AU2008319310A1 - Biphenyl derivatives as modulators of the histamine-H3 receptor useful for the treatment of disorders related thereto - Google Patents

Description

WO 2009/058300 PCT/US2008/012272 BIPHENYL DERIVATIVES AS MODULATORS OF THE HISTAMINE-H3 RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO 5 FIELD OF THE INVENTION The present invention relates to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3-receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-associated disorders, such as, cognitive disorders, epilepsy, brain 10 trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's 15 disease, pain and the like. SUMMARY OF THE INVENTION One aspect of the present invention encompasses certain biphenyl derivatives selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates 20 thereof:

R

1 R3 H I A C-4CH 2 N 4 R2 (Ia) wherein: ring A is heterocyclyl optionally substituted with one, two or three substituents selected from C 1

-C

6 alkyl and oxo; wherein each C 1

-C

6 alkyl is optionally substituted with a C 1

-C

6 25 alkoxy substituent; R' is H, C 1

-C

6 alkoxy, C 1

-C

6 alkyl or halogen;

R

2 is H, C 1

-C

6 alkoxy, C 1

-C

6 alkyl or halogen; R3 is H, C 1

-C

6 alkoxy, C 1

-C

6 alkyl or halogen; R4 is H or C 1

-C

4 alkyl; and 30 nis0,1or2. One aspect of the present invention pertains to methods for treating a histamine H3 receptor associated disorder in an individual comprising administering to said individual in need WO 2009/058300 PCT/US2008/012272 thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. One aspect of the present invention pertains to methods for treating a histamine H3 receptor associated disorder selected from a cognitive disorder, epilepsy, brain trauma, 5 depression, obesity, disorders of sleep and wakefulness, narcolepsy, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and pain. One aspect of the present invention pertains to methods for treating a disorder of sleep 10 and wakefulness. One aspect of the present invention pertains to methods for treating a cognitive disorder. One aspect of the present invention pertains to methods for treating cataplexy. One aspect of the present invention pertains to methods for inducing wakefulness. One aspect of the present invention pertains to methods for treating pain. 15 One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of a histamine H3-receptor associated disorder. One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of a disorder selected from a 20 cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness, narcolepsy, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and pain. 25 One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of a disorder of sleep and wakefulness. One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of a cognitive disorder. 30 One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the treatment of cataplexy. One aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for inducing wakefulness. One aspect of the present invention pertains to the use of a compound of the present 35 invention in the manufacture of a medicament for the treatment of pain. One aspect of the present invention pertains to compounds of the present invention for use in a method of treatment of the human or animal body by therapy. 2 WO 2009/058300 PCT/US2008/012272 One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a histamine H3-receptor associated disorder. One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a histamine H3-receptor associated disorder selected from a 5 cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness, narcolepsy, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and pain. One aspect of the present invention pertains to compounds of the present invention for 10 use in a method for the treatment of a disorder of sleep and wakefulness. One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a cognitive disorder. One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of cataplexy. 15 One aspect of the present invention pertains to compounds of the present invention for use in a method of inducing wakefulness. One aspect of the present invention pertains to compounds of the present invention for use in a method of treating pain. One aspect of the present invention pertains to compounds for preparing a composition 20 comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier. These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds. 25 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows two representative methods for preparing intermediates that are useful in the synthesis of the compounds of the present invention. The first method involves the reduction of an aryl amino acid derivative followed by cyclization of the resulting amino alcohol with triphosgene to give a 4-substituted cyclic carbamate. The second method involves the 30 reduction of an aryl amino ketone derivative followed by cyclization of the resulting amino alcohol with triphosgene to give a 5-substituted oxazolidinone. Figure 2 shows two representative methods of introducing a substituent R 5 onto the nitrogen of a heterocycle, ring A. Both processes involve the reaction of a cyclic carbamate with an alkyl or alkoxyalkyl derivative in the presence of a base. The step can be carried out either 35 before or after the formation of the biphenyl moiety. Figure 3 shows a general synthesis of compounds of Formula (Ia). The first step is the conversion of an aryl halide derivative into a boronic acid with a trialkyl borate in the presence 3 WO 2009/058300 PCT/US2008/012272 of a base. Next, a palladium-catalyzed coupling is used to form the biphenyl moiety. Then, the silyl protecting group is removed and replaced with a leaving group. Finally, reaction between the biphenyl derivative and a cyclic amine in the presence of base, gives the molecule of Formula (Ia). 5 Figure 4 shows a general method for preparing an aryl triflate for use in the palladium catalyzed coupling reaction. First, a hydroxyphenyl amino acid derivative is esterified and the amine is converted to a tert-butyl carbamate in one pot. The ester function is reduced and the alcohol is converted to the cyclic carbamate with thionyl chloride. Finally the phenol group is converted to a triflate using triflic anhydride and a base. 10 Figure 5 shows a general method for preparing a molecule of Formula (Ia) in which the right hand side of the molecule is (R)-2-methylpyrolidine. First, (R)-2-methylpyrolidine is reacted in the presence of a base with an arylalkyl derivative activated with a leaving group. The resulting (R)-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl halide is converted to an aryl boronic acid and undergoes a palladium-catalyzed coupling to give the final product. 15 Figure 6 shows a general method for preparing an aryl triflate for use in the palladium catalyzed coupling reaction. Reaction of a phenol derivative with 2-benzamidoacetic acid first provides an aryl amino acid. This is esterified and Boc protected followed by reduction to the alcohol. Cyclization is achieved by reaction with thionyl chloride and the resulting oxazolidinyl phenol is converted to the aryl triflate with triflic anhydride. 20 Figure 7 shows a general synthesis of compounds of Formula (Ia). A 2-(4 hydroxyphenyl)acetic acid derivative is esterified and then reduced to the diol. The pyrrolidine moiety is introduced by reaction of the primary alcohol with a secondary amine in the presence of triflic anhydride, with concomitant triflation of the phenol. This triflate is coupled to a boronic acid derivative, which itself is prepared from another aryl triflate or an aryl halide. 25 Figure 8 shows three methods for preparing intermediates useful in preparing the compounds of the present invention. In the first of these methods, 5-oxopyrrolidine-2-carboxylic acid is reacted with anisole in the presence of phosphorus pentoxide and methanesulfonic acid to give 5-(4-methoxyphenyl)pyrrolidin-2-one, which in turn is converted to the triflate. The second 30 of these methods involves the conversion of a 4-amino-3-(4-chlorophenyl)butanoic acid derivative to a 4-(4-chlorophenyl)pyrrolidin-2-one by aluminum oxide-mediated cyclization. Finally, chlorinated aryl triflate intermediates useful in the preparation of chlorinated compounds of the present invention may be prepared by treating phenol derivatives with N chlorosuccinimide followed by triflation. 35 Figure 9 shows a representative synthesis of aryl triflate intermediates useful in the preparation of compounds of the present invention. A 2-(4-hydroxyphenyl)acetic acid derivative is esterified and then the phenol is protected with a p-methoxybenzyl group. The ester is then 4 WO 2009/058300 PCT/US2008/012272 reduced and the primary alcohol is converted to a leaving group which is displace by a pyrrolidine derivative to give a tertiary amine. The PMB group is then removed with TFA and the phenol converted to the triflate. Figure 10 shows a representative synthesis of aryl triflate intermediates useful in the 5 preparation of compounds of the present invention. In the first step, a 2-(4 methoxyphenyl)acetic acid derivative is reduced to the corresponding primary alcohol. Next the free hydroxyl is activated with a leaving group which is displaced with a secondary amine. Next the methoxy group is removed with boron tribromide and the free phenol is converted to the triflate. 10 Figure 11 shows a general synthesis of compounds of Formula (Ia), wherein Ring A is 2-oxo-1,3-dioxolan-4-yl. First, a 1-(4-bromophenyl)ethane-1,2-diol is converted to the corresponding dimethyldioxolane and then coupled to an aryl boronic acid derivative using a palladium catalyst. The diol is then reformed by treatment with acid and subsequent reaction with 1,1'-carbonyldiimidaxole (CDI) gives the desired heterocycle. 15 Figure 12 shows three general methods for preparing intermediates useful in the preparation of compounds of the present invention. The first method provides 2-oxo-1,3 oxazinan-6-yl intermediates by the reduction aryl-3-oxopropanenitrile derivatives followed by treatment of the resulting hydroxy amine with CDI. The second method provides 2-oxo-1,3 oxazinan-4-yl intermediates via reaction of 1 -amino-3 -hydroxypropyl aryl derivatives with CDI. 20 The third method provides 5-oxomorpholin-3-yl intermediates from 1,2-dihroxyethyl aryl derivatives via the secondary amine by treatment first with sulfuric acid and acetonitrile and then ethyl chloroacetate in the presence of sodium hydride. Figure 13 shows a general method for preparing compounds of Formula (Ia), wherein Ring A is 2-oxo-1,3-dioxolan-4-yl of the present invention. Palladium catalyzed coupling of a 4 25 hydroxymethyl aryl halide with a boronic acid derivative gives a biphenyl intermediate which is oxidized and reacted with ethyl acetate in the presence of LDA. The resulting ester is reduced to the 1,3-diol and converted to the 2-oxo-1,3-dioxan-4-yl derivative by treatment with CDI. DETAILED DESCRIPTION OF THE INVENTION 30 DEFINITIONS For clarity and consistency, the following definitions will be used throughout this patent document. The term "agonists" is intended to mean moieties that interact and activate the receptor, such as the H3 histamine receptor and initiate a physiological or pharmacological response 35 characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes. 5 WO 2009/058300 PCT/US2008/012272 The term "antagonists" is intended to mean moieties that competitively bind to the receptor at the same site as agonists (for example, the endogenous ligand), but which do not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by agonists or partial agonists. Antagonists do not diminish 5 the baseline intracellular response in the absence of an agonist or partial agonist. The term "contact or contacting" is intended to mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system. Thus, "contacting" a H3 histamine receptor with a compound of the invention includes the administration of a compound of the present invention to an individual, preferably a human, having a H3 histamine receptor, as well 10 as, for example, introducing a compound of the invention into a sample containing a cellular or more purified preparation containing a H3 histamine receptor. The term "in need of treatment" and the term "in need thereof' when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, 15 including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or 20 preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder. The term "individual" is intended to mean any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates and most preferably humans. 25 The term "inverse agonists" is intended to mean moieties that bind to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibit the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of agonists or partial agonists, or decrease GTP binding to membranes. Preferably, the baseline intracellular response is inhibited in the presence of 30 the inverse agonist by at least 30%, more preferably by at least 50% and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist. The term "modulate or modulating" is intended to mean an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule. The term "pharmaceutical composition" is intended to mean a composition comprising 35 at least one active ingredient; including but not limited to, salts, solvates and hydrates of compounds of the present invention; whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of 6 WO 2009/058300 PCT/US2008/012272 ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. The term "therapeutically effective amount" is intended to mean the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, 5 system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver; or by an individual, which includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet 10 experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) and 15 (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). CHEMICAL GROUP, MOIETY OR RADICAL 20 The term "Cl-C 6 alkoxy" is intended to mean a C 1

-C

6 alkyl radical, as defined herein, attached directly to an oxygen atom, some embodiments are 1 to 5 carbons, some embodiments are I to 4 carbons, some embodiments are I to 3 carbons and some embodiments are 1 or 2 carbons. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso butoxy, sec-butoxy and the like. 25 The term "C-C 6 alkyl" is intended to mean a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments are 1 to 5 carbons. Some embodiments are 1 to 4 carbons. Some embodiments are 1 to 3 carbons. Some embodiments are 1 or 2 carbons. Some embodiments are I carbon. Examples of an alkyl include, but are not limited to, methyl, ethyl, n propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl, 30 1 -methylbutyl [i.e., -CH(CH 3

)CH

2

CH

2

CH

3 ], 2-methylbutyl [i.e., -CH 2

CH(CH

3

)CH

2

CH

3 ], n hexyl and the like. The term "C,-C 4 alkyl" is intended to mean a straight or branched carbon radical containing 1 to 4 carbons. Some embodiments are 1 to 3 carbons. Some embodiments are I or 2 carbons. Some embodiments are 1 carbon. Examples of a C 1

-C

4 alkyl include methyl, ethyl, n 35 propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and t-butyl. The term "aryl" is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl. 7 WO 2009/058300 PCT/US2008/012272 The term "halogen" or "halo" is intended to mean to a fluoro, chloro, bromo or iodo group. The term "heterocyclic" or "heterocyclyl" is intended to mean a non-aromatic, monocyclic ring containing 3 to 8 ring atoms wherein at least one ring atom is a heteroatom or 5 substituted heteroatom selected from, but not limited to, for example, the group consisting of 0, S, S(=O), S(=0) 2 and NH, wherein the N is optionally substituted as described herein. In some embodiments, the ring carbon atoms are optionally substituted with oxo thus forming a carbonyl group. In some embodiments, ring carbon atoms are optionally substituted with thioxo thus forming a thiocarbonyl group. In some embodiments the ring carbon atoms are optionally 10 substituted with C I-C 6 alkyl. In some embodiments the ring nitrogen atoms are optionally substituted with C 1

-C

6 alkyl. In some embodiments the C 1

-C

6 alkyl substituent is optionally substituted with a C 1

-C

6 alkoxy. In some embodiments a ring carbon is substituted with CI-C 6 alkyl. In some embodiments a ring nitrogen is substituted with CI-C 6 alkyl. In some embodiments the C 1

-C

6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy. 15 In some embodiments the heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered ring. Examples of a heterocyclic group include, but are not limited to, aziridin-2-yl, azetidin-2-yl, azetidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, piperzin-2-yl, piperzin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-oxooxazolidin-4-yl, 2 20 oxooxazolidin-5-yl, 4-oxooxazolidin-2-yl, 4-oxooxazolidin-5-yl, 5-oxooxazolidin-2-yl, 5 oxooxazolidin-4-yl, 2-oxopyrrolidin-3-yl, 2-oxopyrrolidin-4-yl, 2-oxopyrrolidin-5-yl, 3 oxopyrrolidin-2-yl, 3-oxopyrrolidin-4-yl, 3-oxopyrrolidin-5-yl, 2-oxoimidazolidin-4-yl, 4 oxoimidazolidin-2-yl, 4-oxoimidazolidin-5-yl, 2-oxopiperidin-3-yl, 2-oxopiperidin-4-yl, 2 oxopiperidin-5-yl, 2-oxopiperidin-6-yl, 3-oxopiperidin-2-yl, 3-oxopiperidin-4-yl, 3 25 oxopiperidin-5-yl, 3-oxopiperidin-6-yl, 4-oxopiperidin-2-yl, 4-oxopiperidin-3-yl, 2 oxomorpholin-3-yl, 2-oxomorpholin-5-yl, 2-oxomorpholin-6-yl, 3-oxomorpholin-2-yl, 3 oxomorpholin-5-yl, 3-oxomorpholin-6-yl, 2-oxo-1,3-oxazinan-4-yl, 2-oxo-1,3-oxazinan-5-yl, 2 oxo-1,3-oxazinan-6-yl, 4-oxo-1,3-oxazinan-2-yl, 4-oxo-1,3-oxazinan-5-yl, 4-oxo-1,3-oxazinan 6-yl, 5-oxo-1,3-oxazinan-2-yl, 5-oxo-1,3-oxazinan-4-yl, 5-oxo-1,3-oxazinan-6-yl, 6-oxo-1,3 30 oxazinan-2-yl, 6-oxo-1,3-oxazinan-4-yl, 6-oxo-1,3-oxazinan-5-yl and the like. In some embodiments, the heterocyclic group is a 5- or 6-membered heterocyclic group. Examples of a 5- or 6-membered heterocyclic group include, but are not limited to, oxooxazolidinyl, oxopyrrolidinyl, oxoimidazolidinyl, oxopiperidinyl, oxomorpholinyl and oxo 1,3-oxazinanyl. 35 In some embodiments, examples of a 5- or 6-membered heterocyclic groups include, but are not limited to, 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxo-1,3 oxazinanyl, 2-oxopiperidinyl, 3-oxomorpholinyl and the like as shown in Table 1. 8 WO 2009/058300 PCT/US2008/012272 Table 1 Name Structure O 2-oxooxazolidinyl HN O 0 2-oxopyrrolidinyl H N 0 2-oxoimidazolidinyl HN NH \-O 2-oxo-1,3-oxazinanyl HN 0 2-oxopiperidinyl HN 0 3-oxomorpholinyl HN O \-I/ It is understood that any one of the heterocyclic groups shown in Table 1 can be bonded 5 at any available ring carbon as allowed by the respective formulae unless otherwise specified. In some embodiments, examples of a 5- or 6-membered heterocyclic group include, but are not limited to, 2-oxooxazolidinyl, 2-oxo-1,3-oxazinanyl and the like. In some embodiments, examples of a 5- or 6-membered heterocyclic group include, but are not limited to, 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl, 2-oxo-1,3-oxazinan-4-yl, 2-oxo 10 1,3-oxazinan-5-yl, 2-oxo-1,3-oxazinan-6-yl and the like. In some embodiments, examples of a 5- or 6-membered heterocyclic group include, but are not limited to, oxo-1,3-dioxolanyl, oxo-1,3-dioxanyl and the like. In some embodiments, examples of a 5- or 6-membered heterocyclic group include, but are not limited to, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-dioxanyl and the like as shown in Table 2. 9 WO 2009/058300 PCT/US2008/012272 5 Table 2 Name Structure 0 2-oxo-1,3-dioxolanyl 0 O 0 2-oxo-1,3-dioxanyl O In some embodiments, examples of a 5- or 6-membered heterocyclic group include, but 10 are not limited to, 2-oxo-1,3-dioxolan-4-yl, 2-oxo-1,3-dioxan-4-yl and the like. The term "hydrate" as used herein means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non covalent intermolecular forces. The term "oxo" is intended to mean the substituent =0, accordingly, as a result, when a 15 carbon is substituted by an "oxo" group the new group resulting from the carbon and oxo together is a carbonyl group. The term "solvate" as used herein means a compound of the invention or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for 20 administration to humans in trace amounts. COMPOUNDS OF THE INVENTION: One aspect of the present invention pertains to certain compounds as shown in Formula (Ia): 10 WO 2009/058300 PCT/US2008/012272 R1 R 3 H R A C-(CH 2 -- N' R2 (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof; wherein: R', R 2 , Ri, R, ring A and n have the same definitions as described herein, supra and 5 infra. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable 10 subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., R1, R 2 , R3, R, ring A and n) contained within the generic chemical formulae described herein, for example, (Ia), are specifically embraced by the present invention just as if each and every combination was individually explicitly recited, to the extent that such combinations embrace compounds that result in stable compounds (i.e., compounds 15 that can be isolated, characterized and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of uses and medical indications described herein, are also specifically embraced by the present invention just as if each and every subcombination of chemical groups and subcombination of uses and medical indications was individually and 20 explicitly recited herein. As used herein, "substituted" indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group. When a 25 chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by I or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like. Likewise, "substituted with one or more substituents" refers to the substitution of a group with 30 one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different. 11 WO 2009/058300 PCT/US2008/012272 Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention. 5 Compounds of the invention can also include all isotopes of atoms occurring in the intermediates and/or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium. It is understood and appreciated that compounds of Formula (Ia) and formulae related 10 thereto may have one or more chiral centers and therefore can exist as enantiomers and/or diastereomers. The invention is understood to extend to and embrace all such enantiomers, diastereomers and mixtures thereof, including but not limited to racemates. It is understood that compounds of Formula (Ia) and formulae used throughout this disclosure are intended to represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise. 15 The Group R' In some embodiments, R' is selected from the group consisting of H, Ci-C 6 alkoxy, C 1 C 6 alkyl and halogen. In some embodiments, R' is selected from the group consisting of C 1

-C

6 alkoxy, C 1

-C

6 20 alkyl and halogen. In some embodiments, R' is selected from the group consisting of methoxy, methyl, chloro and fluoro. In some embodiments, R' is H. In some embodiments, R' is CI-C 6 alkoxy. 25 In some embodiments, R' is CI-C 6 alkyl. In some embodiments, R' is halogen. The Group R 2 In some embodiments, R 2 is selected from the group consisting of H, CI-C 6 alkoxy, C 1 30 C 6 alkyl and halogen. In some embodiments, R 2 is selected from the group consisting of CI-C 6 alkoxy, Ci-C 6 alkyl and halogen. In some embodiments, R 2 is selected from the group consisting of methoxy, methyl, chloro and fluoro. 35 In some embodiments, R 2 is H. In some embodiments, R2 is CI-C 6 alkoxy. In some embodiments, R2 is CI-C 6 alkyl. 12 WO 2009/058300 PCT/US2008/012272 In some embodiments, R 2 is halogen. The Group R 3 In some embodiments, R 3 is selected from the group consisting of H, C 1

-C

6 alkoxy, CI 5 C 6 alkyl and halogen. In some embodiments, R3 is selected from the group consisting of CI-C 6 alkoxy, CI-C 6 alkyl and halogen. In some embodiments, R 3 is selected from the group consisting of methoxy, methyl, chloro and fluoro. 10 In some embodiments, R 3 is H. In some embodiments, R3 is C 1

-C

6 alkoxy. In some embodiments, R3 is C 1

-C

6 alkyl. In some embodiments, R3 is halogen. 15 The Group RW In some embodiments, R4 is selected from the group consisting of H or C 1

-C

4 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is C 1

-C

4 alkyl. In some embodiments, R4 is methyl 20 The Ring A In some embodiments, ring A is heterocyclyl optionally substituted with one substituent selected from C 1

-C

6 alkyl and oxo; wherein each C 1

-C

6 alkyl is optionally substituted with a C 1 C 6 alkoxy substituent. 25 In some embodiments, ring A is heterocyclyl optionally substituted with two substituents selected from C 1

-C

6 alkyl and oxo; wherein each C 1

-C

6 alkyl is optionally substituted with a CI-C 6 alkoxy substituent. In some embodiments, ring A is heterocyclyl optionally substituted with three substituents selected from C 1

-C

6 alkyl and oxo; wherein each C 1

-C

6 alkyl is optionally 30 substituted with a CI-C 6 alkoxy substituent. In some embodiments, ring A is heterocyclyl optionally substituted with one or two substituents selected from C 1

-C

6 alkyl and oxo; wherein each C 1

-C

6 alkyl is optionally substituted with a C,-C 6 alkoxy substituent. In some embodiments, ring A is heterocyclyl optionally substituted with one, two or 35 three substituents selected from C 1

-C

6 alkyl and oxo; wherein each Cj-C 6 alkyl is optionally substituted with a C 1

-C

6 alkoxy substituent. 13 WO 2009/058300 PCT/US2008/012272 In some embodiments, ring A is selected from oxooxazolidinyl, oxopyrrolidinyl, oxoimidazolidinyl, oxopiperidinyl, oxomorpholinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a CI-C 6 alkyl substituent; and wherein the C 1

-C

6 alkyl substituent is optionally substituted with a Ci-C 6 alkoxy substituent. 5 In some embodiments, ring A is selected from oxooxazolidinyl, oxopyrrolidinyl, oxoimidazolidinyl, oxopiperidinyl, oxomorpholinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a substituent selected from methyl, isopropyl and 2 methoxyethyl. In some embodiments, ring A is selected from oxooxazolidinyl and oxo-1,3-oxazinanyl; 10 wherein each ring A is optionally substituted with a Ci-C 6 alkyl substituent; and wherein the C 1 C 6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy substituent. In some embodiments, ring A is selected from oxooxazolidinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. 15 In some embodiments, ring A is selected from 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2 oxoimidazolidinyl, 2-oxopiperidinyl, 3-oxomorpholinyl and 2-oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a CI-C 6 alkyl substituent; and wherein the CI-C 6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy substituent. In some embodiments, ring A is selected from 2-oxooxazolidinyl, 2-oxopyrrolidinyl, 2 20 oxoimidazolidinyl, 2-oxopiperidinyl, 3-oxomorpholinyl and 2-oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a substituent selected from methyl, isopropyl and 2 methoxyethyl. In some embodiments, ring A is selected from 2-oxooxazolidinyl and 2-oxo-1,3 oxazinanyl; wherein each ring A is optionally substituted with a C 1

-C

6 alkyl substituent; and 25 wherein the Ci-C 6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy substituent. In some embodiments, ring A is selected from 2-uoxooxazolidinyl and 2-oxo-1,3 oxazinanyl; wherein each ring A is optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is selected from 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5 30 yl and 2-oxo-1,3-oxazinan-4-yl; wherein each ring A is optionally substituted with a C 1

-C

6 alkyl substituent; and wherein the Ci-C 6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy substituent. In some embodiments, ring A is selected from 2-oxooxazolidin-4-yl, 2-oxooxazolidin-5 yl and 2-oxo-1,3-oxazinan-4-yl; wherein each ring A is optionally substituted with a substituent 35 selected from methyl, isopropyl and 2-methoxyethyl. 14 WO 2009/058300 PCT/US2008/012272 In some embodiments, ring A is selected from 2-oxooxazolidin-4-yl, 3-methyl-2 oxooxazolidin-4-yl, 3-isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4 yl, 2-oxooxazolidin-5-yl and 2-oxo-1,3-oxazinan-4-yl. In some embodiments, ring A is oxooxazolidinyl optionally substituted with a C 1

-C

6 5 alkyl substituent; wherein the C 1

-C

6 alkyl substituent is optionally substituted with a CI-C6 alkoxy substituent. In some embodiments, ring A is oxopyrrolidinyl optionally substituted with a C 1

-C

6 alkyl substituent; wherein the C 1

-C

6 alkyl substituent is optionally substituted with a C 1

-C

6 alkoxy substituent. 10 In some embodiments, ring A is oxoimidazolidinyl optionally substituted with a C1-C6 alkyl substituent; wherein the C 1

-C

6 alkyl substituent is optionally substituted with a CI-C6 alkoxy substituent. In some embodiments, ring A is oxopiperidinyl optionally substituted with a C 1

-C

6 alkyl substituent; wherein the C 1 -C alkyl substituent is optionally substituted with a C 1

-C

6 alkoxy 15 substituent. In some embodiments, ring A is oxomorpholinyl optionally substituted with a C1-C6 alkyl substituent; wherein the CI-C 6 alkyl substituent is optionally substituted with a C1-C6 alkoxy substituent. In some embodiments, ring A is oxo-1,3-oxazinanyl optionally substituted with aC1-C6 20 alkyl substituent; wherein the C 1

-C

6 alkyl substituent is optionally substituted with a C1-C6 alkoxy substituent. In some embodiments, ring A is oxooxazolidinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is oxopyrrolidinyl optionally substituted with a 25 substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is oxoimidazolidinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is oxopiperidinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. 30 In some embodiments, ring A is oxomorpholinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is oxo-1,3-oxazinanyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 2-oxooxazolidinyl optionally substituted with a C1-C6 35 alkyl substituent; wherein the C 1

-C

6 alkyl substituent is optionally substituted with a CI-C6 alkoxy substituent. 15 WO 2009/058300 PCT/US2008/012272 In some embodiments, ring A is 2-oxopyrrolidinyl optionally substituted with a CI-C 6 alkyl substituent; wherein the G 1

-C

6 alkyl substituent is optionally substituted with a CrC6 alkoxy substituent. In some embodiments, ring A is 2-oxoimidazolidinyl optionally substituted with a C 1

-C

6 5 alkyl substituent; wherein the C 1

C

6 alkyl substituent is optionally substituted with a CrC6 alkoxy substituent. In some embodiments, ring A is 2-oxopiperidinyl optionally substituted with a C-C6 alkyl substituent; wherein the C 1

-C

6 alkyl substituent is optionally substituted with a C-C6 alkoxy substituent. 10 In some embodiments, ring A is 3-oxomorpholinyl optionally substituted with a CrC6 alkyl substituent; wherein the C 1

-C

6 alkyl substituent is optionally substituted with a CrC6 alkoxy substituent. In some embodiments, ring A is 2-oxo-1,3-oxazinanyl optionally substituted with a C 1 C 6 alkyl substituent; wherein the C-C 6 alkyl substituent is optionally substituted with aCrC6 15 alkoxy substituent. In some embodiments, ring A is 2-oxooxazolidinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 2-oxopyrrolidinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. 20 In some embodiments, ring A is 2-oxoimidazolidinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 2-oxopiperidinyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 3-oxomorpholinyl optionally substituted with a 25 substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 2-oxo-1,3-oxazinanyl optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 2-oxooxazolidin-4-yl, optionally substituted with a C

C

6 alkyl substituent; wherein the C-C 6 alkyl substituent is optionally substituted with aC-C6 30 alkoxy substituent. In some embodiments, ring A is 2-oxooxazolidin-5-yl, optionally substituted with a C 1 C 6 alkyl substituent; wherein the C-C 6 alkyl substituent is optionally substituted with a CrC6 alkoxy substituent. In some embodiments, ring A is 2-oxo-1,3-oxazinan-4-yl, optionally substituted with a 35 C-C 6 alkyl substituent; wherein the C-C 6 alkyl substituent is optionally substituted with a C 1 C 6 alkoxy substituent. 16 WO 2009/058300 PCT/US2008/012272 In some embodiments, ring A is 2-oxooxazolidin-4-yl, optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 2-oxooxazolidin-5-yl, optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. 5 In some embodiments, ring A is 2-oxo-1,3-oxazinan-4-yl, optionally substituted with a substituent selected from methyl, isopropyl and 2-methoxyethyl. In some embodiments, ring A is 2-oxooxazolidin-4-yl. In some embodiments, ring A is 3-methyl-2-oxooxazolidin-4-yl. In some embodiments, ring A is 3-isopropyl-2-oxooxazolidin-4-yl. 10 In some embodiments, ring A is 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl. In some embodiments, ring A is 2-oxooxazolidin-5-yl. In some embodiments, ring A is 2-oxo-1,3-oxazinan-4-yl. In some embodiments, ring A is selected from oxopyrrolidinyl, oxo-1,3-dioxolanyl, oxo-1,3-dioxanyl, oxomorpholinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally 15 substituted with a CI-C 6 alkyl substituent; and wherein the C 1

-C

6 alkyl substituent is optionally substituted with a C 1

-C

6 alkoxy substituent. In some embodiments, ring A is selected from oxopyrrolidinyl, oxo-1,3-dioxolanyl, oxo-1,3-dioxanyl, oxomorpholinyl and oxo-1,3-oxazinanyl. In some embodiments, ring A is selected from 2-oxopyrrolidin-4-yl, 2-oxopyrrolidin-5 20 yl, 2-oxo-1,3-dioxolan-4-yl, 2-oxo-1,3-dioxan-4-yl, 3-oxomorpholin-5-yl and 2-oxo-1,3 oxazinan-6-yl. In some embodiments, ring A is 2-oxopyrrolidin-4-yl. In some embodiments, ring A is 2-oxopyrrolidin-5-yl. In some embodiments, ring A is 2-oxo-1,3-dioxolan-4-yl. 25 In some embodiments, ring A is 2-oxo-1,3-dioxan-4-yl. In some embodiments, ring A is 3-oxomorpholin-5-yl. In some embodiments, ring A is 2-oxo-1,3-oxazinan-6-yl. The Variable n 30 In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0 or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0. 35 In some embodiments, n is 1. In some embodiments, n is 2. 17 WO 2009/058300 PCT/US2008/012272 Certain Combinations of the Present Invention: In some embodiments, R' and R2 are both H. In some embodiments, R' and R3 are both H. In some embodiments, R2 and R3 are both H. 5 In some embodiments, R', R2 and R' are all H. Some embodiments of the present invention pertain to compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof: H C

CH

2 NC/I (Ic) wherein: 10 R 4 is H or C 1

-C

4 alkyl; ring A is selected from oxooxazolidinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a CI-C 6 alkyl substituent; and wherein the CI-C 6 alkyl substituent is optionally substituted with a Ci-C 6 alkoxy substituent; and nis0, 1 or2. 15 Some embodiments of the present invention pertain to compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof: H C

CH

2 N2] (Ic) wherein:

R

4 is H or methyl; 20 ring A is selected from 2-oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3 isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2-oxooxazolidin-5 yl and 2-oxo-1,3-oxazinan-4-yl; and n is 0, 1 or 2. Some embodiments of the present invention pertain to compounds of Formula (le) and 25 pharmaceutically acceptable salts, solvates and hydrates thereof: H

C-CH

2 /\ NJ (le) wherein: 18 WO 2009/058300 PCT/US2008/012272 ring A is selected from oxooxazolidinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a C 1

-C

6 alkyl substituent; and wherein the CI-C 6 alkyl substituent is optionally substituted with a C 1

-C

6 alkoxy substituent; and n is 0, 1 or 2. 5 Some embodiments of the present invention pertain to compounds of Formula (Ie) and pharmaceutically acceptable salts, solvates and hydrates thereof: H

AC-CH

2 / N (Ie) wherein: ring A is selected from 2-oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3 10 isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2-oxooxazolidin-5 yl and 2-oxo-1,3-oxazinan-4-yl; and n is 0, 1 or 2. Some embodiments of the present invention pertain to compounds of Formula (Ig) and pharmaceutically acceptable salts, solvates and hydrates thereof: H AC -CH 2 N3 15 (1g) wherein: ring A is selected from oxooxazolidinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a Ci-C 6 alkyl substituent; and wherein the C 1

-C

6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy substituent; and 20 n is 0, 1 or 2. Some embodiments of the present invention pertain to compounds of Formula (Ig) and pharmaceutically acceptable salts, solvates and hydrates thereof: H

AC-CH

2 (Ig) wherein: 25 ring A is selected from 2-oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3 isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2-oxooxazolidin-5 yl and 2-oxo-1,3-oxazinan-4-yl; and n is 0, 1 or 2. 19 WO 2009/058300 PCT/US2008/012272 Some embodiments of the present invention pertain to compounds of Formula (Ii) and pharmaceutically acceptable salts, solvates and hydrates thereof: R1 R3 A C' CH 2 0 R2 (Ii) wherein: 5 R', R 2 and R 3 are each independently selected from H, C 1

-C

6 alkoxy, C 1

-C

6 alkyl and halogen; ring A is selected from oxooxazolidinyl, oxo-1,3-oxazinanyl, oxopyrrolidinyl, oxo-1,3 dioxolanyl, oxo-1,3-dioxanyl, oxomorpholinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a C 1

-C

6 alkyl substituent; and wherein the C 1

-C

6 alkyl substituent is 10 optionally substituted with a C 1

-C

6 alkoxy substituent; and n is 0, 1 or 2. Some embodiments of the present invention pertain to compounds of Formula (Ii) and pharmaceutically acceptable salts, solvates and hydrates thereof: R1 R3 H

R

2 (Ii) 15 wherein: R', R 2 and R 3 are each independently selected from H, methoxy, methyl, chloro and fluoro; ring A is selected from 2-oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3 isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2-oxooxazolidin-5 20 yl, 2-oxo-1,3-oxazinan-4-yl, 2-oxopyrrolidin-4-yl, 2-oxopyrrolidin-5-yl, 2-oxo-1,3-dioxolan-4 yl, 2-oxo-1,3-dioxan-4-yl, 3-oxomorpholin-5-yl and 2-oxo-1,3-oxazinan-6-yl; and nis0, 1 or2. Some embodiments of the present invention include every combination of one or more 25 compounds selected from the following group shown in TABLE A and TABLE B. TABLE A 20 WO 2009/058300 PCT/US2008/012272 Cmpd Chemical Structure Chemical Name No. 0 (S)-4-((4'-(2-((R)-2 O NH methylpyrrolidin-1 yl)ethyl)biphenyl-4 N yl)methyl)oxazolidin-2-one H (S)-4-(4'-(2-((R)-2 2 O /methylpyrrolidin-1 N ] yl)ethyl)biphenyl-4 yl)oxazolidin-2-one 0 H (R)-4-(4'-(2-((R)-2 methylpyrrolidin-1 3 - yl)ethyl)biphenyl-4 yl)oxazolidin-2-one 0 (R)-4-((4'-(2-((R)-2 O NH methylpyrrolidin-1 yl)ethyl)biphenyl-4 N3 yl)methyl)oxazolidin-2-one 0 (R)-3-methyl-4-(4'-(2-((R) 5 \ 2-methylpyrrolidin- 1 N yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (R)-3-(2-methoxyethyl)-4 o(4'-(2-((R)-2 6 O N methylpyrrolidin-1 o N] yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (R)-3-isopropyl-4-(4'-(2 N ((R)-2-methylpyrrolidin-1 o N yl)ethyl)biphenyl-4 yl)oxazolidin-2-one 21 WO 2009/058300 PCT/US2008/012272 Cmpd Chemical StructureChmclN e No. 0 (R)-3-methyl-4-((4'-(2-((R) Ok N 2-methylpyrrolidin-1 8 - yl)ethyl)biphenyl - N~jJ yl)methyl)oxazolidin-2-one (R)-3-(2-methoxyethyl)-4 O'kN)(('(-R)2 9 methylpyrrolidin- 1 - \ / -yl)ethyl)biphenyl-4 N3 yl)methyl)oxazolidin-2-one 0oR4(4-(-()2 04 methylpyrrolidin- 1 10 -N \ - yl)ethyl)biphenyl-4 - ~ / N7J yl)methyl)- 1,3 -oxazinan-2 one 0 (S)-3 -methyl-4-((4'-(2-((R) o N 2-methylpyrrolidin-1I 11 - -. yl)ethyl)biphenyl-4 - ~ / N~jJ yl)methyl)oxazolidin-2-one I (S)-3-(2-methoxyethyl)-4 0 Q. 12 0 Nmethylpyrrolidin- 1 \ / -yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one 0 (ST-4-((4'-(2-((R)-2 NH methylpyrrolidin- 1 13 /\ -- yl)ethyl)biphenyl-4 - '~' N"~1 yl)methyl)-1 ,3-oxazinan-2 one HN /-( -2(-)2 14 O~O '/ Q methylpyrrolidin-1 yl)oxazolidin-2-one 22 WO 2009/058300 PCT/US2008/012272 Gmpd Chemical StructureChmclN e No. / (S)-3 -methyl-4-(4'-(2-((R) 15 O~N /\s 2-methylpyrrolidin-1I 0 yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (SJ-3 -(2 -methoxyethyl)-4 o 4-2-()2 16 0 ~N , -methylpyrrolidin-1 o0 '/ ~ 7 yl)ethyl)biphenyl-4 yl)oxazolidin-2-one 0~~ H (R)-4-(4'-(2-(pyrrolidin- 1 yl)oxazolidin-2-one TABLE B Cmpd Chemical StructureChmclN e No. HCI (R)-4-(2,6-dichloro-4'-(2 18/ ((R)-2-methylpyrrolidin- 1 o18 / Nj yl)ethyl)biphenyl-4 CI yl)oxazolidin-2-one H (R)-4-(2-methyl-4'-(2-((R) 19 '~zf- \ -2-methylpyrrolidin-1I o0 N2 J yl)ethyl)biphenyl-4 yl)oxazolidin-2-one H (R)-4-(2-chloro-4'-(2-((R) 20 TyN 2-methylpyrrolidin-1I 20 0' / N3 yl)ethyl)biphenyl-4 CI yl)oxazolidin-2-one H (R)-4-(2-methoxy-4'-(2 21 0-T ((R)-2-methylpyrrolidin-1I / yl)oxazolidin-2-one 23 WO 2009/058300 PCT/US2008/012272 Cmpd Chemical Structure Chemical Name No. H CI (S)-4-(2'-chloro-4'-(2-((R) 22 0 2-methylpyrrolidin- 1 0 NC] yl)ethyl)biphenyl-4 yl)oxazolidin-2-one F (S)-4-(3'-fluoro-4'-(2-((R) 23 0 2-methylpyrrolidin-1 o0/ NC yl)ethyl)biphenyl-4 yl)oxazolidin-2-one H 4-(3-methyl-4'-(2-((R)-2 O N methylpyrrolidin-1 O/ NC] yl)ethyl)biphenyl-4 yl)oxazolidin-2-one 4-(4'-(2-((R)-2 0 25 OH methylpyrrolidin-1 HN -N"/ yl)ethyl)biphenyl-4 yl)pyrrolidin-2-one 4-(4'-(2-((R)-2 26 O methylpyrrolidin-1 NC] yl)ethyl)biphenyl-4-yl)-1,3 dioxolan-2-one 6-(4'-(2-((R)-2 2 methylpyrrolidin-1 27 HN- NII yl)ethyl)biphenyl-4-yl)-1,3 oxazinan-2-one H4-(4'-(2-((R)-2 NH 8methylpyrrolidin-1 28 O NQ yl)ethyl)biphenyl-4-yl)-1,3 oxazinan-2-one 0 4-(4'-(2-((R)-2 0 - methylpyrrolidin-1 29 O/ N yl)ethyl)biphenyl-4-yl)-1,3 dioxan-2-one 24 WO 2009/058300 PCT/US2008/012272 Cmpd Chemical Structure Chemical Name No. 05-(4'-(2-((R)-2 30 O-methylpyrrolidin- 1 30N yl)ethyl)biphenyl-4 yl)pyrrolidin-2-one 0 5-(4'-(2-((R)-2 NH- methylpyrrolidin-1 31 aO7 - - N yl)ethyl)biphenyl-4 yl)morpholin-3-one (S)-4-(2'-methyl-4'-(2 32 O (pyrrolidin-1 o NJ yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (S)-4-(2'-methoxy-4'-(2 mm 0 3 H (pyrrolidin-1 1- \ yl)ethyl)biphenyl-4 yl)oxazolidin-2-one Additionally, individual compounds and chemical genera of the present invention, for example those compounds found in TABLE A and TABLE B including diastereomers and enantiomers thereof, encompass all pharmaceutically acceptable salts, solvates and particularly 5 hydrates, thereof. The compounds of the Formula (Ia) of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples. Protection and deprotection may be carried out by procedures generally known in the art (see, 10 for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3 d Edition, 1999 [Wiley]; incorporated herein by reference in its entirety). It is understood that the present invention embraces each diastereomer, each enantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral 15 carbon. Separation of the individual isomers (such as, by chiral HPLC, recrystallization of diastereomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. 25 WO 2009/058300 PCT/US2008/012272 INDICATIONS AND METHODS OF PROPHYLAXIS AND/OR TREATMENT Histamine [2-(imidazol-4-yl)ethylamine] exerts its physiological effects through four distinct G-protein coupled receptors (GPCRs), termed HI, H2, H3 and H4. The histamine H3 receptor was first identified in 1983, when it was determined that the H3-receptor acted as an 5 autoreceptor controlling both the synthesis and release of histamine (see: Arrang et al. Nature 1983, 302, 832-7). At least four human and three rat splice variants have proven functional activity in pharmacological assays (Passani et al., Trends in Pharmacol. Sci. 2004, 25, 618-625). Rat and human histamine H3-receptors also show constitutive activity which means that they can transduce a signal even in the absence of a ligand. Histamine H3-receptors also function as 10 heteroceptors, modulating the release of a number of other transmitter substances including serotonin, acetylcholine, dopamine and noradrenaline (see: Brown et al. Prog. Neurobiol. 2001, 63, 637-672). Thus, there are a number of therapeutic applications for ligands. which target the histamine H3-receptor, where the ligand functions as either an antagonist or inverse agonist (for reviews see: Leurs et al. Nat. Rev. Drug. Discov. 2005, 4, 107-120; Passani et al. Trends 15 Pharmacol. Sci. 2004, 25, 618-625). Accordingly, preclinical studies have identified a number of indications which are amenable to treatment with histamine H3-receptor antagonists and inverse agonists, such as compounds of the present invention. The compounds disclosed herein are believed to be useful in the treatment and/or prevention of several diseases and disorders, and in the amelioration of 20 symptoms thereof. These compounds can be used alone or in combination with other compounds for the treatment and/or prevention of diseases and disorders. Without limitation, these diseases and disorders include the following. Histamine H3-receptor antagonists have been shown to increase wakefulness (e.g. Lin J. S. et al. Brain Research 1990, 523, 325-330). This effect demonstrates that H3-receptor 25 antagonists can be useful for disorders of sleep and wakefulness (Parmentier et al. J. Neurosci. 2002, 22, 7695-7711; Ligneau et al. J. Pharmacol. Exp. Ther. 1998, 287, 658-666). For example, histamine H3-receptor antagonists and inverse agonists can be used to treat the somnolence syndrome associated with different pathological conditions, for example, sleep apnea and Parkinson's disease or circumstances associated with lifestyle, for example, daytime 30 somnolence from sleep deprivation as a result of nocturnal jobs, overwork, or jet-lag (see Passani et al., Trends Pharmacol. Sci. 2004, 25, 618-625). Somnolence is one of the major problems of public health because of its high prevalence (19-37% of the general population) and risk for causing work and traffic accidents. Sleep apnea (alternatively sleep apnoea) is a common sleep disorder characterized by 35 brief interruptions of breathing during sleep. These episodes, called apneas, last 10 seconds or more and occur repeatedly throughout the night. People with sleep apnea partially awaken as they struggle to breathe, but in the morning they may not be aware of the disturbances in their 26 WO 2009/058300 PCT/US2008/012272 sleep. The most common type of sleep apnea is obstructive sleep apnea (OSA), caused by relaxation of soft tissue in the back of the throat that blocks the passage of air. Central sleep apnea (CSA) is caused by irregularities in the brain's normal signals to breathe. The hallmark symptom of the disorder is excessive daytime sleepiness. Additional symptoms of sleep apnea 5 include restless sleep, loud snoring (with periods of silence followed by gasps), falling asleep during the day, morning headaches, trouble concentrating, irritability, forgetfulness, mood or behaviour changes, weight gain, increased heart rate, anxiety, and depression. Few drug-based treatments of obstructive sleep apnea are known despite over two decades of research and tests. Oral administration of the methylxanthine theophylline 10 (chemically similar to caffeine) can reduce the number of episodes of apnea, but can also produce side effects such as palpitations and insomnia. Theophylline is generally ineffective in adults with OSA, but is sometimes used to treat CSA, and infants and children with apnea. In 2003 and 2004, some neuroactive drugs, particularly modern-generation antidepressants including mirtazapine, have been reported to reduce incidences of obstructive sleep apnea. 15 When other treatments do not completely treat the OSA, drugs are sometimes prescribed to treat a patient's daytime sleepiness or somnolence. These range from stimulants such as amphetamines to modern anti-narcoleptic medicines. The drug modafinil is seeing increased use in this role as of 2004. In addition, for example, histamine H3-receptor antagonists and inverse agonists can be 20 used to treat narcolepsy (Tedford et al. Soc. Neurosci. Abstr. 1999, 25, 460.3). Narcolepsy is a neurological condition most often characterized by Excessive Daytime Sleepiness (EDS), episodes of sleep and disorder of REM or rapid eye movement sleep. The main characteristic of narcolepsy is overwhelming Excessive Daytime Sleepiness (EDS), even after adequate nighttime sleep. A person with narcolepsy is likely to become drowsy or to fall asleep, often at 25 inappropriate times and places. In addition, nighttime sleep may be fragmented with frequent wakenings. Classic symptoms of narcolepsy include, for example, cataplexy which is sudden episodes of loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles, or inability to speak clearly) to complete body collapse. Episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or 30 fear, and may last from a few seconds to several minutes. Another symptom of narcolepsy is sleep paralysis, which is the temporary inability to talk or move when waking up. Other symptoms include, for example, hypnagogic hallucinations which are vivid, often frightening, dream-like experiences that occur while dozing, falling asleep and/or while awakening, and automatic behaviour which occurs when a person continues to function (talking, putting things 35 away, etc.) during sleep episodes, but awakens with no memory of performing such activities. Daytime sleepiness, sleep paralysis, and hypnagogic hallucinations also occur in people who do 27 WO 2009/058300 PCT/US2008/012272 not have narcolepsy, such as in people who are suffering from extreme lack of sleep. Cataplexy is generally considered unique to narcolepsy. Currently the treatments available for narcolepsy treat the symptoms, but not the underlying cause. For cataplexy and REM-sleep symptoms, antidepressant medications and 5 other drugs that suppress REM sleep are prescribed. The drowsiness is normally treated using stimulants such as methylphenidate (Ritalin), amphetamines (Adderall), dextroamphetamine (Dexedrine), methamphetamine (Desoxyn), modafinil (Provigil), etc. Other medications used are codeine and selegiline. The cataplexy is treated using clomipramine, imipramine, or protriptyline but this need only be done in severe cases. The drug gamma-hydroxybutyrate 10 (GHB) (Xyrem) is approved in the USA by the Food and Drug Administration to treat both the cataplexy and excessive daytime sleepiness associated with narcolepsy. Interestingly, modafinil (Provigil) has recently been shown to increase hypothalamic histamine release (Ishizuka et al. Neurosci. Lett. 2003, 339, 143-146). In addition, recent studies using the classic Doberman model of narcolepsy with a non 15 imidazole histamine H3-receptor antagonist showed that a histamine H3-receptor antagonist can reduce the number of cataplectic attacks and the duration of the attacks (Carruthers Ann. Meet. Eur. Histamine Res. Soc. 2004, Abs. p31). In summary, histamine H3-receptor antagonists and inverse agonists can be used for the treatment and/or prevention of conditions associated with excessive daytime sleepiness such as 20 hypersomnia, narcolepsy, sleep apnea, time zone change disorder, and other disorders which are associated with excessive daytime sleepiness such as fibromyalgia, and multiple sclerosis (Parmentier et al., J. Neurosci. 2002, 22, 7695-7711; Ligneau et al. J. Pharmacol. Exp. Ther. 1998, 287, 658-666). Other conditions include excessive sleepiness due to shift work, medical disorders, psychiatric disorders, narcolepsy, primary hypersomnia, and the like. Histamine H3 25 receptor antagonists and inverse agonists can also be used occasionally to promote wakefulness or vigilance in shift workers, sleep deprivation, post anesthesia grogginess, drowsiness as a side effect from a medication, military use and the like. In addition, wakefulness is a prerequisite for several brain functions including attention, learning, and memory and is required for appropriate behaviours in response to environmental 30 challenges. Histamine H3-receptor antagonists and inverse agonists have been shown to improve cognitive performance in various animal models (Hancock and Fox in Milestones in Drug Therapy, ed. Buccafusco, 2003). These compounds can be used as pro-cognitive agents and can increase vigilance. Therefore, histamine H3-receptor antagonists and inverse agonists can be used in aging or degenerative disorders in which vigilance, attention and memory are 35 impaired, for example, as in Alzheimer's disease or other dementias. Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia. It is characterized clinically by progressive cognitive deterioration together with 28 WO 2009/058300 PCT/US2008/012272 neuropsychiatric symptoms and behavioural changes. The most striking early symptom is memory loss, which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language, 5 skilled movements, recognition and functions closely related to the frontal and temporal lobes of the brain such as decision-making and planning. There is currently no cure for AD, although there are drugs which offer symptomatic benefit, specifically with respect to short-term memory impairment. These drugs include acetylcholinesterase inhibitors such as donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon) and NMDA antagonists such as memantine. 10 Histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent cognitive disorders (Passani et al. Trends Pharmacol. Sci. 2004, 25, 618-625), epilepsy (Vohora et al. Pharmacol. Biochem. Behav. 2001, 68, 735-741), depression (Perez-Garcia et al. Psychopharmacol. 1999, 142, 215-220), attention deficit hyperactivity disorder (ADHD), (Fox et al. Behav. Brain Res. 2002, 131, 151-61), and schizophrenia (Fox et al. J. Pharmacol. Exp. 15 Ther. 2005, 313, 176-190). These indications are described briefly below. For additional information, see reviews by Leurs et al., Nat. Rev. Drug. Discov. 2005, 4, 107-120, and Vohora Investigational Drugs 2004, 7, 667-673). Histamine H3-receptor antagonists or inverse agonists can also be used as a novel therapeutic approach to restore cortical activation in comatose or brain-traumatized patients (Passani et al., Trends in Pharmacol. Sci. 2004, 25, 618-625). 20 As stated above, histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent epilepsy. Epilepsy (often referred to as a seizure disorder) is a chronic neurological condition characterized by recurrent unprovoked seizures. In terms of their pattern of activity, seizures may be described as either partial (focal) or generalized. Partial seizures only involve a localized part of the brain, whereas generalized seizures involve the entire cortex. 25 There are many different epilepsy syndromes, each presenting with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis. Some common seizure syndromes include, for example, infantile spasms (West syndrome), childhood absence epilepsy, and benign focal epilepsy of childhood (Benign Rolandic epilepsy), juvenile myoclonic epilepsy, temporal lobe epilepsy, frontal lobe epilepsy and Lennox-Gastaut 30 syndrome. Compounds of the present invention can be used in combination with various known drugs. For example, compounds of the present invention can be used with one or more drugs that prevent seizures or reduce seizure frequency: these include carbamazepine (common brand name Tegretol), clobazam (Frisium), clonazepam (Klonopin), ethosuximide (Zarontin), 35 felbamate (Felbatol), fosphenytoin (Cerebyx), flurazepam (Dalmane), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), mephenytoin (Mesantoin), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone 29 WO 2009/058300 PCT/US2008/012272 (Mysoline), sodium valproate (Epilim), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene, Convulex), and vigabatrin (Sabril). Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these include diazepam (Valium) and lorazepam (Ativan). Drugs used only in the treatment of refractory 5 status epilepticus include paraldehyde (Paral) and pentobarbital (Nembutal). As stated above, a histamine H3-receptor antagonist or inverse agonist can be used as the sole agent of treatment or can be used in combination with other agents. For example, Vohora et al. show that a histamine H3-receptor antagonist can work as an anti-epilepsy, anti seizure drug and also showed effect with sub-effective doses of the H3-receptor antagonist in 10 combination with sub-effective doses of known anti-epileptic drugs (Vohora et al. Pharmacol. Biochem. Behav. 2001, 68, 735-741). Perez-Garcia et al. (Psychopharmacol. 1999, 142, 215-220) tested the ability of a histamine H3-receptor agonist and antagonist on experimental mouse models of anxiety (elevated plus-maze) and depression (forced swimming test). They found that while the 15 compounds did not have a significant effect on the model of anxiety, a H3-receptor antagonist did have a significant dose-dependent effect in the model of depression. Thus, histamine H3 receptor antagonists or inverse agonists can have antidepressant effects. Clinical depression is a state of sadness or melancholia that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living. Clinical 20 depression affects about 16% of the population on at least one occasion in their lives. Clinical depression is currently the leading cause of disability in the U.S. as well as other countries, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization. Compounds of the present invention can be used in combination with various known 25 drugs. For example, compounds of the present invention can be used with one or more of the drugs currently available that can relieve the symptoms of depression. They include, for example, monoamine oxidase inhibitors (MAOIs) such as Nardil or Moclobemide (Manerix), tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), paroxetine (Paxil), escitalopram (Lexapro), and sertraline (Zoloft), norepinephrine 30 reuptake inhibitors such as reboxetine (Edronax), and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor) and duloxetine (Cymbalta). As stated above, histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent attention deficit hyperactivity disorder (ADHD). According to the Diagnostic and Statistical Manual of Mental Disorders-IV-TR, ADHD is a developmental disorder that 35 arises in childhood, in most cases before the age of 7 years, is characterized by developmentally inappropriate levels of inattention and/or hyperactive-impulsive behavior, and results in 30 WO 2009/058300 PCT/US2008/012272 impairment in one or more major life activities, such as family, peer, educational, occupational, social, or adaptive functioning. ADHD can also be diagnosed in adulthood. The first-line medications used to treat ADHD are mostly stimulants, which work by stimulating the areas of the brain responsible for focus, attention, and impulse control. The use 5 of stimulants to treat a syndrome often characterized by hyperactivity is sometimes referred to as a paradoxical effect, but there is no real paradox in that stimulants activate brain inhibitory and self-organizing mechanisms permitting the individual to have greater self-regulation. The stimulants used include, for example, methylphenidate (sold as Ritalin, Ritalin SR and Ritalin LA), Metadate, Metadate ER, Metadate CD, Concerta, Focalin, Focalin XR or Methylin. The 10 stimulants also include, for example, amphetamines such dextroamphetamine, sold as Dexedrine, Dexedrine Spansules, Adderall, and Adderall XR, a trade name for a mixture of dextroamphetamine and laevoamphetamine salts, methamphetamine sold as Desoxyn, bupropion, a dopamine and norepinephrine reuptake inhibitor, marketed under the brand name Wellbutrin. A non-stimulant medication to treat ADHD is Atomoxetine (sold as Strattera) a 15 norepinephrine reuptake inhibitor. Other drugs sometimes used for ADHD include, for example, benzphetamine, Provigil/Alertec/modafinil and clonidine. Recently it has been reported that in a rat pup model for ADHD, a histamine H3-receptor antagonist was at least as effective as methylphenidate (Ritalin) (Hancock and Fox in Milestones in Drug Therapy, ed. Buccafusco, 2003). Compounds of the present invention can be used in combination with various known 20 drugs. For example, compounds of the present invention can be used with one or more of the drugs used to treat ADHD and related disorders. As stated above, histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent schizophrenia. Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by impairments in the perception or expression of reality and by 25 significant social or occupational dysfunction. A person experiencing untreated schizophrenia is typically characterized as demonstrating disorganized thinking, and as experiencing delusions or auditory hallucinations. Although the disorder is primarily thought to affect cognition, it can also contribute to chronic problems with behavior and emotion. Schizophrenia is often described in terms of "positive" and "negative" symptoms. Positive symptoms include delusions, auditory 30 hallucinations and thought disorder, and are typically regarded as manifestations of psychosis. Negative symptoms are so named because they are considered to be the loss or absence of normal traits or abilities, and include features such as flat, blunted or constricted affect and emotion, poverty of speech and lack of motivation. Some models of schizophrenia include formal thought disorder and planning difficulties in a third group, a "disorganization syndrome." 35 The first line pharmacological therapy for schizophrenia is usually the use of antipsychotic medication. Antipsychotic drugs are only thought to provide symptomatic relief from the positive symptoms of psychosis. The newer atypical antipsychotic medications (such as 31 WO 2009/058300 PCT/US2008/012272 clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) are usually preferred over older typical antipsychotic medications (such as chlorpromazine and haloperidol) due to their favorable side-effect profile. While the atypical antipsychotics are associated with less extra pyramidal side-effects and tardive dyskinesia than the conventional antipsychotics, 5 some of the agents in this class (especially olanzapine and clozapine) appear to be associated with metabolic side effects such as weight gain, hyperglycemia and hypertriglyceridemia that must be considered when choosing appropriate pharmacotherapy. Histamine H3-receptor antagonists or inverse agonists can be used to treat obesity (Hancock, Curr. Opin. Investig. Drugs 2003, 4, 1190-1197). The role of neuronal histamine in 10 food intake has been established for many years and neuronal histamine release and/or signalling has been implicated in the anorectic actions of known mediators in the feeding cycle such as leptin, amylin and bombesin. In the brain, the H3-receptor is implicated in the regulation of histamine release in the hypothalamus. Moreover, in situ hybridization studies have revealed histamine H3-receptor mRNA expression in rat brown adipose tissue, indicating a role in the 15 regulation of thermogenesis (Karlstedt et al., Mol. Cell. Neurosci. 2003, 24, 614-622). Furthermore, histamine H3-receptor antagonists have been investigated in various preclinical models of obesity and have shown to be effective in reducing food intake, reducing weight, and decreasing total body fat in mice (Hancock, et al. Eur. J. Pharmacol. 2004, 487, 183-197). The most common drugs used for the treatment of obesity are sibutramine (Meridia) and orlistat 20 (Xenical), both of which have limited effectiveness and significant side effects. Therefore, novel anti-obesity agents, such as histamine H3-receptor antagonists or inverse agonists, are needed. Histamine H3-receptor antagonists or inverse agonists can also be used to treat upper airway allergic responses (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479) including allergic rhinitis and nasal congestion. Allergic rhinitis is a frequently occurring chronic disease that 25 affects a large number of people. Recent analysis of histamine H3-receptor expression in the periphery by quantitative PCR revealed that H3 -receptor mRNA is abundantly expressed in human nasal mucosa (Varty et al. Eur. J. Pharmacol. 2004, 484, 83-89). In addition, in a cat model of nasal decongestion, a combination of histamine H3 -receptor antagonists with the H 1 receptor antagonist chlorpheniramine resulted in significant nasal decongestion without the 30 hypertensive effect seen with adrenergic agonists. (McLeod et al. Am. J Rhinol. 1999, 13, 391 399). Thus, histamine H3-receptor antagonists or inverse agonists can be used alone or in combination with HI receptor blockage for the treatment of allergic rhinitis and nasal congestion. Histamine H3-receptor antagonists or inverse agonists have therapeutic potential for the 35 treatment of pain (Medhurst et al. Biochemical Pharmacology (2007), 73(8), 1182-1194). PHARMACEUTICAL COMPOSITIONS 32 WO 2009/058300 PCT/US2008/012272 A further aspect of the present invention pertains to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier. 5 Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier. Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required 10 proportions and then, if necessary, forming the resulting mixture into a desired shape. Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral preparations may be 15 in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing 20 an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms. A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically acceptable carriers, outside those mentioned herein, are known in the art; for example, see 25 Remington, The Science and Practice ofPharmacy, 2 0 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.) While it is possible that, for use in the prophylaxis or treatment, a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or 30 composition further comprising a pharmaceutically acceptable carrier. The invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible 35 with the other ingredients of the formulation and not overly deleterious to the recipient thereof. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub 33 WO 2009/058300 PCT/US2008/012272 cutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with a minimum of degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single 5 pressure sensitive adhesive and a removable protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the needs of the artisan. The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages 10 thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, 15 with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably 20 made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such 25 as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier. Compounds of the present invention or a solvate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as H3 30 histamine receptor modulators. By the term "active ingredient" is defined in the context of a "pharmaceutical composition" and is intended to mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized as providing no pharmaceutical benefit. The dose when using the compounds of the present invention can vary within wide 35 limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether 34 WO 2009/058300 PCT/US2008/012272 an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention. Representative doses of the present invention include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg 5 to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein. 10 The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, 15 typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the 20 disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The 25 dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention. 30 The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If 35 appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated. 35 WO 2009/058300 PCT/US2008/012272 For preparing pharmaceutical compositions from the compounds of the present invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances 5 which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding 10 capacity in suitable proportions and compacted to the desire shape and size. The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium 15 stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are 20 included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration. For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized 25 molds, allowed to cool and thereby to solidify. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid form preparations include solutions, suspensions and emulsions, for example, 30 water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic 35 parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as 36 WO 2009/058300 PCT/US2008/012272 a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds according to the present invention may thus be formulated for 5 parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. 10 Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening 15 agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly 20 before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. For topical administration to the epidermis the compounds according to the invention 25 may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. 30 Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Solutions or suspensions are applied directly to the nasal cavity by conventional means, 35 for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient 37 WO 2009/058300 PCT/US2008/012272 administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump. Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable 5 propellant. If the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well known 10 to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, 15 CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve. In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 20 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed. Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch 25 derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the 30 preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. 35 Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions. 38 WO 2009/058300 PCT/US2008/012272 The compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, 5 camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed in Journal ofPharmaceutical Sciences, 66:1-19 (1977), incorporated herein by reference 10 in its entirety. The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention may form solvates with standard low molecular weight 15 solvents using methods known to the skilled artisan. Compounds of the present invention can be converted to "pro-drugs." The term "pro drugs" refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the invention containing one 20 or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drug" approach is utilized to facilitate oral absorption. A thorough discussion is provided in T. Higuchi and V. Stella, Pro drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and 25 Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. Some embodiments of the present invention include a method of producing a pharmaceutical composition for "combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable 30 carrier. It is noted that when the H3 histamine receptor modulators are utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other non-human mammals as well. Indeed, recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as H3 histamine receptor 35 modulators, for the treatment of a H3-associated disease or disorder in companionship animals (e.g., cats, dogs, etc.) and in livestock animals (e.g., cows, chickens, fish, etc.) Those of ordinary 39 WO 2009/058300 PCT/US2008/012272 skill in the art are readily credited with understanding the utility of such compounds in such settings. HYDRATES AND SOLVATES 5 The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate of a compound of the invention. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned 10 herein, are well known to those in the art; see for example, pages 202-209 of K.J. Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc., New York, 1999, incorporated herein by reference in its entirety. Accordingly, one aspect of the present invention pertains to hydrates and solvates of compounds of Formula (Ia), as described herein, that can be 15 isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like. OTHER UTILITIES 20 Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the H3 histamine receptor in tissue samples, including human and for identifying H3 histamine receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this invention to develop novel 113-receptor 25 assays of which comprise such radio-labeled compounds. The present invention embraces isotopically-labeled compounds of the present invention. Isotopically or radio-labeled compounds are those which are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number most 30 commonly found in nature. Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3 H (also written as T for tritium), "C, 3 C, 14C, 3 N, 15N, 150, 170, 180 'F, 35S, 3 6 C1, 7 5 Br, 76 Br, 77 Br, 82Br, 1231, 1241, 1251 and 'I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For 35 example, for in vitro H3 histamine receptor labeling and competition assays, compounds that incorporate 3H, '4C, 82 Br, 1251 1311 or 35S will generally be most useful. For radio-imaging applications "C, 8 F, 1251 I, 141 i 7s Br, 76Br or 77Br will generally be most useful. 40 WO 2009/058300 PCT/US2008/012272 It is understood that a "radio-labeled " or "labeled compound" is a compound of Formula (Ia), (Ic), (Ie), (Ig) or (Ii) that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of 3 H, ' 4 C, 121, "S and 82 Br. 5 Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. In some embodiments the radionuclide 3 H and/or 14C isotopes are useful in these studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in 10 some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are useful are discussed infra. Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most 15 commonly occurring isotope of such atoms or the scarcer radio-isotope or nonradioactive isotope. Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art. These synthetic methods, for example, incorporating activity levels of tritium into target molecules, are as 20 follows: A. Catalytic Reduction with Tritium Gas: This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors. B. Reduction with Sodium Borohydride ['H]: This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, 25 esters and the like. C. Reduction with Lithium Aluminum Hydride [ 3 H]: This procedure offers products at almost theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like. D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors 30 containing exchangeable protons to tritium gas in the presence of a suitable catalyst. E. N-Methylation using Methyl Iodide [ 3 H]: This procedure is usually employed to prepare 0-methyl or N-methyl ( 3 H) products by treating appropriate precursors with high specific activity methyl iodide ( 3 H). This method in general allows for higher specific activity, such as for example, about 70-90 Ci/mmol. 35 Synthetic methods for incorporating activity levels of 1251 into target molecules include: A. Sandmeyer and like reactions: This procedure transforms an aryl amine or a heteroaryl amine into a diazonium salt, such as a diazonium tetrafluoroborate salt and 41 WO 2009/058300 PCT/US2008/012272 subsequently to 1251 labeled compound using Na1 25 1. A represented procedure was reported by Zhu, G-D. and co-workers in J. Org. Chem., 2002, 67, 943-948. B. Ortho 12 5 lodination of phenols: This procedure allows for the incorporation of 12s1 at the ortho position of a phenol as reported by Collier, T. L. and co-workers in J. Labelled 5 Compd. Radiopharm., 1999, 42, S264-S266. C. Aryl and heteroaryl bromide exchange with 1251: This method is generally a two step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph 3

P)

4 ] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., 10 (CH 3

)

3 SnSn(CH 3

)

3 ]. A representative procedure was reported by Le Bas, M.-D. and co-workers in J. Labelled Compd. Radiopharm. 2001, 44, S280-S282. A radiolabeled H3 histamine receptor compound of Formula (Ia) can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of 15 the "radio-labeled compound of Formula (Ia)" to the H3-receptor. Accordingly, the ability of a test compound to compete with the "radio-labeled compound of Formula (Ta)" for the binding to the H3 histamine receptor directly correlates to its binding affinity. The labeled compounds of the present invention bind to the H3 histamine receptor. In one embodiment the labeled compound has an IC 50 less than about 500 pM, in another 20 embodiment the labeled compound has an IC 50 less than about 100 pM, in yet another embodiment the labeled compound has an IC 50 less than about 10 pAM, in yet another embodiment the labeled compound has an IC 50 less than about 1 ptM and in still yet another embodiment the labeled inhibitor has an IC 5 o less than about 0.1 pM. Other uses of the disclosed receptors and methods will become apparent to those in the 25 art based upon, inter alia, a review of this disclosure. As will be recognized, the steps of the methods of the present invention need not be performed any particular number of times or in any particular sequence. Additional objects, advantages and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are intended to be illustrative and 30 not intended to be limiting. EXAMPLES Example 1: Syntheses of compounds of the present invention. Illustrated syntheses for compounds of the present invention are shown in Figures 1 35 through 13 where the symbols have the same definitions as used throughout this disclosure. The compounds of the invention and their syntheses are further illustrated by the following examples. The following examples are provided to further define the invention 42 WO 2009/058300 PCT/US2008/012272 without, however, limiting the invention to the particulars of these examples. The compounds described herein, supra and infra, are named according to the CS ChemDraw Ultra Version 7.0.1, AutoNom version 2.2, or CS ChemDraw Ultra Version 9.0.7. In certain instances common names are used and it is understood that these common names would be recognized by 5 those skilled in the art. Chemistry: Proton nuclear magnetic resonance ('H NMR) spectra were recorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference. NMR abbreviations are used as follows: s = singlet, d = doublet, dd = 10 doublet of doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of doublets, dt = doublet of triplets, t = triplet, td = triplet of doublets, tt = triplet of triplets, q = quartet, m = multiplet, bs = broad singlet, bt = broad triplet. Microwave irradiations were carried out using a Smith SynthesizerTM or an Emrys Optimizer TM (Biotage). Thin-layer chromatography (TLC) was performed on silica gel 60 F 2 54 (Merck), preparatory thin-layer chromatography 15 (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressure on a BUchi rotary evaporator. LCMS spec: HPLC-pumps: LC-OAD VP, Shimadzu Inc.; HPLC system controller: SCL-1OA VP, Shimadzu Inc; UV-Detector: SPD-1OA VP, Shimadzu Inc; Autosampler: CTC 20 HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2. Example 1.1: Preparation of (R)-4-(4-Chlorophenyl)oxazolidin-2-one. To an ice cooled solution of (R)-2-amino-2-(4-chlorophenyl)acetic acid (2.262 g, 12.19 25 mmol) in THF (49 mL) was added borane (1.0 M in tetrahydrofuran, 48.7 mL, 48.7 mmol) via a dropping funnel. The reaction mixture was stirred an additional 30 min before removal of the ice-bath and let stir overnight thereafter. Methanol (25 niL) was then added via a dropping funnel. After 30 min of stirring, the solvent was removed under reduced pressure. The residue was re-suspended in dichloromethane (122 niL), diisopropylethylamine (21.29 ml, 122 mmol) 30 was added and the mixture was cooled in ice-bath. Triphosgene (3.98 g, 13.41 mmol) was then added resulting in rapid gas evolution. After 30 min, the ice bath was removed and the reaction mixture was let stir overnight. The solution was diluted with ethyl acetate (300 mL), washed twice with I M HCl, then brine, and dried with sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by chromatography on a silica column eluting with 35 40-100% ethyl acetate in hexanes to yield the title compound as a white solid (790 mg, 33%). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 4.14 (dd, J= 8.72, 6.95 Hz, I H), 4.73 (t, J= 8.72 Hz, 1 H), 4.92 - 4.98 (in, 1 H), 6.32 (s, 1 H), 7.27 - 7.30 (m, 2 H), 7.36 - 7.40 (in, 2 H). 43 WO 2009/058300 PCT/US2008/012272 Example 1.2: Preparation of (R)-4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (Compound 3). A mixture of (R)-4-(2-(2-methylpyrrolidin- 1 -yl)ethyl)phenylboronic acid (0.192 g, 5 0.825 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (0.020 g, 0.041 mmol), (R)-4-(4-chlorophenyl)oxazolidin-2-one (0.163 g, 0.825 mmol), potassium phosphate (525 mg, 2.47 mmol), and palladium (U) acetate (3.70 mg, 0.016 mmol) in tetrahydrofuran (4 mL) was placed under microwave irradiation at 120 'C for 1 h. The reaction mixture was filtered and rinsed with acetonitrile. The filtrate was concentrated under reduced pressure and 10 purified by preparative HPLC using a 25 x 250 mm C18 column, eluting with 10-75% acetonitrile in water containing 0.1% trifluoroacetic acid over 55 min. The resulting HPLC fractions were combined and acetonitrile was evaporated. The remaining aqueous solution was made basic with 2 M Na 2

CO

3 , saturated with sodium chloride and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. 15 HCI (1 M in ether, 1 mL) was added to the filtrate and the solvent was removed under reduced pressure. This material was then re-suspended in water, frozen and lyophilized to yield the hydrochloride salt of the title compound (121 mg, 38%). Exact mass calculated for C 2 2

H

2 6

N

2 0 2 : 350.5, Found: LCMS m/z = 351.3 [M+H]; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.34 (d, J = 6.57 Hz, 0.3 H), 1.51 (d, J= 6.57 Hz, 2.7 H), 1.72 - 1.84 (in, I H), 2.03 - 2.24 (in, 2 H), 2.31 20 2.42 (in, 1 H), 3.07 - 3.22 (in, 2 H), 3.25 - 3.33 (m,'2 H), 3.53 - 3.60 (in, 1 H), 3.61 - 3.71 (in, 1 H), 3.74 - 3.84 (in, 1 H), 4.19 (dd, J= 8.59, 6.57 Hz, 1 H), 4.82 (t, J= 8.72 Hz, 1 H), 5.07 (dd, J = 8.72, 6.44 Hz, 1 H), 7.42 - 7.50 (in, 4 H), 7.62 - 7.70 (in, 4 H). Example 1.3: Preparation of (R)-4-(4-Bromobenzyl)oxazolidin-2-one. 25 From (R)-2-amino-3-(4-bromophenyl)propanoic acid (2.026 g, 8.30 mmol), using a similar method to the one described in Example 1.1, the title compound was obtained as a white solid (929 mg, 44%). 'H NMR (400 MHz, CDCl 3 ) 3 ppm 2.84 (dd, J= 6.57, 2.78 Hz, 2 H), 4.02 - 4.15 (in, 2 H), 4.45 (t, J= 8.21 Hz, 1 H), 5.90 (s, 1 H), 7.04 - 7.09 (in, 2 H), 7.44 - 7.50 (in, 2 H). 30 Example 1.4: Preparation of (R)-4-((4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one (Compound 4). From (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.192 g, 0.825 mmol) and (R)-4-(4-bromobenzyl)oxazolidin-2-one (0.163 g, 0.825 mmol), using a similar 35 method to the one described in Example 1.2, the hydrochloride salt of the title compound was obtained (96 mg, 53%). Exact mass calculated for C 2 3

H

28

N

2 0 2 : 364.5, Found: LCMS m/z= 365.5 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.31 (d, J= 6.57 Hz, 0.3 H), 1.50 (d, J 44 WO 2009/058300 PCT/US2008/012272 = 6.57 Hz, 2.7 H), 1.71 - 1.83 (in, 1 H), 2.03 - 2.22 (in, 2 H), 2.32 - 2.42 (in, 1 H), 2.88 - 2.98 (in, 2 H), 3.05 - 3.20 (in, 2 H), 3.23 - 3.33 (in, 2 H), 3.50 - 3.59 (in, I H), 3.67 (d, J= 6.57 Hz, I H), 3.73 - 3.82 (in, 1 H), 4.17 - 4.26 (in, 2 H), 4.40 - 4.48 (in, 1 H), 7.36 (d, J= 8.34 Hz, 2 H), 7.43 (d, J= 8.34 Hz, 2 H), 7.62 (dd, J= 14.02, 8.21 Hz, 4 H). 5 Example 1.5: Preparation of (R)-3-Methyl-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 5). To a solution of (R)-4-(4-chlorophenyl)oxazolidin-2-one (0.155 g, 0.784 mmol) in dimethylformamide (3 mL) under argon was added sodium hydride (0.047 g, 1.177 mmol). 10 Iodomethane (0.098 ml, 1.569 mmol) was then added. The reaction mixture was stirred overnight, diluted with ethyl acetate (50 mL), washed with 1 M HCI (10 mL twice), brine, dried with sodium sulfate and concentrated to give (R)-4-(4-chlorophenyl)-3-methyl-oxazolidin-2 one. From (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.183 g, 0.784 15 mmol) and (R)-4-(4-chlorophenyl)-3-methyl-oxazolidin-2-one made above, using a similar method to the one described in Example 1.2, the hydrochloride salt of the title compound was obtained (153 mg, 49%). Exact mass calculated for C 2 3

H

28

N

2 0 2 : 364.5, Found: LCMS m/z = . 365.6 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 8 ppm 1.35 (d, J= 6.57 Hz, 0.3 H), 1.51 (d, J = 6.57 Hz, 2.7 H), 1.72 - 1.84 (in, 1 H), 2.06 - 2.23 (in, 2 H), 2.32 - 2.43 (in, 1 H), 2.73 (s, 3 H), 20 3.07 - 3.22 (in, 2 H), 3.25 - 3.32 (in, 2 H), 3.53 - 3.60 (in, 1 H), 3.61 - 3.71 (in, 1 H), 3.75 - 3.82 (in, 1 H), 4.15 (dd, J= 8.84, 7.07 Hz, 1 H), 4.73 (t, J= 8.72 Hz, 1 H), 4.90 (dd, J= 8.72, 7.20 Hz, 1 H), 7.42 - 7.49 (in, 4 H), 7.65 - 7.75 (in, 4 H). Example 1.6: Preparation of (R)-3-(2-Methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1 25 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 6). To a solution of (R)-4-(4-chlorophenyl)oxazolidin-2-one (0.157 g, 0.794 mmol) in dimethylformamide (3 mL) under argon was added sodium hydride (0.048 g, 1.192 mmol). 1 Bromo-2-methoxyethane (0.221 g, 1.589 mmol) was then added. The reaction mixture was stirred overnight, diluted with ethyl acetate (50 mL), washed with 1 M HCl (10 mL twice), 30 brine, dried with sodium sulfate and concentrated to give (R)-4-(4-chlorophenyl)-3-(2 methoxyethyl)-oxazolidin-2-one. From (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.185 g, 0.794 mmol) and (R)-4-(4-chlorophenyl)-3-(2-methoxyethyl)-oxazolidin-2-one made above, using a similar method to the one described in Example 1.2, the hydrochloride salt of the title 35 compound was obtained (116 mg, 33%). Exact mass calculated for C 25

H

3 2

N

2 0 3 : 408.5, Found: LCMS m/z = 409.4 [M+H]; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.35 (d, J= 6.57 Hz, 0.3 H), 1.51 (d, J= 6.57 Hz, 2.7 H), 1.72 - 1.85 (in, 1 H), 2.04 - 2.24 (in, 2 H), 2.32 - 2.42 (in, 1 H), 45 WO 2009/058300 PCT/US2008/012272 2.94 - 3.03 (in, 1 H), 3.06 - 3.24 (in, 2 H), 3.25 - 3.36 (in, 5 H), 3.48 (t, J= 5.31 Hz, 2 H), 3.52 3.70 (in, 3 H), 3.74 - 3.83 (in, 1 H), 4.18 (dd, J= 8.84, 6.57 Hz, 1 H), 4.74 (t, J= 8.84 Hz, 1 H), 5.11 (dd, J= 8.97, 6.69 Hz, 1 H), 7.46 (d, J= 8.08 Hz, 4 H), 7.69 (dd, 41H). 5 Example 1.7: Preparation of (R)-3-Isopropyl-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 7). To a solution of (R)-4-(4-chlorophenyl)oxazolidin-2-one (0.417 g, 2.110 mmol) in dimethylformamide (3 mL) under argon was added sodium hydride (0.048 g, 1.192 mmol) followed by 2-iodopropane (0.420 ml, 4.22 mmol). The reaction mixture was stirred overnight, 10 diluted with ethyl acetate (50 mL), washed with 1 M HCl (10 mL twice), brine, dried with sodium sulfate and concentrated to give (R)-4-(4-chlorophenyl)-3-isopropyl-oxazolidin-2-one. From (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.185 g, 0.794 mmol) and (R)-4-(4-chlorophenyl)-3-isopropyl-oxazolidin-2-one made above, using a similar method to the one described in Example 1.2, the hydrochloride salt of the title compound was 15 obtained (200 mg, 22%). Exact mass calculated for C 25

H

32

N

2 0 2 : 392.5, Found: LCMS m/z = 393.3 [M+H]f; 'H NMR (400 MHz, Methanol-d 4 ) & ppm 1.01 (d, J= 6.82 Hz, 3 H), 1.29 (d, J= 7.07 Hz, 3 H), 1.34 (d, J= 6.57 Hz, 0.3 H), 1.51 (d, J= 6.57 Hz, 2.7 H) 1.73 - 1.84 (in, 1 H), 2.04 - 2.22 (in, 2 H), 2.32 - 2.43 (in, 1 H), 3.07 - 3.23 (in, 2 H), 3.25 - 3.33 (in, 2 H), 3.51 - 3.61 (in, I H), 3.61 - 3.71 (in, 1 H), 3.74 - 3.84 (in, 2 H), 4.15 (dd, J= 8.59, 6.06 Hz, 1 H), 4.68 (t, J 20 = 8.84 Hz, 1 H), 5.04 (dd, J= 8.97, 6.19 Hz, 1 H), 7.48 (dd, J= 20.21, 8.34 Hz, 4 H), 7.69 (dd, J = 14.27, 8.21 Hz, 4 H). Example 1.8: Preparation of (R)-3-Methyl-4-((4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)methyl)oxazolidin-2-one (Compound 8). 25 From (R)-4-(4-bromobenzyl)oxazolidin-2-one (0.204 g, 0.797 mmol), iodomethane (0.099 ml, 1.593 mmol), and (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.186 g, 0.796 mmol), using a similar method to the one described in Example 1.5, the hydrochloride salt of the title compound was obtained (179 mg, 54%). Exact mass calculated for C 24

H

30

N

2 0 2 : 378.5, Found: LCMS m/z = 379.4 [M+H]*; 'H NMR (400 MHz, Methanol-d) 6 ppm 1.34 (d, J 30 = 6.32 Hz, 0.3 H), 1.51 (d, J= 6.32 Hz, 2.7 H), 1.72 - 1.84 (in, 1 H), 2.03 - 2.23 (in, 2 H), 2.31 2.43 (in, 1 H), 2.83 - 2.96 (in, 4 H), 3.08 - 3.21 (in, 3 H), 3.24 - 3.32 (in, 2 H), 3.49 - 3.69 (in, 2 H), 3.78 (d, J= 4.04 Hz, 1 H), 4.06 - 4.17 (in, 2 H), 4.24 - 4.33 (in, 1 H), 7.35 (d, J= 8.08 Hz, 2 H), 7.43 (d, J= 7.83 Hz, 2 H), 7.62 (dd, J= 11.75, 7.96 Hz, 4 H). 35 Example 1.9: Preparation of (R)-3-(2-Methoxyethyl)-4-((4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)methyl)oxazolidin-2-one (Compound 9). 46 WO 2009/058300 PCT/US2008/012272 From (R)-4-(4-bromobenzyl)oxazolidin-2-one (0.201 g, 0.785 mmol), 1-bromo-2 methoxyethane (0.148 ml, 1.570 mmol), and (R)-4-(2-(2-methylpyrrolidin-1 yl)ethyl)phenylboronic acid (0.183 g, 0.786 mmol), using a similar method to the one described in Example 1.6, the hydrochloride salt of the title compound was obtained (216 mg, 60%). 5 Exact mass calculated for C 26

H

3 4

N

2 0 3 : 422.6, Found: LCMS m/z = 423.2 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 3 ppm 1.32 (d, J= 6.57 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H) 1.71 1.82 (in, 1 H), 2.03 - 2.19 (in, 2 H), 2.29 - 2.40 (in, 1 H), 2.81 (dd, J= 13.64, 7.58 Hz, 1 H), 3.03 - 3.21 (in, 3 H), 3.22 - 3.31 (in, 2 H), 3.33 - 3.43 (in, 4 H), 3.48 - 3.79 (in, 6 H), 4.08 - 4.14 (in, 1 H), 4.21 - 4.32 (in, 2 H), 7.32 (d, J= 8.34 Hz, 2 H), 7.41 (d, J= 8.34 Hz, 2 H), 7.59 (dd, J= 10 12.88, 8.34 Hz, 4 H). Example 1.10: Preparation of (S)-3-Methyl-4-((4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)methyl)oxazolidin-2-one (Compound 11). To a solution of (S)-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 15 yl)methyl)oxazolidin-2-one hydrochloride (0.202 g, 0.504 mmol) in dimethylformamide (2 mL) under argon was first added sodium hydride (0.050 g, 1.260 mmol) followed by iodomethane (0.031 mL, 0.504 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate (20 niL), washed with 1 M HCl (2 mL twice), brine, dried with sodium sulfate and concentrated. The residue was purified by preparative HPLC using a 21.2 x 250 mm C18 column, eluting with 20 10-75% acetonitrile in water containing 0.1% trifluoroacetic acid over 55 min. The resulting HPLC fractions were combined and acetonitrile was evaporated. The remaining aqueous solution was made basic with 2 M Na 2

CO

3 , saturated with sodium chloride and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. HC (1 M in ether, 1 mL) was added to the filtrate and the solvent was 25 removed under reduced pressure. This material was then re-suspended in water, frozen and lyophilized to yield the hydrochloride salt of the title compound (65 mg, 31%). Exact mass calculated for C 2 4

H

3 oN 2 0 2 : 378.5, Found: LCMS m/z = 379.5 [M+H]*; 1 H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.32 (d, J= 6.57 Hz, 0.3 H) 1.48 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.82 (in, 1 H), 2.00 - 2.22 (in, 2 H), 2.29 - 2.40 (in, 1 H), 2.83 - 2.93 (in, 4 H), 3.04 - 3.18 (in, 3 H), 3.22 30 3.30 (in, 2 H), 3.46 - 3.58 (in, 1 H), 3.58 - 3.69 (in, I H), 3.70 - 3.80 (in, 1 H), 4.05 - 4.15 (in, 2 H), 4.24 - 4.32 (in, I H), 7.33 (d, J= 8.34 Hz, 2 H), 7.41 (d, J= 8.08 Hz, 2 H), 7.55 - 7.64 (in, 4 H). Example 1.11: Preparation of (S)-3-(2-Methoxyethyl)-4-((4'-(2-((R)-2-methylpyrrolidin-1 35 yl)ethyl)biphenyl-4-yl)methyl)oxazolidin-2-one (Compound 12). From (S)-4-((4'-(2-((R)-2-methylpyrrolidin- 1 -yl)ethyl)biphenyl-4-yl)methyl)oxazolidin 2-one hydrochloride (0.209 g, 0.521 mmol) and 1-bromo-2-methoxyethane (0.098 ml, 1.043 47 WO 2009/058300 PCT/US2008/012272 mmol), using a similar method to the one described in Example 1.10, the hydrochloride salt of the title compound was obtained (90 mg, 38%). Exact mass calculated for C 2 rH 3 4

N

2 0 3 : 422.6, Found: LCMS m/z = 423.2 [M+H]+; 'H NMR (400 MHz, Methanol-d 4 ) 5 ppm 1.32 (d, J = 6.57 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.71 - 1.82 (in, 1 H), 2.02 - 2.19 (in, 2 H), 2.29 - 2.39 5 (in, 1 H), 2.81 (dd, J= 13.64, 7.58 Hz, 1 H), 3.08 - 3.18 (in, 3 H), 3.22 - 3.31 (in, 2 H), 3.33 3.43 (in, 4 H), 3.48 - 3.80 (in, 6 H), 4.08 - 4.15 (in, 1 H), 4.21 - 4.33 (in, 2 H), 7.32 (d, J= 8.08 Hz, 2 H), 7.41 (d, J= 8.08 Hz, 2 H), 7.59 (dd, J= 12.76, 8.21 Hz, 4 H). Example 1.12: Preparation of (R)-4-(4-Bromobenzyl)-1,3-oxazinan-2-one. 10 From (R)-3-amino-4-(4-bromophenyl)butanoic acid (1.000 g, 3.87 mmol), using a similar method to the one described in Example 1.1, the title compound was obtained as a white solid (749 mg, 72%). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 1.13 (t, J = 6.82 Hz, 1 H), 1.69 - 1.82 (in, 2 H), 1.91 - 2.02 (in, I H), 3.63 - 3.75 (in, 1 H), 4.15 - 4.27 (in, 1 H), 4.30 - 4.38 (in, 1 H), 5.82 (s, 1 H), 7.07 (d, J= 8.34 Hz, 2 H), 7.46 (d, J= 8.34 Hz, 2 H). 15 Example 1.13: Preparation of (R)-4-((4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)-1,3-oxazinan-2-one (Compound 10). In a 5 mL vial was placed (R)-4-(4-bromobenzyl)-1,3-oxazinan-2-one (0.147 g, 0.544 mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (00.127 g, 0.544 mmol), 20 tetrakis (triphenylphosphine)palladium (0) (0.0 19 g, 0.016 mmol), benzene (3 mL), ethanol (1 mL), and 2 M sodium carbonate (1 mL). The reaction mixture was heated under microwave irradiation for 1 h at 100 'C. The top organic phase was separated and filtered. After removal of solvent from the filtrate, the residue was purified by preparative HPLC using a 25 x 250 mm C1 8 column, eluting with 10-75% acetonitrile in water containing 0.1% trifluoroacetic acid over 25 55 min. The resulting HPLC fractions were combined and acetonitrile was evaporated. The remaining aqueous solution was made basic with 2 M Na 2

CO

3 , saturated with sodium chloride and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. HCI (1 M in ether, 1 mL) was added to the filtrate and the solvent was removed under reduced pressure. This material was then re-suspended in water, 30 frozen and lyophilized to yield the hydrochloride salt of the title compound (17 mg, 8%). Exact mass calculated for C 24

H

3 oN 2 0 2 : 378.5, Found: LCMS m/z = 379.5 [M+H]*; 'H NMR (400 MHz, Methanol-d) 6 ppm 1.32 (d, J = 6.32 Hz, 0.3 H), 1.48 (d, J = 6.32 Hz, 2.7 H), 1.67 - 1.82 (in, 2 H), 1.87 - 1.96 (in, 1 H), 2.02 - 2.20 (in, 2 H), 2.30 - 2.40 (in, 1 H), 2.78 (dd, J= 13.26, 8.21 Hz, 1 H), 2.98 (dd, J= 13.39, 5.31 Hz, 1 H), 3.03 - 3.19 (in, 2 H), 3.23 - 3.31 (in, 2 H), 35 3.50 - 3.57 (in, 1 H), 3.58 - 3.69 (in, I H), 3.70 - 3.80 (in, 2 H), 4.16 - 4.24 (in, 1 H), 4.27 - 4.36 (in, I H), 7.33 (d, J= 7.83 Hz, 2 H), 7.41 (d, J= 8.08 Hz, 2 H), 7.60 (dd, J= 14.53, 7.96 Hz, 4 H). 48 WO 2009/058300 PCT/US2008/012272 Example 1.14: Preparation of (S)-4-(4-Bromobenzyl)-1,3-oxazinan-2-one. From (S)-3-amino-4-(4-bromophenyl)butanoic acid (1.025 g, 3.97 mmol), using a similar method to the one described in Example 1.1, the title compound was obtained as a white 5 solid (730 mg, 68%). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 1.68 - 1.82 (in, 1 H), 1.91 - 2.01 (in, 1 H), 2.78 (d, J= 6.82 Hz, 2 H), 4.15 - 4.24 (in, 1 H), 4.30 - 4.38 (in, 1 H), 5.91 (s, 1 H), 7.07 (d, J = 8.08 Hz, 2 H), 7.46 (d, J= 8.34 Hz, 2 H). Example 1.15: Preparation of (S)-4-((4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 10 yl)methyl)-1,3-oxazinan-2-one (Compound 13). From (S)-4-(4-bromobenzyl)-1,3-oxazinan-2-one (0.137 g, 0.507 mmol) and (R)-4-(2 (2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.118 g, 0.507 mmol), using a similar method to the one described in Example 1.13, the hydrochloride salt of the title compound was obtained as a white solid (125 mg, 59%). Exact mass calculated for C 24

H

30

N

2 0 2 : 378.5, Found: 15 LCMS m/z = 379.5 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 3 ppm 1.32 (d, J= 6.57 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.66 - 1.82 (m, 2 H), 1.87 - 1.96 (m, 1 H), 2.01 - 2.19 (m, 2 H), 2.29 - 2.41 (in, 1 H), 2.77 (dd, J= 13.39, 8.08 Hz, 1 H), 2.98 (dd, J= 13.39, 5.31 Hz, 1 H), 3.04 - 3.20 (in, 2 H), 3.22 - 3.31 (in, 2 H), 3.49 - 3.57 (in, 1 H), 3.58 - 3.68 (in, 1 H), 3.71 - 3.80 (in, 2 H), 4.17 - 4.24 (in, 1 H), 4.28 - 4.35 (in, 1 H), 7.32 (d, J= 8.34 Hz, 2 H), 7.41 (d, J= 8.08 Hz, 2 20 H), 7.59 (dd, J= 13.52, 8.21 Hz, 4 H). Example 1.16: Preparation of 5-(4-Bromophenyl)oxazolidin-2-one. To a slurry of 2-amino-1-(4-bromophenyl)ethanone (1.003 g, 4.69 mmol) in THF (19 mL) was added sodium borohydride (0.222 g, 5.86 mmol) followed by ethanol (10 mL). The 25 reaction slurry was stirred overnight, diluted with ethyl acetate (100 ml), washed with water, dried with sodium sulfate and concentrated. The residue was suspended in dichloromethane (9.5 mL), triethylamine (1.306 ml, 9.37 mmol) was added, the mixture was cooled in an acetone/dry ice bath and triphosgene (0.486 g, 1.639 mmol) was added. After 20 min, the ice bath was removed and the reaction was let stir 90 min. The reaction mixture was diluted with ethyl 30 acetate (50 mL), washed with 1 M HC (10 mL) and brine, dried with sodium sulfate and concentrated. The residue was purified by chromatography on a silica column eluting with 25 75% ethyl acetate in dichloromethane to afford the title compound as a white solid (579 mg, 5 1%). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 3.50 (t, J= 8.08 Hz, 1 H), 3.99 (t, J= 8.72 Hz, 1 H), 5.59 (t, J= 8.08 Hz, 1 H), 5.70 (s, 1 H), 7.27 (d, J= 3.79 Hz, 2 H), 7.52 - 7.57 (in, 2 H). 35 Example 1.17: Preparation of 5-((4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (Compound 14). 49 WO 2009/058300 PCT/US2008/012272 From 5-(4-bromophenyl)oxazolidin-2-one (0.142 g, 0.554 mmol) and (R)-4-(2-(2 methylpyrrolidin-1 -yl)ethyl)phenylboronic acid (0.129 g, 0.5 54 mmol), using a similar method to the one described in Example 1.13, the hydrochloride salt of the title compound was obtained as a white solid (149 mg, 67%). Exact mass calculated for C 2 3

H

2 8

N

2 0 2 : 350.5, Found: LCMS 5 m/z = 351.4 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.32 (d, J= 6.57 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.82 (m, 1 H), 2.02 - 2.20 (in, 2 H), 2.29 - 2.40 (in, 1 H), 3.05 - 3.19 (in, 2 H), 3.22 - 3.30 (m, 2 H), 3.48 - 3.57 (m, 2 H), 3.59 - 3.68 (in, 1 H), 3.72 - 3.80 (m, 1 H), 4.02 (t, J= 8.84 Hz, 1 H), 5.68 - 5.75 (in, 1 H), 7.42 (d, J= 8.34 Hz, 2 H), 7.49 (d, J 8.34 Hz, 2 H), 7.65 (dd, J= 14.27, 8.21 Hz, 4 H). 10 Example 1.18: Preparation of 4-(2-(tert-Butyldimethylsilyloxy)ethyl)phenylboronic acid. A solution of (4-bromophenethoxy) (tert-butyl)dimethylsilane (4.893 g, 15.52 mmol) in THF (39 mL) was cooled to -78 *C in an ice/acetone bath. To this solution n-butyllithium (2.5 M in Hexanes, 8.07 mL, 20.17 mmol) was added slowly and stirred for 90 min. Triisopropyl 15 borate (14.32 mL, 62.1 mmol) was then added and stirred an additional 2 h. The reaction was then allowed to warm to room temperature for 90 min. The resulting cloudy reaction was quenched by the addition of 1 M HCI (40 mL). The reaction mixture was then diluted with ethyl acetate (400 mL) and the aqueous layer was separated. The ethyl acetate layer was washed with brine, dried with sodium sulfate and concentrated. The residue was purified by chromatography 20 on a silica column eluting with 20-50% ethyl acetate in dichloromethane to afford the title compound as a colorless oil (2.31 g, 53%). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 0.00 (s, 6 H), 0.88 (s, 9 H), 2.87 - 2.94 (t, J= 6.95 Hz, 2 H), 3.87 (t, J= 6.95 Hz, 2 H), 7.36 (d, J= 7.83 Hz, 2 H), 8.16 (d, J= 7.83 Hz, 2 H). 25 Example 1.19: Preparation of (R)-4-(4'-(2-(tert-Butyldimethylsilyloxy)ethyl)biphenyl-4 yl)oxazolidin-2-one. A mixture of (R)-4-(4-chlorophenyl)oxazolidin-2-one (0.205 g, 1.037 mmol), 4-(2-(tert butyldimethylsilyloxy)ethyl)phenylboronic acid (0.291 g, 1.037 mmol), 2 (dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (0.025 g, 0.052 mmol), potassium 30 phosphate (0.661 g, 3.11 mmol), and palladium (II) acetate (4.66 mg, 0.021 mmol), in tetrahydrofuran (4 mL) was heated under microwave irradiation at 120 *C for 1 h. The reaction mixture was filtered and the solid was rinsed with acetonitrile. The filtrate was concentrated and the residue was purified by chromatography on a silica column eluting with 20-60% ethyl acetate in hexanes to afford the title compound as a colorless oil (134 mg, 30%). Exact mass 35 calculated for C 2 3

H

3

,NO

3 Si: 397.6, Found: LCMS m/z = 398.3 [M+H]*; 'H NMR (400 MHz, CDCl 3 ) 8 ppm 0.0 (s, 6 H), 0.88 (s, 9 H), 2.86 (t, J= 6.95 Hz, 2 H), 3.84 (t, J= 6.95 Hz, 2 H), 4.16 - 4.27 (m, 1 H), 4.75 (q, J= 8.84 Hz, 1 H), 4.92 - 5.02 (in, 1 H), 7.29 (d, J= 8.08 Hz, 2 H), 50 WO 2009/058300 PCT/US2008/012272 7.35 (d, J= 1.77 Hz, 1 H), 7.40 (d, J= 8.34 Hz, 2 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.61 (d, J= 8.34 Hz, 2 H). Example 1.20: Preparation of (R)-4-(4'-(2-Hydroxyethyl)biphenyl-4-yl)oxazolidin-2-one. 5 To a solution of (R)-4-(4'-(2-(tert-butyldimethylsilyloxy)ethyl)biphenyl-4-yl)oxazolidin 2-one (0.130 g, 0.327 mmol) in IPA (1.3 mL) was added HCI (4 M in dioxane, 1.226 mL, 4.90 mmol). The reaction mixture was stirred for 1 h. After removal of the solvent under reduced pressure, the title compound was obtained (105 mg, 100%). Exact mass calculated for C17H 17

NO

3 : 283.3, Found: LCMS m/z = 284.4 [M+H]*, TLC Rf= 0.32 in 1:1, 10 dichloromethane:ethyl acetate. Example 1.21: Preparation of (R)-2-(4'-(2-Oxooxazolidin-4-yl)biphenyl-4-yl)ethyl methanesulfonate. To a solution of (R)-4-(4'-(2-hydroxyethyl)biphenyl-4-yl)oxazolidin-2-one (0.105 g, 15 0.371 mmol) in DCM (1.5 mL) was added triethylamine (0.129 mL, 0.927 mmol) followed by methanesulfonyl chloride (0.058 ml, 0.741 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 1 M HCl (10 mL, twice), then brine, and dried with sodium sulfate. After removal of the solvent under reduced pressure, the title compound was obtained. TLC Rf = 0.51 in 1:1, dichloromethane:ethyl acetate. 20 Example 1.22: Preparation of (R)-4-(4'-(2-(Pyrrolidin-1-yl)ethyl)biphenyl-4-yl)oxazolidin 2-one (Compound 17). A mixture of (R)-2-(4'-(2-oxooxazolidin-4-yl)biphenyl-4-yl)ethyl methanesulfonate (0.04 g, 0.111 mmol), pyrrolidine (0.014 ml, 0.166 mmol) and potassium carbonate (0.076 g, 25 0.553 mmol) slurried in acetonitrile (2 mL) in a vial was heated under microwave irradiation at 120 *C for 2 h. The reaction mixture was dissolved in water and lyophilized. The residue was purified by preparative HPLC using a 21.2 x 250 mm C18 column, eluting with 5-50% acetonitrile in water containing 0.1% trifluoroacetic acid over 55 min. The HPLC fractions were lyophilized to afford the TFA salt of the title compound (7.5 mg, 15%). Exact mass calculated 30 for C 21

H

24

N

2 0 2 : 336.4, Found: LCMS m/z = 337.5 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.77 - 1.86 (m, 2 H), 1.92 - 2.02 (m, 2 H), 2.84 - 2.98 (m, 4 H), 3.24 - 3.31 (in, 2 H), 3.44 3.53 (m, 2 H), 3.97 (dd, J= 8.59, 6.57 Hz, 1 H), 4.59 (t, J= 8.72 Hz, 1 H), 4.84 (dd, J= 8.72, 6.44 Hz, 1 H), 7.22 (dd, J= 19.96, 8.34 Hz, 4 H), 7.39 - 7.48 (m, 4 H). 35 Example 1.23: Preparation of (S)-3-Methyl-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 15). Step A: Preparation of (S)-4-(4-Chlorophenyl)-3-methyloxazolidin-2-one. 51 WO 2009/058300 PCT/US2008/012272 To a solution of (S)-4-(4-chlorophenyl)oxazolidin-2-one (250 mg, 1.27 mmol) in DMF (5.0 mL) was added sodium hydride (60% dispersion in mineral oil) (76 mg, 1.90 mmol) followed by iodomethane (0.159 mL, 2.53 mmol). The resulting mixture was stirred for 18 h at room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with 1 M 5 HC (2 x 10 mL), extracted twice with EtOAc and washed with brine. The combined organics were dried over MgSO 4 , filtered, and concentrated to afford the title compound as a yellow oil in 100% crude yield. Exact mass calculated for CIOHIOC1N0 2 : 211.0, Found: LCMS m/z = 211.8 [M+H]*; 'H NMR (400 MHz, CDCl 3 ) 6 ppm, 2.71 (s, 3 H), 4.05 (dd, J= 7.83, 6.32 Hz, 1 H), 4.56 - 4.72 (in, 2 H), 7.25 (d, J= 8.59 Hz, 2 H), 7.41 (d, J= 8.34 Hz, 2 H). 10 Step B: Preparation of (S)-3-Methyl-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 15). To a vial was added (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (295 mg, 1.266 mmol), (S)-4-(4-chlorophenyl)-3-methyloxazolidin-2-one (268 mg, 1.266 mmol), 2 (dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (30 mg, 0.063 mmol), potassium 15 phosphate (806 mg, 3.80 mmol) and palladium (H) acetate (5.69 mg, 0.025 mmol) dissolved in THF (4.0 mL). The resulting reaction mixture was heated under microwave irradiation at 120 'C for 1 hr. After I hr, LCMS indicated the reaction was complete. The reaction mixture was diluted with water and the organics separated. The aqueous layer was extracted with EtOAc. The combined organics were concentrated, dissolved in ACN/H 2 0 (with AcOH) and purified by 20 HPLC (0.1% TFA in acetonitrile/0.1% TFA in water). The combined fractions were basified with 2 M Na 2

CO

3 and extracted 3 times with EtOAc. The combined organics were dried over MgSO 4 , filtered, and concentrated. The residue was dissolved in MeOH (5 m). Then, HCl (1 M in Et 2 0, 1 mL) was added followed by EtOAc (5 m). The resulting mixture was concentrated to afford the hydrochloride salt of the title compound as a white solid (408 mg, 25 55% yield). Exact mass calculated for C 2 3

H

2 8

N

2 0 2 : 364.2, Found: LCMS m/z = 365.5 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm, 1.38 (d, J= 6.32 Hz, 3 H), 1.62 - 1.76 (in, 1 H), 1.94 2.11 (m, 2 H), 2.17 - 2.32 (m,1 H), 2.65 - 2.75 (m, 3 H), 2.92 - 3.16 (in, 4 H), 3.18 - 3.35 (m, 2 H), 3.39 - 3.52 (in, 1 H), 3.53 - 3.65 (in, 1 H), 4.13 (dd, J= 8.72, 6.95 Hz, 1 H), 4.70 (t, J= 8.84 Hz, I H), 7.34 - 7.47 (in, 4 H), 7.55 - 7.76 (in, 4 H). 30 Example 1.24: Preparation of (S)-3-(2-Methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 16). Step A: Preparation of (S)-4-(4-Chlorophenyl)-3-(2-methoxyethyl)oxazolidin-2-one. To a solution of (S)-4-(4-chlorophenyl)oxazolidin-2-one (250 mg, 1.27 mmol) in DMF 35 (5.0 mL) was added sodium hydride (60% dispersion in mineral oil) (76 mg, 1.90 mmol) followed by 1-bromo-2-methoxyethane (0.235 mL, 2.53 mmol). The resulting mixture was stirred for 18 h at room temperature. The reaction mixture was diluted with EtOAc (50 mL) 52 WO 2009/058300 PCT/US2008/012272 washed with 1 M HCI (2 x 10 mL), extracted twice with EtOAc and washed with Brine. The combined organics were dried over MgSO 4 , filtered, and concentrated to give a yellow oil in 100% crude yield. Exact mass calculated for C1 2 H1 4 ClN0 3 : 255.1, Found: LCMS m/z = 256.5 [M+H]; 'H NMR (400 MIHz, CDCl 3 ) 8 ppm, 2.84 - 2.98 (in, 1 H), 3.29 (s, 3 H), 3.36 - 3.45 (in, 5 1 H), 3.49 - 3.67 (in, 2 H), 4.07 (dd, J= 8.84, 6.57 Hz, 1 H), 4.63 (t, J= 8.84 Hz, 1 H), 4.97 (dd, J= 8.84, 6.82 Hz, 1 H), 7.25 (d, J= 8.34 Hz, 2 H), 7.39 (d, J= 8.34 Hz, 2 H). Step B: Preparation of (S)-3-(2-Methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 16). To a vial was added (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (294 10 mg, 1.263 mmol), (S)-4-(4-chlorophenyl)-3-(2-methoxyethyl)oxazolidin-2-one (323 mg, 1.263 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (30 mg, 0.063 mmol), potassium phosphate (804 mg, 3.79 mmol), palladium (H) acetate (5.67 mg, 0.025 mmol) and THF (4.0 mL). The resulting reaction mixture was heated at 120 'C under microwave irradiation for 1 h. The reaction mixture was diluted with water and the organics separated. The aqueous 15 layer was extracted with EtOAc. The combined organics were concentrated, dissolved in

ACN/H

2 0 (with AcOH) and purified by HPLC (0.1% TFA in acetonitrile/0.1% TFA in water). The combined fractions were basified with 2 M Na 2

CO

3 and extracted 3 times with EtOAc. The combined organics were dried over MgSO 4 , filtered, and concentrated. The residue was dissolved in MeOH (5 mL). Then, HC (1 M in Et 2 0, 1 mL) was added followed by EtOAc (5 20 mL). The resulting mixture was concentrated to afford the hydrochloride salt of the title compound as a white solid (281 mg, 50% yield). Exact mass calculated for C 2 5

H

3 2

N

2 0 3 : 408.2, Found: LCMS m/z = 409.4 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) a ppm 1.33 (d, J= 6.32 Hz, 3 H), 1.56 - 1.72 (m, 1 H), 1.89 - 2.04 (m, 2 H), 2.11 - 2.27 (m, 1 H), 2.81 - 3.14 (m, 6 H), 3.27 - 3.43 (in, 4 H), 3.45 (t, J= 5.31 Hz, 2 H), 3.47 - 3.63 (in, 2 H), 4.16 (dd, J= 8.72, 6.69 Hz, 25 1 H), 4.71 (t, J= 8.84 Hz, I H), 5.08 (dd, J= 8.84, 6.57 Hz, 1 H), 7.40 (dd, J= 16.04, 8.21 Hz, 4 H), 7.61 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.34 Hz, 2 H). Example 1.25: Preparation of (S)-4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (Compound 2). 30 Step A: Preparation of (S)-2-Amino-2-(4-chlorophenyl)ethanol. To a solution of (S)-2-amino-2-(4-chlorophenyl)acetic acid (10.0 g, 53.9 mmol) in THF (216 mL) was added 1.0 M borane tetrahydrofuran complex (216 mL, 216 mmol) via addition funnel over 45 min at 0 *C. The ice-bath was removed and the reaction mixture was stirred for 3.25 h at room temperature. Water (6.79 mL, 377 mmol) was added followed by sodium 35 hydroxide solution (40.4 mL, 202 mmol) (dropwise over 15 min). The reaction was heated to 65 *C and stirred for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and the organic phase was separated and washed with 53 WO 2009/058300 PCT/US2008/012272 water (200 mL). The aqueous phase was further extracted with DCM (2 x 250 mL). The organics were combined, dried over Na 2

SO

4 , and concentrated under reduced pressure to afford the title compound as a white solid (8.55 g, 92% yield). Exact mass calculated for C 8 HioClNO: 171.1, Found: LCMS m/z (%) = 172.2 ([M+H]*, 3 5 Cl, 100), 174.2 ([M+H]*, 37 CI, 33). 'H NMR 5 (400 MHz, Methanol-d 4 ) 6 ppm 3.47 - 3.57 (in, 1 H), 3.59 - 3.69 (in, 1 H), 3.93 (dd, J= 7.58, 5.05 Hz, 1 H), 7.23 - 7.42 (in, 4 H). Step B: Preparation of (S)-4-(4-Chlorophenyl)oxazolidin-2-one. To a solution of (S)-2-amino-2-(4-chlorophenyl)ethanol hydrochloride (2.00 g, 9.61 mmol) and diisopropylethylamine (6.71 mL, 38.4 mmol) in DCM (40 mL) was added 10 triphosgene (3.14 g, 10.6 mmol) at 25 *C resulting in an evolution of a large volume of gas. The mixture was stirred for 18 h and concentrated under reduced pressure. The solid residue was dissolved in 5% HCI (50 mL) solution and extracted with EtOAc (2 x 75 mL). The organic phase was washed with brine (60 mL), dried over Na 2

SO

4 , filtered and concentrated under reduce pressure. The crude residue was purified by flash chromatography (40-100% 15 EtOAc/Hexane) to give the title compound as a clear oil (0.400 g, 21% yield). Exact mass calculated for C 9 HsCINO 2 : 197.0, Found: LCMS m/z = 198.1; 'H NMR (400 MHz, CDCl 3 ) 5 ppm 4.13 (dd, J= 8.59, 6.82 Hz, 1 H), 4.72 (t, J= 8.72 Hz, 1 H), 4.91 - 4.97 (in, 1 H), 6.44 (s, I H), 7.27 (d, J= 8.34 Hz, 2 H), 7.37 (d, J= 8.59 Hz, 2 H). Step C: Preparation of (S)-4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 20 yl)oxazolidin-2-one (Compound 2). To a solution of (S)-4-(4-chlorophenyl)oxazolidin-2-one (0.150 g, 0.759 mmol), (R)-4 (2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.212 g, 0.911 mmol), potassium acetate (0.483 mL, 2.28 imol), and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (18.1 mg, 0.038 mmol) in anhydrous THF (4 mL) was added palladium (II) acetate (3.41 mg, 0.015 25 mmol). The reaction was heated at 120 *C under microwave irradiation for 45 min. The reaction mixture was filtered through CeliteTM and the filter cake was washed with EtOAc (30 mL). The filtrate was concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the trifluoroacetic acid salt of the title compound (0.100 g, 29% yield). The trifluoroacetic acid salt was converted to the hydrochloride salt, which was a 30 white solid. Exact mass calculated for C 22

H

2 6

N

2 0 2 : 350.2, Found: LCMS m/z = 351.3 [M+H]*; 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 1.23 (s, 0.3 H), 1.40 (d, J= 5.31 Hz, 2.7 H), 1.54 - 1.70 (in, 1 H), 1.87 - 2.04 (in, 2 H), 2.11 - 2.27 (bs, I H), 2.96 - 3.23 (in, 4 H), 3.27 - 3.71 (in, 2 H), 4.04 (dd, J= 8.34, 6.32 Hz, 1 H), 4.70 (t, J= 8.59 Hz, 1 H), 4.96 - 5.03 (in, 1 H), 7.42 (t, J= 7.58 Hz, 4 H), 7.68 (dd, J= 17.31, 8.21 Hz, 4 H), 8.22 (s, I H), 10.15 (s, 1 H). 35 Example 1.26: Preparation of (S)-4-((4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one (Compound 1). 54 WO 2009/058300 PCT/US2008/012272 Step A: Preparation of (S)-2-Amino-3-(4-bromophenyl)propan-1-ol. The title compound was prepared in a similar manner as described in Example 1.25, Step A. Exact mass calculated for C 9 H1 2 BrNO: 229.0, Found: LCMS m/z (%) = 230.2; 'H NMR (400 MHz, CDCl 3 ) 3 ppm 2.84 (d, J= 6.82 Hz, 3 H), 4.04 - 4.15 (in, 2 H), 4.46 (t, J= 8.21 Hz, 1 5 H), 5.62 (s, 1 H), 7.07 (d, J= 8.34 Hz, 2 H), 7.45 - 7.50 (m, 2 H). Step B: Preparation of (S)-4-(4-Bromobenzyl)oxazolidin-2-one. The title compound was prepared in a similar manner as described in Example 1.25, Step B. Exact mass calculated for CioHiBrNO 2 : 255.0, Found: LCMS m/z (%) = 256.2 [M+H]*; 'H NMR (400 MHz, CDC1 3 ) 6 ppm 2.75 - 2.92 (in, 2 H), 4.00 - 4.19 (in, 2 H), 4.43 (t, J= 8.21 10 Hz, 1 H), 5.94 - 6.07 (in, 1 H), 7.06 (d, J= 8.34 Hz, 2 H), 7.46 (d, J= 8.34 Hz, 2 H). Step C: Preparation of (S)-4-((4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one (Compound 1). To a solution of (S)-4-(4-bromobenzyl)oxazolidin-2-one (0.150 g, 0.586 mmol), (R)-4 (2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (0.137 g, 0.586 mmol), and 2.0 M 15 aqueous sodium carbonate (0.5 86 mL, 1.17 mmol) solution in a mixture of ethanol/benzene (4 mL, 1:3 EtOH:benzene) was added tetrakis (triphenylphosphine)palladium (0) (20.3 mg, 0.018 mmol). The reaction was heated at 100 'C under microwave irradiation for 1 h. The organic phase was separated and the aqueous phase was extracted with EtOAc (25 mL). The combined organics were concentrated under reduced pressure. The residue was purified by preparative 20 HPLC. The combined pure fractions were lyophilized to give the trifluoroacetic acid salt of the title compound (0.152 g, 56% yield). Exact mass calculated for C 23

H

2 8

N

2 0 2 : 364.2, Found: LCMS m/z = 365.2 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.34 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.57 Hz, 2.7 H), 1.72 - 1.85 (in, 1 H), 2.01 - 2.22 (in, 2 H), 2.31 - 2.43 (m, 1 H), 2.87 - 2.99 (in, 2 H), 3.05 - 3.22 (m, 2 H), 3.24 - 3.31 (in, 2 H), 3.50 - 3.60 (in, 1 H), 3.60 - 3.71 25 (m, 1 H), 3.73 - 3.82 (in, 1 H), 4.15 - 4.26 (m, 2 H), 4.44 (s, 1 H), 7.35 (d, J= 8.08 Hz, 2 H), 7.43 (d, J= 8.08 Hz, 2 H), 7.62 (dd, J= 13.26, 8.21 Hz, 4 H). Example 1.27: Preparation of (R)-4-(4'-(2-(R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one Hydrochloride Salt (Compound 3). 30 Step A: Preparation of (R)-Methyl 2-(tert-Butoxycarbonylamino)-2-(4 hydroxyphenyl)acetate. To a suspension of (R)-(4-hydroxy)phenylglycine (83.58 g, 500.0 mmol) in methanol (500 mL), cooled in an ice bath, was added dropwise thionyl chloride (36.5 mL, 500 mmol). The reaction mixture was stirred at reflux for 18 h, and then cooled to room temperature. NN 35 diisopropylethylamine (87 mL, 500 mmol) was then added, followed by a solution of di-tert butyl dicarbonate (109 g, 500 mmol) in methanol (200 mL), added dropwise over 1 h. A mild exotherm resulted, which was controlled by gradual addition, and the reaction temperature was 55 WO 2009/058300 PCT/US2008/012272 maintained below reflux at all times. After stirring for 2 h, the reaction appeared to be incomplete by LCMS, with the formation of about 5% of the free acid of the product. The pH of the reaction mixture (initially 10) had dropped to 4. Additional NN-diisopropylethylamine was added until the pH was 9-10. Additional di-tert-butyl dicarbonate (3.2 g, 15 mmol) in methanol 5 (10 mL) was added, and stirring was continued for one additional hour. The solvent was then reduced to half the original volume, and the resulting solution was poured into water (1.2 L), forming a white precipitate. After swirling manually and allowing the resulting suspension to stand for 1 h, a white solid was collected by filtration. This material was then dissolved in hot isopropanol (200 mL, 60 *C), and then cooled to 10 *C in an ice bath, seeding the solution with 10 a small amount of pure product. Upon standing for 1 h with occasional agitation, a white solid was collected by filtration, rinsing with cold isopropanol (50 mL). The filtrate was concentrated to about 100 mL, chilled in an ice bath, and then filtered to furnish a second crop. The combined solids were dried to constant weight in a vacuum oven at 60 'C to afford the title compound as a white solid (119.6 g, 85%). Exact mass calculated for C1 4 HIN0 5 : 281.3; found: LCMS m/z = 15 282.5 [M+H]*. 'H NMR (400 MHz, DMSO-d 6 ) 6 1.38 (s, 9 H), 3.59 (s, 3 H), 5.06 (d, J= 7.84 Hz, 1 H), 6.71 (d, J= 8.43 Hz, 2 H), 7.82 (d, J= 8.48 Hz, 2 H), 7.61 (d, J= 7.82 Hz, 1 H), 9.49 (s, 1 H). Step B: Preparation of (R)-tert-Butyl 2-Hydroxy-1-(4 hydroxyphenyl)ethylcarbamate. 20 A solution of (R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate (56.3 g, 200.0 mmol) in anhydrous THF (2.0 L) was cooled to 5 *C in an ice bath. Lithium aluminum hydride (23.6 g, 620 mmol) was added slowly over 1 h, maintaining an internal reaction temperature of less than 25 'C. Stirring was continued for 1 h, and then the reaction was carefully quenched with 1 N NH 4 Cl (150 mL) over 45 min, maintaining a temperature less than 25 30 *C, followed by 0.3 N HCI (400 mL). The resulting suspension was then filtered through CeliteTm and rinsed with ethyl acetate (2.0 L). 1 N HC (250 mL) was added to the filtrate in order to acidify the aqueous layer to pH 1. The aqueous extract was discarded, and the organic extract was rinsed with water (400 mL), brine (200 mL), and dried over MgSO 4 . Solvent removal, followed by drying in a vacuum oven at 60 *C gave a white solid (46.2 g, 9 1%). Exact 30 mass calculated for C1 3

H

19

NO

4 : 253.2; found: LCMS m/z = 254.3 [M+H]*; 'H NMR (400 MHz DMSO-d 6 ) 6 1.36 (s, 9 H), 3.42 (t, J= 5.88 Hz, 2 H), 4.41 (in, 1 H), 4.69 (t, J= 5.70 Hz, 1 H), 6.67 (d, J= 8.36 Hz, 2 H), 7.06 (in, 3 H), 9.22 (s, 1 H). Step C: Preparation of (R)-4-(4-Hydroxyphenyl)oxazolidin-2-one. A solution of (R)-tert-butyl 2-hydroxy-1 -(4-hydroxyphenyl)ethylcarbamate (35 g, 138 35 mmol) in THF (420 mL) was cooled to 1.2 *C (internal; ice bath). Thionyl chloride (11.09 mL, 152 mmol) was added slowly with cooling and there was a mild exotherm to 3.0 *C. After the addition the mixture was cooled to 0.5 *C, held at that temperature for 10-12 min, gradually 56 WO 2009/058300 PCT/US2008/012272 warmed up to room temperature and stirred overnight. The reaction mixture was concentrated to approximately 35 mL by distillation under reduced pressure (385 mL collected). The residual slurry was stirred in room temperature and MTBE (40 mL) was added. The product started to crystallize out. The slurry was stirred for 15 min and filtered. The filter cake was washed twice 5 with MTBE. The solid was dried in a vacuum oven at 50 *C to afford the title compound (15.05 g, 60.8%). Exact mass calculated for C 9

H

9

NO

3 , 179.06; found: LCMS m/z = 180.2 [M+H]*. 'H NMR (400 MHz, DMSO-d 6 ) 8 3.93 (dd, J, = 8 Hz, J 2 = 12 Hz, 1 H), 4.59 (t, J= 8 Hz, 1 H), 4.81 (t, J= 8 Hz, 1 H), 6.76 (d, J= 8.8 Hz, 2 H), 7.12 (d, J= 8.4 Hz, 2 H), 8.05 (s, 1 H), 9.48 (s, 1 H). 10 Step D: Preparation of (R)-4-(2-Oxooxazolidin-4-yl)phenyl Trifluoromethanesulfonate. To a slurry of (R)-4-(4-hydroxyphenyl)oxazolidin-2-one (15.05 g, 84 mmol) in acetonitrile (180 mL) was added pyridine (20.38 mL, 252 mmol). The mixture was stirred under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (17.03 mL, 101 mmol) was added 15 slowly maintaining the reaction temperature at 17 to 20 *C (ice bath). The reaction mixture was stirred at 16 to 20 *C for 30 min, followed by 1.5 h at room temperature. The solvent was removed under reduced pressure. Water (150 mL) was added and the mixture was stirred for 30 min. The solid precipitate was collected by filtration, washed twice with water and dried in air under reduced pressure to obtain a solid cake (29.26 g). The above solid was dissolved in warm 20 EtOH (125 mL) at 25 *C, water (80 mL) was added slowly and the mixture was stirred well, maintaining the internal temperature at 17 to 18 'C. The mixture was stirred overnight at 17-19 'C. The solid precipitate was collected by filtration, washed twice with 1:1 EtOH/H 2 0 and dried overnight in a vacuum oven at 50 *C to give the first crop of the title compound (18.7 g). The mother liquor was diluted with more water and a second crop of solids was isolated by filtration 25 and dried to give the title compound (2.77 g). Exact mass for CoH 8

F

3

NO

5 S: 311.01; found: LCMS m/z = 312.3 [M+H]*. 'H NMR (400 MHz, DMSO-d) 4.02 (dd, Ji = 8 Hz, J 2 = 8 Hz, 1 H), 4.68 (t, J= 8 Hz, 1 H), 5.01 (dd, J = 12 Hz, J 2 = 8Hz, 1 H), 7.55 (s, 4 H), 8.28 (s, 1 H). Step E: Preparation of (R)-1-(4-Bromophenethyl)-2-methylpyrrolidine. To a solution of 4-bromophenethyl methanesulfonate (120 g, 0.43 mol) in acetonitrile 30 (1.2 L) was added (R)-2-methylpyrrolidine tartrate (121 g, 0.516 mol) followed by potassium carbonate (184 g, 1.33 mol). The mixture was heated to 60 *C, water (60 mL) was added and the mixture was stirred under nitrogen overnight. The mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. The residue was taken up in EtOAc (400 mL) and the ethyl acetate layer was washed with water (2 x 150 mL). The organic 35 layer was extracted with.2 N HC (2 x 150 mL). The aqueous acid layer was basified with 50% aq. NaOH to pH 12-14 and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water (2 x 100 mL), dried over MgSO 4 and concentrated to give the 57 WO 2009/058300 PCT/US2008/012272 title compound (104.4g, 90% yield). Exact mass calculated for C1 3 Hi 8 BrN, 267.06; found: LCMS m/z = 268.2. 'H NMR (400 MHz, CDCl 3 ) 6 1.09 (d, J= 6 Hz, 3 H), 1.38-1.48 (in, 1 H), 1.66-1.96 (in, 3 H), 2.14-2.34 (in, 3 H), 2.7-2.83 (in, 2 H), 2.97 (in, 1 H), 3.22 (in, 1 H), 7.09 (d, J= 6.4Hz, 2 H), 7.39 (d, J= 6.4Hz, 2 H). 5 Step F: Preparation of (R)-4-(2-(2-Methylpyrrolidin-1-yl)ethyl)phenylboronic Acid Hydrochloride Salt. A solution of (R)- 1 -(4-bromophenethyl)-2-methylpyrrolidine (30.0 g, 112 mmol) in anhydrous THF (300 mL) was purged with argon and cooled in a dry ice/acetone bath at -78 *C. n-Butyllithium (91 mL, 145 mmol) was added dropwise to maintain the reaction temperature at 10 -72 "C to -68 *C. Additional anhydrous THF (50 mL) was used to rinse the funnel. After addition of butyllithium was completed, the mixture was stirred for 15 min. Triisopropyl borate (104 mL, 447 mmol) was added at -72 *C to -66 *C. Additional THF (50 mL) was again used to rinse the funnel. After addition of triisopropyl borate was completed, the reaction mixture was gradually brought to room temperature (over 20 min) and stirred at the room temperature for 1 15 h. HCl (2 M, 130 mL) was added dropwise until an off-white suspension formed and the mixture was acidic. The mixture was stirred overnight. The white solid crystals were filtered,. washed with THF (150 mL), and dried under reduced pressure to give the HCl salt of the title compound (26.538 g, 88%); Exact mass calculated for C1 3

H

2 0

BNO

2 233.1; found, LCMS m/z = 234.3 [M+H]*. 20 Step G: Preparation of (R)-4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one. (R)-4-(2-Oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate (8.25 g, 26.5 mmol) was transferred to a 500 mL 3-necked round-bottomed flask fitted with a temperature probe, condenser and nitrogen inlet. (R)-4-(2-(2-methylpyrrolidin-1 -yl)ethyl)phenylboronic acid 25 hydrochloride (7.86 g, 29.2 mmol) was added, followed by toluene (100 mL). The mixture was stirred and a solution of sodium carbonate (8.99 g, 85 mmol) in water (33.0 mL) was added at 21 'C (there was an exotherm to 33 C). The mixture was stirred under nitrogen and heated up to 40 *C. Pd(PPh 3

)

4 (0.919 g, 0.795 mmol) was added (at approximately 40 *C) and the reaction mixture was heated to 90 *C till a mild refluxing was observed. The mixture was stirred for 80 30 min. The mixture was cooled to room temperature and stirred overnight. The solid precipitate was filtered, washed with water several times and dried in a vacuum oven at 50 *C for 3 h to afford the title compound (9.11 g, 98%) as a free base. Exact mass calculated for C 22

H

2 6

N

2 0 2 , 350.2; found: LCMS m/z = 351.2 [M+H]*. 'H NMR (400 MHz, DMSO-d)) 6 1.0 (d, J = 6 Hz, 3 H), 1.28 (in, 1 H), 1.63 (in, 2 H), 1.85 (m, 1 H), 2.11 (q, J, =17.6 Hz, J 2 = 8.8 Hz, 1 H), 2.24 (in, 35 2 H), 2.67-2.83 (in, 2 H), 2.97 (in, 1 H), 3.13 (in, 1 H), 4.04 (dd, J, = 8.4 Hz, J 2 = 8.4 Hz, 1 H), 4.69 (t, J= 8.4 Hz, 1 H), 4.98 (t, J= 8 Hz, 1 H), 7.32 (d, J= 8 Hz, 2 H), 7.41 (d, J= 8 Hz, 2 H), 7.57 (d, J= 8 Hz, 2 H), 7.68 (d, J= 8 Hz, 2 H), 8.22 (s, 1 H). 58 WO 2009/058300 PCT/US2008/012272 Step H: Preparation of (R)-4-(4'-(2-(R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one Hydrochloride Salt. The freebase of (R)-4-(4'-(2-(R)-2-methylpyrrolidin- 1 -yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (9.11 g, 26.0 mmol) was transferred to a 250 mL 3-necked round-bottomed 5 flask fitted with a temperature probe, an addition funnel and nitrogen inlet. Ethanol (91 mL) was added, the slurry was warmed to 40 *C and a clear solution was obtained. It was further heated to 45 *C and hydrochloric acid (1.25 M in EtOH; 42.4 mL, 53.0 mmol) was added dropwise. The HC salt started to crystallize out when approximately 85% of the HCI solution has been added. After addition was completed, the slurry was stirred for 5 min at 47-48 *C, gradually 10 cooled to room temperature and stirred overnight. The volume of the mixture was reduced to approximately 58 mL by distilling off EtOH under reduced pressure and the residue became a paste. EtOH (10 mL) was added to make it a slurry, which was filtered. The solid cake was washed with EtOH (10 mL), MTBE, and dried in a vacuum oven at 50 *C for 3 h. The above solid (8.47 g) was recrystallized from EtOH (160 mL) to give the title compound (7.68 g, 80% 15 yield). Exact mass calculated for C 22

H

26

N

2 0 2 : 350.2 (free base); found: LCMS m/z = 351.2 [M+H]*. 'H NMR (400 MHz, DMSO-d 6 ) 6 1.42 (d, J= 6.4 Hz, 3 H), 1.64 (in, 1 H), 1.95 (m, 2 H), 2.18 (in, 1 H), 3.13 (in, 4 H), 3.35-3.52 (in, 2 H), 3.62 (in, 1 H), 4.04 (dd, J = 8.4 Hz, J2 = 8.4 Hz, 1 H), 4.69 (t, J= 8.4 Hz, 1 H), 4.98 (t, J = 8 Hz, 1 H), 7.41 (dd, J, = 6.8 Hz, J2 = 6.8 Hz, 4 H), 7.65 (d, J= 8 Hz, 2 H), 7.69 (d, J= 8.4 Hz, 2 H), 8.25 (s, 1 H), 10.67 (bs, 1 H). 20 Example 1.28: Preparation of (R)-3-(2-Methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one Hydrochloride (Compound 6). Step A: Preparation of (R)-3-(2-Methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. 25 To a slurry of sodium hydride (0.279 g, 11.63 mmol) (465 mg, 60% dispersion in mineral oil) in DMF (15 mL) was added (R)-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one hydrochloride (1.5 g, 3.88 mmol) under N 2 , with efficient stirring followed by 1 -bromo-2-methoxyethane (0.437 mL, 4.65 mmol). The reaction mixture was stirred for 5 h at room temperature. LCMS analysis showed 51.8% product (m/z 30 409.4; [M+H]*) formation and 48.2% of starting material remained. 1 -Bromo-2 methoxypropane (128 pL) was added and the reaction was stirred overnight at room temperature. LCMS analysis showed 92.6% product formed. The mixture was diluted with water (35 mL) and extracted with ethyl acetate (2 x 30 mL). The ethyl acetate layer was extracted with 2 N aqueous HCl (2 x 25 mL). The aqueous phases were combined and washed 35 with ethyl acetate (1 x 25 mL) followed by heptane (1 x 25 mE). The aqueous phase was cooled (ice water bath) and basified to pH 12-14 by slow addition of 50% aqueous NaOH solution and extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water 59 WO 2009/058300 PCT/US2008/012272 (2 x 25 mL), dried (Na 2

SO

4 ) and the solvent was removed under reduced pressure to obtain a brown oil. Step B: Preparation of (R)-3-(2-methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one Hydrochloride Salt. 5 The product of Example 1.28, Step A was dissolved in ethanol (1.5 mL) and the solution was stirred well. Hydrochloric acid (6.20 mL, 7.75 mmol) (1.25 M in ethanol) was added and the mixture was stirred overnight. MTBE was added and the mixture was left at -4 *C for two days. Solvents were removed under reduced pressure and the residue was dried overnight under reduced pressure to obtain the HC salt as a foamy solid (1.02 g, 59%). Exact 10 mass calculated for C 2 5

H

32

N

2 0 3 (free base), 408.53; found, 409.5 [M+H]*; 'H NMR (Bruker, 400 MHz, DMSO-d 6 ) 6 1.43 (d, 3 H, J= 6.4 Hz), 1.95 (in, 2 H), 1.64 (m, 1 H), 2.17 (m, 1 H), 2.80 (m, 1 H), 3.12 (m, 4 H), 3.19 (s, 3 H), 3.36 (m, 3 H), 3.50 (in, 2 H), 3.62 (in, 1 H), 4.05 (dd, J, = 6.8 Hz, J2 = 6.8 Hz, 1 H), 4.65 (t, J= 8.8 Hz, 1 H), 5.02 (t, J= 8 Hz, 1 H), 7.41 (dd, J, = 8Hz, J2 = 8 Hz, 4 H), 7.66 (d, J= 8 Hz, 2 H), 7.72 (d, J = 8 Hz, 2 H), 10.85 (bs, 1 H). 15 Example 1.29: Preparation of (R)-3-Isopropyl-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one Hydrochloride (Compound 7). Step A: Preparation of (R)-3-Isopropyl-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. 20 To a slurry of sodium hydride (0.279 g, 11.63 mmol) (465 mg, 60% dispersion in mineral oil) in DMIF (15 mL) was added (R)-4-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one hydrochloride (1.5 g, 3.88 mmol) under N 2 and the mixture was stirred well. 2-Iodopropane (0.465 mL, 4.65 mmol) was added and the mixture was stirred at room temperature for 4 h. LCMS analysis showed -18% of product. The reaction 25 mixture was heated to 55 *C and stirred overnight. LCMS analysis showed -60.5% product and -39.5% starting material remained. Sodium hydride (0.186 g, 60% dispersion) was added followed by 2-iodopropane (0.155 mL) and the reaction was stirred at 55 *C for 2 h. More NaH (0.186 g, 60% dispersion) and 2-iodopropane (0.155 mL) was added after 2 h. Another batch of NaH (0.186 g, 60% dispersion) and 2-iodopropane (0.155 mL) was added and the mixture was 30 allowed to stir overnight. LCMS analysis showed 79.4% product and -20% starting material. The final portions of NaH (0.186 g, 60% dispersion) and 2-iodopropane (0.155 mL) were added and the reaction mixture was stirred overnight. LCMS analysis showed -95% product. The reaction mixture was cooled to room temperature and diluted with water (35 mL). The aqueous mixture was extracted with ethyl acetate (2 x 30 mL). The ethyl acetate layer was extracted with 35 2 N aqueous HC1 (2 x 25 mL). The HC phase was washed with ethyl acetate (1 x 25 mL) followed by heptane (1 x 25 mL). The aqueous phase was cooled (ice bath) and slowly basified with 50% aqueous NaOH and extracted with ethyl acetate (2 x 25 mL). The ethyl acetate layer 60 WO 2009/058300 PCT/US2008/012272 was washed with water (2 x 25 mL), dried (Na 2

SO

4 ) and the solvent was removed under reduced pressure to obtain the product (free base) as a waxy solid, 1.02 g. Exact mass for C 25

H

32

N

2 0 2 , 392.53; found 393.3 [M+H]*; 'H NMR (Bruker, 400 MHz, DMSO-d 6 ) 3 0.89 (d, J= 8 Hz, 3 H), 1.0 (d, J= 6.4 Hz, 3 H), 1.18 (d, J= 6.8 Hz, 3 H), 1.28 (in, 1 H), 1.62 (in, 2 H), 1.84 (in, 1 H), 5 2.11 (q, J= 8.8 Hz, 1 H), 2.24 (in, 2 H), 2.83-2.69 (in, 2 H), 2.97 (in, 1 H), 3.13 (in, I H), 3.62 (in, 1 H), 4.02 (dd, J = 6.4Hz, J 2 = 6.4 Hz, 1 H), 4.59 (t, J, = 8.8 Hz, 1 H), 4.99 (dd, J1 = 6.4Hz, J2= 6.4Hz, 1 H), 7.32 (d, J= 8 Hz), 7.47 (d, 2 H, J= 8.4 Hz), 7.59 (d, 2 H, J= 8 Hz), 7.69 (d, 2 H, J= 8 Hz). Step B: Preparation of (R)-3-Isopropyl-4-(4'-(2-((R)-2-methylpyrrolidin-1 10 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one Hydrochloride. The free base of Example 1.29, Step A was dissolved in ethanol (1.5 mL) and HCI (1.25 M in ethanol; 4.15 mL; 2 eq.) was added slowly with stirring. MTBE was added until the solution was cloudy. The mixture was stirred overnight at room temperature. The solvents were removed under reduced pressure and the residue was dried under reduced pressure, to obtain the 15 HC salt as a foamy solid (1.09 g 65.5%, 95.5% purity by LCMS). 'H NMR (Bruker, 400 MHz, DMSO-d 6 ) 3 0.89 (d, J= 6.8 Hz, 3 H), 1.18 (d, J= 6.8 Hz, 3 H), 1.42 (d, J= 6.4 Hz, 3 H), 1.62 (in, 1 H), 1.95 (in, 2 H), 2.19 (in, 1 H), 3.19-3.05 (in, 5 H), 3.50 (in, 1 H), 3.63 (in, 2 H), 4.01 (dd, J = 6.4 Hz, J 2 = 6.4 Hz, 1 H), 4.59 (t, J= 8.8 Hz, 1 H), 5.0 (dd, J = 6.4 Hz, J 2 = 6.4 Hz, 1 H), 7.41 (d, J= 8 Hz, 2 H), 7.48 (d, J= 8 Hz, 2 H), 7.67 (d, J= 8 Hz, 2 H), 7.71 (d, J= 8 Hz, 2 20 H), 10.50 (bs, 1 H). Example 1.30: Preparation of (R)-4-(2-Methyl-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 19). Step A: Preparation of 2-Benzamido-2-(4-hydroxy-3-methylphenyl)acetic Acid. 25 To a suspension of a-hydroxyhippuric acid (4.0 g, 21 mmol) in concentrated sulfuric acid (2 mL) and glacial acetic acid (18 mL) at 0 'C was added o-cresol (5.5 g, 51 mmol). The cold bath was allowed to expire while stirring continued overnight. The reaction was quenched by pouring into a beaker containing ice and NaHCO 3 (40 g). The reaction was extracted with EtOAc (thrice), and the aqueous phase was acidified with concentrated HCI to pH 2. A 30 precipitate formed was collected, washed with water, and then dried under reduced pressure to give the title compound as a pale peach-colored powder (2.9 g, 50%). Exact mass calculated for Cr, 6

H

5 N0 4 : 285.1, found: LCMS m/z = 286.3 [M+H]*. Step B: Preparation of 2-Amino-2-(4-hydroxy-3-methylphenyl)acetic Acid. A solution of 2-benzamido-2-(4-hydroxy-3-methylphenyl)acetic acid (1.0 g, 3.5 mmol) 35 in 10% aqueous HCI (10 mL) was heated at reflux for 1 week. After cooling to room temperature, the mixture was washed once with MTBE and then the aqueous phase was concentrated to give a brown solid residue. The residue was diluted with acetonitrile and water, 61 WO 2009/058300 PCT/US2008/012272 frozen, and lyophilized to give the hydrochloride salt of the title compound (0.67 g, 88%). Exact mass calculated for CGH N0 3 : 181.1, found: LCMS m/z = 182.2 [M+H]. Step C: Preparation of Methyl 2-(tert-Butoxycarbonylamino)-2-(4-hydroxy-3 methylphenyl)acetate. 5 A stirring suspension of 2-amino-2-(4-hydroxy-3-methylphenyl)acetic acid hydrochloride (0.70 g, 3.2 mmol) in MeOH (4 mL) was cooled to 0 *C. Thionyl chloride (0.25 mL, 3.4 mmol) was added dropwise, and then the ice bath was allowed to expire while stirring the red solution overnight. N-ethyl-N-isopropylpropan-2-amine (2.8 mL, 16 mmol) was added dropwise, then the mixture was placed into a 0 *C ice bath. Di-tert-butyldicarbonate (0.77 g, 3.5 10 mmol) was added in portions. The mixture was stirred for 2 h at 0 *C, before removing the ice bath and stirring for another 2 h at room temperature. The mixture was concentrated to give a solid residue. The solid material was loaded onto a fitted funnel and washed with water while under reduced pressure. The solid which remained was partitioned between EtOAc and water at pH 8. The aqueous phase was extracted twice more with EtOAc. The combined organics were 15 washed with brine, dried over sodium sulfate, and concentrated to give the title compound as a pale pink solid (0.9 g, 95%). Exact mass calculated for C 1 5

H

21

NO

5 : 295.1, found: LCMS m/z = 296.4 [M+H]*. Step D: Preparation of tert-Butyl 2-Hydroxy-1-(4-hydroxy-3 methylphenyl)ethylcarbamate. 20 To a stirring 0 *C solution of methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxy-3 methylphenyl)acetate (0.87 g, 3.0 mmol) in THF (20 mL) was added lithium aluminum hydride (3.0 mL of 1 M THF solution, 3.0 mmol). The cold bath was removed and the mixture was stirred overnight. The reaction was quenched by pouring onto ice. The slurry was diluted with EtOAc and the solution was adjusted to pH 2 with 10% aqueous HCl. The organic phase was 25 separated and washed with brine, then dried over sodium sulfate. The volatiles were evaporated to give the title compound (0.60 g, 76%). Exact mass calculated for C 14

H

2 1

NO

4 : 267.2, found: LCMS m/z = 268.4 [M+H]*. Step E: Preparation of 4-(4-Hydroxy-3-methylphenyl)oxazolidin-2-one. To a stirring 0 *C solution of tert-butyl 2-hydroxy-1-(4-hydroxy-3 30 methylphenyl)ethylcarbamate (0.60 g, 2.2 mmol) in THF (7 mL) was added thionyl chloride (0.18 mL, 2.5 mmol) dropwise. The ice bath was removed and the mixture was stirred overnight at room temperature. The solvents were evaporated. The residue was washed with MTBE, decanted and dried to give the title compound (0.37 g, 84%). Exact mass calculated for

C

1 oH 11 N0 3 : 193.1, found: LCMS m/z = 194.2 [M+H]+. 35 Step F: Preparation of 2-Methyl-4-(2-oxooxazolidin-4-yl)phenyl Trifluoromethanesulfonate. 62 WO 2009/058300 PCT/US2008/012272 To a stirred slurry of 4-(4-hydroxy-3-methylphenyl)oxazolidin-2-one (0.40 g, 2.1 mmol) in acetonitrile (6 mL) was added pyridine (0.67 mL, 8.3 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (0.53 mL, 3.1 mmol) was added dropwise. The ice bath was removed and the clear red solution was stirred at room temperature. LCMS after 2 h 5 indicated the reaction was incomplete, so another equivalent of Tf 2 O (0.35 mL, 2.1 mmol) was added. The reaction was stirred for another 30 min. The solvent was evaporated and the residue was diluted with aqueous HCL. The slurry was extracted with EtOAc (thrice), the combined organics were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel flash column chromatography to give the title compound (with minor 10 impurities, 48 mg). Exact mass calculated for C 11 HioF 3

NO

5 S: 325.0, found: LCMS m/z = 326.2 [M+H]*. Step G: Preparation of 4-(2-Methyl-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl 4-yl)oxazolidin-2-one. A mixture of 2-methyl-4-(2-oxooxazolidin-4-yl)pheny trifluoromethanesulfonate (48 15 mg, 0.15 mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (40 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 4 pimol), sodium carbonate (0.22 mL of 2.0 M aqueous solution, 0.44 mmol), benzene (1 mL), and ethanol (0.3 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 'C for 90 min. The mixture was filtered through a pad of Celite@ with EtOAc, and the filtrate was 20 concentrated. The residue was purified by preparative HPLC. The appropriate fractions were combined and lyophilized to give the title compound as a TFA salt (14 mg, 26%). Exact mass calculated for C 2 3

H

2 8

N

2 0 2 : 364.2, found: LCMS m/z = 365.5 [M+H]*; 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 1.38 (d, J= 6.5 Hz, 311), 1.61 (dddd, J= 12.9, 9.0, 9.0, 9.0 Hz, 111), 2.10-1.86 (in, 2H), 2.28-2.17 (in, 1H), 3.10-2.91 (in, 211), 3.29-3.16 (in, 2H), 3.60-3.40 (in, 2H), 3.66 25 (dddd, J= 11.5, 8.0, 5.5, 5.5 Hz, 1H), 3.78 (s, 3H), 4.07 (dd, J= 8.6, 6.6 Hz, 1H), 4.70 ( dd, J= 8.6, 8.6 Hz, 111), 4.98 (dd, J= 7.6, 7.6 Hz, 1H), 7.00 (d, J= 7.8 Hz, 1H), 7.09 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.35 (d, J= 8.2 Hz, 2H), 7.45 (d, J= 8.2 Hz, 2H), 8.20 (s, 1H), 9.38 (bs, 1H). Example 1.31: Preparation of 4-(3-Methyl-4'-(2-((R)-2-methylpyrrolidin-1 30 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 24). Step A: Preparation of 2-Benzamido-2-(4-hydroxy-2-methylphenyl)acetic Acid. To a suspension of 2-benzamido-2-hydroxyacetic acid (4.0 g, 21 mmol) in concentrated sulfuric acid (2 mL) and glacial acetic acid (18 mL) at 0 *C was added m-cresol (5.4 mL, 51 mmol). The cold bath was allowed to expire while stirring continued overnight. The reaction 35 was quenched by pouring into a beaker containing ice and NaHCO 3 (40 g). The reaction was extracted with EtOAc (thrice). The aqueous phase was acidified with concentrated HCI to pH 1 and extracted with EtOAc (thrice). The combined organic phase from the acidified extraction 63 WO 2009/058300 PCT/US2008/012272 was washed with brine, dried over sodium sulfate, and concentrated. Half of the residue was purified by silica gel flash column chromatography followed by preparative HPLC to give the title compound as a white solid (0.63 g, 11%). Exact mass calculated for C 16

H

15

NO

4 : 285.1, found: LCMS m/z = 286.1 [M+H]*. 5 Step B: Preparation of 2-Amino-2-(4-hydroxy-2-methylphenyl)acetic Acid. A solution of 2-benzamido-2-(4-hydroxy-2-methylphenyl)acetic acid (0.63 g, 2.2 mmol) in 10% aqueous HC (10 mL) was heated at reflux for 6 days. After cooling to room temperature, the mixture was washed with MTBE (4 times) and then the aqueous phase was evaporated to give the hydrochloride salt of the title compound as a tan powder which was used 10 in the next reaction without further purification. Exact mass calculated for C 9 HI IN0 3 : 181.1, found: LCMS m/z = 182.2 [M+H]*. Step C: Preparation of Methyl 2-(tert-Butoxycarbonylamino)-2-(4-hydroxy-2 methylphenyl)acetate. A stirring suspension of 2-amino-2-(4-hydroxy-2-methylphenyl)acetic acid 15 hydrochloride (0.48 g, 2.2 mmol) in MeOH (2.2 mL) was cooled to 0 *C. Thionyl chloride (0.17 mL, 2.3 mmol) was added dropwise, then the ice bath was allowed to expire while stirring overnight. The mixture was placed into a 0 *C ice bath and N-ethyl-N-isopropylpropan-2-amine (1.3 mL, 7.3 mmol) was added dropwise, followed by the addition of di-tert-butyldicarbonate (0.48 g, 2.2 mmol) in portions. The mixture was stirred for 20 h before another equivalent of di 20 tert-butyldicarbonate (0.48 g, 2.2 mmol) was added. After additional 16 h, the reaction mixture was concentrated and the residue was dissolved in EtOH (5 mL). Sodium bicarbonate (0.61 g, 7.3 mmol) was added and the mixture was stirred at room temperature over the weekend. After 60 h the reaction mixture was concentrated and the residue was diluted with DCM and treated with dilute HCI to pH 2. The aqueous phase was extracted twice with DCM. The combined 25 organic phase was washed with brine, dried over sodium sulfate, and concentrated to give the title compound as an off-white solid (0.56 g, 86%). Exact mass calculated for C 1 5

H

21

NO

5 : 295.1, found: LCMS m/z = 296.2 [M+H]*. Step D: Preparation of tert-Butyl 2-Hydroxy-1-(4-hydroxy-2 methylphenyl)ethylcarbamate. 30 To a stirring 0 *C solution of methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxy-2 methylphenyl)acetate (0.55 g, 1.9 mmol) in THF (12 mL) was added lithium aluminum hydride (1.9 mL of I M THF solution, 1.9 mmol). The cold bath was removed and the mixture was stirred overnight. The reaction was quenched by pouring onto ice. The slurry was diluted with EtOAc and the solution was adjusted to pH 2 with 10% aqueous HCl. The organic phase was 35 separated and the aqueous phase was extracted twice more with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give the title 64 WO 2009/058300 PCT/US2008/012272 compound (0.47 g, 94%). Exact mass calculated for C1 4

H

2 1 N0 4 : 267.2, found: LCMS m/z 268.4 [M+H]*. Step E: Preparation of 4-(4-Hydroxy-2-methylphenyl)oxazolidin-2-one. To a stirring 0 *C solution of tert-butyl 2-hydroxy-1-(4-hydroxy-2 5 methylphenyl)ethylcarbamate (0.46 g, 1.7 mmol) in THF (6 mL) was added thionyl chloride (0.14 mL, 1.9 mmol). The ice bath was removed and the mixture was stirred overnight at room temperature. The solvents were evaporated and the residue was washed with MTBE. The MTBE solution was collected and concentrated to give the title compound (with minor impurities, 0.37 g). Exact mass calculated for CoH,,N0 3 : 193.1, found: LCMS m/z = 194.2 [M+H]*. 10 Step F: Preparation of 3-Methyl-4-(2-oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate. To a stirred slurry of 4-(4-hydroxy-2-methylphenyl)oxazolidin-2-one (0.10 g, 0.52 mmol) in acetonitrile (2 mL) was added pyridine (0.17 mL, 2.1 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (0.13 mL, 0.78 mmol) was added dropwise. 15 After 30 min the solvent was evaporated and the residue was washed with (10:1) MTBE/EtOAc. The decanted liquid was collected and evaporated to give the title compound as an oily solid (with minor impurities, 0.18 g). Exact mass calculated for CnHIOF 3

NO

5 S: 325.0, found: LCMS m/z= 326.3 [M+H]+. Step G: Preparation of 4-(3-Methyl-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl 20 4-yl)oxazolidin-2-one. A mixture of 3-methyl-4-(2-oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate (0.17 g, 0.52 mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (0.14 g, 0.52 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.017 mmol), sodium carbonate (0.83 mL of 2.0 M aqueous solution, 1.7 mmol), benzene (2.2 mL), and ethanol (0.62 25 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 30 min. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a TFA salt (0.055 g, 29% yield). Exact mass calculated for C 23

H

28

N

2 0 2 : 364.2, found: LCMS m/z = 365.5 [M+H]*; 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 1.38 (d, J= 6.5 Hz, 30 3H), 1.68 (dddd, J= 12.9, 9.0, 9.0, 9.0 Hz, 1H), 2.06-1.87 (in, 2H), 2.27-2.17 (m, 1H), 2.33 (s, 3H), 3.11-2.93 (in, 2H), 3.28-3.16 (m, 2H), 3.60-3.40 (in, 2H), 3.65 (dddd, J= 11.4, 8.0, 5.5, 5.5 Hz, 1H), 3.97 (dd, J= 8.4, 6.2 Hz, 1H), 4.77 (dd, J= 8.6, 8.6 Hz, 111), 5.18 (dd, J= 8.5, 6.5 Hz, 1H), 7.43-7.38 (m, 3H), 7.57-7.49 (m, 2H), 7.65 (d, J= 8.3 Hz, 2H), 8.14 (s, IH), 9.36 (bs, IH). 35 Example 1.32: Preparation of (S)-4-(2'-Methyl-4'-(2-(pyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (Compound 32). Step A: Preparation of Ethyl 2-(4-Hydroxy-3-methylphenyl)acetate. 65 WO 2009/058300 PCT/US2008/012272 To a stirring solution of 2-(4-hydroxy-3-methylphenyl)acetic acid (5.0 g, 30 mmol) in absolute ethanol (150 mL) was added concentrated sulfuric acid (1.6 mL, 30 mmol). The mixture was heated to 75 *C for 3 h, and then the heat was removed and the mixture was stirred at room temperature overnight. After 18 h, the volatiles were evaporated and the residue was 5 diluted with water and extracted into EtOAc (thrice). The combined organic extract was washed with brine, dried over sodium sulfate, and the solvents were evaporated to give the title compound as an oil (5.8 g, 100%). Exact mass calculated for C 11

H

14 0 3 : 194.1, found: LCMS m/z = 195.2 [M+H]*. Step B: Preparation of 4-(2-Hydroxyethyl)-2-methylphenol. 10 To a stirring solution of ethyl 2-(4-hydroxy-3-methylphenyl)acetate (5.8 g, 30 mmol) in THF (149 mL) at 0 *C was added lithium aluminum hydride (30 mL of 1.OM THF solution, 30 mmol). The cold bath was removed and the mixture was stirred at ambient temperature. After 2.5 h, the reaction was quenched with ice water and the slurry was treated with concentrated sulfuric acid to pH 3. The mixture was extracted 4 times with EtOAc. The combined organic 15 extract was washed with a concentrated aqueous solution of Rochelle's salt and then with brine. The extract was dried over sodium sulfate and concentrated to give the title compound as a faintly pink solid (4.6 g). Exact mass calculated for CgH 12 0 2 : 152.1, found: LCMS m/z= 135.2 [M -H 2 0 + H]*. Step C: Preparation of 2-Methyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl 20 trifluoromethanesulfonate. To a stirred slurry of 4-(2-hydroxyethyl)-2-methylphenol (2.0 g, 13 mmol) in acetonitrile (44 mL) was added pyrrolidine (5.5 mL, 66 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (6.7 mL, 39 mmol) was added dropwise. After 2.5 h the cold bath was removed and the mixture was stirred at ambient temperature. After 1 h, more 25 triflic anhydride (3.0 mL, 18 mmol) was added. After another 30 min, the reaction mixture was again charged with triflic anhydride (3.0 mL, 39 mmol). After an additional 1 h, the solvent was evaporated to give a dark residue which was extracted with EtOAc (thrice). The combined organic extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give the title compound as a TFA salt. The salt was 30 dissolved in water and EtOAc, then the mixture was treated with a 50% aqueous sodium hydroxide solution to pH 9. The layers were separated, and the aqueous phase was extracted twice more with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to give the title compound as an oil (0.52 g, 12%). Exact mass calculated for C 14

H

8

F

3

NO

3 S: 337.1, found: LCMS m/z = 338.5 [M+H]+; 'H NMR (400 MHz, 35 DMSO-d 6 ) 8 ppm 1.71-1.63 (in, 4H), 2.30 (s, 3H), 2.51-2.45 (in, 4H), 2.66-2.60 (in, 2H), 2.78 2.72 (in, 2H), 7.28-7.21 (in, 2H), 7.34-7.31 (in, 1H). 66 WO 2009/058300 PCT/US2008/012272 Step D: Preparation of (S)-4-(2'-Methyl-4'-(2-(pyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one. A mixture of 2-methyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl trifluoromethanesulfonate (0.23 g, 0.69 mmol), (S)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2 5 one (0.2.0 g, 0.69 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol), sodium carbonate (0.70 mL of 2.0 M aqueous solution, 1.4 mmol), benzene (1.8 mL), and ethanol (0.5 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 3 h. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC. The appropriate 10 fractions were combined and neutralized with 50% aqueous sodium hydroxide. The slurry was extracted with EtOAc (thrice). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to provide the title compound as an oil (0.15 g, 62%). Exact mass calculated for C 22

H

26

N

2 0 2 : 350.2, found: LCMS m/z = 351.4 [M+H]+; 'H NMR (400 MHz, CDCl 3 ) 5 ppm 1.88-1.80 (in, 4H), 2.23 (s, 3H), 2.72-2.65 (in, 4H), 2.91-2.76 (in, 4H), 4.25 (dd, 15 J= 8.6, 6.9 Hz, 1H), 4.76 (dd, J= 8.6, 8.6 Hz, 1H), 4.99 (dd, J= 8.6, 7.1 Hz, 1H), 6.28 (bs, 1H), 7.13-7.06 (in, 3H), 7.40-7.32 (m, 4H). Example 1.33: Preparation of (R)-4-(2,6-Dichloro-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 18). 20 Step A: Preparation of (R)-4-(3,5-Dichloro-4-hydroxyphenyl)oxazolidin-2-one. To a solution of (R)-4-(4-hydroxyphenyl)oxazolidin-2-one (0.100 g, 0.558 mmol) in DCM (10 mL) in an appropriate microwave vial was added N-chlorosuccinimide (0.224 g, 1.67 mmol). The mixture was irradiated under microwave conditions at 100 *C for 3 h. The reaction was quenched with water and extracted with DCM (thrice). The combined organics were 25 washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give the title compound as a white solid (35 mg, 25%). Exact mass calculated for C 9

H

7 C1 2

NO

3 : 247.0, found: LCMS m/z = 247.9, [M+H]*. Step B: Preparation of (R)-2,6-Dichloro-4-(2-oxooxazolidin-4-yl)phenyl Trifluoromethanesulfonate. 30 To a stirred slurry of (R)-4-(3,5-dichloro-4-hydroxyphenyl)oxazolidin-2-one (0.40 g, 1.6 mmol) in acetonitrile (5 mL) was added pyridine (0.52 mL, 6.5 mmol). The mixture was cooled to 0 'C and trifluoromethanesulfonic anhydride (0.41 mL, 2.4 mmol) was added dropwise. The ice bath was removed and the clear red solution was stirred at room temperature. After 2 h the solvent was evaporated to give a white residue which was washed with MTBE/EtOAc (10:1). 35 The decanted solvents were treated with diluted aqueous HCl, and then the mixture was extracted with EtOAc (thrice). The combined organics were washed with brine, dried over 67 WO 2009/058300 PCT/US2008/012272 sodium sulfate and concentrated to provide the title compound (with minor impurities, 0.72 g). Exact mass calculated for CioH 6 Cl 2

F

3

NO

5 S: 378.9, found: LCMS m/z = 380.1 [M+H]*. Step C: Preparation of (R)-4-(2,6-Dichloro-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. 5 A mixture of (R)-2,6-dichloro-4-(2-oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate (0.6 g, 1.6 mmol), (R)-4-(2-(2-methylpyrrolidin-1 yl)ethyl)phenylboronic acid hydrochloride (0.4 g, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.04 mmol), sodium carbonate (2.4 mL of 2.0 M aqueous solution, 4.8 mmol), benzene (3.8 mL), and ethanol (1.1 mL) were combined in a 10 suitable microwave vial and irradiated under microwave conditions at 100 *C for 90 min. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC. The appropriate fractions were combined and concentrated. The residue was treated with 50% aqueous NaOH to pH 14, and then extracted with DCM (thrice). The combined organics were washed with brine, dried over sodium sulfate, 15 and concentrated to give the title compound, which was then treated with 1 M HCl in Et 2 O to give a hydrochloride salt (0.04 g, 6%). Exact mass calculated for C 2 2

H

2 4 Cl 2

N

2 0 2 : 418.1, found: LCMS m/z = 419.3 [M+H]*; 'H NMR (400 MHz, CDCl 3 ) 8 ppm 1.13 (d, J= 6.0 Hz, 3H), 1.51 1.39 (in, 1H), 2.01-1.66 (in, 3H), 2.22 (ddd, J= 8.8, 8.8, 8.8 Hz, 1H), 2.41-2.31 (in, 2H), 2.96 2.80 (in, 2H), 3.09 (ddd, J= 11.4, 11.4, 5.8 Hz, 1H), 3.27 (ddd, J= 8.8, 8.8, 2.4 Hz, IH), 4.22 20 (dd, J= 8.4, 7.0 Hz, 1H), 4.77 ( dd, J= 8.7, 8.7 Hz, 1H), 4.98-4.91 (in, 1H), 6.63 (bs, 1H), 7.15 (d, J= 8.0 Hz, 2H), 7.31 (d, J 8.0 Hz, 2H), 7.39 (s, 2H). Example 1.34: Preparation of (R)-4-(2-Chloro-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 20) 25 Step A: Preparation of (R)-4-(3-Chloro-4-hydroxyphenyl)oxazolidin-2-one. To a solution of (R)-4-(4-hydroxyphenyl)oxazolidin-2-one (0.50 g, 2.8 mmol) in DCM (20 mL) was added N-chlorosuccinimide (0.37 g, 2.8 mmol). The mixture was stirred at room temperature for 18 h. The reaction was quenched with water and extracted with DCM (thrice). The combined organics were washed with brine and dried over sodium sulfate. The solvents were 30 evaporated and the solid residue was washed with MeOH. The decanted MeOH was concentrated to give a crude title compound (0.26 g). Exact mass calculated for C 9

H

8 ClNO 3 : 213.0, found: LCMS m/z = 214.1, [M+H]*. Step B: Preparation of (R)-2-Chloro-4-(2-oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate. 35 To a stirred slurry of impure (R)-4-(3-chloro-4-hydroxyphenyl)oxazolidin-2-one (0.26 g, 1.2 mmol) in acetonitrile (4 mL) was added pyridine (0.39 mL, 4.9 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (0.31 mL, 1.8 mmol) was added 68 WO 2009/058300 PCT/US2008/012272 dropwise. The clear red solution was stirred at 0 *C. After I h the solvent was evaporated to give a white residue which was diluted with EtOAc and dilute aqueous HCl. The mixture was extracted with EtOAc (thrice). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to provide the title compound with impurities (0.30 g). Exact 5 mass calculated for CioH 7 ClF 3

NO

5 S: 345.0, found: LCMS m/z = 345.9 [M+H]*. Step C: Preparation of (R)-4-(2-Chloro-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. A mixture (R)-2-chloro-4-(2-oxooxazolidin-4-yl)pheny trifluoromethanesulfonate (0.3 g, 0.9 mmol) from above, (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid 10 hydrochloride (0.2 g, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol), sodium carbonate (1.3 mL of 2.0 M aqueous solution, 2.6 mmol), benzene (2.0 mL), and ethanol (0.57 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 90 min. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to provide the 15 title compound as a TFA salt (0.09 g, 28%). Exact mass calculated for C 22

H

25 C1N 2 0 2 : 384.2, found: LCMS m/z = 385.3 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 8 ppm 1.48 (d, J= 6.6 Hz, 3H), 1.76 (dddd, J= 13.2, 9.1, 9.1, 9.1, Hz, 1H), 2.25-2.01 (m, 2H), 2.41-2.30 (m, 1H), 3.21-3.03 (m, 2H), 3.33-3.23 (m, 2H), 3.53 (dddd, J= 15.8, 6.8, 6.8, 6.8 Hz, 1H), 3.66 (ddd, J= 12.5, 11.0, 5.8 Hz, 1H), 3.77 (ddd, J= 13.1, 8.0, 5.3 Hz, 1H), 4.18 (dd, J= 8.8, 6.2 Hz, 1H), 20 4.80 (dd, J= 8.8, 8.8 Hz, 1H), 5.05 ( dd, J= 8.8, 6.2 Hz, 1H), 7.43-7.36 (in, 6H), 7.52-7.50 (in, 1H). Example 1.35: Preparation of (S)-4-(2'-Chloro-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 22). 25 Step A: Preparation of Methyl 2-(3-Chloro-4-hydroxyphenyl)acetate. To a solution of 2-(3-chloro-4-hydroxyphenyl)acetic acid (10.0 g, 53.6 mmol) in MeOH (250 mL) was added concentrated sulfuric acid. The resulting mixture was heated at reflux for 16 h. The MeOH was evaporated to give an oil which was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (thrice). The combined organics were 30 washed with brine, dried over sodium sulfate, and then evaporated to give the title compound (10.5 g, 98%) as an amber oil. 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 3.57 (s, 2H), 3.64 (s, 3H), 6.09 (d, J= 8.3 Hz, 1H), 7.02 (dd, J= 8.3, 2.1 Hz, 1H), 7.23 (d, J= 2.1 Hz, 1H), 10.03 (s, IH). Step B: Preparation of Methyl 2-(3-Chloro-4-(4-methoxybenzyloxy)phenyl)acetate. To a stirring solution of methyl 2-(3-chloro-4-hydroxyphenyl)acetate (2.19 g, 10.9 35 mmol) in acetone (27 mL) was added PMBCl (p-methoxybenzyl chloride) (1.88 g, 12.0 mmol), tetrabutylammonium iodide (TBAI) (4.03 g, 10.9 mmol), and potassium carbonate (2.26 g, 16.4 mmol). The mixture was heated at 55 *C for 60 h. The reaction mixture was diluted with a 69 WO 2009/058300 PCT/US2008/012272 solution of 10% acetone in hexanes and a small amount of DCM, heated briefly, and then cooled to room temperature and passed through a column of Celite@/silica gel. The column was washed with 10-20% acetone/hexanes (700 mL), and the colorless eluent was concentrated to give the title compound as an off-white solid (3.4 g, 97%) with minor impurities. TLC (20% 5 acetone/hexanes) Rf= 0.27. Step C: Preparation of 2-(3-Chloro-4-(4-methoxybenzyloxy)phenyl)ethanol. To a stirring 0 *C solution of methyl 2-(3-chloro-4-(4 methoxybenzyloxy)phenyl)acetate (0.50 g, 1.6 mmol) in THF (15 mL) was added lithium aluminum hydride (1.6 mL of 1 M THF solution, 1.6 mmol). The cold bath was allowed to 10 expire while the reaction stirred overnight. The reaction was quenched by pouring onto ice, then the slurry was extracted with EtOAc (thrice). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give the title compound (with minor impurities, 0.49 g). Step D: Preparation of 3-Chloro-4-(4-methoxybenzyloxy)phenethyl 15 Methanesulfonate. To a stirring 0 'C solution of methyl 2-(3-chloro-4-(4 methoxybenzyloxy)phenyl)ethanol (0.49 g, 1.7 mmol) in DCM (4 mL) was added triethylamine (0.70 mL, 5.0 mmol) and MsCl (0.16 mL, 1.2 mmol). After stirring 1 h, the reaction was quenched by the addition of 10% aqueous HC1 (2 mL). The mixture was diluted with water and 20 extracted with DCM (thrice). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give the title compound as an amber oil (with minor impurities, 0.62 g). TLC (50% acetone/hexanes) Rf = 0.60. Step E: Preparation of (R)-1-(3-Chloro-4-(4-methoxybenzyloxy)phenethyl)-2 methylpyrrolidine. 25 To a stirring solution of impure 3-chloro-4-(4-methoxybenzyloxy)phenethy methanesulfonate (0.60 g, 1.6 mmol) was added (R)-2-methylpyrrolidine, benzene sulfonate (0.47, 1.9 mmol) and potassium carbonate (0.49 g, 3.6 mmol). The mixture was heated at 60 *C for 18 h. The white heterogeneous mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc and water, treated with 10% HCl 30 to pH 2, and then the aqueous phase was separated and washed twice more with EtOAc. The aqueous phase was then basified with 50% NaOH to pH 9, followed by extraction with EtOAc (thrice). The combined organic phase from the basic extraction was washed with brine, dried over sodium sulfate, and concentrated to give the title compound as an orange oil (with minor impurities, 0.29 g, 50%). Exact mass calculated for C 21

H

2 6 C1N 2 0 2 : 359.2, found: LCMS m/z = 35 360.4 [M+H]-. Step F: Preparation of (R)-2-Chloro-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenol. 70 WO 2009/058300 PCT/US2008/012272 To a stirring solution of (R)-1 -(3-chloro-4-(4-methoxybenzyloxy)phenethyl)-2 methylpyrrolidine (0.26 g, 0.72 mmol) in DCM (1.5 mL) was added 2,2,2-trifluoroacetic acid (1.5 mL, 20 mmol). After 10 min, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate and adjusted to pH 9. The mixture was extracted with DCM (thrice), 5 washed with brine, and dried over sodium sulfate. The solvents were evaporated to give the title compound (70 mg). Exact mass calculated for C1 3

HI

8 ClNO: 239.1, found: LCMS m/z = 240.1 [M+H]*. Step G: Preparation of (R)-2-Chloro-4-(2-(2-methylpyrrolidin-1-yl)ethyl)pheny Trifluoromethanesulfonate. 10 To a stirred slurry of (R)-2-chloro-4-(2-(2-methylpyrrolidin-1 -yl)ethyl)phenol (0.070 g, 0.29 mmol) in acetonitrile (1 mL) was added pyridine (0.094 mL, 1.2 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (0.074 mL, 0.44 mmol) was added dropwise. After 2 h the mixture was evaporated to give a solid residue which was washed with MTBE/EtOAc (10:1). The resulting white solid contained no desired product and was discarded. 15 To the filtrate was added dilute aqueous HCL. The acidified mixture was then extracted with EtOAc (thrice), the combined organic fractions were washed with brine, and then dried over sodium sulfate. The solvent was evaporated to give the title compound (0.11 g). Exact mass calculated for C1 4

H

17 ClF 3

NO

3 S: 371.1, found: LCMS m/z = 372.2 [M+H]*. Step H: Preparation of (S)-4-(2'-Chloro-4'-(2-((R)-2-methylpyrrolidin-1 20 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. A mixture of (R)-2-chloro-4-(2-(2-methylpyrrolidin- 1 -yl)ethyl)phenyl trifluoromethanesulfonate (0.085 g, 0.29 mmol), (S)-4-(4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)phenyl)oxazolidin-2-one (0.11 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.0088 mmol), sodium carbonate (0.29 mL 25 of 2.0 M aqueous solution, 0.59 mmol), benzene (1.0 mL), and ethanol (0.29 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 15 min. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to provide the title compound as a TFA salt (2.2 mg, 20%). Exact mass calculated for C 2 2

H

25 ClN 2 0 2 : 384.2, found: LCMS m/z = 30 385.2 [M+H]*; 'H NMR (400 MIz, Methanol-d 4 ) 8 ppm 1.48 (d, J= 6.6 Hz, 3H), 1.81-1.70(m, 1H), 2.22-2.02 (in, 2H), 2.41-2.32 (in, 1H), 3.10-3.01 (in, 1H), 3.20-3.11 (in, 1H), 3.37-3.23 (in, 311), 3.54 (dddd, J= 15.6, 6.6, 6.6, 6.6 Hz, 1H), 3.66 (ddd, J= 12.6, 11.1, 5.9 Hz, 1H), 3.76 (ddd, J= 13.2, 8.1, 5.3 Hz, 1H), 4.20 (dd, J= 8.7, 6.4 Hz, 1H), 4.84-4.75 (in, 1H), 5.07 (dd, J= 8.8, 6.4 Hz, 111), 7.38-7.32 (in, 2H), 7.47-7.44 (in, 4H), 7.53-7.51 (in, 1H). 35 Example 1.36: Preparation of (S)-4-(3'-Fluoro-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 23). 71 WO 2009/058300 PCT/US2008/012272 Step A: Preparation of 2-(2-Fluoro-4-methoxyphenyl)ethanol. To a stirring 0 *C solution of 2-(2-fluoro-4-methoxyphenyl)acetic acid (5.0 g, 27 mmol) in THF (11 mL) was added borane-THF complex (27 mL of 1.0 M solution in THF, 27 mmol). The cold bath was allowed to expire naturally while stirring overnight. After 16 h the reaction 5 was quenched by the careful addition of water until effervescence ceased. The solution was neutralized by stirring with a saturated solution of sodium carbonate. The mixture was then extracted with MTBE (thrice). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give the title compound as a colorless oil (4.3 g, 93%). Exact mass calculated for CH 11 F0 2 : 170.1, found: LCMS m/z = 153.2 [M - H 2 0 + H]*. 10 Step B: Preparation of 2-Fluoro-4-methoxyphenethyl Methanesulfonate. To a stirring 0 *C solution of 2-(2-fluoro-4-methoxyphenyl)ethanol (2.0 g, 12 mmol) in THF (30 mL) was added triethylamine (4.9 mL, 35 mmol) and methanesulfonyl chloride (1.1 mL, 14 mmol). The cold bath was allowed to expire naturally while stirring overnight. After 16 h the reaction was quenched by the careful addition of dilute HCL. The mixture was extracted 15 with DCM (thrice). The combined organic fractions were washed with brine, dried over sodium sulfate, and concentrated to give the title compound as an amber oil (with minor impurities, 3.2 g, 110%). Exact mass calculated for C 1 oH 13

FO

4 S: 248.1, found: LCMS m/z= 153.2 [M - MsOH + H]*. Step C: Preparation of (R)-1-(2-Fluoro-4-methoxyphenethyl)-2-methylpyrrolidine. 20 To a stirring solution of 2-fluoro-4-methoxyphenethyl methanesulfonate (1.5 g, 6.0 mmol) in acetonitrile (15 mL) was added (R)-2-methylpyrrolidine benzene sulfonate (1.8, 7.3 mmol) and potassium carbonate (1.8 g, 13 mmol). The mixture was heated at 60 *C for 18 h. The white heterogeneous mixture was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was dissolved in EtOAc and water, treated with 10% HCl to pH 2, and 25 then the aqueous phase was separated and washed twice more with EtOAc. The aqueous phase was then basified with 50% NaOH to pH 9, followed by extraction with EtOAc (thrice). The combined organic phase from the basic extraction was washed with brine, dried over sodium sulfate, and then concentrated to give the title compound as an orange oil (0.87 g, 62%). Exact mass calculated for C 1 4

H

20 FNO: 237.2, found: LCMS m/z = 238.0 [M+H]. 30 Step D: Preparation of (R)-3-Fluoro-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenol. To a stirring -78 *C solution of (R)-1-(2-fluoro-4-methoxyphenethyl)-2 methylpyrrolidine (0.10 g, 0.42 mmol) in DCM (3 mL) was added dropwise boron tribromide (0.84 mL of 1 M solution in DCM, 0.84 mmol). After I h the cold bath was removed and the mixture was stirred for 3.5 h at room temperature. The mixture was cooled to 0 *C and quenched 35 by the addition of 2 M aqueous sodium carbonate until the mixture reached pH 7. The mixture was extracted with DCM (thrice). The combined organic phase was washed with brine, dried over sodium sulfate, and then evaporated to give the title compound which was used directly in 72 WO 2009/058300 PCT/US2008/012272 the next reaction without further purification. Exact mass calculated for C 1 3 HisFNO: 223.1, found: LCMS m/z = 224.3 [M+H]*. Step E: Preparation of (R)-3-Fluoro-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl. To a stirred slurry of (R)-3-fluoro-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenol (0.10 g, 5 0.45 mmol) in acetonitrile (1.5 mL) was added pyridine (0.15 mL, 1.8 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (0.11 mL, 0.67 mmol) was added dropwise. After 2 h the mixture was evaporated to give an oily residue which was washed with MTBE/EtOAc (10:1). The resulting white solid contained no desired product and was discarded. The filtrate was evaporated to give the title compound with minor impurities as an orange oily 10 solid, which was used directly in the next reaction without further purification. Exact mass calculated for C 14 H1 7

CF

4

NO

3 S: 355.1, found: LCMS m/z = 356.2 [M+H]+. Step F: Preparation of (S)-4-(3'-Fluoro-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. A mixture of (R)-3-fluoro-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl 15 trifluoromethanesulfonate (0.13 g, 0.45 mmol), (S)-4-(4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)phenyl)oxazolidin-2-one (0.16 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0 16 g, 0.0 14 mmol), sodium carbonate (0.45 mL of 2.0 M aqueous solution, 0.90 mmol), benzene (1.8 mL), and ethanol (0.50 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 'C for 3.5 h. The 20 mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to provide the title compound as a TFA salt (49 mg, 24% yield). Exact mass calculated for C 2 2

H

2 5

FN

2 0 2 : 368.2, found: LCMS m/z = 369.2 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 8 ppm 1.47 (d, J= 6.5 Hz, 3H), 1.81-1.70(m, 1H), 2.23-2.02 (m, 2H), 2.42-2.32 (in, 1H), 3.21-3.07 (in, 2H), 3.35-3.25 (in, 3H), 3.67-3.51 (m, 2H), 25 3.83-3.75 (m, 1H), 4.17 (dd, J= 8.7, 6.4 Hz, 111), 4.85-4.74 (m, 1H), 5.05 (dd, J= 8.7, 6.4 Hz, 1H), 7.47 (d, J= 8.4 Hz, 2H), 7.50-7.42 (m, 3H), 7.68 (d, J= 8.4 Hz, 2H). Example 1.37: Preparation of (R)-4-(2-Methoxy-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one (Compound 21). 30 Step A: Preparation of Methyl 2-(tert-Butoxycarbonylamino)-2-(4-hydroxy-3 methoxyphenyl)acetate. A stirring suspension of 2-amino-2-(4-hydroxy-3-methoxyphenyl)acetic acid (0.98 g, 5.0 mmol) in MeOH (6.5 mL) was cooled to 0 *C. Thionyl chloride (0.38 mL, 5.2 mmol) was added dropwise, and then the ice bath was allowed to expire while stirring overnight. After 16 h, 35 N,N-diisopropylethylamine (4.3 mL, 25 mmol) was added dropwise and the mixture was placed into a 0 *C ice bath. Di-tert-butyldicarbonate (1.2 g, 5.5 mmol) was added in portions. After 2 h, the volatiles were evaporated and the residue was diluted with water, then extracted with EtOAc 73 WO 2009/058300 PCT/US2008/012272 (thrice). The combined organic phase was washed with brine, dried over sodium sulfate, and the solvents were evaporated to give the title compound as an amber oil. Exact mass calculated for

CI

5

H

21

NO

6 : 311.1, found: LCMS m/z = 312.2 [M+H]*. Step B: Preparation of tert-Butyl 2-Hydroxy-1-(4-hydroxy-3 5 methoxyphenyl)ethylcarbamate. To a stirring 0 *C solution of methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxy-3 methoxyphenyl)acetate (1.5 g, 4.8 mmol) in THF (50 mL) was added lithium aluminum hydride (5.8 mL of 1M THF solution, 5.8 mmol). The cold bath was removed and the mixture was stirred overnight. The reaction was quenched by pouring onto ice. The slurry was diluted with 10 EtOAc and the solution was adjusted to pH 4 with 10% aqueous HCl. The organic phase was separated and the aqueous phase was extracted twice more with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography to give the title compound as a tan solid (0.50 g, 36%). Exact mass calculated for C 14

H

21

NO

5 : 283.1, found: LCMS m/z = 284.4 [M+H]*. 15 Step C: Preparation of 4-(4-Hydroxy-3-methoxyphenyl)oxazolidin-2-one. To a stirring 0 *C solution of tert-butyl 2-hydroxy-1-(4-hydroxy-3 methoxyphenyl)ethylcarbamate (0.5 g, 1.8 mmol) in THF (7 mL) was added thionyl chloride (0.14 mL, 1.9 mmol). The ice bath was removed and the mixture was stirred overnight at room temperature. The solvents were evaporated to give the title compound (with minor impurities, 20 0.37 g). Exact mass calculated for CIOHIIN0 4 : 209.1, found: LCMS m/z = 210.0 [M+H]*. Step D: Preparation of 2-Methoxy-4-(2-oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate. To a stirred slurry of 4-(4-hydroxy-3-methoxyphenyl)oxazolidin-2-one (0.37 g, 1.8 mmol) in acetonitrile (6 mL) was added pyridine (0.57 mL, 7.1 mmol). The mixture was cooled 25 to 0 *C and trifluoromethanesulfonic anhydride (0.45 mL, 2.7 mmol) was added dropwise. After 30 min the ice bath was removed and the clear red solution was stirred at room temperature. After another 30 min the solvent was evaporated and the residue was extracted with (10:1) MTBE/EtOAc. To the decanted liquid was added dilute aqueous HCl. The layers were separated and the aqueous phase was extracted twice more with EtOAc. The combined organic phase was 30 washed with brine and dried over sodium sulfate. The solvents were evaporated to give the title compound as a red oil (with impurities, 0.77 g). Exact mass calculated for C 11

HIOF

3

NO

6 S: 341.0, found: LCMS m/z = 342.2 [M+H]*. Step E: Preparation of 4-(2-Methoxy-4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. 35 A mixture of 2-methoxy-4-(2-oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate (0.75 g, 2.2 mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (0.59 g, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol), sodium 74 WO 2009/058300 PCT/US2008/012272 carbonate (3.3 mL of 2.0 M aqueous solution, 6.6 mmol), benzene (8 mL), and ethanol (2.3 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 90 min. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a 5 TFA salt (0.10 g). Exact mass calculated for C 23

H

28

N

2 0 3 : 380.2, found: LCMS m/z = 381.3 [M+H]*; 'H NMR (400 MHz, DMSO-d 6 ) 5 ppm 1.38 (d, J= 6.5 Hz, 3H), 1.61 (dddd, J= 12.9, 9.0, 9.0, 9.0 Hz, 1H), 2.08-1.86 (in, 2H), 2.28-2.18 (in, 1H), 3.10-2.92 (in, 2H), 3.28-3.15 (in, 2H), 3.60-3.40 (in, 2H), 3.66 (dddd, J= 11.4, 8.0, 5.5, 5.5 Hz, IH), 3.78 (s, 3H), 4.08 (dd, J= 8.5, 6.6 Hz, 1H), 4.70 (dd, J= 8.6, 8.6 Hz, 1H), 4.98 (dd, J= 8.1, 8.1 Hz, 1H), 7.00 (dd, J= 7.8, 10 1.4 Hz, 1H), 7.09 (d, J= 1.4 Hz, 1H), 7.30 (d, J= 7.8 Hz, 1H), 7.35 (d, J= 8.2 Hz, 2H), 7.44 (d, J= 8.2 Hz, 2H), 8.20 (s, 1H), 9.38 (bs, 1H). Example 1.38: Preparation of (S)-4-(2'-Methoxy-4'-(2-(pyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one (Compound 33). 15 Step A: Preparation of 2-Methoxy-4-(2-(pyrrolidin-1-yl)ethyl)phenyl Trifluoromethanesulfonate. To a stirred slurry of 4-(2-hydroxyethyl)-2-methoxyphenol (homovanillyl alcohol) (2.0 g, 12 mmol) in acetonitrile (40 mL) was added pyrrolidine (5.0 mL, 60 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (6.0 mL, 36 mmol) was added dropwise. 20 After 3 h the cold bath was removed and the mixture was stirred at ambient temperature. After another 18 h, pyridine (5.0 mL, 62 mmol) and more triflic anhydride (5.0 mL, 30 mmol) were added. After another 1 h, the reaction mixture was again charged with triflic anhydride (5 mL, 30 mmol). After an additional 3 h, the solvent was evaporated to give a dark residue which was extracted with EtOAc (thrice). The combined organic extract was washed with brine, dried over 25 sodium sulfate, and then the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a TFA salt. The salt was dissolved in water and EtOAc, then the mixture was treated with a saturated aqueous sodium bicarbonate solution to pH 9. The layers were separated, and the aqueous phase was extracted twice more with EtOAc. The combined organic extract was washed with brine, dried over sodium sulfate, and then the 30 solvent was evaporated to give the title compound as an oil (0.76 g, 18%). Exact mass calculated for C 1 4

H

18

F

3

NO

4 S: 353.1, found: LCMS m/z= 354.2 [M+H]*. Step B: Preparation of (S)-4-(2'-Methoxy-4'-(2-(pyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one. A mixture of 2-methoxy-4-(2-(pyrrolidin- I -yl)ethyl)phenyl trifluoromethanesulfonate 35 (0.20 g, 0.57 mmol), (S)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2 one (0.16 g, 0.57 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol), sodium carbonate (0.57 mL of 2.0 M aqueous solution, 1.1 mmol), benzene (1.5 mL), and 75 WO 2009/058300 PCT/US2008/012272 ethanol (0.4 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 12 h. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a TFA salt (19 mg). Exact mass calculated for C 22

H

26

N

2 0 3 : 366.2, found: 5 LCMS m/z = 367.4 [M+H}*; 'H NMR (400 MHz, DMSO-d 6 ) 6 ppm 1.95-1.82 (in, 2H), 2.10 1.98 (m, 2H), 3.04-2.97 (m, 2H), 3.15-3.04 (in, 2H), 3.60-3.40 (in, 4H), 3.78 (s, 3H), 4.06 (dd, J = 8.5, 6.4 Hz, 1H), 4.70 (dd, J= 8.6, 8.6 Hz, 1H), 4.97 (dd, J= 7.5, 7.5 Hz, 111), 6.96 (dd, J 7.7, 1.4 Hz, 1H), 7.06 (d, J= 1.4 Hz, 1H), 7.25 (d, J= 7.7 Hz, 1H), 7.37 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.2 Hz, 2H), 8.18 (s, 1H), 9.72 (bs, 1H). 10 Example 1.39: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 1,3-dioxolan-2-one (Compound 26). Step A: Preparation of 4-(4-Bromophenyl)-2,2-dimethyl-1,3-dioxolane. To a mixture of 1-(4-bromophenyl)ethane-1,2-diol (1.0 g, 4.6 mmol) in acetone (10 mL) 15 and 2,2-dimethoxypropane (11 mL, 92 mmol) was added pyridiniump-toluenesulfonate (PPTs) (0.12 g, 0.46 nimol). After 16 h, the reaction was quenched with water. The volatiles were evaporated and the aqueous slurry was extracted with DCM (thrice). The combined organic phase was washed with brine, dried over sodium sulfate, and then the solvent was evaporated to give the title compound as a yellow oil (1.2 g, 98%). 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 20 1.39 (s, 3H), 1.45 (s, 3H), 3.55 (dd, J= 8.0, 8.0 Hz, 1 H), 4.30 (dd, J= 8.0, 6.8 Hz, 1 H), 5.05 (dd, J= 6.8, 6.8 Hz, 1 H), 7.33 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 211). Step B: Preparation of (2R)-1-(2-(4'-(2,2-Dimethyl-1,3-dioxolan-4-yl)biphenyl-4 yl)ethyl)-2-methylpyrrolidine. A mixture of 4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane (0.50 g, 2.0 mmol), (R)-4 25 (2-(2-methylpyrrolidin-1 -yl)ethyl)phenylboronic acid hydrochloride (0.52 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol), sodium carbonate (2.0 ml of 2.0 M aqueous solution, 3.9 mmol), benzene (7.6 mL), and ethanol (2.2 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 3 h. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated to 30 give the title compound (with minor impurity, 0.76 g). Exact mass calculated for C 24 11 3 N0 2 : 365.2, found: LCMS m/z = 366.4 [M+H]. Step C: Preparation of 1-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)ethane-1,2-diol. To a solution of crude (2R)-1-(2-(4'-(2,2-dimethyl-1,3-dioxolan-4-yl)biphenyl-4 35 yl)ethyl)-2-methylpyrrolidine (0.60 g, 1.6 mmol) in dioxane (20 mL) was added hydrogen chloride (5 mL of 4 M solution in dioxane, 20 mmol), and water (0.5 mL, 28 mmol). The mixture was stirred at room temperature for 60 h. The reaction was neutralized with 50% 76 WO 2009/058300 PCT/US2008/012272 aqueous sodium hydroxide. The volatiles were evaporated and the residue was purified by preparative HPLC to provide the title compound containing a chloro-alcohol impurity. Exact mass calculated for C 2 1

H

2 7NO 3 : 325.2, found: LCMS m/z = 326.3 [M+H]+. Step D: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 5 1,3-dioxolan-2-one. To a solution of 1-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)ethane-1,2 diol (0.20 g, 0.62 mmol), containing a chloro-alcohol impurity, in THF (12 mL) was added CDI (0.60 g, 3.7 mmol). The mixture was stirred at 40 *C for 30 min, then cooled to room temperature before quenching with 10% aqueous HCl. The mixture was stirred for another 20 10 min, then the reaction was neutralized by the addition of a saturated aqueous sodium bicarbonate solution. The mixture was extracted with MTBE (thrice) and the combined organic phase was washed with brine, and then dried over sodium sulfate. The volatiles were evaporated and the residue was purified by preparative HPLC to give the title compound as a TFA salt (3.1 mg). Exact mass calculated for C 22

H

2 5

NO

3 : 351.2, found: LCMS m/z = 352.3 [M+H]*; 'H NMR (400 15 MHz, Methanol-d 4 ) 8 ppm 1.47 (d, J= 6.5 Hz, 3H), 1.81-1.70 (in, 1H), 2.21-2.00 (in, 2H), 2.40 2.30 (in, 1H), 3.20-3.01 (in, 2H), 3.33-3.22 (in, 2H), 3.80-3.50 (in, 3H), 4.43 (dd, J= 8.6, 7:6 Hz, 1H), 4.89 (dd, J= 8.6, 8.6 Hz, 1H), 5.84 (dd, J= 7.9, 7.9 Hz, 1H), 7.42 (d, J= 8.2 Hz, 2H), 7.52 (d, J= 8.2 Hz, 2H), 7.65 (d, J= 8.3 Hz, 2H), 7.71 (d, J= 8.3 Hz, 2H). 20 Example 1.40: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)pyrrolidin-2-one (Compound 25). Step A: Preparation of 4-(4-Chlorophenyl)pyrrolidin-2-one. To a solution of 4-amino-3-(4-chlorophenyl)-butanoic acid (baclofeh) (1.0 g, 4.7 mmol) in toluene (80 mL) was added neutral alumina (1.4 g, 14 mmol). The mixture was heated to 25 reflux for 16 h, then cooled to room temperature and filtered. The filtrate was evaporated to give the title compound as a white solid (0.82 g, 90%). Exact mass calculated for CioHioClNO: 195.1, found: LCMS m/z = 196.1 [M+H]*. Step B: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)pyrrolidin-2-one. 30 A mixture of 4-(4-chlorophenyl)pyrrolidin-2-one (0.15 g, 0.77 mmol), (R)-4-(2-(2 methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (0.21 g, 0.77 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (XPHOS) (18 mg, 0.03 8 mmol), potassium phosphate (0.49 g, 2.3 mmol), palladium acetate (3.4 mg, 0.015 mmol) and THF (1.0 mL) were combine in a sealed vial which was then heated in an oil bath at 100 *C for 26 h. The 35 mixture was filtered through a pad of Celite@ with acetonitrile, and the solvents were evaporated. The residue was dissolved in EtOAc and washed with 10% aqueous HCL. The aqueous phase was then treated with 50% aqueous NaOH to pH 12, and extracted with EtOAc 77 WO 2009/058300 PCT/US2008/012272 (thrice). The combined organic phase from the basic extraction was washed with brine, dried over sodium sulfate, and then the solvent was evaporated. The residue was purified by preparative HPLC to give the title compound as a TFA salt (3.8 mg). Exact mass calculated for

C

23

H

28

N

2 0: 348.2, found: LCMS m/z = 349.3 [M+H]*; 'H NMR (400 MHz, Methanol-d) 8 5 ppm 1.47 (d, J= 6.5 Hz, 3H), 1.76 (dddd, J= 13.2, 9.1, 9.1, 9.1 Hz, 1H), 2.20-2.00 (in, 2H), 2.40-2.30 (in, 1H), 2.53-2.45(m, 1H), 2.78-2.70 (in, 1H), 3.19-3.02 (in, 2H), 3.32-3.22 (in, 3H), 3.46-3.39 (in, 1H), 3.58-3.48 (in, 1H), 3.63 (dddd, J= 10.7, 10.7, 10.7, 5.9 Hz, 1H), 3.84-3.72 (in, 3H), 7.42-7.36 (in, 4H), 7.63-7.57 (in, 4H). 10 Example 1.41: Preparation of 5-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)pyrrolidin-2-one (Compound 30). Step A: Preparation of 5-(4-Methoxyphenyl)pyrrolidin-2-one. To a stirring mixture of phosphorous pentoxide (0.64 g, 4.5 mmol), methanesulfonic acid (4.3 mL, 67 mmol), and anisole (0.93 mL, 8.5 mmol) was added (S)-5-oxopyrrolidine-2 15 carboxylic acid (pyroglutamic acid) (1.0 g, 7.8 mmol). The neat mixture was heated at 100 "C for 30 min. The reaction was quenched by pouring onto ice. The aqueous slurry was extracted with DCM (thrice). The organic extracts were combined, washed with brine, dried over sodium sulfate, and then the solvents were evaporated. The residue was purified by preparative HPLC. The appropriate fractions were combined and the solvents evaporated. The residue was extracted 20 with DCM (thrice). The organic extracts were combined, washed with brine, dried over sodium sulfate, and then the solvents were evaporated to give the title compound as a white solid (0.40 g, 27%). Exact mass calculated for C,,H1 3

NO

2 : 191.1, found: LCMS m/z = 192.2 [M+H]*. Step B: Preparation of 5-(4-Hydroxyphenyl)pyrrolidin-2-one. To a stirring -78 'C solution of 5-(4-methoxyphenyl)pyrrolidin-2-one (0.38 g, 2.0 25 mmol) in DCM (13 mL) was added dropwise boron tribromide (2.6 mL of 1 M solution in DCM, 2.6 mmol). After 1 h the cold bath was removed and the mixture continued to stir at ambient temperature overnight. The solvent was evaporated to give a tan solid. The reaction was diluted with DCM and quenched by the addition of an aqueous sodium bicarbonate solution until pH 7. The mixture was filtered to collect the title compound as an off-white solid (0.20 g, 30 57%). Exact mass calculated for C1 0 H1N0 2 : 177.2, found: LCMS m/z = 178.1 [M+H]*. Step C: Preparation of 4-(5-Oxopyrrolidin-2-yl)phenyl trifluoromethanesulfonate. To a stirred slurry of 5-(4-hydroxyphenyl)pyrrolidin-2-one (0.20 g, 1.1 mmol) in acetonitrile (4 mL) was added pyridine (0.37 mL, 4.5 mmol). The mixture was cooled to 0 *C and trifluoromethanesulfonic anhydride (0.29 mL, 1.7 mmol) was added dropwise. After 30 min 35 the solvent was evaporated and the dark residue was washed with (10:1) MTBE/EtOAc. A solid precipitated which contained no desired product. The decanted liquid was evaporated to give the 78 WO 2009/058300 PCT/US2008/012272 title compound with impurities as an oily solid (0.30 g, 85%). Exact mass calculated for CioH,,N0 2 : 309.0, found: LCMS m/z = 310.4 [M+H]*. Step D: Preparation of 5-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)pyrrolidin-2-one. 5 A mixture of 4-(5-oxopyrrolidin-2-yl)phenyl trifluoromethanesulfonate (0.30 g, 0.97 mmol), (R)-4-(2-(2-methylpyrrolidin-1 -yl)ethyl)phenylboronic acid hydrochloride (0.26 g, 0.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.034 g, 0.029 mmol), sodium carbonate (1.5 mL of 2.0 M aqueous solution, 2.9 mmol), benzene (2.5 mL), and ethanol (0.80 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 10 5 h. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was partitioned between water and DCM. The aqueous phase was extracted twice more with DCM. The combined organic phase was washed with brine, dried over sodium sulfate, and then the solvents were evaporated. The residue was purified by preparative HPLC. The appropriate fractions were combined and lyophilized to give the title 15 compound as a TFA salt (7.0 mg, 1.6%). Exact mass calculated for C 2 3

H

28

N

2 0: 348.2, found: LCMS m/z = 349.3 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 8 ppm 1.47 (d, J= 6.5 Hz, 3H), 1.76 (dddd, J= 13.2, 9.0, 9.0, 9.0 Hz, 1H), 2.02-1.91 (in, 111), 2.18-2.02 (in, 2H), 2.40-2.30 (in, 1H), 2.48-2.42 (in, 2H), 2.62 (dddd, J= 12.8, 8.2, 8.2, 6.3 Hz, 1H), 3.19-3.02 (in, 2H), 3.35-3.22 (in, 3H), 3.59-3.49 (in, 111), 3.64 (ddd, J= 16.6, 10.8, 5.9 Hz, 1H), 3.76 (ddd, J= 13.1, 8.0, 4.6 20 Hz, 1H), 4.87-4.82 (in, 1H), 7.43-7.38 (in, 4H), 7.65-7.60 (in, 4H). Example 1.42: Preparation of 6-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 1,3-oxazinan-2-one (Compound 27). Step A: Preparation of 3-Amino-1-(4-bromophenyl)propan-1-ol. 25 A solution of 3-(4-bromophenyl)-3-oxopropanenitrile (1.0 g, 4.5 mmol) in THF (89 mL) was heated to reflux. Borane-THF complex (13 mL of 1 M solution, 13 mmol) was added dropwise. After 3.5 h the mixture was cooled to room temperature, then MeOH (20 mL) was added. The volatiles were evaporated to give a white residue, which was then dissolved in MTBE. The clear solution was treated with a 1 M ethereal HCl solution. The solvents were 30 evaporated and the residue was partitioned between water and DCM. The organic phase was set aside. The aqueous phase was neutralized with a 50% aqueous sodium hydroxide solution, and then extracted with DCM (thrice). The combined organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated to give the title compound in impure form as a colorless oil (0.85 g) which was used without further purification. Exact mass 35 calculated for C 9

,

2 BrNO: 229.0, found: LCMS m/z = 230.3 [M+H]*. Step B: Preparation of 6-(4-Bromophenyl)-1,3-oxazinan-2-one. 79 WO 2009/058300 PCT/US2008/012272 A solution of impure 3-amino-1-(4-bromophenyl)propan-1-ol (0.85 g, 3.7 mmol) and 1,1 '-carbonyldiimidazole (3.6 g, 22 mmol) in THF (74 mL) was heated to 40 *C. After 18 h the solvent was evaporated and the residue was treated with water and extracted with DCM (thrice). The combined organic extract was washed with brine, dried over sodium sulfate, and the solvent 5 was evaporated. The residue was purified by preparative HPLC, the appropriate fractions were combined, and the volatiles were evaporated. The aqueous residue was extracted with DCM (thrice), the combined organic extract was washed with brine, and the solvent was evaporated to give the title compound (45 mg). Exact mass calculated for C1 0

H,

0 BrNO 2 : 255.0, found: LCMS m/z = 256.5 [M+H]*. 10 Step C: Preparation of 6-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 1,3-oxazinan-2-one. A mixture of 6-(4-bromophenyl)-1,3-oxazinan-2-one (0.045 g, 0.18 mmol), (R)-4-(2-(2 methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (0.047 g, 0.18 mmol), tetrakis(triphenylphosphine)palladium(O) (0.006 g, 0.005 mmol), sodium carbonate (0.18 mL of 15 2.0 M aqueous solution, 0.35 mmol), benzene (0.68 mL), and ethanol (0.20 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 3 h. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a white TFA salt (15 mg). Exact mass calculated for C 23

H

28

N

2 0 2 : 364.2, found: LCMS m/z = 365.6 [M+H]*; 'H 20 NMR (400 MHz, Methanol-d 4 ) S ppm 1.47 (d, J= 6.5 Hz, 3H), 1.75 (dddd, J= 13.2, 9.0, 9.0, 9.0 Hz, 1H), 2.21-2.00 (in, 3H), 2.30-2.23 (in, 1H), 2.41-2.31 (m, 1H), 3.20-3.02 (in, 2H), 3.38 3.23 (in, 4H), 3.59-3.42 (in, 2H), 3.70-3.60 (in, 1H), 3.75 (ddd, J= 15.3, 12.6, 7.2 Hz, 1H), 5.45 (dd, J= 10.1, 2.6 Hz, 1H), 7.41 (d, J= 8.1 Hz, 2H), 7.49 (d, J= 8.3 Hz, 2H), 7.67-7.61 (in, 4H). 25 Example 1.43: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 1,3-oxazinan-2-one (Compound 28). Step A: Preparation of 4-(4-Bromophenyl)-1,3-oxazinan-2-one. A solution of 3-amino-3 -(4-bromophenyl)propan- 1 -ol (0.10 g, 0.44 mmol) and 1,1' carbonyldiimidazole (0.70 g, 0.44 mmol) in THF (9 mL) was heated to 40 *C. After 3 d the 30 solvent was evaporated and the residue was partitioned between water and DCM. The aqueous phase was extracted twice more with DCM. The combined organic extract was washed with brine, dried over sodium sulfate and concentrated. The residue was subjected to acidic and basic extraction conditions. The organic extract was washed with brine and dried over sodium sulfate. The solvent of the extract was evaporated to give the title compound as a colorless oil. Exact 35 mass calculated for CioH 10 BrNO 2 : 255.0, found: LCMS m/z = 256.4 [M+H]*. Step B: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 1,3-oxazinan-2-one. 80 WO 2009/058300 PCT/US2008/012272 A mixture of impure 4-(4-bromophenyl)-1,3-oxazinan-2-one (0.35 g, 1.4 mmol), (R)-4-(2 (2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (0.37 g, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.041 mmol), sodium carbonate (2.1 mL of 2.0 M aqueous solution, 4.1 mmol), benzene (4.6 mL), and ethanol (1.3 mL) were combined in a 5 suitable microwave vial and irradiated under microwave conditions at 100 'C for 24 h. The mixture was filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The residue was partitioned between water and DCM. The aqueous phase was extracted twice more with DCM. The combined organic phase was washed with brine, dried over sodium sulfate, and then the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound 10 as a white TFA salt (3.0 mg). Exact mass calculated for C 23

H

28

N

2 0 2 : 364.2, found: LCMS m/z = 365.5 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 8 ppm 1.47 (d, J= 6.5 Hz, 3H), 1.81-1.70 (in, 1H), 2.21-1.93 (in, 3H), 2.40-2.27 (in, 2H), 3.20-3.02 (in, 2H), 3.33-3.23 (in, 3H), 3.59-3.50 (in, 1H), 3.68-3.60 (in, 1H), 3.75 (ddd, J= 13.1, 7.9, 5.3 Hz, IH), 4.38-4.25 (in, 2H), 4.73(dd, J= 7.4, 5.3 Hz, 1H), 7.46-7.38 (in, 4H), 7.67-7.61 (in, 4H). 15 Example 1.44: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 1,3-dioxan-2-one (Compound 29). Step A: Preparation of (R)-(4'-(2-(2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methanol. 20 A mixture of (4-bromophenyl)methanol (0.50 g, 2.7 mmol), (R)-4-(2-(2-methylpyrrolidin-1 yl)ethyl)phenylboronic acid hydrochloride (0.72 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.093 g, 0.080 mmol), sodium carbonate (4.0 mL of 2.0 M aqueous solution, 8.0 mmol), benzene (10 mL), and ethanol (3 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 90 min. The mixture was 25 filtered through a pad of Celite@ with EtOAc, and the solvents were evaporated. The crude material was partitioned between water and DCM. The aqueous phase was extracted twice more with DCM. The combined organic phase was washed with brine, dried over sodium sulfate, and then the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a white TFA salt (0.35 g, 44%). Exact mass calculated for C 20

H

25 NO: 295.2, found: LCMS m/z= 30 296.3 [M+H]*. Step B: Preparation of (R)-4'-(2-(2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 carbaldehyde. To a stirring solution of (R)-(4'-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methanol (0.35 g, 1.2 mmol) in DCM (5 mL) was added 4A molecular sieves (0.60 g), NMO 35 (0.21 g, 1.8 mmol), and TPAP (0.025 g, 0.071 mmol). After 3 days the mixture was filtered through a plug of Celite@/SiO 2 , washing with DCM and EtOAc. The solvents were evaporated 81 WO 2009/058300 PCT/US2008/012272 to give the title compound as an oil (0.17 g, 49 %). Exact mass calculated for C 20

H

23 NO: 293.2, found: LCMS m/z = 294.0 [M+H]*. Step C: Preparation of Ethyl 3-Hydroxy-3-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)propanoate. 5 To a stirring solution of diisopropylethylamine (0.15 mL, 1.1 mmol) in THF (1 mL) at -78 'C was added nBuLi (0.44 mL of 2.5 M hexane solution, 1.1 mmol). After 15 min, a solution of EtOAc (0.11 mL, 1.1 mmol) in THF (0.2 mL) was added. After 30 min, a solution of (R)-4'-(2-(2-methylpyrrolidin- 1 -yl)ethyl)biphenyl-4-carbaldehyde (0.16 g, 0.55 mmol) in THF (0.2 mL) was added. After 30 min, the cold bath was removed and the mixture was allowed to 10 reach ambient temperature. After 2 h, the reaction was quenched with water and extracted with EtOAc (thrice). The combined organic extract was washed with brine and dried over sodium sulfate. The solvent was evaporated to give the title compound as an amber oil (0.19 g, 90%). Exact mass calculated for C 24

{

31

NO

3 : 381.2, found: LCMS m/z = 382.5 [M+H]*. Step D: Preparation of 1-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 15 yl)propane-1,3-diol. To a stirring solution of ethyl 3-hydroxy-3-(4'-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)biphenyl-4-yl)propanoate (0.19 g, 0.49 mmol) in THF (3 mL) at 0 'C was added lithium aluminum hydride (0.49 mL of 1.0 M THF solution, 0.49 mmol). The cold bath was removed and the mixture was stirred at ambient temperature overnight. After 16 h, the reaction 20 was quenched with ice water and extracted with EtOAc (thrice). The combined organic extract was treated with dilute aqueous HCl to pH 1. The mixture was extracted with water (thrice), then the combined aqueous extract was basified with 50% NaOH to pH 10. The basic solution was extracted with EtOAc (thrice), then the combined organic extract was washed with brine and dried over sodium sulfate. The solvent was evaporated to give the title compound as an 25 amber oil (0.13 g, 77%). Exact mass calculated for C 2 2

H

2 9

NO

2 : 339.2, found: LCMS m/z= 340.4 [M+H]*. Step E: Preparation of 4-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl) 1,3-dioxan-2-one. To a stirring solution of 1-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 30 yl)propane-1,3-diol (0.13 g, 0.38 mmol) in THF (8 mL) at 0 'C was added 1,1' carbonyldiimidazole (CDI) (0.061 g, 0.38 mmol). After 1 h the cold bath was removed and the mixture was stirred overnight. After 18 h, more CDI (0.030 g, 0.19 mmol) was added. After 1 h, the solvent was evaporated and the residue was partitioned between water and EtOAc. The aqueous phase was extracted twice more with EtOAc. The combined organic extract was 35 washed with brine and dried over sodium sulfate. The solvents were evaporated to give the title compound as an amber oil (0.16 g). This material was purified by preparative HPLC to give the title compound as a TFA salt (16 mg, 8.8%). Exact mass calculated for C 23

H

27

NO

3 : 365.2, 82 WO 2009/058300 PCT/US2008/012272 found: LCMS m/z = 366.4 [M+H]*; 'H NMR (400 MHz, Methanol-d 4 ) 6 ppm 1.47 (d, J= 6.5 Hz, 3H), 1.75 (dddd, J= 13.2, 9.1, 9.1, 9.1 Hz, 1H), 2.21-2.00 (m, 2H), 2.44-2.26 (m, 3H), 3.20 3.03 (m, 2H), 3.33-3.23 (m, 2H), 3.57-3.50 (m, 1H), 3.64 (ddd, J= 16.6, 10.8, 6.0 Hz, 1H), 3.76 (ddd, J= 13.1, 8.0, 5.3 Hz, 1H), 4.55-4.49 (in, 1H), 4.62 (ddd, J= 11.0, 11.0, 3.7 Hz, 1H), 5.69 5 (dd, J= 10.4, 3.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.50 (d, J= 8.3 Hz, 2H), 7.64 (d, J= 8.2 Hz, 2H), 7.68 (d, J= 8.3 Hz, 2H). Example 1.45: Preparation of 5-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)morpholin-3-one (Compound 31). 10 Step A: Preparation of 2-Amino-2-(4-bromophenyl)ethanol. To a stirring solution of 1-(4-bromophenyl)ethane-1,2-diol (3.0 g, 14 mmol), in acetonitrile (25 mL), was added concentrated sulfuric acid (7.4 mL, 0.14 mol). The resulting solution was stirred at room temperature for 1 h, then heated to reflux. After 2 h, the mixture was cooled to room temperature and water (10 mL) was added. The acetonitrile was removed by 15 rotary evaporation. The resulting aqueous slurry was heated to 100 'C. After 2 h, the mixture was cooled to room temperature and DCM was added. The mixture was stirred for 5 min before separating the layers. The organic layer was extracted once more with water, then the combined organic extract was set aside. The aqueous extract was treated with 50% aqueous NaOH to pH 10, then extracted with EtOAc (thrice). The combined EtOAc extracts were washed with brine, 20 dried over sodium sulfate, and then the solvents were evaporated to give the title compound (1.9 g, 64%). Exact mass calculated for CgH1 0 BrNO: 215.0, found: LCMS m/z = 216.3 [M+H]. Step B: Preparation of 5-(4-Bromophenyl)morpholin-3-one. To a stirring suspension of sodium hydride (1.3 g of 60% dispersion in mineral oil, 32 mmol) in benzene (50 mL) was added a solution of 2-amino-2-(4-bromophenyl)ethanol (1.7 g, 25 7.9 mmol) in benzene (50 mL). The mixture was stirred at room temperature for 30 min, then cooled to 0 *C. A cooled solution of ethyl chloroacetate in benzene (50 mL) was added dropwise at 0 *C. The mixture was stirred for 2.5 h. The reaction was quenched by pouring into ice/MTBE and then treating with 10% HC1 to pH 1. The mixture was extracted with MTBE (thrice), washed with brine, and dried over sodium sulfate. The solvents were evaporated to give 30 a yellow residue. The residue was purified by silica gel flash chromatography to give the title compound as a white solid (0.70 g, 35%).Exact mass calculated for C 0 H1 0 BrNO2: 255.0, found: LCMS m/z = 256.4 [M+H]*. Step C: Preparation of 5-(4'-(2-((R)-2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)morpholin-3-one. 35 A mixture of 5-(4-bromophenyl)morpholin-3-one (0.10 g, 0.39 mmol), (R)-4-(2-(2 methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (0.11 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol), sodium carbonate (0.59 mL of 83 WO 2009/058300 PCT/US2008/012272 2.0 M aqueous solution, 1.2 mmol), benzene (1.0 mL), and ethanol (0.3 mL) were combined in a suitable microwave vial and irradiated under microwave conditions at 100 *C for 30 min. The mixture was filtered through a pad of Celite with EtOAc, and the solvents were evaporated. The residue was purified by preparative HPLC to give the title compound as a TFA salt (20 mg, 5 11%). Exact mass calculated for C 23

H

28

N

2 0 2 : 364.2, found: LCMS m/z = 365.5 [M+H]; 'H NMR (400 MHz, DMSO-d 6 ) 5 ppm 1.38 (d, J= 6.5 Hz, 3H), 1.61 (dddd, J= 12.9, 8.9, 8.9, 8.9 Hz, 1H), 2.11-1.85 (in, 2H), 2.27-2.17 (in, 1H), 3.12-2.93 (in, 2H), 3.28-3.17 (in, 2H), 3.70-3.45 (in, 4H), 3.99 (dd, J= 11.6,4.1 Hz, 1H), 4.11 (s, 2H), 4.70-4.65 (in, 1H), 7.45-7.40 (in, 4H), 7.69-7.63 (in, 4H), 8.46 (s, 1H), 9.34 (bs, 1H). 10 Example 1.46: Preparation of (S)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)phenyl)oxazolidin-2-one. To a three-necked, round-bottom 500 mL flask equipped with a temperature probe, mechanical stirrer and nitrogen inlet was added (S)-4-(2-oxooxazolidin-4-yl)phenyl 15 trifluoromethanesulfonate (20.0 g, 64.3 mmol) followed by toluene (250 mL). The mixture was stirred under N 2 and potassium acetate (13.87 g, 141 mmol) was added followed by 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (24.48 g, 96 mmol), triphenylphosphine (1.011 g, 3.86 mmol) and PdC1 2 (PPh 3

)

2 (1.353 g, 1.928 mmol). The reaction mixture was gradually heated (by an oil bath) to 100 *C (internal). There was a mild exotherm 20 initially and the internal temperature went up to 110 *C. The reaction was cooled to -100 *C and maintained at that temperature for 2 h. LCMS analysis showed there was less than 1% of starting material. The starting material and the product have the same retention time by LCMS; the product formation was analyzed by extracted ion chromatogram data. The reaction was heated for 20 min more, cooled to -30 *C, water (100 mL) was added 25 and the mixture was stirred well for 30 min at room temperature. The product crystallized out and was collected by filtration. The filter cake was washed once with water followed by 1:1 toluene:heptane and dried overnight in a vacuum oven at -50 *C to obtain the product as brown solid (16.09 g). Exact mass calculated for Ci 5

H

2 0 BN0 4 : 289.15, found: LCMS m/z = 290.0 [M+H]*; 92% purity by LCMS. 30 A solution of the above material (16.09 g) was dissolved in EtOAc (100 mL), acetonitrile (50 mL) and methanol (20mL) with warming to -35 *C. The solution was passed through a plug of silica. Then, the plug was eluted with EtOAc three times. The combined solvent (after plug filtration) was concentrated under reduced pressure. Heptane was added and the residual solvent was swapped with heptane. The heptane slurry was concentrated 35 (approximately 2-3 volumes) and filtered. The filter cake was washed with heptane to obtain a beige solid, which was dried in a vacuum oven at ~50 * to leave the title compound (14.35 g). 84 WO 2009/058300 PCT/US2008/012272 Exact mass calculated for C 1 5

H

20 BN0 4 : 289.15, found: LCMS m/z = 290.0 [M+H]*; 95.7% purity by LCMS. Example 2: [ 3 H] N-Alpha-Methyl-Histamine Competitive Histamine H3-receptor Binding 5 Assay. The histamine receptor binding assay was conducted using standard laboratory procedures as described below. A crude membrane fraction was prepared from whole rat brain cortex using a polytron to homogenize the tissue followed by differential centrifugation in a HEPES-based buffer containing protease inhibitors. Membranes where frozen at -80 *C until 10 needed. Frozen membranes were thawed and resuspended in ice-cold assay buffer consisting of 50 mM TRIS containing 5 mM EDTA (pH = 7.4). 50 micrograms (pg) of membrane protein was added to each well of a 96-well assay plate along with test compound and [ 3 H]-N-a-methyl histamine (1 nanomolar (nM) final assay concentration). Imetit was used as an assay positive control at varying concentrations. The plate was incubated for 30 min at room temperature. The 15 assay was terminated by rapid filtration through a 96-well glass fiber filtration plate (GF/C) using a cell harvester (Perkin-Elmer). Captured membranes were washed three times with cold assay buffer and plates were dried at 50 *C. 35 microliters (AL) of scintillation cocktail was added to each well and membrane-bound radioactivity was recorded using a TopCount 96-well plate scintillation counter (Perkin-Elmer). 20 The following table shows the observed activities for certain compounds of the present invention. Compound No. Ki Binding Assay (nM) 7 1.3 12 0.8 13 2.2 14 3.2 15 1.1 Certain other compounds of the invention had activity values ranging from 0.6 nM to 25 24.0 nM in this assay. Example 3: Rat Polysomnography Protocol. Animals: Male Sprague-Dawley rats (225-350 g) (Harlan, San Diego, CA) were singly housed and maintained in a humidity- (30-70%) and temperature- (20-22 *C) controlled facility 30 on a 12 h: 12 h light/dark cycle (lights on at 6:30 A.M.) with free access to food (Harlan-Teklad 85 WO 2009/058300 PCT/US2008/012272 Western Res., Orange, CA, Rodent Diet 8604) and water. Rats were allowed at least three days of habituation to the animal facility before surgery. Procedures: Rats were anaesthetized with a ketamine/xylazine mixture, and surgically prepared for 5 EEG and EMG recording. After 2-3 weeks of post-surgical recovery, rats were habituated to polypropylene test cages for at least three days. On test days, the rats were placed in the test chambers and habituated overnight. At 10 am the next day, the rats were administered the test compound, connected to the recording apparatus, and placed back into the test chambers for 3 h. Data analysis 10 EEG and EMG data were digitized and stored in 10 s epochs over the three hour test period. These data were then visually scored, and each 10 s epoch characterized as either a non REM sleep, REM sleep, or waking episode. Total wake time over the three hour period was calculated for each rat after either vehicle administration or test compound. Percent increase in wakefulness was then derived for each rat. 15 The following table shows the observed percent increase in wakefulness over 1 h after oral administration of a representative compound at 1.0 mg/kg. Cmpd No. % Increase in wakefulness +/- s.e. 2 54.4 15.8 Example 4: Human Histamine H3-Receptor Binding Assay - MDS Pharma Services 20 (Taiwan). Compounds of the invention were tested for their ability to bind to the human histamine H3-receptor using the MDS Pharma Services (Taiwan) assay, Catalogue No. 239810. Certain compounds of the present invention and their corresponding activity values are shown in following table. 25 Compound No. Binding Assay (Ki, nM) 1 6.9 2 4.4 Certain other compounds of the invention had activity values ranging from about 4.4 nM to about 23 nM in this assay. 30 Example 5: Blockade of RAMH-Induced Drinking Assay. When administered to rodents, H3 agonists such as R-a-methyl-histamine (RAMH) induce a drinking response that is sensitive to reversal with an H3 antagonist. Blockade of 86 WO 2009/058300 PCT/US2008/012272 RAMH-induced drinking can therefore be utilized as an in vivo assay for functional H3 antagonist activity. In this assay, male Sprague Dawley rats (250-350g) were housed three per cage and maintained under a reverse 12 h light cycle (lights off at 1130 h). At 1030 h on the day of test, rats were individually housed in new cages and food was removed. 120 min later, rats 5 were administered test article (vehicle or H3 antagonist, 0.3 mg/kg PO). 30 min later, water was removed, and RAMH (vehicle or RAMH 3 mg/kg salt SC) was administered. 10 min after administration of RAMH, weighed water bottles were placed in the cages, and drinking was allowed for 20 min. Water consumption was determined for each animal by weighing each bottle to the nearest 0.1 g. Data is expressed as percentage reduction in water intake according to 10 the following formula: [((VEH/RAMH) - (ANTAGONIST/RAMH)) / ((VEH/RAMH) - (BASELINE DRINKING: lmL))]*100 Compound No. % inhibition of RAMH-induced drinking 4 109.5 5 50.6 11 83.3 15 Those skilled in the art will recognize that various modifications, additions, substitutions and variations to the illustrative examples set forth herein can be made without departing from the spirit of the invention and are, therefore, considered within the scope of the invention. All documents referenced above, including, but not limited to, printed publications 20 and provisional and regular patent applications, are incorporated herein by reference in their entirety. 87

Claims (6)

1. 2. A compound according to any one of claims 1 to 2, wherein R1, R 2 and R 3 are all H. 20 3. A compound according to claim 1, wherein R' is selected from C 1 -C 6 alkoxy, C 1 -C 6 alkyl and halogen.
2. 4. A compound according to claim 3, wherein R' is selected from methoxy, methyl, chloro and fluoro. 25
3. 5. A compound according to claim 1, wherein R 2 is selected from CI-C 6 alkoxy, C 1 -C 6 alkyl and halogen.
4. 6. A compound according to claim 5, wherein R 2 is selected from methoxy, methyl, chloro 30 and fluoro.
5. 7. A compound according to claim 1, wherein R 3 is selected from C 1 -C 6 alkoxy, CI-C 6 alkyl and halogen.
6. 88- WO 2009/058300 PCT/US2008/012272 8. A compound according to claim 7, wherein R3 is selected from methoxy, methyl, chloro and fluoro. 5 9. A compound according to any one of claims 1 to 8, wherein Re is H. 10. A compound according to any one of claims I to 8, wherein R 4 is C 1 -C 4 alkyl. 11. A compound according to any one of claims 1 to 8, wherein R4 is methyl. 10 12. A compound according to any one of claims 1 to 11, wherein n is 0. 13. A compound according to any one of claims 1 to 11, wherein n is 1. 15 14. A compound according to any one of claims I to 11, wherein n is 2. 15. A compound according to any one of claims 1 to 14, wherein ring A is selected from oxooxazolidinyl, and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a C 1 -C 6 alkyl substituent; and wherein the C 1 -C 6 alkyl substituent is optionally 20 substituted with a C 1 -C 6 alkoxy substituent. 16. A compound according to any one of claims I to 14, wherein ring A is selected from 2 oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3-isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2-oxooxazolidin-5-yl and 2-oxo-1,3 25 oxazinan-4-yl. 17. A compound according to any one of claims 1 to 14, wherein ring A is selected from oxopyrrolidinyl, oxo-1,3-dioxolanyl, oxo-1,3-dioxanyl, oxomorpholinyl and oxo-1,3 oxazinanyl; wherein each ring A is optionally substituted with a CI-C 6 alkyl substituent; 30 and wherein the C 1 -C 6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy substituent. 18. A compound according to any one of claims I to 14, wherein ring A is selected from 2 oxopyrrolidin-4-yl, 2-oxopyrrolidin-5-yl, 2-oxo-1,3-dioxolan-4-yl, 2-oxo-1,3-dioxan-4 35 yl, 3-oxomorpholin-5-yl and 2-oxo-1,3-oxazinan-6-yl. 89 WO 2009/058300 PCT/US2008/012272 19. The compound according to claim 1, selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof: H AC-(CH 2 N2 (Ic) wherein: 5 R 4 is H or C 1 -C 4 alkyl; ring A is selected from oxooxazolidinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a C 1 -C 6 alkyl substituent; and wherein the C 1 -C 6 alkyl substituent is optionally substituted with a C 1 -C 6 alkoxy substituent; and n is 0, 1 or 2. 10 20. The compound according to claim 1, selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates and hydrates thereof: H AC-(CH 2 / N21 (Ic) wherein: 15 R 4 is H or methyl; ring A is selected from 2-oxooxazolidin-4-yl, 3-isopropyl-2-oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2 oxooxazolidin-5-yl and 2-oxo-1,3-oxazinan-4-yl; and n is 0, 1 or 2. 20 21. The compound according to claim 1, selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, solvates and hydrates thereof: H AC(CH 2 (1g) wherein: 25 ring A is selected from oxooxazolidinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a C,-C 6 alkyl substituent; and wherein the CI-C 6 alkyl substituent is optionally substituted with a CI-C 6 alkoxy substituent; and n is 0, 1 or 2. 90 WO 2009/058300 PCT/US2008/012272 22. The compound according to claim 1, selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, solvates and hydrates thereof: H AC -CH 2 (Ig) 5 wherein: ring A is selected from 2-oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3 isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2 oxooxazolidin-5-yl, 2-oxo-1,3-oxazinan-4-yl; and n is 0, 1 or 2. 10 23. The compound according to claim 1, selected from compounds of Formula (Ii) and pharmaceutically acceptable salts, solvates and hydrates thereof: R' R3 H CA C-CH 2 R2 (Ii) wherein: 15 R', R2 and R3 are each independently selected from H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl and halogen; ring A is selected from oxooxazolidinyl, oxo-1,3-oxazinanyl, oxopyrrolidinyl, oxo-1,3-dioxolanyl, oxo-1,3-dioxanyl, oxomorpholinyl and oxo-1,3-oxazinanyl; wherein each ring A is optionally substituted with a C 1 -C 6 alkyl substituent; and 20 wherein the C 1 -C 6 alkyl substituent is optionally substituted with a C 1 -C 6 alkoxy substituent; and nis0, 1 or2. 24. The compound according to claim 1, selected from compounds of Formula (Ii) and 25 pharmaceutically acceptable salts, solvates and hydrates thereof: 91 WO 2009/058300 PCT/US2008/012272 R1 R3 H AC -CH 2 ) R2 (Ii) wherein: R', R 2 and R3 are each independently selected from H, methoxy, methyl, chloro and fluoro; 5 ring A is selected from 2-oxooxazolidin-4-yl, 3-methyl-2-oxooxazolidin-4-yl, 3 isopropyl-2-oxooxazolidin-4-yl, 3-(2-methoxyethyl)-2-oxooxazolidin-4-yl, 2 oxooxazolidin-5-yl, 2-oxo-1,3-oxazinan-4-yl, 2-oxopyrrolidin-4-yl, 2-oxopyrrolidin-5 yl, 2-oxo-1,3-dioxolan-4-yl, 2-oxo-1,3-oxazinan-6-yl, 2-oxo-1,3-dioxan-4-yl and 3 oxomorpholin-5-yl; and 10 nis0,1or2. 25. A compound according to claim I selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: (S)-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 15 yl)methyl)oxazolidin-2-one; (S)-4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)oxazolidin-2-one; (R)-4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)oxazolidin-2-one; (R)-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one; 20 (R)-3-methyl-4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; (R)-3-(2-methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; (R)-3-isopropyl-4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 25 yl)oxazolidin-2-one; (R)-3-methyl-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one; (R)-3-(2-methoxyethyl)-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl 4-yl)methyl)oxazolidin-2-one; 30 (R)-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)methyl)-1,3 oxazinan-2-one; (S)-3-methyl-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one; 92 WO 2009/058300 PCT/US2008/012272 (S)-3-(2-methoxyethyl)-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)methyl)oxazolidin-2-one; (S)-4-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)methyl)-1,3 oxazinan-2-one; 5 5-((4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)oxazolidin-2-one; (S)-3-methyl-4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; (S)-3-(2-methoxyethyl)-4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; and 10 (R)-4-(4'-(2-(pyrrolidin-1-yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. 26. A compound according to claim I selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: (R)-4-(2,6-dichloro-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 15 yl)oxazolidin-2-one; (R)-4-(2-methyl-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; (R)-4-(2-chloro-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; 20 (R)-4-(2-methoxy-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; (R)-4-(2'-chloro-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 yl)oxazolidin-2-one; (R)-4-(3'-fluoro-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4 25 yl)oxazolidin-2-one; 4-(3-methyl-4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)oxazolidin 2-one; 4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)pyrrolidin-2-one; 4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)-1,3-dioxolan-2-one; 30 6-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)-1,3-oxazinan-2-one; 4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)-1,3-oxazinan-2-one; 4-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)-1,3-dioxan-2-one; 5-(4'-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)pyrrolidin-2-one; 5 -(4'-(2-((R)-2-methylpyrrolidin- 1 -yl)ethyl)biphenyl-4-yl)morpholin-3-one; 35 (S)-4-(2'-methyl-4'-(2-(pyrrolidin- 1 -yl)ethyl)biphenyl-4-yl)oxazolidin-2-one; and (S)-4-(2'-methoxy-4'-(2-(pyrrolidin-1-yl)ethyl)biphenyl-4-yl)oxazolidin-2-one. 93 WO 2009/058300 PCT/US2008/012272 27. A pharmaceutical composition comprising a compound according to any one of claims I to 26 and a pharmaceutically acceptable carrier. 5 28. A method for treating a histamine H3-receptor associated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 27. 10 29. A method according to claim 28, wherein said histamine H3-receptor associated disorder is selected from a cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness, narcolepsy, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, 15 allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and pain. 30. A method according to claim 28, wherein said histamine H3-receptor associated disorder is a disorder of sleep and wakefulness. 20 31. A method according to claim 28, wherein said histamine H3-receptor associated disorder is a cognitive disorder. 32. A method according to claim 28, wherein said histamine H3-receptor associated disorder is cataplexy. 25 33. A method of inducing wakefulness in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims I to 26 or a pharmaceutical composition according to claim 27. 30 34. A method for treating pain in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims I to 26 or a pharmaceutical composition according to claim 27. 35. Use of a compound according to any one of claims 1 to 26 in the manufacture of a 35 medicament for the treatment of a histamine H3-receptor associated disorder. 94 WO 2009/058300 PCT/US2008/012272 36. Use of a compound according to any one of claims I to 26 in the manufacture of a medicament for the treatment of a disorder selected from a cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness, narcolepsy, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, 5 attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and pain. 37. Use of a compound according to any one of claims 1 to 26 in the manufacture of a 10 medicament for the treatment of a disorder of sleep and wakefulness. 38. Use of a compound according to any one of claims I to 26 in the manufacture of a medicament for the treatment of a cognitive disorder. 15 39. Use of a compound according to any one of claims I to 26 in the manufacture of a medicament for the treatment of cataplexy. 40. Use of a compound according to any one of claims 1 to 26 in the manufacture of a medicament for inducing wakefulness. 20 41. Use of a compound according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of pain. 42. A compound according to any one of claims I to 26 for use in a method of treatment of 25 the human or animal body by therapy. 43. A compound according to any one of claims 1 to 26 for use in a method for the treatment of a histamine H3-receptor associated disorder. 30 44. A compound according to any one of claims I to 26 for use in a method for the treatment of a histamine H3-receptor associated disorder selected from a cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness, narcolepsy, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic 35 responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and pain. 95 WO 2009/058300 PCT/US2008/012272 45. A compound according to any one of claims I to 26 for use in a method for the treatment of a disorder of sleep and wakefulness. 46. A compound according to any one of claims I to 26 for use in a method for the 5 treatment of a cognitive disorder. 47. A compound according to any one of claims I to 26 for use in a method for the treatment of cataplexy. 10 48. A compound according to any one of claims I to 26 for use in a method of inducing wakefulness. 49. A compound according to any one of claims 1 to 26 for use in a method of treating pain. 15 50. A process for preparing a composition comprising admixing a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier. 96