WO2011034828A1

WO2011034828A1 - Substituted para-biphenyloxymethyl dihydro oxazolopyrimidinones, preparation and use thereof

Info

Publication number: WO2011034828A1
Application number: PCT/US2010/048687
Authority: WO
Inventors: Pascal George; Daniel Hall; Ryan Hartung; Jr. Raymond W. Kosley; Anthony C. Scotese
Original assignee: Sanofi-Aventis
Priority date: 2009-09-15
Filing date: 2010-09-14
Publication date: 2011-03-24
Also published as: TW201121978A; AR078173A1

Abstract

The present invention relates to a series of substituted para-biphenyloxymethyl dihydro oxazolopyrimidinones of formula (I) as defined herein. This invention also relates to methods of making these compounds including novel intermediates. The compounds of this invention are modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2 receptor. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic neurodegenerative conditions, psychoses, cognition deficit disorders, convulsions, anxiety, depression, migraine, pain, sleep disorders and emesis.

Description

SUBSTITUTED PARA-BIPHENYLOXYMETHYL DIHYDRO OXAZOLOPYRIMIDINONES, PREPARATION AND USE THEREOF

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a series of substituted dihydro biphenyloxymethyl oxazolopyrimidinones. More specifically, the present invention relates to a series of substituted 2-biphen-4-yloxymethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-ones. This invention also relates to methods of making these compounds. The compounds of this invention are allosteric modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases including diseases associated with the central nervous system.

Description of the Art

Recently, there has been a considerable amount of research involving L-glutamate, which is the most abundant neurotransmitter in the central nervous system (CNS). More specifically, L-glutamate mediates the major excitatory pathways in mammals, and is therefore referred to as an excitatory amino acid (EAA). Thus the receptors that respond to glutamate are known as excitatory amino acid receptors (EAA receptors). Based on the extensive research performed lately it can be readily discerned that EAAs are of great physiological importance. Particularly, EAAs are known to play a role in several physiological processes including long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation and sensory perception, just to name a few. See, e.g., Watkins & Evans, Annual Reviews in Pharmacology and Toxicology, 21 : 165 (1981); Monaghan, Bridges, and Coltman, Annual Reviews in Pharmacology and Toxicology, 29:365 (1989); Watkins, Krogsgaard-Larsen and Honore, Transactions in Pharmaceutical Science, 11 :25 (1990).

Broadly, the EAA receptors are classified into two types: 1) "ionotropic" - which are directly coupled to the opening of cation channels in the cell membrane of the neurons; and 2) "metabotropic" - which are G-protein coupled receptors (GPCR). The excessive or inappropriate stimulation of EAA receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. Thus there is a renewed interest in developing small molecule new drugs to alleviate these conditions.

The metabotropic glutamate receptors (mGluR) are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. One function of these receptors is to modulate the presynaptic release of glutamate and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Thus it has been reported widely in the literature that agonists and antagonists of these receptors are useful in the treatment of a variety of disease conditions including acute and chronic neurodegenerative conditions, psychoses, convulsions, anxiety, depression, migraine, pain, sleep disorders and emesis.

The metabotropic glutamate receptors (mGluR) are again classified into three groups based on receptor homology and signaling mechanisms. Among them, recent pharmacological and histochemical studies have suggested that the group II mGluR (mGluR2 and mGluR3) plays crucial roles in the control of emotional states. For example, MGS0039, a selective group II mGluR antagonist, has been shown to exhibit dose-dependent antidepressant-like effects in some animal models. See, e.g., Kawashima, et al, Neurosci. Lett., 2005, 378(3): 131-4.

Recently, it has also been reported that glutamate/N-methyl-D-aspartate glutamate receptors (NMDAR) are implicated in schizophrenia. This was indeed supported by the observation that administration of NMDAR blockers to human volunteers is psychotomimetic and administration to schizophrenia patients exacerbates pre-existing symptoms. For example, systemic administration of group II mGluR agonists suppress phencyclidine (PCP) induced behavioral effects and the increase in glutamate efflux. It has also been observed that activation of group II mGluRs (mGluR2 and mGluR3) decreases glutamate release from presynaptic nerve terminals, suggesting that group II mGluR agonists may be beneficial in the treatment of schizophrenia. See, e.g., Chavez-Noriega et al, Current Drug Targets - CNS & Neurological Disorders, 2002, 1, 261-281.

Although there is a great deal of interest in developing small molecule drugs that are active at the mGluR sites, the researchers are faced with a lack of potent and selective molecules. In spite of this, there are innumerable reports highlighting the great interest around these potential therapeutic targets. See, e.g., Sabbatini and Micheli, Expert Opin. Ther. Patents (2004) 14(11): 1593-1604.

However, there is still a need to develop selective compounds for one subtype over another metabotropic glutamate receptor site. One strategy that has recently emerged involves the discovery of allosteric modulators that do not bind at the glutamate binding site. An allosteric modulator only works if the agonist (glutamate) is present at the orthosteric binding site; thus, an allosteric modulator will only potentiate or block effects produced by the presence of an agonist, but have no activity on its own. Such a strategy is believed to confer greater specificity to desired pharmacological effects because they affect the normal physiological activity of the agonist.

In addition, there is still a considerable interest in developing small molecule "drug like" compounds that exhibit improved potency and modulation of mGluR2 as well as improved brain penetration. There is also an interest in developing modulators of mGluR2 that are devoid of typical side effects exhibited by typical and atypical antipsychotic compounds, such as for example extrapyramidal symptoms including tardive dyskinesia, weight gain, etc. It is also expected that allosteric modulators that exhibit improved subtype selectivity will feature an improved pharmacological safety profile. It is further believed that a selective modulator of mGluR2 will also exhibit efficacy on cognitive dysfunction in schizophrenia patients thereby improving working memory and positive symptoms.

WO2008/112483 discloses a series of 2-substituted-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-ones and 2-substituted-2,3 ,5 ,6-tetra-hydro-oxazolo[3 ,2-a]pyrimidin-7-ones, which are allosteric modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2.

In addition to exhibiting required allosteric modulation properties the intended drug substance must also meet various "drug-like" properties including but not limited to good adsorption, distribution, metabolism and excretion (ADME) properties as well as pharmacokinetics. For instance, in order for the drug substance to be effective it must interact suitably with various enzymes produced in the body, including cytochrome P450 enzyme or CYPs, esterases, proteases, reductases, dehydrogenases, and the like. Generally it is necessary that the compounds that are suitable as "drugs" must have good CYP-isozyme interaction properties. More notably, it has been observed generally that compounds exhibiting minimal CYP induction and optimal CYP contribution are considered to possess favorable "drug like" properties among other desirable properties. Specific CYP isozymes include CYP3A4, CYP2D6, CYP2C9, among others.

Accordingly, the compounds of the instant invention, notably, substituted 2-biphen-4- yloxymethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-ones are found to be not only effective potentiators of mGluR2 but also exhibit improved "drug-like" properties as described herein.

SUMMARY OF THE INVENTION

Thus in accordance of this invention there are provided compounds of the formula I:

wherein:

Pvi is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2- fluoroethyl and propyl;

P 2 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, 1 ,1-difluoropropyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, phenyl, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, tetrahydrofuranylmethoxymethyl, cyclopropyl and cyclopentyloxymethyl; and

P 3, P , P 5, Re, P 7 and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF₃, (Ci-C4)alkyl, (Ci-C4)alkoxy; or

two of Re, R₇ and Rs are on adjacent carbons and taken together with the phenyl ring form a naphthalene ring; or

two of R6, R₇ and Rs are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered ring; or one of R6, R₇ and Rs bonds with the adjacent phenyl ring to form a fluorenyl ring; or a salt thereof.

In addition, various embodiments of this invention including pharmaceutical compositions comprising various compounds of this invention as well as their use in the treatment of a variety of disorders and/or disease conditions as disclosed herein are also part of this invention all of which are described in detail below.

DETAILED DESCRIPTION OF THE INVENTION

The terms as used herein have the following meanings:

As used herein, the expression "(Ci_C₄)alkyl" includes methyl and ethyl groups, and straight-chain or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. It should particularly be noted that any of the feasible branched (Ci-C₄)alkyl group known in the art is encompassed by this expression. Derived expressions such as "(Ci_C₄)alkoxy", "(Ci_C₄)thioalkyl", "(Ci_C₄)alkoxy(Ci_C₄)alkyl" or "hydroxy(Ci_C₄)alkyl", "(Ci_C₄)alkylcarbonyl", "(Ci_C₄)alkoxycarbonyl(Ci_C₄)alkyl", "(Ci_C₄)alkoxycarbonyl", "amino(Ci_C₄)alkyl", "(Ci_C₄)alkylamino",

"(Ci_C₄)alkylcarbamoyl(Ci_C₆)alkyl", "(Ci_C₄)dialkylcarbamoyl(Ci_C₄)alkyl" "mono- or di- (Ci_C₄)alkylamino(Ci-C₄)alkyl", "amino(Ci_C₄)alkylcarbonyl" "diphenyl(Ci_C₄)alkyl", "phenyl(Ci_C₄)alkyl", "phenylcarboyl(Ci_C₄)alkyl", "phenoxy(Ci_C₄)alkyl" and "(Ci_C₄)alkylsulfonyl," are to be construed accordingly. Similarly other derived expressions, such as (Ci-C₄)alkoxyethoxy shall be construed accordingly. Another derived expression mono- or di-fluoro(Ci-C₄)alkyl shall mean that one or two of the hydrogens are replaced with fluorine. Representative examples of monofluoro(Ci-C₄)alkyl include fluoromethyl, 2-fluoro- eth-l-yl or 1-fluoro-eth-l-yl, 1-fluoro-l-methyl-eth-l-yl, 2-fluoro-l-methyl-eth-l-yl, 3-fluoro- prop-l-yl, and the like. Representative examples of difluoro(Ci-C₄)alkyl include difluoromethyl, 2,2-difluoro-eth-l-yl, 1,2-difluoro-eth-l-yl or 1,1-difluoro-eth-l-yl, 1,2- difluoro-l-methyl-eth-l-yl, 2,2-difluoro-l-methyl-eth-l-yl, 1,3-difluoro-prop-l-yl, and the like.

As used herein, the expression "(C₃-C₇)cycloalkyl" or "(C₃-C₇)carbocyclic ring" includes all of the known cyclic radicals. Representative examples of "cycloalkyl" or "carbocyclic" includes without any limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Derived expressions such as "cycloalkoxy" or "cycloalkyloxy", "cycloalkyloxyethoxy", "cycloalkylalkyl", "cycloalkylaryl", "cycloalkylcarbonyl" are to be construed accordingly. It should further be noted that the expression "(C5-C8)carbocyclic" shall have the same meaning as

"Halogen" (or "halo") means chlorine (chloro), fluorine (fluoro), bromine (bromo), and iodine (iodo).

As used herein, "patient" means a warm blooded animal, such as for example rats, mice, dogs, cats, guinea pigs, and primates such as humans.

As used herein, the expression "pharmaceutically acceptable carrier" means a nontoxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral administration.

The term "pharmaceutically acceptable salts" as used herein means that the salts of the compounds of the present invention can be used in medicinal preparations. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. The acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed. Also, the salts so formed may present either as mono- or di- acid salts and can exist substantially anhydrous or can be hydrated. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

As used herein, the term "prodrug" shall have the generally accepted meaning in the art. One such definition includes a pharmacologically inactive chemical entity that when metabolized or chemically transformed by a biological system such as a mammalian system is converted into a pharmacologically active substance. The expression "stereoisomers" is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. Typically it includes mirror image isomers that are usually formed due to at least one asymmetric center (enantiomers). Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers, also certain individual molecules may exist as geometric isomers (cis/trans). Similarly, certain compounds of this invention may exist in a mixture of two or more structurally distinct forms that are in rapid equilibrium, commonly known as tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

The term "solvate" as used herein means that an aggregate that consists of a solute ion or molecule with one or more solvent molecules. Similarly, a "hydrate" means that a solute ion or molecule with one or more water molecules.

In a broad sense, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a few of the specific embodiments as disclosed herein, the term "substituted" means substituted with one or more substituents independently selected from the group consisting of (Ci_C₂o)alkyl, (C₂_C₆)alkenyl, (Ci_C₆)perfluoroalkyl, phenyl, hydroxy, -C0₂H, an ester, an amide, (Ci-C₆)alkoxy, (Ci-Ce)thioalkyl, (Ci-C₆)perfluoroalkoxy, -NH₂, CI, Br, I, F, CN, SF₅, -NH-lower alkyl, and -N(lower alkyl)₂, unless otherwise noted. However, any of the other suitable substituents known to one skilled in the art can also be used in these embodiments.

"Therapeutically effective amount" means an amount of the compound which is effective in treating the named disease, disorder or condition.

The term "treating" refers to:

(i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it;

(ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.

Thus, in accordance with the practice of this invention there is provided a compound of the formula I:

wherein:

Ri is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2- fluoroethyl and propyl;

R₂ is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl,

2-fluoroethyl, propyl, 1,1-difluoropropyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, phenyl, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, tetrahydrofuranylmethoxymethyl, cyclopropyl and cyclopentyloxymethyl; and R₃, R4, R5, R^, R₇ and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF₃, (Ci-C₄)alkyl, (C₃-C₆)cycloalkyl, (Ci-C₄)alkoxy; or

two of R6, R₇ and Rs are on adjacent carbons and taken together with the phenyl ring form a naphthalene ring; or

two of R6, R₇ and Rs are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered ring; or one of R6, R₇ and Rs bonds with the adjacent phenyl ring to form a fluorenyl ring. As already mentioned above, the compound of formula (I) may be present as a salt when such possibility exists. All forms of salts that can be envisaged are part of this invention.

In an embodiment of this invention the compound of formula (I) of this invention has the following definitions for the substituents Ri through R₈:

Ri is selected from the group consisting of hydrogen, methyl and ethyl;

R₂ is selected from the group consisting of hydrogen, methyl, fluoromethyl,

1,1-difluoropropyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, isopropoxymethyl, phenyl, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, cyclopropyl and cyclopentyloxymethyl; and R₃, R4, R₅, R6, R₇ and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, cyclopropyl and ethoxy.

Again, in this embodiment of the invention the compounds of formula (I) may present in any of the possible salt form, all of which are part of this invention.

In another embodiment of this invention the compound of formula (I) is having the following substituents:

Ri is hydrogen or ethyl;

R₂ is hydrogen;

R₃, R₄, R₅, R₆, R₇ and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy and ethoxy.

Additionally, as noted above all of the compounds of this embodiment may also present as a salt where possible and such salts are also part of this invention.

As another embodiment of this invention the compound of formula (I) is having the following substituents:

Ri is selected from the group consisting of hydrogen, methyl and ethyl;

R₂ is hydrogen;

R₃, R₄, R5 are hydrogen; and

two of R₆, R₇ and Rs are on adjacent carbons and taken together with the phenyl ring form a naphthalene ring; or

two of R₆, R₇ and Rs are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered ring.

All possible salts of this embodiment is also part of this invention.

As specific examples of compounds of formula (I), the following compounds may be enumerated without any limitations:

(S)-2-(biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-2-(biphenyl-4-yloxymethyl)-5-ethoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-cyclopentyloxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-(tetrahydro-i iran-2-ylmethoxymethyl)-2,3-dihyd oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; and

(S)-2-(biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one.

As further specific examples of compounds of formula (I), the following compounds may be enumerated without any limitations:

(S)-2-(3'-chloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(3'-bromo-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(3'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-6-ethyl-2-(2-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-6-ethyl-2-(2'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2'-methyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(3'-methyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(3'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-6-ethyl-2-(2'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

(S)-2-(2'-ethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2-ethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-ethoxymethyl-2-(4'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)-5-phenyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-cyclopentyloxymethyl-2-(4'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(3'-propyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2'-isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(3'-isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-5-(2-fluoro-ethoxymethyl)-2-(3'-isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-fluoromethyl-2-(3'-isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(3'-butyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(3'-isobutyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(3'-tert-butyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(3'-trifluoromethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2'-trifiuoromethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(3'-cyclopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

(S)-2-(2'-cyclohexyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7 one;

(S)-2-(3'-methoxy-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-5-isopropoxymethyl-2-(4'-methoxy-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; and

(S)-2-(2'-acetyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. The following compounds are further enumerated as specific examples of this invention:

(S)-2-(2',3'-difluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

(S)-2-(2',3'-difluoro-biphenyl-4-yloxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(3',4'-difluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a] pyrimidin-7 one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7 one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-methoxymethyl -2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',4'-dichloro-biphenyl-4-yloxymethyl -2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-5-cyclopropyl-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2 '-dichloro-biphenyl-4-yloxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2 '-dichloro-biphenyl-4-yloxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-ethoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-phenyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-5-cyclopentyloxymethyl-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2- ylmethoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(3^5'-dibromo-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(4 ' -fluoro-3 ' -methyl-biphenyl-4-yloxymethyl)-2,3 -dihydro-oxazolo [3 ,2- a]pyrimidin-7-one;

(S)-2-(3'-fluoro-4'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(2'-fluoro-4'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; (S)-2-(2,6-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7^ one;

(S)-2-(3^5'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-methoxy-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-cyclopropyl-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazole[3,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2\4'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-6-ethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2,2'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(2,2'-dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-ethoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-phenyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-cyclopentyloxymethyl-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2- ylmethoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-(2-fiuoro-ethoxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-5-(l , 1 -difluoro-propyl)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2-methyl-3'-propyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; and

(S)-2-(2',3'-dimethoxy-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one.

As further examples of specific compounds the following may be mentioned without any limitations:

(S)-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin 7-one;

(S)-2-(2',3',4'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin 7-one;

(S)-5-methyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-hydroxymethyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-methoxymethyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazole[3,2-a]pyrimidin-7-one;

(S)-5-(2-hydroxy-ethyl)-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-5-ethoxymethyl-2-(2',3^5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-isopropoxymethyl-2-(2 3^5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-cyclopentyloxymethyl-2-(2',3\5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2-(2 3^5'-trifluoro-biphenyl-4- yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-5-(2-fluoro-ethoxymethyl)-2-(2',3^5'-trifluoro-biphenyl-4-yloxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-5-fluoromethyl-2-(2 3^5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3',5'-trichloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-5-fluoromethyl-2-(2',3',5'-trichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2 ' ,4 ' ,5 ' -trimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2,2',3'-trimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(2-ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2-ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo [3, 2 -a]pyrimidin-7-one;

(S)-2-(2-methoxy-2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; and

2',3'-dimethyl-4-((S)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethoxy)- biphenyl-2-carbonitrile.

Finally, the following compounds are enumerated as few other specific examples of compounds of formula (I) of this invention:

(S)-2-(4-naphthalen-l-yl-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

(S)-2-(4-indan-5-yl)-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-indan-4-yl)-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-[4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-phenoxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-[4-(5,6,7,8-tetrahydro-naphthalen-l-yl)-phenoxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; and

(S)-2-(9H-fluoren-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.

The compounds of this invention can be synthesized by any of the procedures known to one skilled in the art. Specifically, several of the starting materials used in the preparation of the compounds of this invention are known or are themselves commercially available. The compounds of this invention and several of the precursor compounds may also be prepared by methods used to prepare similar compounds as reported in the literature and as further described herein.

More specifically, the compounds disclosed herein can be synthesized according to the following procedures of Schemes 1 - 5, wherein the Ri, R₂, R₃, R4, R5, R5, R7 and Rg are as defined for Formula I unless otherwise indicated. Schemes 6-8 illustrate various procedures that can be employed for the preparation of the intermediate biphenols of formula (VI) that are employed in the preparation of the compounds of formula (I). Scheme 9 illustrates further a specific synthetic route for the preparation of meta-biphenoxy compounds which are found to have much inferior biological activities when compared with the para-analogs as described further in detail below.

Scheme 1 illustrates the synthesis of several of the compounds of formula (I) of this invention wherein Ri is hydrogen. However, a similar synthetic scheme can be adopted for other compounds of formula (I) of this invention wherein Ri is other than hydrogen as defined herein.

Scheme 1

In Step 1, Scheme 1, (S)-glycidyltosylate of formula (II) is reacted with a suitable cyanamide compound to form an oxazolylamine of formula (III) in a suitable solvent. Any of the known cyanamide compounds that react with an epoxide to form oxazolylamines can be employed in this reaction. Suitable cyanamides for this purpose include without any limitation, sodium hydrogen cyanamide, lithium hydrogen cyanamide, potassium hydrogen cyanamide, cesium hydrogen cyanamide, and the like. For instance, Scheme 1 exemplifies sodium hydrogen cyanamide as a suitable cyanamide compound. The reaction can generally be carried out in alcoholic solvents such as methanol, ethanol, isopropanol and the like or a mixture thereof. The reaction is further carrier out at a suitable temperature, for example, at about ambient to super-ambient temperatures.

In Step 2, Scheme 1, the oxazolylamine of formula (III) is reacted with an α,β- unsaturated alkynoic ester of formula (IV), wherein R_c is (Ci-C4)alkyl, phenyl or benzyl, to form the compound of formula (V). This reaction can again be carried out using any of the procedures known to one skilled in the art. Typically, such an addition reaction is carried out in a suitable alcoholic solvent such as methanol, ethanol or isopropanol or a mixture thereof. Such addition reactions can also be carried out using α,β-unsaturated alkynoic ester of formula (IV) itself as the solvent. The reaction is generally carried out at ambient to super- ambient temperature conditions. More generally, the reaction is carried out at the reflux temperature of the solvent. However, super-ambient temperatures involving the microwave oven can also be employed to carry out this reaction at a temperature ranging from about 100°C to about 200°C.

In Step 3, Scheme 1, the compound of formula (V) obtained in Step 2 is reacted with a biphenol of formula (VI), which can be prepared in accordance with any of the known procedures, for example using the procedures of Schemes 6-9 described below. Such substitution reactions are generally carried out in an aprotic polar solvent, such as DMF or acetonitrile and in the presence of a suitable base such as alkali carbonates for example cesium carbonate or an organic base such as triethylamine. Alternatively a compound of formula (V) in an aprotic solvent such as DMF or acetonitrile/dichloromethane/DMSO can be treated with a mixture of sodium hydride and compound of formula (VI) in a suitable solvent such as acetonitrile or DMF. The reaction temperatures can be sub-ambient to ambient to super-ambient, but typically the reaction is carried out under ambient to moderately higher temperatures in the range of 30 to 60°C. Various other compounds of formula (I) can similarly be prepared using appropriate starting materials.

Scheme 2 illustrates another approach for the preparation of compounds of this invention wherein Ri is hydrogen in the compound of formula (I). In this approach, the addition of biphenol of formula (VI) is performed first with the oxazolylamine of formula (III) in order to obtain compound of formula (VII) in Step 1 , Scheme 2. In Step 2, Scheme 2, the compound of formula (VII) is reacted with alkynoic ester of formula (IV) to obtain compound of formula (I). Again, variations of this schematic approach can be used for preparing other variants of the compound of formula (I) wherein Ri is other than hydrogen.

Scheme 2

In Step 1 , Scheme 2, the oxazolylamine of formula (III) is reacted with a biphenol of formula (VI), which as noted above can be prepared in accordance with any of the known procedures, for example, using the procedures of Schemes 6-9 described below. Such substitution reactions are generally carried out in the same fashion as described above for Step 3 of Scheme 1. Generally, such substitution reactions are carried out in an aprotic polar solvent, such as DMF or acetonitrile and in the presence of a suitable base such as alkali carbonates for example cesium carbonate or an organic base such as triethylamine. Alternatively a compound of formula (III) in an aprotic solvent such as DMF or acetonitrile/dichloromethane/DMSO can be treated with a mixture of sodium hydride and compound of formula (VI) in a suitable solvent such as acetonitrile or DMF. The reaction temperatures can be sub-ambient to ambient to super-ambient, but typically the reaction is carried out under ambient to moderately higher temperatures in the range of 30 to 60°C.

In Step 2, Scheme 2, the compound of formula (VII) obtained in Step 1 is reacted with an α,β-unsaturated alkynoic ester of formula (IV), wherein R_c is (Ci-C₄)alkyl, phenyl or benzyl, to form the compound of formula (V). This reaction can again be carried out using any of the procedures known to one skilled in the art, such as for example as described above in Step 2, Scheme 1. Typically, such an addition reaction is carried out in a suitable alcoholic solvent such as methanol, ethanol or isopropanol or a mixture thereof. Such addition reactions can also be carried out using α,β-unsaturated alkynoic ester of formula (IV) itself as the solvent. The reaction is generally carried out at ambient to super-ambient temperature conditions. More generally, the reaction is carried out at the reflux temperature of the solvent. However, super-ambient temperatures involving the microwave oven can also be employed to carry out this reaction at a temperature ranging from about 100°C to about 200°C. Various other compounds of formula (I) can similarly be prepared using appropriate starting materials in accordance with Scheme 2.

Scheme 3 illustrates another approach for the preparation of compounds of formula (I) in which first phenoxy substituted pyrimidinones of formula (XI) are prepared and are converted to compounds of formula (I) by a suitable phenylation reaction in a subsequent step.

In Step 1, Scheme 3, a suitably substituted bromophenol of formula (VIII) is reacted with R-epichlorohydrin in an organic solvent to form a substituted bromophenoxy oxirane of formula (IX). Such substitution reactions can be carried out using any of the known procedures in the art. For example such reactions are generally carried out in a suitable organic solvent in the presence of a suitable base at ambient to super-ambient temperature conditions. Solvents that can be used in this step can be any of the solvents routinely used for such reactions. For instance, suitable solvents are ketones, such as acetone, methyl ethyl ketone (MEK) and the like. Suitable base for this reaction include but not limited to lithium carbonate, sodium carbonate, potassium carbonate, and the like. Generally, potassium carbonate is employed. However, sub-ambient temperature conditions can also be employed depending upon the type of bromophenol of formula (VIII) employed. It has been also observed that the temperature at which the reaction is carried out may control the stereoselectivity of this reaction. For example, a temperature of the reaction below 50°C favors higher stereoselectivity. More specifically, a temperature range of about 40°C to about 50°C can be employed depending upon the solvent used and, the substituents on compound of formula (VII).

In Step 2, Scheme 3, the oxirane of formula (IX) is reacted with a cyanamide compound to form a oxazolylamine of formula (X). Such reactions can be carried out using similar procedures as described above in Step 1, Scheme 1, such as for example employing sodium cyanamide as illustrated in Scheme 3.

Scheme 3

(I )

In Step 3, Scheme 3, the oxazolylamine of formula (X) is reacted with an α,β- unsaturated alkynoic ester of formula (IV), wherein R_c is (Ci-C₄)alkyl, phenyl or benzyl, to form the compound of formula (V). This reaction can again be carried out using any of the procedures known to one skilled in the art, such as for example as described above in Step 2, Scheme 1 or Step 2, Scheme 2. In Step 4, Scheme 3, the substituted phenoxy-pyrimidinone of formula (XI) is further subjected to phenylation reaction to form compounds of formula (I) of this invention. Variation known arylation and/or phenylation reactions can be employed for this purpose. For example, compound of formula (XI) is reacted with substituted phenyl boronic acid of formula (XII) under suitable reaction conditions to obtain compound of formula (I).

Scheme 4 illustrates another variation of Scheme 3 to prepare compounds of formula (I) in which the order of addition of alkynoic acid and phenylation is reversed such that phenylation is first carried out followed by addition with an alkynoic acid ester.

Scheme 4

In Step 1, Scheme 4, the phenylation of compound of formula (X) can be carried out using similar procedures as described above for Step 4, Scheme 3. In Step 2, Scheme 4, the addition of α, β -unsaturated alkynoic ester of formula (IV), wherein R_c is (Ci-C4)alkyl, phenyl or benzyl, is carried out using similar procedures as described above such as for example in Step 2, Scheme 1 or Step 2, Scheme 2 or Step 3, Scheme 3.

Scheme 5 illustrates another approach for the preparation of compounds of formula (I) wherein R₂ is hydrogen. However, various modifications thereof can be made to prepare various compounds of formula (I) as disclosed herein.

Scheme 5

In Step 1, Scheme 5, oxazolylamine of formula (III) is reacted with a β-formyl- alkanoic ester of formula (XIV) wherein R is (Ci-C4)alkyl, phenyl or benzyl. This step is typically carried out using a variety of art recognized reaction conditions. For instance, it can be carried out in an organic solvent in the presence of a suitable base to form a compound of formula (XV).

In Step 2, Scheme 5, the compound of formula (XV) is then allowed to react with a biphenol compound of formula (VI). Such substitution reactions are generally carried out similar to the procedures employed in Step 3, Scheme 1 as described above in order to obtain compound of formula (I).

Schemes 6-9 illustrates various different methods that can be employed for the preparation of para-biphenol compounds of formula (VI) which are employed for the preparation of compounds of formula (I).

Scheme 6

(VI) In Scheme 6, a substituted bromophenol of formula (VIII) is reacted with a substituted phenyl boronic acid of formula (XII) in order to obtain a substituted biphenol of formula (VI). This reaction can be carried out using any of the art-recognized reaction conditions.

Scheme 7

(VI)

Scheme 7 illustrates another approach for the preparation of substituted biphenyl compound of formula (VI) in which a substituted bromobenzene of formula (XVI) is reacted with a substitued para-hydroxy boronic acid of formula (XVII) to form compound of formula (VI). Again such reactions can be carried out using any of the art-recognized procedures.

Scheme 8

In Step 1, Scheme 8, a substituted para-iodo-phenyl acetate of formula (XVIII) is reacted with a substituted boronic acid of formula (XII) to obtain a substituted biphenyl acetate of formula (XIX). Such reactions can be carried out using any of the procedures known in the art. In Step 2, Scheme 8, the acetate of formula (XIX) is subjected to a hydrolysis reaction to form substitued biphenol of formula (VI). Any of the acid catalyzed, base catalyzed and/or neutral reaction conditions can be employed to carry out this hydrolysis reaction. Scheme 9 illustrates a procedure that can be employed for the preparation of meta- biphenyl pyrimidinone of formula (XXII) which are closely related to the compounds of formula (I) of this invention.

In Step 1 , Scheme 9, oxazolylamine of formula (III) is reacted with a substituted meta- iodophenol of formula (XIX) to form a oxazolylamine of formula (XX). Such substitution reactions can be carried out using any of the known procedures such as for example similar procedures as used in Step 1 , Scheme 2.

In Step 2, Scheme 9, the oxazolylamine of formula (XIV) is reacted with β-formyl- alkanoic ester of formula (XIV) wherein R is (Ci-C4)alkyl, phenyl or benzyl. This step is typically carried out using a variety of art recognized reaction conditions. For instance, it can be carried out in an organic solvent in the presence of a suitable base to form a compound of formula (XXI).

In Step 3, Scheme 9, the compound of formula (XXI) is finally reacted with a substituted phenyl boronic acid of formula (XII) to form a meta-biphenyloxymethyl pyrimidinone of formula (XXII).

Scheme 9

In another aspect of this embodiment, this invention also relates to a method of modulating one or more metabotropic glutamate receptor functions in a patient requiring such treatment. Such a method involves administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

More specifically, it has now been found that the compounds of formula (I) exhibit surprisingly superior biological properties even when compared with the corresponding meta- biphenoxymethyl substituted pyrimidinones as further discussed below. In particular, it has now been observed that the compounds of this invention not only exhibit superior mGluR2 receptor potentiation activity but also exhibit desirable metabolic stability thereby providing significant advantages over other structural variants including the corresponding meta- biphenoxymethy 1-pyrimidinone compounds .

In this aspect of the embodiment of this invention the compounds of formula (I) of this invention are also useful in the preparation of a medicament for modulating one or more metabotropic glutamate receptor functions in a patient requiring such modulation. The medicaments can be prepared using any of the methods known in the art. For example, compounds of formula (I) or a pharmaceutically acceptable salt thereof can be mixed with one or more pharmaceutically excipients, diluents or carriers in order to form the medicament.

In a further embodiment, this invention also involves a method of treating a specific disease, a disorder or a condition using an effective amount of a compound of formula (I) of this invention. Specific diseases that can be treated using the compounds of formula (I) of this invention include, without any limitation, neurological or psychiatric disorders.

As used herein "psychiatric disorders" shall have the same meaning as "psychotic disorder" as defined in Diagnostic and Statistical Manual of Mental Disorders, 4^th Ed., ("DSM-IV") American Psychiatric Association, 1995, incorporated herein by reference. The essential feature of brief psychotic disorder is a disturbance that involves the sudden onset of at least one of the following positive psychotic symptoms: delusions, hallucinations, disorganized speech, (e.g., frequent derailment or incoherence), or grossly disorganized or catatonic behavior (Criterion A). An episode of the disturbance lasts at least one day but less than one month, and the individual eventually has a full return to the premorbid level of functioning (Criterion B). The disturbance is not better accounted for by a mood disorder with psychotic features, by schizoaffective disorder, or by schizophrenia and is not due to the direct physiological effects of a substance (e.g., hallucinogen) or a general medical condition (e.g., subdural hematoma) (Criterion C). It should further be noted that a skilled artisan recognizes that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders described herein and that these systems evolve with medical scientific progress.

It is also recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of formula (I) of this invention. Thus, the terms "treatment" and "treating" are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, and is intended to include prophylactic treatment of such neurological and psychiatric disorders.

In a further embodiment of this invention, specific diseases that can be treated using the compounds of formula (I) of this invention include without any limitation: anxiety, migraine, schizophrenia, epilepsy and pain.

One of skill in the art readily appreciates that the pathologies and disease states expressly stated herein are not intended to be limiting rather to illustrate the efficacy of the compounds of the present invention. Thus it is to be understood that the compounds of this invention may be used to treat any disease involving the effects of metabotropic glutamate receptor functions. That is, the compounds of the present invention are modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2, and may be effectively administered to ameliorate any disease state which is mediated all or in part by mGluR2.

All of the various embodiments of the compounds used in the methods of this invention as disclosed herein can be used in the method of treating various disease states as described herein. As stated herein, the compounds used in the method of this invention are capable of modulating the effects of mGluR2 and thereby alleviating the effects and/or conditions caused due to the activity of mGluR2. In another embodiment of the method of this invention, the compounds of this invention can be administered by any of the methods known in the art. Specifically, the compounds of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal, intracerebroventricular (icv) or topical route.

Finally, in yet another embodiment of this invention, there is also provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) of this invention, including pharmaceutically acceptable salts, solvates or derivatives thereof, with said compound having the general structure shown in formula I as described herein.

As described herein, the pharmaceutical compositions of this invention feature modulation of mGluR2 and thus are useful in treating any disease, condition or a disorder involving the effects of mGluR2 in a patient. Again, as described above, all of the preferred embodiments of the compounds of this invention as disclosed herein can be used in preparing the pharmaceutical compositions as described herein. Thus in accordance with this invention various compounds of formula (I) as described herein can be used in the preparation of pharmaceutical formulations for modulating the effects of mGluR2 and to treat all of the diseases as disclosed herein.

Preferably the pharmaceutical compositions of this invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of formula (I) of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Flavored unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be administered by any of the methods known in the art. In general, the pharmaceutical compositions of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal, intracerebroventricular (icv) or topical route. The preferred administrations of the pharmaceutical composition of this invention are by oral and intranasal routes. Any of the known methods to administer pharmaceutical compositions by an oral or an intranasal route can be used to administer the composition of this invention.

In the treatment of various disease states as described herein, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 20 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

This invention is further illustrated by the following examples which are provided for illustration purposes and in no way limit the scope of the present invention.

Examples (General)

Reactions generally are run under a nitrogen atmosphere. Solvents are dried over sodium or magnesium sulfate and are evaporated under vacuum on a rotary evaporator. TLC analyses are performed with EM Science silica gel 60 F254 plates with visualization by UV irradiation wherever possible. Flash chromatography is performed using Isco prepacked silica gel cartridges. The 1H NMR spectra are run at 300 MHz on a Gemini 300 or Varian VXR 300 spectrometer and are determined in a deuterated solvent, such as DMSO-d₆ or CDC1₃ unless otherwise noted. Chemical shifts values are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard. The LC/MS are run on a Micromass Platform LCZ.

As used in the examples and preparations that follow, the terms used therein shall have the meanings indicated: "kg" refers to kilograms, "g" refers to grams, "mg" refers to milligrams, "μ£' refers to micrograms, "pg" refers to picograms, "lb" refers to pounds, "oz" refers to ounces, "mol" refers to moles, "mmol" refers to millimoles, "μιηοΐε" refers to micromoles, "nmole" refers to nanomoles, "L" refers to liters, "mL" or "ml" refers to milliliters, "μί" refers to microliters, "gal" refers to gallons, "°C" refers to degrees Celsius, "R_f " refers to retention factor, "mp" or "m.p." refers to melting point, "dec" refers to decomposition, "bp" or "b.p." refers to boiling point, "mm of Hg" refers to pressure in millimeters of mercury, "cm" refers to centimeters, "nm" refers to nanometers, "abs." refers to absolute, "cone." refers to concentrated, "c" refers to concentration in g/mL, "THF" refers to tetrahydrofuran, "DMF" refers to dimethylformamide, "NMP" refers to l-methyl-2- pyrrolidinone, "EtOH" refers to ethyl alcohol, "MeOH" refers to methyl alcohol, "EtOAc" refers to ethyl acetate; "brine" refers to a saturated aqueous sodium chloride solution, "M" refers to molar, "mM" refers to millimolar, "μΜ" refers to micromolar, "nM" refers to nanomolar, "N" refers to normal, "TLC" refers to thin layer chromatography, "HPLC" refers to high performance liquid chromatography, "i.p." refers to intraperitoneally, "i.v." refers to intravenously, anhyd = anhydrous; aq = aqueous; min = minute; mins = minutes; h or hr = hour; d = day; psi = pounds per square inch; atm = atmosphere; sat. = saturated; s = singlet, d = doublet; t = triplet; q = quartet; m = multiplet; dd = doublet of doublets; br = broad; LC = liquid chromatograph; MS = mass spectrograph; ESI = electrospray ionization; CI = chemical ionization; RT = retention time; M = molecular ion. Optical rotations [α]ο²⁵ were measured using a Perkin Elmer polarimeter model 341 with a sodium lamp, D line (589 nm), path length 100 mm at 25°C temperature at a concentration (g/100 ml) and solvent as specified in the respective examples below.

Example 1

(S)-2-(4-Bromo-phenoxymethyl)-[3,2-a]pyrimidin-7-one

Step 1 : (S)-2-(4-Bromo-phenoxymethyl)oxirane O

o Br

A stirred mixture of 4-bromophenol (9.34 g, 54mmol), (R)-(+)-epichlorohydrin (10.04 g, 108 mmol) and potassium carbonate (7.46 g, 54 mmol) in acetone (70 ml) was heated at

45 C for 4 days. The mixture was filtered and the filtrate concentrated. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate/ heptane to provide the title compound as an oil (4.5 g, 37%).

Step 2: (S)-5-(4-Bromo-phenox methyl)-4,5-dihydro-oxazol-2-ylamine

To a mixture of sodium hydrogen cyanamide (1.15 g, 18 mmol) in methanol (10 ml) was added a solution of (S)-2-(4-bromo-phenoxymethyl)oxirane (4.1 g, 17.9 mmol) in methanol (20 ml) dropwise over 5 minutes. The mixture was stirred at room temperature for 18 hours. The insoluble material was collected to give the title compound, 160-2°C mp (0.9 g,

19%).

Step 3: (S)-2-(4-Bromo-phenox methyl)-[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(4-bromo-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (4.0 g,14.76 mmol) and ethyl propiolate (1.47 g, 15 mmol) in ethanol (25 ml) was heated at reflux for 6 hours. The solution was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% methanol/ methylene chloride and finally 2% triethylamine/10% methanol/ methylene chloride to provide an oil which was triturated with ethyl acetate and the insoluble material collected to give the title compound, 192-5 C (0.7 g).

Example 2

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-2-(4-bromo-phenoxymethyl)-[3,2-a]pyrimidin-7-one (0.22 g, 2.72 mmol), 2-chlorophenylboronic acid (0.52 g, 2.72 mmol), tetrakis(triphenylphosphine)- palladium (0) (0.18 g, 0.16 mmol) and sodium carbonate (0.29 g, 2.72 mmol) in anhydrous ethylene glycol dimethyl ether (25 ml) was heated at reflux for 3 hours. The mixture was diluted with 10 ml of methanol and was filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography on silica gel using 0-10% methanol/dichloromethane. The product-containing fractions were combined and concentrated to provide the title compound as a solid, mpl85-188°C (0.05 g, 19%).

[<X]D = -37.8 ⁰ (c = 0.36, DMSO)

Ci₉Hi₄Cl₂N₂0₃ (389.24), LCMS (ESI): 389.06 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.79 (d, 1H), 7.65 (d, 1H), 7.37-7.40 (m, 4H), 7.06 (d, 2H), 5.84 (d, 1H), 5.36-5.38 (m, 1H), 4.38-4.45 (m, 3H), 4.11-4.16 (m, 1H).

Example 3

Toluene -4-sulfonic acid (S)-7-oxo-2,3-dih dro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester

Step 1 : Toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester

To a suspension of sodium hydrogen cyanamide (7.16 g, 112 mmol) in methanol (100 ml) was added a solution of (2S)-(+)-glycidyl tosylate (25 g, 110 mmol) in methanol (100 ml) dropwise over 30 minutes at room temperature. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue treated with water (100 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed twice with water, dried over magnesium sulfate and filtered. The concentrated filtrate was treated with 10% ethyl acetate/heptane. The precipitate which formed was collected to give the title compound as a solid, 108-112°C mp (8.0 g, 27%).

Step 2: Toluene -4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2- ylmethyl ester

A stirred mixture of toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5- ylmethyl ester (8.0 g, 29.6 mmol) and ethyl propiolate(2.8 g, 29.6 mmol) in 50 ml of ethanol was heated at reflux for 4 hours. The solution was cooled and the precipitate was collected to provide the title compound as a solid (4.6 g, 48%).

Example 4

(S)-2-(3'-Methoxy-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H- oxazolo [3, 2-a]pyrimidin-2 -ylmethyl ester (0.16 g, 0.5 mmol), 3'-methoxy-biphenyl-4-ol (prepared from 4-bromophenol and 3-methoxyphenylboronic acid) (0.1 g, 0.5 mmol) and cesium carbonate (0.16 g, 0.5 mmol) in 20 ml of ethylene glycol dimethyl ether was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.028 g, 16%).

C20H18N2O4 (350.37), LCMS (ESI): 351.12 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.78 (d, 1H), 7.64 (d, 2H), 7.32-7.34 (m, 1H), 7.17-7.19 (m, 2H), 7.02-7.05 (m, 2H), 6.88 (d, 1H), 5.82 (d, 1H), 5.35-5.37 (m, 1H), 4.36-4.42 (m, 3H), 4.12-4.16 (m, 1H), 3.81 (s, 3H).

Example 5

(S)-2-(2-Methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.32 g, 1.0 mmol), 2-methyl-biphenyl-4-ol (prepared from 4-bromo-3-methylphenol and phenylboronic acid) (0.18 g, 1.0 mmol) and cesium carbonate (0.32 g, 1.0 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and was filtered. The filtrate was concentrated and the residue was stirred with 20 ml of hot ethyl acetate for 5 minutes. The insoluble material was collected to provide the title compound, mpl75-178°C (0.075 g, 22%).

C20H18N2O3 (334.37), LCMS (ESI): 335.17 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.80 (d, 1H), 7.35-7.46 (m, 5H), 7.08 (d, 1H), 6.82-6.92 (m, 2H), 5.82 (d, 1H), 5.25-5.40 (m, 1H), 4.30-4.40 (m, 3H), 4.10-4.20 (m, 1H), 2.20 (s, 3H).

Example 6

(S)-2-(2,6-Dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (1.44 g, 4.4 mmol), 2,6-dimethyl-biphenyl-4-ol (prepared from 4-bromo-3,5-dimethylphenol and phenylboronic acid) (0.87 g, 4.4 mmol) and cesium carbonate (1.43 g, 4.4 mmol) in 40 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was dried over magnesium sulfate and was filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound.

(0.058 g, 38%).

C₂iH₂oN₂0₃ (348.40), LCMS (ESI): 349.17 (M⁺H) 1H NMR (DMSO-de, 300 MHz) δ: 7.80 (d, IH), 7.41-7.44 (m, 2H), 7.31-7.34 (m, IH), 7.09- 7.12 (m, 2H), 6.72 (s, 2H), 5.85 (d, IH), 5.34-5.35 (m, IH), 4.31-4.41 (m, 3H), 4.09-4.15 (m, IH), 1.93 (s, 6H). Example 7

(S)-2-(2 - Ethyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.48 g, 1.5 mmol), 2'-ethyl-biphenyl-4-ol (prepared from 4- bromophenol and 2-ethylphenylboronic acid) (0.3 g, 1.5 mmol) and cesium carbonate (0.48 g, 1.5 mmol) in 30 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (75 ml). The organic layer was dried over magnesium sulfate and was filtered. The filtrate was concentrated. The residue was treated with ethyl acetate (50 ml) and the insoluble material was collected to provide the title compound, 168- 172°C mp (0.2 g, 38%).

C₂iH₂oN₂0₃ (348.40), LCMS (ESI): 349.14 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.78 (d, IH), 7.28-7.31 (m, 5H), 7.1 1-7.13 (m, 2H), 6.99- 7.02 (d, IH), 5.84 (d, IH), 5.34-5.36 (m, IH), 4.36-4.42 (m, 3H), 4.1 1-4.17 (m, IH), 2.50 (q, 2H), 1.02 (t, 3H).

Example 8

(S)-2-(2',3 '- Dimethoxy-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.6 g, 1.86 mmol), 2',3 '-dimethoxy-biphenyl-4-ol (prepared from 4-bromophenol and 2,3-dimethoxyphenylboronic acid) (0.43 g, 1.86 mmol) and cesium carbonate (0.6 g, 1.86 mmol) in 30 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was dried over magnesium sulfate and was filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound (0.09 g, 13%). [a]_D ²⁵ = -32.4 ° (c = 0.63, MeOH).

C₂iH₂oN₂0₃ (380.40), LCMS (ESI): 381.15 (ΜΉ)

1H NMR (DMSO-de, 300 MHz) δ: 7.80 (d, 1H), 7.41 (d, 2H), 6.85-6.89 (m, 4H), 6.83 (d, 1H), 5.83 (d, 1H), 5.36-5.38 (m, 1H), 4.36-4.42 (m, 3H), 4.14-4.17 (m, 1H), 3.83 (s, 6H).

Example 9

(S)-2-(2',3'- Difluoro-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 2',3'-Difluoro-biphenyl-4-ol

A mixture of 4-bromophenol (1.7 g, 10 mmol), 2,3-difluorolphenylboronic acid (3.1 g, 20 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and a 2M sodium carbonate solution (6ml ) in 40 ml of 1 ,2-dimethoxy ethane was heated at reflux for 4 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (100ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 0-20% ethyl acetate/heptane to provide the title compound (0.55g, 27%).

Step 2: (S)-2-(2',3'- Difluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.85 g, 2.67 mmol), 2',3'-difluoro-biphenyl-4-ol (0.55 g, 2.67 mmol) and cesium carbonate (0.85 g, 2.67 mmol) in 30 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with boiling ethyl acetate (50 ml). The insoluble material was collected to provide the title compound (0.46 g, 48%), mp 202-205°C.

C19H14F2N2O3 (356.33), LCMS (ESI): 357.13 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.76 (d, 1H), 7.52 (d, 2H), 7.26-7.39 (m, 3H), 7.08 (d, 2H), 5.84 (d, 1H), 5.35-5.38 (m, 1H), 4.39-4.44 (m, 3H), 4.10-4.16 (m, 1H), 3.83 (s, 6H).

Example 10

(S)-2-(3',5'- Dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.48 g, 1.5 mmol), 3',5'-dimethyl-biphenyl-4-ol (prepared from 4-bromophenol and 3,5-dimethylphenylboronic acid) (0.3 g, 1.5 mmol) and cesium carbonate (0.48 g, 1.5 mmol) in 30 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1%> trifiuoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.06 g, 12%).

C₂iH₂oN₂0₃ (348.40), LCMS (ESI): 349.15 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.79 (d, 1H), 7.57 (d, 2H), 7.21 (s, 2H), 7.00 (d, 2H), 6.94 (s, 1H), 5.07 (d, 1H), 5.36-5.38 (m, 1H), 4.39-4.42 (m, 3H), 4.1 1 -4.17 (m, 1H), 2.32 (s, 6H).

Example 1 1

(S)-2-(4- Naphthalen-l-yl-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.58 g, 1.8 mmol), 4-naphthalen-l-yl-phenol (prepared from 4-bromophenol and naphthalene- 1-ylboronic acid) (0.4 g, 1.8 mmol) and cesium carbonate (0.58 g, 1.8 mmol) in 30 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was dried over magnesium sulfate and was filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound (0.15g, 23%).

C₂₃Hi₈N₂0₃ (370.41), LCMS (ESI): 371.14 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.98 (d, 1H), 7.92 (d, 1H), 7.80 (d, 2H), 7.32-7.57 (m, 6H), 7.10 (d, 2H), 5.85 (d, 1H), 5.40-5.42 (m, 1H), 4.42-4.48 (m, 3H), 4.15-4.20 (m, 1H). Example 12

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-methoxymethyl -2,3-dihydro- oxazolo[3,2-a] rimidin-7-one

Step 1 : Toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H- oxazolo [3, 2-a]pyrimidin-2 -ylmeth l ester

A stirred mixture of toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5- ylmethyl ester (0.9 g, 3.33 mmol) and 4-methoxy-but-2-ynoic acid ethyl ester (prepared from the reaction of methyl propargyl ether and methyl chloro formate) (0.46 g, 3.6 mmol) in 15 ml of ethanol was heated at reflux for 3 hours. The solution was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% methanol/methylene chloride to give the title compound as a foam (0.6 g, 50%>).

Step 2: (S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-methoxymethyl -2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.6 g, 1.6 mmol), 2',3'-dichloro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dichlorophenylboronic acid) (0.38 g, 1.6 mmol) and cesium carbonate (0.52 g, 1.6 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.24 g, 35%>).

C₂iHi₈Cl₂N₂0₄ (433.29), LCMS (ESI): 432.99 (M H)

1H NMR (DMSO-de, 300 MHz) δ: 7.62 (d, 1H), 7.36-7.44 (m, 4H), 7.06 (d, 2H),

1H), 5.37-5.39 (m, 1H), 4.34-4.44 (m, 5H), 4.16-4.21 (m, 1H), 3.33 (s, 3H).

Example 13

(S)-2-(2',3'- Dimethyl-biphenyl-4-yloxymethyl)-5-methoxy-2,3-dihydro- oxazolo[3,2-a] rimidin-7-one

Step 1 : 2',3'-Dimethyl-biphenyl-

A mixture of acetic acid 4-iodo-phenylester (prepared from 4-iodophenol and acetyl chloride) (2.6 g, 10 mmol), 2,3-dimethylphenylboronic acid (3.0 g, 20 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and a 2M sodium carbonate solution (6 ml ) in 50 ml of 1 ,2-dimethoxyethane was heated at reflux for 6 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was treated with ethyl acetate (10 ml) and the insoluble material was filtered off. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane (l .Og). A mixture of this compound in 10% sodium hydroxide (20 ml) containing ethanol (10 ml) was warmed to give a solution which was stirred at room temperature for 30 minutes. The solution was poured into water (40 ml) and was acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (50 ml) and the organic layer was dried over magnesium sulfate and filtered. The concentrated filtrate was recrystallized from heptane to provide the title compound, 90-92°C mp (0.4 g,

50%).

Step 2: (S)-2-(2',3'- Dimethyl-biphenyl-4-yloxymethyl)-5-methoxy-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2- a]pyrimidin-2-ylmethyl ester (0.6 g, 1.6 mmol), 2',3'-dimethyl-biphenyl-4-ol (0.3 g, 1.6 mmol) and cesium carbonate (0.52 g, 1.6 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.26 g, 42%).

C₂₃H₂₄N₂0₄ (392.46), LCMS (ESI): 393.18 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.20 (d, 1H), 7.02-7.13 (m, 3H), 6.99-7.01 (m, 2H), 5.86 (s, 1H), 5.34-5.38 (m, 1H), 4.34-4.44 (m, 5H), 4.16-4.22 (m, 2H), 3.32 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H).

Example 14

(S)-2-(4'- Ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.55 g, 1.71 mmol), 4'-ethyl-biphenyl-4-ol (prepared from l-bromo-4-ethylbenzene and 4-hydroxyphenyllboronic acid) (0.34 g, 1.71 mmol) and cesium carbonate (0.55 g, 1.71 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.2 g, 34%>).

C₂iH₂₀N₂O₃ (348.40), LCMS (ESI): 349.14 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.76 (d, 1H), 7.54-7.60 (m, 4H), 7.25 (d, 2H), 7.01 (d, 2H), 5.82 (d, 1H), 5.35-5.37 (m, 1H), 4.35-4.41 (m, 3H), 4.10-4.15 (m, 1H), 2.61 (q, 2H), 1.20 (t, 3H).

Example 15

(S)-2-[4-(5,6,7,8-Tetrahydro-naphthalen-2-yl)-phenoxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 2-Bromo-5,6,7,8-tetrahydronaphthalene

To aluminum oxide (neutral Brockman grade 1) (8 g) was added 1,2,3,4- tetrahydronaphthalene (1.06g, 8mmol). The mixture was stirred to give a homogeneous mixture. To this mixture was added over 5 minutes a mixture of bromine (1.44g, 9mmol) on alumina (8g). After stirring for another 5 minutes the mixture was added to a plug of silica gel was washed with methylene chloride (200ml). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 100% heptane to give the title compound containing some starting material (0.65g, 42%).

Step 2: 4-[5,6,7,8-Tetrahydro-naphthalen-2-yl]phenol

A mixture of 2-bromo-5,6,7,8-tetrahydronaphthalene (1.3 g, 6.16 mmol), 4- hydroxyphenylboronic acid (1.27 g, 9.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.69 mmol) in 1 ,2-dimethoxyethane (20 ml) containing 2M sodium carbonate (6 ml) was heated at reflux for 4 hours. The mixture was added to aqueous ammonium chloride and was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane. The resulting material was recrystallized from heptane to give the title compound (0.3 g, 23%).

1H NMR (CDCls, 300 MHz) δ: 7.43-7.46 (d, 2H), 7.24-7.27 (m, 2H), 7.09-7.12 (d, 1H), 6.86- 6.89 (d, 2H), 4.69 (s, 1H), 2.79-2.82 (m, 4H), 1.80-1.83 (m, 4H).

Step 3 : (S)-2-[4-(5,6,7,8-Tetrahydro-naphthalen-2-yl)-phenoxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo-

[3,2-a]pyrimidin-2-ylmethyl ester (0.43 g, 1.33 mmol), 4-[5,6,7,8-tetrahydro-naphthalen-2- yljphenol (0.3 g, 1.33 mmol) and cesium carbonate (0.43 g, 1.33 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered.

The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile- 0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.12 g, 24%).

C₂₃H₂₂N₂03 (374.44), LCMS (ESI): 375.19 (M⁺H) 1H NMR (DMSO-de, 300 MHz) δ: 7.77 (d, 1H), 7.55 (d, 2H), 7.29-7.32 (m, 2H), 7.08 (d, 1H), 7.02 (d, 2H), 5.83 (d, 1H), 5.35-5.37 (m, 1H), 4.35-4.42 (m, 3H), 4.10-4.16 (m, 1H), 2.49-2.51 (m, 4H), 1.75 (s, 4H).

Example 16

(S)-2-[4-(5,6,7,8-Tetrahydro-naphthalen-l-yl)-phenoxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : Bromo-5,6,7,8-tetrahydronaphthalene

To a thick mixture of 5,6,7,8-tetrahydro-l-naphthlyamine (2.94 g, 20 mmol) in 48% tetrafluoroboric acid (20 ml) cooled in an ice bath was added a solution of sodium nitrite (1.6 g, 23 mmol) in water (20 ml) over 10 minutes. The mixture was filtered and the filter cake was washed with cold 5% tetrafluoroboric acid (10 ml) and then with cold water (10 ml). The filter cake was added in portions to copper (II) bromide (5.6 g, 25 mmol) in dimethyl sulfoxide (50 ml). The mixture was stirred for 30 minutes and was added to water (150 ml). The mixture was extracted with ethyl acetate (150 ml) and the organic layer was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel using heptane to give the title compound (1.0 g, 24%).

Step 2: 4-[5,6,7,8-Tetrahydro-naphthalen-l-yl]phenol

A mixture of 4-hydroxyphemylboronic acid (1.0 g, 7.1 mmol), 1 -bromo-5, 6,7,8- tetrahydro-naphthalene (1.0 g, 4.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.69 mmol) and a 2M sodium carbonate solution (6 ml) in 20 ml of 1 ,2-dimethoxy ethane was heated at reflux for 4 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography using 20-30% ethyl acetate/heptane to provide the title compound as a semi-solid. A sample was recrystallized from heptane to give the title compound, 108-110°C mp (1.1 g, 69%>). Step 3: (S)-2-[4-(5,6,7,8-Tetrahydro-naphthalen-l-yl)-phenoxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.43 g, 1.33 mmol), 4-[5,6,7,8-tetrahydro-naphthalen-l- yljphenol (0.3 g, 1.33 mmol) and cesium carbonate (0.43 g, 1.33 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile- 0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound (0.055 g, 11%).

C₂₃H₂₂N₂03 (374.44), LCMS (ESI): 375.20 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.79 (d, 1H), 7.20 (d, 2H), 6.92-7.12 (m, 5H), 5.87 (d, 1H), 5.37-5.41 (m, 1H), 4.35-4.43 (m, 3H), 4.12-4.17 (m, 1H), 2.76-2.80 (m, 2H), 2.49-2.53 (m, 2H), 1.61-1.74 (m, 4H).

Example 17

(S)-2-(4-Indan-5-yl)- henoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 4-Bromoindan

To a thick mixture of 4-aminoindan (2.66 g, 20 mmol) in 48% tetrafluoroboric acid (20 ml) cooled in an ice bath was added a solution of sodium nitrite (1.6 g, 23 mmol) in water (20 ml) over 10 minutes. The mixture was stirred in ice for 10 minutes and was filtered and the filter cake was washed with cold 5% tetrafluoroboric acid (10 ml) and then with cold water (10 ml). The filter cake was added in portions to copper (II) bromide (5.6 g, 25 mmol) in dimethyl sulfoxide (50 ml). The mixture was stirred for 30 minutes and was added to water (150ml). The mixture was extracted with ethyl acetate (150 ml) and the organic layer was washed with water. The organic layer was dried over magnesium sulfate and was filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using heptane to give the title compound (0.6g, 15%). Step 2: (S)-2-(4-Indan-5-yl)-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.38 g, 1.19 mmol), 4-indan-4-yl-phenol (prepared from 4-bromoindan and 4-hydroxyphenyllboronic acid) (0.25 g, 1.19 mmol) and cesium carbonate (0.38 g, 1.19 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound.

(0.17 g, 40%).

C₂₂H₂oN₂0₃ (360.41), LCMS (ESI): 361.15 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.77 (d, 1H), 7.39 (d, 2H), 7.19 (d, 2H), 7.12-7.16 (m, 1H), 7.03 (d, 2H), 5.86 (d, 1H), 5.36-5.38 (m, 1H), 4.36-4.40 (m, 3H), 4.11-4.17 (m, 1H), 2.88-2.93 (m, 4H), 1.95-1.99 (m, 2H).

Example 18

(S)-2-(4-Indan-4-yl)- henoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Stepl : 5-Bromoindan

To aluminum oxide (neutral Brockman grade 1) (8 g) was added indan (0.94 g, 8 mmol). The mixture was stirred to give a homogeneous mixture. To this mixture was added over 3 minutes a mixture of bromine (1.44 g, 9 mmol) on alumina (8 g). After stirring for another 3 minutes the mixture was added to a plug of silica gel was washed with methylene chloride (200 ml). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 100% heptane to give the title compound (0.65 g, 33%). Step 2: (S)-2-(4-Indan-4-yl)-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.3 g, 0.95 mmol), 4-indan-5-yl-phenol (prepared from 5- bromoindan and 4-hydroxyphenyllboronic acid) (0.2 g, 0.95 mmol) and cesium carbonate (0.3 g, 0.95 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product- containing fractions concentrated by lyophilization to provide the title compound. (0.055 g, 16%). C₂₂H₂oN₂0₃ (360.41), LCMS (ESI): 361.15 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.77 (d, 1H), 7.55 (d, 2H), 7.45 (s, 1H), 7.34 (d, 1H), 7.25 (d, 1H), 7.00 (d, 2H), 5.85 (s, 1H), 5.35-5.37 (m, 1H), 4.31-4.42 (m, 3H), 4.10-4.16 (m, 1H), 2.84-2.93 (m, 4H), 2.01-2.09 (m, 2H).

Example 19

(S)-5-Cyclopropyl-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Stepl : Cyclopropyl-propynoic acid ethyl ester

To a solution of cyclopropylacetylene (4 g, 60.0 mmol) in anhydrous ethyl ether (100 ml) cooled to -78°C was added a 2.5 M n-butyl lithium solution (25.6 ml, 64 mmol) dropwise over 5 minutes. The mixture was allowed to stir for 30 minutes at this temperature. To this mixture was then added ethyl chloro formate (9 ml, 94 mmol) dropwise over 15 minutes. The mixture was stirred for 30 minutes and was allowed to warm to room temperature over 1 hour. The mixture was added to aqueous ammonium chloride and was extracted with ether (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 0-20% ethyl acetate/heptane to afford the title compound as an oil (5.2 g, 62%).

Step2: Toluene-4-sulfonic acid (S)-5-cyclopropyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester

A stirred mixture of toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5- ylmethyl ester (2.6 g, 9.6 mmol) and cyclopropyl-propynoic acid ethyl ester (1.4 g, 10.1 mmol) in 20ml of ethanol was heated at reflux for 4 hours. The solution was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% methanol/methylene chloride to give the title compound as a foam (0.41 g, 12%).

Step 3 : (S)-5-Cyclopropyl-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-cyclopropyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.18 g, 0.5 mmol), 2',3'-dichloro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dichlorophenylboronic acid) (0.12 g, 0.5 mmol) and cesium carbonate (0.16 g, 0.5 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.08 g, 37%).

C23H22N2O3 (374.44), LCMS (ESI): 375.17 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.62 (d, 1H), 7.37-7.40 (m, 3H), 7.04 (d, 2H), 5.57 (s, 1H), 5.40-5.42 (m, 1H), 4.27-4.32 (m, 3H), 4.41-4.45 (t, 2H), 1.84-1.88 (m, 1H), 0.00-1.02 (d, 2H), 0.82-0.87 (m, 2H).

Example 20

(S)-5-Cyclopropyl-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazole[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-cyclopropyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.23 g, 0.63 mmol), 2',3'-dimethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dimethylphenylboronic acid) (0.12 g, 0.63 mmol) and cesium carbonate (0.20 g, 0.63 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.1 g, 40%).

C₂4H₂₄N₂0₃ (388.47), LCMS (ESI): 389.19 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.21 (d, 2H), 7.11-7.13 (m, 1H), 7.00 (d, 4H), 5.57 (s, 1H), 5.36-5.41 (m, 1H), 4.58 (t, 1H), 4.30-4.42 (m, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 1.81-1.84 (m, 1H), 0.99-1.01 (m, 2H), 0.81-0.84 (m, 2H).

Example 21

(S)-2-(2',3'-Difluoro-biphenyl-4-yloxymethyl)-5-methoxymethyl -2,3-dihydro- oxazolo[3,2-a] rimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.5 g, 1.36 mmol), 2',3'-difluoro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-difluorophenylboronic acid) (0.28 g, 1.36 mmol) and cesium carbonate (0.44 g, 1.36 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.135 g, 25%).

C₂iHi₈F₂N₂0₄ (400.38), LCMS (ESI): 401.14 (ΜΉ)

1H NMR (DMSO-de, 300 MHz) δ: 7.52 (d, 2H), 7.38-7.42 (m, 3H), 7.07 (d, 2H), 5.82 (s, 1H), 5.38-5.40 (m, 1H), 4.40-4.45 (m, 5H), 4.35-4.36 (m, 1H), 3.34 (s, 3H).

Example 22

(S)-2-(2',3',5'- Trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.5 g, 1.55 mmol), 2',3',5'-trifluoro-biphenyl-4-ol (prepared using scheme A from 4-bromophenol and 2,3,5-trifluorophenylboronic acid) (0.34 g, 1.55 mmol) and cesium carbonate (0.5 g, 1.55 mmol) in 30 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (125 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue recrystallized from methanol to provide the title compound, 251-254°C mp (0.13 g, 22%).

C19H13F3N2O3 (374.32), LCMS (ESI): 375.10 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.76 (d, 1H), 7.56 (d, 1H), 7.48-7.52 (m, 2H), 7.26-7.30 (m, 1H), 7.08 (d, 2H), 5.82 (d, 1H), 5.36-5.38 (m, 1H), 4.39-4.45 (m, 3H), 4.10-4.15 (m, 1H).

Example 23

(S)-2-(2',3',4'- Trifluoro-bi henyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.47 g, 1.47 mmol), 2',3',4'-trifluoro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3,4-trifluorophenylboronic acid) (0.33 g, 1.47 mmol) and cesium carbonate (0.48 g, 1.47 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.3 g, 54%>).

C19H13F3N2O3 (374.32), LCMS (ESI): 375.09 (ΜΉ) 1H NMR (DMSO-de, 300 MHz) δ: 7.78 (d, 1H), 7.49 (d, 2H), 7.35-7.41 (m, 2H), 7.07 (d, 1H), 5.35-5.40 (m, 1H), 4.39-4.46 (m, 4H), 4.11-4.16, (m, 2H).

Example 24

(S)-2-(2',4'-Dichloro-biphenyl-4-yloxymethyl -2,3-dihydro- oxazolo[3,2-a] rimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.47 g, 1.46 mmol), 2',4'-dichloro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,4-dichlorophenylboronic acid) (0.35 g, 1.46 mmol) and cesium carbonate (0.48 g, 1.46 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.18 g, 32%).

Ci₉Hi₄Cl₃N₂0₃ (389.24), LCMS (ESI): 389.09 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.78 (d, 1H), 7.71 (s, 1H), 7.47-7.51 (m, 1H), 7.37-7.43 (m, 3H), 7.03 (d, 2H), 5.84 (d, 1H), 5.37-5.38, (m, 1H), 4.38-4.42 (m, 3H), 4.11-4.17 (m, 1H).

Example 25

(S)-2-(2',3'- Dimethyl-biphenyl-4-yloxymethyl)-5-methyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : Toluene -4-sulfonic acid (S)-5-methyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester A stirred mixture of toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5- ylmethyl ester (2.7 g, 10 mmol) and ethyl 2-butynoate (1.12 g, 10 mmol) in 20 ml of ethanol was heated at reflux for 4 hours. The solution was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% methanol/methylene chloride to give the title compound as a tacky solid (1.0 g, 30%)

Step 2: (S)-2-(2',3'- Dimethyl-biphenyl-4-yloxymethyl)-5-methyl-2,3-dihydro-oxazolo[3,2-a] pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-methyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester (0.5 g, 1.48 mmol), 2',3'-dimethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dimethylphenylboronic acid) (0.29 g, 1.48 mmol) and cesium carbonate (0.5 g, 1.48 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.08 g, 15%).

C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.15 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.21 (d, 2H), 7.11-7.13 (m, 2H), 7.00 (d, 3H), 5.73 (s, 1H), 5.34-5.36 (m, 1H), 4.35-4.46 (m, 3H), 4.19-4.22, (m, 1H), 2.28 (s, 3H), 2.23(s, 3H), 2.09 (s, 3H).

Example 26

(S)-2-(2',3'- Dichloro-biphenyl-4-yloxymethyl)-5-methyl-2,3-dihydro-oxazolo[3,2-a] pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-methyl-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.5 g, 1.48 mmol), 2',3'-dichloro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dichlorophenylboronic acid) (0.35 g, 1.48 mmol) and cesium carbonate (0.5 g, 1.48 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1 % trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.09 g, 15%).

C₂oHi₆Cl₂N₂0₃ (403.26), LCMS (ESI): 403.09 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.62 (d, 1H), 7.36-7-42 (m, 4H), 7.04 (d, 2H), 5.73 (s, 1H), 5.35-5.36 (m, 1H), 4.37-4.42 (m, 3H), 4.17-4.22, (m, 1H), 2.22 (s, 3H).

Example 27

(S)-2-(2 ' ,4 ' ,5 ' - Trimethyl-biphenyl-4-yloxymethyl)-2,3 -dihydro-oxazolo [3 ,2-a]pyrimidin-7- one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo-

[3,2-a]pyrimidin-2-ylmethyl ester (0.5 g, 1.55 mmol), 2',4',5 '-trimethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,4,5-trimethylphenylboronic acid) (0.33 g, 1.55 mmol) and cesium carbonate (0.5 g, 1.55 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1 %> trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.24 g, 42%).

C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.19 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.77 (d, 1H), 7.22 (d, 2H), 6.93-7.00 (m, 4H), 5.83 (d, 1H), 5.36-5.37 (m, 1H), 4.35-4.42 (m, 3H), 4.1 1-4.17, (m, 1H), 2.20 (s, 6H), 214 (s, 3H).

Example 28

(S)-2-(3',4'- Difluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.5 g, 1.55 mmol), 3',4'-difluoro-biphenyl-4-ol (prepared from acetic acid 4- iodo-phenylester and 3,4-difluorophenylboronic acid ) (0.4 g, 1.9 mmol) and cesium carbonate (0.6 g, 1.9 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.18 g, 32%).

C19H14F2N2O3 (356.33), LCMS (ESI): 357.11 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.77 (d, 1H), 7.72-7.76 (m, 2H), 7.69 (d, 1H), 7.45-7.50 (m, 2H), 7.03 (d, 2H), 5.83 (d, 1H), 5.36-5.37, (m, 1H), 4.33-4.42 (m, 3H), 4.10-4.16 (m, 1H).

Example 29

(S)-2-(2',3',5'- Trichloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (0.47 g, 1.46 mmol), 2',3',5'-trichloro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3,5-trichlorophenylboronic acid) (0.4 g, 1.46 mmol) and cesium carbonate (0.5 g, 1.46 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound (0.28 g, 45%). Ci₉Hi3Cl₃N₂03 (423.68), LCMS (ESI): 423.01 (ΜΉ)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.85 (s, 1H), 7.77 (d, 1H), 7.40-7.45 (m, 4H), 7.04 (d, 1H), 5.83 (d, 1H), 5.37-5.38 (m, 1H), 4.36-4.46, (m, 3H), 4.11-4.16 (m, 1H). Example 30

(S)-2-(3',5'- Dibromo-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (0.29 g, 0.91 mmol), 3',5'-dibromo-biphenyl-4-ol (prepared from acetic acid 4- iodo-phenylester and 3,5-dibromophenylboronic acid) (0.3 g, 0.91 mmol) and cesium carbonate (0.3 g, 0.91 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1%> trifiuoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound (0.135 g, 31%).

Ci₉Hi₄Br₂N₂0₃ (478.14), LCMS (ESI): 478.93 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.85 (s, 1H), 7.69-7.79 (m, 5H), 7.03 (d, 2H), 5.82 (d, 1H), 5.35-5.37 (m, 1H), 4.36-4.45 (m, 3H), 4.10-4.15 (m, 1H).

Example 31

(S)-2-(2',3'- Dimethyl-biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Step 1 : 4-Tetrahydro-pyran-2-yloxy-but-2-ynoic acid ethyl ester

To a solution of tetrahydro-2-(2-propynloxy)-2H-pyran (17.44 g, 124.4 mmol) in 400 ml of anhydrous ethyl ether cooled to -78°C was added a 2.5N n-butyl lithium solution (52.3 ml, 130.7 mmol) dropwise over 10 minutes. The mixture was stirred for 1.5 hours at this temperature. To this mixture was added a solution of ethyl chloro formate (20.4 g, 188 mmol) in 25 ml of ether dropwise over 15 minutes. The mixture was stirred at this temperature for 2 hours and was allowed to stir at room temperature for 18 hours. The mixture was added to aqueous ammonium chloride and was extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography using 0-10% ethyl acetate/heptane to afford the title compound (19.7 g, 75%).

Step 2: 4-Hydroxy-but-2-ynoic acid ethyl ester

A solution of 4-tetrahydro-pyran-2-yloxy-but-2-ynoic acid ethyl ester (8.2 g, 38.6 mmol) and p-toluenesulfonic acid monohydrate (0.1 g) in 30 ml of ethanol was stirred at room temperature for 24 hours. The solution was concentrated at room temperature and the residue was treated with aqueous sodium bicarbonate and was extracted with ether (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated at room tem erature and dried under high vacuum to constant weight (4.4

To a solution of 4-hydroxy-but-2-ynoic acid ethyl ester (4.4 g, 34.3 mmol) in 100 ml of anhydrous methylene chloride cooled to -78°C was added diethylaminosulfur trifluoride (DAST) (5.0 g, 31 mmol) dropwise over 5 minutes. The mixture was stirred at this temperature for 1 hour and allowed to warm to room temperature over 4 hours. To this mixture was added 15 ml of water. The organic layer was dried over magnesium sulfate and was filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 0-5%) ethyl acetate/heptane to give the title compound as a foam (0.5 g, 11%). Step 4: p-Tolyl-methanesulfonic acid (S)-5-fluoromethyl-7-oxo-2,3-dihydro oxazolo[3,2-a]pyrimidin-2-ylmethyl ester

A stirred mixture of toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5- ylmethyl ester (0.94 g, 3.5 mmol) and 4-fluoro-but-2-ynoic acid ethyl ester (0.46 g, 3.6 mmol) in 20ml of ethanol was heated at reflux for 4 hours. The solution was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% methanol/methylene chloride to give the title compound as a foam (0.4g, 33%).

Step 5: (S)-2-(2',3'- Dimethyl-biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-fluoromethyl-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2-ylmethyl ester (0.4 g, 1.13 mmol), 2',3'-dimethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dimethylphenylboronic acid) (0.23 g, 1.13 mmol) and cesium carbonate (0.38 g, 1.13 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization. The resulting material was stirred in an aqueous sodium bicarbonate solution for 30 minutes. The insoluble material was collected to give the title compound (0.1 g, 31%>).

C₂₂H₂iFN₂0₃ (380.42), LCMS (ESI): 381.13 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.21 (d, 2H), 7.11-7.13 (m, 2H), 6.97-7.02 (m, 3H), 5.98 (s, 1H), 5.40-5.41 (m, 1H), 4.37-4.43 (m, 3H), 4.20-4.24 (m, 1H), 3.32 (s, 2H), 2.28 (s, 3H), 2.09 (s, 3H).

Example 32

(S)-2-(2',3'- Dichloro-biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-fluoromethyl-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2-ylmethyl ester (0.5 g, 1.4 mmol), 2',3'-dichloro-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dichlorophenylboronic acid) (0.34 g, 1.4 mmol) and cesium carbonate (0.46 g, 1.4 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was dissolved in hot ethyl acetate and was filtered. The filtrate was diluted with heptane until the solution became cloudy. The precipitate which formed was collected to give the title compound as a solid, 138-140°C mp (0.31 g, 53%).

C₂oHi₅Cl₂FN₂0₃ (421.25), LCMS (ESI): 421.01 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.63 (d, 1H), 7.33-7.42 (m, 4H), 7.04 (d, 2H), 5.98 (s, 1H), 5.40-5.42 (m, 1H), 4.39-4.46 (m, 3H), 4.18-4.23 (m, 1H), 3.32 (s, 2H).

Example 33

(S)-2-(4'- Fluoro-3 '-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (0.71 g, 2.2 mmol), 4'-fluoro-3 '-methyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 4-fluoro-3-methylphenylboronic acid) (0.45 g, 2.2 mmol) and cesium carbonate (0.72g, 2.2mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization. This material was stirred in an aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was dissolved in hot ethyl acetate (100 ml) and filtered. The filtrate was diluted with heptane (50ml). The insoluble material was collected to provide the title compound as a solid, 173-175°C mp (0.25 g, 32%).

C₂oHi₇FN₂0₃ (352.36), LCMS (ESI): 353.12 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.76 (d, 1H), 7.53-7.60 (m, 3H), 7.42-7.47 (m, 1H), 7.15- 7.18 (m, 1H), 7.01-7.04 (d, 2H), 5.82 (d, 1H), 5.35-5.37 (m, 1H), 4.36-4.42 (m, 3H), 4.10-4.15 (m, 1H), 2.29 (s, 3H).

Example 34

(S)-2-(3'- Fluoro-4'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (0.39 g, 1.23 mmol), 3'-fluoro-4'-methyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 3-fluoro-4-methylphenylboronic acid) (0.25 g, 1.23 mmol) and cesium carbonate (0.39 g, 1.23 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization. The resulting material was stirred in an aqueous sodium bicarbonate for 1 hour. The insoluble material was collected to give the title compound as a solid, 223-226°C mp (0.14 g, 32%).

[<X]D = -18.2⁰ (c = 0.74, DMSO). C₂₀Hi₇FN₂O₃ (352.36), LCMS (ESI): 353.04 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.76 (d, 1H), 7.63 (d, 2H), 7.30-7.39 (m, 3H), 7.01-7.04

(d, 2H), 5.82 (d, 1H), 5.35-5.36 (m, 1H), 4.36-4.41 (m, 3H), 4.09-4.15 (m, 1H), 2.25 (s, 3H).

Example 35 (S)-2-(2'- Fluoro-4'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.5 g, 1.55 mmol), 2'-fluoro-4'-methyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2-fluoro-4-methylphenylboronic acid) (0.31 g, 1.55 mmol) and cesium carbonate (0.5 g, 1.55 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with boiling ethyl acetate (20 ml). The insoluble material was collected to give the title compound as a solid, 215-218°C mp (0.3 g, 55%).

[a]_D ²⁵ = -16.4 ° (c = 0.68, DMSO). C₂₀Hi₇FN₂O₃ (352.36), LCMS (ESI): 353.12 (M⁺H) 1H NMR (DMSO-de, 300 MHz) δ: 7.76 (d, 1H), 7.45 (d, 1H), 7.34-7.40 (m, 2H), 7.03-7.09 (d, 4H), 5.82 (d, 1H), 5.35-5.37 (m, 1H), 4.36-4.41 (m, 3H), 4.10-4.15 (m, 1H), 2.34 (s, 3H).

Example 36

(S)-5-Methoxymethyl-2-(2',3 ',5 '-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazole[3,2- a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2- a]pyrimidin-2-ylmethyl ester (0.28 g, 0.76 mmol), 2',3 ',5 '-difluoro-biphenyl-4- ol (prepared using scheme A from 4-bromophenol and 2,3,5-trifluoro phenylboronic acid) (0.17 g, 0.76 mmol) and cesium carbonate (0.25 g, 0.76 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was treated with 10 ml of hot ethyl acetate. The solution which formed was cooled in ice to precipitate the title compound, 183-185°C mp (0.14 g, 44%). [a]_D ²⁵ = + 2.4 ° (c = 0.68, DMSO). C₂iHi₈F₂N₂0₄ (400.38), LCMS (ESI): 401.14 (M⁺H) 1H NMR (DMSO-de, 300 MHz) δ: 7.58 (d, 2H), 7.53-7.56 (m, 1H), 7.26-7.31 (m, 1H) 7.08 (d, 2H), 5.85 (s, 1H), 5.37-5.38 (m, 1H), 4.34-4.46 (m, 5H), 4.14-4.20 (m, 1H), 3.33 (s, 3H).

Example 37

(S)-5-Methyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo- [3,2-a]pyrimidin-2-ylmethyl ester (0.5 g, 1.48 mmol), 2',3',5'-difluoro-biphenyl-4-ol (prepared from 4-bromophenol and 2,3,5-trifluoro phenylboronic acid) (0.33 g, 1.48 mmol) and cesium carbonate (0.48 g, 1.48 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was dissolved in 10ml of hot ethyl acetate and was filtered. The filtrate was cooled in ice to precipitate the title compound, 110-120°C mp (0.05 g, 9%>).

C₂iHi₈F₂N₂0₄ (400.38), LCMS (ESI): 401.14 (M⁺H)

1H NMR (DMSO-de, 300 MHz) δ: 7.57 (d, 2H), 7.48-7.54 (m, 1H), 7.26-7.32 (m, 1H) 7.09 (d, 2H), 5.70 (s, 1H), 5.33-5.35 (m, 1H), 4.38-4.44 (m, 3H), 4.14-4.20 (m, 1H), 2.21 (s, 3H).

Example 38

(S)-2-(2'3'-Dimethyl-biphenyl-4-yloxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 4-Prop-2-ynyl-morpholine

To a mixture of morpholine (7.32 g, 84.1 mmol) and potassium carbonate (6.4 g, 46 mmol) in methanol (100 ml) cooled in an ice bath was added a 80% solution of propargyl bromide in toluene (9.34 ml, 84.1 mmol) over 5 minutes. The mixture was stirred in ice for 30 minutes and then at room temperature for 5 hours. The mixture was filtered and the filtrate was concentrated. The residue was treated with methylene chloride (100 ml) and was filtered. The filtrate was concentrated and the residue was treated with ether (100 ml) and was filtered. The solution was dried over magnesium sulfate, filtered and the filtrate concentrated to provide the title compound as an oil (5.9 g, 56%).

Step 2: 4-Morpholin-4-yl-but-2-ynoic acid ethyl ester

To a solution of 4-prop-2-ynyl-morpholine (5.9 g, 47 mmol) in anhydrous ether (100 ml) cooled to -78°C was added 2.5 M n-butyllithium (18.8 ml, 47 mmol) dropwise over 5 minutes. The mixture was stirred for 30 minutes. To this mixture was added ethyl chloroformate (6.5 g, 60 mmol) dropwise over 5 minutes. The mixture was stirred at -78°C for 30 minutes and then was warmed to room temperature over 3 hours. The mixture was added to aqueous ammonium chloride and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 20- 100%) ethyl acetate/heptane to give the title compound (0.4 g, 4%).

Step 3 : Toluene-4-sulfonic acid (S)-5 morholinomethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester

A mixture of toluene-4-sulfonic acid (S) -2-amino-4,5-dihydro-oxazolo-5-ylmethy ester (0.54 g, 2 mmol) and 4-morpholin-4-yl-but-2-ynoic acid ethyl ester (0.4 g, 2 mmol) in ethanol (20 ml) was heated at reflux for 4 hours. The solution was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% methanol/methylene chloride to give the title compound (0.3 g, 37%).

Step 4: (S)-2-(2'3'-Dimethyl-biphenyl-4-yloxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5 morholinomethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.3 g, 0.71 mmol), 2',3'-dimethyl-biphenyl-4-ol (0.14 g, 0.71 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in anhydrous acetonitrile (20 ml) was heated at reflux for one hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization and the resulting material treated with aqueous sodium bicarbonate and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a foam(0.05 g, 16%). [a]_D ²⁵ = +11.9 ° (c = 0.48, MeOH). C₂₆H₂₉N₃0₄ (447.54), LCMS (ESI): 448.23 (M⁺H) 1H NMR (DMSO-de, 300 MHz δ: 7.00-7.13 (d, 3H), 7.11-7.13 (m, 2H), 7.20 (d, 2H) 5.79 (s, 1H), 5.38-5.40 (m, 1H), 4.52-4.55 (t, 1H), 4.35-4.39 (m, 3H), 3.38 (s,2H), 3.32 (s, 4H), 2.42 (s, 4H), 2.28 (s, 3H), 2.09(s, 3H).

Example 39

(S)-2-(2'3'-Dichloro-biphenyl-4-yloxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5 morpholinomethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.3 g, 0.71 mmol), 2',3'-dichloro-biphenyl-4-ol (0.17 g, 0.71 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in anhydrous acetonitrile (20 ml) was heated at reflux for one hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization and the resulting material was treated with aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a foam (0.075g, 21%). [a]_D ²⁵ = -10.2⁰ (c = 0.65, MeOH).

C₂₄H₂₃C1₂N₃0₄ (488.37), LCMS (ESI): 488.08 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.62-7.65 (d, 1H), 7.36-7.42 (m, 4H), 7.04 (d, 2H) 5.79 (s, 1H), 5.36-5.40 (m, 1H), 4.52-4.55 (t, 1H), 4.35-4.41 (m, 3H), 3.50 (s, 4H), 3.39 (s, 2H), 2.42 (s, 4H).

Example 40

(S)-2-(2'3'-Dimethyl-biphenyl-4-yloxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : 4-Prop-2-ynyl-pyrrolidine

To a mixture of pyrrolidine (6.0 g, 84.3 mmol) and potassium carbonate (6.4 g, 46 mmol) in ether (250 ml) cooled in an ice bath was added an 80% solution of propargyl bromide in toluene (9.3 ml, 84.3 mmol) over 10 minutes. The mixture was stirred in ice for 20 minutes and then at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated in a rotary evaporator with no heat. The residue was treated with ether (100 ml) and was passed through a silica gel plug. The filtrate was dried over magnesium sulfate and was filtered. The filtrate was concentrated with no heat to produce the title compound (2.2 g, 14%).

Step 2: 4-Pyrrolidin-4-yl-but-2-ynoic acid ethyl ester

To a solution of 4-prop-2-ynyl-pyrrolidine (2.2 g, 20 mmol) in anhydrous ether (100 ml) cooled to -78°C was added 2.5 M n-butyllithium (8.0 ml, 20 mmol) dropwise over 5 minutes. The mixture was stirred for 10 minutes. To this mixture was added a solution of ethyl chloroformate (6.5 g, 60 mmol) in ether (15 ml) dropwise over 5 minutes. The mixture was stirred at -78°C for 30 minutes and then was warmed to 0°C. The mixture was added to aqueous sodium bicarbonate and was extracted with ether (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 50-100% ethyl acetate/heptane to give the title compound (l .Og, 27%).

Step 3: Toluene-4-sulfonic acid (S)-5 pyrrolidinomethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester A mixture of toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethy ester (1.49 g, 5.5 mmol) and 4-pyrrolidin-4-yl-but-2-ynoic acid ethyl ester (1.0 g, 5.5 mmol) in ethanol (20 ml) was heated at reflux for 4 hours. The solution was concentrated and the residue was purified by flash chromatography on silica gel using 0-5% methanol/methylene chloride to give the title compound (0.5g , 22%>).

Step 4: (S)-2-(2'3'-Dimethyl-biphenyl-4-yloxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5 pyrrolidinomethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.5 g, 1.23 mmol), 2',3 '-dimethyl-biphenyl-4-ol (0.24 g, 1.23 mmol) and cesium carbonate (0.4 g, 1.23 mmol) in anhydrous acetonitrile (25 ml) was heated at reflux for one hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization. The resulting material was treated with aqueous sodium bicarbonate and was extracted with ethyl acetate (75 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a foam (0.03 g ;:, 6%).

[α]ο = +15.0 ° (c = 0.32, MeOH). C₂₆H₂₉N₃0₃ (431.53), LCMS (ESI): 432.22 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.20-7.23 (d, 2H), 7.11-7.13 (m, 2H), 7.00 (d, 3H) 5.78 (s, 1H), 5.34-5.38 (m, 1H), 4.52-4.54 (t, 1H), 4.32-4.40 (m, 3H), 3.48-3.49 (d, 2H), 2.28 (s, 3H), 2.09 (s, 3H), 2.50 (s, 4H), 1.70 (s, 4H).

Example 41

(S)-2-(9H-Fluoren-2- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.5 g, 1.55 mmol), 2-hydroxyfluorene (0.28 g, 1.55 mmol) and cesium carbonate (0.5 g, 1.55 mmol) in 25 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was cooled and was added to water (100 ml). The insoluble material was collected and vacuum dried. This material was heated with ethyl acetate (300 ml). The insoluble material was collected to provide the title compound, 227-30°C mp (0.085 g, 16%). [a]_D ²⁵ = -28.3 ° (c = 0.68, DMSO). C₂oHi₆N₂0₃ (332.36), LCMS (ESI): 333.1 1 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.79-7.81 (m, 3H), 7.55 (d, 1H), 7.32-7.34 (m, 1H) 57.20-7.26 (m, 2H), 6.96-6.99 (d, 1H), 5.82-5.85 (d, 1H), 5.36 (s, 1H), 4.37-4.45 (m, 3H), 4.14-4.17 (m, 1H), 3.88 (s, 2H).

Example 42

(S)-2-(2,2',3'.Trimethyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : Acetic acid 4-bromo-3.methyl-phenylester

To a solution of 4-bromo-3-methylphenol (1.87 g, 10 mmol) and triethylamine (1.2 g, 12 mmol) in methylene chloride (40 ml) was added acetyl chloride (0.94 g, 12 mmol) dropwise over 3 minutes. The mixture was stirred at room temperature for 30 minutes. The mixture was added to water (100 ml) and was extracted with methylene chloride (100 ml). The organic layer was dried over magnesium sulfate and was filtered. The filtrate was concentrated to give the title compound (1.5 g, 66%).

Step 2: Methyl, 2',3'-dimethyl-biphenyl-4-ol

A mixture of acetic acid 4-bromo-3-methyl-phenylester (1.5 g, 6.57 mmol), 2,3- dimethylphenylboronic acid (1.38 g, 9.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and a 2M sodium carbonate solution (6 ml) in 60 ml of 1 ,2-dimethoxyethane was heated at reflux for 4 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ethyl acetate (10 ml) and the insoluble material was filtered off. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane (1.6 g). A mixture of this compound in 10% sodium hydroxide (5 ml) containing ethanol (15 ml) and water (10 ml) was warmed with a heat gun to give a solution. This solution was stirred at room temperature for 30 minutes. The solution was poured into water and was acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (100 ml) and the organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to provide the title compound (0.9 g, 64%).

Step 3 : (S)-2-(2,2',3'.Trimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.4 g, 1.24 mmol), 2-methyl, 2',3'-dimethyl-biphenyl-4-ol (0.26 g, 1.24 mmol) and cesium carbonate (0.4 g, 1.24 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (200 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was dissolved in the minimum of hot ethyl acetate. The solution was diluted with heptane until the solution became cloudy to precipitate the title compound, 188-91°C mp (0.06 g, 13%). [a]_D ²⁵ = -8.9 ° (c = 0.40, DMSO)

C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.13 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.77-7.79 (d, 1H), 7.10-7.12 (m, 2H), 6.95-6.98 (d, 1H), 6.80-6.89 (m, 3H), 5.82-5.84 (d, 1H), 5.33-5.37 (m, 1H), 4.33-4.38 (m, 3H), 4.13-4.16 (m, 1H), 2.28 (s, 3H), 1.95 s, 3H), 1.89 (s, 3H).

Example 43

(S)-2-(2',4'.Dimethyl-bi henyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.5 g, 1.55 mmol), 2',4'-dimethyl-biphenyl-4-ol (prepared from acetic acid 4- iodo-phenylester and 2,4-dimethylphenylboronic acid) (0.3 g, 1.55 mmol) and cesium carbonate (0.5 g, 1.55 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was heated with ethyl acetate (20 ml). The insoluble material was collected to give the title compound, 233-35° C mp (0.22 g, 40%). [a]_D ²⁵ = -13.3 ⁰ (c = 0.54, DMSO) C₂iH₂₀N₂O₃ (348.40), LCMS (ESI): 349.14 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.23-7.26 (m, 2H), 6.98-7.04 (m, 6H), 5.82-5.84 (d, 1H), 5.33-5.37 (m, 1H), 4.35-4.42 (m, 3H), 4.11-4.16 (m, 1H), 2.29 (s, 3H), 2.18 s, 3H).

Example 44

(S)-2-(2'-Isopropyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.7 g, 2.17 mmol), 2'-isopropyl-biphenyl-4-ol (prepared from acetic acid 4- iodo-phenylester and 2-isopropylphenylboronic acid) (0.7 g, 3.3 mmol) and cesium carbonate (l .g, 3. mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization. The resulting material was treated with aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was treated with heptane (25 ml) for 15 minutes. The insoluble material was collected to provide the title compound, 128-130° C mp (0.07 g, 9%).

[a]_D ²⁵ = -22.0 ° (c = 0.56, MeOH). C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.16 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.77-7.79 (d, 1H), 7.33-7.46 (m, 4H), 7.19-7.22 (d, 2H), 6.99-7.02 (d, 1H), 6.62-6.64 (d, 2H), 5.82-5.84 (d, 1H), 5.36-5.38 (m, 1H), 4.36-4.42 (m, 3H), 4.13-4.14 (m, 1H), 1.09-1.11 (d, 6H).

Example 45

(S)-2-(3'-Trifluoromethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (0.27 g, 0.84 mmol), 3'-trifluoromethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 3-trifluoromethylphenylboronic acid) (0.2 g, 0.84 mmol) and cesium carbonate (0.27 g, 0.84 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The residue was dissolved in hot ethyl acetate (10 ml) and was filtered. The filtrate was cooled in ice to precipitate the product, 133-6°C mp (0.08g, 24%). [a]_D ²⁵ = -40.7⁰ (c = 0.74, MeOH)

C₂oHi₅F₃N₂03 (388.34), LCMS (ESI): 389.10 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.93-7.96 (m, 2H), 7.67-7.92 (m, 5H), 7.06-7.09 (d, 2H), 5.82-5.89 (d, 1H), 5.36-5.38 (m, 1H), 4.35-4.46 (m, 3H), 4.10-4.16 (m, 1H).

Example 46

(S)-2-(3'-Isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.6 g, 1.86 mmol), 3'-isopropyl-biphenyl-4-ol (prepared from acetic acid 4- iodo-phenylester and 3-isopropylphenylboronic acid) (0.5 g, 2.36 mmol) and cesium carbonate (0.75 g, 2.36 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes and the product-containing fractions combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with heptane (50 ml) for 10 minutes. The insoluble material was collected to provide the title compound, 153-56°C mp (0.13 g, 19%).

C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.20 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.59-7.62 (d, 2H), 7.32-7.40 (m, 3H), 7.18-7.21 (d, 1H), 7.02-7.05 (d, 2H), 5.82-5.84 (d, 1H), 5.35-5.37 (m, 1H), 4.36-4.42 (m, 3H), 4.14-4.16 (m, 1H), 2.93-2.97 (m, 1H), 1.23-1.26 (d, 6H).

Example 47

(S)-2-(2'3'-Dichloro-biphenyl-4-yloxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-5 pyrrolidinomethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.25 g, 0.61 mmol), 2',3'-dichloro-biphenyl-4-ol (0.15 g, 0.61 mmol) and cesium carbonate (0.2 g, 0.61 mmol) in anhydrous acetonitrile (15 ml) was heated at reflux for one hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoro acetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization. The resulting material was treated with aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with ether (50ml) for one hour. The insoluble material was collected to provide the title compound, 152-55°C mp (0.07 g, 24%). [a]_D ²⁵ = +11.4⁰ (c = 0.68, MeOH). C₂₄H₂₃C1₂N₃0₃ (472.37), LCMS (ESI): 472-474 (M H)

1H NMR (DMSO-d₆, 300 MHz), δ: 7.62-7.65 (d, 1H), 7.33-7.44 (m, 4H), 7.02-7.05 (d, 2H) 5.78 (s, 1H), 5.34-5.35 (m, 1H), 4.28-4.55 (m, 4H), 3.32 (s, 3H), 2.50 (s, 4H), 1.70 (s, 4H).

Example 48

(S)-2-(3'-Bromo-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.38 g, 1.2 mmol), 3'-bromo-biphenyl-4-ol (prepared from acetic acid 4-iodo- phenylester and 3-bromophenylboronic acid) (0.3 g, 1.2 mmol) and cesium carbonate (0.38 g, 1.2 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water and the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with hot ethyl acetate (25 ml) and was filtered. The insoluble material gave the title compound, 173-6°C mp (0.13 g, 27%). [a]_D ²⁵ = -19.0 ° (c = 0.68, DMSO).

Ci₉Hi₅Br₂N₂0₃ (399.24), LCMS (ESI): 398,400 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.81 (m, 2H), 7.63-7.67 (m, 3H), 7.42-7.45 (d, 1H), 7.36-7.39 (d, 1H), 7.03-7.06 (d, 2H), 5.82-5.84 (d, 1H), 5.35-5.37 (m, 1H), 4.33-4.45 (m, 3H), 4.1-4.15 (m, 1H).

Example 49

(S)-2-(2'-Methyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.61 g, 1.9 mmol), 2'-methyl-biphenyl-4-ol (prepared from acetic acid 4-iodo- phenylester and 2-methylphenylboronic acid) (0.35 g, 1.9 mmol) and cesium carbonate (0.6 g, 1.9 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC using 10- 100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with heptane (50 ml). The insoluble material was collected to provide the title compound, 192-4 C mp (0.125 g, 20%). [a]_D ²⁵ = -11.0 ° (c = 0.62, DMSO).

Ci₉oHi₈N₂0₃ (334.37), LCMS (ESI): 335.19 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.77-7.79 (d, 1H), 7.15-7.29 (m, 6H), 7.00-7.02 (d, 2H), 5.82-5.84 (d, 1H), 5.33-5.38 (m, 1H), 4.36-4.45 (m, 3H), 4.11-4.17 (m, 1H), 2.22 (s, 3H).

Example 50

(S)-2-(3'-Ethyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.5 g, 1.5 mmol), 3'-ethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo- phenylester and 3-ethylphenylboronic acid) (0.6 g, 3.0 mmol) and cesium carbonate (0.5 g, 1.5 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC using 10- 100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with heptane. The insoluble material was collected to provide the title compound (0.140 g, 28%>). [a]_D ²⁵ = -45.2 ° (c = 0.67, MeOH). C₂iH₂₀N₂O₃ (348.40), LCMS (ESI): 349.11 (M⁺H) 1H NMR (DMSO-d₆, 300 MHz), δ: 7.77-7.79 (d, 1H), 7.60-7.62 (m, 2H), 7.34-7.45 (m, 3H), 7.15-7.17 (d, 1H), 7.02-7.05 (d, 2H), 5.82-5.84 (d, 1H), 5.35-5.37 (m, 1H), 4.32-4.41 (m, 3H), 4.10-4.16 (m, 1H), 2.62-2.67 (q, 2H), 1.20-1.25 (t, 3H).

Example 51

(S)-2-(3'-Methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.47 g, 1.45 mmol), 3'-methyl-biphenyl-4-ol (prepared from acetic acid 4- iodo-phenylester and 3-methylphenylboronic acid) (0.6 g, 3.26 mmol) and cesium carbonate (0.47 g, 1.45 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoro acetic acid) over 20 minutes. The product- containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was dissolved in hot ethyl acetate and was filtered. The filtrate was diluted with heptane and the precipitate was collected to give the title compound, 183-5°C mp (0.07 g, 14%).

[a]_D ²⁵ = -18.5 ⁰ (c = 0.72, DMSO). C₂oHi₈N₂0₃ (334.37), LCMS (ESI): 335.16 (M⁺H) 1H NMR (DMSO-d₆, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.59-7.62 (m, 2H), 7.29-7.43 (m, 3H), 7.1 1-7.14 (d, 1H), 7.02-7.04 (d, 2H), 5.82-5.84 (d, 1H), 5.32-5.37 (m, 1H), 4.32-4.45 (m, 3H), 4.10-4.16 (m, 1H), 2.36 (s, 3H).

Example 52

(S)-2-(3 '-Chloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.55 g, 1.7 mmol), 3 '-chloro-biphenyl-4-ol (prepared from acetic acid 4-iodo- phenylester and 3-chlorophenylboronic acid) (0.35 g, 1.7 mmol) and cesium carbonate (0.5 g, 1.7 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC using 10- 100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was dissolved in hot ethyl acetate (200 ml) and was filtered. The filtrate was diluted with heptane (200 ml) and the precipitate was collected to give the title compound, 185-9°C mp (0.065 g, 1 1%). [a]_D ²⁵ = -22.4 ⁰ (c = 0.67, DMSO). Ci₉ Hi₅ClN₂0₃ (354.79), LCMS (ESI): 335, 357 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.59-7.68 (m, 4H), 7.36-7.48 (m, 2H), 7.03-7.06 (d, 2H), 5.82-5.84 (d, 1H), 5.32-5.37 (m, 1H), 4.33-4.45 (m, 3H), 4.10-4.15 (m, 1H).

Example 53

(S)-2-(3'-tert-Butyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.21 g, 0.66 mmol), 3'-tert-butyl-biphenyl-4-ol (prepared from 4- hydroxyphenylboronic acid and 3-tert-butyl-bromobenzene) (0.15 g, 0.66 mmol) and cesium carbonate (0.2 g, 0.66 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with boiling ethyl acetate (20ml) and was filtered. The insoluble material gave the title compound, 188-91°C mp (0.07 g, 28%). [a]_D ²⁵ = -15.8 ⁰ (c = 0.68, DMSO).

C₂₃H24N₂0₃ (376.45), LCMS (ESI): 377.19 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.57-7.62 (m, 3H), 7.34-7.41 (m, 3H), 7.02-7.05 (d, 2H), 5.82-5.84 (d, 1H), 5.35-5.40 (m, 1H), 4.36-4.45 (m, 3H), 4.10-4.16 (m, 1H), 1.53 (s, 9H).

Example 54

(S)-2-(3'-Propyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : l-(3-Bromophenyl)-l-propanol

To a mixture of 3M ethyl magnesium bromide solution in ether (6.7 ml, 20 mmol) in anhydrous ether (25 ml) cooled in ice was added a solution of 3-bromobenzaldehyde (1.85 g, 10 mmol) in ether (10 ml) drop wise over 5 minutes. The mixture was stirred in ice for 1 hour. The mixture was poured into 10% HC1 and was extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to provide the title compound as an oil (1.9 g, 88%).

Step 2: 3-Propyl-bromobenzene

A mixture of l-(3-bromophenyl)-l-propanol (3.3 g, 15.3 mmol), triethylsilane (20 ml) and borontrifluoride (20 ml) was heated at reflux for 3 hours. The mixture was poured into 10% HC1 (150 ml) and was extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was treated with heptane (20 ml) and was filtered. The filtrate was concentrated to provide the title compound (2.1 g, 70%>).

Step 3 : (S)-2-(3'-Propyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.45 g, 1.4 mmol), 3 '-propyl -biphenyl-4-ol (0.3 g, 1.4 mmol) and cesium carbonate (0.45 g, 1.4 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was recrystallized from ethyl acetate to give the title compound, 138-42°C mp (0.13 g, 25%). [a]_D ²⁵ = -51.3 ⁰ (c = 0.60, MeOH). C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.19 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.59-7.62 (m, 2H), 7.30-7.48 (m, 3H), 7.12-7.15 (m, 1H), 7.02-7.05 (d, 2H), 5.82-5.84 (d, 1H), 5.32-5.37 (m, 1H), 4.32-4.45 (m, 3H), 4.10-4.16 (m, 1H), 2.58-2.63 (t, 2H), 1.57-1.67 (m, 2H), 0.89-0.94 (t, 3H).

Example 55

(S)-2-(3'-Butyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (1.0 g, 3.0 mmol), 3'-butyl-biphenyl-4-ol (prepared from 4- hydroxyphenylboronic acid and 3-butyl-bromobenzene) (0.7 g, 3.0 mmol) and cesium carbonate (1.0 g, 3.0 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC using 10- 100% (acetonitrile - 0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was triturated with heptane (50ml). The insoluble material was collected to provide the title compound, 148-52°C mp (0.130 g, 12%). [a]_D ²⁵ = -40.9 ° (c = 0.70, MeOH).

C23H24N2O3 (376.45), LCMS (ESI): 377.18 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.59-7.62 (d, 2H), 7.30-7.42 (m, 3H), 7.12-7.15 (d, 1H), 7.02-7.05 (d, 2H), 5.82-5.84 (d, 1H), 5.32-5.37 (m, 1H), 4.32-4.45 (m, 3H), 4.10-4.16 (m, 1H), 2.61-2.66 (t, 2H), 1.54-1.64 (m, 2H), 1.27-1.39 (m, 2H), 0.89-0.94 (t, 3H).

Example 56

(S)-2-(3'-Isobutyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-

Step 1 : l-(3-Bromo-phenyl)-2-methyl-propan-l-ol

To a mixture of 2M isopropylmagnesium chloride solution in tetrahydrofuran (10 ml, 20 mmol) in anhydrous ether (70 ml) cooled in ice was added a solution of 3- bromobenzaldehyde (1.85 g, 10 mmol) in ether (10 ml) dropwise over 3 minutes. The mixture was stirred in ice for 1 hour. The mixture was poured into 10% hydrochloric acid and was extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel using 0-10% ethyl acetate/ heptane to give the title compound (0.6 g, 26%).

Step 2: 3-Isobutyl-bromobenzene

A mixture of l-(3-bromo-phenyl-2-methyl-propan-l-ol (1.4 g, 6.5 mmol), triethylsilane (4 ml) and borontrifluoride (4 ml) was heated at reflux for 3 hours. The mixture was poured into 10% hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to provide the title compound (0.8 g, 58%).

Step 3 : (S)-2-(3'-Isobutyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (0.4 g, 1.3 mmol), 3'-isobutyl-biphenyl-4-ol (prepared from 4- hydroxyphenylboronic acid and 3-isobutyl-bromobenzene) (0.3 g, 1.3 mmol) and cesium carbonate (0.4 g, 1.3 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with heptane. The insoluble material was collected to provide the title compound (0.1 g, 20%). [a]_D ²⁵ = -38.9 ° (c = 0.70, MeOH). C₂₃H₂₄N₂0₃ (376.45), LCMS (ESI): 377.19 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.59-7.62 (d, 2H), 7.31-7.44 (m, 3H),

7.09- 7.12 (d, 2H), 7.02-7.05 (d, 1H), 5.82-5.84 (d, 1H), 5.35-5.37 (m, 1H), 4.32-4.45 (m, 3H),

4.10- 4.16 (m, 1H), 2.50-2.51 (s, 2H), 1.86-1.93 (m,lH), 0.88-0.90 (d, 6H).

Example 57

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one

Step 1 : 2-Formyl-butyric acid ethyl ester

To a solution of diisopropylamine (7.06 ml, 50 mmol) in anhydrous tetrahydrofuran (50 ml) cooled to -78°C was added 2.5M n-butyllithium (20 ml, 50 mmol) dropwise over 5 minutes. The mixture was warmed to 0°C and was kept in ice for 30 minutes. The mixture was again cooed to -78°C and ethyl butyrate (5.9 ml, 44.6 mmol) was added dropwise over 5 minutes. After stirring for 30 minutes, ethyl formate(12.2 ml, 150 mmol) was added over 5 minutes. The cooling bath was removed and the mixture was stirred for 3 hours at room temperature. To this mixture was added acetic acid (8.5 ml). The mixture was poured into aqueous sodium bicarbonate and was extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 0-10% ethyl acetate/ heptane to give the title compound as a mixture with the enol isomer (2.4 g, 37%).

Step 2: (S)-5-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (1.37 g, 5.0 mmol), 2',3'-dimethyl-biphenyl-4-ol (prepared from acetic acid 4- iodo-phenylester and 2,3-dimethylphenylboronic acid) (1.0 g, 5.0 mmol) and cesium carbonate (1.6 g, 5.0 mmol) was heated in anhydrous acetonitrile (20 ml) at reflux for 6 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue treated with ethyl acetate (20 ml). The solid which formed was collected to give the title compound, 136-9°C mp (0.6 g, 40%>).

Step 3 : (S)-2-(2 ' ,3 ' -Dimethyl-biphenyl-4-yloxymethyl)-6-ethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2- ylamine toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.6 g, 2.0 mmol) and 2-formyl-butyric acid ethyl ester (0.5 g, 3.47 mmol) in ethanol (20 ml) was heated at reflux for 20 hours. The solution was concentrated and the residue treated with ethyl acetate (10 ml). The precipitate which formed was collected to give the title compound, 178-82°C mp (0.145 g, 19%). [a]_D ²⁵ = -4.8 ° (c = 0.66, MeOH).

C23H24N2O3 (376.45), LCMS (ESI): 377.18 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.63 (s, 1H), 7.20-7.23 (d, 2H), 7.08-7.15 (m, 2H), 7.02- 7.06 (m, 4H), 5.33-5.35 (m, 1H), 4.31-4.45 (m, 3H), 4.13-4.16 (q, 2H), 2.28 (s, 3H), 2.09(s, 3H), 1.03-1.08 (t, 3H).

Example 58

(Biphenyl-4- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.32 g, 1.0 mmol), 4-phenylphenol (0.17 g, 1.0 mmol) and cesium carbonate (0.32 g, 1.0 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate. The insoluble material was collected. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was combined with the first insoluble material and the combined material was treated with hot ethyl acetate (50 ml) and filtered. The insoluble material gave the title compound, 247-50°C mp (0.18 g,

56%).

[α]ο = -22.7 ° (c = 0.75, DMSO). Ci₉Hi₆N₂0₃ (320.35), LCMS (ESI): 321.14 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.61-7.63 (m, 4H), 7.41=7.46 (t, 2H), 7.29-7.34 (m, 1H), 7.03-7.06 (d, 2H), 5.82-5.84 (d, 1H), 5.32-5.37 (m, 1H), 4.43-4.45 (m, 3H), 4.10-4.16 (m, 1H).

Example 59

(S)-6-Ethyl-2-(2'-ethyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : (S)-5-(2'-Ethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (2.2 g, 8.1 mmol), 2'-ethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo- phenylester and 2-ethylphenylboronic acid) (1.61 g, 8.1 mmol) and cesium carbonate (2.6 g, 8.1 mmol) was heated in anhydrous acetonitrile (25 ml) at reflux for 6 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 1 : 1 ethyl acetate/heptane then 10-20% methanol/ethyl acetate to provide the title compound (0.6 g, 25%).

Step 2: (S)-6-Ethyl-2-(2'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2'-ethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (1.7 g, 5.74 mmol) and 2-formyl-butyric acid ethyl ester (1.3 g, 9.0 mmol) in ethanol (25 ml) was heated at reflux for 24 hours. The solution was concentrated and the residue purified by flash chromatography on silica gel using 0-20% methanol/ ethyl acetate. The most polar spot was again purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated.

The residue was treated with a little ether. The insoluble material was collected to give the title compound, 196-98°C mp (0.023 g, 1%).

C23H24N2O3 (376.45), LCMS (ESI): 377.17 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz), δ: 7.63 (s, 1H), 7.11-7.32 (m, 6H), 7.02-7.05 (d, 2H), 5.32-

5.38 (m, 1H), 4.32-4.45 (m, 3H), 4.10-4.16 (m, 1H), 2.50-2.58 (m, 2H), 2.21-2.28 (q, 2H),

1.02-1.08 (m, 6H).

Example 60

(S)-2-(2-Methyl-3'-propyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (0.5 g, 1.56 mmol), 2-methyl-3'-propyl-biphenyl-4-ol (prepared from acetic acid 4-bromo-3-methyl-phenylester (from 4-bromo-3-methylphenol and acetyl chloride) and 3-propylphenylboronic acid) (0.49 g, 2.17 mmol) and cesium carbonate (0.7 g, 2.17 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ether (15 ml) and the insoluble material was collected to give the title compound (0.06 g, 10%). [a]_D ²⁵ = -37.8 ⁰ (c = 0.36, MeOH).

C23H24N2O3 (376.45), LCMS (ESI): 377.19 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.66-7.79 (d, 1H), 7.29-7.34 (t, 1H), 7.08-7.31 (m, 4H), 6.82-6.89 (m, 2H), 5.82-5.84 (d, 1H), 5.31-5.39 (m, 1H), 4.29-4.45 (m, 3H), 4.03-4.15 (m, 1H), 2.50-2.67 (t, 2H), 2.20 (s, 3H), 1.55-1.68 (m, 2H), 0.88-0.93 (t, 3H).

Example 61

2',3'-Dimethyl-4-((S)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethoxy)-biphenyl-

2-carbonitrile

Step 1 : 4-Bromo-3-cyanophenol

To a mixture of 3-cyanophenol (3.2 g, 26.8 mmol) in glacial acetic acid (20 ml) was added a solution of bromine (4.2 g, 23.3 mmol) in acetic acid (5 ml) dropwise over 5 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was filtered. The filtrate was added to water (100 ml) containing a few mg of sodium thiosulfate. The insoluble material was collected and the filter cake was added to warm methanol (15 ml) and was filtered through celite. The filtrate was slowly diluted with water and the precipitate was collected and dried to give the title compound, 183-5°C, mp (1.0 g, 22%).

Step 2: 2-Cyano-2',3'-dimethyl-biphenyl-4-ol

A mixture of 4-bromo-3-cyanophenol (1.0 g, 5 mmol), 2,3-dimethylphenylboronic acid (1.1 g, 8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmol) and a 2M sodium carbonate solution (5 ml ) in 50 ml of 1 ,2-dimethoxyethane was heated at reflux for 6 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane to provide the title compound, 133-7°C, mp (0.33 g, 30%).

Step 3 : 2',3'-Dimethyl-4-((S)-7-oxo-2,3-dihydro-7H-oxazolo[3 ,2-a]pyrimidin-2-ylmethoxy)- biphenyl-2-carbonitrile

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.47 g, 1.56 mmol), 2-cyano-2',3'-dimethyl-biphenyl-4-ol (0.33 g, 1.4 mmol) and cesium carbonate (0.5 g, 1.5 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product- containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ether and the insoluble material was collected to give the title compound (0.13g, 25%).

[a]_D ²⁵ = -21.9 ° (c = 0.47, MeOH). C₂₂Hi₉N₃0₃ (373.41), LCMS (ESI): 374.15 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.76-7.79 (d, 1H), 7.57 (s, 1H), 7.35 (s, 2H), 7.15-7.32 (m, 2H), 7.01-7.03 (d, 1H), 5.82-5.85 (d, 1H), 5.37-5.39 (m, 1H), 4.39-4.54 (m, 3H), 4.10- 4.15 (m, 1H), 2.31 (s, 3H), 2.00 (s, 3H).

Example 62

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2-a] rimidin-7-one

Step 1 : 2-Formyl-propionic acid ethyl ester

To a solution of diisopropylamine (7.06 ml, 50 mmol) in anhydrous tetrahydrofuran (50 ml) cooled to -78°C was added 2.5M n-butyllithium (20 ml, 50 mmol) dropwise over 5 minutes. The mixture was warmed to 0 C and was kept in ice for 30 minutes. The mixture was again cooed to -78°C and ethyl propionate (5.17 ml, 44.6 mmol) was added dropwise over 5 minutes. After stirring for 30 minutes, ethyl formate(12.2 ml, 150 mmol) was added over 5 minutes. The cooling bath was removed and the mixture was stirred for 3 hours at room temperature. To this mixture was added acetic acid (8.5 ml). The mixture was poured into aqueous sodium bicarbonate and was extracted with ether (200 ml). The ether layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated over low heat and the residue was used without further purification to give the title compound (4.2 g, 73%).

Step 2: (S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2- ylamine toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.75 g, 2.53 mmol) and 2-formyl-propionic acid ethyl ester (containing some enol isomer) (0.6 g, 4.6 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The precipitate which formed was collected to give the title compound, 251-3°C mp (0.15 g, 16%).

[a]_D ²⁵ = -2.0 ° (c = 0.70, DMSO). C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.18 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.68(s, 1H), 7.20-7.23 (d, 2H), 7.08-7.15 (m, 2H), 6.98- 7.02 (d, 3H), 5.31-5.38 (m, 1H), 4.31-4.44 (m, 3H), 4.10-4.15 (m, 1H), 2.28 (s, 3H), 2.09 (s, 3H), 1.81 (s, 3H).

Example 63

(S)-2-(2-Methoxy-2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a] rimidin-7-one

Step 1 : 4-Bromo-3-methoxyphenol

To a solution of 3-methoxyphenol (12.4 g, 100 mmol) in acetonitrile (400 ml) was added solid N-bromosuccinimide (19.5 g, 110 mmol) in portions over 10 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated in a rotary evaporator and the residue was treated with ether (70 ml). The insoluble material was filtered off. The filtrate was washed with water (40 ml) and the organic layer dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane to give the title compound (2.4 g, 12%).

Step 2: 2-Methoxy-2',3'-dimethyl-biphenyl-4-ol

A mixture of 4-bromo-3-methoxyphenol (2.2 g, 10.8 mmol), 2,3- dimethylphenylboronic acid (2.4 g, 16.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and a 2M sodium carbonate solution (6 ml) in 1 ,2-dimethoxyethane(70 ml) was heated at reflux for 4 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane to provide the title compound (0.4 g, 16%).

Step 3: (S)-2-(2-Methoxy-2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.5 g, 1.6 mmol), 2-methoxy-2',3'-dimethyl-biphenyl-4-ol (0.4 g, 1.75 mmol) and cesium carbonate (0.57 g, 1.75 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1%> trifluoro acetic acid) over 20 minutes. The product- containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was stirred with ether (20 ml) and the insoluble material was collected to give the title compound, 204-7°C mp (0.13 g, 22%). [a]_D ²⁵ = -35.7 ° (c = 0.66, MeOH).

C₂₂H₂₂N₂0₄ (378.43), LCMS (ESI): 379.17 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.77-7.79(d, 1H), 7.04-7.11 (m, 2H), 6.96-6.99 (d, 1H), 6.88-6.90 (d, 1H), 6.58-6.65 (m, 2H), 5.82-5.85 (d, 1H), 5.33-5.38 (m, 1H), 4.33-4.46 (m, 3H), 4.11-4.17 (m, 1H), 3.68 (s, 3H), 2.26 (s, 3H), 1.91 (s, 3H). Example 64

^■Ethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of (S)-5-(2'-ethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.2 g, 0.67 mmol) and 2-formyl-propionic acid ethyl ester (0.18 g, 1.3 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was treated with ethyl acetate (10 ml). The precipitate which formed was collected to give the title compound 223-5°C mp (0.020 g, 8%). [a]_D ²⁵ = -1.6⁰ (c = 0.70, DMSO).

C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.0 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz), δ: 7.69 (s, 1H), 7.19-7.32 (m, 5H), 7.11-7.13 (d, 1H), 6.99- 7.10 (d, 2H), 5.34-5.36 (m, 1H), 4.31-4.44 (m, 3H), 4.10-4.15 (m, 1H), 2.50-2.58 (q, 2H), 1.81(s, 3H), 0.99-1.04 (t, 3H).

Example 65

(S)-2-(2-Ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one

Step 1 : 4-Bromo-3-ethylphenol

To a solution of 3-ethylphenol (3.0 g, 24.6 mmol) in acetic acid (20 ml) was added bromine (4 g, 22 mmol) in acetic acid (10 ml) dropwise over 5 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was poured into water (100 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with aqueous sodium bicarbonate and then water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 100% heptane and then 9: 1 heptane: ethyl acetate to give the title compound as an oil (1.6 g, 36%). Step 2: 2-Ethyl-2',3'-dimethyl-biphenyl-4-ol

A mixture of 4-bromo-3-ethylphenol (1.6 g, 7.96 mmol), 2,3-dimethylphenylboronic acid (1.2 g, 7.96 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and a 2M sodium carbonate solution (6 ml) in 1 ,2-dimethoxyethane(70 ml) was heated at reflux for 6 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 100% heptane, then 9: 1 heptane:ethyl acetate to provide the title compound (0.7 g, 39%).

Step 3: (S)-2-(2-Ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.4 g, 1.24 mmol), 2-ethyl-2',3 '-dimethyl-biphenyl-4-ol (0.3 g, 1.3 mmol) and cesium carbonate (0.42 g, 1.3 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was stirred with ether (50ml) for 1 hour and the insoluble material was collected to give the title compound, 110-13°C mp (0.11 g, 23%). [a]_D ²⁵ = -30.4 ° (c = 0.70, MeOH).

C23H24N2O3 (376.45), LCMS (ESI): 377.19 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.77-7.80 (d, 1H), 7.07-7.16 (m, 2H), 6.80-6.95 (m, 4H), 5.82-5.85 (d, 1H), 5.33-5.41 (m, 1H), 4.31-4.46 (m, 3H), 4.12-4.18 (m, 1H), 3.33-3.42 (q, 2H), 2.24(s, 3H), 1.88 (s, 3H), 0.91-0.96 (t,3H).

Example 66

(S)-2-(2-Ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : (S)-5-(2-Ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.47 g, 1.74 mmol), 2',3'-dimethyl-2-ethyl-biphenyl-4-ol (prepared using scheme 7 from 4-bromo-3-ethylphenol and 2,3-dimethylphenylboronic acid) (0.4 g, 1.75 mmol) and cesium carbonate (0.56 g, 1.75 mmol) was heated in anhydrous acetonitrile (20 ml) at reflux for 6 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 100% ethyl acetate then 1 : 1 ethyl acetate :methanol and finally 95:5 methanol :triethylamine to provide the title compound (0.3 g, 53%).

Step 2: (S)-2-(2-Ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2-Ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-4,5-dihydro- oxazol-2-ylamine (0.7 g, 2.16 mmol) and 2-formyl-propionic acid ethyl ester (contains some hydroxyl isomer) (0.45 g, 3.46 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was purified by reverse phase HPLC using 10- 100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ether (20 ml) and the insoluble material was collected to provide the title compound, 225- 8°Cmp (0.028 g, 2%).

C₂₄H₂₆N₂03 (390.48), LCMS (ESI): 391.21 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.69 (s, 1H), 7.07-7.16 (m, 2H), 6.80-6.95 (m, 4H), 5.30- 5.35 (m, 1H), 4.29-4.44 (m, 3H), 4.10-4.16 (m, 1H), 2.17-2.51 (m, 5H), 1.18 (s, 3H), 1.81 (s, 3H), 0.91-0.96 (t, 3H).

Example 67

(S)-2-(Biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2 -a]pyrimidin-7-one

Step 1 : (S)-5-(Biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (2.2 g, 7.77 mmol), 4-phenylphenol (1.28 g, 7.5 mmol) and cesium carbonate (2.5 g, 7.6 mmol) was heated in anhydrous acetonitrile (25 ml) at reflux for 6 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The insoluble material was collected and dried to give 0.6 g. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was treated with hot ethyl acetate (50 ml). The insoluble material was collected (0.2 g) and was combined with the first insoluble amount to give the title compound 180-4°C mp (0.8 g, 40%).

Step 2: (S)-2-(Biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2 -a]pyrimidin-7- one

A mixture of (S)-5-(Biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.8 g, 2.9mmol) and 2-formyl-butyric acid ethyl ester (contained some hydroxyl isomer) (0.86 g, 5.9 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1%> trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ether (50ml) and the insoluble material was collected to provide the title compound, 224-7°Cmp (0.09 g, 9%>).

[a]_D ²⁵ = +0.8 ⁰ (c = 0.64, DMSO). C₂iH₂oN₂0₃ (348.40), LCMS (ESI): 349.15 (M⁺H) 1H NMR (DMSO-d₆, 300 MHz), δ: 7.57-7.60 (d, 5H), 7.37-7.40 (t, 2H), 7.25-7.30 (m, 1H), 6.99-7.02 (d, 2H), 5.26-5.34 (m, 1H), 4.28-4.41 (m, 3H), 4.00-4.11 (m, 1H), 2.17-2.25 (t, 2H), 1.00-1.04 (t, 3H).

Example 68

(S)-6-Ethyl-2-(methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2 -a]pyrimidin-7-one

Step 1 : (S)-5-(2-Methyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (1.1 g, 4.0 mmol), ), 2-methyl-biphenyl-4-ol (prepared using scheme 7 from 4- bromo-3-methylphenol and phenylboronic acid) (0.8 g, 4.3 mmol) and cesium carbonate (1.4 g, 4.3 mmol) was heated in anhydrous acetonitrile (20 ml) at reflux for 6 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound, 80-85°C mp (0.6 g, 54%).

Step 2: (S)-6-Ethyl-2-(methyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2-Methyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.6 g, 2.1 mmol) and 2-formyl-butyric acid ethyl ester (contained some hydroxyl isomer) (0.6 g, 4.2mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ether (20 ml) and the insoluble material was collected to provide the title compound, 175-7°C mp (0.045 g, 6%>). [a]_D ²⁵ = -13.1° (c = 0.36, DMSO). C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.18 (M⁺H) 1H NMR (DMSO-de, 300 MHz), δ: 7.59 (s, 1H), 7.24-7.41 (m, 5H), 7.08-7.11 (d, 1H), 6.79- 6.86 (m, 2H), 5.26-5.30 (m, 1H), 4.25-4.37 (m, 3H), 4.05-4.11 (m, 1H), 2.20-2.47 (q, 2H), 2.17 (s, 3H), 0.99-1.04 (t, 3H). Example 69

(S)-2-(2-Ethyl-biphenyl-4- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.48 g, 1.5 mmol), 2-ethyl-biphenyl-4-ol (prepared using scheme 7 from 4- bromo-3-ethylphenol and phenylboronic acid (0.3 g, 1.5 mmol) and cesium carbonate (0.49 g, 1.5 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was stirred with ether (20 ml) and the insoluble material was collected to give the title compound, 120-4 C mp (0.12 g, 23%).

C₂iH₂oN₂0₃ (348.40), LCMS (ESI): 349.16 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.73-7.75 (d, 1H), 7.21-7.41 (m, 5H), 7.04-7.07 (d, 1H), 6.79-6.87 (m, 2H), 5.82-5.87 (d, 1H), 5.28-5.36 (m, 1H), 4.27-4.41 (m, 3H), 4.07-4.12 (m, 1H), 2.44-2.49 (q, 2H), 0.96-1.01 (t, 3H).

Example 70

(S)-6-Ethyl-2-(2'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2 -a]pyrimidin-7- one

A mixture of (S)-5-(2'-methy-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.6 g, 2.12 mmol) and 2-formyl-butyric acid ethyl ester (contained some hydroxyl isomer) (0.6 g, 4.25 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was purified by reverse phase HPLC using 10-100%) (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ether (30 ml) and the insoluble material was collected to provide the title compound, 113-16 Cmp (0.07 g, 9%). [a]_D ²⁵ = -7.0 ° (c = 0.52, MeOH).

C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.17 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.63 (s, 1H), 7.10-7.36 (m, 5H), 7.07-7.10 (m, 1H), 7.00- 7.03 (d, 2H), 5.28-5.36 (m, 1H), 4.28-4.42 (m, 3H), 4.14-4.20 (m, 1H), 2.22-2.30 (q, 2H), 2.20 (s, 3H), 1.00-1.04 (t, 3H).

Example 71

(S)-2-(2-Ethyl-biphenyl-4-ylox methyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : (S)-5-(2-Ethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine

A mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2- a]pyrimidin-2- ylmethyl ester (1.6 g, 6.0 mmol), 2-ethyl-biphenyl-4-ol (prepared using scheme 7 from 4- bromo-3-ethylphenol and phenylboronic acid ) (1.3 g, 6.9 mmol) and cesium carbonate (2.2 g, 6.9 mmol) was heated in anhydrous acetonitrile (30 ml) at reflux for 18 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound, (0.6 g, 77%>). Step 2: (S)-2-(2-Ethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2-ethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.6 g, 2.0 mmol) and 2-formyl-propionic acid ethyl ester (contained some hydroxyl isomer) (0.5 g, 4.0 mmol) in ethanol (25 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was treated with ethyl acetate (10 ml). The precipitate which formed was collected to give the title compound 224-7°C mp (0.105 g, 15%).

[a]_D ²⁵ = -0.6⁰ (c = 0.66, DMSO). C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.17 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.64 (s, 1H), 7.38-7.41 (m, 2H), 7.30-7.33 (m, 1H), 7.24-

7.28 (t, 2H), 7.06-7.09 (d, 1H), 6.88 (s, 1H), 6.80-6.82 (d, 1H), 5.29-5.37 (m, 1H), 4.36-4.40

(m, 2H), 4.30-4.34 (m, 1H), 4.07-4.11 (m, 1H), 2.42-2.48 (q, 2H), 2.41 (s, 3H), 0.98-1.01 (s,

3H).

Example 72

(S)-2-(2'-Methyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Step 1 : (S)-5-(2'-Methyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.5 g, 1.85 mmol), 2'-methyl-biphenyl-4-ol (prepared from acetic acid 4-iodo- phenylester and 2-methylphenylboronic acid) (0.4 g, 2.1 mmol) and cesium carbonate (0.68 g, 2.1 mmol) was heated in anhydrous acetonitrile (25 ml) at reflux for 18 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound, 130-4°C mp (0.3 g, 57%).

Step 2 : (S)-2-(2'-Methyl-biphenyl-4-yloxymethyl)-6-methyl-2,3 -dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2'-methyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.3 g, 1.1 mmol) and 2-formyl-propionic acid ethyl ester (contained some hydroxyl isomer) (0.27 g, 2.2 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was treated with ethyl acetate (10 ml). The precipitate which formed was collected to give the title compound 226-9°C mp (0.034 g, 9%).

[a]_D ²⁵ = -46.9 ° (c = 0.48, CHC1₃). C₂iH₂₀N₂O₃ (348.40), LCMS (ESI): 349.16 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ: 7.70 (s, 1H), 7.10-7.36 (m, 6H), 6.99-7.03 (d, 2H), 5.32-

5.40 (m, 1H), 4.38-4.45 (m, 3H), 4.10-4.18 (m, 1H), 2.52 (s, 3H), 1.80 (s, 3H).

Example 73

(S)-2-(2,2'-Dimethyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : Acetic acid-2-methyl-2'-meth l-biphenyl-4-ol

A mixture of acetic acid 4-bromo-3-methylyphenol (4.2 g, 18.3 mmol), 2- methylphenylboronic acid (5.0 g, 36.8 mmol), tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol) and a 2M sodium carbonate solution (8 ml) in 1 ,2-dimethoxyethane(70 ml) was heated at reflux for 7 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 100% heptane , then 20: 1 heptane:ethyl acetate to provide the title compound (2.5 g, 57%).

Step 2: 2-Methyl-2'-methyl-biphen l-4-ol

A mixture of acetic acid-2-methyl-2'-methyl-biphenyl-4-ol (2.5 g, 10.4 mmol), 10% sodium hydroxide (5 ml), water (5 ml) in ethanol (10 ml) was heated with a heat gun to give a solution. The solution was stirred at room temperature for 1 hour. The mixture was poured into water and was acidified with concentrated HC1. The mixture was extracted with ethyl acetate (100 ml) and the organic layer was washed with water. The organic layer was dried over magnesium sulfate and was filtered. The filtrate was concentrated to give the title compound (2.1 g, 100%).

Step 3 : (S)-2-(2,2'-Dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.48 g, 1.5 mmol), 2-methyl-2'-methyl-biphenyl-4-ol (0.3 g, 1.5 mmol) and cesium carbonate (0.48 g, 1.5 mmol) in 20 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was stirred with ether (50 ml) and the insoluble material was collected to give the title compound, 160-3°C mp (0.085 g, 16%).

C₂iH₂oN₂0₃ (348.40), LCMS (ESI): 349.17 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz), δ: 7.78-7.80 (d, 1H), 7.20-7.36 (m, 3H), 6.90-7.08 (m, 2H), 6.80-6.88 (m, 2H), 5.82-5.84 (d, 1H), 5.32-5.42 (m, 1H), 4.30-4.42 (m, 3H), 4.08-4.20 (m, 1H, 1.90 (s, 3H), 1.94 (s, 3H).

Example 74

(S)-2-(2,2'-Dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2-a] rimidin-7-one

Step 1 : (S)-5-(2,2'-Dimethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin-2- ylmethyl ester (1.1 g, 8.5 mmol), ), 2,2'-dimethyl-biphenyl-4-ol (prepared using scheme 7 from 4-bromo-3-methylphenol and 2-methylphenylboronic acid) (1.8g, 9.1mmol) and cesium carbonate (2.9 g, 9.1 mmol) was heated in anhydrous acetonitrile (40 ml) at reflux for 18 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product- containing fractions were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a foam (0.8 g, 32%).

Step 2: (S)-2-(2,2'-Dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

A mixture of (S)-5-(2,2'-dimethyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2- ylamine (0.8 g, 2.7 mmol) and 2-formyl-propionic acid ethyl ester (contained some hydroxyl isomer) (0.55 g, 4.2 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue was treated with ethyl acetate (10 ml). The precipitate which formed was collected to give the title compound 246-8°C mp (0.14 g, 14%).

C₂₂H₂₂N₂0₃ (362.43), LCMS (ESI): 363.16 (ΜΉ)

1H NMR (DMSO-d₆, 300 MHz), δ: 7.65 (s, 1H), 7.17-7.30 (m, 3H), 7.00-7.02 (d, 1H), 6.96- 6.98 (d, 1H), 6.90 (s, 1H), 6.80-6.82 (d, 1H), 5.32-5.38 (m, 1H), 4.28-4.38 (m, 3H), 4.10-4.14 (m, 1H), 1.96-1.98 (s, 3H), 1.92-1.94 (s, 3H), 1.76-1.78 (s, 3H).

Example 75

(S)-2-(Biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Step 1 : Toluene -4-sulfonic acid (S)-7-oxo-5-(tetrahydro-pyran-2-yloxymethyl)-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester

To a solution of toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (Example 3, Step 1) (5.0 g, 18.50 mmol) in ethanol (80 ml) was added 4-(tetrahydro- pyran-2-yloxy)-but-2-ynoic acid ethyl ester (Example 31, Step 1) (4.72 g, 22.20 mmol). The reaction mixture was stirred at reflux for 3 hours. The mixture was cooled to room temperature and purified via flash column chromatography (silica gel 1-6 % MeOH/ CH₂C1₂) to afford 2.70 g of toluene-4-sulfonic acid (S)-7-oxo-5-(tetrahydro-pyran-2-yloxymethyl)-2,3- dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester as a white solid.

C₂oH₂4N₂0₇S, (436.13), LCMS (ESI): 437.09 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.76 (dd, 2H), 7.37 (d, 2H), 5.94 (s, 1H), 5.15 (m, 1H), 4.66 (s, 1H), 4.46 (m, 2H), 4.43 (s, 2H), 4.29 (m, 2H), 3.81 (m, 1H), 3.53 (m, 1H), 2.46 (s, 3H), 1.78 (m,2H), 1.58 (m, 4H)

Step 2: Toluene -4-sulfonic acid (S)-7-oxo-5-(hydroxymethyl)-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester

Toluene-4-sulfonic acid (S)-7-oxo-5-(tetrahydro-pyran-2-yloxymethyl)-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester was treated with p-toluenesulfonic acid in ethanol (see Example 31) to provide the title compound.

Step 3 : (S)-2-(Biphenyl-4-yloxymethyl)-5-(hydroxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-5-(2-hydroxy-methyl)-7-oxo-2,3-dihydro-7H-oxazolo [3,2-a]pyrimidin-2-ylmethyl ester (150 mg, 0.43 mmol) was dissolved in DMF (6 mL) along with 1.0 equivalent of the 4-phenylphenol. To the mixture was added cesium carbonate (200 mg, 0.6 mmol). The reaction was closed to the air and heated at 35°C for 2 hours. The reaction mixture was then quenched with water, extracted with ethyl acetate (2 x 30mL), dried over Na₂S0₄, concentrated under vacuum, purified by column chromatography on silica gel (40 g column, 35 mL/min, 10% methanol in dichloromethane) and concentrated to yield the title compound. [a]_D ²⁵ = -0.4 ° (c = 0.70, DMSO).

C₂oHi₈N₂0₄ Calculated (350.12), LCMS (ESI): 351.12 (M⁺+H). 1H NMR ((CD₃)₂SO 300MHz) δ: 7.63 (d, 4H), 7.44 (t, 2H), 7.32 (t, 1H), 7.05 (d, 2H), 5.82-5.78 (m, 2H), 5.38- 5.36 (m, 1H), 4.48-4.31 (m, 4H), 4.19 (dd, 1H), OH not observed. OR [<x]_D = -°

Example 76

■Ethyl-biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 75 and employing the appropriate starting materials. C22H22N2O4 Calculated (378.43), LCMS (ESI): 379.15 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.58 (d, 2H), 7.52 (d, 2H), 7.26 (d, 2H), 7.03 (d, 2H), 5.80 (s, 1H), 5.72 (t, 1H), 5.37-5.35 (m, 1H), 4.47-4.27 (6H), 4.17 (dd, 1H), 1.20 (t, 3H), OH not observed.

Example 77

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 76 and employing the appropriate starting materials.

[a]_D ²⁵ = -1.7 ° (c = 0.70, DMSO). C22H22N2O4 (378.43), LCMS (ESI): 379.14 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.96 (s, 1H), 7.22 (d, 2H), 7.13 (s, 1H), 7.11 (s, 1H), 7.02 (d, 2H), 5.81 (s, 1H), 5.77-5.75 (m, 1H), 5.38-5.37 (m, 1H), 4.48-4.33 (m, 4H), 4.20 (dd, 1H), 2.28 (s, 3H), 2.09 (s, 3H), OH not observed.

Example 78

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

C₂oHi₆Cl₂N₂0₄ Calculated (418.04), LCMS (ESI): 419.04 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.63 (dd, 1H), 7.45-7.33 (m, 4H), 7.05 (d, 2H), 5.80 (s, 1H), 5.72 (t, 1H), 5.38-5.36 (m, 1H), 4.47-4.33 (m, 4H), 4.18 (dd, 1H), OH not observed.

Example 79

(S)-5-Hydroxymethyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro

a]pyrimidin-7-one

[<X]D = -2.5° (c = 0.55, DMSO). C₂oHi₅F₃N₂04 (404.09), LCMS (ESI): 405.08 (M⁺+H). 1H NMR ((CD₃)₂SO 300MHz) δ: 7.57 (dd, 2H), 7.54-7.48 (m, 1H), 7.31-7.26 (m, 1H), 7.09 (d, 2H), 5.80 (s, 1H), 5.73 (t, 1H), 5.38-5.36 (m, 1H), 4.48-4.34 (m, 4H), 4.18 (dd, 1H), OH not observed.

Example 80

(S)-2-(Biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Step 1 : Toluene -4-sulfonic acid (S)-5-(2-(tetrahydro-pyran-2-yloxy)-ethyl)-7-oxo-2,3- dihydro-7H-oxazolo [3,2-a]pyrimidin-2-ylmethyl ester

Toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (see Example 3, step 1) (4.35 g, 16 mmol) was dissolved in 115 mL of ethanol. 5-(Tetrahydro- pyran-2-yloxy)-pent-2-ynoic acid methyl ester (3.74 g, 17.7 mmol) was added and the reaction mixture was heated to 85°C for 24 h. The reaction mixture was then cooled to rt and concentrated under vacuum. The crude material was directly purified by column chromatography on silica gel (120 g column; 40 mL/min; 10% methanol in dichloromethane to provide the title compound as an orange foam (0.9 g, 12%).

C₂iH₂₆N₂0₇S Calculated (450.14), LCMS (ESI): 451.09 (M⁺+H).

1H NMR (CDC1₃ 300MHz) δ: 7.75 (d, 2H), 7.37 (d, 2H), 5.85 (s, 1H), 5.15-5.14 (m, 1H), 4.57-4.56 (m, 1H), 4.51-4.44 (m, 1H), 4.33 (t, 2H), 4.28-4.19 (m, 1H), 4.04-3.97 (m, 1H), 3.80-3.39 (m, 4H), 2.72 (t, 2H), 2.46 (s, 3H), 1.73-1.52 (m, 5H).

Step 2: Toluene -4-sulfonic acid (S)-5-(2-hydroxy-ethyl)-7-oxo-2,3-dihydro-7H-oxazolo [3,2- a]pyrimidin-2-ylmethyl ester

Toluene-4-sulfonic acid (S)-5-(2-(tetrahydro-pyran-2-yloxy)-ethyl)-7-oxo-2,3- dihydro-7H-oxazolo [3,2-a]pyrimidin-2-ylmethyl ester (0.9 g, 2 mmole) was dissolved in 20 mL of ethanol. 0.27 g of Amberlyst-15 was added and the reaction mixture was heated to 60°C for 3 h. The reaction mixture was filtered to remove the Amberlyst beads and the mother liquor concentrated under vacuum to provide the title compound as a beige solid (760 mg, 100% yield).

CieHisNzOeS Calculated (366.08), LCMS (ESI): 367.11 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.80 (d, 2H), 7.50 (d, 2H), 5.69 (s, IH), 5.16-5.15 (m, IH),

4.42-4.32 (m, 3H), 3.96 (dd, IH), 3.64 (t, 2H), 2.55 (t, 2H), 2.43 (s, 3H).

Step 3 : (S)-2-(Biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-5-(2-hydroxy-ethyl)-7-oxo-2,3-dihydro-7H-oxazolo [3,2- a]pyrimidin-2-ylmethyl ester (150 mg, 0.41 mmol) was dissolved in 6 mL of DMF. 4- Phenylphenol (0.41 mmol) was added followed by Cs₂C0₃ (187 mg, 0.57 mmol). The reaction mixture was heated to 35°C for 5 hours and stirred at rt overnight. The reaction mixtures were then quenched with water and brine and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (40 g column; 35 mL/min; 15% MeOH in CH₂C1₂) to give the title compound.

C₂iH₂oN₂0₄ Calculated (364.14), LCMS (ESI): 365.14 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.63 (d, 4H), 7.43 (t, IH), 7.31 (t, IH), 7.05 (d, 2H), 5.72 (s, IH), 5.34-5.32 (m, IH), 4.95 (t, IH), 4.51-4.30 (m, 3H), 4.21 (dd, IH), 3.69 (q, 2H), 2.64 (t, 2H).

Example 81

■Ethyl-biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 81 and employing the appropriate starting materials. C23H24N2O4 Calculated (392.17), LCMS (ESI): 393.17 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.59 (d, 2H), 7.52 (d, 2H), 7.26 (d, 2H), 7.03 (d, 2H), 5.72 (s, IH), 5.33-5.32 (m, IH), 4.95 (t, IH), 4.51-4.29 (m, 3H), 4.21 (dd, IH), 3.69 (q, 2H), 2.66- 2.61 (m, 4H), 1.20 (t, 3H).

Example 82

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in

Example 81 and employing the appropriate starting materials.

C23H24N2O4 Calculated (392.17), LCMS (ESI): 393.16 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.22 (d, 2H), 7.15-7.11 (m, 2H), 7.02-6.98 (m, 3H), 5.72 (s, IH), 5.34-5.33 (m, IH), 4.95 (t, IH), 4.52-4.29 (m, 3H), 4.22 (dd, IH), 3.69 (q, 2H), 2.64 (t, 3H), 2.28 (s, 3H), 2.09 (s, 3H).

Example 83

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 81 and employing the appropriate starting materials.

C₂iHi₈Cl₂N₂04 Calculated (432.06), LCMS (ESI): 433.06 (M⁺+H).

1H NMR ((CD₃)₂SO 300MHz) δ: 7.64 (dd, IH), 7.44-7.33 (m, 4H), 7.05 (d, 2H), 5.73 (s, IH), 5.35-5.34 (m, IH), 4.96 (t, IH), 4.52-4.32 (m, 3H), 4.23 (dd, IH), 3.70 (q, 2H), 2.65 (t, 3H).

Example 84

(S)-5-(2-Hydroxy-ethyl)-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

C₂iHi₇F₃N₂04 Calculated (418.1 1), LCMS (ESI): 419.1 1 (M⁺+H). 1H NMR ((CD₃)₂SO 300MHz) δ: 7.57 (d, 2H), 7.52-7.49 (m, 1H), 7.30-7.26 (m, 1H), 7.09 (d, 2H), 5.72 (s, 1H), 5.35-5.33 (m, 1H), 4.95 (t, 1H), 4.52-4.33 (m, 3H), 4.22 (dd, 1H), 3.69 (q, 2H), 2.64 (t, 3H).

Example 85

(S)-2-(Biphenyl-4-yloxymethyl -5-ethoxymethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : Toluene -4-sulfonic acid (S)-5-ethoxymethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester

Toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (see

Example 3, step 1) (1.34 g, 5 mmol) was dissolved in 35 mL of ethanol. 4-Ethyloxy-but-2- ynoic acid methyl ester (0.7 g, 5 mmol) was added and the reaction mixture was heated to

85°C for 3 h. The reaction mixture was then cooled to rt and concentrated under vacuum.

The crude material was directly purified by column chromatography on silica gel (80 g column; 35 mL/min; 10% methanol in dichloromethane to provide the title compound as a colorless viscous oil (0.53 g, 29%>).

Ci₇H₂₀N₂O₆S Calculated (398.09), LCMS (ESI): 399.10 (M⁺+H).

1H NMR (CDC1₃ 300MHz) δ: 7.4 (d, 2H), 7.36 (d, 2H), 5.86 (s, 1H), 5.27-5.22 (m, 1H), 4.50

(t, 1H), 4.36 (t, 2H), 4.27 (dd, 2H), 4.23 (dd, 1H), 3.53 (q, 2H), 2.44 (s, 3H), 1.21 (t, 3H).

Step 2: (S)-2-(Biphenyl-4-yloxymethyl)-5-ethoxymethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-5-ethoxymethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester (106 mg, 0.28 mmol) was dissolved in 4 mL of DMF. The appropriate biphenyl phenol (0.28 mmol) was added followed by Cs₂C0₃ (127 mg, 0.39 mmol). The reaction mixture was heated to 35°C for 5 hours and stirred at rt overnight. The reaction mixtures were then quenched with water and brine and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (40 g column; 35 mL/min; 5% MeOH in CH₂C1₂) to obtain the title compound. [a]_D ²⁵ = +2.7⁰ (c = 0.60, DMSO).

C₂₂H₂₂N₂0₄ Calculated (378.15), LCMS (ESI): 379.14 (M⁺+H).

1H NMR (CDCls 300MHz) δ: 7.53-7.48 (m, 4H), 7.40 (t, 2H), 7.30 (t, 1H), 6.92 (d, 2H), 5.92 (s, 1H), 5.34-5.29 (m, 1H), 4.52 (t, 1H), 4.44-4.25 (m, 5H), 3.55 (q, 2H), 1.20 (t, 3H).

Example 86

(S)-5-Ethoxymethyl-2-(4'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 85 and employing the appropriate starting materials.

C₂₄H₂₆N₂0₄ Calculated (406.18), LCMS (ESI): 407.19 (M⁺+H). 1H NMR (CDC1₃ 300MHz) δ: 7.50 (d, 2H), 7.45 (d, 2H), 7.25 (d, 2H), 6.92 (d, 2H), 5.98 (s, 1H), 5.30-5.25 (m, 1H), 4.52-4.26 (m, 6H), 3.56 (q, 2H), 2.68 (q, 2H), 1.27 (t, 3H), 1.23 (t, 3H).

Example 87

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-5-ethoxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

C₂₄H₂₆N₂0₄ Calculated (406.18), LCMS (ESI): 407.19 (M⁺+H).

1H NMR (CDCI₃ 300MHz) δ: 7.21 (d, 2H), 7.16-7.14 (m, 2H), 7.09-7.02 (m, 1H), 6.91 (d, 2H), 5.96 (s, 1H), 5.35-5.30 (m, 1H), 4.56-4.27 (m, 6H), 3.57 (q, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.23 (t, 3H). Example 88

(S)-2-(2 3'-Dichloro-biphenyl-4-yloxymethyl)-5-ethoxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 86 and employing the appropriate starting materials.

C₂2H₂oCl₂N₂0₄ Calculated (446.08), LCMS (ESI): 447.08 (M⁺+H).

1H NMR (CDC1₃ 300MHz) δ: 7.43 (dd, IH), 7.32 (d, 2H), 7.29-7.16 (m, 2H), 6.93 (d, 2H), 5.93 (s, IH), 5.36-5.35 (m, IH), 4.56 (t, IH), 4.46-4.27 (m, 5H), 3.56 (q, 2H), 1.22 (t, 3H).

Example 89

(S)-5-Ethoxymethyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro

a]pyrimidin-7-one

C₂₂Hi₉F₃N₂0₄ Calculated (432.12), LCMS (ESI): 433.12 (M⁺+H).

1H NMR (CDC1₃ 300MHz) δ: 7.45 (d, 2H), 6.96 (d, 2H), 6.91-6.84 (m, 3H), 5.94 (s, IH), 5.36-5.31 (m, IH), 4.54 (t, IH), 4.46-4.27 (m, 5H), 3.57 (q, 2H), 1.22 (t, 3H).

Example 90

(S)-2-(Biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Step 1 : Toluene -4-sulfonic acid (S)-5-isopropoxymethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester

Toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (1.08 g, 4 mmol) was dissolved in 30 mL of ethanol. 4-isopropoxy-but-2-ynoic acid methyl ester (0.63 g, 4 mmol) was added and the reaction mixture was heated to 85°C for 3 h. The reaction mixture was then cooled to rt and concentrated under vacuum. The crude material was directly purified by column chromatography on silica gel (80 g column; 35 mL/min; 10% methanol in dichloromethane to provide the title compound as a white solid (0.46 g, 29%). C₁₈H₂₂N₂O₆S. 1H NMR (CDCI₃ 300MHz) δ: 7.4 (d, 2H), 7.36 (d, 2H), 5.87 (s, 1H), 5.26- 5.21 (m, 1H), 4.50 (t, 1H), 4.50 (t, 1H), 4.41 (t, 1H), 4.36 (t, 2H), 4.32-4.20 (m, 1H), 3.72 (t, 1H), 2.45 (s, 3H), 1.19 (d, 6H).

Step2: (S)-2-(Biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-5-isopropoxymethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester (106 mg, 0.28 mmole) was dissolved in 4 mL of DMF. The appropriate 4-phenylphenol (0.28 mmol) was added followed by CS₂CO₃ (127 mg, 0.39 mmol). The reaction mixture was heated to 35°C for 5 hours and stirred at rt overnight. The reaction mixture was then quenched with water and brine and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (40 g column; 35 mL/min; 5% MeOH in CH₂C1₂) to give the title compound.

C₂3H₂₄N₂0₄ Calculated (392.17), LCMS (ESI): 393.16 (M⁺+H).

1H NMR (CDCI3 300MHz) δ: 7.53-7.48 (m, 4H), 7.40 (t, 2H), 7.30 (t, 1H), 6.93 (d, 2H), 5.93 (s, 1H), 5.33-5.29 (m, 1H), 4.52 (t, 1H), 4.44-4.25 (m, 5H), 3.70 (sept, 1H), 1.19 (d, 6H).

Example 91

(S)-2-(4'-Ethyl-biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 90 and employing the appropriate starting materials.

[a]_D ²⁵ = +0.5° (c = 0.75, DMSO). C₂₅H₂₈N₂0₄ (420.20), LCMS (ESI): 421.19 (M⁺+H).

1H NMR (CDCI3 300MHz) δ: 7.48 (d, 2H), 7.44 (d, 2H), 7.24 (d, 2H), 6.91 (d, 2H), 5.94 (s, IH), 5.34-5.29 (m, IH), 4.52 (t, IH), 4.45-4.25 (m, 5H), 3.70 (sept, IH), 2.67 (q, 2H), 1.26 (t, 3H), 1.19 (d, 6H).

Example 92

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

[a]_D ²⁵ = +10.9 ° (c = 0.65, DMSO). C₂₅H₂₈N₂0₄ (420.20), LCMS (ESI): 421.19 (M⁺+H). 1H NMR (CDC1₃ 300MHz) δ: 7.22-7.19 (m, 2H), 7.16-7.11 (m, 2H), 7.08-7.01 (m, IH), 6.93- 6.90 (m, 2H), 5.95 (s, IH), 5.38-5.33 (m, IH), 4.47 (t, IH), 4.43-4.26 (m, 5H), 3.72 (sept, IH), 2.95 (s, 3H), 2.32 (s, 3H), 1.19 (d, 6H).

Example 93

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 91 and employing the appropriate starting materials.

[a]_D = +10.3 ⁰ (c = 0.60, DMSO). C₂₃H₂₂N₂0₄C1₂ (460.09), LCMS (ESI): 461.09 (M⁺+H). 1H NMR (CDC1₃ 300MHz) δ: 7.43 (dd, IH), 7.32 (d, 2H), 7.25-7.17 (m, 2H), 6.94 (d, 2H), 5.93 (s, IH), 5.38-5.33 (m, IH), 4.56 (t, IH), 4.46-4.27 (m, 5H), 3.72 (sept, IH), 1.20 (d, 6H). Example 94

(S)-5-Isopropoxymethyl-2-(2',3^5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

[a]_D ²⁵ = -14.3 ° (c = 0.65, DMSO). C₂3H₂iN₂0₄F3 (446.14), LCMS (ESI): 447.1 1 (M⁺+H). 1H NMR (CDCI₃ 300MHz) δ: 7.74 (d, IH), 7.44 (d, 2H), 7.35 (d, IH), 6.97 (d, 2H), 5.93 (s, IH), 5.38-5.33 (m, IH), 4.56 (t, IH), 4.47-4.23 (m, 5H), 3.71 (sept, IH), 1.19 (d, 6H).

Example 95

(S)-5-Isopropoxymethyl-2-(4'-methoxy-biphenyl-4-yloxymethyl)-2,3-dihydro

a rimidin-7-one

C₂₄H₂₆N₂0₅ (422.18), LCMS (ESI): 423.16 (M⁺+H). 1H NMR (CDCI₃ 300MHz) δ: 7.45 (d, 2H), 7.45 (d, 2H), 6.94 (d, 2H), 6.91 (d, 2H), 5.95 (s, IH), 5.32-5.27 (m, IH), 4.54-4.26 (m, 6H), 3.84 (s, 3H), 3.71 (sept, IH), 1.20 (d, 6H).

Example 96

(S)-2-(4'-Ethyl-biphenyl-4-yloxymethyl)-5-phenyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Step 1 : Toluene -4-sulfonic acid (S)-7-oxo-5-phenyl-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester Toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (1.16 g, 4.3 mmol) was dissolved in 33 mL of ethanol. 4-phenyl-prop-2-ynoic acid methyl ester (0.82 g, 5.16 mmol) was added and the reaction mixture was heated to 85°C for 24 h. The reaction mixture was then cooled to rt and concentrated under vacuum. The crude material was directly purified by column chromatography on silica gel (40 g column; 35 mL/min; 5% methanol in dichloromethane. This yielded compound II as a white foam (0.121 g, 7%).

C₂₀Hi₈N₂O₅S (398.09), LCMS (ESI): 399.10 (M⁺+H).

1H NMR (CDC1₃ 300MHz) δ: 7.74 (d, 2H), 7.53-7.43 (m, 5H), 7.35 (d, 2H), 5.93 (s, 1H), 5.21-5.16 (m, 1H), 4.34-4.26 (m, 3H), 4.05 (dd, 1H), 2.45 (s, 3H).

Step 2: (S)-2-(4'-Ethyl-biphenyl-4-yloxymethyl)-5-phenyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-7-oxo-5-phenyl-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin- 2-ylmethyl ester (40 mg, 0.1 mmol) was dissolved in 1 mL of DMF. 4-(4'-ethyl)phenylphenol (0.1 mmol) was added followed by Cs₂C0₃ (46 mg, 0.14 mmol). The reaction mixture was heated to 35°C for 5 hours and stirred at 30°C overnight. The reaction mixture was then quenched with water and brine and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (40 g column; 35 mL/min; 6% MeOH in CH₂C1₂) to provide the title compound.

[α]ο = +66.0 ° (c = 0.60, DMSO). C₂₇H₂₄N₂0₃ (424.17), LCMS (ESI): 425.24 (M⁺+H). 1H NMR (CDC1₃ 300MHz) δ: 7.57-7.42 (m, 9H), 7.23 (d, 2H), 6.91 (d, 2H), 6.02 (s, 534-5.29 (m, 1H), 4.42-4.35 (m, 2H), 4.28-4.17 (m, 2H), 2.67 (q, 2H), 1.26 (t, 3H).

Example 97

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-5-phenyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 96 and employing the appropriate starting materials.

C27H24N2O3 (424.17), LCMS (ESI): 425.24 (M⁺+H). 1H NMR (CDC1₃ 300MHz) δ: 7.57- 7.48 (m, 5H), 7.23 (d, 2H), 7.13 (d, 2H), 7.02 (dd, 1H), 6.90 (d, 2H), 6.03 (s, 1H), 5.34-5.33 (m, 1H), 4.44-4.37 (m, 2H), 4.30-4.19 (m, 2H), 2.32 (s, 3H), 2.12 (s, 3H).

Example 98

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-phenyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

[a]_D ²⁵ = +64.0 ° (c = 0.55, DMSO). C₂₅Hi₈Cl₂N₂0₃ (464.06), LCMS (ESI): 465.14 (M⁺+H). 1H NMR (CDCI₃ 300MHz) δ: 7.58-7.51 (m, 5H), 7.43 (dd, 1H), 7.31 (d, 2H), 7.28-7.16 (m, 2H), 6.93 (d, 2H), 6.01 (s, 1H), 5.39-5.34 (m, 1H), 4.46-4.40 (m, 2H), 4.32-4.18 (m, 2H).

Example 99

(S)-2-(Biphenyl-4-yloxymethyl)-5-cyclopentyloxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

Step 1 : Prop-2-ynyloxy-cyclopentane

DMF (200 mL) was cooled to 0°C and cyclopentanol (6 g, 70 mmol, 1 eq) was added. Solid NaH (60% in oil, 2.94 g, 73.5 mmol, 1.05 mmol) was added portion- wise, stirred for 10 min and then an 80% solution of propargyl bromide in xylenes (7.77 mL, 70 mmol, 1 eq) was added. The reaction mixture was allowed to warm to rt and was stirred for an additional 3 h. The reaction mixture was then diluted with 800 mL of H₂O and extracted with diethyl ether (2 x 100 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (120 g column, 35 mL/min, 5% ethyl acetate in heptanes) to provide 1.62 g (19%) of the title compound as a light yellow oil.

1H NMR (CDCls 300MHz) δ: 4.15-4.10 (m, 1H), 4.12 (d, 2H), 2.40 (t, 1H), 1.91-1.44 (m,

8H).

Step 2: 4-Cylcopentyloxy-but-2-ynoic acid methyl ester

Prop-2-ynyloxy-cyclopentane (1.62 g, 13 mmol, 1 eq) was dissolved in 130 mL of THF and cooled to - 78°C in a dry ice acetone bath. A 2.5 M solution of nBuLi in hexanes (5.2 mL 13 mmol, 1 eq) was slowly added and the light yellow solution became a dark black. After 15 min methyl chloro formate (1.03 mL, 13 mmol, 1 eq) was added and the reaction mixture turned slightly lighter and was allowed to warm to rt. The reaction mixture was then diluted with 200 mL of H₂0 and extracted with diethyl ether (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (120 g column, 35 mL/min, 10% ethyl acetate in heptanes) to provide 1.4 g (60%>) of the title compound as a light yellow oil.

1H NMR (CDCI3 300MHz) δ: 4.23 (s, 2H), 4.13-4.11 (m, 1H), 3.78 (s, 3H), 1.77-1.53 (m, 8H).

Step 3: Toluene -4-sulfonic acid (S)-5-cyclopentyloxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester

Toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (2.09 g, 7.7 mmol) was dissolved in 60 mL of ethanol. 4-Cylcopentyloxy-but-2-ynoic acid methyl ester (1.4 g, 7.7 mmol) was added and the reaction mixture was heated to 85°C for 2.5 h. The reaction mixture was then cooled to rt and concentrated under vacuum. The crude material was directly purified by column chromatography on silica gel (40 g column; 35 mL/min; 5% methanol in dichloromethane), which provided the title compound (1.27 g, 39%) as a light yellow semi-solid.

C₂oH₂₄N₂0₆S Calculated (420.13), LCMS (ESI): 421.20 (M⁺+H).

1H NMR (CDCI₃ 300MHz) δ: 7.74 (d, 2H), 7.36 (d, 2H), 5.86 (s, 1H), 5.25-5.20 (m, 1H),

4.51-4.19 (m, 6H), 3.99-3.97 (m, 1H), 2.45 (s, 3H), 1.68-1.55 (m, 8H).

Step 4: (S)-2-(Biphenyl-4-yloxymethyl)-5-cyclopentyloxymethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-5-cyclopentyloxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (80 mg, 0.19 mmol) was dissolved in 2 mL of DMF. 4-phenylphenol (0.2 mmol) was added followed by Cs₂C0₃ (89 mg, 0.27 mmol). The reaction mixture was heated to 35°C for 5 hours and stirred at 30°C overnight. The reaction mixture was then quenched with water and brine and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (40 g column; 35 mL/min; 6% MeOH in CH₂C1₂) to give the title compound. [a]_D ²⁵ = +47.0⁰ (c = 0.60, DMSO).

1H NMR (CDCls 300MHz) δ: 7.43 (t, 4H), 7.32 (t, 2H), 7.22 (t, 1H), 6.84 (d, 2H), 5.85 (s, 1H), 5.27-5.21 (m, 1H), 4.43 (t, 1H), 4.33-4.13 (m, 5H), 3.91 (m, 1H), 1.66-1.45 (m, 8H).

Example 100

(S)-5-Cyclopentyloxymethyl-2-(4'-ethyl-biphenyl-4-yloxymethyl)-2,3-dihydro

a rimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 99 and employing the appropriate starting materials.

[a]_D ²⁵ = +4.4⁰ (c = 0.75, DMSO).

1H NMR (CDCI3 300MHz) δ: 7.40 (d, 2H), 7.36 (d, 2H), 7.16 (d, 2H), 6.83 (d, 2H), 5.85 (s, 1H), 5.25-5.20 (m, 1H), 4.42 (t, 1H), 4.33-4.13 (m, 5H), 3.93-3.89 (m, 1H)2.63 (q, 2H), 1.67- 1.46 (m, 8H), 1.19 (t, 3H). Example 101

(S)-5-Cyclopentyloxymethyl-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

[a]_D ²⁵ = +3.3 ⁰ (c = 0.70, DMSO). 1H NMR (CDCI3 300MHz) δ: 7.14 (d, 2H), 7.08-7.01 (m, 2H), 6.97-6.94 (m, 1H), 6.83 (d, 2H), 5.88 (s, 1H), 5.28-5.23 (m, 1H)4.44 (t, 1H), 4.36-4.16 (m, 5H), 3.95-3.91 (m, 1H), 2.25 (s, 3H), 2.05 (s, 3H), 1.67-1.47 (m, 8H).

Example 102

(S)-5-Cyclopentyloxymethyl-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

[a]_D ²⁵ = +5.6 ⁰ (c = 0.50, DMSO).

1H NMR (CDCI3 300MHz) δ: 7.43 (dd, 1H), 7.32 (d, 2H), 7.25-7.13 (m, 2H), 6.93 (d, 2H), 5.94 (s, 1H), 5.37-5.32 (m, 1H), 4.53 (t, 1H), 4.42-4.23 (m, 5H), 4.02-4.00 (m, 1H), 1.75-1.54 (m, 8H).

Example 103

(S)-5-Cyclopentyloxymethyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

[a]_D ²⁵ = +4.2 ⁰ (c = 0.65, DMSO).

1H NMR (CDCI3 300MHz) δ: 7.44 (d, 2H), 6.96 (d, 2H), 6.90-6.84 (m, 2H), 5.94 (s, 1H), 5.38-5.33 (m, 1H), 4.53 (t, 1H), 4.42-4.23 (m, 5H), 4.00 (m, 1H), 1.74-1.54.

Example 104 (S)-2-(Biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : 2-Prop-2-ynyloxymethyl-tetrahydro-furan

DMF (200 mL) was cooled to 0°C and tetrahydrofurfural alcohol (6.7 mL, 70 mmol, 1 eq) was added. Solid NaH (60% in oil, 2.94 g, 73.5 mmol, 1.05 mmol) was added portion- wise, stirred for 10 min and then an 80% solution of propargyl bromide in xylenes (7.77 mL, 70 mmol, 1 eq) was added. The reaction mixture was allowed to warm to rt and was stirred for an additional 3 h. The reaction mixture was then diluted with 800 mL of H₂0 and extracted with diethyl ether (2 x 100 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (200 g column, 50 mL/min, 20% ethyl acetate in heptanes) to provide 2.57 g (26%) of the title compound as a light yellow oil.

1H NMR (CDCls 300MHz) δ: 4.22 (t, 2H), 4.10-4.05 (m, 1H), 3.93-3.85 (m, 1H), 3.81-3.73 (m, 1H), 3.61-3.48 (m, 2H), 2.43 (t, 1H), 2.01-1.85 (m, 3H), 1.69-1.61 (m, 1H).

Step 2: 4-(Tetrahydro-furan-2-ylmethoxy)-but-2-ynoic acid methyl ester

2-Prop-2-ynyloxymethyl-tetrahydro-furan (2.57 g, 18.4 mmol, 1 eq) was dissolved in 184 mL of THF and cooled to - 78°C in a dry ice acetone bath. A 2.5 M solution of nBuLi in hexanes (7.4 mL 18.4 mmol, 1 eq) was slowly added and the light yellow solution became dark black. After 15 min methyl chloroformate (2.9 mL, 36.8 mmol, 2 eq) was added and the reaction mixture turned slightly lighter and was allowed to warm to rt. The reaction mixture was then diluted with 200 mL of H₂0 and extracted with diethyl ether (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (120 g column, 35 mL/min, 10% ethyl acetate in heptanes) to provide 1.53 g (42%>) of the title compound as a light yellow oil.

1H NMR (CDCI3 300MHz) δ: 4.35 (d, 2H), 4.10-4.03 (m, 1H), 3.92-3.85 (m, 1H), 3.81-3.74 (m, 1H), 3.79 (s, 3H), 3.61 (dd, 1H), 3.51 (dd, 1H), 2.01-1.84 (m, 3H), 1.68-1.60 (m, 1H). Step 3: Toluene -4-sulfonic acid (S)-7-oxo-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3- dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester Toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (2.1 g, 7.7 mmol) was dissolved in 60 mL of ethanol. 4-(Tetrahydro-furan-2-ylmethoxy)-but-2-ynoic acid methyl ester (1.53 g, 7.7 mmol) was added and the reaction mixture was heated to 85°C for 2.5 h. The reaction mixture was then cooled to rt and concentrated under vacuum. The crude material was directly purified by column chromatography on silica gel (80 g column; 35 mL/min; 8% methanol in dichloromethane), which provided the title compound (1.6 g, 47%) as a light yellow semi-solid.

C₂oH₂4N₂0₇S Calculated (436.13), LCMS (ESI): 437.13 (M⁺+H).

1H NMR (CDCls 300MHz) δ: 7.76 (dd, 2H), 7.37 (d, 2H), 5.93 (s, 1H), 5.14-5.10 (m, 1H), 4.56-4.44 (m, 1H), 4.38-4.30 (m, 5H), 4.08-4.04 (m, 1H), 3.86-3.75 (m, 2H), 3.57 (dd, 1H), 3.44-3.35 (m, 1H), 2.46 (s, 3H), 2.00-1.84 (m, 3H), 1.55-1.51 (m, 1H).

Step 4: (S)-2-(Biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-7-oxo-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3- dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (100 mg, 0.23 mmol) was dissolved in 2 mL of CH₃CN. 4-Phenylphenol (0.23 mmol) was added followed by Cs₂C0₃ (104 mg, 0.32 mmol). The reaction mixture was heated to 40°C and stirred overnight. The reaction mixture was then quenched with water and brine and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (40 g column; 35 mL/min; 8% MeOH in CH₂C1₂) to provide the title compound. [a]_D ²⁵ = +17.2 ⁰ (c = 0.75, DMSO).

C₂₅H₂₆N₂0₅ Calculated (434.18), LCMS (ESI): 435.20 (M⁺+H).

1H NMR (CDC1₃ 300MHz) δ: 7.51-7.46 (m, 4H), 7.38 (t, 2H), 7.33-7.28 (m, 1H), 6.91 (d, 2H), 5.90 (s, 1H), 5.31-5.28 (m, 1H), 4.56-4.28 (m, 6H), 4.02-3.99 (m, 1H), 3.79-3.67 (m, 2H), 3.56-3.51 (m, 1H), 3.44-3.39 (m, 1H), 1.92-1.77 (m, 3H), 1.52-1.48 (m, 1H).

Example 105

(S)-2-(4'-Ethyl-biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 104 and employing the appropriate starting materials.

[a]_D ²⁵ = +3.6 ⁰ (c = 0.70, DMSO). C₂₇H₃oN₂0₅ (462.21), LCMS (ESI): 463.26 (M⁺+H). 1H NMR (CDCI₃ 300MHz) δ: 7.47 (d, 2H), 7.42 (d, 2H), 7.23 (d, 2H), 6.91 (d, 2H), 5.93 (s, 1H), 5.31-5.30 (m, 1H), 4.57-4.28 (m, 6H), 4.03-4.00 (m, 1H), 3.81-3.68 (m, 2H), 3.57-3.53 (m, 1H), 3.46-3.40 (m, 1H), 2.67 (q, 2H), 1.92-1.78 (m, 3H), 1.52-1.49 (m, 1H), 1.26 (t, 3H).

Example 106

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3- dihydro-oxazolo 3,2-a]pyrimidin-7-one

[a]_D ²⁵ = +10.8 ⁰ (c = 0.65, DMSO). C₂₇H₃₀N₂O₅ (462.21), LCMS (ESI): 463.26 (M⁺+H). 1H NMR (CDCI₃ 300MHz) δ: 7.21 (d, 2H), 7.14-7.11 (m, 2H), 7.04-7.01 (m, 1H), 6.91 (d, 2H), 5.95 (s, 1H), 5.39-5.31 (m, 1H), 4.61-4.31 (m, 6H), 4.05-4.02 (m, 1H), 3.82-3.72 (m, 2H), 3.60-3.55 (m, 1H), 3.48-3.42 (m, 1H), 2.33 (s, 3H), 2.13 (s, 3H), 1.93-1.80 (m, 3H), 1.59-1.51 (m, 1H).

Example 107

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2,3- dihydro-oxazolo 3,2-a]pyrimidin-7-one

[<X]D = +5.2 ⁰ (c = 0.60, DMSO). C₂₅H₂₄C1₂N₂0₅ (502.10), LCMS (ESI): 503.15 (M⁺+H). 1H NMR (CDCI3 300MHz) δ: 7.35 (dd, IH), 7.23 (d, 2H), 7.17-7.09 (m, 2H), 6.85 (d, 2H), 5.85 (s, IH), 5.27-5.26 (m, IH), 4.53-4.25 (m, 6H), 3.97-3.92 (m, IH), 3.74-3.61 (m, 2H), 3.52-3.47 (m, IH), 3.39-3.34 (m, IH), 1.87-1.72 (m, 3H), 1.47-1.43 (m, IH).

Example 108

(S)-5-(Tetrahydro-furan-2-ylmethoxymethyl)-2-(2',3^5'-trifluoro-biphenyl-4-yloxymethyl)-

2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 105 and employing the appropriate starting materials.

[a]_D ²⁵ = +5.7 ⁰ (c = 0.70, DMSO). C₂₅H₂3F₃N₂0₅ (488.15), LCMS (ESI): 489.20 (M⁺+H). 1H NMR (CDC1₃ 300MHz) δ: 7.36 (dd, 2H), 6.88 (d, 2H), 6.82-6.78 (m, 2H), 5.85 (s, IH), 5.27-5.26 (m, IH), 4.54-4.25 (m, 6H), 3.97-3.93 (m, IH), 3.74-3.61 (m, 2H), 3.51-3.47 (m, IH), 3.39-3.34 (m, IH), 1.86-1.72 (m, 3H), 1.51-1.39 (m, IH).

Example 109

(S)-5-(2-Fluoro-ethoxymethyl)-2-(3'-isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : 3-(2-Fluoro-ethoxy)-propyne

DMF (200 mL) was cooled to 0°C and 2-fluoroethanol (4.11 mL, 70 mmol, 1 eq) was added. Solid NaH (60% in oil, 2.94 g, 73.5 mmol, 1.05 mmol) was added portion-wise, stirred for 10 min after which an 80% solution of propargyl bromide in xylenes (7.77 mL, 70 mmol, 1 eq) was added. The reaction mixture was allowed to warm to rt and was stirred for an additional 3 h. The reaction mixture was then diluted with 800 mL of H₂0 and extracted with diethyl ether (2 x 100 mL). The combined organics were dried over Na₂S0₄ and purified by distillation (115°C) to provide 1.65 g (23%) of the title compound as a light yellow oil.

1H NMR (CDC1₃ 300MHz) δ: 4.67 (dd, IH), 4.51 (dd, IH), 4.23 (d, 2H), 3.83 (dd, IH), 3.76 (dd, IH), 2.44 (t, IH). Step2: 4-(2-Fluoro-ethoxy)-but-2-ynoic acid methyl ester

3-(2-Fluoro-ethoxy)-propyne (1.65 g, 16.7 mmol, 1 eq) was dissolved in 70 mL of THF and cooled to - 78°C in a dry ice acetone bath. A 2.5 M solution of nBuLi in hexanes (6.8 mL 17.0 mmol, 1 eq) was slowly added and the light yellow solution became a dark black. After 15 min methyl chloroformate (1.41 mL, 17.8 mmol, 1.1 eq) was added and the reaction mixture turned slightly lighter and was allowed to warm to rt. The reaction mixture was then diluted with 200 mL of H₂0 and extracted with diethyl ether (2 x 50 mL). The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (80 g column, 35 mL/min, 5% ethyl acetate in heptanes) to provide 0.605 g (22%) of the title compound as a light yellow oil.

1H NMR (CDCI3 300MHz) δ: 4.67 (dd, 1H), 4.51 (dd, 1H), 4.37 (s, 2H), 3.85 (dd, 1H), 3.79 (s, 3H), 3.76 (dd, 1H).

Step 3: Toluene -4-sulfonic acid (S)-5-(2-fluoro-ethoxymethyl)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester

Toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (1.13 g,

4.16 mmol) was dissolved in 35 mL of ethanol. 4-(2-Fluoro-ethoxy)-but-2-ynoic acid methyl ester (0.605 g, 3.78 mmol) was added and the reaction mixture was heated at 85°C for 3 h.

The reaction mixture was then cooled to rt and concentrated under vacuum. The crude material was directly purified by column chromatography on silica gel (80 g column; 40 mL/min; 5% methanol in dichloromethane), to provide the title compound (0.823 g, 50%) as a light yellow semi-solid.

Ci₇Hi₉FN₂0₆S (398.09), LCMS (ESI): 399.12 (M⁺+H).

1H NMR (CDCI3 300MHz) δ: 7.73 (d, 2H), 7.35 (d, 2H), 5.86 (s, 1H), 5.27-5.22 (m, 1H),

4.64-4.20 (m, 8H), 3.80-3.77 (m, 2H), 3.70-3.67 (m, 2H), 2.43 (s, 3H).

Step 4: (S)-5-(2-Fluoro-ethoxymethyl)-2-(3'-isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Toluene-4-sulfonic acid (S)-5-(2-fluoro-ethoxymethyl)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (100 mg, 0.25 mmol) was dissolved in 2 mL of

CH3CN. 4'-Isopropylphenylphenol (0.275 mmol) was added followed by Cs₂C0₃ (117 mg, 0.36 mmol). The reaction mixture was heated to 30°C and stirred overnight. The reaction mixture was then quenched with water and brine and extracted with ethyl acetate (2 x 50 mL).

The combined organics were dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (40 g column; 35 mL/min; 5% MeOH in CH₂CI₂) to provide the title compound.

[a]_D ²⁵ = +2.8 ⁰ (c = 0.50, DMSO). C₂₅H27FN₂04 (438.19), LCMS (ESI): 439.19 (M⁺+H). 1H NMR (CDCI₃ 300MHz) δ: 7.41 (d, 2H), 7.29 (s, 1H), 7.25 (d, 2H), 7.10 (dt, 1H), 6.84 (d, 2H), 5.85 (s, 1H), 5.26-5.21 (m, 1H), 4.55-4.16 (m, 8H), 3.73-3.70 (m, 1H), 3.63-3.60 (m, 1H), 2.87 (septet, 1H), 1.20 (d, 6H).

Example 110

(S)-2-(Biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 109 and employing the appropriate starting materials.

[a]_D ²⁵ = +3.1 ⁰ (c = 0.70, DMSO). C₂₂H₂₁FN₂O₄ (396.14), LCMS (ESI): 397.16 (M⁺+H). 1H NMR (CDCI₃ 300MHz) δ: 7.53-7.48 (m, 4H), 7.40 (t, 2H), 7.32-7.27 (m, 1H), 6.92 (d, 2H), 5.93 (s, 1H), 5.33-5.28 (m, 1H), 4.63-4.24 (m, 8H), 3.81-3.78 (m, 2H), 3.71-3.68 (m, 2H).

Example 111

(S)-2-(4'-Ethyl-biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

[a]_D ²⁵ = +3.9 ⁰ (c = 0.70, DMSO). C₂4H2₅FN₂04 (424.17), LCMS (ESI): 425.20 (M⁺+H).

1H NMR (CDCI₃ 300MHz) δ: 7.47 (d, 2H), 7.43 (d, 2H), 7.23 (d, 2H), 6.90 (d, 2H), 5.87 (s, 1H), 5.33-5.28 (m, 1H), 4.63-4.23 (m, 8H), 3.81-3.78 (m, 2H), 3.71-3.68 (m, 2H), 2.67 (q, 2H), 1.26 (t, 3H). Example 1 12

(S)-2-(2',3'-Dimethyl-biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in

Example 109 and employing the appropriate starting materials.

[a]_D ²⁵ = +5.7 ⁰ (c = 0.60, DMSO). C₂₄H₂₅FN₂04 (424.17), LCMS (ESI): 425.19 (M⁺+H). 1H NMR (CDCls 300MHz) δ: 7.21 (d, 2H), 7.19-7.10 (m, 2H), 7.04-7.01 (m, 1H), 6.90 (d, 2H), 5.94 (s, 1H), 5.37-5.31 (m, 1H), 4.67-4.26 (m, 8H), 3.83-3.81 (m, 2H), 3.73-3.71 (m, 2H), 2.32 (s, 3H), 2.12 (s, 3H).

Example 1 13

(S)-2-(2',3'-Dichloro-biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

C₂₂Hi₉Cl₂FN₂0₄ (464.07), LCMS (ESI): 465.08 (M⁺+H).

1H NMR (CDCI₃ 300MHz) δ: 7.43 (dd, 1H), 7.31 (d, 2H), 7.28-7.16 (m, 2H), 6.93 (d, 2H), 5.93 (s, 1H), 5.37-5.32 (m, 1H), 4.65-4.28 (m, 8H), 3.83-3.81 (m, 2H), 3.73-3.71 (m, 2H).

Example 1 14

(S)-5-(2-Fluoro-ethoxymethyl)-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared in accordance with the procedures set out in Example 109 and employing the appropriate starting materials. [<X]D = +3.6 ⁰ (c = 0.50, DMSO). C₂₂Hi₈F₄N₂04 (450.12), LCMS (ESI): 451.14 (M⁺+H). 1H NMR (CDCI3 300MHz) δ: 7.43 (dd, 2H), 6.95 (d, 2H), 6.93-6.82 (m, 2H), 5.92 (s, IH), 5.40-5.31 (m, IH), 4.67-4.27 (m, 8H), 3.83-3.81 (m, 2H), 3.73-3.71 (m, 2H).

Example 115

(S)-5-(l,l-Difluoro-propyl)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-5-(l,l-difluoro- propyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.188 mmol) and 2',3'-dimethyl-biphenyl-4-ol (0.281 mmol [prepared from acetic acid 3-iodo-phenylester and 2,3,dimethylphenyl boronic acid as in Example 13]) according to the procedure described in Comparative Example 1, Step 4 to afford 20.6 mg (26%) of title compound.

C₂₄H₂₄F₂N₂0₃ (426.17), LCMS (ESI): 427.17 (M⁺+H).

1H NMR ((CDCI3), 300MHz) δ: 7.25-7.22 (d, 2H), 7.16-7.10 (m, 2H), 6.92-6.89 (d, IH), 6.25 (s, IH), 5.30-5.24 (m,lH), 4.54-4.50 (m,2H), 4.44-4.39 (dd, IH), 4.31-4.27 (dd, 1), 2.33 (s, 3H), 2.30-2.19 (m, 2H), 2.13 (s, 3H), 1.20-1.18 (t, 3H).

Example 116

(S)-5-Fluoromethyl-2-(3'-isopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro

a rimidin-7-one

To a solution of toluene-4-sulfonic acid (S)-5-fluoromethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (Example 32) (100 mg, 0.282 mmol) in acetonitrile (6 mL) was added 3'-isopropyl-biphenyl-4-ol (66 mg, 0.31 mmol, [prepared from acetic acid 4-iodo-phenylester and 3-isopropylphenylboronic acid]) followed by cesium carbonate (128.4 mg, 0.395 mmol). The reaction mixture was stirred at 35-45° C for 18 hours. The reaction mixture cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under vacuum and purified by column chromatography on silica gel (0-10%) methanol/ dichloromethane to afford 55.2 mg (50%) of the title compound.

C₂3H₂₃FN₂03 (394.16), LCMS (ESI): 395.14 (M⁺+H).

1H NMR ((CDC1₃), 300MHz) δ: 7.54-7.51 (d, 2H), 7.38-7.35 (m, 3H), 7.21-7.18 (m, 1H), 6.96- 6.93 (d, 2H), 6.02-6.01 (d,lH), 5.36-5.30 (m, 2H), 5.14 (s, 1H), 4.55-4.51 (t, 1H), 4.43- 4.28 (m, 3H), 2.99-2.94 (m, 1H), 1.31-128 (d, 6H).

Example 117

(S)-2-(Biphenyl-4-yloxymeth l)-5-fluoromethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-5-fluoromethyl-7- oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.282 mmol) and 4- phenylphenol (0.31 mmol) according to the procedure described in Example 116 to afford 56.6 mg (54%) of title compound. [a]_D ²⁵ = -6.4 ⁰ (c = 0.67, DMSO)

C₂₀Hi₇FN₂O₃ (352.12), LCMS (ESI): 353.10 (M⁺+H).

1H NMR ((CDCI₃), 300MHz) δ: 7.55-7.52 (d, 4H),7.45- 7.40 (t, 2H), 7.35-7.32 (t, 1H). 6.97- 6.94 (d, 2H), 6.08-6.07 (d, 1H), 5.35- 5.27 (m, 2H), 5.14 (s, 1H), 4.49-4.29 (m, 4H).

Example 118

(S)-5-Fluoromethyl-2-(2',3',5'-trichloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-5-fluoromethyl-7- oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.282 mmol) and 2',3',5'- trichloro-biphenyl-4-ol (0.31 mmol according to the procedure described in Example 116 to afford 81.6 mg (64%>) of the title compound. [<X]D = -4.0 ⁰ (c = 0.74, DMSO). C₂oHi4Cl₃FN₂03 (454.00), LCMS (ESI): 454.99 (M⁺+H). 1H NMR ((CDC1₃), 300MHz) δ: 7.47-7.46 (d, IH), 7.34-7.31 (d,2H), 7.21-7.20(d, IH), 6.97- 6.94 (d, 2H), 6.02-6.01 (d, IH), 5.39-5.33 (m, IH), 5.31 (s, 1), 5.15 (s, IH), 4.58-4.51 (t, IH), 4.45-4.32 (m, 3H).

Example 119

(S)-5-Fluoromethyl-2-(2',3',5'-trifiuoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-5-fluoromethyl-7- oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.282 mmol) and 2',3',5'- trifluoro-biphenyl-4-ol (0.31 mmol according to the procedure described in Example 116 to afford 83.4 mg (73%) of the title compound. [a]_D ²⁵ = -6.6 ⁰ (c = 0.68, DMSO).

C₂oHi₄F₄N₂0₃ (406.09), LCMS (ESI): 407.06 (M⁺+H). 1H NMR ((CDC1₃), 300MHz) δ: 7.47-7.45 (d, 2H), 6.99-6.96 (d, 2H), 6.95-6.85 (m, 2H), 6.01-6.00 (d, IH), 5.39-5.32 (m, IH), 5.30 (s, IH), 5.15 (s, IH), 4.57-4.51 (t, IH), 4.44-4.30 (m, 3H).

Example 120

(S)-2-(2'-Trifluoromethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

The title compound was prepared from toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.31 mmol) and 2'-trifluoromethyl-biphenyl-4- ol (0.34 mmol [prepared from 4-iodophenol and 2-trifluoromethylphenyl boronic acid]) according to the procedure described in Example 117 to afford 15.3 mg (13%) of the title compound.

C₂₀Hi₅F₃N₂O₃ (388.10), LCMS (ESI): 389.09 (M⁺+H). 1H NMR ((CDCI₃), 300MHz) δ: 7.74-7.72 (d, IH), 7.57-7.52 (t, IH), 7.48-7.43 (t, IH), 7.31- 7.24 (m, 3H), 6.92-6.89 (d, IH), 6.08-6.05 (d, IH), 5.37-5.31 (m, IH), 4.44-4.30 (m, 4H).

Example 121

(S)-2-(2'-Acetyl-biphenyl-4- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.31 mmol) and 2'-acetyl-biphenyl-4-ol (0.34 mmol [prepared from 4-iodophenol and 2-acetylphenyl boronic acid]) according to the procedure described in Comparative Example 3 to afford 63.4 mg (57%) of the title compound.

[a]_D ²⁵ = -4.3 ⁰ (c = 0.46, DMSO). C₂iHi₈N₂0₄ (362.12), LCMS (ESI): 363.1 1 (M⁺+H).

1H NMR ((CDCI₃), 300MHz) δ: 7.37-7.34 (m, 2H), 7.32-7.25 (m, 2H), 7.22-7.1 1 (m, 2H), 6.96-6.93 (d, IH), 6.88-6.85 (d, IH), 6.84 (s, IH), 6.05-6.03 (d, IH), 5.34-5.31 (m, IH), 4.47- 4.24 (m, 4H), 3.05-2.96 (m, IH), 1.16-1.14 (d, 6H).

Example 122

(S)-2-(3'-Methyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

A mixture of (S)-5-(3'-methyl-biphenyl-4-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.4 g, 1.4mmol) and 2-formyl-propionic acid ethyl ester (0.36 g, 2.8 mmol) in ethanol (20 ml) was heated at reflux for 18 hours. The solution was concentrated and the residue treated with ethyl acetate (10ml). The precipitate which formed was collected to give the title compound, 212-15^°C mp (0.058 g, 6%). [a]_D ²⁵ = -6.4 ⁰ (c = 0.72, DMSO).

C₂iH₂₀N₂O₃ (348.40), LCMS (ESI): 349.12 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ 7.70 (s, IH), 7.58-7.62 (d, 2H), 7.28-7.46 (m, 3H), 7.15- 7.18 (d, IH), 7.00-7.06 (d, 2H), 5.32-5.40 (m, IH), 4.32-4.45 (m, 3H), 4.10-4.18 (m, IH), 2.52 (s, 3H), 1.80 (s, 3H). Example 123

(S)-2-(3'-Cyclopropyl-bi henyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : Acetic acid 3 '-bromo-biphenyl-4-yl ester

A mixture of acetic acid 4-iodo-phenylester (prepared from 4-iodophenol and acetyl chloride) (2.6 g, 10 mmol), 3-bromophenylboronic acid (4.0 g, 20 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and 2 M sodium carbonate solution (6 ml) in 60 ml of 1 ,2-dimethoxyethane was heated at reflux for 6 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane. The product-containing fractions were combined and evaporated. The residue was recrystallized from heptane to give the title compound (0.34g, 12%).

Step2: Acetic acid 3'-cyclopropyl-biphenyl-4-yl ester

A mixture of acetic acid 3'-bromo-biphenyl-4-yl ester (0.68 g, 2.33 mmol), cyclopropylboronic acid (0.25g, 2.9mmol), palladium acetate (0.0 25g, 0.11 mmol), tricyclohexylphosphine (0.65 g, 2.3 mmol) and potassium phosphate tribasic (1.7 g, 7.7 mmol) in toluene (60ml) containing water (2 ml) was heated at reflux for 6 hours. The mixture was added to water and was extracted with ethyl acetate (150ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue purified by flash chromatography over silica gel using 0-10% ethyl acetate/heptane to provide the title compound (0.3g, 51%).

Step 3: 3'-Cyclopropyl-biphenyl-4-ol

A mixture of acetic acid 3'-cyclopropyl-biphenyl-4-yl ester (0.3 g, 1.2 mmol) in ethanol (15 ml) containing 10% sodium hydroxide (4 ml) and water (3 ml) was heated to give a solution. The solution was stirred at room temperature for 1 hour. The mixture was poured into water (50 ml) and was acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (100 ml) and the organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil (0.2 g, 80%).

Step4: (S)-2-(3'.Cyclopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one

A mixture of toluene-4-sulfonic acid (S)-5 morholinomethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.4 g, 1.2 mmol), 3'-cyclopropyl-biphenyl-4-ol (0.3 g, 1.4 mmol) and cesium carbonate (0.45 g, 1.4mmol) in anhydrous acetonitrile (20 ml) was heated at reflux for 2 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (150ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was purified by reverse phase HPLC using 10- 100% (acetonitrile-0.1% trifluoroacetic acid) over 20 minutes. The product-containing fractions were combined, treated with aqueous sodium bicarbonate and extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue treated with ether (20 ml). The insoluble material was collected to give the title compound (0.14 g, 32%).

[a]_D ²⁵ = -18.4 ⁰ (c = 0.73, DMSO)

C₂₂H₂oN₂0₃ (360.41), LCMS (ESI): 361.16 (M⁺H)

1H NMR (DMSO-de, 300 MHz), δ 7.76-7.79 (d, 1H), 7.59-7.62 (d, 2H), 7.26-7.37 (m, 3H) 6.99-7.04 (m, 3H), 5.82-5.84 (d, 1H), 5.35-5.37 (m, 1H), 4.32-4.45 (m, 3H), 4.10-4.16

(m,lH), 1.93-2.02 (m, 1H), 0.91-1.11 (m, 2H), 0.71-0.80 (m, 2H).

Example 124

(S)-2-(2',3'-Dimethyl-biphen l-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared following the procedures as set forth in Example 49 and employing a mixture of toluene -4-sulfonic acid (S)-7-oxo-2,3-dioxazolo[3,2-a]pyrimidin- 2-ylmethyl ester, 2',3'-dimethyl-biphenyl-4-ol (prepared from acetic acid 4-iodo-phenylester and 2,3-dimethylphenylboronic acid) and cesium carbonate. Example 125

(S)-2-(2'-Cyclohexyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 2'-Cyclohexyl-biphenyl-4-ol

A mixture of 2-bromocyclohexylbenzene (2.39 g, 10 mmol), 4-hydroxyphenylboronic acid (2.4 g, 18 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and a 2M sodium carbonate solution (4 ml) in 60 ml of 1 ,2-dimethoxyethane was heated under reflux for 18 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water and was dried over magnesium sulfate and was filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel using 100% heptane and then 9: 1 heptane:ethyl acetate. The second group of product fractions were combined and evaporated to give the product (0.45 g, 18%).

Step 2: (S)-2-(2'-Cyclohexyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one

A mixture of toluene-4-sulfonic acid (S)-5 morholinomethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.38 g, 1.19 mmol), 2'-cyclohexyl-biphenyl-4-ol (0.3 g, 1.19 mmol) and cesium carbonate (0.39 g, 1.19 mmol) in anhydrous acetonitrile (20 ml) was heated under reflux for 2 hours. The mixture was added to aqueous sodium bicarbonate and was extracted with ethyl acetate (100 ml). The organic layer was washed with water and was dried over magnesium sulfate and was filtered. The filtrate was evaporated and the residue was treated with boiling ethyl acetate (10 ml). The insoluble material was collected to afford the title compound (0.15 g, 31%).

C₂₅H₂₆N₂0₃ (402.49), LCMS (ESI): 403.19 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz), δ 7.77-7.80 (d, 1H), 7.30-7.38 (m, 2H), 7.08-7.28 (m, 4H) 7.00-7.02 (d, 2H), 5.82-5.85 (d, 1H), 5.36-5.38 (m, 1H), 4.33-4.46 (m, 3H), 4.12-4.18 (m,lH), 2.50-2.63 (m, 1H), 1.63-1.72 (m, 4H), 1.41-1.49 (m, 2H), 1.06-1.24 (m, 4H).

Comparative Example 1

(S)-5-(l , 1 -Difluoro-propyl)-2-(3'-isopropyl-biphenyl-3-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 4-Oxo-hex-2-ynoic acid methyl ester

To a solution of 4-hydroxy-hex-2-ynoic acid methyl ester (1.50 g, 10.55 mmol) in dichloromethane (30 mL) was added Dess-Martin periodinane (6.0 g, 14.14 mmol) and stirred at room temperature for 18 hours. Additional periodinane (4.5 g) was added to the reaction mixture and stirred at room temperature for 6 hours. Aqueous NaHC03 was added to reaction mixture, and precipitate was filtered and washed with dichloromethane. Aqueous phase was extracted with dichloromethane, and combined organic phase was washed with water, brine, dried over Na₂S0₄, filtered and concentrated under vacuum to afford 1.48 g (100%) of title compound. C₇H₈0₃ (140.04)

1H NMR ((CDC1₃), 300MHz) δ: 3.84 (s, 3H), 2.70-2.63 (q, 2H), 1.19-1.14 (t, 3H).

Step 2: 4,4-Difluoro-hex-2-ynoic acid methyl ester

To a solution of 4-oxo-hex-2-ynoic acid methyl ester (1.48 g, 10.55 mmol) in dichloromethane (100 mL) was added diethylaminosulfur trifluoride (DAST) (5.1 g, 31.7 mmol) and stirred at room temperature for 18 hours. Reaction mixture was poured onto chopped ice and stirred for a few hours. The aqueous phase was extracted with dichloromethane, and combined organic phases washed with water, brine, dried over Na₂S0₄, filtered and concentrated under vacuum to afford 1.45 g (85%) of title compound. C₇H₈F₂0₂ (162.04)

1H NMR ((CDC1₃), 300MHz) δ: 3.84 (s, 3H), 2.15-2.05 (m, 2H), 1.14-1.09 (t, 3H).

Step 3 : Toluene -4-sulfonic acid (S)-5-(l , l-difluoro-propyl)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester

To a solution of toluene -4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (2.17 g, 8.02 mmol) in ethanol (lOmL) was added 4,4-difluoro-hex-2-ynoic acid methyl ester (1.30 g, 8.02 mmol). The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature, concentrated under vacuum, and purified by column chromatography on silica gel (0-10%) methanol /dichloromethane to afford 0.750 g (23%) of the title compound.

Ci₇Hi₈F₂N₂0₅S (400.09), LCMS (ESI): 401.10 (M⁺+H). 1H NMR ((CDCI3), 300 MHz): δ 7.77-7.75 (d, 2H), 7.39-7.36 (d, 2H), 6.17 (s, 1H), 5.16-5.09 (m, 1H), 4.50-4.44 (t, 1H), 4.34-4.29 (m, 3H), 2.47 (s, 3H), 2.29-2.12 (m, 2H), 1.17-1.12 (t, 3H).

Step 4: (S)-5-(l,l-Difluoro-propyl)-2-(3'-isopropyl-biphenyl-3-yloxymethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

To a solution of toluene-4-sulfonic acid (S)-5-(l ,l-difluoro-propyl)-7-oxo-2,3- dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (75 mg, 0.188 mmol) in acetonitrile (6 mL) was added 3'-isopropyl-biphenyl-3-ol (60 mg, 0.281 mmol) followed by cesium carbonate (107 mg, 0.325 mmol). The reaction mixture was stirred at reflux until complete. The reaction mixture cooled to room temperature, diluted with ethyl acetate, washed with water, dried over Na₂S0₄, filtered and concentrated under vacuum. The material was purified by column chromatography on silica gel (0-10%) methanol in dichloromethane to afford 44.0 mg (53%) of the title compound. [a]_D ²⁵ = +1.7 ⁰ (c = 0.54, DMSO).

C₂₅H₂₆F₂N₂0₃ (440.19), LCMS (ESI): 441.19 (M⁺+H).

1H NMR ((CDC1₃), 300MHz) δ: 7.40-7.33 (m, 4H), 7.24-7.23 (d, 1H), 7.07 (s, 1H), 6.86-6.83

(d, 1H), 6.23 (s, 1H), 5.32-5.26 (m, 1H), 4.54-4.41 (m, 3H), 4.33-4.29 (d, 1H), 3.02-2.93 (m,

1H), 2.37-2.20 (m, 2H), 1.31-1.29 (d, 6H), 1.16-1.10 (t, 3H).

Comparative Example 2

(S)-5-(l,l-Difluoro-propyl)-2-(2',3'-dimethyl-biphenyl-3-yloxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-5-(l,l-difluoro- propyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.188 mmol) and 2',3'-dimethyl-biphenyl-3-ol ( 0.34 mmol, [prepared from acetic acid 3-iodo-phenylester and 2,3,dimethylphenyl boronic acid]) according to the procedure described in Comparative Example 1 to afford 32.9 mg (41%) of title compound.

C₂₄H₂₄F₂N₂0₃ (426.17), LCMS (ESI): 427.17 (M⁺+H).

1H NMR ((CDC1₃), 300MHz) δ: 7.35-7.29 (t, 1H), 7.18-7.11 (m, 2H), 7.05-7.03 (d, 1H), 6.97-6.94 (d, 1H), 6.84-6.82 (d, 1H), 6.80 (s, 1H), 6.22 (s, 1H), 5.29-5.24 (m, 1H), 4.56-4.48 (m, 2H), 4.42-4.39 (dd, IH), 4.28-4.24 (dd, IH), 2.34 (s, 3H), 2.31-2.17 (m, 2H), 2.13 (s, 3H), 1.18-1.13 (t, 3H).

Comparative Example 3

(S)-2-(3'-Acetyl-biphenyl-3- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : l -(3'-Hydroxy-biphenyl-3-yl)-ethanone

To a mixture of 3-iodophenol (2.0 g, 9.1 mmol), 3-acetylphenyl boronic acid (1.97 g, 12.0 mmol), dichloro[l, -bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (0.743 g, 0.91 mmol) and cesium carbonate (5.92 g, 18.2 mmol) was added 1-4 dioxane (9 mL) and water (3 mL). The reaction mixture was heated in a microwave reactor for 22 minutes at 100° C. The mixture was cooled to room temperature, ethyl acetate and water were added and contents transferred to a separatory funnel. The organic phase was washed with water, brine, dried over Na₂S0₄, concentrated under vacuum, and purified by column chromatography on silica gel (0-100%) ethyl acetate in heptanes to afford 1.45 g (75%) of l-(3'-hydroxy-biphenyl-3-yl)-ethanone.

Ci₄Hi₂0₂ (212.25), LCMS (ESI): 213.08 (M⁺+H).

1H NMR ((CDCls), 300MHz) δ: 8.17 (s, IH), 7.94-791 (d, IH), 7.78-7.75 (d, IH), 7.54-7.51 (t, IH), 7.35-7.30 (t, IH), 7.18-7.15 (d, IH), 7.13 (s, IH), 6.91-6.89 (d, IH), 6.17 (bs, IH), 2.66 (s, 3H).

Step 2: (S)-2-(3'-Acetyl-biphenyl-3- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

To a solution of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester (100 mg, 0.31 mmol) in acetonitrile (7 mL) was added l-(3'- hydroxy-biphenyl-3-yl)-ethanone (73 mg, 0.34 mmol) followed by cesium carbonate (142 mg, 0.435 mmol). The reaction mixture was stirred at 35-45° C for 18 hours. The reaction mixture cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by column chromatography on silica gel (0-10%) methanol in dichloromethane to afford 31.9 mg (28%) of the title compound.

C₂iHi₈N₂0₄ (362.38), LCMS (ESI): 363.08 (M⁺+H).

1H NMR ((CDCls), 300MHz) δ: 8.13 (s, 1H), 7.94-7.91 (d, 1H), 7.76-7.74 (d, 1H), 7.55-7.50 (t, 1H), 7.40-7.23 (m, 3H), 7.1 1 (s, 1H), 6.91-6.88 (d, 1H), 6.04-6.02 (d, 1H), 5.39-5.31 (m, 1H), 4.47-4.43 (q, 1H), 4.40-4.30 (m, 3H), 2.65 (s, 3H).

Comparative Example 4

(S)-2-(2',3 '-Dimethyl-biphen l-3-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.31 mmol) and 2',3 '-dimethyl-biphenyl-3-ol (0.34 mmol, [prepared from acetic acid 3-iodo-phenylester and 2,3,dimethylphenyl boronic acid] according to the procedure described in Comparative Example 3, to afford 44.5 mg (41%) of title compound. [a]_D ²⁵ = -3.1 ⁰ (c = 0.65, DMSO).

C₂iH₂₀N₂O₃ (348.40), LCMS (ESI): 349.1 1 (M⁺+H).

1H NMR ((CDCI3), 300MHz) δ: 7.31-7.26 (m, 2H), 7.15-7.09 (m, 2H), 7.05-7.02 (d, 1H), 6.95-6.93 (d, 1H), 6.86-6.83 (d, 1H), 6.79 (s, 1H), 6.03-6.00 (d, 1H), 5.35-5.28 (m, 1H), 4.47- 4.41 (t, 1H), 4.38-4.24 (m, 3H), 2.33 (s, 3H), 2.12 (s, 3H).

Comapartive Example 5

(S)-2-(2',3 '-Dichloro-biphen l-3-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.31 mmol) and 2',3 '-dichhloro-biphenyl-3-ol (0.34 mmol [prepared from 3-iodophenol and 2,3-dichlorophenylboronic acid] according to the procedure described in Comparative Example 3, to afford 68.3 mg (56%) of title compound. [a]_D ²⁵ = -1.9 ⁰ (c = 0.73, DMSO).

Ci₉Hi₄Cl₂N₂0₃ (388.03), LCMS (ESI): 389.04 (M⁺+H).

1H NMR ((CDC1₃), 300MHz) δ: 7.47-7.44 (d, 1H), 7.37-7.21 (m, 4H), 7.04-7.01 (d, 2H), 6.92-6.89 (d, 2H), 6.02-5.99 (d, 1H), 5.37-5.30 (m, 1H), 4.51-4.45 (t, 1H), 4.40-4.25 (m, 3H).

Comparative Example 6

(S)-2-(3'-Isopropyl-biphenyl-3- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-

7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.31 mmol) and 3'-isopropyl-biphenyl-3-ol (0.34 mmol (prepared from 3-iodophenol and 3-isopropylbenzen boronic acid) according to the procedure described in Comparative Example 3 to afford 48.0 mg (43%) of the title compound. [a]_D ²⁵ = -6.5 ⁰ (c = 0.46, DMSO).

C₂₂H₂₂N₂0₃ (362.16), LCMS (ESI): 363.16 (M⁺+H).

1H NMR ((CDCI3), 300MHz) δ: 7.40-7.34 (m, 3H), 7.31-7.30 (d, 1H), 7.26-7.21 (m, 3H), 7.07 (s, 1H), 6.85-6.82 (d, 1H), 6.03-6.00 (d, 1H), 5.34-5.29 (m, 1H), 4.48-4.41 (t, 1H), 4.40- 4.30 (m, 3H), 2.99-2.92 (m, 1H), 1.28-1.26 (d, 6H). Comparative Example 7

3'-((S)-7-Oxo-2,3-dihydro-7H-oxazolo 3,2-a]pyrimidin-2-ylmethoxy)-biphenyl-3-carbonitrile

The title compound was prepared from toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.31 mmol) and 3'-hydroxy-biphenyl-3- carbonitrile (0.34 mmol) (prepared from 3-iodophenol and 3-cyanophenyl boronic acid ) according to the procedure described in Comparative Example 3 to afford 87.3 mg (82%) of the title compound. [a]_D ²⁵ = -7.4 ⁰ (c = 0.72, DMSO).

C₂₀Hi₅N₃O₃ (345.1 1), LCMS (ESI): 346.1 1 (M⁺+H). 1H NMR ((CDCI3), 300MHz) δ: 7.81-7.76 (m, 2H), 7.64-7.61 (d, 1H), 7.56-7.51 (t, 1H), 7.41-7.36 (t, 1H), 7.32-7.30 (d, 1H), 7.20-7.17 (d, 1H), 7.06 (s, 1H), 6.94-6.91 (d, 1H), 6.04- 6.02 (d, 1H), 5.40-5.33 (m, 1H), 4.52-4.31 (m, 4H).

Comparative Example 8

(S)-2-(2',3'-Dimethyl-biphenyl-3-yloxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one

Step 1 : (S)-5-(3-Iodo-phenoxymeth l)-oxazolidin-2-ylideneamine

A solution of toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazolo-5-ylmethyl ester (1.0 g, 3.69 mmol), 3-iodophenol (0.812 g , 3.69 mmol), and cesium carbonate (1.74 g, 5.40 mmol) in acetonitrile (50 mL) was stirred at reflux until completion. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was transferred to a separatory funnel, the organic fraction separated, washed with water, dried over Na₂S0₄, concentrated under vacuum and purified by column chromatography on silica gel (0-10%) methanol in dichloromethane to afford 0.40 g (34%) of the title compound.

CioHiiIN₂0₂ (317.98), LCMS (ESI): 319.0 (M⁺+H).

1H NMR ((CDCI3), 300MHz) δ: 7.33-7.27 (m, 2H), 7.03-6.98 (t, 1H), 6.90-6.86 (d, 1H),

4.95-4.87 (m, 1H), 4.45-4.40 (bs, 2H), 4.09-3.88 (m, 3H), 3.64-3.57 (q, 1H).

Step 2: (S)-6-Ethyl-2-(3-iodo-phenox methyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

To a mixture of (S)-5-(3-iodo-phenoxymethyl)-oxazolidin-2-ylideneamine (2.17 g, 6.82 mmol) in ethanol (20 mL) was added 2-formyl-butyric acid ethyl ester (1.47 g, 10.2 mmol) and the mixture stirred for 40 hours at reflux. The mixture was cooled to room temperature, concentrated under vacuum, and purified by column chromatography on silica gel (0-10%) 2-propanol in dichloromethane to afford 0.244 g (9%) of the title compound. Ci₅Hi₅IN₂0₃ (398.02), LCMS (ESI): 398.98 (M⁺+H).

1H NMR ((CDC1₃), 300MHz) δ: 7.36-7.34 (d, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 7.04-6.99 (t, 1H), 6.87-6.84 (d, 1H), 5.29-5.22 (m, 1H), 4.41-4.38 (t, 1H), 4.33-4.21 (m, 3H), 2.48-2.40 (q, 2H), 1.18-1.15 (t, 3H).

Step 3 : (S)-2-(2',3'-Dimethyl-biphenyl-3-yloxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

A mixture of (S)-6-ethyl-2-(3-iodo-phenoxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one (0.063 g, 0.162 mmol), 2,3,dimethylphenyl boronic acid (0.036 g, 0.243 mmol), dichloro[l , -bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (0.016 g, 0.02 mmol) and cesium carbonate (0.132 g, 0.405 mmol) in 1 ,4-dioaxne (6 mL) and water (1 mL) was stirred at room temperature for 4 hours and at 40° C for 3 hours. The mixture was cooled to room temperature, ethyl acetate added and contents transferred to a separatory funnel. The organic phase was washed with water, brine, dried over Na₂S0₄, concentrated under vacuum, and purified by column chromatography on silica gel (0-10%) 2- propanol in dichloromethane to affordO.036 g (60%) of the title compound.

C₂₃H₂₄N₂0₃ (376.17), LCMS (ESI): 377.16 (M⁺+H).

1H NMR ((CDCI3), 300MHz) δ: 7.34-7.29 (t, 1H), 7.18-7.10 (m, 2H), 7.05-7.03 (m, 2H), 6.96-6.93 (d, 1H), 6.86-6.83 (d, 1H), 6.80 (s, 1H), 5.27-5.23 (m, 1H), 4.42-4.24 (m, 4H), 2.47- 2.40 (q, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 1.16-1.12 (t, 3H).

Comparative Example 9

(S)-6-Ethyl-2-(3'-isopropyl-biphenyl-3-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

The title compound was prepared from (S)-6-ethyl-2-(3-iodo-phenoxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one (0.344 mmol), and 3-isopropylphenyl boronic acid (0.52 mmol) according to the procedure described in Comparative Example 8 to afford 0.105 g (78%) of the title compound. [a]_D ²⁵ = +7.8 ⁰ (c = 0.65, DMSO).

C₂₄H₂₆N₂0₃ (390.19), LCMS (ESI): 391.18 (M⁺+H). 1H NMR ((CDCI3), 300MHz) δ: 7.40-7.33 (m, 4H), 7.25-7.23 (d, 2H), 7.09-7.06 (d, 2H), 6.87-6.84 (d, 1H), 5.29-5.24 (m, 1H), 4.43-4.28 (m, 4H), 3.02-2.93 (m, 1H), 2.47-2.42 (q, 2H), 1.31-1.29 (d, 6H), 1.17-1.12 (t, 3H).

Comparative Example 10

(S)-2-(Biphenyl-3-ylox methyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

A mixture of toluene-4-sulfonic acid (S)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (1.5g, 4.7mmol), biphenyl-3-ol (prepared from 3- bromophenol and phenylboronic acid) (0.8g, 4.7mmol) and cesium carbonate (1.5g, 4.7mmol) in 30 ml of anhydrous acetonitrile was heated at reflux for 1 hour. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and was extracted with methylene chloride (75ml). The organic layer was dried over magnesium sulfate and was filtered. The concentrated filtrate was purified by reverse phase HPLC using 10-100% (acetonitrile-0.1% trifluoro acetic acid) over 20 minutes and the product-containing fractions concentrated by lyophilization to provide the title compound. (0.53g, 35%).

Ci₉Hi₆N₂0₃ (320.35), LCMS (ESI): 321.12 (M⁺H)

1H NMR (DMSO-d₆, 300 MHz) δ: 7.80 (d, 1H), 7.66 (d, 2H), 7.37-7.46 (m, 4H), 7.21-7.25 (m, 2H), 6.83 (d, 1H), 5.83 (d, 1H), 5.34-5.38 (m, 1H), 4.42-4.49 (m, 3H), 4.1 1-4.17 (m, 1H).

Comparative Example 1 1

(S)-2-(2'-Methyl-biphenyl-3- loxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from (S)-2-toluene-4-sulfonic acid methyl-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one (0.31 mmol) and 2'-methyl-biphenyl-3-ol (0.34 mmol [prepared from 3-iodophenol and 2-methylphenyl boronic acid]) according to the procedure described in Example 1 17 to afford 40.3 mg of the title compound. C₂oHi₈N₂0₃ (334.13), LCMS (ESI): 335.12 (M⁺+H).

1H NMR ((CDC1₃), 300MHz): δ 7.32-7.16 (m, 6H), 6.97-6.95 (d, 1H), 6.87-6.81 (m, 2H), 6.03-6.01 (d, 1H), 5.35-5.28 (m, 1H), 4.44-4.4.39 (t, 1H) 4.37-4.24 (m, 3H), 2.24 (s, 3H).

Comparative Example 12

(S)-2-(2'-Trifluoromethyl-biphenyl-3-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

The title compound was prepared from (S)-2-toluene-4-sulfonic acid methyl-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one and 2'-trifluoromethyl-biphenyl-3-ol [prepared from 3-iodophenol and 2-trifluoromethylphenyl boronic acid]) according to the procedure described in Example 117 to afford the title compound.

Biological Examples

Example 125

A calcium ion (Ca²⁺) mobilization assay was used to identify and determine the activity for allosteric modulators of the rat or human mGluR2 receptor. Two formats were used: (1) examine the ability of glutamate to affect the potency of the modulator, by looking at a concentration-response curve of compound at different submaximal glutamate concentrations, and (2) look at the ability of the modulator to affect the potency of glutamate by looking at a concentration-response curve of glutamate at a maximal modulator concentration.

To monitor functional receptor response using calcium mobilization, a cell line stably expressing the rat or human mGluR2 receptor (normally coupled to its intracellular effector molecules through an inhibitory G-protein, Gcri) and Ga₁₆, in a tetracycline-inducible vector was created. G l 6 can promiscuously couple Gs and Gi-coupled receptors to the inositol phospholipid signaling pathway by activating phospholipase CP resulting in a Ca²⁺ signal (normally Gaq-mediated), that can be monitored with fluorescence plate readers such as FLIPR (Molecular Devices, Fluorescence Imaging Plate Reader), FDSS6000 (Hamamatsu, Fluorescence Drug Screening System), or FlexStation (Molecular Devices). The Ca²⁺ mobilization assay was based on the detection of intracellular calcium changes using a selective, calcium-chelating dye: Fluo-3, Fluo-4, or Calcium-3. A large fluorescence intensity increase was observed upon calcium association with the dye. The dye was delivered either with the acetoxy-methyl ester, and washed off, or using a no-wash kit (Molecular Devices). Fluorescence signals stimulated by glutamate were recorded and used to generate the following pharmacological parameters: (1) the potency (EC50) of the compound(s) of interest at approx. EC 10 for glutamate at the rat and human mGluR2 receptors respectively, and (2) a fold-shift of the glutamate EC50 by maximal concentration of compound(s) of interest.

Generally the compounds of this invention exhibit good mGluR2 potentiation (EC50). Broadly speaking the activity of the compounds of this invention is in the range of about 1 - 1000 nM, and certain of the compounds exhibit mGluR2 potentiation in the range of 1 - 100 nM. The results obtained for a few of the representative compounds of formula (I) of this invention tested in accordance with this procedure are summarized in Table 1 , which lists the mGluR2 potentiation (EC50). For comparative purposes also listed are the mGluR2 potentiation (EC50) obtained for the corresponding meta-biphenyloxymethyl compounds described herein as comparative examples.

Table I

The efficacy of the compounds of formula (I) of this invention in treating a variety of diseases as disclosed herein can be confirmed by any of the methods known to one skilled in the art. For instance, the efficacy in treating anxiety can be confirmed by using Vogel conflict test. See, for example, Tatarczynska et al, Psychopharmacology (Berl). 2001 Oct;158(l):94- 9 incorporated herein by reference in its entirety. Specifically, Tatarczynska et al. disclose the antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors.

The preclinical anxiety and psychosis models also include stress induced hyperthermia, fear potentiated startle and PCP-induced hyperlocomotion. See Rorick-Kehn et al, J. Pharmacol. Exp. Ther. 2006 Feb;316(2):905-13. Epub 2005 Oct 13. Also see, Johnson et al, Psychopharmacology (Berl). 2005 Apr;179(l):271-83. Epub 2005 Feb 17. Fear- potentiated startle and elevated plus maze models have been used by Helton et al., J Pharmacol Exp Ther. 1998 Feb;284(2):651-660 in order to demonstrate the anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors.

Various anxiety models to show efficacy in humans are also known in the art. See Kellner et al, Psychopharmacology (Berl). 2005 Apr;179(l):310-5. Epub 2004 Sep 30, where the effects of a metabotropic glutamate(2/3) receptor agonist on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans has been reported.

In addition, the efficacy of the compounds of formula (I) of this invention in treating schizophrenia may also be ascertained by various known models in the art. For instance, PCP-induced hyperlocomotion, PCP-disrupted prepulse inhibition, stress-induced hyperthermia, and elevated plus maze models have been used to demonstrate the efficacy of allosteric modulators of mGluR2. See, Galici et al., J Pharmacol Exp Ther. 2006 Jul; 318(1): 173-85. Epub 2006 Apr 11 , where it is shown that biphenyl-indanone A, a positive allosteric modulator of the mGluR2, has antipsychotic- and anxiolytic-like effects in mice.

The efficacy of the compounds of formula (I) of this invention in improving the working memory in humans can be ascertained by a variety of methods known in the art. For instance, Krystal et al, Psychopharmacology (Berl). 2005 Apr;179(l):303-9. Epub 2004 Aug 10, reported that the attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. In another example, Patil et al, Nature Medicine. 2007 Sep;13(9): l 102-7. Epub 2007 Sep 2. reported that the group II metabotropic glutamate receptor agonist, LY2140023, showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo.

The compounds of formula (I) of this invention are also useful in treating sleep disorders and depression. Feinberg et al, Pharmacol Biochem Behav. 2002, 73(2) 467-74, have reported that the selective group mGluR2/3 receptor agonist, LY379268, suppresses rapid eye movement (REM) sleep and fast EEG in the rat. Gewirtz et al., Pharmacol Biochem Behav. 2002 Sep;73(2):317-26, have examined the effects of mGluR2/3 agonists on BDNF mRNA expression in medial prefrontal cortex induced by the hallucinogen and 5HT₂A/2B/2C agonist. Also, see Schechter et al, NeuroRx. 2005 Oct;2(4):590-611. Review, where innovative approaches for the development of antidepressant drugs are reviewed.

The activity of allosteric modulators of mGluR2 in pain models has also been reported in the literature. See, Jones et al, Neuropharmacology. 2005; 49 Suppl 1 :206-18, where analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists are disclosed.

The efficacy of compounds of formula (I) of this invention in treating epilepsy can also be ascertained by various methods used in the art. For example, see, Alexander et al, Epilepsy Res. 2006, 71(1), 1-22, where metabotropic glutamate receptors as a strategic target for the treatment of epilepsy is discussed. Also see, Klodzinska et al, Pol J Pharmacol. 1999, 51(6), 543-5, which discloses selective group II glutamate metabotropic receptor agonist LY354740 attenuates pentylenetetrazole- and picrotoxin-induced seizures. Roles of metabotropic glutamate receptor subtypes in modulation of pentylenetetrazole-induced seizure activity in mice is disclosed by Thomsen et al, Neuropharmacology. 1998, 37(12), 1465-73. Finally, Thomsen et al, J Neurochem. 1994, 62(6), 2492-5, disclose that (S)-4-carboxy-3- hydroxyphenylglycine, an antagonist of metabotropic glutamate receptor (mGluR) la and an agonist of mGluR2, protects against audiogenic seizures in DBA/2 mice.

It has also been reported in the literature that modulation mGluR2 receptors may also improve cognitive functions. See for example Moghaddam, Psychopharmacology (2004) 174:39-44. Accordingly, it has been further suggested that modulation of mGluR2 receptors may also improve cognitive deficits in patients suffering from either Parkinson's disease as well as Alzheimer's disease. See specifically Lee et al., Brain Research 1249 (2009), 244-250 for Alzheimer's disease and Samadi et al, Neuropharmacology 54 (2008) 258-268 for Parkinson's disease.

Example 126

Stress Induced Hyperthermia (Anxiety Model)

Stress-induced hyperthermia (SIH) reflects the elevation in core body temperature experienced by mammals following a stressful experience. Clinically active anxiolytics prevent SIH, indicating that this model may be useful in identifying novel anxiolytic agents (See, Olivier et al. Eur J Pharmacol. 2003, 463, 117-32). SIH is measured in mice using the rectal test procedure adaptation of the classic SIH paradigm described by Borsini et al, Psychopharmacology (Berl). 1989, 98(2), 207-11. Individually housed mice are subjected to two sequential rectal temperature measurements, separated by a 10-minute interval. The first measurement captured the animal's basal core body temperature (Tl), while the second temperature (T2) captured body temperature following the mild stress imposed by the first temperature measurement. The difference between the first and second temperature (T2-T1 or ΔΤ) is the SIH. Temperature measurements are made to the nearest 0.1°C with a lubricated thermistor probe inserted 2 cm into the rectum of each subject. Test compounds are administered 60 minutes before the first temperature measurement to allow for any stress effect created by the injection to dissipate completely.

Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Claims

What is claimed is:

A compound of the formula I:

wherein:

R₂ is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, 1,1-difluoropropyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, phenyl, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, tetrahydrofuranylmethoxymethyl, cyclopropyl and cyclopentyloxymethyl; and

R₃, R4, R₅, R6, R₇ and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF₃, (Ci-C₄)alkyl, (C₃-C₆)cycloalkyl, (Ci-C₄)alkoxy; or

The compound according to claim 1 , wherein:

Ri is selected from the group consisting of hydrogen, methyl and ethyl;

R₂ is selected from the group consisting of hydrogen, methyl, fluoromethyl,

1,1-difluoropropyl, methoxymethyl, ethoxymethyl,

2-fluoroethoxymethyl, isopropoxymethyl, phenyl, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, cyclopropyl and cyclopentyloxymethyl; and

R₃, R4, R₅, R6, R₇ and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, cyclopropyl and ethoxy;

or a salt thereof.

3. The compound according to claim 1, wherein:

Ri is hydrogen or ethyl;

R₂ is hydrogen;

R₃, R4, R₅, R6, R₇ and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy and ethoxy;

or a salt thereof.

4. The compound according to claim 1, wherein:

Ri is selected from the group consisting of hydrogen, methyl and ethyl;

R₂ is hydrogen;

R3, R4, R5 are hydrogen; and

two of R6, R₇ and Rs are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered ring;

or a salt thereof.

5. The compound according to claim 1, which is selected from the group consisting of:

(S)-2-(biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(biphenyl-4-yloxymethyl)-5-hydroxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

(S)-2-(3'-chloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(3'-bromo-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(3'-butyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; S)-2-(3'-isobutyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

S)-2-(3'-tert-butyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

S)-2-(3'-trifluoromethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

S)-2-(2'-trifluoromethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

S)-2-(3'-cyclopropyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

S)-2-(2'-cyclohexyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

S)-2-(3'-methoxy-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

S)-5-isopropoxymethyl-2-(4'-methoxy-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

S)-2-(2'-acetyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; S)-2-(2\3'-difluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one;

S)-2-(2',3'-difluoro-biphenyl-4-yloxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

S)-2-(3',4'-difluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a] pyrimidin-7- one;

S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-methoxymethyl -2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

S)-2-(2',4'-dichloro-biphenyl-4-yloxymethyl -2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

S)-5-cyclopropyl-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-2-(2',3'-dichloro-biphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4 ' -fluoro-3 ' -methyl-bipheny l-4-yloxymethyl)-2,3 -dihydro-oxazolo [3 ,2- a]pyrimidin-7-one;

(S)-2-(2'-fluoro-4'-methyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(2,6-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one; (S)-2-(3^5'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimid^ 7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin^ 7-one;

7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-ethoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-isopropoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-(tetrahydro-furan-2- ylmethoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)-5-(2-fluoro-ethoxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(2-methyl-3'-propyl-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(2',3'-dimethoxy-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2',3\5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin

7-one;

(S)-2-(2',3\4'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin 7-one;

(S)-5-(2-hydroxy-ethyl)-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-ethoxymethyl-2-(2',3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-isopropoxymethyl-2-(2 3',5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-5-cyclopentyloxymethyl-2-(2',3\5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-(tetrahydro-furan-2-ylmethoxymethyl)-2-(2',3',5'-trifluoro-biphenyl-4- yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-5-fluoromethyl-2-(2',3^5'-trifluoro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-fluoromethyl-2-(2',3^5'-trichloro-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(2-ethyl-2',3'-dimethyl-biphenyl-4-yloxymethyl)-6-methyl-2,3-dihydro- oxazolo[3,2 -a]pyrimidin-7-one;

(S)-2-(2-methoxy-2',3'-dimethyl-biphenyl-4-yloxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

2',3'-dimethyl-4-((S)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethoxy)- biphenyl-2-carbonitrile;

(S)-2-(4-naphthalen-l-yl-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (S)-2-(4-indan-5-yl)-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(4-indan-4-yl)-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-[4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-phenoxymethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(9H-fluoren-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. A pharmaceutical composition comprising one or more compounds of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.

Use of a compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition, which compound is capable of modulating one or more metabotropic glutamate receptor functions for treating neurological or psychiatric disorders.

Use of a compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition, which compound is capable of modulating one or more metabotropic glutamate receptor functions for treating anxiety, migraine, schizophrenia, cognitive disorders, epilepsy and pain.