WO2011034832A1

WO2011034832A1 - Substituted phenoxymethyl dihydro oxazolopyrimidinones, preparation and use thereof

Info

Publication number: WO2011034832A1
Application number: PCT/US2010/048697
Authority: WO
Inventors: Raymond Walter Kosley, Jr.; Rosy Sher; Kent W. Neuenschwander; Vieroslava Gurunian
Original assignee: Sanofi-Aventis
Priority date: 2009-09-15
Filing date: 2010-09-14
Publication date: 2011-03-24
Also published as: AR078172A1; TW201124421A

Abstract

The present invention relates to a series of substituted phenoxymethyl dihydro oxazolopyrimidinones of formula (I) 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 PHENOXYMETHYL DIHYDRO OXAZOLOPYRIMIDINONES,

PREPARATION AND USE THEREOF

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a series of substituted dihydro benzocycloalkyloxymethyl oxazolopyrimidinones. More specifically, the present invention relates to a series of substituted 2-phenoxymethyl-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- phenoxymethyl-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 o ounds of the formula I:

(I)

wherein:

is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, hydroxyethyl, 2-(tetrahydro-pyran-2-yloxy)-ethyl;

is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, -COOH, phenyl, benzyl, 2-, 3-, 4-, o 5 -fluorophenyl, 2-, 3-, 4-, or 5-f uorobenzyl, 2,4-dif uorophenyl, 2,4- difluorobenzyl, phenoxy, benzyloxy, 2-, 3-, 4-, or 5-fluorophenoxy, 2-, 3-, 4-, or 5-fluorobenzyloxy, 2,4-difluorophenoxy, 2,4-dif uorobenzyloxy,

hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, tetrahydrofuranylmethoxymethyl, phenyl, cyclopropyl, cyclopropylmethyl and cyclopentyloxymethyl; and P 3, P and R₅ are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF₃, (Ci-C₆)alkyl, (Ci-C₆)alkoxy, cyclohexyl, 1-methylcyclohexyl, 4-methoxycyclohexyl,

4,4'-difluorocyclohexyl, cyclohexenyl, 4-fluoro-cyclohexenyl, bicyclo[3,3,l]nonyl, bicyclo[3,3,l]nonylethyl, 1,1 ',1",3,3',3"— hexafluoro-2- hydroxy-propyl; or

two of R₃, P and R₅ 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, diastereoisomers or tautomers of compound of formula (I) are also part of this invention.

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-Cv)cycloalkyl" or "(C₃-Cy)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 non- toxic 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-C₆)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, propyl, hydroxyethyl, 2-(tetrahydro-pyran-2-yloxy)-ethyl;

R₂ is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, -COOH, phenyl, benzyl, 2-, 3-, 4-, or 5 -fluorophenyl, 2-, 3-, 4-, or 5-f uorobenzyl, 2,4-dif uorophenyl, 2,4- difluorobenzyl, phenoxy, benzyloxy, 2-, 3-, 4-, or 5-fluorophenoxy, 2-, 3-, 4-, or 5-fluorobenzyloxy, 2,4-difluorophenoxy, 2,4-dif uorobenzyloxy, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, tetrahydrofuranylmethoxymethyl, phenyl, cyclopropyl, cyclopropylmethyl and cyclopentyloxymethyl; and

R₃, R4 and R₅ are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF₃, (Ci-C₆)alkyl, (Ci-C₆)alkoxy, cyclohexyl, 1-methylcyclohexyl, 4-methoxycyclohexyl,

4,4'-difluorocyclohexyl, cyclohexenyl, 4-f uoro-cyclohexenyl, bicyclo [3 ,3,1 ]nonyl, bicyclo [3,3,1 ]nonylethyl, 1, ,1",3,3' ,3 "— hexafluoro-2- hydroxy-propyl; or two of R₃, R4 and R₅ are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered 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. As also all other possible forms of diastereoisomers or tautomers of compound of formula (I) are also 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 R5 :

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

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

2-fluoroethoxymethyl, isopropoxymethyl, hydroxymethyl, morpholinylmethyl and pyrrolidinylmethyl; and

R₃, R₄ and R₅ are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, iso-propyl, iso-butyl, tert-butyl, cyclohexyl, methoxy 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 and R₅ are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, 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 specific examples of compounds of formula (I), the following compounds may be enumerated without any limitations:

(S)-2-[4-(9-methyl-bicyclo[3.3.1]non-9-yl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-[4-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-[4-(4-methoxy-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

2-[4-(3-oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

2-[4-(5,5-dimethyl-3-oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

2-[4-(l-methyl-3-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2a]pyrimidin-7-one;

2-[4-(l,3,3-trimethyl-5-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

2-[4-(2,6,6-trimethyl-4-oxo-bicyclo[3.1.1 ]hept-2-yl)-phenoxymethyl]-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

2-[4-(3-hydroxy-l,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

2-(l-oxo-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

2-(3-oxo-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-[4-(2,2-dimethyl-propyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin

7-one; and

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-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-(4-tert-butyl-2-fluoro-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one; and

(S)-2-(4-tert-butyl-3-methoxy-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one.

The following compounds are further enumerated as specific examples of this invention:

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-5-methyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-[4-(2,2-dimethyl-propyl)-phenoxymethyl]-5-methyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; (S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-5-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-[4-(2,2-dimethyl-propyl)-phenoxymethyl]-5-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-5-ethyl-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

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

(S)-2- [4-(4-fluoro-cyclohex-3 -enyl)-phenoxymethyl] -5 -methoxymethyl-2,3 -dihydro- oxazolo [3, 2-a]pyrimidin-7-one;

(S)-5-cyclopropyl-2-[4-(4,4-difluoro-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-cyclopropyl-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

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

(S)-5-fluoromethyl-2-[4-(9-methyl-bicyclo[3.3.1 ]non-9-yl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-5 -fluoromethyl-2- [4-( 1 -methyl-cyclohexyl)-phenoxymethyl] -2,3 -dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-5-fluoromethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

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

(S)-2-(4-tert-butyl-phenoxymethyl)-5-(l,l-difluoro-propyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohexyl-phenoxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohexyl-phenoxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-2-[4-(4,4-difluoro-cyclohexyl)-phenoxymethyl]-5-pyrrolidin-l-ylmethyl-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohexyl-phenoxymethyl)-5-piperidin-l-ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohexyl-phenoxymethyl)-5-(tetrahydro-pyran-2-yloxymethyl)-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-bicyclo [3.3.1 ]non-9-yl-phenoxymethyl)-5 -(tetrahydro-pyran-2-yloxymethyl)

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

(S)-2-(4-cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidine-5-carboxylic acid;

(S)-2-(4-bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-hydroxymethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohexyl-phenoxymethyl)-5-(4-fluoro-benzyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-6-methyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-6-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

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

(S)-2-(4-tert-butyl-phenoxymethyl)-6-(2,2,2-trifluoro-ethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-propyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-6-propyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-isopropyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin 7-one; (S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-6-isopropyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-phenyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-6-phenyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; and

(S)-2-(4-tert-butyl-phenoxymethyl)-6-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-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-(4-bicyclo[3.3.1 ]non-9-yl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohex-l-enyl-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-5-methoxymethyl-2-[4-(9-methyl-bicyclo[3.3.1 ]non-9-yl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohexyl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-2-fluoro-phenoxymethyl)-5-ethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-2-fluoro-phenoxymethyl)-6-methyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-2-fluoro-phenoxymethyl)-6-ethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; and

(S)-2-(4-tert-butyl-3-methoxy-phenoxymethyl)-5-ethyl-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 - 4, wherein the Ri, R₂, R₃, R4 and R₅ are as defined for Formula I unless otherwise indicated.

Scheme 1 illustrates the synthesis of several of the compounds of formula (I) of this invention wherein Ri is hydrogen. However, a modified synthetic scheme may 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 suitably substituted phenol of formula (VI), which can be prepared in accordance with any of the known procedures or may be available from commercial sources. 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 Step 1, Scheme 2, a suitably substituted phenol of formula (VI) is reacted with R-epichlorohydrin to form a substituted phenoxy oxirane of formula (VII). 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. 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 phenol of formula (VI). However, sub-ambient temperature conditions can also be employed depending upon the type of phenol of formula (VI) employed.

Scheme 2

In Step 2, Scheme 2, the oxirane of formula (VII) is reacted with a cyanamide compound to form a oxazolylamine of formula (VIII). 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 2.

In Step 3, Scheme 2, the oxazolylamine of formula (VIII) 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 (I) wherein Ri is hydrogen. 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.

Scheme 3 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 3

In Step 1, Scheme 3, oxazolylamine of formula (III) is reacted with a β-formyl- alkanoic ester of formula (IX) 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 (X).

In Step 2, Scheme 3, the compound of formula (X) is then allowed to react with a suitably substituted phenol 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 compounds of formula (I) wherein R₂ is hydrogen.

Scheme 4 illustrates another approach for the preparation of compounds of formula (I) of this invention wherein R₂ is hydrogen. In this approach the oxazolylamine of formula (VIII) as prepared in accordance with the procedures of Step 2, Scheme 2 is reacted with β-formyl- alkanoic ester of formula (IX) wherein R is (Ci-C₄)alkyl, phenyl or benzyl. This step can be carried out using any of the procedures known in the art such as for example as described above in Step 1, Scheme 3 to obtain compounds of formula (I) wherein R₂ is hydrogen.

Scheme 4

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 (R)- enantiomers 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 (R)-enantiomers.

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, "mrnol" refers to millimoles, "μιηοΐε" refers to micromoles, "nmole" refers to nanomoles, "L" refers to liters, "mL" or "ml" refers to milliliters, "μΕ" 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 1 -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-Bicyclo[3.3.1 ]non-9-yl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : Toluene-4-sulfonic acid (S)-5-methoxymethyl-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-oxazol-5-ylmethyl ester (prepared in accordance with the procedures described in WO 2008/1 12483) (6.14 g,

22.7 mmol) in EtOH (120 ml), was added 4-methoxy-but-2-ynoic acid ethyl ester (4.2 g, 29.56 mmol). The reaction mixture was heated at reflux for 3.5 hours. The reaction mixture was then concentrated. The residue was purified by silica gel chromatography

(EtOH/CH₂Cl2) to provide 3.55 g of the title compound.

Ci₆Hi₈N₂0₆S (366.09), LCMS (ES⁺): 367.12 (M⁺+H).

1H NMR (CDCls, 300MHz), δ 7.76 (d, 2H), 7.38 (d, 2H), 5.91 (s, 1H), 5.14 (m, 1H), 4.42 (t, 1H), 4.3. (m, 5H), 3.39(s, 3H), 2.46 (s, 3H), 1.22. Step 2: 9-(2-Fluoro-4-methoxy-phenyl)-bicyclo[3.3.1]nonan-9-ol

l-Bromo-2-fluoro-4-methoxy-benzene (4.10 g, 20 mmol) was dissolved in THF (30 ml) and cooled to -78°C. To the solution was added n-BuLi (1.6 M in THF, 12.5 ml, 20 mmol) dropwise. The reaction mixture was stirred at -78°C for 20 min, after which bicyclo[3.3.1]nonan-9-one (2.76 g, 20 mmol) in THF (20 ml) was added dropwise. The reaction mixture was stirred at -78°C for 2.5 hours and quenched at the same temperature with aqueous NH₄C1 solution. Water and EtOAc were added. The reaction mixture was extracted with EtOAc three times. The organic phase was washed with brine and dried (Na₂S0₄). Silica gel chromatography (EtO Ac/heptane) provided 3.4 g of the title compound.

Ci₆H₂iF0₂ (264.15), LCMS (EI⁺): 264.14 (M⁺).

1H NMR (CDCI3, 300MHz), δ 7.41 (t, 1H), 6.55-6.71 (m, 2H), 3.80 (s, 3H), 2.61 (br. s, 1H), 2.39 (m, 2H), 1.49-2.17 (m, 12H).

Step 3: 9-(2-Fluoro-4-methoxy-phenyl)-bicyclo[3.3.1]nonane

To a solution of 9-(2-fluoro-4-methoxy-phenyl)-bicyclo [3.3.1 ]nonan-9-ol (2.83 g, 10.7 mmol) in CH₂CL₂ ( 50 ml) was added Et₃SiH ( 1.87 g, 16.1 mmol) followed by TFA (4.9 g, 42.9 mmol). The reaction mixture was stirred at rt for 15 min. To the reaction mixture was added Na₂C0₃ (4.5 g). The mixture was partitioned between water and EtOAc after which it was stirred for 15 min. The organic layer was separated, dried (Na₂S0₄) and concentrated. The residue was purified by chromatography ((EtOAc/haptane) to provide 2.45 g (92%) of the title compound.

Ci₆H₂iFO (248.16), LCMS (EI⁺): 248.16 (M⁺).

1H NMR (CDC1₃, 300MHz), δ 7.36 (t, 1H), 6.56-6.68 (m, 2H), 3.79 (s, 3H), 2.99 (br. s, 1H),

2.24 (br.s, 2H), 1.46-2.04 (m, 12H).

Step 4: 4-Bicyclo[3.3.1]non-9-yl-3-fluoro-phenol

To a solution of 9-(2-fluoro-4-methoxy-phenyl)-bicyclo[3.3.1]nonane (2.45 g, 9.88 mmol) in CH₂C1₂ (30 ml) was added BBr₃ in CH₂C1₂ (1M solution, 19.8 mmol) at 0°C, dropwise. This mixture was stirred at 0°C for 1.5 hours. The reaction mixture was quenched with MeOH (3 ml). Aqueous sodium hydrogen carbonate (10 ml) was added. The reaction mixture was stirred at rt overnight. The organic phase was separated and washed with water, brine and dried (Na₂S0₄). The solution was passed through a silica gel plug. The filtrate was concentrated to provide the title compound (2.3 g).

Ci₅Hi₉FO (234.14), LCMS (CI⁺): 234.13 (M⁺). 1H NMR (CDCI3, 300MHz), δ 7.32 (t, 1H), 6.55 (t, 2H), 4.64 (s, 1H), 2.97 (br. s, 1H), 2.23 (br.s, 2H), 1.49-2.02 (m, 12H).

Step5 : (S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3-dihydro oxazolo[3,2-a]pyrimidin-7-one

To a solution of toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.59 g, 1.6 mmol) in acetonitrile (20 ml) was added 4-bicyclo[3.3.1]non-9-yl-3-fluoro-phenol (0.41 g, 1.76 mmol), followed by cesium carbonate (0.57 g, 1.76 mmol). The reaction mixture was stirred at reflux for 1 hour. It was then concentrated and the residue was dissolved in ethyl acetate/water. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with 3% HC1 aqueous solution, saturated aqueous NaHC0₃ solution, brine, and dried (Na₂S0₄). Silica gel chromatography (silica, EtOH/methylene chloride) provided 0.40 g of the title compound.

C₂₄H₂₉FN₂0₄ (428.21), LCMS (ES⁺): 429.21 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.38 (t, 1H), 6.52-6.65 (m, 2H), 6.01 (s, 1H), 5.24 (m, 1H), 4.26 (s, 2H), 4.19-4.48 (m, 4H), 3.41(s, 3H), 2.99 (br.s, 1H), 2.23 (br.s, 2H), 1.48-1.98 (m, 12H).

Example 2

(S)-2-(4-Cyclohex-l-enyl-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : 1 - [4-(Tetrahydro-pyran-2-yloxy)-phenyl] -cyclohexanol

2-(4-Bromo-phenoxy)-tetrahydro-pyran (2.7 g, 10.4 mmol) was dissolved in THF (20 ml) and cooled to -78°C. n-BuLi (1.6 M in hexane, 7.1 ml, 11.5 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Cyclohexanone (1.0 g, 10.4 mmol) in THF (10 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature slowly and then stirred at rt overnight. The reaction mixture was quenched with aqueous NH₄C1 solution. The organic phase was separated and the aqueous phase was extracted twice with EtOAc. The organic phases were combined, washed with brine and dried (Na₂S0₄). Silica gel chromatography (EtO Ac/heptane) provided 2.3 g of the title compound. Ci₇H₂₄0₃ (276.17), LCMS (EI ): 276.18 (M⁺).

1H NMR (CDC1₃, 300MHz), δ 7.41 (d, 2H), 7.02 (d, 2H), 5.41 (t, 1H), 3.92 (m, 1H), 3.60 (m, 1H), 1.22-2.05 (m, 17H).

Step 2: 4-Cyclohex-l-enyl-phenol

l-[4-(Tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanol (2.0 g, 7.2 mmol) was dissolved in EtOH (100 ml) after which concentrated hydrochloric acid (10 ml) was added. This mixture was stirred at 50°C for 2 hours. The solvent was removed under reduced pressure. Water (15 ml) was added. The mixture was basified with aqueous ammonia and extracted three times with EtOAc. The organic phase was dried and concentrated to provide 0.68 g of the title compound.

Ci₂Hi₄0 (174.10), LCMS (ES⁺): 175.10 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.27 (d, 2H), 6.77 (d, 2H), 6.02 (m, 1H), 4.59 (s, 1H), 2.37 (m, 2H), 2.19 (m, 2H), 1.77 (m, 2H), 1.65 (m, 2H).

Step 3 : (S)-2-(4-Cyclohex-l-enyl-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from 4-cyclohex-l -enyl-phenol employing the procedure described in Example 1.

C₂iH₂₄N₂0₄ (368.17), LCMS (ES⁺): 369.17 (M⁺+H).

1H NMR (CDCI₃, 300MHz), δ 7.31 (d, 2H), 6.81 (d, 2H), 6.04 (br.s, 1H), 5.98 (s, 1H), 5.24 (m, 1H), 4.26 (s, 2H), 4.20-4.50 (m, 4H), 3.39(s, 3H), 2.36 (br. s, 2H), 2.19 (br.s, 2H), 1.77 (m, 2H), 1.65 (m, 2H).

Example 3

(S)-5-Methoxymethyl-2-[4-(9-methyl-bicyclo[3.3.1 ]non-9-yl)-phenoxymethyl]-2,3-dihydro- oxaz lo[3,2-a]pyrimidin-7-one

Step 1 : 9-(4-Benzyloxy-phenyl)-9-methyl-bicyclo[3.3.1 Jnonane

9-(4-Benzyloxy-phenyl)-bicyclo[3.3.1]nonan-9-ol (prepared according to the procedure in Example 2 from l-benzyloxy-4-bromo-benzene and bicyclo[3.3.1]nonan-9-one) (0.62 g, 1.9 mmol) was dissolved in CH₂C1₂ (12 ml) and cooled to -78°C. AlMe₃ (2M in toluene, 4.0 ml, 8 mmol) was added, followed by BF₃ Et₂0 (0.28 g, 2.0 mmol). The reaction mixture allowed to warm to rt and stirred overnight. The reaction mixture was cooled to 0°C and carefully quenched with water. It was then extracted with CH₂CI₂. The organic phase was dried (Na₂S0₄). Silica gel chromatography (EtO Ac/heptane) provided 0.46 g of the title compound.

C₂₃H₂₈0 (320.21), LCMS (CI): 320.20 (M⁺).

1H NMR (CDC1₃, 300MHz), δ 7.26-7.48 (m, 7H), 6.94 (d, 2H), 5.05 (s, 2H), 2.27 (br.s, 2H),

1.23-2.26 (m, 12H), 1.19 (s, 3H).

Step2: 4-(9-Methyl-bicyclo[3.3.1]non-9-yl)-phenol

To a solution of 9-(4-benzyloxy-phenyl)-9-methyl-bicyclo[3.3.1]nonane (0.46 g, 1.44 mmol) in MeOH (300 ml) and THF (100 ml) was added 10% Pd/C (0.09 g) under N₂. This mixture was stirred under H₂ (1 atm) overnight. The reaction mixture was filtered through celite. The filtrate was concentrated. Silica gel chromatography (EtO Ac/heptane) provided the title compound (0.31 g).

Ci₆H₂₂0 (230.17), LCMS (CI): 230.16 (M⁺).

1H NMR (CDC1₃, 300MHz), δ 7.22 (d, 2H), 6.78 (d, 2H), 4.50 (s, 1H), 2.25 (br.s, 2H),

1.23-2.24 (m, 12H), 1.17 (s, 3H).

Step3 : (S)-5-Methoxymethyl-2-[4-(9-methyl-bicyclo[3.3.1 ]non-9-yl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from 4-(9-methyl-bicyclo[3.3.1]non-9-yl)-phenol employing the procedure described in Example 1.

C₂₅H₃₂N₂0₄ (424.24), LCMS (ES⁺): 425.24 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.27 (d, 2H), 6.83 (d, 2H), 6.01 (s, 1H), 5.24 (m, 1H), 4.25 (s, 2H), 4.22-4.45 (m, 4H), 3.40 (s, 3H), 2.26 (br.s, 2H), 1.40-2.23 (m, 12H), 1.17 (s, 3H). Example 4

(S)-2-(4-Cyclohexyl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : 1 -Cyclohex- 1 -enyl-2-fluoro-4-methoxy-benzene l-(2-Fluoro-4-methoxy-phenyl)-cyclohexanol (prepared as in Example 2 from 1- bromo-2-fluoro-4-methoxy-benzene and cyclohexanone) (2.5 g, 1 1.2 mmol) was dissolved in EtOH (200 ml) and concentrated hydrochloric acid (20 ml) was added. The mixture was stirred at 50°C overnight. The solvent was removed under reduced pressure. Water and EtOAc were added and the mixture was basified with aqueous ammonia and extracted three times with EtOAc. The organic phase was dried and concentrated. Silica gel chromatography (EtO Ac/heptane) provided the title compound (1.9 g).

CisHisFO (206.1 1), LCMS (EI⁺): 206.12 (M⁺).

1H NMR (CDCls, 300MHz), δ 7.13 (t, 1H), 6.54-6.65 (m, 2H), 5.87 (br.s, 1H), 3.79 (s, 3H), 2.33 (br.s, 2H), 2.18 (m, 2H), 1.61-1.79 (m, 4H).

Step 2: l-Cyclohexyl-2-fluoro-4-methoxy-benzene

To a solution of l-cyclohex-l-enyl-2-fluoro-4-methoxy-benzene (2.0 g, 9.7 mmol) in

EtOAc (80 ml) and MeOH (20 ml) was added 10% Pd/C (0.4 g) under N₂. This mixture was stirred under H₂ (1 arm) overnight. The reaction mixture was filtered through celite. The filtrate was concentrated. Silica gel chromatography (EtO Ac/heptane) provided the title compound (1.9 g).

CisHivFO (208.13), LCMS (EI⁺): 208.12 (M⁺).

1H NMR (CDCI3, 300MHz), δ 7.1 1 (t, 1H), 6.54-6.67 (m, 2H), 3.77 (s, 3H), 2.76 (m, 1H),

1.69-1.88 (m, 5H), 1.17-1.48 (m, 5H).

Step 3 : 4-Cyclohexyl-3-fluoro-phenol

To l-cyclohexyl-2-fluoro-4-methoxy-benzene (1.9 g, 9.2 mmol) in CH₂C1₂ (25 ml) was added BBr₃ (1M in CH₂C1₂, 18.5 mmol) dropwise at 0°C. The mixture was stirred at 0°C for two hours. The reaction mixture was then quenched with MeOH (3 ml). Aqueous sodium hydrogen carbonate (10 ml) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with CH₂C1₂. The organic phase was washed with brine, dried (Na₂S0₄) and concentrated. Silica gel chromatography (EtOAc/heptane) provided 1.7 g of the title compound.

Ci₂Hi₅FO (194.1 1), LCMS (EI⁺): 194.1 1 (M⁺).

1H NMR (CDCI₃, 300MHz), δ 7.06 (t, 1H), 6.48-6.58 (m, 2H), 4.65 (s, 1H), 2.77 (m, 1H), 1.67-1.92 (m, 5H), 1.18-1.49 (m, 5H).

Step 4: (S)-2-(4-Cyclohexyl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one The title compound was prepared from 4-cyclohexyl-3-fluoro-phenol employing the procedure as described in Example 1.

C₂iH₂₅FN₂0₄ (388.18), LCMS (ES⁺): 389.16 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.13 (t, 1H), 6.53-6.65 (m, 2H), 5.97 (s, 1H), 5.24 (m, 1H), 4.27 (s, 2H), 4.19-4.49 (m, 4H), 3.40 (s, 3H), 2.78 (br.s, 1H), 1.71-1.89 (m, 5H), 1.18-1.48 (m, 5H).

Example 5

(S)-2-[4-(4,4-Difluoro-cyclohexyl)-phenoxymethyl]-5-methoxymethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : 4-(4,4-Difluoro-cyclohexyl)-phenol

To a solution of 4-(4-hydroxy-phenyl)-cyclohexanone (5 g, 26.3 mmol) was added bis(2-methoxyethyl)amino)sulfur trifluoride (29.1 g, 131 mmol) under nitrogen in a plastic bottle. The reaction mixture was stirred at room temperature for 48 hours. EtOH (20 drops) was added, and the reaction mixture allowed to stir for an additional 24 hours. The reaction mixture was poured into ice and the aqueous layer extracted twice with dichloromethane. The organic phase was washed with brine and dried (Na₂S0₄). Silica gel chromatography

(EtO Ac/heptane) afforded the title compound (1.2 g).

Ci₂Hi₄F₂0 (212.10), LCMS (EI⁺): 212.10 (M⁺).

1H NMR (CDCI3, 300MHz), δ 7.08 (d, 2H), 6.78 (d, 2H), 4.58 (s, 1H), 2.54 (m, 1H), 2.18 (m,

2H), 1.68-1.99 (m, 6H).

Step 2: (S)-2-[4-(4,4-Difluoro-cyclohexyl)-phenoxymethyl]-5-methoxymethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from 4-(4,4-difluoro-cyclohexyl)-phenol employing the procedure described in Example 1.

C₂iH₂₄F₂N₂0₄ (406.17), LCMS (ES⁺): 407.14 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.14 (d, 2H), 6.82 (d, 2H), 5.99 (s, 1H), 5.24 (m, 1H), 4.26 (s 4.19-4.49 (m, 4H), 3.40(s, 3H), 2.57 (m, 1H), 2.19 (m, 2H), 1.67-1.98 (m, 6H). Example 6

(S)-2-[4-(4-Fluoro-cyclohex-3-enyl)-phenoxymethyl]-5-methoxymethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

The title compound was prepared from 4-(4-fluoro-cyclohex-3-enyl)-phenol employing the procedure described in Example 1.

C₂iH₂₃FN₂0₄ (386.16), LCMS (ES⁺): 387.14 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.15 (d, 2H), 6.82 (d, 2H), 5.98 (s, 1H), 5.19-5.32 (m, 2H), 4.20-4.50 (m, 4H), 4.25 (s, 2H), 3.40 (s, 3H), 2.76 (m, 1H), 1.79-2.46 (m, 6H).

Example 7

(S)-5-Cyclopropyl-2-[4-(4,4-difluoro-cyclohexyl)-phenoxymethyl]-2,3-dihydro

a rimidin-7-one

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

Toluene-4-sulfonic acid (S)-5-cyclopropyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester was prepared using the procedure of Example 1 with toluene-4- sulfonic acid (S)-2-amino-4,5-dihydro-oxazol-5-ylmethyl ester and cyclopropyl-propynoic acid ethyl ester as starting materials.

Ci₇Hi₈N₂0₅S (362.09), LCMS (ES⁺): 363.09 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.76 (d, 2H), 7.38 (d, 2H), 5.64 (s, 1H), 5.18 (m, 1H), 4.46 (t,

1H), 4.22-4.39 (m, 3H), 2.46(s, 3H), 1.59 (m, 1H), 1.07 (d, 2H), 0.82 (d, 2H).

Step 2: (S)-5-Cyclopropyl-2-[4-(4,4-difluoro-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one The title compound was prepared from toluene-4-sulfonic acid (S)-5-cyclopropyl-7- oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester and 4-(4,4-difluoro- cyclohexyl)-phenol employing the procedures described in Example 1.

C₂₂H₂₄F₂N₂0₃ (402.17), LCMS (ES⁺): 403.17 (M⁺+H).

1H NMR (CDCls, 300MHz), δ 7.15 (d, 2H), 6.83 (d, 2H), 5.68 (s, 1H), 5.26 (m, 1H), 4.21-4.52 (m, 4H), 2.57 (m, 1H), 2.20 (m, 2H), 1.53-1.95 (m, 7H), 1.08 (dd, 2H), 0.85 (m, 2H).

Example 8

(S)-5-Fluoromethyl-2-[4-(9-methyl-bicyclo[3.3.1 ]non-9-yl)-phenoxymethyl]-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

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

The title compound was prepared according to the procedure in Example 1 with toluene-4-sulfonic acid (S)-2-amino-4,5-dihydro-oxazol-5-ylmethyl ester and 4-fluoro-but-2- ynoic acid ethyl ester as starting materials.

Ci₅Hi₅FN₂0₅S (354.36), LCMS (ES⁺): 355.06 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.76 (d, 2H), 7.39 (d, 2H), 6.00 (d, 1H), 5.19 (dd, 2H), 5.16 (m, 1H), 4.43 (t, 1H), 4.23-4.37 (m, 3H), 2.47 (s, 3H).

Step 2: (S)-5-Fluoromethyl-2-[4-(9-methyl-bicyclo[3.3.1]non-9-yl)-phenoxymethyl]-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 and 4-(9-methyl- bicyclo[3.3.1]non-9-yl)-phenol employing the procedures described in Example 1.

C₂₄H₂₉FN₂0₃ (412.21), LCMS (ES⁺): 413.22 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.28 (d, 2H), 6.84 (d, 2H), 6.05 (d, 1H), 5.29 (m, 1H), 5.21 (d, 2H), 4.24-4.51 (m, 4H), 2.27 (br. s, 2H), 1.40-2.25 (m, 12H), 1.17(s, 3H).

Example 9 (S)-2-[4-(9-Methyl-bicyclo[3.3.1]non-9-yl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a rimidin-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 (prepared in accordance with the procedures described in WO 2008/1 12483) and 4-(9-methyl-bicyclo[3.3.1]non-9-yl)-phenol employing the procedures described in Example 1.

C₂₃H₂₈N₂0₃ (380.21), LCMS (ES⁺): 381.22 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.23-7.31 (m, 3H), 6.83 (d, 2H), 6.09 (d, 1H), 5.28 (m, 1H), 4.22-4.43 (m, 4H), 2.26 (br. s, 2H), 1.40-2.24 (m, 12H), 1.17(s, 3H).

Example 10

(S)-5-Fluoromethyl-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro

a rimidin-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 and 4-(l -methyl-cyclohexyl)- phenol employing the procedures described in Example 1. [α]ο²⁵ = -34.7⁰ (c = 0.86 , CHC1₃) C₂iH₂₅FN₂0₃ (372.18), LCMS (ES⁺): 373.17 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.30 (d, 2H), 6.84 (d, 2H), 6.07 (d, 1H), 5.28 (m, 1H), 5.20 (d, 2H), 4.23-4.50 (m, 4H), 1.95 (m, 2H), 1.35-1.61 (m, 8H), 1.15(s, 3H).

Example 1 1

(S)-2-(4-Cyclohexyl-phenoxymethyl)-5-(tetrahydro-pyran-2-yloxymethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (1.6 g, 5.83 mmol) (prepared in accordance with the procedures described in WO 2008/112483) in ethanol (25 ml) was added 4-(tetrahydro-pyran-2-yloxy)-but-2-ynoic acid ethyl ester (1.48 g, 6.99 mmol). The reaction mixture heated at reflux for 3 hours. It was then concentrated and loaded on silica gel column. Chromatography with EtOH/methylene chloride gave 1.94 g of title compound. [a]_D ²⁵ = -12.9 ° (c = 0.64, CHC1₃).

C₂₅H₃₂N₂0₅ (440.23), LCMS (ES⁺): 441.34 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.13 (d, 2H), 6.80 (dd, 2H), 6.03 (s, 1H), 5.24 (m, 1H), 4.67 (br.s, 1H), 4.20-4.50 (m, 6H), 3.80 (m, 1H), 3.55 (m, 1H), 2.45 (m, 1H),1.18-1.88 (m, 16H).

Example 12

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

Step 1 : (S)-2-[4-(l-Methyl-cyclohexyl)-phenoxymethyl]-oxirane

To a mixture of (R)-epichlorohydrin (5.35 g, 57.81 mmol) and 4-(l-methyl- cyclohexyl)-phenol (5.5 g, 28.90 mmol) in acetone (130 ml) was added potassium carbonate (4.0 g, 28.90 mmol). The mixture was stirred at 45°C for 7 days. The reaction mixture was then concentrated to remove acetone. The residue was partitioned between dichloromethane and water and extracted twice with dichloromethane. The organic phases were combined and washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography (silica, methylene chloride/heptane) to give 4.5 g of the title compound.

Ci₆H₂₂0₂ (246.16), LCMS (ES⁺): 288.12 (M⁺+H+CH₃CN).

1H NMR (CDCI3, 300MHz), δ 7.28 (d, 2H), 6.88 (d, 2H), 4.19 (dd, 1H), 3.98 dd, 1H), 3.35 (m, 1H), 2.90 (t, 1H), 2.76 (m, 1H), 1.96(m, 2H), 1.36-1.61 (m, 8H), 1.16 (s, 3H).

Step2: (S)-5-[4-(l-Methyl-cyclohexyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine

To a vigorously stirred solution of sodium hydrogen cyanamide (1.2 g, 18.27 mmol) in methanol (30 ml) was added slowly (S)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2- yloxymethyl)-oxirane (4.5 g, 18.27 mmol) in MeOH (20 ml). The reaction mixture was stirred at room temperature overnight after which it was concentrated. Anhydrous diethyl ether (200 ml) was added. The resulting white precipitate was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (silica, 7N NH₃ in methanol/methylene chloride) to give 2.81 g of the title compound.

Ci₇H₂₄N₂0₂ (288.18), LCMS (ES⁺): 289.16 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.28 (d, 2H), 6.88 (d, 2H), 4.92 (m, IH), 3.86-4.14 (m, 3H), 3.61 (dd, IH), 1.96 (m, 2H), 1.31-1.62 (m, 8H), 1.15 (s, 3H).

Step3 : (S)-2-[4-(l-Methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one

To a solution of (S)-5-[4-(l-Methyl-cyclohexyl)-phenoxymethyl]-4,5-dihydro-oxazol- 2-ylamine (0.5 g, 1.77 mmol) in ethanol (12 ml) was added ethyl propiolate (0.19 g, 1.95 mmol). The reaction mixture was heated at reflux for 5 hours. It was then concentrated and loaded on silica gel column. Chromatography with 7N NH₃ in methanol/methylene chloride gave 0.37 g of the title compound. [a]_D ²⁵ = -52.5 ⁰ (c = 0.83 , CHC1₃).

C₂₀H₂₄N₂O₃ (340.18), LCMS (ES⁺): 341.16 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.29 (d, 2H), 7.24 (d, IH), 6.83 (d, 2H), 6.09 (d, IH), 5.27 (m, IH), 4.22-4.41 (m, 4H), 1.96 (m, 2H), 1.33-1.62 (m, 8H), 1.15 (s, 3H).

Example 13

(S)-5-Cyclopropyl-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(l-methyl-cyclohexyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and cyclopropyl-propynoic acid ethyl ester employing the procedure described in Example 12.

C₂₃H₂₈N₂0₃ (380.21), LCMS (ES⁺): 381.17 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.30 (d, 2H), 6.84 (d, 2H), 5.68 (s, IH),

5.26 (m, IH), 4.25-4.51 (m, 4H), 1.95 (m, 2H), 1.34-1.65 (m, 9H), 1.15 (s, 3H), 1.08 (dd, 2H), 0.84 (m, 2H).

Example 14 (S)-5-Ethyl-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(l-methyl-cyclohexyl)- ixymethyl]-4,5-dihydro-oxazol-2-ylamine and ethyl 2-pentynoate employing the procedures described in Example 12. [a]_D = -29.4⁰ (c = 0.71, CHC1₃).

C₂₂H₂₈N₂0₃ (368.21), LCMS (ES⁺): 369.18 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.29 (d, 2H), 6.83 (d, 2H), 5.88 (s, 1H),

5.24 (m, 1H), 4.22-4.38 (m, 4H), 2.49 (q, 2H), 1.95 (m, 2H), 1.33-1.65 (m, 8H), 1.27 (t, 3H), 1.15 (s, 3H).

Example 15

(S)-2-(4-tert-Butyl-phenoxymeth l)-6-propyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : (S)-5-(4-tert-Butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine

(S)-5-(4-tert-Butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine was prepared in accordance with the procedures described in Example 12.

Ci₄H₂₀N₂O₂ (248.15), LCMS (ES⁺): 249.14 (M⁺+H).

1H NMR (CDCI₃, 300MHz), δ 7.31 (d, 2H), 6.86 (d, 2H), 4.91 (m, 1H), 3.88-4.12 (m, 3H),

3.61 (dd, 1H), 1.30(s, 9H).

Step 2: 2-Formyl-pentanoic acid ethyl ester

The title compound was prepared from pentanoic acid ethyl ester and ethyl formate employing the procedures described in Comparative Example 1.

C₈Hi₄0₃ (158.09), LCMS (ESI): 159.10(M⁺+H).

Step 3 : (S)-2-(4-tert-Butyl-phenoxymethyl)-6-propyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 2-formyl-pentanoic acid ethyl ester employing the procedures described in Comparative Example 1. [α]ο²⁵ = -26.8 ⁰ (c = 0.44, CHCI3)

C₂oH₂₆N₂0₃ (342.19), LCMS (ES⁺): 343.18 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.31 (d, 2H), 7.05 (s, 1H), 6.81 (d, 2H), 5.23 (m, 1H), 4.22-4.38 (m, 4H), 2.38 (t, 2H), 1.58 (m, 2H), 1.30(s, 9H), 0.96 (t, 3H).

Example 16

(S)-2-(4-tert-Butyl-phenoxymeth l)-6-isopropyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Stepl : 2-Formyl-3 -methyl-butyric acid ethyl ester

The title compound was prepared from 3 -methyl-butyric acid ethyl ester and ethyl formate employing the procedures described in Comparative Example 1.

C₈Hi₄0₃ (158.09), LCMS (ESI): 159.10(M⁺+H).

Step 2: (S)-2-(4-tert-Butyl-phenoxymethyl)-6-isopropyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 2-formyl-3 -methyl-butyric acid ethyl ester employing the procedures described in Comparative Example 1. [a]_D ²⁵ = -18.6 ⁰ (c = 0.59 , CHC1₃)

C₂₀H₂₆N₂O₃ (342.19), LCMS (ES⁺): 343.19 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.31 (d, 2H), 7.01 (s, 1H), 6.82 (d, 2H), 5.22 (m, 1H), 4.23-4.39 (m, 4H), 3.06 (qn, 1H), 1.30(s, 9H), 1.17 (dd, 6H).

Example 17

(S)-2-(4-tert-Butyl-phenoxymeth l)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Stepl : 2-Methyl-3-oxo-propionic acid ethyl ester

The title compound was prepared from propionic acid ethyl ester and ethyl formate employing the procedures described in Comparative Example 1. C₆Hio0₃ (130.06), LCMS (ESI): 131.08(M⁺+H).

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

The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 2-methyl-3-oxo-propionic acid ethyl ester employing the procedures described in Comparative Example 1.

Ci₈H₂₂N₂0₃ (314.16), LCMS (ES⁺): 315.18 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.31 (d, 2H), 7.12 (s, 1H), 6.81 (d, 2H), 5.24 (m, 1H), 4.19-4.37 (m, 4H), 2.01 (s, 3H), 1.29 (s, 9H).

Example 18

(S)-2-(4-tert-Butyl-phenox methyl)-6-phenyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 3 -Oxo-2-phenyl-propionic acid ethyl ester

The title compound was prepared from phenyl-acetic acid ethyl ester and ethyl formate employing the procedures described in Comparative Example 1.

C11H12O3 (192.08), LCMS (ESI): 193.11(M⁺+H).

Step 2: (S)-2-(4-tert-Butyl-phenoxymethyl)-6-phenyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 3-oxo-2-phenyl-propionic acid ethyl ester employing the procedures described in Comparative Example 1. [α]ο²⁵ = +35.6⁰ (c = 0.63, CHC1₃)

C₂₃H₂₄N₂0₃ (376.18), LCMS (ES⁺): 377.20 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.59 (d, 2H), 7.28-7.43 (m, 6H), 6.83 (d, 2H), 5.29 (m, 1H), 4.25-4.46 (m, 4H), 1.29 (s, 9H).

Example 19

(S)-2-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-6-phenyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Ste l : (S)-5-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine

(S)-5-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine was prepared from 4-(l,l-dimethyl-propyl)-phenol and R-epichlorohydrin employing the procedure described in Example 12.

Ci₅H₂₂N₂0₂ (262.17), LCMS (ES⁺): 263.17 (M⁺+H).

1H NMR (CDCls, 300MHz), δ 7.24 (d, 2H), 6.86 (d, 2H), 4.91 (m, 1H), 3.87-4.11 (m, 3H), 3.60 (dd, 1H), 1.61 (q, 2H), 1.26 (s, 6H), 0.67 (t, 3H).

Step2: (S)-2-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-6-phenyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared from (S)-5-[4-(l,l-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and 2-formyl-pentanoic acid ethyl ester employing the procedures described in Comparative Example 1. [α]ο²⁵ = +29.8 ⁰ (c = 0.41 ,

C₂₄H₂₆N₂0₃ (390.19), LCMS (ES⁺): 391.26 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.57 (d, 2H), 7.31-7.43 (m, 5H), 7.23 (s, 1H), 6.82 (d, 2H), 5.28 (m, 1H), 4.22-4.48 (m, 4H), 1.53-1.66 (m, 2H), 1.26 (s, 6H), 0.66 (t, 3H).

Example 20

(S)-2-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-6-propyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(l,l-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and 2-formyl-pentanoic acid ethyl ester employing the procedures described in Comparative Example 1. [a]_D ²⁵ = -26.6 ⁰ (c = 0.64,

CHC1₃)

C₂iH₂₈N₂0₃ (356.21), LCMS (ES⁺): 357.27 (M⁺+H). 1H NMR (CDCI3, 300MHz), δ 7.24 (d, 2H), 7.06 (s, 1H), 6.81 (d, 2H), 5.24 (m, 1H), 4.37 (t, 1H), 4.21-4.32 (m, 3H), 2.37 (t, 2H), 1.51-1.67 (m, 4H), 1.25 (s, 6H), 0.96 (t, 3H), 0.66 (t, 3H).

Example 21

(S)-2-[4-(l ,l-Dimethyl-propyl)-phenoxymethyl]-6-isopropyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(l , l-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and 2-formyl-3 -methyl-butyric acid ethyl ester employing the procedures described in Comparative Example 1. [a]_D ²⁵ = -19.6 ⁰ (c = 0.72, CHCI₃)

C₂iH₂₈N₂0₃ (356.21), LCMS (ES⁺): 357.28 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.25 (d, 2H), 7.01 (s, 1H), 6.82 (d, 2H), 5.24 (m, 1H), 4.25-4.40 (m, 4H), 3.05 (qn, 1H), 1.55-1.66 (m, 2H), 1.25 (s, 6H), 1.17 (dd, 6H), 0.66 (t, 3H).

Example 22

(S)-2-[4-(l , l-Dimethyl-propyl)-phenoxymethyl]-6-ethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(l , l-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and 2-formyl-butyric acid ethyl ester employing the procedures described in Comparative Example 1. [α]ο²⁵ = -25.6 ⁰ (c = 0.34,

CHC1₃)

C₂₀H₂₆N₂O₃ (342.19), LCMS (ES⁺): 343.26 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.24 (d, 2H), 7.04 (s, 1H), 6.82 (d, 2H), 5.23 (m, 1H), 4.24-4.40 (m, 4H), 2.45 (q, 2H), 1.54-1.66 (m, 2H), 1.26 (s, 6H), 1.15 (t, 3H), 0.66 (t, 3H). Example 23

(S)-2-[4-(2,2,2-Trifluoro- 1 -hydroxy- 1 -triflu^

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 4-(2,2,2-trifluoro- 1 -hydroxy- 1 -trifluoromethyl- ethyl)-phenol employing the procedures described in Example 1. [α]ο²⁵ = + 4.7 ⁰ (c = 0.57, DMSO).

Ci₆Hi₂F₆N₂0₄ (410.07), LCMS (ES⁺): 411.04 (M⁺+H).

1H NMR (DMSO-de, 300MHz), δ 7.76 (d, IH), 7.62 (d, 2H), 7.06 (d, 2H), 5.82 (d, IH), 5.36 (m, IH), 4.30-4.45 (m, 3H), 4.12 (m, IH).

Example 24

(S)-2-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-6-methyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(l,l-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and 2-methyl-3-oxo-propionic acid ethyl ester employing the procedures described in Comparative Example 1. [a]_D ²⁵ = -44.4 ⁰ (c = 0.56,

CHC1₃).

Ci₉H₂₄N₂0₃ (328.18), LCMS (ES⁺): 329.15 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.24 (d, 2H), 7.12 (s, IH), 6.81 (d, 2H), 5.24 (m, IH), 4.20-4.39 (m, 4H), 2.00 (s, 3H), 1.59 (q, 2H), 1.25 (s, 6H), 0.66 (t, 3H).

Example 25

(S)-6-Ethyl-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared from(S)-5-[4-(l-methyl-cyclohexyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and 2-formyl-butyric acid ethyl ester employing the procedures described in Comparative Example 1.

C₂₂H₂₈N₂0₃ (368.21), LCMS (ES⁺): 369.18 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.30 (d, 2H), 7.04 (s, 1H), 6.84 (d, 2H), 5.24 (m, 1H), 4.23-4.38 (m, 4H), 2.46 (q, 2H), 1.95 (m, 2H), 1.32-1.62 (m, 8H), 1.16 (s, 3H), 1.15 (t, 3H).

Example 26

(S)-2-(4-tert-Butyl-phenoxymethyl)-6-(2,2,2-trifiuoro-ethyl)-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

Step 1 : 4,4,4-Trifluoro-2-formyl-butyric acid ethyl ester

The title compound was prepared from 4,4,4-trifluoro-butyric acid ethyl ester and ethyl formate employing the procedures described in Comparative Example 1.

C₇H₉F0₃ (198.05), LCMS (ESI): 199.06(M⁺+H).

Step 2: (S)-2-(4-tert-Butyl-phenoxymethyl)-6-(2,2,2-trifluoro-ethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 4,4,4-trifluoro-2-formyl-butyric acid ethyl ester employing the procedures described in Comparative Example 1.

Ci₉H₂iF₃N₂0₃ (382.15), LCMS (ES⁺): 383.15 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.36 (s, 1H), 7.32 (d, 2H), 6.81 (d, 2H), 5.28 (m, 1H), 4.23-4.44 (m, 4H), 3.35 (m, 2H), 1.29 (s, 9H).

Example 27

(S)-2-(4-tert-Butyl-phenoxymethyl)-6-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 2-Formyl-4-(tetrahydro-pyran-2-yloxy)-butyric acid methyl ester

The title compound was prepared from 4-(tetrahydro-pyran-2-yloxy)-butyric acid methyl ester and ethyl formate employing the procedures described in Comparative Example 1.

Step2: (S)-2-(4-tert-Butyl-phenoxymethyl)-6-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 2-formyl-4-(tetrahydro-pyran-2-yloxy)-butyric acid methyl ester employing the procedures described in Comparative Example 1. [α]ο²⁵ = -13.6 ⁰ (c = 0.73, CHCls).

C₂₄H₃₂N₂0₅ (428.23), LCMS (ES⁺): 429.23 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.31 (d, 2H), 7.29 (s, 1H), 6.82 (d, 2H), 5.24 (m, 1H), 4.54 (br.s, 1H), 4.22-4.39 (m, 4H), 3.95 (m, 2H), 3.68 (m, 1H), 3.50 (m, 1H), 2.70 (m, 2H), 1.46-1.79 (m, 4H), 1.29 (s, 9H), 1.21 (d, 2H).

Example 28

(S)-2-(4-tert-Butyl-phenoxymethyl)-6-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-2-(4-tert-butyl-phenoxymethyl)-6-[2- (tetrahydro-pyran-2-yloxy)-ethyl] -2,3 -dihydro-oxazolo [3 ,2-a]pyrimidin-7-one employing p- toluenesulfonic acid in methanol.

Ci₉H₂₄N₂0₄ (344.17), LCMS (ES⁺): 345.17 (M⁺+H).

1H NMR (CDCI3, 300MHz), δ 7.32 (d, 2H), 7.23 (s, 1H), 6.82(d, 2H), 5.27 (m, 1H), 4.21-4.42 (m, 4H), 3.83 (q, 2H), 3.24 (t, 1H), 2.66 (q, 2H), 1.30 (s, 9H). Example 29

(S)-2-(4-tert-Butyl-2-fluoro- henoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 4-tert-Butyl-3-fluoro-phenol

4-tert-Butyl-3-fluoro-phenol was prepared from 2-fluorophenol and t-butyl chloride following the procedures of J. Org. Chem. 1981, 46, 3784-3789.

C₁₀H₁₃FO (168.09), LCMS (EI⁺): 168.01 (M⁺).

1H NMR (CDC1₃, 300MHz), δ 7.00-7.12 (m, 2H), 6.91 (t, IH), 4.93 (br.s, IH), 1.28 (s, 9H). Step 2: (S)-2-(4-tert-Butyl-2-fluoro-phenoxymethyl)-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 4-tert-butyl-3-fluoro-phenol employing the procedure described in Example 1. [α]ο²⁵ = -33.1 ⁰ (c = 0.70, CHC1₃)

Ci₇Hi₉FN₂0₃ (318.13), LCMS (ES⁺): 319.16 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.26 (d, IH), 7.04-7.13 (m, 2H), 6.92(t, IH), 6.06 (d, IH), 5.27 (m, IH), 4.27-4.44 (m, 4H), 1.28 (s, 9H).

Example 30

(S)-2-(4-tert-Butyl-2-fluoro-phenoxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Step 1 : (S)-5-(4-tert-Butyl-2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine

(S)-5-(4-tert-butyl-2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine was prepared from 4-tert-butyl-3-fluoro-phenol and R-epichlorohydrin employing the procedures described in Example 12.

Ci₄Hi₉FN₂0₂ (266.14), LCMS (ES⁺): 267.12 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.00-7.15 (m, 2H), 6.91 (t, IH), 4.91 (m, IH), 3.88-4.20 (m, 3H), 3.60 (q, IH), 1.28 (s, 9H). Step 2: (S)-2-(4-tert-Butyl-2-fluoro-phenoxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared from (S)-5-(4-tert-butyl-2-fluoro-phenoxymethyl)- 4,5-dihydro-oxazol-2-ylamine and 2-formyl-butyric acid ethyl ester employing the procedures described in Comparative Example 1. [α]ο²⁵ = -6.0⁰ (c = 0.82, CHCI3).

Ci₉H₂₃FN₂0₃ (346.17), LCMS (ES⁺): 347.16 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.04-7.13 (m, 2H), 7.05 (s, 1H), 6.92 (t, 1H), 5.22 (m, 1H), 4.31-4.39 (m, 4H), 2.44 (q, 2H), 1.28 (s, 9H), 1.15 (t, 3H).

Example 31

(S)-2-(4-tert-Butyl-2-fluoro-phenoxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one

The title compound was prepared from (S)-5-(4-tert-butyl-2-fluoro-phenoxymethyl)- 4,5-dihydro-oxazol-2-ylamine and 2-methyl-3-oxo-propionic acid ethyl ester employing the procedures described in Comparative Example 1.

Ci₈H₂iFN₂0₃ (332.15), LCMS (ES⁺): 333.14 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.03-7.16 (m, 3H), 6.92(t, 1H), 5.22 (m, 1H), 4.31-4.38 (m, 4H), 1.99 (s, 3H), 1.28 (s, 9H).

Example 32

(S)-2-(4-tert-Butyl-2-fluoro-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

The title compound was prepared from (S)-5-(4-tert-butyl-2-fluoro-phenoxymethyl)- 4,5-dihydro-oxazol-2-ylamine and ethyl 2-pentynoate employing the procedures described in Example 1. [a]_D ²⁵ = -15.0⁰ (c = 0.76, CHC1₃).

Ci₉H₂₃FN₂0₃ (346.17), LCMS (ESI): 347.16 (M⁺+H). 1H NMR (CDCI₃, 300MHz), δ 7.03-7.16 (m, 2H), 6.93 (t, 1H), 5.87 (s, 1H), 5.22 (m, 1H), 4.28-4.42 (m, 4H), 2.51 (q, 2H), 1.28 (s, 9H), 1.28 (t, 3H).

Example 33

(S)-2-[4-(4-Methoxy-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Step 1 : 4-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-cyclohexanol

To a suspension of 4-(4-hydroxy-cyclohexyl)-phenol (5.0 g, 26.0 mmol) in CH₂CI₂ (200 ml) and triethyl amine (3.95 g, 39 mmol) was added tert-butyl-chloro-dimethyl-silane (4.12 g, 26.8 mmol) at rt. The reaction mixture was stirred at room temperature overnight. 4- (N,N-Dimethyl)-aminopyridine (0.63 g, 8.5 mmol) was added. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was quenched with brine and extracted with CH₂C1₂ twice. The organic phase was washed with water, brine, dried (Na₂S0₄) and concentrated. 1.58 g of 4-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]- cyclohexanol was isolated by silica gel chromatography (EtO Ac/heptane).

1H NMR (CDCI₃, 300MHz), δ 7.04 (d, 2H), 6.75 (d, 2H), 3.67 (m, 1H), 2.43 (m, 1H), 2.08 (m, 2H), 1.91 (m, 2H), 1.34-1.53 (m, 5H), 0.97 (s, 9H), 0.19 (s, 6H).

Step 2: tert-Butyl-[4-(4-methoxy-cyclohexyl)-phenoxy]-dimethyl-silane

To sodium hydride (0.25 g, 6.19 mmol) in THF (10 ml) was added 4-[4-(tert-butyl- dimethyl-silanyloxy)-phenyl]-cyclohexanol (1.58 g, 5.16 mmol) in THF (10 ml) slowly. The reaction mixture was stirred at rt for 0.5 hour. Iodomethane (2.93 g, 20.64 mmol) was then added. The reaction mixture was stirred at rt for 3 hours. The reaction mixture was poured into ice and extracted with EtO Ac three times. The combined organic extracts were washed with water, brine, dried (Na₂S0₄) and concentrated. The residue was purified by silica gel chromatography (EtO Ac/heptane) to provide 1.23 g of the title compound.

1H NMR (CDCI₃, 300MHz), δ 7.04 (d, 2H), 6.75 (d, 2H), 3.39 (s, 3H), 3.19 (m, 1H), 2.45 (m, 1H), 2.17 (m, 2H), 1.92 (m, 2H), 1.24-1.55 (m, 4H), 0.97 (s, 9H), 0.18 (s, 6H).

Step 3: 4-(4-Methoxy-cyclohexyl)-phenol

To a solution of tert-butyl-[4-(4-methoxy-cyclohexyl)-phenoxy]-dimethyl-silane (1.23 g, 3.84 mmol) in THF (10 ml) was added tetrabutylammonium fluoride in THF (1M solution, 4.6 ml, 4.6 mmol). The reaction mixture was stirred at rt for one hour. The reaction mixture was poured into ice and extracted with EtOAc three times. The combined organic extracts were washed with water, brine, dried (Na₂S04) and concentrated. Silica gel chromatography afforded 0.72 g of the title compound.

Ci₃Hi₈0₂ (206.13), LCMS (ES⁺): 245.20 (M⁺+H+CH₃CN).

1H NMR (CDC1₃, 300MHz), δ 7.07 (d, 2H), 6.75 (d, 2H), 4.69 (s, 1H), 3.39 (s, 3H), 3.21 (m,

1H), 2.46 (m, 1H), 2.19 (m, 2H), 1.92 (m, 2H), 1.27-1.55 (m, 4H).

Step 4: (S)-2-[4-(4-Methoxy-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared from 4-(4-methoxy-cyclohexyl)-phenol and (S)-2- toluene-4-sulfonic acid methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one employing the procedure described in Example 9.

C₂oH₂₄FN₂04 (356.17), LCMS (ES⁺): 357.16 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.24 (d, 1H), 7.13 (d, 2H), 6.80 (d, 2H), 6.09(d, 1H), 5.27 (m, 1H), 4.20-4.40 (m, 4H), 3.39 (s, 3H), 3.20 (m, 1H), 2.47 (m, 1H), 2.18 (m, 2H), 1.92 (m, 2H), 1.24-1.53 (m, 4H).

Example 34

(S)-2-(4-Cyclohexyl-phenoxymethyl)-5-cyclopropylmethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

(5)-5-(4-Cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), (see Example 1 1 ; prepared starting from R-epichlorohydrin and 4-cyclohexylphenol), was dissolved in ethanol (5 ml). 4-Cyclopropyl-but-2-ynoic acid methyl ester (0.333 g, 2.19mmol) (J Org Chem 1990, Vol. 55, No. 8, pp 2374-237) was added. The mixture was heated in a microwave oven at 170°C for 30 minutes. The resulting crystalline solid was isolated by filtration, washed with hexane 3 times, and dried under vacuum to afford 0.23 g of the title compound as a white solid.

C₂₃H₂₈N₂0₃ (380.21), LCMS (ESI): 381.20 (M⁺+H) 1H NMR (300 MHz, CDC1₃): δ 7.13 (d, 2H), 6.83 (d, 2H), 6.10 (s, 1H), 5.22 (m, 1H), 4.36- 4.19 (m, 4H), 2.36 (br, s, 1H), 2.38 (d, 2H), 1.88-1.69 (m, 5H), 1.46-1.20 (m, 5H), 0.95 (m, 1H), 0.68 (q, 2H), 0.24 (q, 2H).

Example 35

(S)-2-(4-Cyclohexyl-phenoxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

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

The title compound was prepared in accordance with the literature procedures (see Tetrahedron Letters, Volume 48, Issue 3, 2007, 377-380).

CyHiiNO, (125.08), LCMS (ESI): 126.09 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 3.75 (t, 4H), 3.29 (d, 2H), 2.57 (t, 4H), 2.27 (t, 1H)

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

The title compound was prepared from 4-prop-2-ynyl-morpholine and ethyl chloroformate following the literature procedure (see Tetrahedron, 2006, 5697-5708)

CioHi₅N0₃, (197.11), LCMS (ESI): 198.10 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 4.24 (q, 2H), 3.75 (t, 4H), 3.45 (s, 2H), 2.62 (t, 4H), 1.33 (t,

3H)

Step 3 : (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from (5)-5-(4-cyclohexyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 4-morpholin-4-yl-but-2-ynoic acid ethyl ester in accordance with procedure in Example 34.

C₂₄H₃iN₃0₄, (425.23), LCMS (ESI): 426.19 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.14 (d, 2H), 6.79 (d, 2H), 5.93 (s, 1H), 5.22 (m, 1H), 4.52 (m, 2H), 4.27 (m, 2H), 3.66 (m, 4H), 3.33 (s, 2H), 2.49 (br.s, 4H), 2.46 (br.s., 1H), 1.89-1.68 (m, 5H), 1.48-1.14 (m, 5H).

Example 36 (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

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

The title compound was prepared from pyrrolidine and 3-bromo-propyne following the literature procedure (see Tetrahedron Letters, Volume 48, Issue 3, 2007, Pages 377-380). CyHnN, (109.09), LCMS (ESI): 1 10.09 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 3.42 (d, 2H), 2.63 (m, 4H), 2.21 (t, 1H), 1.81 (m, 4H)

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

The title compound was prepared from l-prop-2-ynyl-pyrrolidine and ethyl chloroformate following the literature procedure (see Tetrahedron, 2006, 5697-5708).

CioHi₅N0₂, (181.1 1), LCMS (ESI): 182.10 (M⁺+H)

1H NMR (300 MHz, CDC13): δ 4.23 (q, 2H), 3.59 (s, 2H), 2.65 (m, 4H), 1.83 (m, 4H), 1.31 (t, 3H)

Step 3 : (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-pyrrolidin- 1 -ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

To a solution of (5)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.757 g, 2.76 mmol), (see Example 1 1) in ethanol (30 ml) was added 4-pyrrolidin-l-yl-but- 2-ynoic acid ethyl ester (0.550 g, 3.04 mmol). The reaction mixture was heated at reflux for 3 hours, after which it was allowed to cool to room temperature. The solvent was removed under vacuum and the residue purified by flash column chromatography (silica gel, 7N NH₃ in MeOH/CH₂Cl₂) to afford 0.227 g of the title compound as a white solid. [a]_D ²⁵ = -1.0 ⁰ (c = 0.71 , CHC1₃)

C₂₄H₃iN₃0₃, (409.24), LCMS (ESI): 410.24 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.13 (d, 2H), 6.81 (d, 2H), 5.59 (s, 1H), 5.21 (m, 1H), 4.49 (AB-m, 2H), 4.25 (AB-m, 2H), 3.42 (s, 2H), 2.60-2.48 (m, 4H), 2.45 (m, 1H), 1.90-1.69 (m, 9H), 1.45-1.18 (m, 5H).

Example 37 (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-piperidin-l -ylmethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

Step 1 : 1 -Prop-2-ynyl-piperidine

The title compound was made from piperidine and 3-bromo-propyne following the literature procedure (see Tetrahedron Letters, Volume 48, Issue 3, 2007, Pages 377-380). C₈Hi₃N, (123.1 1), LCMS (ESI): 124.10 (M⁺+H)

Step 2: 4-piperdine-l-yl-but-2-ynoic acid ethyl ester

To a solution of l-prop-2-ynyl-piperidine (10 g, 81.2 mmol) in diethyl ether (300 ml) was added methyllithium, as complex with lithium bromide, 1.5M solution in diethyl ether (48.7 ml, 73. Immol) at -78°C. The reaction mixture was stirred for one hour after which ethyl chloroformate (8.82 g, 81.2mmol) was added. The reaction mixture was allowed to warm to room temperature over 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride. The organic phase was washed with water and brine, and dried over Na₂S0₄. Silica gel chromatography (1% MeOH/CH₂Cl₂) afforded 7.30 g of the title compound as yellow oil.

CiiHi₇N0₂, (195.13), LCMS (ESI): 196.17 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 4.23 (q, 2H), 3.44 (s, 2H), 2.52 (m, 4H), 1.62 (m, 4H), 1.45 (m, 2H), 1.27 (t, 3H).

Step 3 : (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-piperidin- 1 -ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

To a solution of (5)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (2.53 g, 9.22 mmol), (see Example 1 1), in ethanol (20 ml) was added 4-piperdine-l-yl-but-2- ynoic acid ethyl ester (1.80 g, 9.22 mmol). The reaction mixture was heated at reflux for 2.5 hours after which it was allowed to cool to room temperature. The solvent was removed under vacuum and the residue purified by flash column chromatography (silica gel, 0-2% 7N NH₃ in MeOH/CH₂Cl₂) to afford 1.44 g of the title compound as a white solid. [a]_D ²⁵ = +2.4⁰ (c = 0.67, CHC1₃)

C₂₅H₃₃N₃0₃, (423.25), LCMS (ESI): 424.24 (M⁺+H) 1H NMR (300 MHz, CDC1₃): δ 7.12 (d, 2H), 6.81 (d, 2H), 5.91 (s, 1H), 5.22 (m, 1H), 4.52 (m, 2H), 4.25 (AB-m, 2H), 3.25 (s, 2H), 2.52-2.34 (m, 4H), 1.93-1.69 (m, 6H), 1.58-1.16 (m, 1 1H).

Example 38

(S)-2-(4-tert-Butyl-3-methox -phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : l-tert-Butyl-2, 4-dimethoxy-benzene

In 100 ml round bottom flask were placed 1 ,3-dimethoxy-benzene (20 g, 145 mmol), 2-chloro-2-methyl-propane (40.27 g, 435 mmol), ReBr(CO)₅ (0.588 g, 1.45 mmol), and dichloroethane (260 ml). The reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was then cooled to room temperature. Evaporation of the solvent and purification by silica gel chromatography (0-10% EtO Ac/heptane) afforded 15.9 g of l-tert-butyl-2, 4- dimethoxy-benzene as clear oil.

C₁₂H₁₈0₂, (194.13), MS (EI): 194.1 (M⁺)

1H NMR (300 MHz, CDC1₃): δ 7.17 (d, 1H), 6.47 (d, 1H), 6.41 (dd, lH), 3.80 (s, 3H), 3.78 (s, 3H), 1.34 (s, 9H)

Step 2: 4-tert-Butyl-3-methoxy-phenol

To a stirred solution of l-tert-butyl-2, 4-dimethoxy-benzene (2 g, 10.3 mmol) in CH₂C1₂ (40 ml) at -78°C was added a 1M solution of BBr₃ in dichloromethane. The reaction mixture was stirred at -50°C for 4 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHC0₃ and extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, and dried (Na₂S0₄). Silica gel chromatography (0-20% EtO Ac/heptane) provided 0.560 g of the title compound as yellow oil.

CiiHi₆0₂, (180.12), LCMS (ESI): 181.12 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.16 (d, 1H), 6.42 (m, 2H), 5.62 (br.s., lH), 3.77 (s, 3H), 1.36 (s, 9H)

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

To a suspension of sodium hydrogen cyanamide (5.6 g, 88 mmol) in methanol (170 ml) was added (2S)-(+)-glycidyl tosylate (20 g, 88 mmol) at room temperature. The mixture was stirred at room temperature for 18 hours after which the mixture was concentrated. The residue was treated with water (100 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with brine, dried over Na₂S0₄, filtered, and concentrated. Further drying under high vacuum for four hours at room temperature afforded 11.9 g of the title compound as a white solid.

CnHi₄N₂0₄S, (270.08), LCMS (ESI): 271.08 (M⁺+H)

Step 3: Toluene -4-sulfonic acid (S)-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-oxazol-4-ylmethyl ester (2 g, 7.4 mmol) in ethanol (30 ml) was added ethyl propiolate (0.8 g, 8.15 mmol). The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature and purified by flash column chromatography on silica gel (2-9% MeOH/CH₂Cl₂) to afford 1.1 g of the title compound as a white solid.

Ci₄Hi₄N₂0₅S, (322.06), LCMS (ESI): 323.05 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.77 (d, 2H), 7.38 (d, 2H), 7.20 (d, 1H), 6.07 (d, 1H), 5.15 (m,

1H), 4.37-4.28 (m, 3H), 4.26- 4.19 (m, 1H), 2.47 (s, 3H).

Step 4: (S)-2-(4-tert-Butyl-3-methoxy-phenoxymethyl)-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 (0.683 g, 2.12 mmol) in acetonitrile (50 ml) was added 4-tert- butyl-3-methoxy-phenol (0.420 g, 2.33 mmol) followed by cesium carbonate (0.691 g, 2.12 mmol). The reaction mixture was heated at reflux for 1 hour, after which it was allowed to cool to room temperature. The solvent from the reaction mixture was removed under vacuum. The residue was treated with water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over Na₂S0₄, filtered, and concentrated. Purification by flash column chromatography (silica gel, 0-5% MeOH/CH₂Cl₂) afforded 0.124 g of the title compound as a white solid. [α]ο²⁵ = -66.5⁰ (c = 0.72, CHC1₃).

Ci₈H₂₂N₂0₄, (330.16), LCMS (ESI): 331.16 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.23 (d, 1H), 7.17 (d, 1H), 6.42 (d, 1H), 6.37 (dd, 1H), 6.11 (d, 1H), 5.28 (m, 1H), 4.31 (m, 4H), 3.82 (s, 3H), 1.34 (s, 9H)

Example 39 (S)-2-(4-tert-Butyl-3-methoxy-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-

7-one

Step 1 : Toluene -4-sulfonic acid (S)-5-ethyl-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 (see Example 39) (4 g, 14.8 mmol) in ethanol (150 ml) was added pent-2-ynoic acid ethyl ester (3.74 g, 29.6 mmol). The reaction mixture was stirred at reflux for 3 hours. The mixture was cooled to room temperature and purified by flash column chromatography (silica gel, 0-5 % 7N NH₃ in MeOH/CH₂Cl₂) to afford 2.08 g of the title compound as a white solid. Ci₆Hi₈N₂0₅S, (350.09), LCMS (ESI): 351.1 1 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.74 (d, 2H), 7.38 (d, 2H), 5.76 (s, 1H), 5.21 (m, 1H), 4.35 (m, 3H), 4.1 1 (m, 1H), 2.45 (s, 3H), 2.43 (m, 2H), 1.22(t, 3H)

Step 2: (S)-2-(4-tert-Butyl-3-methoxy-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

To a solution of toluene-4-sulfonic acid (S)-5-ethyl-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.37 g, 1.06 mmol) in acetonitrile (50 ml) was added 4-tert-butyl-3-methoxy-phenol (Example 39) (0.21 g, 1.16 mmol), followed by cesium carbonate (0.378 g, 1.16 mmol). The reaction mixture was heated at reflux for 3 hours, after which it was allowed to cool to room temperature. The reaction mixture was concentrated under vacuum and purified by flash column chromatography (silica gel, 0-5 % 7N NH₃ in MeOH/CH₂Cl₂) to afford 0.124 g of the title compound as a white solid.

[a]_D ²⁵ = - 48.8⁰ (c = 0.75, CHC1₃)

C₂₀H₂₆N₂O₄, (358.19), LCMS (ESI): 359.21 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.18 (d, 1H), 6.42 (d, 1H), 6.39 (dd, 1H), 5.87 (s, 1H), 5.27 (m, 1H), 4.27 (m, 4H), 3.81(s, 3H), 2.48 (q, 2H), 1.33(s, 9H), 1.27 (t, 3H).s

Example 40

(S)-2-(4-Cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidine-5- carboxylic acid

Step 1 : (S)-2-(4-Cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidine-5-carboxylic acid tert-butyl ester

(5)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (2 g, 7.3 mmol), (see Example 35), was dissolved in ethanol (50 ml). But-2-ynedioic acid di-tert-butyl ester (1.65 g, 7.3 mmol) was added. The reaction mixture was heated at reflux for 2 hours. The reaction mixture was allowed to reach room temperature. Solvent from the reaction mixture was removed under reduced vacuum and the residue was used with no further purification. C₂₄H₃oN₂0₅, (426.22), LCMS (ESI): 427.20 (M⁺+H)

Step 2: (S)-2-(4-Cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidine-5-carboxylic acid

To a solution of (S)-2-(4-cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidine-5-carboxylic acid tert-butyl ester (3.1 g, 7.3 mmol) in CH₂C1₂ (70 ml) was added trifluoroacetic acid (0.832 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 72 hours. Solvent from the reaction mixture was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, 2- 5% MeOH/CH₂Cl₂) to afford 0.08 g of the title compound as a white solid.

[<X]D = + 9.4⁰ (c = 0.70, DMSO)

C₂₀H₂₂N₂O₅, (370.15), LCMS (ESI): 371.16 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.15 (d, 2H), 6.82 (d, 2H), 6.70 (s, 1H), 5.22 (m,lH), 4.71 (m, 2H), 4.27 (m, 2H), 2.44 (br.s.,lH), 1.91-1.66(m, 5H), 1.58 (s, 1H), 1.48-1.16 (m, 5H).

Example 41

(S)-2-[4-(2,2-Dimethyl- ropyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 4-(2,2-Dimethyl-propyl)-phenol

The title compound was prepared from l-(2,2-dimethyl-propyl)-4-methoxy-benzene

(see J. Chem. Soc, Perkin Trans. 1, 1989, 1705 - 1 706) in accordance with procedures described in Example 39. CnHieO (164.12), MS (EI): 164.10 (M⁺)

1H NMR (300 MHz, CDC1₃): δ 7.01 (d, 2H), 6.74(d, 2H), 4.59 (s, IH), 2.42 (s, 2H),

0.89 (s, 9H)

Step 2: (S)-2-[4-(2,2-Dimethyl-propyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

(S)-5-[4-(2,2-Dimethyl-propyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine (0.4 g, 1.52 mmol), (see Example 35) was dissolved in ethanol (20 ml). Ethyl propiolate (0.299 g, 3.05 mmol) was added. The reaction mixture was heated in a microwave oven at 170°C for 20 minutes. The solvent was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 0-5% MeOH/CH₂Cl₂) to afford 0.106 g of the title compound as a white solid. [a]_D ²⁵ = - 54.0° (c = 0.46, CHC1₃)

Ci₈H₂₂N₂0₃, (314.16), LCMS (ESI): 315.15 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.29 (d, IH), 7.06 (d, 2H), 6.79(d, 2H), 6.08 (d, IH), 5.29 (m, IH), 4.44-4.22 (m, 4H), 2.43 (s, 2H), 0.89 (s, 9H)

Example 42

(S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(tetrahydro-pyran-2-yloxymethyl)-2,3- dih dro-oxazolo[3,2-a]pyrimidin-7-one

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

The title compound was prepared from 2-prop-2-ynyloxy-tetrahydro-pyran and ethyl chloroformate following the literature procedure (see Tetrahedron, 2006, 5697-5708).

CiiHi₆0₄ (212.11), LCMS (ESI): 213.12 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 4.81(m, IH), 4.38 (s, 2H), 4.23 (q, 2H), 3.82 (m,lH), 3.53 (m, IH), 1.89-1.47 (series of m, 6H), 1.31 (t, 3H)

Step 2: 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 39) (5 g, 18.5 mmol) in ethanol (80 ml) was added 4-(tetrahydro-pyran-2- yloxy)-but-2-ynoic acid ethyl ester (4.72 g, 22.2 mmol). The reaction mixture was stirred at reflux for 3 hours. The mixture was cooled to room temperature and purified by flash column chromatography (silica gel 1-6 % MeOH/ CH₂CI₂) to afford 2.7 g of the title compound 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 3 : (S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(tetrahydro-pyran-2- yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

To a solution 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 (2.69 g, 6.16 mmol) in anhydrous acetonitrile (70 ml) was added 4-bicyclo[3.3.1]non-9-yl-phenol (see WO 2008/112483 ), (1.47 g, 6.8 mmol), followed by cesium carbonate (2 g, 6 mmol). The reaction mixture was heated at reflux for 1 hour, after which it was allowed to cool to room temperature. The reaction mixture was concentrated under vacuum. The residue was treated with sodium bicarbonate (50 ml) and extracted with CH₂C1₂ (150 ml). The organic layer was washed with water and brine, dried over Na₂S0₄, filtered, and concentrated. Flash column chromatography (silica gel, 0-5 % MeOH/ CH₂C1₂) afforded 0.95 g of the title compound as a white solid. [a]_D ²⁵ = + 11.7⁰ (c = 0.68, DMSO)

C₂₈H₃6N₂0₅, (480.26), LCMS (ESI): 481.27(M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.30 (d, 2H), 6.86 (dd, 2H), 6.05 (s, 1H), 5.23 (m, 1H), 4.67 (br. s, 1H), 4.57-4.23 (m, 6H), 3.82 (m, 1H), 3.56 (m, 1H), 2.73 (br.s, 1H), 2.38 (br.s, 2H), 2.00-1.35 ( series ofm, 18H).

Example 43

(S)-2-(4-Bicyclo[3.3.1]non-9-yl-phenoxymethyl)-5-hydroxymethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

To a solution of (S)-2-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-5-(tetrahydro-pyran- 2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (see Example 43 (0.7 g, 1.46 mmol) in methanol (100 ml) was added /?-toluenesulfonic acid monohydrate (0.111 g, 0.525 mmol). The reaction mixture was stirred at room temperature for 18 hours. Flash column chromatography (silica gel, 2% MeOH/CH₂Cl₂) afforded 0.465 g of (S)-2-(4- bicyclo[3.3.1]non-9-yl-phenoxymethyl)-5-hydroxymethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one as a white solid. [a]_D ²⁵ = + 3.0 ° (c = 0.61, DMSO)

C₂₃H₂₈N₂0₄, (396.21), LCMS (ESI): 397.21(M⁺+H)

1H NMR (300 MHz, DMSO-d6): δ 7.29 (d, 2H), 6.89 (d, 2H), 5.80 (s, 1H), 5.69 (s, 1H), 5.32 (m, 1H), 4.47-4.09 (m, 6H), 2.67 (s, 1H), 2.37 (s, 2H), 2.01-1.27 (series of m, 12H)

Example 44

(S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : (S)-2-(4-bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

To a solution of toluene-4-sulfonic acid 7-oxo-5-(tetrahydro-pyran-2-yloxyethyl)-2,3- dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (2.1 g, 4.7 mmol), prepared in accordance with the procedure in Step 3 of Example 39 from toluene-4-sulfonic acid (S)-7- oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester and 5-(tetrahydro-pyran-2- yloxy)-pent-2-ynoic acid ethyl ester (see WO 2008/112483), in acetonitrile (70 ml) was added 4-bicyclo[3.3.1]non-9-yl-phenol, (see Example 43), (1.1 g, 5.09 mmol) followed by cesium carbonate (1.53g, 4.7 mmol). The reaction mixture was heated at reflux for 3 hours, after which it was allowed to cool to room temperature. The reaction mixture was concentrated under vacuum. The residue was treated with sodium bicarbonate (50 ml) and extracted with CH₂C1₂ (150 ml). The organic layer was washed with water and brine, dried over Na₂S0₄, filtered, and concentrated. Flash column chromatography (silica gel, 1-4 % MeOH/CH₂Cl₂) afforded 0.69 g of the title compound as a white solid.

C₂₉H₃₈N₂0₅, (494.28), LCMS (ESI): 495.27 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.29(d, 2H), 6.85 (d, 2H), 5.93 (s, 1H), 5.23 (m, 1H), 4.95- 4.31 (m, 3H), 4.26 (m, 2H), 4.04 (m, 1H), 3.76 (m, 1H), 3.66 (m, 1H), 3.48 (m, 1H), 2.74 (m, 3H), 2.36 (br.s, 2H), 2.00-1.33 (series of m, 18H). Step 2 : (S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared from (S)-2-(4-bicyclo [3.3.1 ]non-9-yl- phenoxymethyl)-5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one in accordance with the procedure in Example 44. [α]ο²⁵ = + 6.8 ⁰ (c = 0.74, DMSO)

C₂₄H₃oN₂0₄, (410.22), LCMS (ESI): 411.23 (M⁺+H)

1H NMR (300 MHz, DMSO-d6): δ 7.26 (d, 2H), 6.93 (d, 2H), 5.72 (s, 1H), 5.30 ( m, 1H), 4.94 (br.s, 1H), 4.46(t, 1H), 4.39-4.15 (m, 3H), 3.68(t, 2H), 2.68(s, 1H), 2.63( t, 2H ) 2.37 (br.s, 2H), 1.99-1.28 (series of m, 12H).

Example 45

(S)-2-(4-Cyclohexyl-phenoxymethyl)-5-(4-fluoro-benzyl)-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

Step 1 : [3-(4-Fluoro-phenyl)-prop-l-ynyl]-trimethyl-silane

To 2-dicyclohexyl-phosphino-2',4',6'-tri-z^'-propyl-l, -biphenyl (XPhos) (1 g, 2.1 mmol), PdCl₂(CH₃CN)₂ (0.18 g, 0.7 mmol) and Cs₂C0₃ (11.84 g, 36.3 mmol) was added anhydrous acetonitrile (50 ml), ethynyl-trimethyl-silane (4.42 g, 45 mmol), and 1- chloromethyl-4-fluoro-benzene (5 g, 34.6 mmol). The reaction mixture was stirred at 65°C for 9 hours. After the mixture had been cooled to room temperature, water (50 ml) was added and the product was extracted with ethyl acetate three times (150ml). The combined organic extracts were washed with brine, dried over Na₂S0_4, filtered and concentrated. Flash column chromatography (silica gel, 1-10 % methyl acetate/ hexane) afforded 6.14g of the title compound as yellow oil.

1H NMR (300 MHz, CDC1₃): δ 7.29 (m, 2H), 7.02 (m, 2H), 3.61 (s, 2H), 0.19 (s, 9H)

Step 2: 1 -Fluoro-4-prop-2-ynyl-benzene

To a suspension of [3-(4-fluoro-phenyl)-prop-l-ynyl]-trimethyl-silane (1 g, 4.85 mmol) in DMF (30 ml) was added KF-2H₂0 (0.912 g, 9.7 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 3N HC1 (120 ml) and extracted with heptanes. The combined organic extracts were washed with sodium bicarbonate, water, and brine; dried over Na₂SC"4, filtered and concentrated. Flash column chromatography (silica gel, 0-2 % methyl acetate/hexane) afforded 0.5 g of the title compound as a yellow oil.

C₉H₇F, (134.05), MS, (EI): 134.02 (M⁺)

1H NMR (300 MHz, CDC1₃): δ 7.31 (m, 2H), 7.02 (m, 2H), 3.57 (d, 2H), 2.20 (t, 1H)

Step 3: 4-(4-Fluoro-phenyl)-but-2-ynoic acid ethyl ester

The title compound was prepared from 1 -fluoro-4-prop-2-ynyl-benzene and ethyl chloroformate following the literature procedure (see Tetrahedron, 2006, 5697-5708).

C₁₂H₁₁FO₂, (206.07), MS, (EI): 206.05 (M⁺)

1H NMR (300 MHz, CDC13): 7.30 (m, 2H), 7.02 (m, 2H), 4.24 (q, 2H), 3.69(s, 2H), 1.31 (t, 3H)

Step 4: (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-(4-fluoro-benzyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

(5)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), (see Example 35), was dissolved in ethanol (3 ml). 4-(4-Fluoro-phenyl)-but-2-ynoic acid ethyl ester (0.45 g, 2.19 mmol) was added. The reaction mixture was heated in a microwave oven at 170°C for 30 minutes. The resulting crystalline solid was isolated by filtration, washed with hexane, and dried under vacuum to afford 0.7 g of the title compound as a beige solid.

C₂₆H₂₇FN₂0₃ (434.20), LCMS (ESI): 435.21 (M⁺+H)

1H NMR (300 MHz, DMSO-d6): δ 7.33 (m, 2H), 7.16 (m, 4H), 6.80(d, 2H), 5.51 (s, 1H), 5.28 (m, 1H), 4.29 (m, 2H), 4.21 (m, 1H), 4.05 (m, 1H), 3.92 (s, 2H), 2.44 (br.s, 1H), 1.82-1.63 (m, 5H), 1.41-1.15 (m, 5H)

Example 46

(S)-2-[4-(4,4-Difluoro-cyclohexyl)-phenoxymethyl]-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo 3,2-a]pyrimidin-7-one

Step 1 : Toluene -4-sulfonic acid (S)-7-oxo-5-pyrrolidin-l-ylmethyl-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 (see Example 39) (12 g, 45.0 mmol) in ethanol (300 ml) was added 4-pyrrolidin-l-yl- but-2-ynoic acid ethyl ester, (see Example 37), (8.16 g, 45 mmol). The reaction mixture was stirred at reflux for 3 hours. The mixture was cooled to room temperature and purified by flash column chromatography (silica gel 1-6 % MeOH/ CH₂CI₂) to afford 5.0g of the title compound as a beige solid.

Ci₉H₂₃N₃0₅S, (405.14), LCMS (ESI): 406.16 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.76 (d, 2H), 7.38 (d, 2H), 5.89 (s, 1H), 5.09 (m, 1H), 4.47 (AB-m, 2H), 4.30 (d, 2H), 3.42 (s, 2H), 2.51 (m, 4H), 2.46 (s, 3H), 1.80 (m, 4H)

Step 2: (S)-2-[4-(4,4-Difluoro-cyclohexyl)-phenoxymethyl]-5-pyrrolidin-l-ylmethyl-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one

To a solution of toluene-4-sulfonic acid (S)-7-oxo-5-pyrrolidin-l-ylmethyl-2,3- dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (5 g, 12.3 mmol) in acetonitrile (300 ml) was added 4-(4,4-difluoro-cyclohexyl)-phenol, (see WO 2008/112483) (2.62g, 12.3 mmol) followed by cesium carbonate (4 g, 12.3 mmol). The reaction mixture was heated at reflux for 1 hour, after which it was allowed to cool to room temperature. The reaction mixture was concentrated under vacuum. The residue was treated with sodium bicarbonate (100 ml) and extracted with CH₂CI₂ (150 ml). The organic layer was washed with water and brine, dried over Na₂S0₄, filtered, and concentrated. Flash column chromatography (silica gel, 0-5% MeOH/ CH₂C1₂) afforded 1.1 g of the title compound as a white solid. [a]_D ²⁵ = + 1.8 ° (c = 0.56, CHC1₃)

C₂₄H₂9F₂N₃0₃, (445.22), LCMS (ESI): 446.19 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.13 (d, 2H), 6.81 (d, 2H), 5.93 (s, 1H), 5.51 (m, 1H), 4.50 (AB-m, 2H), 4.26 (AB-m, 2H), 3.42 (s, 2H), 2.54 (m, 5H), 2.18 (m, 2H), 1.97-1.66 (series of m, 10H).

Example 47

(S)-2-(4-tert-Butyl-phenoxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

To a solution of (5)-5-(4-tert-butylphenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see WO 2008/112483) (0.4 g, 1.6 mmol) in ethanol (3 ml) was added 4-morpholin-4-yl-but-2- ynoic acid ethyl ester (see Example 36), (0.381 g, 1.93 mmol). The reaction mixture was heated in a microwave oven at 170°C for 30 minutes. The solvent from the reaction mixture was removed under vacuum and the residue was purified by flash column chromatography (silica gel, 0-3% EtOH/ CH₂CI₂) to afford 0.596 g of the title compound as a light brown solid.

C₂₂H₂9N₃0₄, (399.22), LCMS (ESI): 400.24 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.32 (d, 2H), 6.80 (d, 2H), 5.94 (s, 1H), 5.20 (m, 1H), 4.53 (AB-m, 2H), 4.29 (AB-m, 2H), 3.66 (m, 4H), 3.32 (d, 2H), 2.49 (m, 4H), 1.30 (s, 9H).

Example 48

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

(S)-5-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine (2 g, 7.6 mmol), (see WO 2008/112483), was dissolved in ethanol (10 ml). Ethyl propiolate (0.824 g, 8.4 mmol) was added. The reaction mixture was heated in a microwave oven at 170°C for 20 minutes. The resulting crystalline solid was isolated by filtration, washed with hexane, and dried under vacuum to afford 0.918 g of the title compound as a white solid. [α]ο^{25 =} - 55.4 ° (c = 0.74, CHC1₃)

Ci₈H₂₂N₂0₃ (314.16), LCMS (ESI): 315.17 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.23 (m, 3H), 6.82 (d, 2H), 6.10(d, 1H), 5.29 (m, 1H), 4.34 (m, 4H), 1.60 (q, 2H), 1.24 (s, 6H), 0.68 (t, 3H)

Example 49

(S)-2-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-5-methyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

The title compound was prepared as described in Example 49, and starting from (S)-5- [4-(l , l-dimethyl-propyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and but-2-ynoic acid ethyl ester. [a]_D ²⁵ = - 38.3 ⁰ (c = 0.60, CHC1₃)

Ci₉H₂₄N₂0₃ (328.18), LCMS (ESI): 329.17 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.25 (d, 2H), 6.82 (d, 2H), 5.85(s, 1H), 5.27 (m, 1H), 4.31 (m, 4H), 2.25 (s, 3H), 1.61 (q, 2H), 1.25 (s, 6H), 0.66 (t, 3H)

Example 50

(S)-2-[4-(l , l-Dimethyl-propyl)-phenoxymethyl]-5-ethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from ((S)-5-[4-(l , l-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and pent-2-ynoic acid ethyl ester in accordance with the procedures described in Example 49. [a]_D ²⁵ = - 32.6° (c = 0.61 , CHC1₃) C₂₀H₂₆N₂O₃ (342.19), LCMS (ESI): 343.18 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.26 (d, 2H), 6.81 (d, 2H), 5.88 (s, 1H), 5.24 (m, 1H), 4.32 (m, 4H), 2.49 (q, 2H), 1.61 (q, 2H), 1.26 (m, 9H), 0.66 (t, 3H)

Example 51

(S)-2-[4-(l ,l-Dimethyl-propyl)-phenoxymethyl]-5-fluoromethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

To (S)-5-[4-(l , l-dimethyl-propyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine (0.9 g, 3.43 mmol), (Example 49) in ethanol (30ml) was added 4-fluoro-but-2-ynoic acid ethyl ester (0.5 g, 3.84 mmol), (see J Org Chem 1981 , 46, 1532). The reaction mixture is stirred at reflux for 4 hours, after which it was allowed to cool to room temperature. The solvent was removed under vacuum and the residue purified by flash column chromatography (silica gel, 0-5 % MeOH/CH₂Cl₂) to afford 0.5 g of the title compound as a white solid. [a]_D ²⁵ = - 32.1 ⁰

Ci₉H₂₃FN₂0₃ (346.17), LCMS (ESI): 347.17 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.24 (d, 2H), 6.82 (d, 2H), 6.00(d, 1H), 5.31 (m, 1H), 5.20 (dd, 2H), 4.50 (t, 1H), 4.32 (m, 3H),1.60 (q, 2H), 1.25 (s, 6H), 0.66 (t, 3H).

Example 52

(S)-2-[4-(2,2-Dimethyl-propyl)-phenoxymethyl]-5-methyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(2,2-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and but-2-ynoic acid ethyl ester. [α]ο²⁵ = - 36.4 ° (c = 0.73, CHC1₃)

Ci₉H₂₄N₂0₃ (328.18), LCMS (ESI): 329.17 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.05 (d, 2H), 6.80(d, 2H), 5.86 (s, 1H), 5.25 (m, 1H), 4.38 (t, 1H), 4.27 (m, 3H), 2.44 (s, 2H), 2.24 (s, 3H), 0.89 (s, 9H). Example 53

(S)-2-[4-(2,2-Dimethyl-propyl)-phenoxymethyl]-5-ethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(2,2-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and pent-2-ynoic acid ethyl ester. [α]ο²⁵ = - 34.4 ° (c = 0.68, CHC1₃)

C₂₀H₂₆N₂O₃ (342.19), LCMS (ESI): 343.19 (M⁺+H) 1H NMR (300 MHz, CDC1₃): δ 7.05 (d, 2H), 6.79(d, 2H), 5.90 (s, 1H), 5.25 (m, 1H), 4.29 (m, 4H), 2.50 (q, 2H), 2.43 (s, 2H), 1.28 (t, 3H), 0.89 (s, 9H).

Example 54

(S)-2-[4-(2,2-Dimethyl-propyl)-phenoxymethyl]-5-fluoromethyl-2,3-dihydro-oxazolo[3,2- a rimidin-7-one

The title compound was prepared from (S)-5-[4-(2,2-dimethyl-propyl)- phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine and 4-fluoro-but-2-ynoic acid ethyl ester (see J Org Chem. 1981, 46,1532). [a]_D ²⁵ = - 35.5° (c = 0.60, CHC1₃)

Ci₉H₂₃FN₂0₃ (346.17), LCMS (ESI): 347.16 (M⁺+H)

1H NMR (300 MHz, CDC1₃): δ 7.05 (d, 2H), 6.78(d, 2H), 6.05 (d,lH), 5.30 (m, 1H), 5.21 (d, 2H), 4.51-4.21 (m, 4H), 2.44 (s, 2H), 0.88 (s, 9H)

Example 55

2-[4-(3-Oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 3-(4-Hydroxy-phenyl)-cyclohex-2-enone

3-Ethoxy-2-cyclohexenon-l-one (3.68 ml, 25 mmol) was added dropwise to 50 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide. The reaction was stirred overnight and then quenched with 25 ml of a 2.4 N aqueous HC1 solution. After stirring 3 hrs. at room temperature the reaction mixture was poured into water and extracted with ether. The organic phase was extracted with brine, dried over 5 A molecular sieves, filtered, and concentrated under vacuum. The resulting yellow solid was recrystallized from ethyl acetate and heptane to yield 2.95 g the title compound as a tan solid. M.P. 160° -

162° C.

+

Ci₂Hi₂0₂ (188.23) LCMS (ESI): 189.8 (M+H) 1H NMR (CDCI3, 300MHz), δ 7.50 (d, 2H), 6.90 (d, 2H), 6.42 (s, 1H), 6.23 (br s, 1H), 2.78 (t, 2H), 2.51 (t, 2H), 2.15 (m, 2H).

Step 2: 2-[4-(3-Oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

Cs₂C0₃ (0.78 g, 2.4 mmol) was added to a solution of 3-(4-hydroxy-phenyl)-cyclohex- 2-enone (0.376 g, 2 mmol) in 40 ml of MeCN. The mixture was stirred overnight at room temperature. Solid toluene-4-sulfonic acid 7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.645 g, 2 mmol) was added and the resulting mixture stirred 1 week at room temperature. The thick reaction mixture was filtered and concentrated under vacuum. The residue was partially dissolved in dichloromethane and extracted with saturated NaHC0₃. The dichloromethane extract was dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 0.34 g of a light yellow solid. The solid was dissolved in dichloromethane and diluted with ether. The resulting white solid was isolated by filtration, washed with ether, and dried under vacuum to afford 0.16 g of the title compound as a white solid. M. P. 184° - 185° C (dec). [a]_D ²⁵ = - 80.0 ° (c = 0.73, CHC1₃)

Ci₉Hi₈N₂0₄ (338.37) LCMS (ESI): 339.13 (M⁺ +H).

1H NMR (CDC1₃, 300MHz), δ 7.50 (d, 2H), 7.25 (d, 1H), 6.90 (d, 2H), 6.35 (s, 1H), 6.02 (d, 1H), 5.35 (m, 1H), 4.45 - 4.25 (m, 4H), 2.70 (t, 2H), 2.45 (t, 2H), 2.15 (m, 2H).

Example 56

2-[4-(5,5-Dimethyl-3-oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- -7-one

Step 1 : 5,5-Dimethyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohex-2-enone

Ν,Ν,Ν',Ν'-Tetramethylethylenediamine (0.04 ml, 0.25 mmol) was added to a suspension of Cul (0.048 g, 0.25 mmol) in 10 ml of THF. The suspension dissolved to give a clear green solution. This green solution was added to an ice-cold solution of 3-chloro-5,5- dimethyl-cyclohex-2-ene-l-one (5 g, 31.5 mmol) in 100 ml of ether. To this ice-cold solution was added dropwise 50 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide. The reaction was allowed to slowly warm to room temperature and stirred overnight. The mixture was poured into saturated NH₄C1 and extracted with ether. The ether layer was extracted once more with saturated NH₄CI, once with saturated NaHC0₃ and once with brine. The ether layer was concentrated under vacuum and the residue was purified by chromatography on silica gel using 1/5 ethyl acetate /heptane as the eluent to afford 3.95 g of the title compound as a light yellow solid.

1H NMR (CDC1₃, 300MHz), δ 7.50 (d, 2H), 7.08 (d, 2H), 6.39 (s, 1H), 5.45 (m, 1H), 3.95-3.8 (m, 1H), 3.65-3.55 (m, 1H), 2.6 (s, 2H), 2.3 (s, 2H), 2.1-1.55 (m, 6H), 1.1 (s, 6H).

Step 2: 3-(4-Hydroxy-phenyl)-5,5-dimethyl-cyclohex-2-enone

5,5-Dimethyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohex-2-enone (3.95 g, 13.2 mmol) was dissolved in 400 ml of MeOH and treated with p-toluenesulfonic acid monohydrate (0.25 g, 1.32 mmol). The solution became bright red in color. The mixture was stirred 15 hrs. at room temperature and concentrated under vacuum. The residue was dissolved in ether and extracted two times with saturated NaHC0₃ and one time with brine. The ether layer was dried over 3A molecular sieves, filtered and concentrated under vacuum. The resulting solid was recrystallized from ethyl acetate and heptane to yield 1.58 g of the title compound as yellow-orange crystals. M.P. = 190° - 192° C.

Ci₄Hi₆0₂ (216.28) LCMS (ESI): peak at 0.84 minutes, mass 217.1 (M+H)⁺

1H NMR (CDC1₃, 300MHz), δ 7.45 (d, 2H), 6.85 (d, 2H), 6.4 (s, 1H), 5.35 (s, 1H), 2.6 (s, 2H), 2.35 (s, 2H), 1.1 (s, 6H).

Step 3 : 2-[4-(5,5-Dimethyl-3-oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Cs₂C0₃ (0.78 g, 2.4 mmol) was added to a solution of 3-(4-hydroxy-phenyl)-5,5- dimethyl-cyclohex-2-enone (0.433 g, 2 mmol) in 40 ml of MeCN. The mixture was stirred overnight at room temperature. Solid toluene-4-sulfonic acid 7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.645 g, 2 mmol) was added. The mixture was stirred 1 week at room temperature. The thick reaction mixture was filtered and concentrated under vacuum. The residue was partially dissolved in dichloromethane and extracted with an aqueous solution of NaHC0₃. The aqueous NaHC0₃ layer was extracted three more times with dichloromethane. The combined organic extracts were dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 0.43 g of a light yellow solid. The solid was dissolved in dichloromethane and diluted with ether. The resulting white solid was isolated by filtration, washed with ether, and dried under vacuum to yield 0.28 g of the title compound as a white solid. M. P. 193° - 199° C. [<X]D = - 70.5 ⁰ (c = 0.72, CHCls)

C₂iH₂₂N₂0₄ (366.42) LCMS (ESI): 367.21 (M⁺ +H).

1H NMR (CDCI3, 300MHz), δ 7.50 (d, 2H), 7.25 (d, 1H), 6.93 (d, 2H), 6.35 (s, 1H), 6.1 (d, 1H), 5.35 (m, 1H), 4.5 - 4.25 (m, 4H), 2.6 (s, 2H), 2.33 (s, 2H), 1.15 (s, 6H).

Example 57

2-[4-(l-Methyl-3-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2a]pyrimidin-7- one

Step 1 : 3-Methyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone

Ν,Ν,Ν',Ν'-Tetramethylethylenediamine (0.04 ml, 0.25 mmol) was added to a suspension of Cul (0.048 g, 0.25 mmol) in 50 ml of ether. The mixture was stirred 15 minutes at room temperature until all the Cul had dissolved. The mixture was cooled to 0°C and 50 ml of a 0.5 M THF solution of 4-(2-tetrahydro-2H-pyranoxy)phenyl magnesium bromide was added. The mixture was stirred for 15 minutes at 0°C, after which a 0.5 M ether solution of 3-methyl-2-cyclohexenone (2.9 ml, 25 mmol) was added dropwise over a 30 minute period. The thick reaction mixture was allowed to warm to room temperature and stirred overnight. After 15 hours at room temperature the thick reaction mixture had dissolved to give a clear solution. The clear solution was poured into 30 ml of 1 N HC1 and after shaking the layers were separated. The organic layer was extracted with saturated NaHC0₃, brine, dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 8.8 g of a yellow oil. The yellow oil was purified by chromatography on silica gel using ethyl acetate/heptane(l/10) as the eluent to give 1.97 g of the title compound as a white solid.

1H NMR (CDC1₃, 300MHz), δ 7.21 (d, 2H), 7.0 (d, 2H), 5.4 (m, 1H), 3.95-3.88 (m, 1H), 3.63- 3.58 (m, 1H), 2.84 (d, 1H), 2.4 (d, 1H), 3.30 (t, 2H), 2.2-2.1 (m, 1H), 2.1-1.5 (m, 9H), 1.3 (s, 3H).

Step 2: 3-(4-Hydroxy-phenyl)-3-methyl-cyclohexanone

3-Methyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone (1.97 g, 6.83 mmol) was dissolved in 120 ml of MeOH and treated with p-toluenesulfonic acid monohydrate (0.13 g, 0.68 mmol). The mixture was stirred 15 hrs. at room temperature and concentrated under vacuum. The residue was dissolved in ether and extracted twice with saturated NaHC03 and once with brine. The ether layer was dried over 3A molecular sieves, filtered and concentrated under vacuum to give 0.86 g of the title compound as a light-yellow oil.

Ci₃Hi₆0₂ (204.27) LCMS (ESI): peak at 0.75 minutes, mass 205.0 (M+H)⁺

1H NMR (CDC1₃, 300MHz), δ 7.15 (d, 2H), 6.75 (d, 2H), 6.0 (s, 1H), 2.9 (d, 1H), 2.4 (d, 1H), 2.3 (t, 2H), 2.25-2.1 (m, 1H), 1.95-1.8 (m, 2H), 1.7-1.55 (m, 1H), 1.3 (s, 3H).

Step 3 : 2-[4-(l -Methyl-3-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo [3 ,2a]pyrimidin-7-one

Cs₂C0₃ (1.3 g, 4 mmol) was added to a solution of 3-(4-hydroxy-phenyl)-3-methyl- cyclohexanone (0.817 g, 4 mmol) in 100 ml of MeCN. The mixture was stirred overnight at room temperature. Solid toluene-4-sulfonic acid 7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester (0.645 g, 2 mmol) was added. The mixture was stirred 1 week at room temperature. The reaction mixture was concentrated under vacuum. The residue was partially dissolved in dichloromethane and extracted with an aqueous solution of NaHC0₃. The aqueous NaHC0₃ layer was extracted three times with dichloromethane. The combined dichloromethane extracts were dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 0.54 g of a light yellow oil. The oil was partially dissolved in ethyl acetate and filtered. The filtrate was diluted with heptane until cloudy. The cloudy mixture was allowed to stand and the ethyl acetate to evaporate. The mother liquors were decanted from a white solid and the white solid was dried under vacuum to provide 0.05 g of the title compound. M. P. 1 16° - 1 19° C. [a]_D ²⁵ = - 5.5 ⁰ (c = 0.74, DMSO)

C₂oH₂₂N₂0₄ (354.41) LCMS (ESI): 355.16 (M⁺ +H).

1H NMR (CDCI3, 300MHz), δ 7.26-7.2 (m, 3H), 6.8 (d, 2H), 6.1 (d, 1H), 5.35-5.25 (m, 1H), 4.45 - 4.2 (m, 4H), 2.85 (d, 1H), 2.42 (d, 1H), 2.3 (t, 2H), 2.2-2.1 (m, 1H), 1.95-1.8 (m, 2H), 1.7-1.55 (m, 1H), 1.3 (s, 3H).

Example 58

2-[4-(l ,3,3-Trimethyl-5-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one

Step 1 : 3,3,5-Trimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone Ν,Ν,Ν',Ν'-Tetramethylethylenediamine (0.15 ml, 1 mmol) was added to a suspension of Cul (0.095 g, 0.5 mmol) in 100 ml of ether. The mixture was stirred 15 minutes at room temperature until all the Cul had dissolved. The mixture was cooled to 0°C and 100 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide was added. The mixture was stirred for 15 minutes at 0°C after which a 0.5 M ether solution of 3,5,5- trimethyl-cyclohex-2-enone (isophorone) (7.66 ml, 50 mmol) was added dropwise over a 90 minute period. The reaction mixture was allowed to warm to room temperature and stirred overnight. After 15 hours at room temperature the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. The quenched reaction mixture was poured into water and extracted with ether. The organic layer was extracted with an aqueous solution of Na₂S₂0s and K₂CO₃ and then brine. The ether layer was dried over 5 A molecular sieves, filtered and concentrated under vacuum to yield 16 g of a yellow oil. The yellow oil was purified by chromatography on silica gel using ethyl acetate / heptane (1/20) as the eluent to give 7 g of the title compound as a colorless oil.

1H NMR (CDCI3, 300MHz), δ 7.25 (d, 2H), 6.95 (d, 2H), 5.35 (m, 1H), 3.95-3.85 (m, 1H), 3.63-3.58 (m, 1H), 3.0 (d, 1H), 2.35 (d, 1H), 2.25-1.75 (m, 7H), 1.7-1.5 (m, 3H), 1.3 (s, 3H), 1.0 (s, 3H), 0.4 (s, 3H).

Step 2: 3-(4-Hydroxy-phenyl)-3,5,5-trimethyl-cyclohexanone

3,3,5-Trimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone (1.89 g, 6 mmol) was dissolved in 60 ml of MeOH and treated with p-toluenesulfonic acid monohydrate (0.1 14 g, 0.6 mmol). The mixture was stirred 15 hrs. at room temperature and concentrated under vacuum. The residue was dissolved in ether and extracted twice with saturated NaHC03 and three times with 1 N NaOH. The combined NaOH extracts were extracted with ether and then acidified with concentrated HC1. The cloudy aqueous extract was extracted with ether. This ether layer was extracted with a NaHC0₃ solution and then with brine. The ether layer was dried over 3A molecular sieves, filtered and concentrated under vacuum to give 0.85 g of a white solid. The white solid was recrystallized from ether/heptane to yield 0.8 g the title compound as white crystals. M.P. = 138°-140° C.

Ci₅H₂₀O₂ (232.33) LCMS (ESI): 233.1 (M+H)⁺

1H NMR (CDC1₃, 300MHz), δ 7.2 (d, 2H), 6.75 (d, 2H), 6.65 (br s, 1H), 3.05 (d, 1H), 2.35 (d, 1H), 2.2 (dd, 2H), 2.1 (d, 1H), 1.95 (d, 1H), 1.35 (s, 3H), 1.0 (s, 3H), 0.3 (s, 3H).

Step 3 : 3,3,5-Trimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone CS₂CO₃ (0.39 g, 1.2 mmol) was added to a solution of 3-(4-hydroxy-phenyl)-3,5,5- trimethyl-cyclohexanone (0.232 g, 1 mmol) in 20 ml of MeCN. The mixture was stirred overnight at room temperature. Solid toluene-4-sulfonic acid 7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.322 g, 1 mmol) was added. The mixture was stirred for 6 days at room temperature. The reaction mixture was poured into dichloromethane and extracted with an aqueous solution of NaHC0₃. The aqueous NaHC0₃ layer was extracted three more times with dichloromethane. The combined dichloromethane extracts were dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 0.27 g of a light yellow oil. The oil was partially dissolved in ethyl acetate and filtered. The filtrate was diluted with heptane until cloudy. The cloudy mixture was allowed to stand and the ethyl acetate to evaporate. The mother liquors were decanted from a white solid and the white solid was dried under vacuum to yield 0.11 g of the title compound. M. P. 137° -

139° C. [<x]_D = - 45.0 ° (c = 0.70, CHC1₃)

C₂₂H₂₆N₂0₄ (382.46) LCMS (ESI): 383.19 (M⁺ +H).

1H NMR (CDCI3, 300MHz), δ 7.26-7.2 (m, 3H), 6.78 (d, 2H), 6.05 (d, 1H), 5.35-5.25 (m, 1H), 4.42 (t, 1H), 4.35 - 4.2 (m, 3H), 3.0 (d, 1H), 2.35 (d, 1H), 2.2 (dd, 2H), 2.1 (d, 1H), 1.95 (d, 1H), 1.35 (s, 3H), 1.0 (s, 3H), 0.35 (s, 3H).

Example 59

2-[4-(2,6,6-Trimethyl-4-oxo-bicyclo[3.1.1 ]hept-2-yl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Step 1 : 4,6,6-Trimethyl-4-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-bicyclo[3.1.1 ]heptan-2-one Ν,Ν,Ν',Ν'-Tetramethylethylenediamine (0.15 ml, 1 mmol) was added to a suspension of Cul (0.095 g, 0.5 mmol) in 100 ml of ether. The mixture was stirred 15 minutes at room temperature until all of the Cul had dissolved. The mixture was cooled to 0°C and 100 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide was added. The mixture was stirred for 15 minutes at 0°C, after which a 0.5 M ether solution of (IS, 5S)- 4,6,6-trimethyl-bicyclo[3.1.1]hept-3-en-2-one ((-)-verbenone) (7.51 g, 50 mmol) was added dropwise over a 90 minute period. The reaction mixture was allowed to warm to room temperature and stirred overnight. After 15 hours at room temperature the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. The quenched reaction mixture was poured into water and extracted with ether. The organic layer was extracted with an aqueous solution of Na₂S₂0s and K₂CO₃ and then brine. The organic extract was dried over 5A molecular sieves, filtered and concentrated under vacuum to yield 16.5 g of a yellow oil. The yellow oil was purified by chromatography on silica gel using ethyl acetate / heptane (1/20 then 1/10) as the eluent to give 10 g the title compound as a light yellow oil that was contaminated with a small amount of verbenone.

1H NMR (CDCI₃, 300MHz), δ 7.15 (d, 2H), 7.0 (d, 2H), 5.4 (m, 1H), 4.0-3.85 (m, 1H), 3.65- 3.55 (m, 1H), 3.15 (d, 1H), 2.77 (d, 1H), 2.65-2.5 (m, 3H), 2.1-1.5 (m, 7H), 1.45 (s, 3H), 1.4 (s, 3H), 1.1 (s, 3H).

Step 2 : 4-(4-Hydroxy-phenyl)-4,6,6-trimethyl-bicyclo[3.1.1 ]heptan-2-one

4,6,6-Trimethyl-4-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-bicyclo[3.1.1 ]heptan-2-one (6.75 g, 20.6 mmol) was dissolved in 300 ml of MeOH and treated with p-toluenesulfonic acid monohydrate (0.6 g, 3.15 mmol). The mixture was stirred for 15 hrs. at room temperature and concentrated under vacuum. The residue was dissolved in ether and extracted twice with saturated NaHC03 and three times with 1 N NaOH. The combined NaOH extracts were extracted with ether and then acidified with concentrated H₂SO₄. The thick aqueous layer was extracted with ether. This ether layer was washed with a saturated NaHC0₃ solution and then with brine. The ether layer was dried over 3A molecular sieves, filtered and concentrated under vacuum to give 3.85 g of a yellow solid. The yellow solid was recrystallized from tetrahydrofuran/heptane to yield 1.59 g of the title compound as a light-yellow solid. M.P. = I74⁰.I77⁰ c.

Ci₆H₂₀O₂ (244.34) LCMS (ESI): 245.1 (M+H)⁺

1H NMR (CDCI3, 300MHz), δ 7.1 (d, 2H), 6.8 (d, 2H), 4.8 (br s, 1H), 3.15 (d, 1H), 2.8 (d,

1H), 2.65-2.5 (m, 3H), 1.45-1.3 (m, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 1.14 (s, 3H).

Step 3 : 2-[4-(2,6,6-Trimethyl-4-oxo-bicyclo[3.1.1 ]hept-2-yl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

Cs₂C0₃ (0.717 g, 2.2 mmol) was added to a solution of 4-(4-hydroxy-phenyl)-4,6,6- trimethyl-bicyclo[3.1.l]heptan-2-one ( 0.489 g, 2 mmol) in 40 ml of MeCN. The mixture was stirred overnight at room temperature. Solid toluene -4-sulfonic acid 7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.645 g, 2 mmol) was added. The mixture was stirred two weeks at room temperature. The reaction mixture was poured into dichloromethane and washed with an aqueous solution of NaHC0₃. The aqueous NaHC0₃ layer was extracted five times with dichloromethane. The combined dichloromethane extracts were dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 0.5 g of a colorless oil. The oil was partially dissolved in ethyl acetate and filtered. The filtrate was diluted with heptane until cloudy. The cloudy mixture was allowed to stand and the ethyl acetate to evaporate. The mother liquors were decanted from a white solid and the white solid was washed with ether and dried under vacuum to yield 0.18 g of the title compound. M. P. 169° - 172° C. [a]_D ²⁵ = - 34.7° (c = 0.73, DMSO)

C₂₃H₂₆N₂0₄ (394.47) LCMS (ESI): 395.2 (M⁺ +H).

1H NMR (CDC1₃, 300MHz), δ 7.3 (d, 1H), 7.15 (d, 2H), 6.82 (d, 2H), 6.05 (d, 1H), 5.35-5.25 (m, 1H), 4.42 (t, 1H), 4.38 - 4.2 (m, 3H), 3.13 (d, 1H), 2.8 (d, 1H), 2.63-2.5 (m, 3H), 1.46-1.2 (m, 1H), 1.46 (s, 3H), 1.4 (s, 3H), 1.16 (s, 3H).

Example 60

2-[4-(3-Hydroxy-l,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- -7-one

Step 1 : 3,3,5-Trimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone

Ν,Ν,Ν',Ν'-Tetramethylethylenediamine (0.15 ml, 1 mmol) was added to a suspension of Cul (0.095 g, 0.5 mmol) in 100 ml of ether. The mixture was stirred for 15 minutes at room temperature until all the Cul had dissolved. The mixture was cooled to 0°C and 100 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide was added. The mixture was stirred for 15 minutes at 0°C, after which a 0.5 M ether solution of 3,5,5-trimethyl-cyclohex-2-enone (isophorone) (7.66 ml, 50 mmol) was added dropwise over a 90 minute period. The reaction mixture was allowed to warm to room temperature and stirred overnight. After 15 hours at room temperature the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. The quenched reaction mixture was poured into more water and extracted with ether. The organic layer was extracted with an aqueous solution of Na₂S₂0₅ and K₂C0₃ and then brine. The ether extract was dried over 5 A molecular sieves after which it was filtered and concentrated under vacuum to yield 16 g of a yellow oil. The yellow oil was purified by chromatography on silica gel using ethyl acetate / heptane (1/20) as the eluent to give 7 g of the title compound as a colorless oil.

Step 2: 1 ,3,3,5-Tetramethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanol

A 3 M THF solution of methyl magnesium chloride (8 ml, 24 mmol) was added dropwise to an ice cold 0.1 M THF solution of 3,3,5-trimethyl-5-[4-(tetrahydro-pyran-2- yloxy)-phenyl]-cyclohexanone. The mixture was allowed to warm to room temperature and stirred overnight. After 15 hr. the reaction was quenched with the dropwise addition of water followed by a saturated aqueous solution of NH₄C1. The mixture was poured into water and the aqueous mixture was extracted with ether. The ether layer was washed with brine, dried over 5 A molecular sieves, filtered, and concentrated under vacuum to yield 4.2 g of a colorless oil. The oil was purified by chromatography on silica gel using ethyl acetate / heptane (1/20 then 1/10) as the eluent. Two products were isolated resulting from syn- and anti-addition to the ketone.

Product 1 (TLC 1/5 EtO Ac/heptane R_f = 0.12) 1H NMR (CDC1₃, 300MHz), δ 7.44 (d, 2H), 6.95 (d, 2H), 5.36 (t, 1H), 4.0-3.85 (m, 1H), 3.63-3.53 (m, 1H), 2.67 (d, 1H), 2.4 (d, 1H), 2.05- 1.2 (m, 11H), 1.2 (s, 3H), 1.08 (s, 3H), 0.92 (s, 3H), 0.75 (s, 3H).

Product 2 (TLC 1/5 EtOAc/heptane R_f = 0.09) 1H NMR (CDC1₃, 300MHz), δ 7.3 (d, 2H), 7.0 (d, 2H), 5.4 (m, 1H), 4.0-3.9 (m, 1H), 3.65-3.58 (m, 1H), 2.1-1.1 (m, 12H), 1.53 (s, 3H), 1.35 (s, 3H), 1.35-1.3 (br s, 1H), 1.25 (s, 3H), 0.9 (s, 3H).

Step 3: 4-(3-Hydroxy-l,3,5,5-tetramethyl-cyclohexyl)-phenol

Product 1 from step 2, l,3,3,5-tetramethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]- cyclohexanol (2.22 g, 6.68 mmol), was dissolved in 100 ml of MeOH and treated with p- toluenesulfonic acid monohydrate (0.095 g, 0.5 mmol). The mixture was stirred 1 hr. at room temperature and concentrated under vacuum. The residue was dissolved in ether and extracted twice with saturated NaHC03 and with brine. The ether layer was dried over 4 A molecular sieves, filtered and concentrated under vacuum to give 1.5 g of the title compound as white crystals.

C16H24O2 (248.37) LCMS (ESI): 231.19 (M - H₂0 + H)⁺ mass spectra shows parent ion at 248.16 1H NMR (CDCI₃, 300MHz), δ 7.4 (d, 2H), 6.62 (d, 2H), 6.25(br s, 1H), 2.7 (d t, 1H), 2.4 (d t, 1H), 1.8 (br s, 1H), 1.5 (d t, 1H), 1.35 (d, 1H), 1.3-1.1 (m, 2H), 1.28 (s, 3H), 1.12 (s, 3H), 0.93 (s, 3H), 0.77 (s, 3H).

Product 2 from step 2, l,3,3,5-tetramethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]- cyclohexanol (1.6 g, 4.8 mmol), was dissolved in 100 ml of MeOH and treated with p- toluenesulfonic acid monohydrate (0.095 g, 0.5 mmol). The mixture was stirred for 1 hr. at room temperature and concentrated under vacuum. The residue was dissolved in ether and extracted twice with saturated NaHC03 and with brine. The ether layer was dried over 4A molecular sieves, filtered and concentrated under vacuum to give 1.16 g of the title compound as an off- white foam.

C16H24O2 (248.37) LCMS (ESI): 231.19 (M - H₂0 + H)⁺ mass spectra shows parent ion at 248.17

1H NMR (CDCI₃, 300MHz), δ 7.25 (d, 2H), 6.8 (d, 2H), 4.8 (br s, 1H), 2.0-1.85 (m, 1H), 1.82-1.7 (m, 2H), 1.62-1.5 (m, 3H), 1.49 (s, 3H), 1.25 (s, 3H), 1.22 (s, 3H), 1.05 (br s, 1H), 0.9 (s, 3H).

Step 4: 2-[4-(2,6,6-Trimethyl-4-oxo-bicyclo[3.1.1]hept-2-yl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one

CS₂CO₃ (0.717 g, 2.2 mmol) was added to a solution of 4-(3-hydroxy-l,3,5,5- tetramethyl-cyclohexyl)-phenol (1.16 g, 4.7 mmol) in 50 ml of a 1/1 MeCN/THF solution. The mixture was stirred overnight at room temperature. Solid toluene-4-sulfonic acid 7-oxo- 2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.645 g, 2 mmol) was added. The mixture was stirred for two weeks at room temperature. The reaction mixture was concentrated under vacuum and the residue was redissolved in dichloromethane and water. A saturated aqueous solution of NaHC0₃ was added to the water layer and the layers were separated. The aqueous NaHC0₃ layer was extracted three times with dichloromethane. The combined dichloromethane extracts were dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield a colorless oil. The oil was partially dissolved in a small amount of dichloromethane and filtered. The filtrate was diluted with heptane until cloudy. The cloudy mixture was allowed to stand and the dichloromethane to evaporate. The mother liquors were decanted from a white solid and the white solid was recrystallized a second time from THF and heptane to yield 0.01 g ot the title compound. M. P. 90° - 94° C.

C₂₃H₃₀N₂O₄ (398.51) LCMS (ESI): 399.23 (M⁺ +H). 1H NMR (CDCI₃, 300MHz), δ 7.33 (d, 2H), 7.22 (d, 1H), 6.8 (d, 2H), 6.05 (d, 1H), 5.33-5.2 (m, 1H), 4.4 - 4.2 (m, 4H), 2.0-1.9 (m, 1H), 1.78 (d, 2H), 1.63-1.5 (m, 4H), 1.5 (s, 3H), 1.3 (s, 3H), 1.25 (s, 3H), 0.9 (s, 3H).

Example 61

2-(l-Oxo-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

CS₂CO₃ ( 1.95 g, 6 mmol) was added to a solution of 5-hydroxyindanone ( 0.89 g, 6 mmol) in 30 ml of MeCN. The mixture was stirred overnight at room temperature. Solid toluene-4-sulfonic acid 7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.976 g, 3 mmol) was added. The mixture was stirred for 3 weeks at room temperature and then briefly heated to reflux to complete the reaction. The cooled reaction mixture was filtered and concentrated under vacuum. The residue was redissolved in MeCN and allowed to stand at 5°. The mother liquors were decanted from the resulting solid to provide 0.48 g of the title compound as an off-white solid. M. P. 235° - 237° C (dec).

C₁₆H₁₄N₂O₄ (298.30) LCMS (ESI): peak at 1.57 minutes, mass 299.07 (M⁺ +H). 1H NMR (DMSO d-6, 300MHz), δ 7.77 (d, 1H), 7.58 (d, 1H), 7.12 (s, 1H), 6.97 (dd, 1H), 5.83 (d, 1H), 5.39 - 5.34 (m, 1H), 4.48 - 4.39 (m, 3H), 4.15 - 4.09 (m, 1H), 3.07 - 3.04 (m, 2H), 2.61 - 2.50 (m, 2H).

Example 62

2-(3-Oxo-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

CS₂CO₃ ( 1.14 g, 3.5 mmol) was added to a solution of 6-hydroxyindanone (0.518 g, 3.5 mmol) in 30 ml of MeCN. The mixture was briefly heated to reflux, then cooled to room temperature. Solid toluene-4-sulfonic acid 7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2- ylmethyl ester (0.976 g, 3 mmol) was added. The mixture was stirred 11 days at room temperature and then briefly heated to reflux to complete the reaction. The cooled reaction mixture was filtered and concentrated under vacuum. The residue was partially dissolved in dichloromethane, filtered, and diluted with ether. A resulting white precipitate was isolated by filtration, washed with ether, and dried under vacuum to yield 0.31 g of a white solid. M. P. 202° - 206° C (dec).

Ci₆Hi₄N₂0₄ (298.30) LCMS (ESI): 299.12 (M⁺ +H).

1H NMR (CDCI3, 300MHz), δ 7.39 (d, 1H), 7.28 (d, 1H), 7.16 (s, 1H), 7.14 (d, 1H), 6.08 (d, 1H), 5.37 - 5.30 (m, 1H), 4.46 - 4.25 (m, 4H), 3.10 - 3.07 (m, 2H), 2.74 - 2.70 (m, 2H).

Example 63

(S)-2-(4-tert-Butyl-phenoxymethyl)-5-(l,l-difluoro-propyl)-2,3-dihydro-oxazolo[3,2- a rimidin-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 4- tert-butyl-phenol (0.281 mmol,) according to the procedure described in Example 1 to afford 36.6 mg of the title compound.

C₂oH2₄F₂N203 (378.17), LCMS (ESI): 379.20 (M⁺+H).

1H NMR ((CDCI3), 300MHz): δ 7.32-7.29 (d, 2H), 6.81-6.79 (d, 2H), 6.22 (s, 1H), 5.29-5.22 (m, 1H), 4.51-4.45 (m, 2H), 4.37-4.32 (dd, 1H), 4.25-4.21 (dd, 1H), 2.28-2.20 (m, 2H), 1.29 (s, 9H), 1.17-1.13 (t, 3H).

Comparative Example 1

(R)-2-(4-tert-Butyl-phenoxymeth l)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one

Stepl : 2-Formyl-butyric acid ethyl ester

A solution of diisopropylamine (10.1 g, 100 mmol) in THF (100 ml) was treated with n-butyllithium (1.6M in hexane, 63 ml, 100 mmol) at room temperature under N₂. The resulting pale yellow solution was cooled to -78°C. A solution of butyric acid ethyl ester (10.4 g, 89.2 mmol) in THF (28 ml) was added. Stirring was continued for a half hour at - 78°C, after which ethyl formate (22.0 g, 300 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for three hours under N₂. The reaction mixture was quenched with acetic acid (-17 ml), diluted with diethyl ether, washed with water, brine, dried (Na₂S0₄). Silica gel chromatography (methyl acetate/hexane) provided 12.5 g of the title compound as a mixture of isomers.

C₇Hi₂0₃ (144.08), LCMS (ESI): 145.08(M⁺+H).

Step 2: (R)-2-(4-tert-Butyl-phenoxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one

To a solution of (R)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (3.67 g, 14.81 mmol) (prepared in accordance with the procedures described in WO 2008/1 12483) in ethanol (40 ml) was added 2-formyl-butyric acid ethyl ester (0.39 g, 2.7 mmol). The reaction mixture heated at reflux for 24 hours. It was then concentrated and loaded on a silica gel column. Chromatography with 2-propanol/methylene chloride gave 0.9 g of title compound.

Ci₉H₂₄N₂0₃ (328.18), LCMS (ES⁺): 329.14 (M⁺+H).

1H NMR (CDC1₃, 300MHz), δ 7.31 (d, 2H), 7.05 (s 1H), 6.82 (d, 2H), 5.24 (m, 1H), 4.25-4.39 (m, 4H), 2.46 (q, 2H), 1.30 (s, 9H), 1.16 (t, 3H).

Biological Examples

Example 64

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 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 65

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

CLAIMS What is claimed is:

1. A compound of the formula I:

R₂ is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, -COOH, phenyl, benzyl, 2-, 3-, 4-, or 5 -fluorophenyl, 2-, 3-, 4-, or 5-f uorobenzyl, 2,4-dif uorophenyl, 2,4- difluorobenzyl, phenoxy, benzyloxy, 2-, 3-, 4-, or 5-fluorophenoxy, 2-, 3-, 4-, or 5-fluorobenzyloxy, 2,4-difluorophenoxy, 2,4-difluorobenzyloxy, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, tetrahydrofuranylmethoxymethyl, phenyl, cyclopropyl, cyclopropylmethyl and cyclopentyloxymethyl; and

R₃, R₄ and R₅ are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF₃, (Ci-C₆)alkyl, (Ci-C₆)alkoxy, cyclohexyl, 1-methylcyclohexyl, 4-methoxycyclohexyl,

4,4'-difluorocyclohexyl, cyclohexenyl, 4-fluoro-cyclohexenyl, bicyclo [3 ,3,1 ]nonyl, bicyclo [3,3,1 ]nonylethyl, 1, ,1",3,3' ,3 "— hexaf uoro-2- hydroxy-propyl; or

two of R₃, R₄ and R₅ 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 or a diastereoisomer or a tautomer thereof.

2. 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,

R₃, R₄ and R₅ are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, iso-propyl, iso-butyl, tert-butyl, cyclohexyl, methoxy and ethoxy;

or a salt thereof.

The compound according to claim 1, wherein:

Ri is hydrogen or ethyl;

R₂ is hydrogen;

R3, R₄ and R₅ are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, tert-butyl, methoxy and ethoxy; or a salt thereof.

The compound according to claim 1, which is selected from the group consisting of: (S)-2-[4-(9-methyl-bicyclo[3.3.1]non-9-yl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-[4-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-[4-(4-methoxy-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

2-[4-(5,5-dimethyl-3-oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

2-[4-(l-methyl-3-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo [3 ,2a]pyrimidin-7-one;

2-[4-(l,3,3-trimethyl-5-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; 2-[4-(2,6,6-trimethyl-4-oxo-bicyclo[3.1.1 ]hept-2-yl)-phenoxymethyl]-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

2-(l-oxo-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

2-(3-oxo-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;

7-one;

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin 7-one;

(S)-2-(4-tert-butyl-2-fluoro-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one;

(S)-2-(4-tert-butyl-3-methoxy-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

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

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-5-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-[4-(4-fluoro-cyclohex-3-enyl)-phenoxymethyl]-5-methoxymethyl-2,3-dihydro- oxazolo [3, 2-a]pyrimidin-7-one;

(S)-5-cyclopropyl-2-[4-(4,4-difluoro-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

(S)-5-cyclopropyl-2-[4-(l-methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(4-cyclohexyl-phenoxymethyl)-5-cyclopropylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one;

(S)-5 -fluoromethyl-2- [4-( 1 -methyl-cyclohexyl)-phenoxymethy 1] -2,3 -dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-5-(l,l-difluoro-propyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo [3, 2-a]pyrimidin-7-one;

(S)-2-(4-cyclohexyl-phenoxymethyl)-5-pyrrolidin-l-ylmethyl-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one;

(S)-2-[4-(4,4-difluoro-cyclohexyl)-phenoxymethyl]-5-pyrrolidin-l-ylmethyl-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

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

(S)-2-(4-bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo [3 ,2-a]pyrimidin-7-one; (S)-2-(4-cyclohexyl-phenoxymethyl)-5-(4-fluoro-benzyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-isopropyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one;

(S)-2-[4-(l,l-dimethyl-propyl)-phenoxymethyl]-6-isopropyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-(2-hydroxy-ethyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-phenoxymethyl)-6-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-cyclohex-l-enyl-phenoxymethyl)-5-methoxymethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; (S)-5-methoxymethyl-2-[4-(9-methyl-bicyclo[3.3.1 ]non-9-yl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-2-fluoro-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-2-fluoro-phenoxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one;

(S)-2-(4-tert-butyl-2-fluoro-phenoxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one; and

(S)-2-(4-tert-butyl-3-methoxy-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one .

A pharmaceutical composition comprising one or more compounds of any of claims 1 to 4 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 4 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 4 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.