in to ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (3x40 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 100 mg of desired compound. The racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcR)-9-chloro-10-methyl-l,2,3,5,6,l lc- hexahydroindolizino[7,8-b]indol-7-yl]-l-(3-pyridyl)ethanol (30 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 98: Preparation of Compound Nos. V-353, V-353a, V-353b, V-353c and V-353d

[0244] (R)-8,10-Dimethyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (228 mg, 0.95 mmol) was dissolved in 4 mL of DMF, sodium hydride (114 mg, 2.85 mmol ) added and stirred for 5 min. 2-cyclohexyl-2-methyloxirane (200 mg, 1.42 mmol) was added and the reaction mixture was heated at 70 °C for 18 h. After consumption of starting material, the reaction mixture was poured in to ice water (20 mL) and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (3x50 mL), dried over sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase

chromatography to obtain 100 mg of 2-cyclohexyl-l-((R)-8,10-dimethyl-2,3,5,6-tetrahydro- lH-indolizino[7,8-b]indol-7(l lcH)-yl)propan-2-ol. The racemate was separated by chiral HPLC to obtain 10 mg of (S)-2-cyclohexyl-l-((R)-8,10-dimethyl-2,3,5,6-tetrahydro-lH- indolizino[7,8-b]indol-7(l lcH)-yl)propan-2-ol. Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 99: Preparation of Compound Nos. V-354, V-354a, V-354b, V-354c and V-354d

[0245] The carboline (100 mg, 0.416 mmol) was dissolved in DMF (2 mL), sodium hydride (50 mg, 1.25 mmol) was added at RT and stirred at RT for 5 min. 4-(Oxiran-2-yl) pyridine (90 mg, 0.742 mmol) was added and the reaction was allowed RT stir at RT for 3 h. The reaction was monitored with LCMS. The reaction mixture was poured into 20 mL ice cold water and extracted with EtOAc (3x20 mL). The organic layer was washed with water (2x50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the product that was washed with hexane and purified with reverse phase column chromatography to obtain the product as mixture of diastereoisomers. The mixture of diastereoisomers was separated with chiral chromatography to obtained 5 mg of desired product. Other

diastereomers can be prepared by using appropriate chiral starting materials.

Example 100: Preparation of Compound Nos. V-355, V-355a, V-355b, V-355c and V-355d

[0246] (1 lcR)-9-Chloro-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (150 mg, 0.57 mmol) was dissolved in DMF (3 mL) and sodium hydride (68 mg, 1.7 mmol) was added at 0 °C and stirred for 5 min. 3-(2-Methyloxiran-2-yl)pyridine (132 mg, 0.9 mmol) was dissolved in DMF (2 mL) and added dropwise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (2x100 mL). The combined organic layer was washed with water (4x50 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase

chromatography to obtain 110 mg of desired compound. The racemic mixture was separated by chiral chromatography to obtain (2S)-l-[(l lcR)-9-chloro-10-methyl-l,2,3,5,6,l lc- hexahydroindolizino[7,8-b]indol-7-yl]-2-(3-pyridyl ) propan-2-ol (15 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 101: Preparation of Compound Nos. V-356, V-356a, V-356b, V-356c and V-356d

[0247] (l lcR)-10,l lc-Dimethyl-l,2,3,5,6,7-hexahydroindolizino[7,8-b]indole (150 mg, 0.6 mmol) was dissolved in DMF (2 mL) and sodium hydride (75 mg, 1.8 mmol) was added at 0 °C and stirred for 5 min. 4-(Oxiran-2-yl)pyridine (121 mg, 1.0 mmol) was dissolved in DMF (2 mL) and added dropwise into the reaction mixture was allowed to RT and stirred for 18 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (4x25 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of desired compound. The racemic mixture was separated by chiral chromatography to obtain (lS)-2-[(l lcR)-10,l lc-dimethyl-2,3,5,6-tetrahydro H-indolizino[7,8-b]indol-7-yl]-l-(4- pyridyl) ethanol (15 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 102: Preparation of Compound Nos. V-357, V-357a, V-357b, V-357c and V-357d

[0248] (1 lcR)-10-(Trifluoromethyl)-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (250 mg, 0.89 mmol) was dissolved in DMF (2 mL) and sodium hydride (52 mg, 2.23 mmol) was added at 0 °C and stirred for 5 min. 4-(2-Methyloxiran-2-yl)pyridine (180 mg, 1.34 mmol) was dissolved in DMF (2 mL) and added dropwise into the reaction mixture was allowed to RT and stirred for 12 h. After consumption of starting material, the reaction mixture was poured into ice cold water and extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (5x25 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was recrystallized in ether in hexane to obtained 190 mg of desired compound. The racemic mixture was separated by chiral chromatography to obtain (2S)-l-[(l lcR)-10-(trifluoromethyl)-l,2,3,5,6,l lc- hexahydroindolizino[7,8-b]indol-7-yl]-2-(4-pyridyl)propan-2-ol (80 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 103: Preparation of Compound Nos. V-358, V-358a, V-358b, V-358c and V-358d

[0249] To a solution of 2-[(l lcR)-8,10-dimethyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8- b]indol-7-yl]-l-(4-pyridyl)ethanol (300 mg, 0.831 mmol) in DMF (3 mL) was added sodium hydride (100 mg, 2.49 mmol) at 0 °C. After 10 min of stirring, bromomethylcyclobutane (372 mg, 2.49 mmol) was added dropwise. The reaction mixture was allowed to stir at RT for 2 h. The progress of reaction was monitored by TLC& LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (5x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product, which was purified by reverse phase HPLC to afford 70 mg desired compound which was purified by chiral HPLC to obtain (1 lcR)-7-[(2S)-2-(cyclobutylmethoxy)-2-(4- pyridyl)ethyl]-8,10-dimethyl-l,2,3,5, 6,11 c-hexahydroindolizino [7,8-b]indole (10 mg). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 104: Preparation of Compound Nos. V-359, V-359a, V-359b, V-359c and V-359d

[0250] 8,10-Dimethyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (100 mg, 0.272 mmol) in 2 mL DCM was stirred at 0 °C. Dess-Martin periodinane (188 mg, 0.435 mmol) was added and reaction mixture was stirred at RT for 12 h. The reaction was monitored by LCMS, and upon completion, sodium thiosulfate sulfate solution (2 mL) was added, followed by sodium bicarbonate solution (2 mL). The mixture was extracted with DCM (3x250 mL). The combined organic layer was washed with water (3x20 mL), dried over sodium sulfate and concentrated to obtain the crude product that was purified by preparative HPLC, to obtain 65 mg of l-cyclohexyl-2-(8,10-dimethyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8- b]indol-7-yl)ethanone as a racemate. The racemate was separated by chiral HPLC to obtain 8 mg of 2-[(l lcR)-8,10-dimethyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l- cyclohexyl-ethanone (Cpd. No. V-359a) and 11 mg of 2-[(l lcS)-8,10-dimethyl-l,2,3,5,6,l lc- hexahydroindolizino[7,8-b]indol-7-yl]-l-cyclohexyl-ethanone (Cpd. No. V-359b). Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 105: Preparation of Compound Nos. V-360, V-360a, V-360b, V-360c and V-360d

[0251] The carboline (100 mg, 0.44 mmol) was dissolved in DMF (3 mL), sodium hydride (53 mg, 1.32 mmol) was added and stirred for 5 min. 2-Cyclohexyloxirane (73 mg, 0.57 mmol) was added and the reaction mixture was heated at 60 °C for 12 h. The reaction was monitored by LCMS. The reaction mixture was poured in to ice water (30 mL), extracted with EtOAc (3x25 mL), dried over sodium sulfate and concentrated to obtain the crude product that was purified by preparative HPLC to obtain 180 mg of the product as a racemate. The racemate was separated by chiral HPLC to obtain 24 mg of Cpd. No. V-360a, 9 mg of Cpd. No. V-360b, 23 mg of Cpd. No. V-360c and 11 mg of Cpd. No. V-360d.

Example 106: Preparation of Compound Nos. V-361, V-361a, V-361b, V-361c and V-361d

[0252] To a solution of (l lcR)-l l-bromo-10-methyl-2,3,5,6,7,l lc-hexahydro-lH- indolizino[7,8-b]indole (150 mg, 0.49 mmol) in DMF (2 mL) was added sodium hydride (58 mg, 1.47 mmol) at 0 °C. After 5 min of stirring, 4-(oxiran-2-yl)pyridine (95 mg, 0.78 mmol) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product, which was purified by reverse phase HPLC to afford 80 mg of desired compound which was purified by chiral HPLC to obtain 8 mg of (lS)-2-[(l lcR)-l 1-bromo-lO-methyl- 1,2,3,5,6,1 lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4-pyridyl)ethanol. Other

diastereomers can be prepared by using appropriate chiral starting materials.

Example 107: Preparation of Compound Nos. V-362, V-362a, V-362b, V-362c and V-362d

[0253] To a solution of (l lcR)-9-bromo-10-methyl-2,3,5,6,7,l lc-hexahydro-lH- indolizino[7,8-b]indole (150 mg, 0.49 mmol) in DMF (2 mL) was added sodium hydride (59 mg, 1.47 mmol) at 0 °C. After 5 min of stirring, 4-(oxiran-2-yl)pyridine (101 mg, 0.83 mmol) was added dropwise. The reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product, which was purified by reverse phase HPLC to afford 100 mg of desired compound, which was purified by chiral HPLC to obtain 20 mg of (lS)-2-[(l lcR)-9-bromo-10-methyl- 1,2,3,5,6,1 lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4-pyridyl)ethanol. Other

diastereomers can be prepared by using appropriate chiral starting materials.

Example 108: Preparation of Compound Nos. V-363, V-363a, V-363b, V-363c and V-363d

[0254] (R)-10-Methyl-8-vinyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (200 mg, 0.793 mmol) was charged in DMF (3 mL). Sodium hydride (95 mg, 2.3808 mmol) was added at 0 °C and stirred for 10 min. 4-(Oxiran-2-yl)pyridine (154 mg, 1.269 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water. The compound precipitated and was filtered and purified by column chromatography to get the racemic compound (80 mg). The racemate was purified by Chiral HPLC to give 10 mg of Cpd. No. V-360a and 15 mg of Cpd. No. V-360b. Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 109: Preparation of Compound Nos. V-364, V-364a and V-364b

[0255] l,l,2,8-Tetramethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole (80 mg, 0.350 mmol) was dissolved in DMF (1.5ml), sodium hydride (42 mg, 1.05mmol) was added and stirred for 5 min. 4-Oxiranyl-pyridine (63.6 mg, 0.52 mmol) was added and the reaction mixture was allowed to RT and stirred for 4 h. The progress of reaction was monitored by LCMS. The reaction mixture was poured in to ice water (50 mL), the product extracted, dried over sodium sulfate, and evaporated to obtain the crude product that was purified by preparative HPLC to obtain 18 mg of l-(pyridin-4-yl)-2-(l,l,2,8-tetramethyl-3,4-dihydro-lH-pyrido[4,3- b]indol-5(2H)-yl)ethanol as a racemate. The racemate was separated by chiral HPLC to obtain 7 mg of (lR)-2-[3-[l-(dimethylamino)-l-methyl-ethyl]-5-methyl-indol-l-yl]-l-(4- pyridyl)ethanol (Cpd. No. V-364a) and 6 mg of (lS)-l-(4-pyridyl)-2-(l,l,2,8-tetramethyl-3,4- dihydropyrido[4,3-b]indol-5-yl)ethanol (Cpd. No. V-364b).

Example 110: Preparation of Compound No. V-365

[0256] To a solution of carboline (200 mg, 0.9 mmol) in NMP (2 mL) was added powdered potassium hydroxide (100 mg, 1.8 mmol), 2-(trifluoromethyl)-5-vinyl-pyridine (234 mg, 1.33 mmol) was added dropwise. The reaction mixture was heated at 40 °C for 1 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, water was added to the reaction mixture and the product was extracted with EtOAc (4x50 mL). The combined organic layer was washed with brine solution (6x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product, which was purified by reverse phase HPLC to afford 20 mg desired compound.

Example 111: Preparation of Compound No. V-366

[0257] To a solution of carboline (500 mg, 2.26 mmol) in DMF (3 mL) was added sodium hydride (271 mg, 6.78 mmol) at 0 °C. After 5 min of stirring, 2-(6-methyl-3-pyridyl) ethyl 4- methylbenzenesulfonate (1.05 g, 3.61 mmol) was added portionwise. The reaction mixture was allowed to stir at RT for 5 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc (5x50 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product, which was purified by reverse phase HPLC to afford 250 mg desired compound.

Example 112: Preparation of Compound Nos. V-367, V-367a, V-367b, V-367c and V-367d

[0258] 5-[l-Hydroxy-2-(10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7- yl)ethyl]pyridine-2-carbonitrile (4.0g, 10.72 mmol) and KOH (2.40 g, 42.895 mmol) in (t- butanol 15 mL) was heated for 100 °C for 45 min. The reaction was monitored by LCMS. The reaction mixture was concentrated, water was added, extracted with EtOAc and concentrated to obtain the crude product that was purified by preparative HPLC to get 300 mg of the required compound. This was separated by chiral HPLC to get 32 mg of Cpd. No. V-367a, 30 mg of Cpd. No. V-367b, 20 mg of Cpd. No. V-367c and, 30 mg of Cpd. No. V- 367d.

Example 113: Preparation of Compound Nos. V-368, V-368a, V-368b, V-368c and V-368d

[0259] (1 lcR)-9-Methoxy-10-methyl-2,3,5,6,7,l lc-hexahydro-lH-indolizino[7,8-b]indole (80mg, 0.313 mmol) was charged in DMF (2 mL). NaH (38 mg, 1.560 mmol) was added under at 0 °C and stirred for 10 min. 4-(Oxiran-2-yl)pyridine (76 mg, 0.625 mmol) was added and the reaction mixture was allowed to stir at RT for 18 h. The progress of reaction was monitored by LCMS. After completion of the reaction, ice-cold water was added to the reaction mixture and the product was extracted with EtOAc. The combined organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product, which was purified by reverse phase HPLC to afford 50 mg desired compound which was purified by chiral HPLC to obtain 10 mg of (lS)-2- [(l lcR)-9-methoxy-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7-yl]-l-(4- pyridyl)ethanol. Other diastereomers can be prepared by using appropriate chiral starting materials.

Example 114: Preparation of Compound Nos. V-369, V-369a, V-369b, V-369c and V-369d

[0260] (2R)-1-[(1 lcR)-8-Fluoro-10-methyl-l,2,3,5,6,l lc-hexahydroindolizino[7,8-b]indol-7- yl]-2-(3-pyridyl)propan-2-ol (250 mg, 0.659 mmol) was dissolved in DMF (2 mL). Cesium carbonate (644 mg, 1.98 mmol) and sodium iodide (50 mg, 0.333 mmol) were added portionwise. Bromomethyl-cyclobutane (198 mg, 1.32 mmol) was added at RT, and the reaction mixture was heated at 80 °C for 90 min. After consumption of starting material, the reaction mixture was poured in to water and extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (4x25 mL) and dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase chromatography to obtain 80 mg of (l lcR)-7-[(2R)-2-(cyclobutylmethoxy)-2-(3- pyridyl)propyl]-8-fluoro- 10-methyl- 1,2,3,5, 6, l lc-hexahydroindolizino[7,8-b]indole. Other diastereomers can be prepared by using appropriate chiral starting materials.

[0261] Representative compounds made according to the general procedures, and associated chemical characterization data (1H NMR) are provided in Table 6.

Table 6. Chemical characterization data ( H NMR) for representative compounds of the invention.

Compound NMR Data

No.

V-14 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.0 (s, IH), 7.77 (s, 2H), 7.47 (s, IH),

7.38 (s, IH), 7.02 (s, IH), 6.9 (s, IH), 4.78 (m, IH), 4.38 (m, IH), 4.1 (bs, IH), 4.0 (m, IH), 3.9 (bs, IH), 3.6 (m, IH), 3.1-3.27 (m, 5H), 2.8 (t, 2H), 2.7 (s, 3H), 2.4 (s, 3H), 1.99 (s, 3H).

V-15 1H NMR (CDCI₃, Free base) δ (ppm): 8.41 (s, IH), 7.5 (m, 2H), 7.4 (d, IH),

7.18 (s, IH), 7.08 (d, IH), 3.6 (s, 2H), 3.0 (t, 2H), 2.83 (t, 2H), 2.58 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H).

V-16 1H NMR (CDCI3, TFA salt) δ (ppm): 8.38 (s, IH), 8.0 (s, IH), 7.5 (d, 2H), 7.4

(d, IH), 4.4 (t, 2H), 3.58 (s, 2H), 3.2 (t, 2H), 2.68 (t, 2H), 2.5 (t, 2H), 2.47 (s, 3H), 2.38 (s, 3H).

V-17 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.98 (s, IH), 8.78 (d, IH), 8.0 (d, IH),

7.38 (d, 2H), 7.18 (d, IH), 7.1 (d, IH), 4.76 (d, IH), 4.4 (d, IH), 3.85 (bs, IH), 3.6 (bs, IH), 3.2 (m, 2H), 3.18 (s, 3H), 3.1 (s, 2H), 2.64 (s, 3H), 2.05 (s, 3H), 1.5 (t, 3H).

V-18 ^lH NMR (CD₃OD, HC1 salt) δ (ppm): 7.92 (d, 2H), 7.7 (d, 2H), 7.58 (d, IH),

7.38 (s, IH), 7.23 (d, IH), 4.7 (d, IH), 4.4 (d, IH), 3.96 (m, IH), 3.63 (m, IH), 3.37 (m, 2H), 3.18 (s, 3H), 2.42 (s, 3H).

V-19 1H NMR (CDCI3, Free base) δ (ppm): 7.9 (d, 2H), 7.6 (d, 2H), 7.4 (d, IH), 7.3

(s, IH), 7.1 (d, IH), 3.78 (s, 2H), 2.82 (t, 2H), 2.79 (t, 2H), 2.6 (s, 3H), 2.42 (s, 3H).

V-20 ^lH NMR (CD₃OD, HC1 salt) δ (ppm): 7.57 (d, IH), 7.46 (d, IH), 7.36 (m, 2H),

7.21 (d, IH), 4.42 (s, 2H), 3.71 (s, 2H), 3.3 (m, 2H), 3.1 (s, 3H), 2.42 (s, 3H).

V-21 1H NMR (CDCI₃, TFA salt) δ (ppm): 8.2 (s, IH), 8.04 (s, IH), 7.43 (s, IH),

7.18 (d, IH), 7.0 (d, IH), 4.3 (t, 2H), 3.6 (s, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 2.5 (s, 8H), 2.4 (s, 3H).

V-22 1H NMR (CDCI₃, TFA salt) δ (ppm): 8.4 (s, IH), 8.2 (s, IH), 7.7 (d, IH), 7.5

(d, IH), 7.4 (d, IH), 7.0 (s, IH), 4.4 (s, 2H), 3.6 (s, 2H), 3.2 (s, 2H), 2.78 (s, 2H), 2.6 (s, 2H), 2.5 (s, 3H).

V-23 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.87 (s, IH), 8.75 (d, IH), 8.0 (d, IH),

7.3 (s, IH), 7.24 (d, IH), 7.17 (d, IH), 6.8 (s, IH), 4.77 (d, IH), 4.38 (d, IH), 3.9 (bs, IH), 3.4 (bs, IH), 3.3 (m, IH), 3.18 (m, IH), 3.12 (s, 3H), 2.8 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H).

V-24 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.7 (d, 2H), 8.0 (d, 2H), 7.58 (s, IH),

7.37 (s, IH), 7.1 (d, IH), 7.05 (d, IH), 4.7 (bs, IH), 4.4 (bs, IH), 3.5 (d, 2H), 3.18 (s, 3H), 2.42 (s, 3H), 1.97 (s, 3H), 1.57 (bs, 6H).

V-25 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.97 (s, IH), 8.66 (d, IH), 7.9 (d, IH),

7.42 (s, IH), 7.37 (s, IH), 7.1 (q, 2H), 4.7 (m, IH), 4.37 (m, IH), 3.5 (m, 2H), 3.2 (s, 3H), 2.8 (s, 3H), 2.42 (s, 3H), 1.97 (s, 3H), 1.5 (bs, 6H).

V-26 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.4 (s, IH), 7.8 (d, IH), 7.72 (d, IH),

7.24 (d, 2H), 7.02 (d, IH), 4.67 (d, IH), 4.6 (t, 2H), 4.35 (d, IH), 3.47 (d, IH), 3.4 (d, IH), 3.24 (t, 2H), 3.17 (s, 3H), 2.4 (s, 3H), 1.48 (s, 3H), 1.45 (s, 3H).

V-27 ^lH NMR (CDCI₃, TFA salt) δ (ppm): 8.42 (s, IH), 8.31 (d, IH), 7.7 (d, IH),

7.57 (d, IH), 7.1 (d, IH), 7.0 (t, IH), 4.5 (t, 2H), 3.63 (s, 2H), 3.2 (t, 2H), 2.57 (s, 8H), 1.42 (s, 6H).

V-28 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.48 (s, IH), 8.3 (d, IH), 7.97 (d, IH),

7.9 (d, IH), 7.7 (d, IH), 7.2 (t, IH), 4.6 (m, 3H), 4.3 (m, IH), 3.5 (d, 2H), 3.38 (bs, 2H), 3.2 (s, 3H), 1.6 (s, 6H). Compound NMR Data

No.

V-29 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.92 (s, IH), 8.65 (d, IH), 7.90 (d, IH),

7.36 (d, 2H), 7.18 (d, IH), 7.16 (d, IH), 4.50 (s, 2H), 3.65 (t, 2H), 3.10 (t, 2H), 2.80 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).

V-30 ^lH NMR (CD₃OD, Formate salt) δ (ppm): 8.67 (s, IH), 8.0 (d, IH), 7.5 (s, IH),

7.4 (d, IH), 7.27 (d, IH), 7.23 (d, IH), 7.1 (s, IH), 4.7 (s, 2H), 4.42 (s, 2H), 3.6 (t, 2H), 3.1 (t, 2H), 3.05 (s, 3H), 2.6 (s, 3H), 1.28 (s, 3H).

V-31 1H NMR (DMSO, Formate salt) δ (ppm): 8.55-8.50 (d, 2H), 8.05-8.00 (d, IH),

7.85-7.80 (d, IH), 7.65-7.55 (d, 2H), 7.25 (s, IH), 7.15-7.10 (m, IH), 6.80-6.75 (d, IH), 3.58 (s, 2H), 3.05 (t, 2H), 2.78 (t, 2H), 2.41 (s, 3H), 2.38 (s, 3H).

V-32 1H NMR (CDCI₃, Free base) δ (ppm): 8.54 (d, 2H), 7.68 (d, IH), 7.55 (d, IH),

7.28 (d, 2H), 7.22 (s, IH), 7.10 (d, IH), 6.63 (d, IH), 4.06 (d, 2H), 3.28 (t, 2H), 2.91 (t, 2H), ), 2.46 (s, 3H).

V-33 ^lH NMR (CD₃OD, Free base) δ (ppm): 8.4 (d, 2H), 7.4 (s, IH), 7.27-7.38 (m,

3H), 7.18 (d, IH), 5.1 (t, IH), 4.62 (s, 2H), 4.3 (d, 2H), 4.0 (dd, 2H), 3.2 (m, IH), 3.1 (m, 2H), 2.73 (m, IH), 2.7 (s, 3H).

V-34 1H NMR (CD₃OD, formate salt) δ (ppm): 8.4 (d, 2H), 7.48 (d, 2H), 7.4 (s, IH),

7.18 (d, IH), 6.98 (d, IH), 4.6 (bs, IH), 4.4 (s, 2H), 4.3 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 3.1 (m, 2H).

V-35 1H NMR (CDCI₃, Free base) δ (ppm): 8.6 (d, 2H), 7.24 (s, IH), 7.2 (d, 2H), 7.0

(d, 2H), 5.98 (m, IH), 5.2 (dd, 2H), 5.0 (m, IH), 4.1 (m, 2H), 3.6 (dd, 2H), 3.22 (d, 2H), 2.7-2.9 (m, 3H), 2.6 (m, IH), 2.4 (s, 3H).

V-36 1H NMR (CD₃OD, formate salt) δ (ppm): 8.41 (d, 2H), 7.38 (d, 2H), 7.2 (m,

2H), 6.99 (d, IH), 5.03 (t, IH), 4.4 (bs, 2H), 4.3 (d, 2H), 3.93 (t, 2H), 3.45-3.62 (m, 2H), 3.2 (m, 2H), 2.9 (m, 2H), 2.4 (s, 3H).

V-37 ^lH NMR (CD₃OD, formate salt) δ (ppm): 8.42 (d, 2H), 7.4 (d, 2H), 7.2 (d, 2H),

6.9 (d, IH), 5.03 (t, IH), 4.6 (bs, IH), 4.57 (bs, 2H), 4.3 (m, 2H), 3.8 (s, 2H), 3.7 (bs, 2H), 3.0 (m, IH), 2.3 (s, 3H).

V-38 1H NMR (CDCI₃, Free base) δ (ppm): 8.58 (d, 2H), 7.17-7.21 (m, 4H), 7.0 (d,

IH), 4.6 (m, IH), 4.0 (m, 2H), 3.38 (dd, 2H), 2.8 (m, IH), 2.7 (m, 2H), 2.6 (m, 1H), 2.18 (s, 3H).

V-39 1H NMR (CDCI₃, Free base) δ (ppm): 8.7 (d, 2H), 7.3 (s, IH), 7.2 (d, IH), 7.19

(d, 2H), 7.17 (d, IH), 4.7 (t, IH), 4.0 (d, 2H), 3.5 (dd, 2H), 2.82 (m, IH), 2.7 (m, 2H), 2.58 (m, IH), 2.4 (s, 3H), 1.4 (s, 9H).

V-40 ^lH NMR (CD₃OD, formate salt) δ (ppm): 8.43 (bs, 2H), 7.39 (d, 2H), 7.23 (s,

IH), 7.2 (d, IH), 7.0 (d, IH), 5.07 (t, IH), 4.48 (bs, 2H), 4.23 (m, 2H), 3.7 (t, 2H), 3.6 (bs, 2H), 3.4 (t, 2H), 3.2 (m, IH), 2.95-3.03 (m, IH), 2.4 (s, 3H), 2.03 (bs, 2H).

V-41 1H NMR (CDCI₃, Free base) δ (ppm): 8.5 (d, 2H), 8.2 (d, IH), 7.7 (d, IH), 7.23

(d, 2H), 7.9 (m, IH), 5.08 (m, IH), 4.5 (d, IH), 4.3 (d, IH), 3.6 (dd, 2H), 2.9 (m, IH), 2.8 (m, IH), 2.7 (m, IH), 2.6 (m, IH), 2.5 (s, 3H).

V-42 1H NMR (CD₃OD, Free base) δ (ppm): 7.58 (d, IH), 7.2 (s, IH), 7.1 (s, IH), 7.0

(d, IH), 6.8 (d, IH), 6.4 (d, IH), 4.6 (bs, IH), 4.17 (m, 2H), 4.0 (m, 2H), 3.1- 3.25 (m, 2H), 2.97 (m, IH), 2.8 (s, 3H), 2.4 (s, 3H), 1.6 (s, 3H).

V-43 ^lH NMR (CD₃OD, Free base) δ (ppm): 8.41 (d, 2H), 7.42 (s, IH), 7.39 (d, 2H),

7.3 (d, IH), 7.19 (d, IH), 5.08 (t, IH), 4.66 (s, 2H), 4.4 (s, 2H), 4.3 (m, 2H), 3.5 (m, 2H), 3.2 (m, IH), 2.9 (m, IH). Compound NMR Data

No.

V-44 IH NMR, (CDCI₃, Free base) δ (ppm): 8.58 (s, 2H), 7.36 (m, 2H), 7.2 (m, 2H),

7.02 (d, IH), 5.1 (s, IH), 4.3 (m, IH), 4.1 (m, 2H), 4.0 (m, 2H), 3.56 (m, IH), 3.37 (m, IH), 3.1-3.3 (m, 2H), 2.8 (m, 2H), 2.42 (s, 3H), 1.2 (d, 3H).

V-45 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.6 (d, 2H), 7.27 (m, 2H), 7.2 (m, 2H),

7.0 (d, IH), 5.08 (t, IH), 4.19 (m, 2H), 3.9 (bs, 2H), 3.0-3.1 (m, 2H), 2.9 (m, IH), 2.6 (s, 2H), 2.56 (m, IH), 2.21 (s, 3H), 1.21 (s, 6H).

V-46 1H NMR (CD₃OD, Free base) δ (ppm): 7.3 (d, IH), 7.2 (s, IH), 7.05 (dd, IH),

6.7 (d , IH), 6.6 (s , IH), 6.53 (d , IH), 4.8 (t, IH), 4.21 (m, 3H), 4.05 (dd, IH), 3.34 (m, IH), 3.3 (m, IH), 2.88 (dt, IH), 2.81 (s, 3H), 2.5 (dt, IH), 2.4 (s, 3H).

V-47 1H NMR (CD₃OD, Free base) δ (ppm): 8.4 (d, IH), 8.37 (s, IH), 7.8 (d, IH),

7.4 (d, IH), 7.39 (m, IH), 7.2 (d, IH), 7.02 (d, IH), 5.1 (t, IH), 4.33 (d, 2H), 4.3 (s, 2H), 3.38-3.5 (m, 2H), 3.1 (m, IH), 2.9 (m, IH).

V-48 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.86 (d, IH), 8.19 (d, IH), 7.97 (d, IH),

7.78 (t, IH), 7.41 (d, IH), 7.56 (t, IH), 7.2 (d, IH), 6.93-7.01 (m, 2H), 5.57 (t, IH), 4.2 (dd, IH), 4.1 (dd, IH), 3.37 (dd, 2H), 2.83 (m, IH), 2.71 (bs, 3H), 2.4 (s, 3H), 2.38 (s, 3H).

V-49 ^lH NMR (CDCI₃, Free base) δ (ppm): 7.2 (s, IH), 7.19 (d, IH), 6.95 (d, IH),

4.15 (dd, IH), 3.92 (dd, IH), 3.7 (m, IH), 3.6 (s, 2H), 2.99 (m, IH), 2.8 (m, 3H), 2.58 (s, 3H), 2.42 (s, 3H), 1.9 (d, IH), 1.8(m, 2H), 1.7 (d, 2H), 1.52 (m, IH), 1.22 (m, 5H).

V-50 1H NMR (CD₃OD, TFA salt) δ (ppm): 7.5 (m, IH), 7.23 (s, IH), 7.2 (s, IH),

7.19 (d, IH), 6.5 (s, IH), 4.62 (d, IH), 4.19-4.37 (m, 3H), 3.8 (m, IH), 3.5 (m, IH), 3.24 (m, 2H), 3.1 (m, 4H), 2.4 (s, 3H).

V-51 1H NMR (CDCI₃, Free base) δ (ppm): 8.41 (d, 2H), 7.31 (s, IH), 7.18 (m, 4H),

4.79 (t, IH), 4.0 (m, 2H) , 3.68 (m, 3H), 3.56 (d, IH), 2.8 (m, 3H), 2.65 (m, 2H), 2.58 (m, IH).

V-52 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.39 (d, IH), 8.2 (s, IH), 7.6 (d, IH),

7.27 (s, IH), 7.2 (m, 2H) , 7.16 (d, IH), 4.8 (m, IH), 4.1 (dd, IH), 4.0 (dd, IH), 3.7 (m, 2H), 3.6 (d, IH), 3.5 (d, IH), 2.85 (m, 3H), 2.8 (m, IH), 2.63 (m, 2H).

V-53 1H NMR (CD₃OD, Free base) δ (ppm): 8.45 (d, 2H), 7.40 (d, 2H), 7.26 (s, IH),

7.23 (d, IH), 7.00 (s, IH), 5.06 (t, IH), 4.59 (m, 2H), 4.29 (m, 2H), 3.71 (t, 4H), 3.55 (m, 2H), 3.0 (d, IH), 2.4 (s, 3H).

V-54 1H NMR (CDCI₃, Free base) δ (ppm): 8.42 (d, 2H), 7.25 (s, IH), 7.15 (d, IH),

6.92 (d, 2H), 6.9 (d, IH) , 6.2 (d, IH), 5.3 (q, IH), 4.4 (dd, IH), 4.25 (dd, IH), 3.58 (dd, 2H), 2.6 (m, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 2.3 (m, 2H), 2.03 (s, 3H).

V-55 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.48-8.58 (m, 2H), 8.36 (d, IH), 7.67 (t,

IH), 7.16 (s, IH), 6.79 (s, 2H), 4.61 (d, IH), 4.55 (d, IH), 4.33 (d, IH), 3.90 (d, IH), 3.69-3.90 (m, 4H), 3.41-3.57 (m, IH), 3.20-3.36 (m, 2H), 2.34 (s, 3H), 1.77 (s, 3H).

V-56 ^lH NMR (CD₃OD, Free base) δ (ppm): 8.38 (d, 2H), 8.0 (s, IH), 7.63 (s, IH),

7.1 (d ,2H), 4.4 (t, 2H), 3.8 (s, 2H), 3.15 (t, 2H), 3.0 (t, 2H), 2.75 (t, 2H), 2.61 (s ,3H), 2.4 (s, 3H).

V-57 1H NMR, (CDCI₃, Free base) δ (ppm): 8.07 (s, IH), 7.28 (m, 2H), 7.07 (d, IH),

7.0 (s, 2H), 4.72 (m, IH), 4.3 (m, IH), 4.18 (m, IH), 3.31 (m, IH), 3.2 (m, IH), 3.12 (m, IH), 3.0 (m, 2H), 2.7 (m, IH), 2.51 (m, IH), 2.5 (s, 3H), 2.48 (s, 3H), 2.4 (d, IH), 2.28 (m, IH), 2.2 (m, IH), 2.0 (m, IH), 1.8 (m,lH). Compound NMR Data

No.

V-58 ^lH NMR, (CDCI₃, Free base) δ (ppm): 8.45 (s, IH), 7.6 (dd, IH), 7.22 (m, 2H),

7.1 (t, IH), 7.05 (t, IH), 5.08 (q, IH), 4.8 (dt, IH), 3.5 (m, 2H), 3.4 (m, 2H), 3.1 (d, IH), 3.0 (m, IH), 2.8 (m, IH), 2.6 (m, 2H), 2.5 (s, 3H), 2.41 (s, 3H), 2.1 (m, 3H).

V-59 1HNMR (CDCI₃, Free base) δ (ppm): 8.21 (s, IH), 8.07 (s, IH), 7.6 (s, IH),

7.21 (d, IH), 7.0 (d, IH), 4.3 (m, 2H), 3.28 (d, IH), 3.08 (m, IH), 3.0 (m, 4H), 2.54 (m, IH), 2.54 (s, 3H), 2.5 (m, IH), 2.4 (m, IH), 2.4 (s, 3H), 2.3 (d, IH), 1.9 (m, IH), 1.72 (m, 2H), 1.5 (q, 2H).

V-60 1H NMR (CDCI₃, Free base) δ (ppm): 8.7 (s, IH), 8.41 (d, IH), 8.02 (s, IH), 7.8

(d, IH), 7.5 (s, IH) , 7.19 (dd, IH), 4.3 (dd, 2H), 3.6 (d, IH), 3.5 (d, IH), 2.8 (m, 2H), 2.65 (m, IH), 2.55 (s, 3H), 2.49 (m, IH), 2.4 (s, 3H), 1.6 (s, 3H).

V-61 1H NMR (CDCI₃, Free base) δ (ppm): 8.42 (s, IH), 8.0 (s, IH), 7.5 (s, IH), 7.47

(d, IH), 7.07 (d, IH) , 5.1 (m, IH), 4.37 (dd, IH), 4.26 (dd, IH), 3.59 (dd, 2H), 2.78 (m, IH), 2.7 (m, 2H), 2.52 (s, 3H), 2.5 (s, 3H), 2.45 (m, IH), 2.42 (s, 3H).

V-62 1H NMR (CD₃OD, Free base) δ (ppm): 8.5 (s, IH), 8.39 (d, IH), 7.8 (d, IH),

7.26 (m, 2H), 7.1 (d, IH), 7.0 (d, IH), 4.6 (s,2H), 4.21 (q, 2H), 3.62 (s, 2H), 2.79 (m ,4H), 2.49 (s, 3H), 1.64 (s, 3H).

V-63 1H NMR (CD₃OD, Free base) δ (ppm): 8.5 (s, IH), 8.3 (d, IH), 7.82 (d, IH),

7.4 (s ,1H), 7.3 (dd, IH), 7.0 (m, 2H), 4.6 (s,2H), 4.4 (dd, 2H), 4.41 (d, IH), 4.2 (d, IH), 3.5 (m, 2H), 3.21 (m, IH), 3.0 (m, IH), 1.64 (s, 3H).

V-64 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.7 (s, IH), 8.25 (d, IH), 7.8 (d, IH), 7.4

(bs ,1H), 7.27 (d, IH), 7.2 (m, 2H), 7.0 (d,lH), 4.79 (d,lH), 4.6 (d, IH), 4.2 (d ,1H), 4.05 (d, IH), 3.85 (m, IH), 3.6 (m, IH), 3.4 (m, IH), 2.64 (m, IH), 2.4 (s, 3H), 1.6 (s, 3H).

V-65 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.18 (s, IH), 7.53 (s, IH), 6.82 (m, 4H),

4.86 (m , IH), 4.44 (m IH), 4.26 (m,lH) , 3.47 (m, IH), 3.3 (m, 2H), 3.12 (m, 2H), 2.89 (q, IH), 2.56 (m, IH), 2.49 (m, IH), 244 (s, 3H), 2.29 (m, IH), 1.8 (m, IH).

V-66 1H NMR (CDCI₃, Free base) δ (ppm): 7.35 (s, IH), 7.0 (s, IH), 6.9 (d, IH), 6.8

(d ,1H), 6.2 (s ,1H), 4.9 (t, IH), 4.2 (dd, 2H), 3.55 (d,lH), 3.4 (d, IH), 2.8 (m ,2H), 2.6 (m, 2H), 2.5 (s, 3H), 2.39 (s, 3H).

V-67 1H NMR (CDCI₃, Free base) δ (ppm): 8.81 (s, IH), 8.0 (m, 2H), 7.6 (d, IH),

7.52 (s, IH), 4.23 (q, 2H), 3.6 (d, IH), 3.5 (d, IH), 2.8 (m, IH), 2.72 (m, 3H), 2.5 (s, 3H), 2.4 (m, IH), 2.4 (s, 3H), 1.6 (s, 3H).

V-68 1H NMR (CDCI3, Free base) δ (ppm): 8.8 (s, IH), 8.15 (s, 1H),8.0 (d, IH), 7.68

(s, IH), 7.6 (d, IH), 4.23 (q, 2H), 3.6 (d, IH), 3.5 (d, IH), 2.8 (m, 3H), 2.72 (m, 1H), 2.5 (s, 3H), 2.4 (m, IH), 1.6 (s, 3H).

V-69 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.62 (s, IH), 8.1 (s, IH), 8.05 (d, IH),

7.95 (d ,1H), 7.8 (s ,1H), 5.23 (t, IH), 4.7 (d, IH), 4.53 (d, IH), 4.4 (m, 2H), 3.83 (m, IH), 3.6 (m, IH), 3.4 (m, 2H), 3.2 (s, 3H), 2.43 (s, 3H).

V-70 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.25 (s, IH), 8.2 (d, IH), 7.6 (d, IH), 7.4

(m ,3H), 7.2 (s ,1H), 7.19 (m, 3H), 6.65 (d, IH), 6.4 (d, IH), 5.5 (s, IH), 4.0 (d, IH), 3.43 (d, IH), 3.2 (m, IH), 3.0 (m, 3H), 2.6 (s, 3H), 2.3 (s, 3H), 1.6 (s, 3H).

V-71 1H NMR (CD₃OD, Free base) δ (ppm): 8.17 (d, 2H), 7.35 (m, 4H), 7.09 (d,

2H), 7.0 (m, 3H), 6.9 (d, IH), 4.8 (t, IH), 4.6 (s, IH), 4.08 (dd, IH), 3.45 (dd, IH), 3.0 (m, IH), 2.8 (m, 2H), 2.6 (m, IH), 2.4 (s, 3H), 2.2 (s, 3H). Compound NMR Data

No.

V-72 ^lH NMR (CD₃OD, Free base) δ (ppm): 8.38 (d, IH), 8.15 (s, IH), 7.45 (d, IH),

7.22 (t, IH), 7.1 (s, IH), 7.0 (s, IH), 6.8 (d, IH), 4.43 (d, IH), 4.2 (d, IH), 3.7 (d, IH), 3.5 (d, IH), 2.8 (m, 2H), 2.53 (m, IH), 2.5 (s, 3H), 2.4 (s, 3H), 2.2 (m, IH), 2.07 (d, 6H).

V-73 1H NMR (CDCI₃, Free base) δ (ppm): 8.62 (s, IH), 8.03 (s, IH), 7.73 (d, IH),

7.6 (d, IH), 7.5 (s, IH), 5.25 (d, IH), 4.45 (d, IH), 4.3 (dd, IH), 3.55 (dd, 2H), 2.8 (m, IH), 2.7 (m, 2H), 2.5 (s, 3H), 2.45 (s, 3H), 2.4 (m, IH).

V-74 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.0 (d, 2H), 7.31 (d, IH), 7.3

(s ,1H), 7.04 (d, IH), 5.45 (m, IH), 4.7 (d, IH), 4.59 (t, IH), 4.4 (m, 2H), 3.9 (d, IH), 3.6 (m, IH), 3.4 (m, IH), 3.2 (m, IH), 3.1 (s, 3H), 2.4 (s, 3H).

V-74 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.0 (d, 2H), 7.31 (d, IH), 7.3

V-75 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.74 (s, 2H), 7.91 (s, 2H), 7.28 (m, 2H),

7.04 (t, IH), 6.2 (m IH), 4.7 (d IH) , 4.59 (m, 2H), 4.3 (m, IH), 3.5 (t, IH),

3.34 (m, IH), 3.31 (m, 2H), 3.12 (s, 3H), 2.4 (s, 3H), 2.3 (m, 2H), 2.1 (m, IH),

1.35 (m, 2H), 1.22 (m, 2H), 1.15 (m, 3H), 0.86 (t,3H).

V-78 1H NMR (CDCI₃, Free base) δ (ppm): 8.6 (d, 2H), 8.07 (s, IH), 7.55 (s, IH),

7.27 (d ,2H), 5.23 (m IH), 4.37 (dd,lH) , 4.19 (m, IH), 3.62 (dd, 2H), 2.88 (m, 2H), 2.82 m, 2H), 2.56 (s, 3H), 2.42 (s, 3H).

V-79 IH NMR (CD₃OD, TFA salt) δ (ppm): 8.2 (s, IH), 8.0 (s, IH), 7.68 (d, 2H), 7.6

(d ,2H), 5.2 (dd, IH), 4.5 (dd, IH), 4.45 (s, 2H), 4.33 (dd, IH), 3.6 (t, 2H), 3.25 (d, IH), 3.1 (d, 1H), 2.5 (s, 3H).

V-80 1H NMR (CDCI₃, Free base): δ (ppm): 8.55 (d, IH), 8.5 (s, IH), 7.2 (d, IH),

7.18 (m, 3H), 6.9 (d, IH), 4.3 (dd, 2H), 3.65 (d, IH), 3.52 (d, IH), 2.65 (m, 2H), 2.5 (m, 2H), 2.5 (s, 3H), 2.4 (s, 3H), 2.3 (d,lH), 2.0 (s, 3H), 2.0 (m, IH), 1.2 (s, 9H).

V-84 1H NMR (CD₃OD, Di-HCl salt) δ (ppm): 8.7 (m, 3H), 7.79 (d, IH), 7.43 (d,

IH), 6.9 (m, 2H), 4.7 (d, IH), 4.4 (dd, 2H), 4.15 (t, IH), 3.95 (m, IH), 3.8 (m, IH), 3.6 (m, IH), 3.5 (m, IH), 2.4 (m, 4H), 1.9 (m, 3H), 1.8 (d, 3H).

V-85 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.2 (s, 2H), 7.95 (d, IH), 7.8 (s, IH), 7.6

(d ,1H), 5.0 (t ,1H), 4.6 (m, 2H), 3.62 (m, IH), 3.5 (m, 2H), 3.3 (m, 3H), 2.8 (d, IH), 2.63 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.1 (m, IH).

V-86 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.4 (s, 1H),8.1 (d, IH), 7.75 (d, IH), 7.0

(q, 2H), 4.8 (m, IH), 4.0 (m, IH), 3.8 (m, 2H), 3.4 (m, 3H), 3.3 (m, 2H),3.2 (t, 3H),3.0 (s, 3H), 2.7 (s, 3H).

V-87 1H NMR (CD₃OD, HC1 salt) δ (ppm): 7.32 (d, IH), 7.3 (s, IH), 7.1 (t, 2H), 7.0

(m, 3H), 5.08 (t, IH), 4.4 (dd, IH), 4.19 (dd, IH), 3.6 (m, 2H), 3.45 (m, IH), 3.0 (d, IH), 2.6 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.0 (m, IH).

V-88 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 7.4 (m, 2H), 7.2 (m, 2H), 7.0 (m, 3H),

5.08 (t, IH), 4.3 (d, IH), 4.15 (d, IH), 3.65 (m, IH), 3.5 (m, 2H), 3.3 (m, IH), 2.90 (m, 2H), 2.7 (m, IH), 2.4 (s, 3H), 2.2 (m, 3H), 1.62 (s, 3H).

V-89 1H NMR (CD₃OD, Free base) δ (ppm): 8.41 (d, 2H), 8.19 (d, IH), 7.73 (s, IH),

7.36 (d, 2H), 7.06 (m, 1H),5.04 (t, IH), 4.6 (m, IH), 4.33 (m, 2H), 3.76 (dd, 2H), 2.9 (m, 4H), 2.5 (s, 3H). Compound NMR Data

No.

V-90 1H NMR (CD₃OD, Free base) δ (ppm): 8.5 (s, IH), 8.43 (d, 2H), 8.01 (d, IH),

7.4 (d, IH), 7.38 (d, 2H),5.07 (t, IH), 4.4 (m, 2H), 3.68 (s, 2H), 3.3 (s, 2H), 2.85 (m, 4H), 2.45 (s, 3H).

V-91 ^lH NMR (CD₃OD, HC1 salt) δ (ppm): 8.8 (d, 2H), 8.2 (d, 2H), 8.1 (s, IH), 7.9

(s, IH), 5.38 (m, 1H),5.09 (t, IH), 4.68 (dd, 2H), 4.4 (m, IH), 3.75 (m, 4H), 3.43 (m, 2H), 2.7 (m, 2H), 2.46 (s, 3H), 2.2 (m, 3H).

V-92 1H NMR (CD₃OD, Free base) δ (ppm): 8.46 (s, IH), 8.39 (s, IH), 8.36 (d, IH),

7.96 (d, IH), 7.82 (d, 1H),7.37 (d, IH), 7.31 (t, IH), 4.4 (dd, 2H),3.71 (dd, 2H), 3.0 (m, IH), 2.9 (m, IH), 2.72 (m, IH), 2.62 (m, IH), 2.52 (s, 3H), 1.72 (s, 3H).

V-93 1H NMR (CD₃OD, Free base) δ (ppm): 8.51 (s, IH), 8.3 (d, IH), 8.13 (d, IH),

7.83 (d, IH), 7.57 (d, 1H),7.31 (t, IH), 6.99 (t, IH), 4.33 (dd, 2H), 3.78 (dd, 2H), 3.0 (m, IH), 2.85 (m, IH), 2.75 (m, 2H), 2.53 (s, 3H), 1.69 (s, 3H).

V-94 ^lH NMR (CD₃OD, HC1 salt) δ (ppm): 8.70 (d, 3H), 7.98 (s, IH), 7.13 (d, IH),

6.96 (s, IH), 6.76 (t, IH), 4.82 (d, 2H), 4.30-4.44 (m, 2H), 3.84-3.90 (m, 2H), 3.31-3.40 (m, IH), 3.09-3.13 (m, IH), 2.60 (d, IH), 2.30-2.60 (m, 2H), 1.96- 2.05 (m, IH), 1.79 (s, 3H).

V-95 ^lH NMR (CD₃OD, HC1 salt) δ (ppm): 8.72-8.78 (m, 2H), 8.06 (d, IH), 8.01 (d,

IH), 7.23 (s, IH), 7.14 (dd, IH), 6.90-6.98 (m, IH), 5.06 (t, IH), 4.68 (d, 2H), 4.42-4.48 (m, 2H), 4.33 (d, IH), 3.86-2.90 (m, 2H), 3.52-3.62 (m, 2H), 3.19- 3.24 (m, 2H), 3.13 (s, 3H), 2.38 (s, 3H), 1.48-1.58 (m, 2H), 0.84 (t, 2H).

V-96 ^lH NMR (CD₃OD, HC1 salt) δ (ppm): 8.75 (d, 2H), 8.04 (d, 2H), 7.23 (s, IH),

7.12 (d, IH), 6.90-6.99 (m, IH), 5.06 (t, IH), 4.65-4.75 (m, IH), 4.40-4.56 (m, 2H), 4.16-4.20 (m, IH), 3.85-3.3.95 (m, IH), 3.50-3.63 (m, IH), 3.20-3.50 (m, 4H), 3.13 (s, 3H), 2.39 (s, 3H), 1.13 (t, 3H).

V-98 ^lH NMR (CD₃OD, Free base) δ (ppm): 8.28 (s, 2H), 7.64 (d, IH), 7.18-7.22 (m,

IH), 6.99 (s, IH), 6.55 (s, IH), 4.40-4.58 (m, 2H), 4.24 (brs, IH), 3.18-3.22 (m, IH), 2.80-3.12 (m, 3H), 2.48 (s, 3H), 2.38-2.61 (m, 2H), 2.31 (s, 3H), 1.98 (brs, 4H), 1.58 (s, 3H).

V-99 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.58 (d, IH), 7.45 (t, IH), 7.10-7.25 (m,

2H), 7.04 (d, IH), 6.89 (d, IH), 6.68 (d, IH), 5.00-5.05 (m, IH), 4.10-4.40 (m, 4H), 3.33 (d, 2H), 2.42 (s, 3H), 2.25-2.40 (m, 4H), 1.80-2.10 (5H).

V-100 1H NMR (CDCI₃, Free base) δ (ppm): 8.51 (s, IH), 8.33 (d, IH), 7.49 (d, IH),

7.07 (s, IH), 7.05 (d, IH), 6.92 (d, IH), 4.09 (q, 2H), 3.72 (q, 2H), 2.70-2.96 (m, 4H), 2.55 (s, 3H), 2.40 (s, 3H), 1.54 (s, 3H).

V-101 1H NMR (CDCI₃, free base) δ (ppm): 7.96 (s, IH), 7.45 (d, IH), 7.14 (s, 2H),

6.99 (d, IH), 6.51 (d, IH), 4.30 (d, IH), 4.10-4.30 (m, 2H), 4.00 (d, IH), 3.39 (s, 2H), 3.31 (brs, IH), 2.86-3.20 (m, 4H), 2.42 (s, 3H), 2.03 (s, 3H), 1.54 (s, 3H).

V-102 1H NMR (CD₃OD, HC1 salt) δ (ppm): 8.04 (d, IH), 7.38 (d, IH), 7.20 (s, IH),

7.00-7.17 (m, 2H), 6.88 (d, IH), 5.03 (brs, IH), 4.33 (dd, IH), 4.25 (dd, IH), 3.50-3.70 (m, 3H), 3.02-3.40 (m, 3H), 2.65-2.75 (m, IH), 2.38 (s, 3H), 2.10- 2.30 (m, 3H), 1.64 (s, 3H).

V-103 1H NMR (CDCI3, free base) δ (ppm): 8.55 (d, 2H), 7.15 (m, 4H), 7.00 (d, IH),

4.65 (t, IH), 4.15 (dd, IH), 4.05 (dd, IH), 3.78 (m, 2H), 3.35 (m, IH), 2.90 (m, 3H), 2.65 (m, IH), 2.60 (s, 3H), 2.40 (s, 3H), 1.05 (d, 3H), 0.85 (d, 3H).

V-104 ^lH NMR (CDCI₃, free base) δ (ppm): 8.58 (d, 2H), 7.35 (d, 2H), 7.33 (s, IH),

7.32 (s, IH), 4.10 (dd, 2H), 3.95 (m, IH), 3.20 (m, IH), 2.85-2.70 (m, 4H), 2.60 (m, IH), 2.45 (m, IH), 2.40 (s, 3H), 1.90 (m, 3H), 1.60 (s, 3H). Compound NMR Data

No.

V-105 1H NMR (CDCI3, free base) δ (ppm): 8.70 (s, IH), 8.50 (d, IH), 7.55 (d, IH),

7.05 (m, 3H), 6.80 (m, IH), 4.75 (bs, IH), 4.20 (dd, 2H), 3.85 (t, IH), 3.18 (m, IH), 2.85 (m, 2H), 2.75 (m, IH), 2.58 (m, 2H), 2.35 (m, IH), 1.85 (m, 3H), 1.70 (s, 3H).

V-106 1H NMR (CDCI3, free base) δ (ppm): 8.58 (d, 2H), 7.35 (d, 2H), 7.20 (s, IH),

6.85 (d, IH), 4.50 (d, IH), 4.15 (d, IH), 3.80 (t, IH), 3.25 (m, IH), 2.90 (m, 2H), 2.70 (m, 2H), 2.45 (m, 2H), 1.90 (m, 3H), 1.55 (s, 3H).

V-107 1H NMR (CDCI3, free base) δ (ppm): 8.70 (s, IH), 8.55 (d, IH), 7.65 (d, IH),

7.20 (m, 2H), 6.82 (d, IH), 4.55 (d, IH), 4.20 (d, IH), 3.85 (t, IH), 3.25 (m, IH), 2.90-2.70 (m, 4H), 2.45 (m, 2H), 1.90 (m, 3H), 1.60 (s, 3H).

V-108 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.21 (s, IH), 7.78 (d, IH), 7.43 (s, IH),

7.17 (s, IH), 7.02 (d, IH), 6.87 (d, IH), 5.14 (t, IH), 4.16-4.45 (m, 4H), 3.21- 3.42 (m 2H), 2.85-3.20 (2H), 3.09 (s, 3H), 2.90 (s, 3H), 2.84 (s, 3H), 2.36 (s, 3H).

V-109 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.40 (s, IH), 7.98 (d, IH), 7.82 (s, IH),

7.10-7.25 (m, 2H), 6.93-7.10 (m, IH), 5.16 (t, IH), 4.60-4.72 (m, IH), 4.20- 4.40 (m 2H), 3.60-3.95 (m, 3H), 3.09 (s, 3H), 2.80-2.95 (m, IH), 2.40 (s, 3H), 0.84 (d, 2H), 0.66 (brs, 2H).

V-110 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.00 (brs, IH), 7.74 (d, IH), 7.16 (s,

IH), 6.80-6.97 (m, 2H), 6.74 (t, IH), 4.66 (d, IH), 4.17-4.38 (m, 4H), 4.04 (t, 2H), 3.79 (brs, IH), 3.05-3.58 (m, 3H), 3.09 (s, 3H), 2.36 (s, 3H), 1.66 (s, 3H), 0.59 (d, 2H), 0.33 (d, 2H).

V-112 1HNMR (CD₃OD, TFA salt): 8.96 (s, IH), 8.70 (d, IH), 8.18 (d, IH), 8.05 (m,

2H), 7.85 (m, IH), 7.11 (s, IH), 6.60 (d, IH), 6.40 (d, IH), 4.82 (m, IH), 4.50- 4.30 (m, 3H), 3.82 (m, IH), 3.80-3.60 (m, 2H), 3.50 (m, IH), 3.10 (s, 3H), 2.20 (s, 3H), 1.90 (s, 3H).

V-113 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.71 (s, IH), 8.53 (d, IH), 7.66 (d, IH),

7.16-7.21 (m, 2H), 7.57 (d, IH), 6.84 (t, IH), 4.13 (q, 2H), 3.90 (brs, IH), 3.20- 3.26 (m, IH), 2.81-2.92 (m, IH), 2.70-2.81 (m, 3H), 2.38-2.42 (m, 2H), 1.80- 1.97 (m, 3H), 1.66 (s, 3H).

V-114 ^lH NMR (CD₃OD, HC1 salt) δ (ppm): 8.68 (m, 3H), 7.95 (m, IH), 7.29 (d,

IH), 6.9 (m, IH), 4.68 (dd, IH), 4.38 (m, 2H), 4.32 (dd, IH), 3.9 (m, IH), 3.52 (m, 2H), 3.25 (m, IH), 3.12 (s, 3H), 2.35 (d, 3H), 1.83 (d, 3H).

V-115 1H NMR (CD₃OD, Free base) δ (ppm): 8.46 (s, IH), 8.34 (d, IH), 7.82 (d, IH),

7.29 (t, IH), 6.87 (d, IH), 6.77 (d, IH), 4.22 (dd, 2H), 3.99 (q, 2H), 2.73 (m, 4H), 2.5 (s, 3H), 2.3 (s, 3H), 1.66 (s, 3H).

V-116 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.39 (s, IH), 8.12 (d, IH), 7.66 (d, IH),

7.26 (d, IH), 7.1 (d, 1H),4.67 (m, 4H), 3.7 (m, 2H), 3.27 (t, 2H), 3.18 (m, 2H), 3.15 (s, 3H), 2.69 (s, 3H).

V-117 ^lH NMR (CD₃OD, TFA) δ (ppm): 8.37 (s, IH), 8.12 (d, IH), 7.73 (d, IH), 7.02

(dd, IH), 6.86 (t, IH), 5.1 (m, IH), 4.57 (t, 2H), 4.56 (m, IH), 3.85 (m, IH), 3.6 (m, IH), 3.27 (m, 3H), 3.2 m (2,H), 3.1 (s, 3H), 2.69 (s, 3H).

V-118 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.43 (s, IH), 8.18 (d, IH), 7.74 (d, IH),

7.09 (d, IH), 7.04 (d, IH), 4.79 (t, 2H),4.65 b(s, IH), 3.62 b(s, IH), 3.5 (m, 2H), 3.35 (m, 2H), 3.25 (t, 2H), 3.16 (s, 3H), 2.75 (s, 3H). Compound NMR Data

No.

V-119 1H NMR (CD₃OD, HC1 salt) δ (ppm): 8.79 (d, 2H), 8.03 (d, 2H), 7.13 (s, IH),

6.82 (s, IH), 5.22 (dd, 1H),5.01 (t, IH), 4.67 (dd, IH), 4.48 (dd, IH), 4.79 (m, IH), 3.64 (t, 2H), 3.4 (m, 3H), 2.9 (m, IH), 2.73 (s, 3H), 2.37 (s, 3H), 2.22 (m, 3H).

V-120 1H NMR (CD₃OD, HC1 salt): 8.8 (s, IH), 8.6 (d, 2H), 7.88 (s, 2H), 7.84 (d, IH),

4.99 (m, 2H), 4.4 (d, IH), 3.78 (m, 2H),3.4 (m, 2H), 3.4 (m, 2H), 2.7(m, IH), 2.2 (m, 3H), 1.83 (s, 3H).

V-121 1H NMR (CD₃OD, HC1 salt) δ (ppm): 8.66 (dd, 2H), 8.56 (s, IH), 7.92 (t, IH),

7.20 (s, IH), 6.77 (t, 2H), 5.04 (t, IH), 3.75 (dd, 2H),3.72 (m, 2H), 3.6 (m, IH), 3.44 (m, 2H), 3.22 (d, IH), 2.75 (m, IH), 2.73 (s, 3H), 2.16 (m, 3H), 1.8 (s, 3H).

V-122 1H NMR (CD₃OD, HC1 salt) δ (ppm): 8.5 (d, IH), 8.3 (s, IH), 7.79 (d, IH),

7.22 (s, IH), 6.82 (s, 2H), 5.03 (t, IH), 4.38 (dd, 2H), 3.8 (m, IH), 3.66 (m, 2H),3.46 (m, 2H), 3.2 (m, 2H), 2.7 (m, IH), 2.67 (s, 3H), 2.36 (s, 3H), 2.22 (m, 2H), 1.77 (s, 3H).

V-123 1H NMR (CD₃OD, Free base) δ (ppm): 8.5 (d, IH), 8.36 (s, IH), 7.8 (dd, IH),

7.31 (m ,1H), 7.19 (s, IH), 7.1 (d, IH) , 6.88 (d, IH), 4.86 (m, IH), 4.58 (s, IH) , 4.32 (d, IH), 4.25 (m, 2H), 3.94 (m, 2H), 3.8 (m, IH), 3.35 (s, 3H), 3.2 (m ,1H), 3.0 (m, IH), 2.36 (s,3H), 1.69 (s, 3H).

V-124 1H NMR (CD₃OD, TFA salt) δ (ppm): 7.94 (d, IH), 7.58 (s, IH), 7.18 (s, IH),

7.03 (d, IH), 6.84 (brs, 2H), 4.69 (d, 2H), 4.19-4.33 (m, 3H), 3.86 (brs, IH), 3.52 (brs, 2H), 3.19 (s, 6H), 3.11 (s, 3H), 1.95-2.36 (s, 3H), 1.66 (s, 3H).

V-125 ^lH NMR (CDCl₃,Free base) δ (ppm): 8.70 (s, IH), 8.49 (d, IH), 7.62 (d, IH),

7.36 (s, IH), 7.12 (m, 2H), 7.02 (d, IH), 4.17 (q, 2H), 3.86 (t, IH), 3.19 (m, IH), 2.86 (m, IH), 2.74 (m, 3H), 2.41 (m, 2H), 1.85 (m, 3H), 1.7 (s, 3H).

V-126 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.7 (d, IH), 8.53 (s, IH), 8.4 (d, IH),

7.85 (t, IH), 7.25 (s, IH), 7.08 (t, 1H),6.9 (d, IH), 5.28 (t, IH), 5.03 (t, IH), 4.42 (s, 2H), 3.76 (m, IH), 3.6 (m, 2H), 3.4 (m, IH), 3.2 (m, 2H),2.7 (m, IH), 2.38 (s, 3H), 2.2 (m, 3H).

V-127 1H NMR (CD₃OD, Free base) δ (ppm): 8.45 (d, 2H), 7.42 (d, 2H), 7.22 (s, IH),

7.2 (d ,1H), 7.0 (d, IH), 5.09 (m, 2H) , 4.6 (s, IH), 4.45 (dd, IH), 4.29 (m, 2H), 4.19 (m, IH) , 3.96 (m, 2H), 3.81 (d, IH), 3.7 (t, IH), 3.2 (d, IH), 3.1 (m, IH), 3.82 (m ,1H), 2.4 (s, 3H), 2.34 (m,lH), 2.09 (m, IH).

V-128 1H NMR (CDCI3, Free base): δ (ppm): 8.58 (d, 2H), 7.28 (d, IH), 7.25 (s, IH),

7.23 (d, 2H), 7.1 (d, IH), 4.9 (m, IH), 4.42 (t, IH), 4.13 (dd, IH), 3.63 (m, IH), 3.4 (m, 2H), 3.01 (m, 2H), 2.71 (m, 2H), 2.45 (s, 3H), 2.23 (m, 2H), 2.01 (m, IH).

V-129 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.56 (m, 2H), 8.11 (dd, IH), 7.6 (t, IH),

7.2 (s ,1H), 6.85 (m, 2H), 4.67 (d, IH) , 4.47 (d, IH), 4.39 (s, 2H), 3.84 (m, IH), 3.48 (m, IH), 3.34 (m, IH) , 3.12 (s, 3H), 3.12 (m, IH), 2.36 (s, 3H), 2.03 (s, 3H).

V-130 1H NMR (CD₃OD, TFA salt) δ (ppm): 7.43 (d, IH), 7.23 (m, 2H), 7.05 (t, IH),

6.7 (m, IH), 6.5 (d, 1H),4.79 (m, IH), 4.3 (m, 2H), 3.9 (m, 2H), 3.8 (m, IH), 3.6 (m, IH), 3.4 (m, 2H), 3.1 (m, IH), 2.6 (m, IH), 2.4 (s, 3H), 2.3 (m, 2H), 1.9 (m, IH).

V-131 1H NMR (CD₃OD, Free base) δ (ppm): 8.4 (d, 2H), 7.63 (d, IH), 7.29 (dd, 2H),

6.95 (t, IH), 5.0 (t, 1H),4.3 (m, 3H), 3.21 (m, IH), 2.9 (m, 4H), 2.7 (m, IH), 2.57 (s, 3H), 2.52 (m, IH), 1.9 (m, 3H). Compound NMR Data

No.

V-132 1H NMR (CDCI3, Free base) δ (ppm): 8.59 (d, 2H), 7.38 (d, 2H), 7.25 (s, IH),

7.18 (d, IH), 6.96 (d, IH), 4.23 (dd, 2H), 2.89 (m, 2H), 2.75 (m, 4H), 2.6 (m, 2H), 2.43 (s, 3H), 2.42 (s, 3H),1.58 (s, 3H).

V-133 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.74 (s, IH), 8.54 (d, IH), 7.71 (d, IH),

7.26 (s, IH), 7.27 (m, 1H),7.19 (d, IH), 6.96 (d, IH), 4.26 (dd, 2H), 2.91 (m, 2H), 2.9 (m, 4H), 2.74 (m, 2H), 2.44 (s, 6H), 1.63 (s, 3H).

V-134 1H NMR (CDCI₃, Free base) δ (ppm): 7.4 (q, IH), 7.2 (s, IH), 7.18 (d,

1H),7.01 (d, IH), 6.99 (d, IH), 6.92 (d, IH), 5.13 (dd, IH), 4.26 (dd, IH), 4.2 (dd, IH), 2.9 (d, IH), 2.93 (m, 2H), 2.8 (m, IH), 2.83 m (4,H), 2.5 (s, 3H), 2.46 (s, 3H).

V-135 1H NMR (CDCI₃, Free base) δ (ppm): 8.49 (s, IH), 8.04 (d, IH), 7.86 (d, IH),

7.66 (s, IH), 7.01 (s, IH), 6.85 (s, IH), 6.78 bs (NH), 5.48 s (OH),4.16 (dd, 2H), 3.44 (q, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H), 1.6 (s, 3H).

V-137 ^lH NMR (CDCI₃, Free base): δ (ppm): 8.72 & 8.69 (s, IH), 8.25 (t, IH), 7.62 &

7.6 (d, IH), 7.43 (t, IH), 7.22 & 7.19 (m, IH), 6.86 (t, IH), 4.25 (m, 2H),3.2 (m, IH), 2.99 (m, IH), 2.85 (t, 2H), 2.7(m, IH), 2.626 (s, 3H), 2.5 (m, 2H), 2.4 (m, IH), 2.15 (m, IH), 1.85 (m, 2H), 1.69 & 1.66 (s, 3H).

V-138 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 7.67 (s, 2H), 7.28 (m, 3H), 7.04 (d, IH),

5.21 (m, IH), 5.04 (t, IH), 4.39 (m, 2H), 3.67 (m, 3H), 3.25 (m, 2H), 3.03 (m, IH), 2.68 (m, IH), 2.41 (s, 3H), 2.19 (m, 3H).

V-139 1H NMR (CD₃OD, TFA salt) δ (ppm): 7.44 (s, 2H), 7.27 (s, IH), 7.13 (d, IH),

6.99 (d, IH), 5.37 (t, IH), 5.1 (m, 1H),4.56 (dd, IH), 4.46 (dd, IH), 3.67 (m, 3H), 3.42 (m, IH), 3.24 (m, 2H), 2.7 (m, IH), 2.4 (s, 3H),2.2 (m, 3H).

V-140 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.79 (s, IH), 7.4 (s, IH), 7.27 (s, IH),

7.2 (dd, IH), 7.01 (d, IH), 5.18 (t, IH), 5.04 (m, IH), 4.39 (m, 2H), 3.67 (m, 3H), 3.42 (m, 2H), 3.2 (m, IH), 2.7 (m, IH), 2.4 (s, 3H), 2.2 (m, 3H).

V-141 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.9 (d, IH), 8.7 (d, IH), 8.57 (d, IH),

7.11 (s, IH), 6.74 (d, 2H), 4.67 (dd, 1H),4.33 (m, 2H), 4.29 (dd, IH), 3.9 (t, IH), 3.6 (m, 2H), 3.2 (m, IH), 3.11 (s, 3H), 2.3 (s, 3H), 1.79 (d, 3H).

V-142 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.09 (s, IH), 7.18 (s, IH), 6.97 (d, IH),

6.92 (d, IH), 6.8 (s, IH), 4.7 (m, IH), 4.35 (m, 3H), 3.9 (m, IH), 3.56 (m, IH), 3.25 (m, 2H), 3.09 (s, 3H), 2.37 (s, 3H), 1.58 (s, 3H).

V-143 1H NMR (CD₃OD, TFA salt) δ (ppm): 7.79 (d, IH), 7.35 (m, 2H), 7.17 (s, IH),

6.93 (d, IH), 6.34 (t, IH), 4.61 (d, 2H), 4.3 (d, 2H), 3.9 (m, IH), 3.8 (m, IH), 3.36 (m, 2H), 3.1 (s, 3H), 2.37 (s, 3H), 1.51 (s, 3H).

V-144 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.6 (dd, IH), 8.1 (t, IH), 7.9 (t, IH), 7.33

(dd, IH), 7.26 (s, IH), 7.06 (t, IH), 5.3 (t, IH), 4.7 (dd, IH), 4.42 (dd, IH), 4.4 (dd, 2H), 4.3 (m, IH), 3.8 (m, 1H),3.6 (m, IH), 3.34 (dd, IH), 3.1 (d, 3H), 2.4 (s, 3H).

V-145 1H NMR (CDCI₃, Free base): δ (ppm): 8.71 (d, 2H), 8.58 (s, IH), 8.56 (d, IH),

7.64 (d, 2H), 7.32 (d, IH), 7.21 (s, IH), 7.18 (d, 2H), 6.97 (d, IH), 4.45 (dd, 2H), 3.65 (d, IH), 3.57 (d, IH), 2.7 (m, IH), 2.52 (m, IH), 2.49 (s, 3H), 2.46 (s, 3H), 2.43 (m, IH), 2.16 (s, 3H), 2.01 (m, IH).

V-146 1H NMR (CD₃OD, Free base) δ (ppm): 8.46 (d, 2H), 7.33 (d, 2H), 7.27 (d, IH),

7.23 (s, IH), 7.01 (d, IH), 6.07 (t, IH), 4.8 (t, 2H), 4.5 (m, 2H), 3.55 (m, 2H), 3.45 (m, IH), 3.0 (q, 2H), 2.7 (m, IH), 2.54 (m, 2H), 2.39 (s, 3H), 2.37 (m, 1H), 2.1 (m, 4H). Compound NMR Data

No.

V-147 1H NMR (CD₃OD, Free base) δ (ppm): 7.32 (m, 3H), 7.26 (s, IH), 7.13 (m,

2H), 7.09 (d, IH), 5.09 (t, IH), 4.8 (m, IH), 4.32 (m, 2H), 3.44 (m, 2H), 3.3 (m, IH), 3.1 (m, IH), 3.0 (d, IH), 2.8 (m, IH), 2.6 (m, IH), 2.4 (s, 3H), 2.18 (m, 2H), 2.0 (m, IH).

V-148 1H NMR (CD₃OD, TFA salt): δ (ppm): 8.06 (s, IH), 7.48 (s, IH), 7.21 (s, IH),

7.17 (d, 1H),7.00 (d, IH), 4.98 (t, IH), 4.28 (d, 2H), 3.6 (m, 3H), 3.39 (m, 2H), 3.2 (m, IH), 3.15 (s, 6H), 2.8 (m, IH), 2.7 (m, IH), 2.39 (s, 3H), 2.17 (m, 3H).

V-149 1H NMR (CDCI₃, Free base) δ (ppm): 8.45 (d, 2H), 8.17 (s, IH), 7.56 (s, IH),

6.91 (d, 2H), 4.5 (m, 1H),4.42 (t, IH), 4.35 (m, IH), 3.26 (m, 2H), 3.16 (m, 5H), 2.81 (m, IH), 2.45 (m, IH), 2.41 (s, 3H), 2.1 (m, 2H), 1.9 (m, IH).

V-150 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.35 (s, IH), 8.13 (d, IH), 7.73 (d, IH),

6.7 (m, 2H), 4.8 (m, IH), 4.57 (t, 2H),4.5 (m, IH), 3.9 (m, IH), 3.6 (m, IH), 3.35 (m, 2H), 3.19 (m, 2H), 3.13 (s, 3H), 2.69 (s, 3H).

V-151 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.46 (s, IH), 8.18 (d, IH), 7.72 (d, IH),

7.28 (d, IH), 7.18 (d, IH), 5.2 (m, 2H),4.6 (m, 2H), 3.9 (m, IH), 3.6 (m, IH), 3.2 (m, 4H), 3.15 (s, 3H), 2.71 (s, 3H).

V-152 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.43 (s, IH), 8.14 (d, IH), 7.7 (d, IH),

7.35 (d, IH), 7.03 (d, 1H),5.0 (m, 2H), 4.6 (m, 2H), 3.8 (m, IH), 3.6 (m, IH), 3.27 (t, 2H), 3.22 (t, 2H), 3.14 (s, 3H), 2.7 (s, 3H).

V-153 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.42 (s, IH), 8.15 (d, IH), 7.7 (d, IH),

7.1 (dd, IH), 6.8 (t, 1H),4.8 (m, 2H), 4.5 (m, 2H), 3.8 (m, IH), 3.6 (m, IH), 3.3 (t, 2H), 3.2 (t, 2H), 3.1 (s, 3H), 2.7 (s, 3H).

V-154 ^lH NMR (CD₃OD, Free base) δ (ppm): 8.1 (d, 2H), 7.3 (d, IH), 7.13 (s, IH),

6.98 (d, IH), 6.8 (d, 2H), 4.09 (s, 2H), 3.6 (dd, IH), 3.4 (m, 3H), 2.9 (m, 2H), 2.8 (s, 3H), 2.39 (s, 3H), 2.32 (m, IH).

V-155 1H NMR (CDCI3, Free base): δ (ppm): 9.1 & 8.91 (s, IH), 8.8 & 8.7 (s, IH), 8.6

& 8.5 (d, IH), 7.6 & 7.8 (d, IH), 7.18 (s, 2H), 4.4 (dd, IH), 4.2 (m, 2H), 3.32 (m, 2H), 2.7 (dd, IH), 2.66 (s, 3H), 1.99 (m, 2H), 1.9 (m, 2H), 1.76 & 1.67 (s, 3H), 1.6 (m, 3H).

V-156 1H NMR (CD₃OD, TFA salt): δ (ppm): 8.1 (s, 1H),7.4 (s, IH), 7.1 (d, IH), 5.1

(t, IH), 4.42 (m, 2H), 3.6 (m, 3H), 3.2 (m, IH), 3.17 (m, IH), 3.15 (s, 6H), 2.85 (m, 2H), 2.63 (m, IH), 2.42 (s, 3H), 2.3 (m, 2H), 2.15 (m, IH).

V-157 1H NMR (CDCI3, Free base) δ (ppm): 8.65 (d, IH), 8.60 (s, IH), 8.50 (s, IH),

7.8 (d, IH), 7.22 (d, 1H),7.09 (t, IH), 5.1 (m, IH), 4.8 (m, IH), 4.6 (dd, IH), 4.3 (m, IH), 3.45 (m, 3H), 2.97 (m, 2H), 2.84 (m, 2H), 2.6 (m, IH), 2.45 (d, 3H), 2.2 (m, IH), 1.9 m (lH).

V-158 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.48 (s, IH), 8.39 (s, IH), 8.1 (s, IH),

8.06 (s, IH), 7.7 (s, 1H),5.1 (m, IH), 4.64 (t, 2H), 3.7 (m, 4H), 3.03 (t, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 2.15 (m, 4H).

V-159 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.61 (s, IH), 8.56 (d, IH), 7.55 (d, IH),

7.23 (d, IH), 7.16 (s, 1H),7.05 (d, IH), 6.93 (d, IH), 4.3 (m, 2H), 3.8 (dd, 2H), 2.96 (m, IH), 2.9 (m, IH), 2.7 (m, IH), 2.6 (m, IH), 2.58 (s, 3H), 2.41 (s, 3H), 1.75 (d, 3H).

V-160 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.6 (s, IH), 8.57 (d, IH), 7.6 (d, IH),

7.35 (s, IH), 7.2 (m, IH), 7.125 (m, 2H), 4.72 (s, 2H), 4.3 (m, 2H), 3.6 (q, 2H), 2.8 (m, IH), 2.7 (dd, 2H), 2.6 (m, IH), 2.52 (s, 3H), 1.75 (d, 3H). Compound NMR Data

No.

V-161 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.36 (d, 2H), 7.35 (m, IH), 7.22 (s, IH),

6.99 (d, IH), 6.72 b(s, 2H), 4.23 (m, IH), 3.71 (dd, IH), 3.59 (m, 3H), 3.15 (dd, IH), 3.07 (dd, IH), 2.77 (m, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 2.1 (m, 3H).

V-162 1H NMR (DMSO, TFA salt): δ (ppm): 8.5 (d, 2H), 7.3 (d, IH), 7.2 (m, 3H), 6.9

(d, IH), 4.7 (m, 2H), 4.43 (m, 2H), 4.1 (d, IH), 3.3 (m, IH), 3.0 (m, 2H), 2.85 (d, 6H), 2.8 (m, IH), 2.5 (m, 2H), 2.3 (s, 3H), 1.22 (s, 3H).

V-163 1H NMR (CDCI₃, Free base): δ (ppm): 8.51 (d, 2H), 7.17 (m, 4H), 7.003 (d,

IH), 4.16 (m, 2H), 4.05 (dd, IH), 3.79 (dd, 2H), 2.9 (m, IH), 2.83 (m, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.39 (m, IH), 1.99 (s, 2H), 1.7 (m, 2H), 1.5 (m, 2H), 1.4 (m, IH), 1.9 (m, 2H).

V-164 ^lH NMR (CDCI₃, Free base): 8.32 (d, 2H), 7.25 (d, 2H), 7.15 (d, IH), 7.01 (d,

1H),6.63 (d, IH), 4.8 (d, IH), 3.77 (m, 2H), 3.39 (t, 2H), 2.8 (m, IH), 2.7 (m, IH), 2.5 (m, IH), 2.47 (s, 3H), 2.45 (s, 3H), 2.3 (m, IH).

V-165 1H NMR (CD₃OD, TFA salt ): δ (ppm): 8.52 (m, 2H), 7.42 b(s, 2H), 7.30 b(s,

IH), 7.22 (s, IH), 7.02 (m, IH), 4.8 (m, IH), 4.58 (m, 2H), 4.23 (t, IH), 3.72 (m, IH), 3.4 (m, 3H), 3.13 (m, 2H), 2.99 (d, 3H), 2.39 (s, 3H), 1.43 (d, 3H), 1.34 (d, 3H).

V-166 1H NMR (CDCI₃, Free base) δ (ppm): 8.73 (s, IH), 8.47 (d, IH), 7.2 (d, IH),

7.11 (s, IH), 7.04 (d, 2H), 6.90 (d, IH), 4.15 (dd, 2H), 3.78 (dd, IH), 3.6 (dd, IH), 2.9 (m, 2H), 2.7 (dd, IH), 2.43 (s, 3H), 2.4 (s, 3H), 1.6 (s, 3H), 1.14 (d, 3H).

V-167 1H NMR (CDCI₃, Free base) δ (ppm): 8.72 (s, IH), 8.47 (d, IH), 7.52 (d, IH),

7.23 (s, IH), 6.94 (m, 3H),4.10 (dd, 2H), 3.65 (m, IH), 3.40 (m, IH), 2.86 (m, 2H), 2.38 (s, 3H), 2.36 (m, 1H),1.62 (s, 3H), 1.07 (d, 3H).

V-168 ^lH NMR (CDCI₃, Free base) δ (ppm): 9.1 (s, IH), 8.43 (d, IH), 7.38 (d, IH),

7.29 (d, IH), 7.25 (d, IH), 6.97 (d, 1H),4.7 (d, IH), 4.23 (d, IH), 3.63 (m, 2H), 2.8 (m, 2H), 2.75 (m, 2H), 2.51 (s, 3H), 2.41 (s, 3H), 1.71 (s, 3H).

V-169 1H NMR (CD₃OD, TFA salt): δ (ppm): 7.27 (m, IH), 7.21 (m, 3H), 7.10 (m,

3H), 4.60 (m, 3H), 4.50 (m, 1H),4.24 (m, IH), 3.69 (m, IH), 3.44 (m, IH), 3.04 (m, IH), 2.96 (s, 3H), 2.56 (m, IH), 2.41 (s, 3H).

V-170 1H NMR (CDCI₃, Free base): δ (ppm): 7.32 (t, 2H), 7.24 (m, IH), 7.21 (s, IH),

7.01 (m, 3H), 3.91 (m, 2H),3.65 (dd, 2H), 2.80 (m, 3H), 2.62 (m, IH), 2.54 (s, 3H), 2.45 (s, 3H), 2.14 (s, 3H).

V-171 ^lH NMR (CD₃OD,TFA salt): δ (ppm): 8.6 (dd, 2H), 7.63 (d, IH), 7.54 (d, IH),

7.19 (s, IH), 7.10 (d, IH), 6.99 (d, IH), 4.82 (m, 2H), 4.72 (m, IH), 4.6 (m, IH), 4.23 (t, IH), 3.8 (m, 2H), 3.5 (m, IH), 3.2 (m, IH), 3.07 (d, 3H), 2.7 (m, IH), 2.37 (s, 3H), 2.5 (m, 3H), 2.1 (m, IH), 1.8 (m, 2H).

V-172 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.02 (s, IH), 7.54 (s, IH), 7.43 s (OH),

7.37 (t, 2H), 6.93 (t, 2H), 4.37 (d, IH), 4.22 (d, IH), 4.04 (t, IH), 3.23 (dd, IH), 2.9 (m, IH), 2.7 (m, 2H), 2.5 (m, 2H), 2.42 (s, 3H), 2.3 (m, IH), 1.84 (m, 3H), 1.6 (s, 3H).

V-173 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.41 (d, 2H), 7.31 (d, IH), 7.19 (s, IH),

7.1 (d, IH), 6.93 (d, 2H),4.25 (dd, IH), 3.9 (t, 2H), 3.8 (m, IH), 3.67 (dd, IH), 2.87 (m, 3H), 2.71 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H), 2.1 (m, IH), 1.21 s (9H).

V-174 1H NMR (CDCI₃, Free base) δ (ppm): 8.47 (d, 2H), 7.18 (s, IH), 7.16 (d, IH),

6.98 (d, 3H), 4.22 (dd, IH), 4.05 (dd, IH), 3.7 (m, 2H), 3.57 (s, 3H), 3.5 (dd, IH), 2.74 (m, 3H), 2.71 (m, 2H), 2.49 (s, 3H), 2.43 (s, 3H), 2.2 (m, IH). Compound NMR Data

No.

V-175 1H NMR (CDCI3, Free base) δ (ppm): 8.48 (d, 2H), 7.18 (s, IH), 7.1 (d, IH),

7.01 (d, 2H), 6.97 (d, IH), 4.2 (dd, IH), 4.15 (dd, IH), 3.64 (d, IH), 3.56 (m, 2H), 3.4 (m, 2H), 2.7 (m, 3H), 2.4 (m, IH), 2.5 (s, 3H), 2.43 (s, 3H), 1.94 (m, 2H).

V-176 1H NMR (CDCI₃, Free base): δ (ppm): 7.13 (s, IH), 7.05 (d, 1H),7.02 (t, 2H),

6.88 (m, 3H), 4.56 (dd, IH), 3.99 (m, IH), 3.64 (d, IH) 3.54 (dd, IH), 3.46 (d, IH), 2.79 (m, IH), 2.6 (m, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 2.3 (s, 6H), 1.9 (m, IH).

V-177 1H NMR (CDCI₃, Free base) δ (ppm): 8.56 (d, 2H), 7.29 (d, 2H), 7.12 (d, IH),

6.98 (d, IH), 4.9 (dd, IH), 4.79 (q, 2H), 4.13 (m, 2H), 3.78 (d, IH), 3.72 (d, IH), 3.0 (m, IH), 2.8 (m, IH), 2.67 (m, 2H), 2.49 (s, 3H), 2.32 (s, 3H).

V-178 1H NMR (CDCI₃, Free base) δ (ppm): 8.41 (d, 2H), 7.28 b(s, IH), 7.2 (s, IH),

7.1 (d, IH), 6.78 (d, 2H), 4.4 bs (OH), 4.3 (m, IH), 4.0 (m, IH), 3.62 (d, IH), 3.42 (m, 3H), 3.1 (dd, IH), 2.7 (m, 3H), 2.46 (m, IH), 2.43 (s, 6H).

V-179 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.57 (m, 2H), 8.48 (m, IH), 7.85 (m,

IH), 7.21 (s, IH), 6.78 (d, 1H),6.64 (m, IH), 5.72 (m, IH), 4.66 (t, 2H), 4.45 (d, IH), 4.30 (d, IH), 3.78 (m, 2H), 3.16 (s, 3H), 2.31 (s, 3H), 1.87 (s, 3H).

V-180 1H NMR (CDCI₃, Free base) δ (ppm): 8.74 (s, IH), 8.49 (d, IH), 7.60 (d, IH),

7.20 (s, IH), 7.07 (m, 2H),6.90 (d, IH), 4.16 (dd, 2H), 3.72 (m, IH), 2.97 (m, IH), 2.69 (m, 2H), 2.47 (s, 3H), 2.44 (m, 1H),2.42 (s, 3H), 1.66 (s, 3H), 1.42 (d, 3H).

V-181 1H NMR (CDCI₃, Free base) δ (ppm): 8.43 (d, 2H), 7.16 (s, IH), 7.14 (d, IH),

6.99 (d, 3H), 4.3 (dd, 1H),3.98 (d, IH), 3.9 (dd, IH), 3.8 (d, IH), 3.5 (m, IH), 3.15 (dd, IH), 2.84 (m, 3H), 2.59 (s, 3H), 2.42 (s, 3H), 2.3 (dd, IH), 1.85 (dd, IH), 1.15 (s, 3H), 1.02 (s, 3H).

V-182 1H NMR (CDCI₃, Free base) δ (ppm): 8.44 (d, 2H), 7.15 (s, IH), 7.0 (d, IH),

6.94 (d, IH), 6.92 (d, 2H),4.25 (dd, IH), 4.0 (dd, IH), 3.64 (d, IH), 3.51 (m, 2H), 2.88 (dd, IH), 2.73 (t, IH), 2.58 (m, IH), 2.48 (s, 3H), 2.42 (s, 3H), 2.2 (m, IH), 2.02 (t, IH), 1.71 (t, 2H), 0.837 s (9H).

V-183 1H NMR (CDCI3, Free base) δ (ppm): 8.7 (s, IH), 8.5 (d, IH), 7.8 (d, IH), 7.23

(m, IH), 7.15 (d, IH), 6.94 (d, IH), 4.80 (q, 2H), 4.19 (dd, 2H), 4.17 (m, 2H), 3.0 (m, 4H), 2.6 (s, 3H), 2.47 (s, 3H), 1.6 (s, 3H).

V-184 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.6 (d, 2H), 7.8 (d, 2H), 7.25 (s, IH),

7.15 (d, IH), 6.9 (d, IH), 4.63 (t, IH), 4.5 (m, IH), 4.4 (m, IH), 4.3 (dd, IH), 4.0 (m, IH), 3.85 (m, IH), 3.6 (m, IH), 3.2 (m, IH), 3.1 (s, 3H), 3.0 (m, IH), 2.9 (m, 2H), 2.4 (d, 3H).

V-185 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.56 (d, 2H), 7.28 (d, 2H), 7.19 (s, IH),

7.17 (d, IH), 6.94 (d, IH), 4.63 (dd, IH), 4.54 (dd, IH), 4.39 (d, IH), 4.37 (t, IH), 4.0 (m, IH), 3.8 (m, IH), 3.6 (m, IH), 3.45 (m, IH), 3.3 (m, IH), 3.1 (s, 6H), 3.0 (d, 3H), 2.9 (m, 2H), 2.8 (d, 3H).

V-186 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.5 (d, 2H), 7.5 (m, 2H), 7.25 (d, IH),

7.24 (s, IH), 7.05 (t, IH), 4.6 (d, IH), 4.5 (d, IH), 4.3 (m, IH), 4.23 (t, IH), 3.8 (m, IH), 3.5 (m, IH), 3.08 (d, 3H), 2.8 (m, 2H), 2.7 (m, 2H), 2.4 (s, 3H), 2.25 (m, IH), 2.2 (m, IH).

V-187 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.57 b(s, 2H), 7.65 (dd, 2H), 7.23 (d,

IH), 7.21 (s, IH), 6.99 (d, 1H),4.62 (m, IH), 4.48 (m, IH), 4.42 (m, IH), 4.26 (t, IH), 3.81 (m, IH), 3.55 (m, 2H), 3.35 (m, IH), 3.1 (m, IH), 3.0 (s, 3H), 2.9 (m, 2H), 2.83 (s, 6H), 2.4 (m, IH), 2.38 (s, 3H),2.29 (m, IH). Compound NMR Data

No.

V-188 1H NMR (CDCI₃, Free base) δ (ppm): 8.7 (s, IH), 8.42 (d, IH), 7.6 (d, IH), 7.1

(s, IH), 6.9 b(s, 2H), 4.7 (s, 2H), 4.1 (q, 2H), 3.9 (s, 2H), 2.9 (m, 3H), 2.8 (m, IH), 2.6 (s, 3H), 2.39 (s, 3H), 1.6 (s, 3H).

V-189 ^lH NMR (DMSO, Free base) δ (ppm): 8.59 (s, IH), 8.42 (d, IH), 7.73 (d, IH),

7.31 (t, IH), 7.1 (d, IH), 6.73 (d, IH), 4.11 (dd, 2H), 3.74 (s, 2H), 3.4 (m, 2H), 2.6 (m, 2H), 2.37 (s, 6H), 2.22 (s, 3H), 1.5 (s, 3H).

V-190 1H NMR (DMSO, Free base) δ (ppm): 8.60 (s, IH), 8.4 (d, IH), 7.7 (d, IH),

7.28 (t, IH), 7.06 (s, IH), 7.01 (s, IH), 4.11 (dd, 2H), 3.41 (m, 2H), 2.53 (m, 2H), 2.44 (m, 2H), 2.35 (s, 3H), 2.22 (s, 6H), 1.5 (s, 3H).

V-191 1H NMR (CDCI₃, Free base) δ (ppm): 8.61 (d, 2H), 7.42 (d, 2H), 7.23 (d, IH),

7.18 (s, IH), 6.95 (d, IH), 4.17 (dd, 2H), 3.68 (q, 2H), 3.2 (d, IH), 3.1 (m, IH), 2.76 (m, 3H), 2.63 (m, IH), 2.55 (s, 3H), 2.43 (s, 3H).

V-192 ^lH NMR (CD₃OD, TFA) δ (ppm): 8.66 (d, 2H), 7.8 (d, 2H), 7.23 (s, IH), 7.1

(d, IH), 7.0 & 6.9 (d, IH), 4.8 (m, IH), 4.7 (m, IH), 4.4 (m, 3H), 3.85 (m, IH), 3.6 (m, 2H), 3.45 (m, IH), 3.24 (m, 4H), 3.12 (s, 3H), 2.4 (s, 3H).

V-193 1H NMR (CD₃OD, TFA) δ (ppm): 8.75 (s, IH), 8.6 (m, 2H), 7.83 (m, IH), 7.25

(s, IH), 6.9 (d, IH), 6.8 (d, IH), 4.62 (d, IH), 4.45 (dd, 2H), 4.3 (t, IH), 4.05 (t, IH), 3.8 (m, 2H), 3.5 (m, 3H), 3.1 (s, 3H), 2.3 (s, 3H).

V-194 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.49 (d, 2H), 7.53 (d, 2H), 7.3 (t, IH),

7.24 (s, IH), 7.05 (m, IH) , 5.5 (m, IH), 4.6 (t, IH), 4.24 (t, IH), 3.8 (m, 3H), 3.3 (m, 2H), 3.13 (d, 2H), 2.89 (m, IH), 2.77 (m, IH), 2.4 (s, 3H), 1.39 s (9H).

V-195 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.58 (d, 2H), 7.81 (m, 2H), 7.18 (d, IH),

7.05 (m, IH), 6.91 (m, IH) , 4.63 (m, IH), 4.51 (s, 2H), 4.27 (d, IH), 4.18 (m, 2H), 3.58 (m, 2H), 3.48 (m, IH), 3.1 (s, 6H), 2.89 (m, IH), 2.8 (s, 3H), 2.35 (s, 3H).

V-196 1H NMR (CDCI₃, Free base) δ (ppm): 8.52 (d, 2H), 7.18 (s, IH), 7.14 (d, IH),

7.13 (d, 2H), 6.99 (d, IH) , 4.22 (m, 2H), 3.98 (dd, IH), 3.76 (d, IH), 3.70 (d, IH), 2.85 (m, IH), 2.74 (m, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.36 (m, 2H), 0.33 (m, 2H), 0.23 (m, 2H).

V-197 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.65 (m, 2H), 8.43 (dd, IH), 7.75 (m,

IH), 7.18 (d, IH), 6.88 (m, 2H) , 4.67 (d, IH), 4.55 (m, 2H), 4.29 (t, IH), 3.90 (m, 2H), 3.69 (m, IH), 3.5 (m, 2H), 3.1 (m, IH), 3.11 (s, 3H), 2.34 (s, 3H).

V-198 1H NMR (CDCI₃, Free base) δ (ppm): 8.74 (s, IH), 8.50 (d, IH), 7.79 (d, IH),

7.25 (dd, IH), 7.16 (s, IH) , 7.1 (d, IH), 6.97 (d, IH), 4.08 (m, 2H), 3.83 (dd, 2H), 2.98 (m, 4H), 2.74 (d, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 1.98 (s, 6H).

V-209 ^lH NMR (CDCI₃, Free base) δ (ppm): 8.78 (s, IH), 8.30 (s, IH), 7.82 (d, IH),

7.21 (m, 2H), 7.01 (d, IH), 4.40 (t, 2H), 3.80 (m, IH), 3.40 (t, 2H), 3.02 (t, 3H), 2.90-3.05 (m, 2 H), 2.65-2.71 (m, 2H), 2.62 (s, 3H), 2.45 (s, 4H).

V-212 1H NMR (CDCI₃, free base) δ (ppm): 8.6 (d, 2H), 7.41 (d, 2H), 7.24 (s, IH),

7.19 (d, IH), 6.9 (d, IH), 4.2 (dd, IH), 4.1 (dd, IH), 3.2-3.3 (m, 2H), 2.7 (d, IH), 2.7-2.8 (m, IH), 2.3-2.6 (m, 3H), 2.45 (s, 3H), 1.5 (s, 3H).

V-213 ^lH NMR (CDCI₃, free base) δ (ppm): 8.8 (s, IH), 8.6 (s, IH), 7.8 (d, IH), 7.3

(d, IH), 7.2 (s, IH), 7.15 (d, IH), 6.95 (d, IH), 4.1-4.3 (m, 2H), 3.3-3.4 (m, 2H), 2.75 (d, IH), 2.3-2.5 (m, 2H), 2.4 (s, 3H), 1.8-2.1 (m, 2H), 1.5 (s, 3H),

V-214 1H NMR (CD₃OD, TFA salt) δ (ppm): 7.94 (d, IH), 7.58 (s, IH), 7.18 (s, IH),

7.03 (d, IH), 6.84 (brs, 2H), 4.69 (d, 2H), 4.19-4.33 (m, 3H), 3.86 (brs, IH), 3.52 (brs, 2H), 3.19 (s, 6H), 3.11 (s, 3H), 1.95-2.36 (s, 3H), 1.66 (s, 3H). Compound NMR Data

No.

V-220 1HNMR (CD₃OD, TFA salt): 8.48 (d, 2H), 7.82 (d, 2H), 7.21 (s, IH), 6.84 (d,

IH), 6.78 (d, IH), 5.10 (d, IH), 4.75 (d, IH), 4.35 (dd, 2H), 3.40 (m, 2H), 3.18 (s, 3H), 2.70 (m, IH), 2.36 (m, 4H), 2.18 (m, IH), 2.05 (m, IH), 1.82 (m, IH), 1.70 (s, 3H), 1.62 (m, IH).

V-221 1H NMR (CDCI3, freebase) δ (ppm): 8.46 (s, IH), 8.30 (s, IH), 7.50 (d, IH),

7.15-7.25 (m, 3H), 7.06-7.18 (m, 2H), 4.21-4.36 (m, IH), 3.18-3.30 (m, IH), 2.98-3.10 (m, 2H), 2.71-2.95 (m, 2H), 2.38-2.58 (m, 2H), 2.15-2.28 (m, IH), 1.80-1.95 (m, 2H), 1.20-1.27 (m, 3H).

V-222 1H NMR (CDCI₃, freebase) δ (ppm): 8.60 (d, 2H), 7.35 (d, 2H), 7.20 (s, IH),

7.12 (d, IH), 7.00 (d, IH), 4.56 (dd, IH), 4.36 (dd, IH), 4.21 (dd, IH), 3.95- 4.15 (m, 2H), 3.56-3.64 (m, IH), 3.40-3.54 (m, IH), 3.25-3.38 (m, IH), 3.10- 3.24 (m, IH), 2.92-3.02 (m, 2H), 2.84 (s, 3H), 2.42 (s, 3H), 2.02-2.21 (m, 2H), 1.59-1.81 (m, 2H).

V-223 1HNMR (freebase, CDC1₃): 8.60 (d, 2H), 7.25-7.15 (m, 4H), 7.01 (d, IH), 4.60

(t, IH), 4.20-4.01 (m, 2H), 3.81-3.61 (m, 3H), 2.95-2.85 (m, 4H), 2.61 (S, 3H), 2.50 (s, 3H), 1.72- 1.51 (m, 3H), 1.50-1.40 (m, 3H), 1.35-1.21 (m, 2H).

V-224 1H NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.25 (d, IH), 7.18 (s, IH),

7.08 (d, 2H), 6.96 (d, IH), 5.95-6.00 (m, IH), 4.45 (dd, IH), 4.18 (dd, IH), 3.55-3.59 (m, 2H), 3.25-3.43 (m, 4H), 2.47-2.81 (m, 3H), 2.56 (s, 3H), 2.39 (s, 3H), 2.21-2.39 (m, IH), 1.78-1.98 (m, 4H).

V-225 1H NMR (DMSO-d₆, freebase) δ (ppm): 8.62 (brs, 2H), 7.22-7.39 (m, 3H), 7.15

(s, IH), 6.91 (d, IH), 5.78-5.92 (m, IH), 4.35-4.45 (m, 2H), 4.00 (brs, 2H), 2.98-3.55 (m, 4H), 2.59-2.81 (m, 8H), 2.40 (s, 3H), 2.22 (s, 3H), 2.18-2.39 (m, 3H).

V-226 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.34 (s, IH), 7.59-7.68 (m, IH), 7.168 (s,

IH), 7.034 (d, IH), 6.91 (d, IH) , 6.58-6.68 (m, IH), 4.22 (dd, IH), 4.12 (dd, IH), 3.81-3.91 (m, IH), 3.15-3.25 (m, IH), 2.78-2.89 (m, 2H), 2.74-2.79 (m, IH), 2.58-2.64 (m, 2H), 2.41 (s, 3H), 2.36-2.42 (m, IH), 1.82-1.95 (m, 3H), 1.67 (s, 3H).

V-227 1H NMR (CDCI₃, freebase) δ (ppm): 8.56 (d, 2H), 7.66 (d, IH), 7.54 (d, IH),

7.31 (d, 2H), 7.24 (d, IH), 7.18 (d, IH) 6.65 (d, IH), 4.62-4.72 (m, IH), 3.34- 3.45 (m, 3H), 3.09-3.18 (m, 2H), 2.91-3.12 (m, IH), 2.61-2.69 (m, IH), 2.46 (s, 3H), 2.15-2.22 (m, 2H).

V-229 1HNMR (freebase, CDC1₃): 8.60 (d, 2H), 7.30 (d, 2H), 7.28-7.18 (m, 2H), 7.02

(d, IH), 5.10 (m, IH), 4.40 (d, IH), 4.18 (dd, IH), 4.05-3.95 (m, 2H), 2.62 (m, IH), 2.42 (s, 3H), 2.40 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.50 (m, 2H).

V-230 1H NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.19 (s, IH), 7.25 (d, IH),

7.18 (d, 2H), 6.61 (brs, 2H), 5.95-6.00 (m, IH), 4.98 (s, IH), 4.38 (dd, IH), 4.18 (dd, IH), 3.82 (dd, IH), 3.75 (dd, IH), 2.80-2.89 (m, 2H), 2.65-2.71 (m, 2H), 2.60 (s, 3H), 2.39 (s, 3H).

V-231 1H NMR (CDCI₃, TFA salt) δ (ppm): 8.82 (d, 2H), 8.22 (d, 2H), 8.15 (d, IH),

7.65 (s, IH), 7.38 (s, IH), 7.18 (s, IH), 4.8 (dd, IH), 3.15 (s, 3H), 2.35 (s, 3H), 1.5 (d, 2H), 0.99 (s, 9H).

V-233 ^lH NMR (CDCI₃, TFA salt) δ (ppm): 8.62 (s, IH), 8.21 (s, IH), 7.98 (d, IH),

7.74 (d, IH), 7.18-7.21 (m, IH), 6.05 (dd, IH), 5.22 (brs, IH), 4.70-4.95 (m, 4H), 3.75-3.82 (m, 2H), 3.35-3.45 (m, 2H), 2.74-2.81 (m, IH), 2.15 (s, 3H), 2.22-2.39 (m, 4H). Compound NMR Data

No.

V-234 ^lH NMR (CDCI3, freebase) δ (ppm): 8.75 (s, IH), 8.54 (d, IH), 7.61-7.79 (m,

IH), 7.24-7.35 (m, 2H), 7.21 (d, IH) , 6.99 (d, IH), 4.61-4.71 (m, 2H), 4.21 (q, 2H), 4.23-4.25 (m, 2H), 3.65-3.79 (m, 2H), 2.46-2.62 (m, IH), 2.44 (s, 3H), 2.12-2.18 (m, IH), 1.66 (s, 3H), 1.28 (t, 3H).

V-236 1H NMR (CDCI₃, freebase) δ (ppm): 8.5 (s, IH), 8.47 (d, IH), 7.56 (d, IH), 7.4

(d, IH), 7.27-7.31 (m, IH) , 7.19 (t, 2H), 7.08 (t, IH), 4.3 (t, IH), 4.15 (dd, IH), 4.1 (dd, IH), 3.76 (dd, 2H), 2.79-2.85 (m, 3H), 2.50 (s, 3H), 2.35-2.31 (m, IH), 0.847 (s, 9H).

V-238 1H NMR (CDCI₃, freebase) δ (ppm): 8.56 (d, 2H), 7.34 (d, 2H), 7.23 (s, IH),

7.19 (d, IH), 6.96 (d, IH), 4.19 (dd, 2H), 3.98-4.12 (m, IH), 3.22-3.26 (m, IH), 2.83-2.95 (m, 3H), 2.61-2.71 (m, IH), 2.45-2.51 (m, 2H), 2.43 (s, 3H), 1.91- 2.01 (m, 3H), 1.6 (s, 3H).

V-239 ^lH NMR (CD₃OD, freebase) δ (ppm): 8.39 (s, IH), 8.31-8.38 (m, IH), 7.61- 6.71 (m, IH), 6.98-7.23 (m, 2H), 6.99 (t, IH), 5.37-5.44 (m, IH), 4.36 (dd, IH), 4.26 (dd, IH), 3.57-3.65 (m, 3H), 3.25-3.32 (m, IH), 3.15-3.24 (m, 2H), 2.61- 2.68 (m, IH), 2.4 (s, 3H), 2.17-2.22 (m, 4H).

V-240 1H NMR (CDCI₃, freebase) δ (ppm): 8.7 (s, IH), 8.5 (d, IH), 7.72 (d, IH), 7.26

(t, IH), 7.16-7.21 (m, 2H) , 6.96 (d, IH), 4.16 (dd, 2H), 3.93 (d, IH), 3.8 (d, IH), 3.62-3.75 (m, 2H), 2.95-3.11 (m, IH), 2.50-2.68 (m, 2H), 2.41 (s, 6H), 1.36 (s, 3H).

V-241 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.63 (s, IH), 8.44 (s, IH), 7.62 (dd, IH),

7.21-7.29 (m, 3H), 6.97 (d, IH), 4.17-4.25 (m, 2H), 3.81 (dd, 2H), 3.55-3.61 (m, IH), 2.98-3.15 (m, IH), 2.74-2.79 (m, 2H), 2.44 (s, 6H), 2.42-2.49 (m, 2H), 1.63 (d, 3H).

V-242 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.91 (brs,lH), 8.81 (brs,lH), 8.59-8.62

(m, IH), 8.01 (brs,lH), 7.16 (d, IH), 7.06 (d, IH), 5.35 (brs, IH), 5.15-5.19 (m, IH), 4.60 (t, IH), 4.38-4.45 (m, IH), 3.82-3.89 (m, IH), 3.42-3.59 (m, 2H), 3.20-3.44 (m, 2H), 3.14 (s, 3H).

V-243 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.68 (brs, 2H), 7.91 (d, 2H), 7.35-7.44

(m, IH), 7.22 (d, IH), 6.94-6.99 (m, 2H), 5.12-5.24 (m, IH), 5.05-5.11 (m, IH), 4.42-4.51 (m, IH), 4.25-4.37 (m, IH), 3.69-3.82 (m, 3H), 3.18-3.42 (m, IH), 3.15-3.20 (m, 2H), 2.61-2.72 (m, IH), 2.18-2.20 (m, 3H).

V-244 1H NMR (CDCI₃, freebase) δ (ppm): 8.57 (d, 2H), 7.26 (d, 2H), 7.18 (s, IH),

6.74 (s, IH), 4.42-4.58 (m, IH), 4.21-4.38 (m, IH), 4.07-4.15 (m, IH), 3.13- 3.19 (m, IH), 2.75-2.78 (m, 2H), 2.74 (s, 3H), 2.39 (s, 6H), 2.15 (s, IH), 1.87 (brs, 3H), 1.51 (s, 3H).

V-245 ^lH NMR (CD₃OD, freebase) δ (ppm): 8.43 (d, IH), 8.31 (s, IH), 7.76 (d, IH),

7.39 (t, IH), 7.33 (d, IH) , 7.10 (d, IH), 6.98 (t, IH), 5.18 (t, IH), 4.63 (dd, IH), 4.57 (dd, IH), 3.72 (d, IH), 3.57 (d, IH), 3.29-3.35 ( m, IH), 3.03-3.15 (m, IH), 2.78-2.88 (m, IH), 2.59-2.65 (m, IH), 2.5 (s, 3H).

V-246 1H NMR (CD₃OD, TFA salt): 8.27-8.45 (dd, IH), 7.98 (d, IH), 7.38-7.45 (m,

IH), 7.18-7.22 (m, IH), 6.80-6.90 (m, 2H), 4.62-4.72 (dd, IH), 4.38 (s, 3H), 3.80 (brs, IH), 3.41-3.60 (m, 3H), 3.40 (s, 3H), 3.02 (s, 6H), 2.80 (d, 2H), 2.40 (d, 2H), 1.80 (s, IH), 1.00 (d, IH), 0.60 (m, 2H), 0.20-0.40 (m, 2H).

V-247 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.67 (brs, 2H), 7.89 (d, 2H), 7.41 (s,

IH), 7.25 (d, IH), 5.21-5.25-5.24 (m, IH), 5.04-5.12 (m, IH), 4.41-4.46 (m, 1H),4.21- 4.36 (m, IH), 3.66-3.78 (m, 3H), 3.25-3.41 (m, IH), 3.15-3.25 (m, IH), 2.63-2.72 (m, IH), 2.41 (s, 3H), 2.12-2.22 (m, 4H) Compound NMR Data

No.

V-248 ^lH NMR (CD₃OD, TFA salt) δ (ppm): 8.23 (t, 2H), 7.43 (d, 2H), 7.22 (d, IH),

7.21 ( d, IH), 7.00 (t, IH) , 5.11 (t, IH), 5.03 (m, IH), 4.33 (m, 2H), 3.70 (m, IH), 3.63 (m, 2H), 3.4 (m, IH), 3.19 (m, 2H), 3.05 (m, IH), 2.7 (m, IH), 2.4 (s, 3H), 2.19 (m, 3H).

V-249 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.671 (d, 2H), 7.92 (d, 2H), 7.25 (s, IH),

7.2 (d, IH), 7.01 (d, IH), 5.22-5.78 (m, 2H), 4.38-4.45 (m, 2H), 4.12-4.21 (m, 4H), 3.42-3.45 (m, IH), 3.20-3.27 (m, IH), 2.98-3.17 (m, IH), 2.48-2.56 (m, IH), 2.42 (s, 3H), 2.25-2.35 (m, IH).

V-250 1H NMR (CD₃OD, TFA salt) δ (ppm): 8.40-8.61 (m, 2H), 8.20-8.27 (m, IH),

7.61-7.71 (m, IH), 7.25 (s, IH), 7.12- 7.21 (s, IH), 7.06 (m, IH), 5.20-5.50 (m, 2H), 4.68-4.78 (m, IH), 4.50-4.59 (m, 2H), 34.21-4.35 (m, IH), 3.61-3.71 (m, 2H), 3.16 (s, 3H), 2.39 (s, 3H).

V-253 1HNMR (CD₃OD, TFA salt): 8.60 (brs, IH), 8.54 (brs, IH), 8.22-8.32 (m, IH),

7.72-7.80 (m, IH), 7.24 (d, IH), 7.00-7.15 (m, IH), 6.91-7.02 (m, IH), 5.20- 5.29 (m, IH), 4.82 (brs, IH), 4.24-4.52 (m, 3H), 3.72-3.98 (m, 2H), 3.61-3.71 (m, IH), 3.42-3.58 (m, IH), 3.25-3.42 (m, IH), 3.02-3.21 (m, IH), 2.61 (brs, IH), 2.39 (s, 3H), 2.18-2.42 (m, IH), 1.92-2.04 (m, IH)

V-254 1H NMR (CDCI₃, freebase): 8.67 (s, IH), 7.81 (d, IH), 7.71 (d, IH), 7.12 (s,

IH), 7.06 (s, IH), 6.89 (d,lH), 4.20 (d, IH), 4.13 (d, IH), 3.52-3.78 (m, 6H), 2.62-2.82 (m, 4H), 2.54 (s, 3H), 2.41 (s, 3H), 1.80-2.01 (m, 4 H), 1.65 (s, 3H).

V-257 1H NMR (CD₃OD, TFA salt): 8.63 (brs, 2H), 7.89 (brs, 2H), 7.48 (s, IH), 7.22- 7.32 (m, IH), 7.17-7.21 (m, IH), 5.26 (brs, IH), 5.09 (t, IH), 4.67 (s, 2H), 4.41- 4.56 (m, IH), 4.36-4.41 (m, IH), 3.60-3.81 (m, 3H), 3.10-3.46 (m, 3H), 3.71 (brs, IH), 2.10-2.31 (m, 3H)

V-258 1HNMR (CD₃OD, TFA salt): 8.59 (d, IH), 8.48 (d, IH), 8.14 (d, IH), 7.69-7.76

(m, IH), 7.40 (s, IH), 7.33 (d, IH), 7.16 (d, IH), 5.25-5.36 (m, IH), 4.60-4.70 (m, IH), 4.20-4.60 (m, 3H), 3.98-4.16 (m, 2H), 3.18 (s, 3H), 2.42 (s, 3H).

V-260 1H NMR (CDCI3, freebase): 8.5 (d, 2H), 7.3 (d, 2H), 7.19 (m, IH), 7.0 (d, IH),

6.8 (t, IH), 4.2 (dd, 2H), 3.8 (t, IH), 3.3-3.1 (m, IH), 2.9-2.8 (m, 2H), 2.8-2.7 (m, IH), 2.7-2.5 (m, 3H), 2.4-2.3 (m, IH), 2-1.8 (m, 2H), 1.65 (s, 3H).

V-261 1H NMR (CDCI₃, freebase) δ (ppm): 8.56 (d, 2H), 7.19 (s, IH), 7.13 (d, 2H),

7.11 (d, IH), 6.96 (d, IH), 4.50-4.59 (m, IH), 4.13 (dd, IH), 4.05 (dd, IH), 3.62 (d, IH), 3.60 (d, IH), 3.21-3.30 (m IH), 3.10-3.20 (m, IH), 2.70-2.82 (m, 3H), 2.51 (s, 3H), 2.44 (s, 3H), 2.40-2.57 (m, IH), 1.57-1.99 (m, 7H).

V-262 1H NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.69 (s, IH), 7.30-7.40 (m,

2H), 7.20 (d, 2H), 4.52-4.62 (m, IH), 4.07-4.23 (m, 2H), 3.57-3.81 (m, 3H), 2.58-2.95 (m, 4H), 2.54 (s, 3H), 1.86 (brs, 2H), 1.15-1.60 (m, 6H).

V-263 1H NMR (CDCI₃, freebase) δ (ppm): 8.66 (brs, IH), 8.41 (brs, IH), 7.56 (brs,

IH), 7.02 (brs, IH), 6.83 (s, IH), 6.53 (d, IH), 4.20-4.50 (m, 3H), 3.40-3.60 (m, 2H), 2.80-3.12 (m, 3H), 2.58-2.70 (m, IH), 2.34 (s, 3H), 1.80- 2.22 (m, 4H), 1.64 (s, 3H).

V-264 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.40 (brs, 2H), 7.30 (brs, 2H), 6.85 (s,

IH), 6.55 (d, IH), 4.15-4.40 (m, 3H), 3.40-3.60 (m, 2H), 3.05-3.17 (m, IH), 2.88 (brs, 2H), 2.58-2.63 (m, IH), 2.34 (s, 3H), 2.02-2.21 (m, 2H), 1.79-2.00 (m, 2H), 1.57 (s, 3H). Compound NMR Data

No.

V-265 ^lH NMR (CDCI3, freebase) δ (ppm): 8.66 (s, IH), 8.45 (d, IH), 7.43 (brs, IH),

7.00 (s, IH), 6.91 (brs, IH), 6.68 (d, IH), 4.36 (d, IH), 4.23 (d, IH), 3.97 (d, IH), 3.22-3.38 (m 2H), 2.81-3.11 (m, 2H), 2.40-2.62 (m, 2H), 1.70-2.20 (m, 4H), 1.70 (s, 3H).

V-266 1H NMR (CDCI₃, freebase) δ (ppm): 8.66 (d, IH), 8.42 (d, IH), 7.59 (s, IH),

7.48 (d, IH), 7.33 (s, 2H), 6.95 (brs, IH), 4.28 (d, IH), 4.14 (d, IH), 4.12 (brs, IH), 3.17-3.21 (m, IH), 2.88-3.11 (m, 2H), 2.70-2.2.81 (m, 3H), 2.40-2.53 (m, 2H),1.80-2.00 (m, 3H), 1.67 (s, 3H).

V-277 1H NMR (CDCI₃, freebase) δ (ppm): 8.65 (s, IH), 8.55 (d, IH), 7.60 (m, IH),

7.25 (m, IH), 6.95 (d, IH), 6.62 (d, IH), 4.42 (m, 2H), 4.00 (m, IH), 3.22 (m, IH), 2.90-2.75 (m, 4H), 2.70 (s, 3H), 2.40 (m, 2H), 1.90 (m, 3H), 1.62 (s, 3H).

V-278 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.60 (s, IH), 8.40 (d, IH), 7.30 (d, IH),

6.90 (m, IH), 6.70 (d, IH), 6.50 (d, IH), 4.35 (m, 2H), 3.80 (m, IH), 3.30 (m, IH), 3.20 (m, IH), 2.80 (m, 2H), 2.40 (s, 3H), 2.38 (m, IH), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, IH), 1.62 (s, 3H).

V-279 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.32 (d, 2H), 6.95 (d, IH),

6.65 (d, IH), 4.40 (m, 2H), 4.05 (m, IH), 3.22 (m, IH), 2.85 (m, 4H), 2.70 (s, 3H), 2.50 (m, 3H), 1.90 (m, 2H), 1.45 (s, 3H).

V-280 1H NMR (CDCI₃, freebase) δ (ppm): 8.62 (d, 2H), 7.40 (d, 2H), 6.90 (d, IH),

6.65 (d, IH), 4.55 (d, IH), 4.25 (d, IH), 4.20 (d, IH), 3.30 (m, 2H), 2.80 (m, IH), 2.70 (s, 3H), 2.45 (m, 2H), 2.10 (m, 2H), 2.00 (m, 2H), 1.90 (m, IH), 1.40 (s, 3H).

V-281 1H NMR (CDCI₃, freebase) δ (ppm): 8.75 (s, IH), 8.52 (d, IH), 7.70 (d, IH),

7.25 (m, IH), 7.00 (s, IH), 6.65 (d, IH), 4.55 (d, IH), 4.18 (d, IH), 3.98 (m, IH), 3.28 (m, IH), 2.85 (m, IH), 2.75 (m, 3H), 2.42 (m, 2H), 2.40 (s, 3H), 1.90 (m, 3H), 1.60 (s, 3H).

V-283 1H NMR (CDCI3, freebase) δ (ppm): 8.58 (d, 2H), 7.40 (d, 2H), 7.00 (s, IH),

6.65 (d, IH), 4.58 (d, IH), 4.10 (d, IH), 3.95 (m, IH), 3.25 (m, IH), 2.88 (m, IH), 2.80 (m, 2H), 2.45 (m, 2H), 2.40 (s, 3H), 1.90 (m, 4H), 1.55 (s, 3H).

V-284 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.55 (d, 2H), 7.18 (m 4H), 7.00 (d, IH),

4.62 (t, IH), 4.20-4.00 (m, 3H), 3.65 (m, IH), 3.25 (m, IH), 2.90 (m, IH), 2.78 (m, 2H), 2.65 (m, IH), 2.45 (s, 3H), 2.35 (m, IH), 1.90 (m, 3H), 1.40 (m, 4H), 1.25 (m, 2H).

V-287 1H NMR (CDCI₃, freebase) δ (ppm): 8.78 (s, IH), 8.55 (d, IH), 7.75 (d, IH),

7.65 (s, IH), 7.25 (m, 3H), 4.20 (m, 3H), 3.35 (d, IH), 3.25 (t, IH), 2.85 (m, 2H), 2.60 (m, IH), 2.50 (m, IH), 2.35 (m, IH), 2.10 (m, IH), 2.00 (m, IH), 1.90 (m, IH), 1.50 (s, 3H).

V-288 1H NMR (CDCI₃, freebase) δ (ppm): 8.22 (d, 2H), 7.10 (d, 2H), 6.95 (s, IH),

6.62 (d, IH), 4.30 (m, 2H), 3.70 (m, IH), 3.20 (t, IH), 3.15 (m, IH), 2.98 (m, IH), 2.80 (m, IH), 2.42 (m, IH), 2.30 (m, IH), 2.10 (m, IH), 2.00 (m, IH), 1.90 (m, 2H), 1.62 (s, 3H).

V-289 1H NMR (CDCI₃, freebase) δ (ppm): 8.70 (s, IH), 8.55 (d, IH), 7.72 (d, IH),

7.25 (m, IH), 7.15 (d, IH), 7.00 (d, IH), 4.10 (m, 3H), 3.25 (m, IH), 2.85 (m, 3H), 2.65 (m, IH), 2.45 (m, 2H), 2.35 (s, 3H), 1.90 (m, 3H), 1.65 (s, 3H).

V-290 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.55 (d, 2H), 7.35 (d, 2H), 7.00 (d, IH),

6.90 (d, IH), 3.95 (t, IH), 3.22 (m, IH), 2.95-2.75 (m, 7H), 2.60 (m, IH), 2.42 (m, IH), 1.90 (m, 2H), 1.50 (s, 3H). Compound NMR Data

No.

V-291 1H NMR (CDCI3, freebase) δ (ppm): 8.65 (s, IH), 8.45 (m, IH), 7.60 (m, IH),

7.10 (m, IH), 6.95 (m, IH), 6.85 (m, IH), 4.10 (m, IH), 3.25 (m, IH), 3.00 (m, 5H), 2.48 (m , 2H), 2.32 (m, IH), 1.98 (m, 3H), 1.60 (s, 3H).

V-293 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.56 (d, 2H), 7.38 (d, 2H), 7.13 (s, IH),

6.96 (s, IH), 5.15 (brs, IH), 4.20 (brs, IH), 3.98 (brs, IH), 3.22 (brs, IH), 3.18- 3.22 (m, IH), 2.75-2.92 (m, 4H), 2.39-2.58 (m, 2H), 2.40 (s, 3H), 1.85-2.18 (m, 2H), 1.51 (s, 3H).

V-303 1H NMR (CDCI₃, freebase) δ (ppm): 8.75 (s, IH), 8.56 (d, IH), 7.64 (d, IH),

7.25-7.20 (m, 3H), 6.96 (d, IH), 4.16 (m, 3H), 3.50 (m, IH), 2.90 (d, IH), 2.42 (s, 3H), 2.30 (s, 3H), 2.20 (m, 2H), 1.95-1.80 (m, 2H), 1.70 (s, 3H).

V-304 ^lH NMR (CDCI₃, freebase) δ (ppm): 7.40 (m, 2H), 2.27-7.20 (m, 3H), 7.04 (m,

2H), 6.97 (d, IH), 4.19 (d, IH), 4.12 (d, IH), 4.06 (d, IH), 3.45 (m, IH), 2.70 (d, IH), 2.44 (s, 3H), 2.24 (s, 3H), 2.22 (m, 3H), 2.0 (d, IH), 1.82 (m, IH), 1.61 (s, 3H).

V-336 1H NMR (CDCI₃, freebase) δ (ppm): 8.60 (d, 2H), 7.30 (d, 2H), 7.22 (s, IH),

6.88 (d, IH), 5.05 (m, IH), 4.40 (m, IH), 4.15 (m, IH), 3.78 (t, IH), 3.30 (m, IH), 3.08 (m, IH), 2.95 (m, IH), 2.70 (m, 2H), 2.22 (m, 2H), 1.90 (m, 3H).

V-337 1H NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.20 (d, 2H), 6.92 (d, IH),

6.68 (d, IH), 4.90 (m, IH), 4.15 (m, 2H), 3.85 (t, IH), 3.20 (m, IH), 2.85 (m, IH), 2.80 (m, 2H), 2.75 (s, 3H), 2.60 (m, IH), 2.38 (m, IH), 1.85 (m, 4H).

V-338 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.32 (d, 2H), 7.00 (s, IH),

6.70 (d, IH), 5.10 (m, IH), 4.40 (m, IH), 4.10 (m, IH), 3.85 (t, IH), 3.22 (m, IH), 3.05 (m, IH), 2.95 (m, IH), 2.75 (m, 2H), 2.48 (m, IH), 2.42 (s, 3H), 1.90 (m, 4H).

V-339 1H NMR (CDCI₃, freebase) δ (ppm): 8.55 (d, 2H), 7.26 (s, IH), 7.18 (d, IH),

7.10 (d, 2H), 6.98 (d, IH), 4.55 (t, IH), 4.25 (m, IH), 4.10 (m, 2H), 3.22 (m, 3H), 2.82 (m, 4H), 2.48 (m, IH), 2.45 (s, 3H), 2.18 (m, IH), 2.00-1.82 (m, 7H), 1.65 (m, 3H).

V-340 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.75 (s, IH), 8.42 (d, IH), 7.62 (d, IH),

7.2 (s, IH), 7.15 (d, 2H), 6.95 (d, IH), 4.25-4.15 (dd, 2H), 3.8 (t, 2H), 3.6 (s, 2H), 2.88 (t, 2H), 2.8 (t, 2H), 2.75 (t, 2H), 2.6 (s, 3H), 1.7 (s, 3H).

V-341 1H NMR (CDCI₃, freebase) δ (ppm): 8.3 (d, 2H), 7.1 (d, 2H), 7.05 (s, IH), 6.98

(d, IH), 6.9 (d, IH), 4.95 (t, IH), 4.1 (d, 2H), 3.8 (t, 2H), 3.6 (d, IH), 3.4 (d, IH), 3.0 (t, IH), 2.98 (t, IH), 2.92 (t, 2H), 2.85 (t, 2H), 3.05 (s, 3H).

V-342 1H NMR (CDCI3, freebase) δ (ppm): 7.10 (s, IH), 6.70 (s, IH), 4.38 (d, IH),

4.10 (m, IH), 4.0 (m, IH), 3.62 (m, IH), 3.30 (m, IH), 3.08 (m, IH), 2.90 (m, 2H), 2.80 (m, IH), 2.64 (s, 3H), 2.58 (m, IH), 2.42 (m, IH), 2.40 (s, 3H), 1.90 (m, 4H), 1.78 (m, 4H), 1.30-1.10 (m, 6H).

V-343 1H NMR (CDCI3, freebase) δ (ppm): 8.6 (d, 2H), 7.25 (d, 2H), 7.19 (s, IH), 7.0

(s, IH), 5.2 (t, IH), 4.8 (d, IH), 4.2 (t, IH), 3.95 (bs, IH), 3.25 (t, IH), 3.1 (t, IH), 2.95 (t, IH), 2.8 (t, 2H), 2.45 (m, 2H), 2.4 (s, 3H), 1.95 (m, 4H).

V-344 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.42 (s, IH), 7.22 (m, 3H),

7.10 (d, IH), 5.00 (t, IH), 4.18 (m, 2H), 3.82 (t, IH), 3.25 (m, IH), 2.92 (m, 2H), 2.75 (m, 2H), 2.42 (m, 2H), 1.90 (m, 3H).

V-345 1H NMR (CDCI3, freebase) δ (ppm): 8.58 (d, 2H), 7.28 (d, 2H), 6.90 (d, IH),

6.65 (t, IH), 5.05 (m, IH), 4.20 (m, IH), 4.10 (m, IH), 3.78 (t, IH), 3.30 (m, IH), 3.05 (m, IH), 2.92 (m, IH), 2.70 (m, 2H), 2.40 (m, 2H), 1.90 (m, 3H). Compound NMR Data

No.

V-346 ^lH NMR (CD₃OD, freebase) δ (ppm): 8.62 (d, 2H), 7.76 (d, 2H), 7.30 (m, IH),

7.18 (d, IH), 7.10 (d, IH), 5.20 (m, IH), 4.05 (m, IH), 3.95 (m, IH), 3.60-3.40 (m, 2H), 3.18 (s, 3H), 2.50 (m, IH), 2.39 (m, IH), 2.36 (s, 3H).

V-347 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.55 (d, 2H), 7.70 (s, IH), 7.40 (m, 2H),

7.22 (d, 2H), 5.05 (t, IH), 4.22 (d, 2H), 3.95 (t, IH), 3.28 (m, IH), 3.00-2.75 (m, 4H), 2.50 (m, 2H), 1.90 (m, 3H).

V-348 1H NMR (CDCI₃, freebase) δ (ppm): 8.52 (s, IH), 8.30 (d, IH), 7.58 (s, IH),

7.42 (d, IH), 7.35 (m, 2H), 7.10 (m, IH), 5.05 (t, IH), 4.30 (m, IH), 4.15 (m, IH), 3.75 (t, IH), 3.18 (m, IH), 2.88 (m, 2H), 2.75 (m, 2H), 2.50 (m, IH), 2.39 (m, IH), 1.90 (m, 2H), 1.80 (m, IH).

V-349 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.60 (s, IH), 8.52 (d, IH), 7.62 (s, IH),

7.27 (m, IH), 7.19 (m, IH), 6.88 (d, IH), 5.10 (m, IH), 4.38 (m, IH), 4.22 (m, IH), 3.85 (t, IH), 3.30 (m, IH), 3.05 (m, IH), 2.95 (m, IH), 2.80 (m, 2H), 2.45 (m, 2H), 1.85 (m, 3H).

V-350 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.52 (d, 2H), 7.25 (s, IH), 7.20 (d, 2H),

6.90 (s, IH), 4.85 (t, IH), 4.32 (m, 2H), 3.92 (t, IH), 3.22 (m, IH), 3.00 (m, IH), 2.85 (m, 3H), 2.70 (s, 3H), 2.45 (m, 2H), 1.90 (m, 3H).

V-351 1H NMR (CDCI3, freebase) δ (ppm): 8.50 (s, IH), 8.40 (d, IH), 7.48 (d, IH),

7.20 (m, 2H), 6.90 (s, IH), 4.92 (m, IH), 4.48 (m, IH), 4.25 (m, IH), 3.80 (t, IH), 3.18 (m, IH), 2.92 (m, 2H), 2.80 (m, IH), 2.72 (s, 3H), 2.40 (m, 2H), 1.90 (m, 4H).

V-352 1H NMR (CDCI3, freebase) δ (ppm): 8.48 (s, IH), 8.40 (d, IH), 7.50 (d, IH),

7.30 (s, IH), 7.18 (m, 2H), 5.02 (t, IH), 4.19 (m, IH), 4.09 (m, IH), 3.78 (t, IH), 3.18 (m, IH), 2.85 (m, IH), 2.75 (m, 2H), 2.42 (s, 3H), 2.38 (m, 2H), 1.85 (m, 4H).

V-353 1H NMR (CDCI₃, freebase) δ (ppm): 7.06 (s, IH), 6.71 (s, IH), 4.36 (m, 2H),

4.20 (m, IH), 3.30 (m, IH), 3.10-2.92 (m, 4H), 2.70 (m, IH), 2.64 (s, 3H), 2.50 (m, IH), 2.38 (s, 3H), 2.0-1.80 (m, 8H), 1.50 (m, 2H), 1.30 (m, 2H), 1.18 (m, 2H), 0.9 (s, 3H).

V-354 1H NMR (CDCI₃, freebase) δ (ppm): 8.4 (d, 2H), 7.30 (m, 3H), 7.2 (d, IH), 6.9

(d, IH), 5.1 (t, IH), 4.3-4.1 (m, 3H), 2.9 (m, IH), 2.6 (s, 3H), 2.4 (s, 3H), 2.1 (m, 2H), 1.9 (m, IH), 1.6 (m, 2H).

V-355 1H NMR (CDCI3, freebase) δ (ppm): 8.70 (s, IH), 8.55 (d ,1H), 7.70 (d, IH),

7.30 (s, IH), 7.26 (m, 2H), 4.10 (dd, 2H), 3.95 (t, IH), 3.22 (m, IH), 2.85 (m, IH), 2.82-2.65 (m, 3H), 2.45 (s, 3H), 2.39 (m, 2H), 1.90 (m, 3H), 1.65 (s, 3H).

V-356 1H NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.38 (s, IH), 7.28 (d, IH),

7.20 (d, 2H), 7.05 (d, IH), 5.10 (t, IH), 4.25 (m, IH), 4.15 (m, IH), 3.22 (m ,2H), 2.98 (m, IH), 2.62 (m, IH), 2.50 (s, 3H), 2.40 (m, 2H), 2.12 (m, 2H), 1.85 (m, 2H), 1.58 (s, 3H).

V-357 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.55 (d, 2H), 7.70 (s, IH), 7.32 (m, 4H),

4.25 (d, IH), 4.18 (d, IH), 3.95 (t, IH), 3.20 (m, IH), 2.82 (m, 2H), 2.75 (m, IH), 2.65 (m, IH), 2.48 (m, 2H), 1.90 (m, 3H), 1.60 (s, 3H).

V-358 1H NMR (CDCI3, freebase) δ (ppm): 8.55 (d, 2H), 7.10 (m, 3H), 6.95 (s, IH),

4.45 (m, 2H), 4.22 (m, 1H),4.15 (t,lH), 3.22 (m, 2H), 3.08 (m, IH), 2.90 (m, IH), 2.80 (m, IH), 2.70 (s, 3H), 2.65 (m,lH) ,2.45 (m,lH), 2.42 (s, 3H),1.90 (m, 4H), 1.82-1.62 (m, 6H), 1.58 (m, 2H). Compound NMR Data

No.

V-359 ^lH NMR (CDCI₃, freebase) δ (ppm): 7.10 (s, 1H), 6.64 (s, 1H), 5.0 (m, 2H),

4.05 (m, 1H), 3.30 (m, 1H), 2.98-2.82 (m, 2H), 2.74 (m, 2H), 2.50 (s, 3H), 2.42 (m, 1H), 2.38 (s, 3H), 1.90 (m, 3H), 1.80 (m, 4H), 1.68 (m, 1H), 1.40 (m, 2H), 1.24 (m, 3H).

V-360 1H NMR (CDCI₃, freebase) δ (ppm): 7.98 (s, 1H), 7.58 (s, 1H), 4.18 (m, 2H),

3.90 (m, 1H), 3.70 (m, 1H), 3.40 (m, 1H), 3.0 (m, 2H), 2.78 (m, 1H), 2.62 (m, 1H), 2.40 (s, 3H), 1.90 (m, 3H), 1.80 (m, 2H), 1.64 (m, 1H), 1.62-1.50 (m, 5H), 1.30-1.10 (m, 5H).

V-361 1H NMR (CDCI₃, freebase) δ (ppm): 8.50 (d, 2H), 7.20 (d, 2H), 6.95 (m, 2H),

4.82 (t, 1H), 4.42 (t, 1H), 4.05 (m, 2H), 2.95 (m, 3H), 2.75 (m, 2H), 2.58 (m, 1H), 2.42 (s, 3H), 1.95-1.75 (m, 4H).

V-362 1H NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.52 (s, 1H), 7.25 (m, 3H),

5.05 (t, 1H), 4.15 (m, 2H), 3.50 (m, 2H), 3.38 (m, 1H), 2.95 (m, 3H), 2.62 (m, 2H), 2.45 (s, 3H), 2.10-1.90 (m, 3H).

V-363 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.60 (d, 2H), 7.54 (m, 1H), 7.25 (m, 3H),

6.99 (s, 1H), 5.69 (d, 1H), 5.49 (d, 1H), 5.03 (m, 1H), 4.45 (dd, 1H), 4.20 (m, 1H), 4.0 (m, 1H), 3.30 (m, 1H), 3.05 (m, 1H), 2.96 (m, 2H), 2.83 (m, 1H), 2.70 (m, 2H), 2.46 (m, 1H), 2.42 (s, 3H), 1.90 (m, 3H).

V-364 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.42 (s, 1H), 7.25-7.22 (m,

3H), 7.02 (d, 1H), 5.04 (t, 1H), 4.16 (d, 2H), 2.90 (m, 4H), 2.48 (s, 3H), 2.42 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H).

V-365 1H NMR (CDCI₃, freebase) δ (ppm): 8.4 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.45

(d, 1H), 7.41(d, 1H), 4.4 (t, 2H), 3.58 (s, 2H), 3.2 (t, 2H), 2.78 (t, 2H), 2.58 (t, 2H), 2.41 (s, 3H).

V-366 ^lH NMR (CDCI₃, freebase) δ (ppm): 8.2 (d, 2H), 7.62 (s, 1H), 7.19 (d, 1H),

7.0(d, 1H), 4.3 (t, 2H), 3.60 (s, 2H), 3.12 (t, 4H), 2.78 (t, 2H), 2.42 (s, 3H), 2.41(s, 3H).

V-367 1H NMR (CDCI₃, freebase) δ (ppm): 8.44 (s, 1H), 8.20 (d, 1H), 7.86 (d, 1H),

7.80 (bs, 1H), 7.25 (m, 2H), 7.02 (d, 1H), 5.50 (bs, 1H), 5.20 (m, 1H), 4.24 (dd, 1H), 4.19 (dd, 1H), 4.0 (m, 1H), 3.28 (m, 1H), 2.90 (m, 1H), 2.80 (m, 2H), 2.60 (m, 2H), 2.44 (s, 3H), 2.40 (m, 1H), 1.90 (m, 3H).

V-368 1H NMR (CDCI₃, freebase) δ (ppm): 8.58 (d, 2H), 7.22 (d, 2H), 7.19 (s, 1H),

6.70 (s, 1H), 5.02 (t, 1H), 4.15 (d, 2H), 4.05 (t, 1H), 3.85 (s, 3H), 3.28 (m, 1H), 2.90 (m, 4H), 2.45 (m, 2H), 2.30 (s, 3H),1.95-1.80 (m, 3H).

V-369 1H NMR (CDCI3, freebase) δ (ppm): 8.70 (s, 1H), 8.50 (d, 1H), 7.60 (m, 1H),

7.18 (m, 1H), 6.70 (d, 1H), 6.55 (m, 1H), 5.48 (d, 1H), 5.32 (d, 1H), 4.62 (d, 1H), 4.38 (d 1H), 3.62 (m, 1H), 3.30 (m, 2H), 2.50 (m, 2H), 2.40 (s, 3H), 2.18 (m, 1H), 2.10-1.90 (m ,8H), 1.80 (m, 2H), 1.58 (s, 3H), 1.45 (m, 2H).

Example B 1 : Determination of the ability of compounds of the invention to bind a histamine receptor

Histamine Hi

[0262] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant histamine HI receptor expressed in Chinese hamster ovary (CHO) Kl cells (De Backer, M. et al, Biochem. Biophys. Res. Comm. 197(3): 1601, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) was used. Compounds of the invention were incubated with 1.2 nM [ H]Pyrilamine for 180 min at 25 °C. Non-specific binding was estimated in the presence of 1 μΜ Pyrilamine.

Receptor proteins were filtered and washed, the filters were then counted to determine

[ H] Pyrilamine specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 7 below.

Histamine H₂

[0263] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant histamine H2 receptor expressed in Chinese hamster ovary (CHO) Kl cells (Ruat, M., Proc. Natl. Acad. Sci. USA. 87(5): 1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 was used. Compounds of the invention were incubated with 0.1 nM

[ 125 I]Aminopotentidine for 120 min at 25 °C. Non-specific binding was estimated in the presence of 3 μΜ Tiotidine. Receptor proteins were filtered and washed, the filters were then counted to determine [ 125 I]Aminopotentidine specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 7 below.

Histamine H3

[0264] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant histamine H₃ receptor expressed in Chinese hamster ovary (CHO) Kl cells (Krueger, K. et al. J. Pharmacol. Exp. Ther. 314(1):271, 2005; Yanai, K. et al, Jpn. J. Pharmacol. 65(2): 107, 1994 ; Zhu, Y. et al, Mol. Pharmacol. 59(3):434, 2001) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 0.1% BSA) was used. Compounds of invention were incubated with 0.4 nM [ H]Na-Methylhistamine for 12 min at 25 °C. Nonspecific binding was estimated in the presence of 1 μΜ R(-)-a-Methylhistamine. Receptor proteins were filtered and washed, the filters were then counted to determine [ H] R(-)-cc- Methylhistamine specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 7 below.

Example B2: Determination of the ability of compounds of the invention to bind an imidazoline 12 receptor

Central Imidazoline [0265] To evaluate in radioligand binding assays the activity of compounds of the invention, rat central imidazoline I₂ receptor obtained from Wistar Rat cerebral cortex (Brown, C. et al, Br. J. Pharmacol. 99:803, 1990) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used. Compounds of the invention were incubated with 2 nM

[ H]Idazoxan for 30 min at 25 °C. Non-specific binding was estimated in the presence of 1 μΜ Idazoxan. Receptor proteins were filtered and washed, the filters were then counted to determine [ H] Idazoxan specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 7 below.

Table 7. Binding data (percentage inhibition)

Example B3: Determination of the ability of compounds of the invention to bind an adrenergic receptor

Adrenergic OCIA

[0266] To evaluate in radioligand binding assays the activity of compounds of the invention, rat adrenergic ¾A receptor obtained from Wistar Rat submaxillary glands (Michel, A. et al, Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used. Compounds of the invention were incubated with 0.25 nM [ H]Prazosin for 60 min at 25 °C. Non-specific binding was estimated in the presence of 10 μΜ phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [ H]Prazosin specifically bound. Compounds of the invention were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 8 below.

Adrenergic (XIB

[0267] To evaluate in radioligand binding assays the activity of compounds of the invention, rat adrenergic am receptor obtained from Wistar Rat liver (Garcia-S'ainz, J. et al, Biochem. Biophys. Res. Commun. 186:760, 1992; Michel, A. et al, Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used.

Compounds of the invention were incubated with 0.25 nM [ H]Prazosin for 60 min at 25 °C. Non-specific binding was estimated in the presence of 10 μΜ phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [ H]Prazosin specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 8 below.

Adrenergic w

[0268] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic am receptor expressed in human embryonic kidney (HEK- 293) cells (Kenny, B. et al, Br. J. Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, was used. Compounds of invention were incubated with 0.6 nM [ H]Prazosin for 60 min at 25 °C. Non-specific binding was estimated in the presence of 10 μΜ phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine

[ H]Prazosin specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 8 below.

Adrenergic OIA

[0269] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic <¾A receptor expressed in insect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271: 1558, 1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2 mM EDTA) was used. Compounds of invention were incubated with 1 nM [³H]MK-912 for 60 min at 25 °C. MK-912 is (2S-trans)-l,3,4,5',6,6',7,12b-octahydro- ,3'-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4'(rH)-pyrimidin]-2'(3'H)-one hydrochloride Non-specific binding was estimated in the presence of 10 μΜ WB-4101 (2- (2,6-Dimethoxyphenoxyethyl)aminomethyl- 1 ,4-benzodioxane hydrochloride). Receptor proteins were filtered and washed, the filters were then counted to determine [ H]MK-912 specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 8 below.

Adrenergic OC2B

[0270] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic <¾B receptor expressed in Chinese hamster ovary (CHO) Kl cells (Uhlen, S. et al, Eur. J. Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used. Compounds of the invention were incubated with 2.5 nM [ H]Rauwolscine for 60 min at 25 °C. Nonspecific binding was estimated in the presence of 10 μΜ Prazosin. Receptor proteins were filtered and washed, the filters were then counted to determine [ H]Rauwolscine specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle.

Biochemical assay results are presented as the percent inhibition of specific binding in Table 8 below.

Adrenergic OC2C

[0271] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic <¾c receptor expressed in insect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271: 1558, 1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2 mM EDTA) was used. Compounds of the invention were incubated with 1 nM [Ή]ΜΚ-912 for 60 min at 25 °C. Non-specific binding was estimated in the presence of 10 μΜ WB-4101. Receptor proteins were filtered and washed, the filters were then counted to determine [ H]MK-912 specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 8 below.

Example B4: Determination of the ability of compounds of the invention to bind a dopamine receptor

Dopamine D_2L

[0272] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant dopamine D_2L receptor expressed in Chinese hamster ovary (CHO) cells (Grandy, D. et al, Proc. Natl. Acad. Sci. USA. 86:9762, 1989; Hayes, G. et al, Mol.

Endocrinol. 6:920, 1992) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mM Ascorbic Acid, 0.001% BSA, 150 mM NaCl) was used. Compounds of the invention were incubated with 0.16 nM [ H]Spiperone for 120 min at 25 °C. Non-specific binding was estimated in the presence of 10 μΜ Haloperidol. Receptor proteins were filtered and washed, the filters were then counted to determine [ H] Spiperone specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 8 below.

Table 8. Percentage inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention

Example B5: Determination of the ability of compounds of the invention to bind a serotonin receptor

Serotonin (5-Hydroxytryptamine) 5-HTj_A

[0273] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HTiA receptor expressed in Chinese hamster ovary (CHO) Kl cells (Martin, G. et al, Neuropharmacol. 33:261, 1994; May J. et al, J. Pharmacol. Exp. Ther. 306(1):301, 2003) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mM MgS0₄) is used. Compounds of invention are incubated with 1.5 nM [³H]8-OH-DPAT for 60 min at 25 °C. Non-specific binding is estimated in the presence of 10 μΜ Metergoline. Receptor proteins are filtered and washed, the filters are then counted to determine [ H] 8-OH-DPAT specifically bound. Compounds are screened at 1 μΜ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HTj_B

[0274] To evaluate in radioligand binding assays the activity of compounds of the invention, serotonin (5-Hydroxytryptamine) 5-HTiB receptor from Wistar Rat cerebral cortex (Hoyer et al, Eur. J. Pharmacol. 118: 1, 1985 ; Pazos et al, Eur. J. Pharmacol. 106:531, 1985) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μΜ Pargyline, 30 μΜ Isoprenaline) is used. Compounds of invention are incubated with 10 pM

125

[ I]Cyanopindolol for 90 min at 37 °C. Non-specific binding is estimated in the presence of 10 μΜ Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are counted to

125

determine [ I]Cyanopindolol specifically bound. Compounds are screened at 1 μΜ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-ΗΪ2Α

[0275] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₂A receptor expressed in Chinese hamster ovary (CHO) Kl cells (Bonhaus, D. et al, Br. J. Pharmacol. 115:622, 1995; Saucier, C. et al, J. Neurochem. 68: 1998, 1997) in a 50 mM Tris-HCl buffer, pH 7.4, was used. Compounds of the invention were incubated with 0.5 nM [ H]Ketanserin for 60 min at 25 °C. Non-specific binding was estimated in the presence of 1 μΜ Mianserin. Receptor proteins were filtered and washed, the filters were then counted to determine [ H]Ketanserin specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 9 below.

Serotonin (5-Hydroxytryptamine) 5-ΗΪ2Β

[0276] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT_2B receptor expressed in Chinese hamster ovary (CHO) Kl cells (Bonhaus, D. et al, Br. J. Pharmacol. 115:622, 1995) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl₂, 0.1% Ascorbic Acid) is used. Compounds of invention are incubated with 1.2 nM [ H] Lysergic acid diethylamide (LSD) for 60 min at 37 °C. Non-specific binding is estimated in the presence of 10 μΜ Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are then counted to determine [ H]LSD specifically bound. Compounds are screened at 1 μΜ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT₂c

[0277] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₂c receptor expressed in Chinese hamster ovary (CHO) Kl cells (Wolf, W. et al, J. Neurochem. 69: 1449, 1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10 μΜ Pargyline) was used. Compounds of the invention were incubated with 1 nM [ H]Mesulergine for 60 min at 25 °C. Non-specific binding was estimated in the presence of 1 μΜ Mianserin. Receptor proteins were filtered and washed, the filters were then counted to determine [ H]Mesulergine specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 9 below.

Serotonin (5-Hydroxytryptamine) 5-HT₃

[0278] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₃ receptor expressed in human embryonic kidney (HEK-293) cells (Miller, K. et al, Synapse 11:58, 1992; Boess, F. et al, Neuropharmacology 36:637, 1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1 mM EDTA, 5 mM MgCl₂) is used. Compounds of invention are incubated with 0.69 nM [ H]GR-65630 for 60 min at 25 °C. Non-specific binding is estimated in the presence of 10 μΜ MDL-72222. Receptor proteins are filtered and washed, the filters are then counted to determine [ H]GR-65630 specifically bound. Compounds are screened at 1 μΜ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT₄

[0279] To evaluate in radioligand binding assays the activity of compounds of the invention, serotonin (5-Hydroxytryptamine) 5-HT₄ receptor from Duncan Hartley derived Guinea pig striatum (Grossman, C. et al, Br. J. Pharmacol. 109:618, 1993) in a 50 mM Tris-HCl, pH 7.4, is used. Compounds of invention are incubated with 0.7 nM [ H]GR-113808 for 30 min at 25 °C. Non-specific binding is estimated in the presence of 30 μΜ Serotonin (5-HT). Receptor proteins are filtered and washed, the filters are counted to determine [ H]GR-113808 specifically bound. Compounds are screened at 1 μΜ or lower, using 1% DMSO as vehicle. Compounds of the invention are tested in this biochemical assay and percent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_SA

[0280] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HTs_A receptor expressed in Chinese hamster ovary (CHO) Kl cells (Rees, S. et al, FEBS Lett. 355:242, 1994) in a modified Tris- HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used.

Compounds of the invention were incubated with 1.7 nM [ H]Lysergic acid diethylamide (LSD) for 60 min at 37 °C. Non-specific binding was estimated in the presence of 100 μΜ Serotonin (5-HT). Receptor proteins were filtered and washed, the filters were counted to determine [ H]LSD specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 9 below.

Serotonin (5-Hydroxytryptamine) 5-HTe

[0281] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₆ receptor expressed in human HeLa cells (Monsma, F. Jr .et al, Mol. Pharmacol. 43:320, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used. Compounds of the invention were incubated with 1.5 nM [3H]Lysergic acid diethylamide (LSD) for 120 min at 37 °C. Non-specific binding was estimated in the presence of 5 μΜ Serotonin (5-HT). Receptor proteins were filtered and washed, the filters were then counted to determine [3H]LSD specifically bound. Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 9 below.

Serotonin {5 -Hydroxy try ptamine) 5-ΗΤγ

[0282] To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₇ receptor expressed in Chinese hamster ovary (CHO) cells (Roth, B. et al, J. Pharmacol. Exp. Ther. 268: 1403, 1994; Shen, Y. et al, J. Biol. Chem. 268: 18200, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used. Compounds of invention were incubated with 5.5 nM [ H] Lysergic acid diethylamide (LSD) for 2h at 25 °C. Non-specific binding was estimated in the presence of 10 μΜ Serotonin (5-HT). Receptor proteins were filtered and washed, the filters were then counted to determine [ H]LSD specifically bound.

Compounds were screened at 1 μΜ or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Table 9 below.

Table 9. Percentage inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention

Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

32b 89 49 1 16 18

33 98 95 95 48

33a 39 51 -11 25 -8

33b 81 88 5 68 -12

34 102 95 100 79

34a 77 84 31 72 19

34b 67 67 26 48 16

35 36 8 10 12

35a 43 33 6 28 30

35b 21 25 15 25 25

73,

60 77, 87 94 98 28 48 78

86

82,

61 90 91 96 41 51 86

84

62 42 22 31

74 29 13 0 20 44

74a 12 25 27 31 92

77 13 39 71 14 88

78 51 30 37 9 21

83 93 96 102

84 94 2, 87 6, 58 18, 79 97

85 63 29 39 38 84 5 -9 2

86 98 78, 89 90 75, 88 103

87 102 88 93

88 98 100 100

89 96 91 89, 95 99 57 43 85

90 100 93 90

90a 99

90b 99

50,

60, 83, 69,

55, 92, 4, 10, 38, 20, 62,

91 64, 87, 74, 19, 21

63, 93, 98 18 45, 52 35, 40 64, 73 68, 76 88, 91 76, 80

73

92 93 89 83

93 84 81 39

94 98 104 62 95

95 88 93 26 97

96 102 96 95 92 74 87 38

97 91 77 62 66

98 102 99 98 94

99 102 101 103 94

100 93 93 104 98

101 75 70 90 53

102 67 65 55 71

103 66 47 89 69

105 87 60 59 74

106 82 84 88 49

107 82 75 53 68

108 79 86 27 39 82

109 89 73 51 32 79 Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

110 67 74 -14 10 35

111 82 91 82 22 96

112 87 93 57 1 75

113 95 92 25 56 34

114 20 19 43 3 90, 99

115 51 77 61 38 87

116 90 91 8 83 68

117 31 42 32 58 52

118 29 42 25 13 80

119 31 10 10 5 8

120 22 82 73, 83 79, 88 3, 13 90, 93 40, 45

121 78 81 18 35 63

122 81 80 43 1 67

124 50 25 -1 23 15

125 42 41 24 10 27

126 94 90 46 20 71

38, 26,

129d 18, 33 62, 65 87, 93 7

50 32, 35

99,

130a 86 46 103 107 89

101

132 63

133a 24

133b 31

134a 20

134b 15

135a 43

135b 26

136a 41

136b 24

III-l 93 99 96 103 85 70 91

III-2 95 95 82 87 98 75 24 31

III-3 96 97 69 95 100 84 6 49

III-4 96 100 96 101 101 66 87

III-5 100 97 94 103 97 85 62 102 82

III-6 102 92, 94 91, 98 68, 75 97 88, 98 92 71 19, 22 82, 96

III-7 88 68 79 29 89

III-8 80 88 43 26 56

III-9 97 99 14 66 82

III- 10 55 64 94 18 97

III- 11 21 28 89 57 84

III- 12 50 26 24 25 61

III- 13 99 99 103 101 87 88 100

III- 15 99 94 105 92

101,

III- 16 98 96, 98 88, 90 88 52 95

104

III- 17 92 90 47 91 98 24 8 50

III- 18 97 93 76 94 102 59 4 56

III- 19 102 84 27 83 91 43 29

III- 19a 39

III- 19b 58

111-20 99 96 86 104 97 101 95 Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

111-21 92 99 72 99 95 84 74

111-22 97 95 81 100 91 39 85 92

111-23 98 94 91 104 99 79 56 99 99

111-24 99 100 96 102 92 86 96

111-25 88 90 49 101 92 90 90

111-26 92 89 63 99 92 73 91

111-27 96 79 86 82 98

111-28 91 95 68 99 92 77 71

111-29 100 97 95 103 99 99 82 78, 88

111-30 99 98 50 86 89

111-31 99 95 60 103 100 93

111-32 100 99 76 106 95 103

99,

111-33 98 94 89 94, 97 83 82 93

101

111-34 93 107 103

111-35 93 105 87 99 74

111-36 97 89 100

111-37 97 96 100

111-38 100 105 103 93 92 94 90

111-39 97 99 72 98

111-40 94 94 36 87

111-41 102 101 100 93

111-42 103 100 86 94

111-43 100 94 73 93

111-44 102 97 59 87

111-45 98 97 102 96

111-46 94 93 57 96

111-47 100 97 100 100

111-48 98 102 99 94

111-49 100 101 103 97

111-50 99 99 97 94

111-51 99 100 103 94

111-52 98 100 101 100

111-53 99 99 74 96

111-54 99 91 49 84

111-55 98 101 78 93

88, 77,

111-56 99 77, 98 93, 97 76

98 100

111-57 101 98 97 94

111-58 98 99 94 97

111-59 98 99 74 95

111-60 94 103 99 89

111-61 100 98 101 102

111-62 100 99 99 101

111-63 101 99 99 105

111-64 98 100 76 95

111-65 101 102 96 94

111-66 99 99 104 99

111-67 96 91 87 82

97,

111-68 95, 98 82, 87 95, 98 96 96 40 68

100 Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

III-68a 98 94 45 69

III-68b 91 81 38 78

111-69 71 83 45 93

111-70 94 100 46 85

111-71 98 99 97 94

111-72 88 91 69 79

111-73 78 96 38 95

111-74 94 107 92 91

111-75 97 83 38 29

111-76 94 81 82 79

111-77 97 87 28 98

111-78 94 97 65 42

111-79 103 98 81 98

111-80 93 94 68 63 86

111-81 101 98 96 82 87

111-82 110 95 96 88 100

111-83 99 97 99 98

III-83a 99 94 5 97 54

III-83b 87 97 -5 78 80

111-84 67 75 48 69 96

111-85 95 100 16 55 11

111-86 87 90 92 27 100

111-87 82 94 74 73 99

111-88 98 99 97 102 101

111-89 100 100 91 90 99

111-90 39 56 90 50 97

111-91 99 102 94 73 92

111-92 100 97 77 13 91

111-93 94 96 65 28 87

111-94 99 97 94 68 84

111-95 92 90 100 94 100

111-96 100 99 82 90 95

111-97 86 91 51 87 72

111-98 98 99 85 96 97

99,

111-99 99 98

104

III-99a 97 101 65 99 99

III-99b 97 100 5 97 87

III- 100 69 59 22 83

III- 100a 63 73 33 14 91

III- 100b 59 46 -4 11 27

III- 101 95 90 86 85 98

III- 102 97 98 94 96 103

III- 103 77 68 37 28 62

III- 104 99 93 98 68 96

III- 105 94 92 89 103 96

III- 106 93 99 69 62 83

III- 107 89 68 22 22 55

III- 108 46 36 54 29 98

III- 109 67 62 55 72 93

III- 110 68 71 43 28 93 Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

Ill- 111 12 21 67 7 87

III- 112 29 56 86 33 96

III-113 37 46 75 26 89

III- 114 -1 11 89 9 46

III- 115 48 36 85 17 88

III-116 22 10 94 14 85

III- 117 39 59 84 46 36

III- 118 96 96 83 102 98

III- 119 94 99 41 101 99

III- 120 31 26 29 16 92

III- 121 96 86 42 44 33

III- 122 102 94 98 48 102

III- 123 84 94 30 90 60

III- 124 22 47 -10 5 36

III- 125 3 12 9 1 36

III- 126 73 83 76 82 77

III- 127 22 50 42 11 36

III- 128 99 104 78 102 101

III- 129 2 3 2 12 22

III- 130 59 28 64 50 91

III-131 32 11 -8 58 43

III- 132 93 62 82 55 99

III- 133 30 62 -8 7 -1

III- 134 71 88 17 104 56

III- 135 100 103 87 40 95

III- 136 100 99 68 42 88

III- 137 99 92 82 96

III- 138 96 68 17 72 68

III- 139 100 16 99

IV- 1 90 97 91 103 100

IV-2 78, -4 9, 53 63, -2 47, -6 1, 94 -3

14, 66,

IV-3 32, 36 30, 32 30, 45

33 73, 75

IV-4 1, 3 11, -4 9, -1 2, -2 8, 11

IV-5 25 5

IV-6 98 101

IV-7 6 -7 17 16 4

59,

IV-8 101 79, 83 84 93 76 11 69

66, 84

IV-9 -10 6 -12 -6 -15

IV- 10 32 24 17 2 18

IV- 11 15 7 6 5 18

IV- 12 31 15 10 -3 6

IV- 13 35 19 25 34 23

IV- 14 86 70

IV- 15 90 100

IV- 16 95 78 65

IV- 17 88 70 39

IV- 18 74 73 72

IV- 19 69 67 85

IV-20 53 82 61 Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

63,

IV-21 66, 75 83, 84 87 19 18 15 46

75

IV-22 59 81 70

IV-23 64 69 75

IV-24 89 69 57

IV-25 10 57 23

IV-27 26 40 46

IV-28 88 78 94

IV-29 -1 -15 0

IV-30 85 88 83

92,

IV-31 87 88, 90 100 50 38 87

93

IV-32 94 68 66

IV-33 51 39 6

IV-34 16 20 69

IV-35 54 76 79

IV-36 102 94 33 82 88 55 30

IV-37 98 79 86

IV-38 96 99 104

IV-39 27 40 61

IV-40 15 40 64

IV-41 52 76 82

IV-42 97 93 93 96, 97 77 52 85

IV-43 92 87 102 91

IV-44 98 82 39 40 81

IV-45 60 58 76

IV-46 100 87 100 97

IV-47 55 9 11 1 37

IV-48 101 97 101

91,

IV-49 97 83 85, 91 77 40 93

100

IV-50 96 77 81, 88 94, 98 69 30 88

IV-51 74 34 -2 7 39

IV-52 101 94 104

IV-53 76 84 79

96,

IV-54 94 95 100 49 64 90

100

IV-55 95 95 96, 98 100 52 62 92

IV-56 24 31 31

IV-57 97 72 9

IV-58 -7 17 4

IV-59 2 9 13

IV-60 39 31 14

IV-61 27 20 14

IV-62 100 96 87, 90 97 78 55 85

IV-63 39 31 56

IV-64 84 72 64

IV-65 85 80 65

IV-66 95 94 92

IV-67 96 90 93

IV-68 96 92 82 Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

IV-69 97 95 100

IV-70 96 93 81

IV-71 94 92 97

IV-72 87 84 94

IV-73 5 34 4

IV-74 70 54 -5 15 78

IV-75 95 77 46

IV-76 8 29 30

81,

IV-77 90 57 88, 90 97, 99 43 41 83

92

IV-78 100 94 95

IV-79 100 101 103

IV-80 100 98 86

IV-82 41 53 19

IV-83 69 53 6 32 73

69,

IV-84 91 94, 96 99 34 63 88

81

IV-85 65 39 58 64 85

IV-86 100 98 98

IV-87 97 95 104

IV-88 81 75 21

IV-89 57 55 41

43,

IV-90 89, 98 5, 103 97

97

12, 100, 102, -

IV-91 97

100 101 4

91, 101,

IV-92 5, 99 100

98 103

IV-93 52 -1 -4

IV-94 71 82 23

IV-95 77 93 13

IV-96 16 9 3

IV-97 11 -6 -5

IV-98 96 79 29 70 70

IV-99 80 101 48 99

IV- 100 56 79 23 82

IV-101 93 88 96 82

IV- 102 0 2 4 6 17

IV- 103 66 41 14 59

IV- 104 99 100 103 90

IV- 105 -1 12 6 18 49

IV- 106 87 90 43 63

IV- 107 47 49 22 66

IV- 108 16 45 46 74

IV- 109 51 50 18 78

IV-110 56 47 28 74

IV-111 24 -5 2

IV-112 6 1 10

IV-113 7 5 22

IV-114 65 9 24

IV- 126 30 40 50 86 Compound Serotonin (1 μΜ) Serotonin (0.1 μΜ) No. 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇ 5-HT_2A 5-HT_2C 5-HT_5A 5-HT₆ 5-HT₇

IV- 127 31 36 40 30 92

IV- 128 77 92 4 15

IV- 129 81 83, 87 65, 66 86, 91 99 26 32 -12 38, 40 89

65, 81,

IV- 130 65, 91 75, 91 94, 98

92 100

IV-131 77 82 55 89 95

IV-313 3 -8 6 5 7

V-l 54 62 34 91

V-2 95 97 82 91

V-3 93 96 82 87

V-4 48 28 11 5

V-5 65 41 60 0

V-6 43 44 0 56

V-7 87 79 101 82

V-8 102 96 17 47 86

V-9 25 5 70 11 71, 72

V-10 68 80 49 17 10

V-l l 99 92 82 54 56

V-12 -5 -4 24 9 13

V-13 -2 9 4 9 -11

V-14 5 -8 1 13 3

V-15 102 102 37 39 54

V-16 40 9 13 7 12

V-17 100 101 77 30 87

V-18 100 99 52 11 42

V-19 76 76 5 22 22

V-20 97 98 59 50 28

V-21 31 22 -5 14 7

V-22 28 14 4 -2 -3

V-23 70 45 79

V-24 71 26 -4

V-25 78 1 19

V-26 81 12 2

V-27 13 3 1

V-28 0 -3 5

V-62 36

V-63 17

V-64 22

V-65a 21

V-65b 17

Example B6: Determination of Serotonin (5-Hydroxytryptamine) 5-HT?A or 5-HT₇

agonist/antagonist activity of compounds of the invention

[0283] To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant serotonin 5-HT_2A receptor expressed in human embryonic kidney (HEK-293) cells (Jerman et al., Eur. J. Pharmacol. 414:23-30, 2001) or human recombinant serotonin 5-HT₇ receptor expressed in CHO cells (Adham et al, J. Pharmacol. Exp. Ther. 287:508-514, 1998) is used. Cells are suspended in DMEM buffer, and distributed in microplates. For the 5-HT₂A assay, a cytoplasmic calcium fluorescent indicator which varies proportionally to the free cytosolic Ca²⁺ ion concentration is mixed with probenecid in HBSS buffer complemented with 20 mM Hepes (pH 7.4), added into each well and equilibrated with the cells for 30 min at 37 °C followed by 30 min at 22 °C. For the 5-HT₇ assay, the reaction product is cAMP, detected by HTRF.

[0284] To measure 5-HT₂A agonist effects, compounds of the invention, reference agonist or HBSS buffer (basal control) is added to the cells and changes in fluorescence intensity are measured using a microplate reader. For stimulated control measurements, 5-HT at 100 nM is added in separate assay wells. The results are expressed as a percent of the control response to 100 nM 5-HT. The standard reference agonist is 5-HT, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC₅₀ value is calculated.

[0285] To measure antagonist effects, the addition of the compounds of the invention, reference antagonist or HBSS buffer is followed by the addition of 3 nM 5-HT (5-HT₂A), 100 nM 5-HT (5-HT₇) or HBSS buffer (basal control) prior the fluorescence measurements. The results are expressed as a percent inhibition of the control response to 3 nM 5-HT. The standard reference antagonist is ketanserin (5-HT_2A) or mesulergine (5-HT₇), which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC₅₀ value is calculated. Compounds are screened at 3 μΜ or lower, using DMSO as vehicle.

Example B7: Determination of Serotonin (5-Hydroxytryptamine) 5-ΗΤή agonist/antagonist activity of compounds of the invention

[0286] To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant 5-HT₆ receptor is transfected in CHO cells (Kohen, R. et al, J. Neurochem. 66:47, 1996) and the activity of compounds of the invention is determined by measuring their effects on cAMP production using the Homogeneous Time Resolved Fluorescence (HTRF) detection method. Cells are suspended in HBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μΜ IBMX, and then distributed in microplates and incubated for 45 min at 37 °C in the absence (control) or presence of compounds of the invention or the reference agonist or antagonist.

[0287] For agonist determinations, stimulated control measurement, separate assay wells contain 10 μΜ 5-HT. Following incubation, the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added. After 60 min at room temperature, the fluorescence transfer is measured at lex=337 nm and lem=620 and 665 nm using a microplate reader. The cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).

[0288] The results are expressed as a percent of the control response to 10 μΜ 5-HT. The standard reference agonist is 5-HT, which is tested in each experiment at several

concentrations to generate a concentration-response curve from which its EC₅₀ value is calculated.

[0289] For antagonist determinations, the reference agonist 5-HT is added at a final concentration of 100 nM. For basal control measurements, separate assay wells do not contain 5-HT. Following 45 min incubation at 37 °C, the cells are lysed and the fluorescence acceptor (D₂-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added.

[0290] After 60 min at room temperature, the fluorescence transfer is measured as mentioned above. The results are expressed as a percent inhibition of the control response to 100 nM 5- HT. The standard reference antagonist is methiothepin.

Example B8: Determination of Dopamine O t_ antagonist activity of compounds

[0291] To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant dopamine D_2L receptor stably expressed in Chinese hamster ovary (CHO) cells (Senogles, S. et al, J. Biol. Chem. 265(8):4507, 1990) is used. Compounds of the invention are pre-incubated with the membranes (0.1 mg/mL) and 10 mM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, ImM EDTA) for 20 min and Scintillation Proximity Assay (SPA) beads are added for another 60 min at 30 °C. The reaction is initiated by 0.3 nM [ 35 S]GTPyS for an additional

15 min incubation period. Increase of [ 35 S]GTPyS binding by 50% or more (350%) relative to the 1 mM dopamine response by compounds of the invention indicates possible dopamine D_2L receptor agonist's activity. Inhibition of a 10 μΜ dopamine-induced increase of

[ 35 S]GTPyS binding response by 50% or more (350%) by compounds of the invention indicates receptor antagonist activity. Compounds are screened at 3 μΜ or lower, using 0.4% DMSO as vehicle. Assay results are presented as the percent response of specific binding.

Example B9: Determination of Dopamine D?s antagonist activity of compounds of the invention [0292] To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant dopamine D₂s receptor stably expressed in Chinese hamster ovary (CHO) cells (Gilliland, S. et al, Naunyn-Schmiedeberg's Archives of

Pharmacology 361:498, 2000) is used. Compounds of the invention are pre-incubated with the membranes (0.05 mg/mL) and 3 μΜ GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1 mM EDTA) for 20 min and

Scintillation Proximity Assay (SPA) beads are then added for another 60 min at 30 °C. The reaction is initiated by 0.3 nM [ 35 S]GTPyS for an additional 30 min incubation period.

Increase of [ 35 S]GTPyS binding by 50 percent or more (350%) relative to the 100 μΜ dopamine response by compounds of the invention indicates possible dopamine D_2S receptor agonist's activity. Inhibition of a 3 μΜ dopamine-induced increase of r 35S]GTPyS binding response by 50 percent or more (350%) by compounds of the invention indicates receptor antagonist activity. Compounds are screened at 3 μΜ or lower, using 0.4% DMSO as vehicle. Assay results are presented as the percent response of specific binding.

Example B10: Determination for agonist or antagonist activity of compounds of the invention in a histamine functional assay

[0293] To determine for agonist or antagonist activity of compounds of the invention in functional assays, human recombinant Histamine Hi receptor expressed in human embryonic kidney (HEK-293) cells (Miller, T. et al, J. Biomol. Screen. 4: 249-258, 1999) is used. Cells are suspended in DMEM buffer, and then distributed in microplates. A cytoplasmic calcium fluorescent indicator-which varies proportionally to the free cytosolic Ca²⁺ ion concentration is mixed with probenecid in HBSS buffer complemented with 20 mM Hepes (pH 7.4) and is then added into each well and equilibrated with the cells for 30 min at 37 °C and then for another 30 min at 22 °C. To measure agonist effects, compounds of the invention, reference agonist or HBSS buffer (basal control) are added to the cells and changes in fluorescence intensity are measured using a microplate reader. For stimulated control measurements, histamine at 10 μΜ is added in separate assay wells.

[0294] The results are expressed as a percent of the control response to 10 μΜ histamine. The standard reference agonist is histamine, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC₅₀ value is calculated.

[0295] To measure antagonist effects, the addition of the compounds of the invention, reference antagonist or HBSS buffer is followed by the addition of 300 nM histamine or HBSS buffer (basal control) prior the fluorescence measurements. The results are expressed as percent inhibition of the control response to 300 nM histamine. The standard reference antagonist is ketanserin, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC₅₀ value is calculated. Compounds are screened at 3 μΜ or lower, using DMSO as vehicle.

Example Bl l: Determination of binding activity of compounds of the invention at the 5-HT_m receptor with a radioligand binding competition assay

[0296] To determine the binding activity at the human recombinant serotonin 5-HT_1B receptor of compounds of the invention, CHO-K1 cell line expressing the human 5-HT_1B recombinant receptor is amplified to prepare membranes used for the radioligand binding assay throughout the study. Radioligand binding competition on 5-HTiB is performed by adding successively in the wells of a 96 well plate (Master Block, Greiner, 786201) 50 μΐ_^ of test compounds or reference ligand (5-HT, Sigma, H-9523) at increasing concentrations (diluted in binding buffer: 50mM Tris pH 7.4, 12.5 mM MgCl₂, 0.1% Ascorbic Acid, ImM EDTA, pH 7.4), 25 [³H]5-CT (Amersham, TRK1038, diluted in assay buffer for a final concentration of 0.6 nM) and 25 μΐ_^ 5-HT1B membrane extracts (7 μg/well). Non specific binding is determined by co-incubation with 200-fold excess of 5-HT. The plate is incubated 60 min at 25 °C in a water bath and then filtered over GF/B filters (Perkin Elmer, 6005177, presoaked in 0.5% PEI for 2h at room temperature) with a Filtration unit (Perkin Elmer). The filters are washed 3x with 0.5 mL of ice-cold washing buffer (50 mM Tris pH 7.4), 50 μΐ_^ Microscint 20 (Packard) is added and the plate is incubated 15 min on an orbital shaker and then counted with a TopCount™ for 1 min/well.

[0297] On each day of experimentation and prior to the testing of compounds, the reference compound is tested at several concentrations in duplicate (n=2) to obtain a dose-response curve and an estimated IC₅₀ value. The reference value thus obtained for the test is compared to a historical value obtained from the same receptor and used to validate the experimental session. A session is considered as valid only if the reference value is found to be within a 0.5 logs interval from the historical value. For replicate determinations, the maximum variability tolerated in the test is of +/- 20% around the average of the replicates.

[0298] Compounds are tested for binding activity in the radioligand binding competition assay on human 5-HTiB receptor, at one concentration 5 μΜ, in duplicate. Dose-response data from test compounds are analyzed with XLfit (IDBS) software using nonlinear regression applied to a sigmoidal dose-response model. Example B 12: Functional activity on recombinant Dopamine D?T_ and serotonin 5-HTTA receptors using Aequorin, cAMP and GTPyS functional assays

[0299] To study the functional activity of compounds of the invention on the human recombinant dopamine D₂L with Aequorin, GTPyS and cAMP functional assays and on the human recombinant serotonin 5-HT_2A receptor with Aequorin, CHO-K1 cell lines expressing D_2L or 5-HT_2A recombinant receptor, mitochondrial apoaequorin and Gal6 are used for the Aequorin assay. CHO-K1 cell line expressing the recombinant D₂L receptor is used for the cAMP assay and is amplified to prepare membranes used for the GTPyS assay.

[0300] Aequorin Assay Procedure: Aequorin dopamine D_2L (FAST-0101A) or serotonin 5- HT_2A (FAST-0505A) cells, grown 18h prior to the test in media without antibiotics, are detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in "assay buffer" (DMEM/HAM's F12 with HEPES, without phenol red + 0.1% BSA protease free). Cells are incubated at RT for at least 4h with Coelenterazine h

(Molecular Probes). Dose response curves with reference compounds are performed before testing the compounds of the invention. D₂L reference agonist and antagonist are quinpirol (Tocris, 1061) and haloperidol (Tocris, 0931), respectively. 5-HT_2A reference agonist and antagonist are a-methyt-5-HT (Sigma, M- 110) and ketanserin (Tocris, 908), respectively. For agonist testing, 50 μΐ_^ of cell suspension are injected on 50μί of test compound or reference agonist plated in a 96-well plate. The resulting emission of light is recorded using the Hamamatsu Functional Drug Screening System 6000 (FDSS 6000). Following an incubation of 15 min after the first injection, 100 μΐ_^ of reference agonist at a concentration corresponding to its ECgo is injected on the 100 μΐ_^ of the mixture of cell suspension and test compound, for antagonist testing. The resulting emission of light is recorded using the same luminometer as for agonist testing. To standardize the emission of recorded light

(determination of the "100% signal") across plates and across different experiments, some of the wells contain 100 μΜ digitonin or a saturating concentration of ATP (20 μΜ). Plates also contain the reference agonist at a concentration equivalent to the EC₁₀o and ECso obtained during the test validation. Compounds are tested for agonist & antagonist activity at the human dopamine D_2L receptor (FAST-0101A) and serotonin 5-HT_2A receptor (FAST- 0505 A) at the following nanomolar concentrations, in duplicate: Agonist (nM): 10, 30, 100, 300, 1000, 3000, 10000, 30000; Antagonist (nM): 5, 15, 50, 150, 500, 1500, 5000, 15000.

[0301] cAMP Assay Procedure: D_2L CHO-K1 cells (FAST-0101C), grown to mid-log phase in culture media without antibiotics, are detached with PBS-EDTA (5mM EDTA), centrifuged and resuspended in assay buffer (KRH, 1 mM IB MX) at a concentration of 2.1xl0⁵ cells/mL. The test is performed in 96 well plates. For agonist testing, 12 μL· of cells (2,500 cells/well) are mixed with 6 μΐ_^ of increasing concentrations of test compound or reference agonist and 6 μΐ_^ of Forskolin 10 μΜ final concentration (Calbiochem, cat n° 344270). For antagonist testing, 12 μL· of cells (2,500 cells/well) are mixed with 6 μΐ_^ of test compound or reference antagonist at increasing concentrations. After incubation of 10 min at room temperature, 6 μΐ_^ of a mix of Forskolin 10 μΜ final concentration and the reference agonist at a final concentration corresponding to the ECso are added. The plates are then incubated for 30 min at room temperature. During the incubation, the anti-cAMP cryptate antibody (K) and the cAMP-D2 (D2) are prepared according to the manufacturer

specifications (HTRF kit from Cis-Bio International (cat n° 62AM2PEB). 12 of cAMP- D₂ solution followed by 12 of K solution are added to each well. The plate is then covered by a top-seal and incubated for at least lh at room temperature. The plate is then read on the Rubystar and data are analyzed by non-linear regression using a single site model. Compounds are tested for antagonist activity at the human dopamine D_2L receptor (FAST- 0101C) at the following nanomolar concentrations, in duplicate: Antagonist (nM): 5, 15, 50, 150, 500, 1500, 5000, 15000.

[0302] GTPyS Assay Procedure: Assay buffer [20mM HEPES pH 7.4; lOOmM NaCl, 10 μg/mL saponin, 30mM MgCl₂] ; Membranes [Recombinant CHO-Kl-D_2L membrane extracts thawed on ice and diluted in assay buffer to give 1 mg/mL (10μg /ΙΟμί) and kept on ice] ; GDP [diluted in assay buffer to give 3 μΜ final concentration] ; Beads [PVT-WGA

(Amersham, RPNQ0001), diluted in assay buffer at 25 mg/mL (0.25mg/10 μΐ.)] ; GTPy³⁵S [(PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nM final concentration] ; Ligand [Quinpirol (Tocris, 1061) as reference agonist and haloperidol (Tocris, 0931) as reference antagonist, diluted in assay buffer] . Membranes are mixed with GDP (volume: volume) and

35

incubated for at least 15 min on ice. In parallel, GTPy[ S] is mixed with the beads

(volume: volume) just before starting the reaction. For agonist testing, the following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 μΐ_^ of test or reference ligand, 20 μΐ_^ of the membranes:GDP mix, 10 μΐ_^ of assay buffer and 20 μΐ_^ of the

GTPyr 35S] :beads mix. For antagonist testing, the following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 μΐ_^ of test or reference ligand, 20 μΐ_^ of the membranes:GDP mix, and then after an incubation of 15 min at room temperature, 10 μΐ_^ of

35

reference agonist at historical ECm concentration and 20 μί of the GTPy[ S] :beads mix. The plates are covered with a top seal, mixed on an orbital shaker for 2 min, and then incubated for lh at room temperature. Then the plates are centrifuged for 10 min at 2000 rpm, incubated at RT lh and counted for 1 min/well with a Perkin Elmer TopCount reader. Compounds are tested for antagonist activity at the human dopamine D_2L receptor (FAST- 0101G) at the following nanomolar concentrations, in duplicate: Antagonist (nM): 5, 15, 50, 150, 500, 1500, 5000, 15000.

Example B13: Increase of neurite outgrowth of neurons that are cultured with compounds of the invention

Neurite Outgrowth in Cortical Neurons

[0303] Compounds are tested to determine their ability to stimulate neurite outgrowth of cortical neurons. Standard methods are used to isolate cortical neurons. For the isolation of primary rat cortical neurons, the fetal brain from a pregnant rat at 17 days of gestation is prepared in Leibovitz' s medium (L15; Gibco). The cortex is dissected out, and the meninges are removed. Trypsin (Gibco) is used to dissociate cortical C with DNAse I. The cells are triturated for 30 min with a pipette in Dulbecco's Modified Eagle Media ("DMEM"; Gibco) with 10% Fetal Bovine Serum ("FBS") (Gibco) and centrifuged at 350xg for 10 min at RT. The cells are suspended in Neurobasal medium supplemented with 2% B27 (Gibco) and 0.5 mM L-glutamine (Gibco). The cells are maintained at 30,000 cells per well of poly-L-lysine coated plates at 37°C in 5% C0₂-95% air atmosphere. After adhesion, a vehicle control or compounds of the invention are added at different concentrations to the medium. BDNF (50 ng/mL) is used as a positive control for neurite growth. After treatment, cultures are washed in phosphate-buffered saline ("PBS"; Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cells are fixed after 3 days growth. Several pictures (-80) of cells with neurites are taken per condition with a camera. The length measurements are made by analysis of the pictures using software from Image-Pro Plus (France). The results are expressed as mean (s.e.m.). Statistical analysis of the data is performed using one way analysis of variance (ANOVA). Neurite Outgrowth in Rat Mixed Cortical Cultures

[0304] Cortical mixed cultures are prepared from El 8 Wistar rat embryos. The cortices are dissected out and the tissue is cut to small pieces. The cells are separated by 15-min incubation with DNase and papain. The cells are collected by centrifugation (1500 rpm, 5 min). The tissue is triturated with a pipette and the cells are plated using the micro-islet protocol (20,000 cells in 25 μΐ_^ medium) on poly-L-lysine coated 48 wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/mL gentamicin, 10% heat-inactivated fetal bovine serum (FBS-HI) and 10% heat-inactivated horse serum (HS-HI). After the cells attach to the well, 250 μΐ_^ medium is added to the wells. 4h after plating, the medium is changed to fresh medium (MEM with supplements and 5% HS-HI) containing test compound at 0.5, 5 and 50 nM concentrations. As positive controls BDNF (50, 100 and/or 150 ng/niL), and/or NGF (50 ng/mL and/or 100 ng/mL) are used. After 2 days in vitro, the cell's conditioned media are collected from plates before fixing the cells. The media samples are centrifuged 13,000 rpm 3 min to get rid of cell debris. The samples are stored at -20 °C for later analysis. Cells are formaldehyde-fixed and processed for immunocytochemistry.

BDNF levels in the conditioned media are determined with a BDNF ELISA using the manufacturers (Promega, BDNF Emax® ImmunoAssay System, catalog number: G7610) instructions.

[0305] The cultures are fixed with 4% formaldehyde in 0.01 M PBS for 30 min and washed once with PBS. The fixed cells are first permeabilized and non-specific binding is blocked by a 30-min incubation with blocking buffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS. Rabbit anti-MAP-2 (dilution 1: 1000, AB5622, Chemicon, in blocking buffer) is used as a primary antibody. The cells are incubated with the primary antibody for 48h at +4 °C, washed with PBS and incubated with secondary antibody goat anti-rabbit IgG conjugated to Alexa Fluor568 (1:200, Al 1036, Molecular Probes) for 2h at RT. The immunopositive cells are visualized by a fluorescence microscope equipped with appropriate filter set, and documented by a high resolution image capturing. The number of cells per field (4 field per well) are counted, and the neurite outgrowth is quantified using Image Pro Plus software. The number of wells per compound concentration used is 6 (n=6). All data are presented as mean + standard deviation (SD) or standard error of mean (SEM), and differences are considered to be statistically significant at the p<0.05 level. Statistical analysis is performed using StatsDirect statistical software. Differences between group means are analyzed by using 1- way- AN OVA followed by Dunnet's test (comparison to the vehicle treated group).

Example B14: Use of an in vivo model to evaluate the ability of compounds to enhance cognition, learning and memory in scopolamine treated rats

[0306] The two-trial object recognition paradigm developed by Ennaceur and Delacour in the rat is used as a model of episodic short term memory. Ennaceur, A., and Delacour, J. (1988), Behav. Brain Res. 31:47-59. The paradigm is based on spontaneous exploratory activity of rodents and does not involve rule learning or reinforcement. The novel object recognition paradigm is sensitive to the effects of ageing and cholinergic dysfunction. See, e.g., Scali, C. et al, Neurosci. Letts. 170: 117-120, 1994; and Bartolini, L. et al, Biochem. Behav. 53:277- 283, 1996.

[0307] Male Sprague-Dawley rats between six and seven weeks old, weighing between 220- 300 grams are obtained from Centre d'Elevage (Rue Janvier, B.P. 55, Le Genest-Saint-Isle 53940, France). The animals are housed in groups of 2 to 4 in polypropylene cages (with a floor area of 1032 cm ) under standard conditions: at RT (22 + 2 °C), under a 12h light/12h dark cycle, with food and water provided ad libitum. Animals are permitted to acclimate to environmental conditions for at least 5 days before the experiment begins, and are numbered on their tails with indelible marker.

[0308] The experimental arena is a square wooden box (60 cm x 60 cm x 40 cm) painted dark blue, with 15 cm x 15 cm black squares under a clear plexiglass floor. The arena and objects placed inside the arena are cleaned with water between each trial to eliminate any odor trails left by rats. The arena is placed in a dark room illuminated only by halogen lamps directed towards the ceiling in order to produce a uniformly dim light in the box of approximately 60 lux. The day before testing, animals are allowed to freely explore the experimental arena for 3 min in the presence of two objects (habituation). Animals to be tested are placed in the experimental room at least 30 min before testing.

[0309] Novel object recognition test is comprised of two trials separated by an interval of 120 min or 24h. When agents that disrupt memory such as the cholinergic antagonist

scopolamine are used an inter- trial interval of 120 min is preferred. Alternatively a 24h inter- trial interval is used when studying effect of natural forgetting on novel object recognition task. During the first, or acquisition, trial (TO, rats are placed in the arena, where two identical objects have been previously placed. The time required for each animal to complete 15 sec of object exploration is determined, with a cut-off time of 4 min. Exploration is considered to be directing the nose at a distance less than 2 centimeters ("cm") from the object and/or touching the object. During the second, or testing, trial (T₂), one of the objects presented in the first trial is replaced with an unknown or novel object, while the second, familiar object is left in place. Rats are placed back in the arena for 3 min., and exploration of both objects is determined. Locomotor activity of rats (number of times rats cross grid lines visible under the clear plexiglass floor) is scored for during T_\ and T₂. At the conclusion of the experiments, the rats are sacrificed by an overdose of pentobarbital given intraperitoneally.

[0310] The following parameters are measured as part of the novel object recognition task: (1) time required to achieve 15 sec of object exploration during T_\; (2) locomotor activity during Ti (number of crossed lines); (3) time spent in active exploration of the familiar object during T₂ (Tpamiiiar); (4) time spent in active exploration of the novel object during T₂ (T_Novei); and (5) locomotor activity during T₂ (number of crossed lines). The difference between time spent in active exploration of the novel object during T₂ and time spent in active exploration of the familiar object during T₂ (Δ TNovei-TFamiUar) is evaluated. The % of animals in each group with TNovei-TFamiUar greater than or equal to 5 sec is also derived; described as % of good learners.

[0311] Animals not meeting a minimal level of object exploration are excluded from the study as having naturally low levels of spontaneous exploration. Thus, only rats exploring the objects for at least five sec (T_Novei + T_Famii_iar > 5 sec) are included in the study.

[0312] Animals are randomly assigned to groups of 14. Compounds of the invention and controls are administered to animals the groups as follows: Solutions of compounds are prepared freshly each day at a concentration of 0.25 mg/mL using purified water or saline as vehicle. Donepezil, used as a positive control, and scopolamine are administered

simultaneously in a single solution of saline (5 mL/kg) prepared freshly each day.

Scopolamine is purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) is dissolved in saline to a concentration of 0.06 mg/mL.

[0313] Donepezil is administered (e.g., intraperitoneally) 40 minutes before the acquisition trial (Tl). Scopolamine is administered (e.g., intraperitoneally) 30 minutes before the acquisition trial (Tl). Vehicle (purified water) or test compound is administered (e.g., by gavage) 25 minutes before the acquisition trial (Tl), 5 min after scopolamine challenge. The volume of administration is 5 mL/kg body weight for compounds administered

intraperitoneally, and 10 mL/kg for compounds administered orally.

[0314] Recognition scores and % of good learners for compounds of the invention are determined.

Example B15: Use of an in vivo model to determine the ability of compounds to treat, prevent and/or delay the onset and/or the development of schizophrenia (hyperactivity in PCP treated animals)

[0315] In vivo models of schizophrenia can be used to determine the ability of the

compounds described herein to treat and/or prevent and/or delay the onset and/or the development of schizophrenia.

[0316] One exemplary model for testing the activity of one or more compounds described herein to treat and/or prevent and/or delay the onset and/or development of schizophrenia employs phencyclidine (PCP), which is administered to the animal (e.g., non-primate (rat) or primate (monkey)), resulting in dysfunctions similar to those seen in schizophrenic humans. See Jentsch et al, Science 277:953-955, 1997; and Piercey et al, Life Sci. 43(4):375-385, 1988. Standard experimental protocols may be employed in this or in other animal models. One protocol involves PCP-induced hyperactivity.

[0317] Male C57B1/6J mice from Jackson Laboratories (Bar Harbor, Maine) are used. Mice are received at 6-weeks of age. Upon receipt, mice are assigned unique identification numbers (tail marked) and are group housed with 4 mice/cage in OPTIMICE ventilated cages. All animals remain housed in groups of 4 during the remainder of the study. All mice are acclimated to the colony room for at least 2 weeks prior to testing and are subsequently tested at an average age of 8 weeks of age. During the period of acclimation, mice are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals are maintained on a 12h/12h light/dark cycle. The RT is maintained between 20 and 23 °C with a relative humidity maintained between 30% and 70%. Food and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned across treatment groups.

[0318] The following compounds are used for this study: 1) Compound of the invention (0.03, 0.1, 0.3, 1, 3, 10 & 30 mg/kg) is dissolved in 5% PEG-200 in sterile water and administered p.o. 30 min prior to PCP injection; 2) Clozapine (1.0 mg/kg) is dissolved in 10% DMSO and administered i.p. 30 min prior to phencyclidine (PCP) injection; 3) PCP (5.0 mg/kg) is dissolved in sterile water and administered i.p. immediately before the 60 min test. All compounds are administered at a dose volume of 10 mL/kg.

[0319] The open filed (OF) test assesses locomotor behavior to measure mouse locomotor activity at baseline and in response to pharmacological agents. The open field chambers are Plexiglas square chambers (27.3x27.3x20.3 cm; Med Associates Inc., St Albans, VT) surrounded by infrared photobeams (16x16x16) to measure horizontal and vertical activity. The analysis is configured to divide the open field into a center and periphery zone such that the infrared photobeams allow measurement of activity in the center and periphery of the field. Distance traveled is measured from horizontal beam breaks as the mouse moves whereas rearing activity is measured from vertical beam breaks. Mice (10 to 12 animals per treatment group) are brought to the activity experimental room for at least lh acclimation to the experimental room conditions prior to testing. Eight animals are tested in each run. Mice are administered vehicle (e.g., 10% DMSO or 5% PEG200 and 1% Tween 80), Compound of the invention, clozapine (positive control, 1 mg/kg ip) and placed in the OF chambers for 30 min following which they are injected with either water or PCP and placed back in the OF chambers for a 60-min session. At the end of each OF test session the OF chambers are thoroughly cleaned.

[0320] Data are analyzed by analysis of variance (ANOVA) followed by post-hoc

comparisons with Fisher Tests when appropriate. Baseline activity is measured during the first 30 min of the test prior to PCP injection. PCP-induced activity is measured during the 60 min following PCP injection. Statistical outliers that fall above or below 2 standard deviations from the mean are removed from the final analyses. An effect is considered significant if p < 0.05.

Example B16: Use of an in vivo model to determine the ability of compounds to treat, prevent and/or delay the onset and/or the development of schizophrenia (hyperactivity in

amphetamine treated animals)

[0321] Male mice (various strains, e.g., C57B1/6J) from appropriate supplier (for example Jackson Laboratories, Bar Harbor, Maine) are used. Mice typically are received at 6-weeks of age. Mice are acclimated to the colony room for at least two weeks prior to testing.

During the period of acclimation, mice are examined on a regular basis, handled, and weighed to assure adequate health and suitability and maintained on a 12h /12h light/dark cycle. The RT is maintained between 20 and 23 °C with a relative humidity maintained between 30% and 70%. Food and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned between treatment groups.

[0322] The open field test (OF) is used to assess motor activity. The open field chambers are plexiglas square chambers (e.g., 27.3 x 27.3 x 20.3 cm; Med Associates Inc., St Albans, VT) surrounded by infrared photobeam sources (16x16x16). The enclosure is configured to split the open field into a center and periphery zone and the photocell beams are set to measure activity in the center and in the periphery of the OF chambers. Horizontal activity (distance traveled) and vertical activity (rearing) are measured from consecutive beam breaks.

[0323] On the day of testing, animals are brought to the experimental room for at least lh acclimation prior to start of treatment. Animals are administered with vehicle, haloperidol (positive control, 0.1 mg/kg ip) or compound of the invention and placed in the OF. The time of administration of test compound to each animal is recorded. Baseline activity is recorded for 30 min following which mice receive amphetamine (4 mg/kg) or water and are placed back in the OF chambers for a 60-min session. At the end of each open field test session the OF chambers are thoroughly cleaned.

[0324] Typically ten to twelve mice are tested in each group. Test compound doses typically range from 0.01 mg/kg to 60 mg/kg.

[0325] Data are analyzed by analysis of variance (ANOVA) followed by post-hoc comparisons with Fisher Tests when appropriate. Baseline activity is measured during the first 30 min of the test prior to amphetamine injection. Amphetamine-induced activity is measured during the 60 min following amphetamine injection. Statistical outliers that fall above or below 2 standard deviations from the mean are removed from the final analyses. An effect is considered significant if p<0.05. Total distance traveled and total rearing following amphetamine administration are compared between groups treated with compound and groups treated with vehicle and positive control haloperidol.

Example B17: Use of the in vivo conditioned avoidance response (CAR) model to determine the ability of compounds to treat, prevent and/or delay the onset and/or the development of schizophrenia

[0326] All currently approved antipsychotic agents (typical and atypical) are known to have the ability to selectively suppress conditioned avoidance response (CAR) behavior in the rat. This evidence makes CAR one of the primary tests to assess antipsychotic activity of novel compounds.

[0327] The effects of compounds of the invention, at concentrations including 0.1, 0.3, 1, 3, 10 and 20 mg/kg, p.o., in the conditioned avoidance response model are assessed in the male Wistar rat. Risperidone (0.3 mg/kg, s.c.) is used in the present study as a positive reference compound.

[0328] For each testing session, animals are first placed for a 4-min habituation period in a shuttlebox with an electrified grid floor. Then, rats are submitted to 30 trials spaced by intertrial intervals varying at random between 20 and 30 sec. Each trial consists of a 10-sec light stimulus (conditioned stimulus, CS) followed by a 10-sec electric foot shock

(unconditioned stimulus, US) in presence of the light presented in the compartment where the rat is located. If the animal moves to the other compartment during the initial 10-sec of the trial, the light is terminated (no shock is delivered) and the response is recorded as an avoidance response. If the rat changes compartment during the foot shock, the light and the shock are terminated and the response is recorded as an unconditioned response. If the rat does not change compartment during the 10-sec light period (CS) and during the 10-sec shock+light period (US+CS), an escape failure is recorded. If a response is made during an intertrial interval, the response is recorded as an intertrial crossing. Training is performed 5 days per week with one session of 30 trials per day, until rats reach the performance criterion of 80% of avoidance response on at least two consecutive daily sessions. Once the performance criterion is reached, each animal is sequentially administered with vehicle (15% HPBCD, p.o.), compound of the invention (0.1, 0.3, 1, 3, 10 and 20 mg/kg, p.o.) and risperidone (0.3 mg/kg, s.c). A minimal wash-out period of 48h is allowed between 2 treatments. During the wash-out period, animals are trained until they recover an avoidance performance of at least 80%.

[0329] Statistical analysis is performed using a Friedman two-way AN OVA by ranks followed by the Wilcoxon matched-pairs signed-ranks test to test each dose of the test compound administered versus vehicle control treated rats.

Example B18: An animal model of the negative symptoms of schizophrenia - subchronic PCP-induced social interaction deficits

[0330] Phencyclidine (PCP) administered to humans as well to experimental animals induces full-spectrum of schizophrenia symptoms, including negative symptoms and cognitive deficits. A major symptom of schizophrenia is considered to be social isolation/withdrawal as part of the cluster of negative symptoms. Subchronic treatment with PCP in rats leads to the development of clear signs of social withdrawal as measured by deficits in the interaction time with a cage intruder rat.

[0331] Male Sprague Dawley rats (-150 g on arrival) from Harlan (Indiana) are used in this study. Upon receipt, rats are group housed in OPTI rats ventilated cages. Rats are housed in groups of 2-3/cage for the remainder of the study. During the period of acclimation, rats are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Rats are maintained on a 12h/12h light/dark cycle with the light on at 7:00 a.m. The RT is maintained between 20 and 23 °C with a relative humidity maintained between 30% and 70%. Chow and water are provided ad libitum for the duration of the study. Animals are randomly assigned across treatment groups and balanced by age. Animals are not disturbed between test days.

[0332] The following compounds are used. 1) Compound of the invention (0.3, 1 and 3 mg/kg; p.o.) is dissolved in 3% Tween and PBS and administered 30 min prior to test; 2) PCP (2 mg/kg; s.c.) is dissolved in saline and administered twice daily for 5 days prior to test day; 3) Clozapine (2.5 mg/kg; i.p.) is dissolved in 5% PEG:5% Tween 80 in saline and administered 30 min prior to test. All compounds are administered at a dose volume of 1 mL/kg.

[0333] For 5 days prior to test, rats are injected twice daily with either PCP (2 mg/kg; s.c) or saline (s.c). On day 6 and following a 30 min pretreatment with vehicle, clozapine or Compound of the invention, a pair of rats, unfamiliar to each other, receiving the same treatment are placed in a white plexiglas open field arena (24" x 17" x 8 ") and allowed to interact with each other for 6 min. Social interactions ('SI') include: sniffing the other rat; grooming the other rat; climbing over or under or around the other rat; following the other rat; or exploring the ano-genital area of the other rat. Passive contact and aggressive contact are not considered a measure of social interaction. The time the rats spend interacting with each other during the 6 min test is recorded by a trained observer. The social interaction chambers are thoroughly cleaned between the different rats.

[0334] Data are analyzed by analysis of variance (ANOVA) followed by post-hoc analysis (e.g., Fischer, Dunnett) when appropriate. An effect is considered significant if p < 0.05.

Example B 19: An animal model of extrapyramidal syndrome (EPS) - measurement of catalepsy in the mouse bar test

[0335] Antipsychotic drugs are known to induce extrapyramidal syndrome (EPS) in animals and in humans. An animal model considered to be predictive of EPS is the mouse bar test, which measures cataleptic responses to pharmacological agents.

[0336] Male C57B 1I6J mice from Jackson Laboratories (Bar Harbor, Maine) are used. Mice are received at 6-weeks of age. Upon receipt, mice are assigned unique identification numbers (tail marked) and are group housed with 4 mice/cage in OptiMICE ventilated cages. All animals remain housed in groups of four during the remainder of the study. All mice are acclimated to the colony room for at least two weeks prior to testing and are subsequently tested at an average age of 8 weeks. During the period of acclimation, mice are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals are maintained on a 12h /12h light/dark cycle. The RT is maintained between 20 and 23 °C with a relative humidity maintained between 30% and 70%. Chow and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned across treatment groups.

[0337] The following compounds are used for this study. 1) Compound of the invention (0.03, 0.1, 0.3, 1, 3, 10, 30 mg/kg) is dissolved in 3% Tween in PBS and administered orally at a dose volume of 10 mL/kg; 2) Haloperidol (2 mg/kg) is dissolved in 10% DMSO and administered i.p. at a dose volume of 10 mL/kg.

[0338] The front paws of a mouse are placed on a horizontal metal bar raised 2" above a Plexiglas platform and time is recorded for up to 30 sec per trial. The test ends when the animal's front paws return to the platform or after 30 sec. The test is repeated three times and the average of the three trials is reported as the intensity index of catalepsy. Antipsychotic agents such as haloperidol cause rigidity as a side effect. Animals treated with haloperidol will hold on to the bar without moving for several minutes. Mice are brought to the activity experimental room for at least lh acclimation to the experimental room conditions prior to testing. Following injection of either vehicle, Compound of the invention, or haloperidol, catalepsy is assessed at 3 time points: 30 min, lh and 3h. At the end of each trial, the apparatus is thoroughly cleaned with 70% ethanol.

[0339] Data are analyzed by analysis of variance (ANOVA) followed by post-hoc

comparisons with Fisher Tests when appropriate. An effect is considered significant if p < 0.05.

Example B20: Use of the 5-choice serial reaction task to determine the ability of compounds to enhance attention/vigilance and reduce impulsivity

[0340] Attention and impulsivity are characteristic of several disease states. The continuous performance test (CPT), used in humans, is capable of detecting attention deficits in a number of disorders, including attention deficit hyperactivity disorder, schizophrenia and mild cognitive impairment. The pre-clinical analogue of the CPT is the 5-choice serial reaction time task (5CSRTT). In this operant-based test, rats are required to be attentive and withhold responding while they monitor 5 apertures for the appearance of a brief stimulus light in one of the apertures. The brief illumination of the stimulus light in the 5CSRTT is analogous to the appearance of the "correct" letters in the CPT in humans. Upon observing the stimulus light, the rat must nose-poke in the corresponding aperture to receive a food reward. The 5CSRTT allows the measurement of similar behavioral responses as the CPT, including accuracy, speed of responding, impulsive and compulsive responding. In this study, drug tests are performed under altered test parameters which result in increased premature responding. This premature responding is hypothesized to indicate impulsivity, e.g., a failure to withhold an inappropriate response, and has been shown to be sensitive to atomoxetine.

[0341] Thirteen male Long-Evans rats (275-300 g) are obtained from Harlan Laboratories, Indianapolis, IN. At the time of testing for the current study, the rats are approximately 16- 18 months old. Upon arrival, the rats are assigned unique identification numbers (tail marked). Rats are single-housed in OptiRAT cages and acclimated for 7 days prior to commencing a food-restriction regimen: rats are held at 85% of age-matched free-feeding control body weights, receiving approximately 10-20 g of rat chow daily. Water is provided ad libitum, except during testing. Animals are maintained in a 12h /12h light/dark cycle (lights on at 0700 EST) with RT maintained at 22 + 2 °C and the relative humidity

maintained at approximately 50%. All animals are examined, handled and weighed prior to initiation of the study to assure adequate health and suitability and to minimize non-specific stress associated with testing. The 5CSRTT sessions are performed during the animal's light cycle phase. All experiments and procedures are approved by the Institutional Animal Care and Use Committee of PsychoGenics, Inc.

[0342] The apparatus consists of 10 aluminum and Plexiglas chambers with grid floors (width 31.5 cm, depth 25.0 cm, height 33.0 cm), housed in sound-attenuating cabinets. Each cabinet is fitted with a low-level noise extractor fan which also helped to mask external noise. The left wall of each chamber is concavely curved with 5 apertures evenly spaced, located approximately 2.5 cm from the floor. Each aperture contains a standard 3W LED to serve as stimulus lights. The opposite wall contains a food magazine, located approximately 3.0 cm from the floor. Each chamber is illuminated with a 3W house-light located in the center of the ceiling panel. After each test session the apparatus is cleaned with 70% ethanol.

[0343] The following compounds are used for this study. 1) Compound of the invention is dissolved in saline, and administered p.o. at 0.1, 0.3 and 1.0 mg/kg, 30 min prior to testing at 1 mL/kg body weight; 2) The reference compound atomoxetine (1.0 mg/kg) is dissolved in saline and administered i.p. 30 min prior to testing at 1 mL/kg body weight.

[0344] Training: Animals are trained to monitor the five apertures for stimulus light illumination. Each session is initiated by the illumination of the house light, and the delivery of a food reward into the magazine. The first trial begins when the rat opens the magazine to obtain the food pellet. After the inter-trial interval (ITI) one of the stimulus lights is illuminated for 500 msec. The rat must nose-poke in the illuminated aperture either during or within 5 sec of stimulus light illumination. Such a response is defined as a correct response, and is rewarded with delivery of a food pellet. Collection of the pellet initiates the next trial. A nose-poke response in a non-illuminated aperture (incorrect response) or a nose-poke after the 5 sec limited hold (missed trial) results in termination of the trial with extinction of the house-light and imposition of a time-out period. [0345] Testing: After acquisition of the 5CSRTT with a high level of accuracy (at least 75% correct, at least 50 trials completed per session), drug testing begins. Animals are treated with test compound (various doses, appropriate vehicle), vehicle and positive control

(atomoxetine 1 mg/kg ip). During drug test sessions, the ΠΊ is varied between 10, 7, 5 or 4 sec in duration, presented in groups of 4 trials (each of which contains 1 trial at each ITI duration in a randomized order). The session ends when 60 min have elapsed. All rats receive all drug treatments, according to a randomized-order within- subjects design. Drug tests are performed on Wednesdays and Fridays of each week, only when rats perform at least 75% correct trials for a minimum of 50 trials in the previous test session.

[0346] Measures obtained during the test sessions are: (1) percent correct, defined as the number of correct trials xlOO, divided by the total number of correct and incorrect trials, (2) missed trials, defined as responding beyond the 5 sec limited hold or failing to respond, (3) correct latency, defined as the time taken to make a correct response after the illumination of the stimulus, (4) magazine latency, defined as the time taken to enter the magazine to collect the food pellet after making a correct response, (5) premature responding, defined as the total number of nose-poke responses made during the ITI, and (6) perseverative responding, defined as the total number of additional responses emitted after the initial nose-poke.

Example B21: An animal model to test the anxiolytic effects of compounds using the elevated plus maze (EPM) test

[0347] This study aims to test the anxiolytic properties of compounds of the invention using the elevated plus maze (EPM) test in C57B1/6J mice.

[0348] Male C57B1/6J mice from Jackson Laboratories (Bar Harbor, Maine) are used for the open field study. Mice are received at 6-weeks of age. Upon receipt, mice are assigned unique identification numbers (tail marked) and are group housed with 4 mice/cage in OPTI mouse ventilated cages. All animals remain housed in groups of four during the remainder of the study. All mice are acclimated to the colony room for approximately 2 weeks prior to testing and are subsequently tested at an average age of 8 weeks of age. During the period of acclimation, mice and rats are examined on a regular basis, handled, and weighed to assure adequate health and suitability. Animals are maintained on a 12h/12h light/dark cycle. The RT is maintained between 20 and 23 °C with a relative humidity maintained between 30% and 70%. Chow and water are provided ad libitum for the duration of the study. In each test, animals are randomly assigned across treatment groups. All animals are euthanized after the completion of the study. [0349] The following compounds are used for this study: 1) Compound of the Invention (0.03, 0.1 and 1 mg/kg) is dissolved in 5% PEG200 / H₂0 and administered orally at a dose volume of 10 mL/kg 30 min prior to test; 2) Diazepam (2.5 mg/kg) is dissolved in 45% hydroxypropyl-P-cyclodextrin and administered orally at a dose volume of 10 mL/kg 30 min prior to test.

[0350] The elevated plus maze test assesses anxiety. The maze (Hamilton Kinder) consists of two closed arms (14.5 h x 5 w x 35 1 cm) and two open arms (6 w x 35 1 cm) forming a cross, with a square center platform (6 x 6 cm). All visible surfaces are made of black acrylic. Each arm of the maze is placed on a support column 56 cm above the floor.

Antistatic black vinyl curtains (V tall) surround the EPM to make a 5' x 5" enclosure.

Animals are brought to acclimate to the experimental room at least lh before the test. Mice are placed in the center of the elevated plus maze facing the closed arm for a 5-min run. All animals are tested once. The time spent, distance traveled and entries in each arm are automatically recorded by the computer. The EPM is thoroughly cleaned after each mouse.

[0351] Data are analyzed using analysis of variance (AN OVA) followed by Fisher's LSD post hoc analysis when appropriate. An effect is considered significant if p < 0.05.

Example B22: Cell culture and cell viability assay

[0352] SH-SY5Y cells cultured in DMEM/F12 media supplemented with 10% FBS are seeded in 96- well microplates at 150,000 cells/cm . After 24 h, cells are depleted from FBS and kept in culture for 24 h before the experiment. A stock solution is prepared by dissolving the calcium ionophore 4-Br-A23187 (Calbiochem Cat.N°100107 ) in DMSO at 25 mM. Cells are then treated with 4-Br-A23187 ( 2 μΜ), hydrogen peroxide (300 μΜ) or the mitochondrial toxin rotenone (25 μΜ) in the presence of vehicle or Compound of the Invention for 24 h. Cell death is determined by measurements of LDH release according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany). Cell viability is determined by measuring the capacity of cells to metabolize MTS tetrazolium (MTS) according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by the CellTiter 96® AQueous One Solution Cell Proliferation assay (Promega Corporation, Madison, WI, USA). Compounds are screened at 10 nM, using DMSO as vehicle. Assay results for the experiments with Br-A23187 are presented as the MTS reduction capacity (cell viability) of untreated cells (control), 4-Br-A23187-treated cells (vehicle), and co-incubation of Br-A23187 with compounds of the invention treated cells and using p-trifluoromethoxyphenylhydrazone (FCCP) at 10 μΜ for 30 min as a control. This assay assesses the ability of the test compounds to protect against cell death that is mediated by mitochondrial dysfunction. In the assay, the calcium ionophore 4-Br-A23187 is used to challenge the cells, causing calcium levels to rise in mitochondria, which leads to

depolarization and cell death. Test compounds are assessed for their ability to prevent cell death in response to challenge with 4-Br-A23187.

Example B23: Cell culture and cell viability assay

Cell Culture

[0353] SH-SY5Y cells stably transfected with a doxycyline-inducible wild-type a-synuclein (a-syn) gene along with control SH-SY5Y cells over-expressing the β-galactosidase (β-gal) gene (a gift from L. Stefanis, Division of Basic Neurosciences, Biomedical Research

Foundation of the Academy of Athens, Athens, Greece) are cultured as described by

Vekrellis et al.(Vekrellis K, Xilouri M, Emmanouilidou E, Stefanis L. (2009). Inducible over-expression of a-syn in human neuronal cells leads to caspase-dependent non-apoptotic death. J Neurochem 109, 1348-1362). In accordance with this method, cells are cultured and maintained in RPMI 1640, 10% fetal bovine serum supplemented with 250 μg/mL G418 and 50 μg/mL Hygromycin B. Expression of a-syn is switched off in stock cultures with doxycycline (2 μg/mL). For experimental procedures, cells are plated at (4-8x10 4 cells/cm 2 ) and differentiated in absence of doxycycline and in the presence of 20 μΜ all-trans retinoic acid (RA) (Sigma, St Louis, MO, USA).

Viability Assay

[0354] Cells are cultured in 96- well plates. After 24 h, cells are treated with RA and

Compounds of Invention at 0.1 and 10 nM in the absence of doxycyline. Culture medium with RA and drugs is fully replaced after 7 days. Cell viability is measured by the release of lactate dehydrogenase (LDH) from necrotic cells into the culture medium and by measuring the capacity of cells to metabolize MTS tetrazolium (MTS) after 14 days in culture. LDH leakage is assessed according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by the CellTiter 96® AQueous One Solution Cell Proliferation assay (Promega Corporation, Madison, WI, USA).

Immunoblotting of a-synuclein and a-synuclein aggregates

[0355] Cells stably expressing α-synuclein are cultured in 6-well plates at a density of 4 x 10⁴ cells/cm cells per well. Cells are differentiated and treated with Compound of the Invention at 10 nM in absence of dox after 24 h of plating. Drug treatments are repeated after 7 days in freshly prepared medium containing RA. After 14 days, cells are washed twice with cold PBS and lysed in lysis buffer containing 1% Triton X-100, 20 mM HEPES, 150 mM NaCl, 10% glycerol, 1 mM EGTA, 1.5 mM MgCl₂, ImM PMSF pH 7.4, and IX protease inhibitor mixture (Roche, Mannheim, Germany). Lysates are homogenized and subjected to four successive freeze-thaw cycles to disrupt membranes. Triton soluble fractions and triton insoluble pellets are obtained by ultracentrifugation at 100,000 x g for 30 min at 4 °C. The concentration of protein in each fraction is determined by BCA assay (Thermo Scientific). Samples from total, soluble and triton insoluble fractions, are boiled in IX sample buffer (20 mM Tris, 1% glycerol, 180 mM β-mercaptoethanol, 0.003% bromophenol blue, and 2% SDS, pH 6.8), loaded on 12% SDS-PAGE gels, and transferred to polyvinylidene difluoride (PVDF) membranes (0.2 μΜ-pore immobilon Biorad). Membranes are blocked in IX TBS- Tween (20 mM Tris, pH 7.4, 150 mM NaCl, and 0.2% Tween 20) containing 5% milk for 1 h and incubated overnight at 4 °C with the following primary antibodies in blocking solution at the indicated dilutions: monoclonal anti-a-synuclein a-syn-1 (1: 1000; BD Transduction Laboratories). (Perrin, R.J., Payton, J.E., Barnett, D.H., Wraight, C.L., Woods, W.S., Ye, L., and George, J.M. (2003). Epitope mapping and specificity of the anti-a-_synuclein monoclonal antibody Syn-1 in mouse brain and cultured cell lines. Neurosci Lett 349, 133- 135), and monoclonal vimentin (1: 1000; BD PharMingen). Primary antibodies are detected with secondary anti-mouse antibodies conjugated to HRP (1:5000).

Isolation ofRNA and RT -quantitative PCR (RT-qPCR)

[0356] SH-SY5Y cells stably over-expressing a-synuclein are treated with Compound of the Invention (10 nM). Total RNA from these cells as well as control cells not treated with Compound is extracted using the E.Z.N. A RNA extraction Kit (OMEGAbiotek, Norcross, GA). 1 μg of RNA is reverse transcribed to cDNA using the M-Mulv reverse transcriptase enzyme (Promega Corporation, Madison, WI, USA). RT-qPCR of cDNA templates is carried out using TAQMAN probes for human a-synuclein (Hs00240906_Ml) and

TAQMAN masterMix (Applied Biosystems) and a Mx3005P real-time PCR system (Agilent Technologies Inc., Santa Clara, CA). Levels of alpha-tubulin mRNA are used to normalize the amounts of total RNA between samples. Fold changes are calculated as described in Pfaffl, M.W. (2001). A new mathematical model for relative quantification in real-time RT- PCR. Nucleic Acids Res 29, e45. Example B24: Chaperone-mediated autophagy (CMA) Assay

[0357] The ability for using the compounds of the invention can be assessed in a chaperone- mediated autophagy (CMA) assay. (Xilouri M, Vogiatzi T, Vekrellis K, Stefanis L. a- synuclein degradation by autophagic pathways: A potential key to Parkinson's disease pathogenesis. Autophagy. 2008; 4(7):917-9.)

Measurement of chaperone-mediated autophagy ( CMA) in isolated lysosomes

[0358] Sources of chemicals were as described previously in Cuervo, et al., Koga, et al., and Martinez- Vicente, M., et al. (Cuervo, A.M. & Dice, J.F., A receptor for the selective uptake and degradation of proteins by lysosomes. Science, 1996. 273: p. 501-503; Koga, H., et al., A photoconvertible fluorescent reporter to track chaperone-mediated autophagy. Nat. Comm., 2011. 2: p. 386; Martinez- Vicente, M., et al., Cargo recognition failure is responsible for inefficient autophagy in Huntington's Disease. Nat. Neurosci., 2010.) The antibody against mouse LAMP-2A is from Invitrogen. Adult male Wistar rats (Charles River Laboratories) fasted for 48h before sacrifice are used. Lysosomes from rat livers are isolated from a light mitochondrial lysosomal fraction in a discontinuous metrizamide density gradient by the shorter method described previously in Cuervo, et al. (Cuervo, A.M., et al., A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins. J Biol Chem, 1997. 272(9): p. 5606-15.) Lysosomal integrity before and after addition of Compound of the Invention is verified after isolation by measuring β-hexosaminidase latency (Storrie, B. & Madden, E., Isolation of subcellular organelles. Meth Enzymol, 1990. 182: p. 203-225) and only preparations with more than 95% intact lysosomes are used. Mouse fibroblasts cytosolic proteins are metabolically radiolabeled by incubation with [3H]leucine (2μΟ/ιη1) at 37°C for 2 days. This pool of radiolabeled cytosolic proteins is incubated in MOPS buffer ((lOmM 3-(N-morpholino) propanesulfonic acid) (MOPS) pH 7.3, 0.3M sucrose, ImM DTT) with intact lysosomes at 37°C for 30 minutes (Kaushik, S. & Cuervo, A.M., Methods to monitor chaperone-mediated autophagy. Methods Enzymol., 2009. 452: p. 297-324). Degradation of the radiolabeled substrates is measured after acid precipitation and proteolysis is expressed as the percentage of the initial acid-insoluble radioactivity (protein) transformed into acid soluble radioactivity (amino acids and small peptides) at the end of the incubation. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a well-identified CMA substrate, is used as a control that should compete with CMA of the radiolabeled proteins. (Bandy op adhyay, U., et al., The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol. Cell Biol., 2008. 28(18): p. 5747-63.)

Identification ofLAMP-2A multimeric complexes by blue-native electrophoresis

[0359] Lysosomal membranes are solubilized by resuspending them in 20mM MOPS [3- (Nmorpholino) propanesulfonic acid], 150mM NaCl, and 0.5% octylglucoside buffer (except where indicated) and incubating them for 15 minutes on ice. (Kaushik, S. & Cuervo, A.M., Methods to monitor chaperone-mediated autophagy. Methods Enzymol, 2009. 452: p. 297- 324.) After centrifugation for 15 minutes at 16,000 g, the soluble proteins are recovered in the supernatant. The supernatant is supplemented with nonreducing sample buffer and subjected to blue-native electrophoresis (BNE) using 3 to 12% NativePAGE Novex bis-Tris precast gels (In vitro gen).

Cell-based imaging assay of CMA activation

[0360] To evaluate CMA activity, a fluorescent reporter is used. The fluorescent reporter identifies after photo switching the association of an artificial substrate to lysosomes upon discounting the macroautophagy-dependent degradation in mouse fibroblasts (NIH3T3) cell lines and primary mouse fibroblasts. Cells are prepared as indicated in Koga H et al. (Koga, H. et al., A photoconvertible fluorescent reporter to track chaperone-mediated autophagy. Nat. Comm., 2011. 2: p.386). MP-2A-knockdown cells are established by using vector- mediated stable RNA interference (RNAi) directed specifically against the LAMP-2A exon, as described previously in Koga H et al. All cells are cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Sigma) in the presence of 10% newborn calf serum or fetal bovine serum (FBS). Serum removal is performed by thoroughly washing the cells with Hanks' Balanced Salt Solution (Invitrogen) and placing them in serum-free complete medium. The pKFERQ-PS-CFP2 and pKFEFQ-PA-mCherryl expression plasmids are used to establish stable cell lines expressing the CMA reporter, pKFERQ-PS-CFP2-Nl or pPS- CFP2-N1 plasmids, as indicated previously in Koga H et al. Photoconversion of cells grown on coverslips is carried out with a 405/20 nm LED array (Norlux) for 10 minutes using 50 mW cm light intensity. For immunofluorescence, cells grown on coverslips are fixed in 3% formaldehyde in phosphate buffer saline (PBS), blocked with 10% FBS, permeabilized with 0.01% of TritonX-100 for 30 min, and then incubated with the primary and corresponding secondary antibodies diluted in 5% FBS in PBS. [0361] All images are acquired with an Axiovert 200 inverted fluorescence microscope (Zeiss) equipped with a X63 1.4 NA oil objective lens and red (ex. 570/30 nm, em. 615/30 nm), cyan (ex. 365/50 nm and em. 530/45 nm) and green (ex. 475/40 nm and em. 535/45 nm) filter sets (Chroma). Acquired z-stack images are subjected to deconvolution using an Axio- Vision program (Zeiss) and then prepared using Adobe Photoshop 6.0 software (Adobe Systems). High-content microscopy analysis is performed in cells seeded in 384-well plates with transparent bottom and fixed as above but in the presence of Hoechst to stain nuclei. Fluorescence images are acquired and analyzed using the ArrayScan HCS Reader (Thermo Scientific Cellomics). Fluorescence images in the green channel re produced using an ex. 475/40 nm, em. 535/45 nm filter set. Cell bodies are identified after Hoechst staining using an ex. 365/50 nm, em. 535/45 nm filter set. All images are acquired with a high-resolution CCD camera, using a X20 dry objective lens. A sufficient number of fields are acquired to analyze at least 200 cells per well. Images are analyzed with the Cellomics software according to the manufacturer's protocols using the spot detector bioapplication. Briefly, objects are identified as cells, if they had valid nuclei and cell-body measurements based on size and fluorescence intensity.

[0362] Acceptable ranges for these parameters are determined in preliminary studies using untreated cells from multiple cultures. To classify cells as responders, each valid object is sequentially tested against a set of thresholds, and the total fluorescent spot area per cell had to exceed the minimum value (as defined in control cells). The percentage of responders is calculated as the total number of responder cells in a well relative to the selected object count. All numerical results are reported as mean + s.e., and represent data from a minimum of three independent experiments unless otherwise stated. The statistical significance of the difference between experimental groups in instances of single comparisons is determined by the two-tailed unpaired Student's t-test of the means with the Sigma Plot software (Jandel Scientific). In instances of multiple means comparisons, one-way analysis of variance (ANOVA) followed by the Bonferroni post-hoc test are used to determine statistical significance.

Example B25: Stability of Compounds of the invention in the presence of Dog, Rat and Human Hepatocvtes

[0363] Compounds of the invention were tested for stability in the presence of dog, rat and human hepatocytes over a 4 hour period by LC/MS/MS. The study was performed by Integrated Analytical Solutions, Berkeley, California. [0364] Reference Standards and Solutions: Compounds of the invention were stored as powders at ambient temperature in a desiccator and protected from light. Reference stock solutions of Compound Nos. 129d, V-104a, V-104b, V-281a, V-284, and V-293a as 20 mM in DMSO were prepared and subsequently diluted to 2 mM in MeOH to provide working stock solutions (WSS). Unused standard solutions were stored at -20 °C.

[0365] Hepatocyte Preparation: Human (mixed gender), Beagle dog (male) and Sprague Dawley rat (male) cryopreserved hepatocytes were purchased from Life Technologies Corporation. Hepatocytes were removed from liquid nitrogen, quickly thawed in a 37 °C water bath and transferred to Hepatocyte Thawing/Plating Medium (Cryopreserved

Hepatocyte Recovery Medium, CHRM, Life Technologies Inc.). The cells were pelleted by slow speed centrifugation (~100xg, 6 min) and resuspended at a high cell density.

Hepatocyte viability was determined by trypan blue exclusion. Hepatocyte incubation medium (Life Technologies, Inc.) was added to generate a cell density of 2.0xl0⁶ cells/mL.

[0366] Hepatocyte Incubations for Stability: The 2 mM WSS was diluted 1 in 200 in hepatocyte incubation medium (pH 7.4) to 10 μΜ. A solution containing control compounds was prepared similarly to contain 10 μΜ each of dextromethorphan and testosterone. The solutions of test compounds and controls at 10 μΜ in hepatocyte incubation medium were pre-incubated at 37 °C for 10 min. Aliquots (250 μί) of hepatocyte suspensions (at 2.0xl0⁶ cells/mL) were transferred to appropriate 48- well plates and pre-incubated at 37 °C for 10 minutes. Metabolism was initiated by adding 250 μΐ_^ pre-incubated medium (containing test drug) to wells containing cells. A negative control reaction excluding hepatocytes was used to monitor aqueous stability and/or non-specific adsorption. The final reaction mixtures contained 5 μΜ of test or control compound and l .OxlO⁶ cells/mL. All reactions were performed in duplicate and carried at 37 °C in an incubator. Dextromethorphan and testosterone were used as control drugs to verify hepatocyte activity.

[0367] Aliquots were removed from each metabolism reaction at 0, 0.5, 2 and 4 hours. The reactions were terminated by adding each aliquot to a vessel containing 2x volumes (80 μί) of Internal Standard Solution (acetonitrile containing 50 ng/mL 2-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)-l-(pyridin-4-yl)ethanol (ISS1), 50 ng/mL of 2-(2,8- dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)-yl)-l-(piperidin-l-yl)ethanone (ISS2) and 5 ng/mL diphenhydramine. Terminated reactions were centrifuged at 6000g for 30 mins at 4 °C to remove the precipitated proteins and cell debris. Following centrifugation, 20 μΐ_^ of each supernatant was transferred to a deep- well microplate and diluted with 5x volumes (100 μΐ_^) of 0.2% formic acid in water. Compound 129d samples were diluted with 5x volumes (100 μΐ.) of 0.1% HFBA in water. Samples were analyzed by LC/MS/MS.

[0368] Calculation of Metabolism Parameters: Percent remaining was measured by dividing the analyte/IS peak area ratio at the designated sample time by the peak area ratio at time 0. ISS l served as the IS for Compound No. 129d. ISS2 served as the IS for Compound nos. V- 104a, V-104b, V-281a, V-284 and V-293a. The metabolic half-life (Ti_/2) was calculated using all time points unless otherwise noted. The T values were calculated as 0.693/k, where k is the slope of the log analyte/internal standard peak area ratio versus time.

Metabolism rate was calculated by dividing the starting concentration of substrate by the concentration of hepatocytes, then dividing by the T_1/2 value.

[0369] Summaries of the stability results for compounds tested are presented in Table B25. Table B25. Summary of stability results of test compounds in human hepatocytes (average of duplicates).

a Half-life determined using 0- 120 minute time points

[0370] All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.

[0371] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

Claim 1. A method of treating a cognitive disorder, psychotic disorder, neurotransmitter- mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound selected from the group consisting of Compound Nos. 1 to 179, II-l to 11-352, III-l to III-139, IV-1 to IV-371, and V- 1 to V-378, or a pharmaceutically acceptable salt thereof.

Claim 2. The method of claim 1, wherein the compound is selected from the group consisting of Compound Nos. 1 to 179, II-l to 11-352, III-l to III-139, IV-1 to IV-371, and V- 1 to V-335, or a pharmaceutically acceptable salt thereof.

Claim 3. A method of treating a cognitive disorder, psychotic disorder, neurotransmitter- mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound selected from the group consisting of Compound Nos. 6, 9, 10-12, 14, 16-21, 23-28, 39-40, 44-59, 63-72, 75-82, 108- 131, 133-171, 173-179, 11-57, III-7 to III-l 1, 111-14, 111-80 to 111-82, 111-84 to 111-98, III-101 to III-138, IV-115 to IV-125, IV-132 to IV-312, IV-314 to IV-371, and V-l to V-378, or a pharmaceutically acceptable salt thereof.

Claim 4. The method of claim 1, wherein the compound is selected from the group consisting of Compound Nos. 6, 9, 10-12, 14, 16-21, 23-28, 39-40, 44-59, 63-72, 75-82, 108- 131, 133-171, 173-179, 11-57, III-7 to III-l 1, 111-14, 111-80 to 111-82, 111-84 to 111-98, III-101 to III-138, IV-115 to IV-125, IV-132 to IV-312, IV-314 to IV-371, and V-l to V-355, or a pharmaceutically acceptable salt thereof.

Claim 5. Use of a compound selected from the group consisting of Compound Nos. 1 to 179, II-l to 11-352, III-l to III-139, IV-1 to IV-371, and V-l to V-378, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

Claim 6. The use according claim 5, wherein the compound is selected from the group consisting of Compound Nos. 1 to 179, II-l to 11-352, III-l to III-139, IV-1 to IV-371, and V- 1 to V-335, or a pharmaceutically acceptable salt thereof.

Claim 7. Use of a compound selected from the group consisting of Compound Nos. 6, 9,

10- 12, 14, 16-21, 23-28, 39-40, 44-59, 63-72, 75-82, 108-131, 133-171, 173-179, 11-57, III-7 to III-l l, 111-14, 111-80 to 111-82, 111-84 to 111-98, III-101 to III-138, IV-115 to IV-125, IV-132 to IV-312, IV-314 to IV-371, and V-l to V-378, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

Claim 8. A kit comprising a compound selected from the group consisting of Compound Nos. 1 to 179, II I to 11-352, III-l to III-139, IV-1 to IV-371, and V-l to V-378, 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.

Claim 9. The kit of claim 8, wherein the compound is selected from the group consisting of Compound Nos. 1 to 179, II I to 11-352, III-l to III-139, IV-1 to IV-371, and V-l to V-335, or a pharmaceutically acceptable salt thereof.

Claim 10. A kit comprising a compound selected from the group consisting of Compound Nos. 6, 9, 10-12, 14, 16-21, 23-28, 39-40, 44-59, 63-72, 75-82, 108-131, 133-171, 173-179,

11- 57, III-7 to III-l l, 111-14, 111-80 to 111-82, 111-84 to 111-98, III-101 to III-138, IV-115 to IV- 125, IV-132 to IV-312, IV-314 to IV-371, and V-l to V-378, 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.