# Patent

## Title
Oxazolidinone derivatives

## Abstract

The present invention relates to oxazolidinone derivatives of formula (I) wherein Y, R3 and R4 are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as orexin receptor antagonists.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a U. S. Application under 35 U.S.C. 371 claiming benefit of PCT Application No. PCT/IB2010/052068, filed on May 11, 2010, which claims the benefit of PCT Application No. PCT/IB2009/051949, filed on May 12, 2009, the contents of each of which are incorporated herein by reference.
The present invention relates to novel oxazolidinone derivatives of formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
Orexins (orexin A or OX-A and orexin B or OX-B) are novel neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OX1 and OX2 receptors). The orexin-1 receptor (OX1) is selective for OX-A, and the orexin-2 receptor (OX2) is capable to bind OX-A as well as OX-B. Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585). On the other hand, it was also observed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to narcolepsy as well as insomnia and other sleep disorders (Chemelli R. M. et al., Cell, 1999, 98, 437-451). Furthermore, in vitro and in vivo evidence for a critical role of orexin signaling in the ventral tegmental area in neural plasticity relevant to addiction has been published (S. L. Borgland et al. Neuron, 2006, 49, 589-601).
Thus, orexin receptors may have numerous implications in pathologies as known from the literature, such as dysthymic, mood, psychotic and anxiety disorders; diabetes and appetite, taste, eating, or drinking disorders; hypothalamic diseases; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; insomnias related to psychiatric disorders; sleep apnea; narcolepsy; idiopathic insomnias; parasomnias; benign prostatic hypertrophy; all dementias and cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders; and other diseases related to general orexin system dysfunctions. The compound (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide (WO2005/118548) is currently in clinical development for primary insomnia. In the rat, the compound has been shown for example to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently increase the time spent in both REM and NREM sleep (F. Jenck et al., Nature Medicine 2007, 13, 150-155). The compound has also been shown to enhance memory function in a rat model (WO2007/105177) and is also active in a rat model of post-traumatic stress disorder (WO2009/047723).
The present invention provides novel oxazolidinone derivatives, which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of diseases related to the orexin system, especially comprising all types of sleep disorders, of stress-related syndromes, of addictions (especially psychoactive substance use, abuse, seeking and reinstatement), of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
1) A first aspect of the invention consists of compounds of the formula (I)




wherein

    Y represents CH2, CHR1, or CR1R2; wherein
    
        R1 and R2 independently represent (C1-4)alkyl;
    
    
    R3 represents Ar1 or Ar3—Z—Ar2—* wherein the asterisk indicates the bond that is attached to the rest of the molecule; wherein
    
        Ar1 represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C1-3)fluoroalkyl-thio-, and (C3-6)cycloalkyl-(C1-4)alkoxy;
        Ar2 represents phenyl or 5- to 6-membered heteroaryl;
        Z represents a bond, O, or —CH2—O—* wherein the asterisk indicates the bond that is attached to Ar2;
        Ar3 represents phenyl or 5- to 6-membered heteroaryl wherein the phenyl or 5- to 6-membered heteroaryl is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably substituents are selected from (C1-4)alkyl, (C1-4)alkoxy, and (C1-3)fluoroalkyl); and
    
    
    R4 represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4)alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy; wherein, in the specific case wherein said aryl or heteroaryl is a bicyclic ring, the aryl or heteroaryl may also be unsubstituted;

with the exception of the following compounds:

    2-(2-bromophenyl)-3-[(4-methoxyphenyl)methyl]-4-oxazolidinone (CAS 199939-14-5);
    2-(2-bromophenyl)-3-{[4-(trifluoromethyl)phenyl]methyl}-4-oxazolidinone (CAS 199939-13-4);
    2-(2-bromophenyl)-3-(phenylmethyl)-4-oxazolidinone (CAS 199939-09-8); and
    2-(4-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]-5-methyl-4-oxazolidinone (CAS 84711-84-2).


The latter compounds are known from L. Giraud, E. Lacote, P. Renaud; “Preparation of 2-arylbenzaldehyde derivatives via free-radical ipso-substitution of an amidomethyl group” Helv. Chim. Acta (1997), 80(7), 2148-2156; and H. Aoyama, M. Sakamoto, K. Kuwabara, K. Yoshida, Y. Omote; “Photochemical reactions of .alpha.-oxo amides. Norrish type II reactions via zwitterionic intermediates” J. Am. Chem. Soc. (1983), 105(7), 1958-64.
In this patent application, a bond interrupted by a wavy line shows the point of attachment of the radical drawn. For example, the radical drawn below




is the 7-methoxy-quinolin-8-yl group.

The term “halogen” means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
The term “alkyl”, used alone or in combination, refers to a saturated straight or branched chain alkyl group containing one to four carbon atoms. The term “(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C1-4)alkyl group contains from one to four carbon atoms. Examples of (C1-4)alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl. Preferred are methyl and ethyl. Most preferred is methyl. For the substituents R1 and R2 preferred is methyl. For the substituent R15 representing a (C1-4)alkyl group, preferred are ethyl, n-propyl and especially isopropyl.
The term “cycloalkyl”, used alone or in combination, refers to a saturated cyclic alkyl group containing three to six carbon atoms. The term “(Cx-y)cycloalkyl” (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C3-6)cycloalkyl group contains from three to six carbon atoms. Examples of (C3-6)alkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred is cyclopropyl.
The term “alkoxy”, used alone or in combination, refers to an alkyl-O— group wherein the alkyl group is as defined before. The term “(Cx-y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C1-4)alkoxy group means a group of the formula (C1-4)alkyl-O— in which the term “(C1-4)alkyl” has the previously given significance. Examples of (C1-4)alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy and especially methoxy. For substituents of R4 preferred examples are ethoxy and methoxy. For substituents of Ar1 representing a phenyl group preferred examples are methoxy, ethoxy and especially isopropoxy.
The term “fluoroalkyl” refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “(Cx-y)fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (C1)fluoroalkyl groups such as trifluoromethyl. For the substituent R15 preferred examples are trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl (notably trifluoromethyl, difluoromethyl, and 2,2,2-trifluoroethyl).
The term “fluoroalkoxy” refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “(Cx-y)fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are (C1)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.
The term “aryl”, alone or in combination, means a phenyl or a naphthyl group. In addition, the term aryl also comprises phenyl rings fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 to 2 oxygen atoms. Examples of aryl groups are phenyl, naphthyl, indanyl, tetrahydronaphthyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, chromanyl, and chromenyl. In a sub-embodiment, examples are phenyl, naphthyl, indanyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydro-benzo[1,4]dioxinyl. In another sub-embodiment examples are phenyl or naphthyl, notably phenyl. The aryl group may be unsubstituted or substituted as explicitly defined. The sub-group wherein aryl groups are phenyl rings fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 or 2 oxygen atoms is preferably unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of methyl, methoxy, and halogen.
For the substituent Ar1 particular examples of aryl groups are phenyl, 2-naphthyl, 6-methoxy-naphthalen-2-yl, 1-naphthyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 2,6-dimethylphenyl, 3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-6-fluorophenyl, 2-chloro-4-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-difluoro-phenyl, 3,5-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4,5-trifluoro-phenyl, 2-chloro-3,6-difluorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4,6-trimethylphenyl, 4-ethoxyphenyl, 2-ethoxyphenyl, 4-(n-propoxy)phenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-tert.butyl-phenyl, 2,6-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-difluoromethoxy-phenyl, 4-difluoromethoxyphenyl, 4-trifluoromethyl-sulfanyl-phenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2-methyl-3-trifluoromethylphenyl, 2-methyl-5-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 2-fluoro-3-chloro-5-trifluoromethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-chloro-4-trifluoromethoxyphenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-tert.-butoxyphenyl, 4-(cyclopropylmethoxy)-phenyl, benzo[1,3]dioxol-5-yl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, 2,3-dihydrobenzofuran-5-yl, and 2,3-dihydro-benzo[1,4]dioxin-6-yl. In a sub-embodiment examples are 2-naphthyl, 4-chlorophenyl, 2-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-methylphenyl, 2-methylphenyl, 2,6-dimethylphenyl, 3-chloro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-3,6-difluorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2,4,6-trimethylphenyl, 4-ethoxyphenyl, 4-(n-propoxy)phenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethyl-sulfanyl-phenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2-methyl-3-trifluoromethylphenyl, 2-methyl-5-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-fluoro-3-trifluoromethyl phenyl, 2-fluoro-4-trifluoromethyl phenyl, 2-fluoro-5-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethyl phenyl, 2-fluoro-3-chloro-5-trifluoromethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-chloro-4-trifluoromethoxyphenyl, 4-(cyclopropylmethoxy)-phenyl, and benzo[1,3]dioxol-5-yl.
For the substituent R4 particular examples of aryl groups are 2-methoxy-naphthalen-1-yl, 2,6-difluorophenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-methoxy-6-methylphenyl, 2-methoxy-5-methylphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3-chloro-2,6-dimethoxyphenyl, 2-chloro-4,6-dimethoxyphenyl, 2-fluoro-4,6-dimethoxyphenyl, 4-fluoro-2,6-dimethoxyphenyl, 2-ethoxy-6-methoxyphenyl, 2,6-diethoxyphenyl, 2-isopropoxy-6-methoxyphenyl, 3-fluoro-2,6-dimethoxyphenyl, 2,6-dimethoxy-3-methylphenyl, 2,6-dimethoxy-4-methylphenyl, 2-(2-hydroxyethoxy)-6-methoxyphenyl, 2-(2-hydroxypropoxy)-6-methoxyphenyl, 2-(3-hydroxypropoxy)-6-methoxyphenyl, 2-(2,3-dihydroxypropoxy)-6-methoxyphenyl, 2-(2-methoxyethoxy)-6-methoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-trifluoromethylphenyl, 2-methoxy-6-trifluoromethylphenyl, 6-methoxy-indan-5-yl, benzo[1,3]dioxol-4-yl, 5-methoxy-benzo[1,3]dioxol-4-yl, 5-bromo-benzo[1,3]dioxol-4-yl, 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl, 2,3-dihydro-benzo[1,4]dioxin-5-yl, and 6-methoxy-2,3-dihydro-benzo[1,4]dioxin-5-yl. In a sub-embodiment, examples are 2-ethoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-methoxy-6-methylphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2-ethoxy-6-methoxyphenyl, 4-fluoro-2,6-dimethoxyphenyl, 2,6-dimethoxy-4-methylphenyl, 2-(2-hydroxyethoxy)-6-methoxyphenyl, 2-methoxy-6-trifluoromethylphenyl, 5-methoxy-benzo[1,3]dioxol-4-yl, and 6-methoxy-2,3-dihydro-benzo[1,4]dioxin-5-yl. In another sub-embodiment, examples are 2-ethoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-methoxy-6-methylphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2-ethoxy-6-methoxyphenyl, and 2-methoxy-6-trifluoromethylphenyl.
For the substituent Ar1 examples of the particular sub-group of “phenyl rings fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 to 2 oxygen atoms” are 2,2-difluoro-benzo[1,3]dioxol-5-yl, benzo[1,3]dioxol-5-yl, 2,3-dihydrobenzofuran-5-yl, and 2,3-dihydro-benzo[1,4]dioxin-6-yl (notably benzo[1,3]dioxol-5-yl).
For the substituent R4 examples of the particular sub-group of “phenyl rings fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 to 2 oxygen atoms” are 6-methoxy-indan-5-yl, benzo[1,3]dioxol-4-yl, 5-methoxy-benzo[1,3]dioxol-4-yl, 5-bromo-benzo[1,3]dioxol-4-yl, 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl, 2,3-dihydro-benzo[1,4]dioxin-5-yl, and 6-methoxy-2,3-dihydro-benzo[1,4]dioxin-5-yl (notably 5-methoxy-benzo[1,3]dioxol-4-yl, and 6-methoxy-2,3-dihydro-benzo[1,4]dioxin-5-yl).
For the substituent R4 examples of the particular sub-group of “bicyclic aryl” are naphthyl, indanyl, tetrahydronaphthyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, chromanyl, and chromenyl (notably naphthyl, benzo[1,3]dioxolyl, and 2,3-dihydro-benzo[1,4]dioxinyl) which are unsubstituted or substituted as explicitly defined. Particular examples are 2-methoxy-naphthalen-1-yl, 5-methoxy-benzo[1,3]dioxol-4-yl, and 6-methoxy-2,3-dihydro-benzo[1,4]dioxin-5-yl.
The term “heteroaryl”, alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1 to a maximum of 3 heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 4H-furo[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl and imidazo[2,1-b]thiazolyl. In case the heteroaryl group is a 5- to 6-membered heteroaryl as used for the generic groups Ar2 and Ar3, particular examples are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl; notably pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl. The heteroaryl group may be unsubstituted or substituted as explicitly defined.
For the substituent Ar1 particular examples of heteroaryl groups are thiophenyl, pyrrolyl, pyridazinyl, pyridinyl, benzo[b]thiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, benzotriazolyl, quinoxalinyl, and quinolinyl, which are unsubstituted or substituted as explicitly defined; notably thiophen-2-yl, 1-methyl-pyrrol-2-yl, 6-ethoxy-pyridazin-3-yl, pyridin-2-yl, pyridin-4-yl, 2-ethoxy-pyridin-5-yl, 5-ethoxy-pyridin-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, benzofuran-2-yl, 1H-benzimidazol-2-yl, 1-methyl-1H-benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, 1-methyl-1H-indol-6-yl, 1H-indol-2-yl, 1-methyl-1H-indol-2-yl, 1H-indol-3-yl, 1-methyl-1H-benzotriazol-5-yl, quinoxalin-2-yl, quinoxalin-6-yl, quinolin-2-yl, quinolin-6-yl, and quinolin-7-yl (especially benzimidazol-2-yl, benzoxazol-2-yl, and benzothiazol-2-yl).
For the substituent R4 particular examples of heteroaryl groups are pyridinyl, benzo[d]isoxazolyl, benzoxazolyl, and quinolinyl which are unsubstituted or substituted as explicitly defined; notably 2,4-dimethoxypyridin-3-yl, 3,5-dimethoxypyridin-4-yl, 6-methoxy-3-methyl-benzo[d]isoxazol-7-yl, 6-methoxy-2-methyl-benzoxazol-7-yl, and 7-methoxy-quinolin-8-yl.
For the substituent R4 examples of the particular sub-group of “bicyclic heteroaryl” are benzo[d]isoxazolyl, benzoxazolyl, and quinolinyl which are unsubstituted or substituted as explicitly defined. Particular examples are 6-methoxy-3-methyl-benzo[d]isoxazol-7-yl, 6-methoxy-2-methyl-benzoxazol-7-yl, and 7-methoxy-quinolin-8-yl.
For the substituent Ar3 examples of the particular sub-group of “5- to 6-membered heteroaryl” are pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl which are unsubstituted or substituted as explicitly defined; notably pyrrol-1-yl, pyrazol-1-yl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, 3-methyl-pyridin-2-yl, 4-methyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl, 5-methoxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl, 6-trifluoromethyl-pyridin-2-yl, pyrimidin-2-yl, pyrimidin-5-yl, 6-methyl-pyridazin-3-yl, and pyrazin-2-yl. Preferred (for the substituent Ar3, and mutatis mutandis also for the substituent R15) are thiazolyl, pyridyl and pyrazinyl which are unsubstituted or substituted as explicitly defined; notably thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, 4-methyl-pyridin-2-yl, and pyrazin-2-yl; especially thiazol-2-yl, and pyridin-2-yl.
For the substituent Ar2 the phenyl or 5- to 6-membered heteroaryl are preferably substituted by Z and the rest of the molecule in a para (such as phenyl-1,4-diyl) arrangement (for phenyl or 6-membered heteroaryl) or in a 1,3-arrangement (for 5-membered heteroaryl). A particular example of Ar2 representing a 5- to 6-membered heteroaryl group is pyridyl, notably pyridin-2,5-diyl (wherein Z may be attached in either position 2 or 5).
The term “fluoroalkyl-thio” refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine, said group being attached to the rest of the molecule via a sulfur atom. The term “(Cx-y)fluoroalkyl-thio” (x and y each being an integer) refers to a fluoroalkyl-thio group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkyl-thio group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. A representative example of a fluoroalkyl-thio group is trifluoromethyl-sulfanyl (F3C—S—).
The term “(C3-6)cycloalkyl-(C1-4)alkoxy” refers to a (C1-4)alkoxy group as defined before containing one to four carbon atoms in which one hydrogen atom has been replaced with a (C3-6)cycloalkyl group as defined before. A representative example of (C3-6)cycloalkyl-(C1-4)alkoxy groups is cyclopropylmethoxy.
The term “hydroxy-(C1-4)alkoxy” refers to an alkoxy group as defined before containing one to four carbon atoms in which one hydrogen atom has been replaced with hydroxy. Representative examples of hydroxy-(C1-4)alkoxy groups are 2-hydroxy-ethoxy and 2-hydroxy-propoxy (notably 2-hydroxy-ethoxy).
The term “dihydroxy-(C1-4)alkoxy” refers to refers to an alkoxy group as defined before containing one to four carbon atoms in which two hydrogen atoms have been replaced with hydroxy. A representative example of a dihydroxy-(C1-4)alkoxy group is 2,3-dihydroxy-propoxy.
The term “(C1-4)alkoxy-(C1-4)alkoxy” refers to an alkoxy group as defined before containing one to four carbon atoms in which one hydrogen atom has been replaced with a (C1-4)alkoxy group as defined before. A representative example of a (C1-4)alkoxy-(C1-4)alkoxy group is 2-methoxy-ethoxy.
Further embodiments of the invention are presented hereafter:

    2) A further embodiment of the invention relates to compounds according to embodiment 1), which are also compounds of formula (IE1) wherein the stereocenter at position 2 of the oxazolidinone moiety is in absolute (S)-configuration:






    3) A further embodiment of the invention relates to compounds according to embodiment 1), which are also compounds of formula (IE2) wherein the stereocenter at position 2 of the oxazolidinone moiety is in absolute (R)-configuration:






    4) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), wherein Y represents CHR1, or CR1R2; wherein each group forms a particular sub-embodiment.
    5) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 5), wherein Y represents CH2.
    6) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4), wherein, if present, R1 represents methyl and, if present, R2 represents methyl.
    7) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), wherein R3 represents Ar1.
    8) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), wherein R3 represents Ar3—Z—Ar2—* wherein the asterisk indicates the bond that is attached to the rest of the molecule.
    9) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 7), wherein
    
        Ar1 represents aryl which is unsubstituted, or mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C1-3)fluoroalkyl-thio-, and (C3-6)cycloalkyl-(C1-4)alkoxy (notably (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy); or
        Ar1 represents heteroaryl which is unsubstituted, or mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy and (C1-3)fluoroalkyl (notably (C1-4)alkyl).
    
    
    10) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 7), wherein
    
        Ar1 represents aryl which is unsubstituted, or mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C3-6)cycloalkyl-(C1-4)alkoxy, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy).
    
    
    11) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 7), 9) or 10), wherein, in case Ar1 represents aryl, said aryl is
    
        phenyl which is unsubstituted, or mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C1-3)fluoroalkyl-thio-, and (C3-6)cycloalkyl-(C1-4)alkoxy (notably (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy); or
        naphthyl (notably 2-naphthyl) which is unsubstituted, or mono-, or di-substituted (notably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably (C1-4)alkoxy); or
        a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 to 2 oxygen atoms (notably an indanyl, a benzo[1,3]dioxolyl, a 2,3-dihydrobenzofuranyl, or a 2,3-dihydro-benzo[1,4]dioxinyl group) which is (preferably) unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of methyl, methoxy, and halogen.
    
    
    12) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 7), wherein
    
        Ar1 represents heteroaryl which is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy and (C1-3)fluoroalkyl (notably (C1-4)alkyl).
    
    
    13) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), 8) or 11), wherein Ar2 represents phenyl (notably phenyl-1,4-diyl).
    14) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), 8) or 11), wherein Ar2 represents 5- to 6-membered heteroaryl (notably 6-membered heteroaryl).
    15) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), 8), 11), 13) or 14), wherein Z represents a O.
    16) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), 8), 11), 13) or 14), wherein Z represents a bond.
    17) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), 8), 11), or 13) to 16), wherein
    
        Ar3 represents phenyl which is unsubstituted, or mono-, di-, or tri-substituted (notably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably Ar3 represents unsubstituted phenyl); or
        Ar3 represents 5- to 6-membered heteroaryl which is unsubstituted, or mono-, di-, or tri-substituted (notably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably substituents are selected from (C1-4)alkyl, (C1-4)alkoxy, and (C1-3)fluoroalkyl).
    
    
    18) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), 8), 11), or 13) to 16), wherein
    
        Ar3 represents 5- to 6-membered heteroaryl which is unsubstituted, or mono-, di-, or tri-substituted (notably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably substituents are selected from (C1-4)alkyl, (C1-4)alkoxy, and (C1-3)fluoroalkyl).
    
    
    19) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), 8), 11), or 13) to 16), wherein
    
        Ar3 represents phenyl which is unsubstituted, or mono-, di-, or tri-substituted, (notably unsubstituted or mono-substituted) wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably Ar3 represents unsubstituted phenyl).
    
    
    20) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), wherein R3 represents
    
        phenyl which is mono-, or di-substituted, wherein one substituent is (C1-4)alkoxy, or (C1-3)fluoroalkoxy in position 4 of said phenyl and the other (if present) is selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably halogen); or
        Ar3—Z—Ar2—* wherein the asterisk indicates the bond that is attached to the rest of the molecule; wherein
        
            Ar2 represents phenyl or 6-membered heteroaryl which are substituted by Z and the rest of the molecule in a para arrangement,
            Z represents O, and
            Ar3 represents phenyl or 5- to 6-membered heteroaryl wherein the phenyl or 5- to 6-membered heteroaryl is independently unsubstituted or mono-substituted, wherein the substituent is independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably Ar3 represents unsubstituted phenyl or 5- to 6-membered heteroaryl).
        
        
    
    
    21) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 20), wherein
    
        R4 represents aryl which is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4)alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy (notably substituents are selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and hydroxy-(C1-4)alkoxy); wherein, in the specific case wherein said aryl is a bicyclic ring, the aryl may also be unsubstituted; or
        R4 represents heteroaryl which is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4)alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy; (notably substituents are selected from (C1-4)alkyl, and (C1-4)alkoxy) wherein, in the specific case wherein said heteroaryl is a bicyclic ring, the heteroaryl may also be unsubstituted.
    
    
    22) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 21), wherein
    
        R4 represents aryl which is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4)alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy (notably substituents are selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and hydroxy-(C1-4)alkoxy); wherein, in the specific case wherein said aryl is a bicyclic ring, the aryl may also be unsubstituted.
    
    
    23) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 21), wherein
    
        R4 represents heteroaryl which is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4)alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy; (notably substituents are selected from (C1-4)alkyl, and (C1-4)alkoxy) wherein, in the specific case wherein said heteroaryl is a bicyclic ring, the heteroaryl may also be unsubstituted.
    
    
    24) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 22), wherein, in case R4 represents aryl, said aryl is
    
        phenyl which is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4)alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy (notably substituents are selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and hydroxy-(C1-4)alkoxy); or
        naphthyl (notably 1-naphthyl) which is unsubstituted, or mono-, or di-substituted (notably mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably (C1-4)alkoxy); or
        a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 to 2 oxygen atoms (notably a 2,3-dihydro-benzo[1,4]dioxinyl group) which is unsubstituted, or mono-, or di-substituted (notably mono-substituted) wherein the substituents are independently selected from the group consisting of methyl, methoxy, and halogen (notably methoxy).
    
    
    25) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 24), wherein R4 is at least mono-substituted, wherein said substituent is attached in ortho position to the point of attachment of R4 to the rest of the molecule; wherein, in case R4 represents a phenyl group, said substituent is preferably selected from the group consisting of (C1-4)alkoxy, (C1-3)fluoroalkoxy, and hydroxy-(C1-4)alkoxy (notably (C1-4)alkoxy); and, in case R4 represents a group different from phenyl, said substituent is preferably methoxy.
    26) Another embodiment relates to compounds of formula (I) according to embodiment 1) which are also compounds of formula (II):






wherein

    Y1 represents CH2, CH(CH3) or CH(CH3)2;
    R13 represents






wherein

    
    
        R15 represents (C1-4)alkyl or (C1-3)fluoroalkyl;
        
            V1, V2 and V4 are CH, and V3 is CR17, wherein optionally one or two of V′, V2, V3 and V4 may also be N; and
            R17 is hydrogen or halogen; or
        
        
        R15 represents phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is independently unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably R15 represents unsubstituted phenyl or 5- to 6-membered heteroaryl); and one or two of V1, V2, V3 and V4 are CH or N and the remaining are CH; and
    
    
    R14 represents a group selected from the group consisting of:






wherein

    
    
        W1 represents CH and W2 represents CR17 or N, or
        
            W1 represents N and W2 represents CH;
        
        
        R16 represents methyl, (C1-3)alkoxy, halogen, (C1-2)fluoroalkoxy, or trifluoromethyl (notably methyl, methoxy, ethoxy, fluoro, chloro, or trifluoromethyl);
        R17 represents hydrogen, methyl or fluoro (notably hydrogen); and
        n represents the integer 1 or 2;

wherein characteristics described for compounds of formula (I), notably those described in embodiments 2) to 5), apply mutatis mutandis also to compounds of formula (II).

    
    
    27) A further embodiment of the invention relates to compounds of formula (II) according to embodiments 26); wherein,
    
        R15 represents (C1-4)alkyl; (C1-3)fluoroalkyl;
        V1, V2 and V4 are CH, and V3 is CR18, wherein optionally one or two of V1, V2, V3 and V4 may also be N; and
        R18 is hydrogen or halogen.
    
    
    28) A further embodiment of the invention relates to compounds of formula (II) according to embodiments 26) or 27); wherein,
    
        R15 represents phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is independently unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (notably R15 represents unsubstituted phenyl or 5- to 6-membered heteroaryl); and
        one or two of V1, V2, V3 and V4 are CH or N and the remaining are CH.
    
    
    29) A further embodiment of the invention relates to compounds of formula (II) according to any one of embodiments 26) to 28); wherein, R14 represents






wherein

    
    
        W1 represents CH and W2 represents CR17 or N; or
        
            W1 represents N and W2 represents CH;
        
        
        R16 represents methyl, (C1-3)alkoxy, halogen, (C1-2)fluoroalkoxy, or trifluoromethyl (notably methoxy or ethoxy);
        R17 represents hydrogen, methyl or fluoro (notably hydrogen);

wherein each combination of W1, W2, R16 and R17 constitutes a particular sub-embodiment.

    
    
    30) A further embodiment of the invention relates to compounds of formula (II) according to embodiment 29); wherein W1 represents CH; W2 represents CR17; R16 represents methoxy; and R17 represents hydrogen, or fluoro (notably hydrogen);
    31) A further embodiment of the invention relates to compounds of formula (II) according to any one of embodiments 26) to 30); wherein, Y1 represents CH2.
    32) A further embodiment of the invention relates to compounds of formula (II) according to any one of embodiments 26) to 30); wherein, Y1 represents CH(CH3).
    33) A further embodiment of the invention relates to compounds of formula (II) according to any one of embodiments 26) to 30); wherein, Y1 represents CH(CH3)2.


The compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of formulae (I) and (II) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.
Any reference to compounds of formulae (I) or (II) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
The term “pharmaceutically acceptable salts” refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.
34) Another embodiment relates to compounds of formula (I) according to embodiment 1) selected from the group consisting of:

    3-(4-Chloro-3-trifluoromethyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(2-methyl-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(4-trifluoromethyl-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(3-methoxy-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(3-trifluoromethyl-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(3-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(4-fluoro-3-methyl-benzyl)-oxazolidin-4-one;
    3-(3-Chloro-4-fluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    3-(3-Chloro-2-fluoro-5-trifluoromethyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(2-methyl-3-trifluoromethyl-benzyl)-oxazolidin-4-one;
    3-(2-Chloro-5-trifluoromethyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(2-fluoro-5-trifluoromethyl-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(4-fluoro-3-trifluoromethyl-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(3-fluoro-4-trifluoromethyl-benzyl)-oxazolidin-4-one;
    3-(2-Chloro-3,6-difluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    3-(4-Chloro-3-fluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    3-(4-Chloro-2-fluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(2-fluoro-benzyl)-oxazolidin-4-one;
    3-(4-Chloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(2-fluoro-4-trifluoromethyl-benzyl)-oxazolidin-4-one;
    3-(2,6-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(3-methyl-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(4-fluoro-benzyl)-oxazolidin-4-one;
    3-(3,4-Difluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(4-methoxy-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-phenyl)-3-(2-methyl-5-trifluoromethyl-benzyl)-oxazolidin-4-one;
    3-(3,4-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    3-(2,4-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    3-(3-Chloro-4-methyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-trifluoromethyl-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(2-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(3-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    3-(3-Chloro-4-fluoro-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    3-(3-Chloro-2-fluoro-5-trifluoromethyl-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-fluoro-3-trifluoromethyl-benzyl)-oxazolidin-4-one;
    3-(4-Chloro-3-fluoro-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(2,4,6-trimethyl-benzyl)-oxazolidin-4-one;
    3-(2,4-Dichloro-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    3-(3-Chloro-4-methyl-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(2,6-dimethyl-benzyl)-oxazolidin-4-one;
    3-(2-Chloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    3-(2,5-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-naphthalen-2-ylmethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-propoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-trifluoromethoxy-benzyl)-(R)-5-methyl-oxazolidin-4-one;
    3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-naphthalen-2-ylmethyl-oxazolidin-4-one;
    3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-(S)-5-methyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    3-Benzothiazol-2-ylmethyl-2-(2,6-dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
    3-Benzothiazol-2-ylmethyl-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    3-(4-Cyclopropylmethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-(S)-5-methyl-3-naphthalen-2-ylmethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-trifluoromethoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
    3-Benzooxazol-2-ylmethyl-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-oxazolidin-4-one;
    3-Benzo[1,3]dioxol-5-ylmethyl-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-methoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
    (R)-2-(2,6-Dimethoxy-phenyl)-5-methyl-3-(4-propoxy-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-(R)-5-methyl-oxazolidin-4-one;
    3-(4-Cyclopropylmethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-propoxy-benzyl)-oxazolidin-4-one;
    3-(4-Cyclopropylmethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-ethoxy-benzyl)-(R)-5-methyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-3-(4-ethoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
    3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethyl-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-difluoro-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2-methoxy-6-methyl-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    2-(2-Fluoro-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    2-(2-Chloro-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    2-(2-Methoxy-6-trifluoromethyl-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    3-Biphenyl-4-ylmethyl-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanyl-benzyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(6-phenoxy-pyridin-3-ylmethyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(5-phenoxy-pyridin-2-ylmethyl)-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(pyridin-2-yloxy)-benzyl]-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(pyrazin-2-yloxy)-benzyl]-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(6-methyl-pyridazin-3-yloxy)-benzyl]-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(thiazol-2-yloxy)-benzyl]-oxazolidin-4-one;
    2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(pyrimidin-2-yloxy)-benzyl]-oxazolidin-4-one;
    2-(2-Isopropoxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    2-(2-Ethoxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
    2-[2-Methoxy-6-(2-methoxy-ethoxy)-phenyl]-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one; and
    2-[2-(3-Hydroxy-propoxy)-6-methoxy-phenyl]-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one.


The compounds of formulae (I) and (II) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parental administration.
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formulae (I) and (II).
For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.
The compounds according to formulae (I) and (II) are useful for the prevention or treatment of diseases related to the orexin system.
Such diseases related to the orexin system may be selected from the group consisting of all types of sleep disorders, of stress-related syndromes, of addictions (especially psychoactive substance use, abuse, seeking and reinstatement), of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
In a sub-embodiment, such diseases related to the orexin system may be selected from the group consisting of sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders (notably all types of insomnias, especially primary insomnia).
In another sub-embodiment, such diseases related to the orexin system may be selected from the group consisting of cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
In another sub-embodiment, such diseases related to the orexin system may be selected from the group consisting of eating disorders that comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
In another sub-embodiment, such diseases related to the orexin system may be selected from the group consisting of all types of addictions (especially psychoactive substance use, abuse, seeking and reinstatement) that comprise all types of psychological or physical addictions and their related tolerance and dependence components.
Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa. Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance. Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
Sleep disorders include all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness. Insomnia also include stress-related syndromes including post-traumatic stress disorders as well as other types and subtypes of anxiety disorders such as generalized anxiety, obsessive compulsive disorder, panic attacks and all types of phobic anxiety and avoidance.
Addictions may be defined as addiction to one or more rewarding stimuli, notably to one rewarding stimulus. Such rewarding stimuli may be of either natural or synthetic origin. Psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
Cognitive dysfunctions include deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
Besides, any characteristics described in this invention for the compounds of formula (I) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula (IE1), formula (IE2), and formula (II).
Preparation of Compounds of Formula (I):
A further aspect of the invention is a process for the preparation of compounds of formula (I). Compounds according to formula (I) of the present invention can be prepared according to the general sequence of reactions outlined in the schemes below wherein Y, R1, R2, R3, R4, R15, R16, R17, and R18 are as defined for formula (I) or (II). Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In some instances the generic groups Y, R1, R2, R3, R4, R15, R16, R17, and R18 might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. The compounds obtained may also be converted into pharmaceutically acceptable salts thereof in a manner known per se.
In general, all chemical transformations can be performed according to well-known standard methodologies as described in the literature or as described in the procedures below.
Oxazolidin-4-one derivatives (Y is CH2 or CHR1) of formula (I) may be prepared according to scheme 1.




Condensation of an amide (1) with an aldehyde (2) in the presence of an acid such PTSA in a Dean-Stark apparatus and in a solvent such as toluene provided the oxazolidin-4-one derivatives (3). Alkylation with a halide (4) in the presence of a strong base such as NaH in an aprotic solvent such as DMF yields the final compounds of formula (I).
Oxazolidin-4-one derivatives (Y is CR1R2) of formula (I) may be prepared according to scheme 2.




Alternatively, condensation of cyanhydrin (5) with an aldehyde (2) in the presence of an strong acid such sulfuric acid in a mixture of Ac2O and AcOH provides for example 5,5′-dimethyl-oxazolidin-4-one derivatives (6) (Stambach J.-P. et al, Heterocycles, 1997, 45, 9, 1825-1831). Alkylation with a halide (4) in the presence of a strong base such as NaH in an aprotic solvent such as DMF yields the compounds of formula (I).
Halides of formula R3—CH2-L1 and aldehydes of formula R4—CHO are commercially available, well known in the art, or readily available from commercially available precursors. Procedures to transform precursor functional groups into such required halides or aldehydes, such as reduction of carboxylic acids, esters, amides, nitriles; oxidation of alcohols; transformation into halides or equivalent activated alcohols (eg. methane-/toluene-sulphonates); or sequential metallation/formylation of aromatic halides are well known in the art (literature for precursors of heteroaryl-containing groups: see e.g. T. Eicher, S. Hauptmann “The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications”, 2nd Edition 2003, Wiley, ISBN 978-3-527-30720-3; A. R. Katrizky, C. W. Rees, E. F. V. Scriven (Eds.) “Comprehensive Heterocyclic Chemistry II” 1996, Elsevier, ISBN 0-08-042072-9).
In some instances, substituents may also be introduced in a final step onto an appropriate (eg. phenolic) precursor molecule. The hydroxy group of such phenol precursor may be alkylated using standard procedures, or arylated using standard procedures such as the Ullmann reaction with halide derivatives of formula Ar3-L1 in the presence of CuCl, 2,2,6,6-tetramethyl-heptane-3,5-dione and a base such as Cs2CO3 in an aprotic solvent such as NMP (WO2006/0173049).
The synthesis of some particular aldehydes of formula R4—CHO is described in the following schemes 3 to 6.
Methylation of commercially available 2,3-dihydro-benzo[1,4]dioxin-6-ol (7) with dimethyl sulfate gives 6-methoxy-2,3-dihydro-benzo[1,4]dioxine (8) (Guillaumet G. et al. Eur. J. Med. Chem. 1990, 25, 1, 45-51). Formylation with n-BuLi/DMF in the presence of TMDA in an aprotic solvent such as THF affords the aldehyde (9) (Guillaumet G. et al. J. Heterocyclic. Chem. 1989, 26, 1, 193-197).
Methylation of commercially benzo[1,3]dioxol-5-ol (10) with methyl iodide in the presence of a base such as K2CO3 in an aprotic solvent such as acetone affords 5-methoxy-benzo[1,3]dioxole (11) (Schuda P. F. et al, J. Org. Chem. 1987, 52, 10, 1972-1979). Formylation with n-BuLi/DMF in the presence of TMDA in an aprotic solvent such as THF affords aldehyde (12) (Guillaumet G. et al. J. Heterocyclic. Chem. 1989, 26, 1, 193-197).
Riemer-Tiemann reaction with CHCl3 in aq. NaOH of the commercially available 7-hydroxyquinoline (13) gives the aldehyde (14). Methylation with dimethyl sulfate affords 7-methoxy-quinoline-8-carbaldehyde (15) (U.S. Pat. No. 4,342,771).




Benzooxazole and benzo[d]isoxazole aldehyde derivatives of formula R4—CHO may for instance be synthesised according to scheme 4.
Reaction of commercially available 3-amino-2,6-dihydroxy-benzoic acid methyl ester (16) with triethyl orthoacetate in the presence of PTSA gives the ester (17) (WO2006/069155). Methylation with dimethyl sulfate in the presence of a base such as K2CO3 in an aprotic solvent such as acetone affords compound (18). Reduction with LAH in an aprotic solvent such as THF gives the alcohol (19) which can be oxidized with MnO2 in DCM to give 6-methoxy-2-methyl-benzooxazole-7-carbaldehyde (20).
Duff formylation of 3-methyl-benzo[d]isoxazol-6-ol (21) with urotropin in AcOH (Elkasaby M. A. et al Indian Journal of Chemistry 1980, 19B(7), 571-575) gives the aldehyde (22) (Kumari S. S. et al Indian Journal of Chemistry 1986, 25B(8), 870-871). Methylation with dimethyl sulfate affords 6-methoxy-3-methyl-benzo[d]isoxazole-7-carbaldehyde (23).




Further synthetic methods for the preparation of aldehydes R4—CHO are described below for the specific examples shown in schemes 5 and 6.




Formylation with n-BuLi/DMF in an aprotic solvent such as THF of the commercially available 3,5-dimethoxypyridine (21) affords 3,5-dimethoxy-pyridine-4-carbaldehyde (22) (U.S. Pat. No. 6,555,557).
Reaction of the commercially available 2-chloro-4-methoxy-pyridine-3-carbaldehyde (23) with NaOMe in MeOH affords 2,4-dimethoxy-pyridine-3-carbaldehyde (24).




Reaction of commercially 2-fluoro-6-methoxy-benzaldehyde (28) with NaOH in EtOH affords the aldehyde (29) (U.S. Pat. No. 4,367,234).
Vilsmeier-Haack reaction with POCl3 in dry DMF of commercially available 1-fluoro-3,5-dimethoxy-benzene (30) gives a mixture of aldehyde (31) and aldehyde (32) with a ratio of about 1/9 (Stanjeck V. et al. Helvetica Chimica Acta 1998, 81, 9, 1596-1607).
Whenever the compounds of formula (I) or (II) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to the one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1 (R,R) (10 μm) column, a Daicel ChiralCel OD-H (5-10 μm) column, or a Daicel ChiralPak IA (10 μm) or AD-H (5 μm) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.


EXPERIMENTAL SECTION
Abbreviations (as Used Herein)


    Ac acetyl (as in Ac2O=acetic acid anhydride; AcOH=acetic acid)
    aq. aqueous
    Bn benzyl
    BSA bovine serum albumine
    CHO Chinese hamster ovary
    conc. concentrated
    d day(s)
    DCM dichloromethane
    DMF N,N-dimethylformamide
    eq equivalent(s)
    ES electron spray
    ether diethyl ether
    EtOAc ethyl acetate
    FC flash chromatography on silica gel
    FCS foatal calf serum
    FLIPR fluorescent imaging plate reader
    h hour(s)
    HBSS Hank's balanced salt solution
    HEPES 4-(2-hydroxyethyl)-piperazine-1-ethanesulfonic acid
    HPLC high performance liquid chromatography
    LAH lithium aluminium hydride
    LC liquid chromatography
    M molar(ity)
    Me methyl
    MeCN acetonitrile
    MeOH methanol
    min minute(s)
    MS mass spectroscopy
    MW microwave
    n-BuLi n-butyllithium
    NMP 1-methyl-2-pyrrolidone
    prep. preparative
    PTSA (para-) p-toluenesulfonic acid
    RT room temperature
    sat. saturated
    tR retention time
    TBS tert-Butyldimethylsilyl
    TFA trifluoroacetic acid
    THF tetrahydrofuran
    TMDA N,N,N′,N′-tetramethylethylenediamine

I-Chemistry



All temperatures are stated in ° C. Compounds are characterized by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6×50 mm, Zorbax SB-AQ, 5 μm, 120 Å, using two conditions:

    basic: eluent A: MeCN, eluent B: conc. NH3 in water (1.0 mL/L), 5% to 95% CH3CN;
    acidic: eluent A: MeCN, eluent B: TFA in water (0.4 mL/L), 5% to 95% CH3CN), tR is given in min; by TLC (TLC-plates from Merck, Silica gel 60 FF254); or by melting point. Compounds are purified by column chromatography on silica gel or by preparative HPLC (column: X-terra RP18, 50×19 mm, 5 μm, gradient: 10-95% MeCN in water containing 0.5% of formic acid).


The following examples illustrate the preparation of pharmacologically active compounds of the invention but do not at all limit the scope thereof. All example compounds have been synthesized in racemic form or as epimers without control of the stereocenter in position 2 of the oxazolidinone moiety.
A.1 Synthesis of oxazolidin-4-one derivatives
A.1.1 Synthesis of 2-aryl-oxazolidin-4-one derivatives (Y═CH2 or CHR1) (general procedure)




A mixture of the respective aldehyde derivative R4—CHO (1.1 eq), the respective amide (1.0 eq), and PTSA (0.01 eq) in dry toluene (60 mL/20 mmol) is stirred at reflux in a Dean-Stark apparatus for 12 h. After removal of the toluene, the residue is dissolved in DCM, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give a crude oil. FC (EtOAc) gives the desired 4-aryl-oxazolidin-4-one derivative.
2-(2,6-Dimethoxy-phenyl)-oxazolidin-4-one
prepared by reaction of 2,6-dimethoxybenzaldehyde with glycolamide; LC-MS: tR=0.41 min; [M+H]+=224.31.
2-(2-Ethoxy-phenyl)-oxazolidin-4-one
prepared by reaction of 2-ethoxybenzaldehyde with glycolamide; LC-MS: tR=0.75 min; [M+H]+=207.97.
2-(2,6-Dimethoxy-phenyl)-(S)-5-methyl-oxazolidin-4-one
prepared by reaction of 2,6-dimethoxybenzaldehyde with (S)-(−)-2-hydroxypropionamide; LC-MS: tR=0.45 min; [M+H]+=238.28.
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one
prepared by reaction of 2,6-dimethoxybenzaldehyde with (R)-(+)-lactamide; LC-MS: tR=0.45 min; [M+H]+=238.21.
A.1.2 Synthesis of 2-aryl-oxazolidin-4-one derivatives (Y═CR1R2)




2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one
To a mixture of acetone cyanhydrin (851 mg), 2,6-dimethoxybenzaldehyde (1.58 g) in AcOH (10 mL) is added at 10° C. dropwise H2SO4 (1 mL) and Ac2O (0.5 mL). The reaction mixture is stirred at 10° C. for 40 min and then 10 min at RT. The reaction mixture is poured into cracked ice and extracted three times with ether. The combined organic extracts are washed with 10% aq. NaHCO3, dried (Na2SO4), filtered and concentrated to yield a crude oil. FC (EtOAc) gives the title compound as a brown oil (1.3 g, 52%). LC-MS: tR=0.47 min; [M+H]+=252.25.
A.2 Preparation of Examples (Method A)




To a cold (0° C.) solution of the respective 2-substituted oxazolidin-4-one derivative (1.0 eq) in DMF (1 mL/0.1 mmol) is added NaH (50% in mineral oil) (2 eq). The reaction mixture is stirred at RT for 30 min under inert atmosphere. Then the respective halide (1 eq) is added and the reaction mixture is stirred at 70° C. for 1.5 h and then 12 h at RT. The products are directly purified by prep. HPLC to provide the final compounds.
The Examples given in table 1 were synthesized according to method A above:










TABLE 1





Example
Name
[M + H]+
tR


















1
3-(4-Chloro-3-trifluoromethyl-benzyl)-2-(2-ethoxy-
399.97
1.11



phenyl)-oxazolidin-4-one


2
2-(2-Ethoxy-phenyl)-3-(2-methyl-benzyl)-
311.96
0.98



oxazolidin-4-one


3
2-(2-Ethoxy-phenyl)-3-(4-trifluoromethyl-benzyl)-
365.97
1.09



oxazolidin-4-one


4
2-(2-Ethoxy-phenyl)-3-(3-methoxy-benzyl)-
327.98
0.95



oxazolidin-4-one


5
2-(2-Ethoxy-phenyl)-3-(3-trifluoromethyl-benzyl)-
366.01
1.08



oxazolidin-4-one


6
2-(2-Ethoxy-phenyl)-3-(4-trifluoromethoxy-benzyl)-
381.97
1.09



oxazolidin-4-one


7
2-(2-Ethoxy-phenyl)-3-(3-trifluoromethoxy-benzyl)-
382.02
1.09



oxazolidin-4-one


8
2-(2-Ethoxy-phenyl)-3-(4-fluoro-3-methyl-benzyl)-
329.97
1.00



oxazolidin-4-one


9
3-(3-Chloro-4-fluoro-benzyl)-2-(2-ethoxy-phenyl)-
349.96
1.07



oxazolidin-4-one


10
3-(3-Chloro-2-fluoro-5-trifluoromethyl-benzyl)-2-(2-
417.90
1.13



ethoxy-phenyl)-oxazolidin-4-one


11
2-(2-Ethoxy-phenyl)-3-(2-methyl-3-trifluoromethyl-
380.04
1.11



benzyl)-oxazolidin-4-one


12
3-(2-Chloro-5-trifluoromethyl-benzyl)-2-(2-ethoxy-
399.96
1.12



phenyl)-oxazolidin-4-one


13
2-(2-Ethoxy-phenyl)-3-(2-fluoro-5-trifluoromethyl-
384
1.09



benzyl)-oxazolidin-4-one


14
2-(2-Ethoxy-phenyl)-3-(4-fluoro-3-trifluoromethyl-
384
1.09



benzyl)-oxazolidin-4-one


15
2-(2-Ethoxy-phenyl)-3-(3-fluoro-4-trifluoromethyl-
384
1.10



benzyl)-oxazolidin-4-one


16
3-(2-Chloro-3,6-difluoro-benzyl)-2-(2-ethoxy-
367.96
1.07



phenyl)-oxazolidin-4-one


17
3-(4-Chloro-3-fluoro-benzyl)-2-(2-ethoxy-phenyl)-
349.95
1.08



oxazolidin-4-one


18
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2-ethoxy-
415.95
1.12



phenyl)-oxazolidin-4-one


19
3-(4-Chloro-2-fluoro-benzyl)-2-(2-ethoxy-phenyl)-
349.94
1.08



oxazolidin-4-one


20
2-(2-Ethoxy-phenyl)-3-(2-fluoro-benzyl)-oxazolidin-
315.97
1.04



4-one


21
3-(4-Chloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-
331.94
1.07



4-one


22
2-(2-Ethoxy-phenyl)-3-(2-fluoro-4-trifluoromethyl-
384.02
1.10



benzyl)-oxazolidin-4-one


23
3-(2,6-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-
365.93
1.09



oxazolidin-4-one


24
2-(2-Ethoxy-phenyl)-3-(3-methyl-benzyl)-
311.96
0.99



oxazolidin-4-one


25
2-(2-Ethoxy-phenyl)-3-(4-fluoro-benzyl)-oxazolidin-
315.98
0.97



4-one


26
3-(3,4-Difluoro-benzyl)-2-(2-ethoxy-phenyl)-
333.97
1.05



oxazolidin-4-one


27
2-(2-Ethoxy-phenyl)-3-(4-methoxy-benzyl)-
327.99
0.96



oxazolidin-4-one


28
2-(2-Ethoxy-phenyl)-3-(5-methyl-2-trifluoromethyl-
380.02
1.11



benzyl)-oxazolidin-4-one


29
3-(3,4-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-
365.93
1.10



oxazolidin-4-one


30
3-(2,4-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-
365.95
1.11



oxazolidin-4-one


31
3-(3-Chloro-4-methyl-benzyl)-2-(2-ethoxy-phenyl)-
345.95
1.09



oxazolidin-4-one


32
2-(2,6-Dimethoxy-phenyl)-3-(4-trifluoromethyl-
381.99
1.06



benzyl)-oxazolidin-4-one


33
2-(2,6-Dimethoxy-phenyl)-3-(2-trifluoromethoxy-
397.97
1.07



benzyl)-oxazolidin-4-one


34
2-(2,6-Dimethoxy-phenyl)-3-(4-trifluoromethoxy-
397.97
1.07



benzyl)-oxazolidin-4-one


35
2-(2,6-Dimethoxy-phenyl)-3-(3-trifluoromethoxy-
397.97
1.07



benzyl)-oxazolidin-4-one


36
3-(3-Chloro-4-fluoro-benzyl)-2-(2,6-dimethoxy-
365.95
1.05



phenyl)-oxazolidin-4-one


37
3-(3-Chloro-2-fluoro-5-trifluoromethyl-benzyl)-2-
433.90
1.10



(2,6-dimethoxy-phenyl)-oxazolidin-4-one


38
2-(2,6-Dimethoxy-phenyl)-3-(4-fluoro-3-
400.02
1.06



trifluoromethyl-benzyl)-oxazolidin-4-one


39
3-(4-Chloro-3-fluoro-benzyl)-2-(2,6-dimethoxy-
365.96
1.05



phenyl)-oxazolidin-4-one


40
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-
431.91
1.10



dimethoxy-phenyl)-oxazolidin-4-one


41
2-(2,6-Dimethoxy-phenyl)-3-(2,4,6-trimethyl-
356.04
1.01



benzyl)-oxazolidin-4-one


42
3-(2,4-Dichloro-benzyl)-2-(2,6-dimethoxy-phenyl)-
381.91
1.01



oxazolidin-4-one


43
3-(3-Chloro-4-methyl-benzyl)-2-(2,6-dimethoxy-
341.99
1.05



phenyl)-oxazolidin-4-one


44
2-(2,6-Dimethoxy-phenyl)-3-(2,6-dimethyl-benzyl)-
341.94
1.16



oxazolidin-4-one


45
3-(2-Chloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-
331.92
1.06



4-one


46
3-(2,5-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-
365.95
1.11



oxazolidin-4-one


47
2-(2,6-Dimethoxy-phenyl)-3-(4-phenoxy-benzyl)-
406.13
0.78



oxazolidin-4-one


48
2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-
416.13
0.76



trifluoromethoxy-benzyl)-oxazolidin-4-one


49
3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-
380.17
0.70



phenyl)-oxazolidin-4-one


50
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-
433.78
0.80



phenoxy-benzyl)-oxazolidin-4-one


51
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-(4-
420.19
0.79



phenoxy-benzyl)-oxazolidin-4-one


52
3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-
394.16
0.72



phenyl)-(R)-5-methyl-oxazolidin-4-one


53
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-
378.29
0.75



naphthalen-2-ylmethyl-oxazolidin-4-one


54
2-(2,6-Dimethoxy-phenyl)-3-(4-propoxy-benzyl)-
372.20
0.74



oxazolidin-4-one


55
2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-
430.14
0.77



trifluoromethoxy-benzyl)-(R)-5-methyl-oxazolidin-4-



one


56
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-
446.14
0.79



dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one


57
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-
392.24
0.76



naphthalen-2-ylmethyl-oxazolidin-4-one


58
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-
460.11
0.81



dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one


59
2-(2,6-Dimethoxy-phenyl)-(S)-5-methyl-3-(4-
420.22
0.79



phenoxy-benzyl)-oxazolidin-4-one


60
2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-
372.22
0.72



oxazolidin-4-one


61
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-
426.24
0.78



trifluoromethoxy-benzyl)-oxazolidin-4-one


62
3-Benzothiazol-2-ylmethyl-2-(2,6-dimethoxy-
385.12
0.68



phenyl)-(R)-5-methyl-oxazolidin-4-one


63
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-(4-
412.22
0.77



trifluoromethoxy-benzyl)-oxazolidin-4-one


64
3-Benzothiazol-2-ylmethyl-2-(2,6-dimethoxy-
399.21
0.70



phenyl)-5,5-dimethyl-oxazolidin-4-one


65
3-(4-Cyclopropylmethoxy-benzyl)-2-(2,6-
384.28
0.74



dimethoxy-phenyl)-oxazolidin-4-one


66
2-(2,6-Dimethoxy-phenyl)-(S)-5-methyl-3-
378.19
0.75



naphthalen-2-ylmethyl-oxazolidin-4-one


67
2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-
444.13
0.79



trifluoromethoxy-benzyl)-5,5-dimethyl-oxazolidin-4-



one


68
3-Benzooxazol-2-ylmethyl-2-(2,6-dimethoxy-
383.20
0.67



phenyl)-5,5-dimethyl-oxazolidin-4-one


69
3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-
408.19
0.74



phenyl)-5,5-dimethyl-oxazolidin-4-one


70
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(1-
396.22
0.51



methyl-1H-benzoimidazol-2-ylmethyl)-oxazolidin-4-



one


71
3-Benzo[1,3]dioxol-5-ylmethyl-2-(2,6-dimethoxy-
385.73
0.69



phenyl)-5,5-dimethyl-oxazolidin-4-one


72
2-(2,6-Dimethoxy-phenyl)-3-(4-methoxy-benzyl)-
372.22
0.69



5,5-dimethyl-oxazolidin-4-one


73
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-(4-
385.83
0.76



propoxy-benzyl)-oxazolidin-4-one


74
2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-
385.82
0.74



(R)-5-methyl-oxazolidin-4-one


75
3-(4-Cyclopropylmethoxy-benzyl)-2-(2,6-
398.27
0.75



dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one


76
2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-
400.27
0.75



5,5-dimethyl-oxazolidin-4-one


77
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-
400.27
0.77



propoxy-benzyl)-oxazolidin-4-one


78
3-(4-Cyclopropylmethoxy-benzyl)-2-(2,6-
412.23
0.76



dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one


79
2-(2,6-Dimethoxy-phenyl)-3-(4-ethoxy-benzyl)-(r)-
372.23
0.71



5-methyl-oxazolidin-4-one


80
2-(2,6-Dimethoxy-phenyl)-3-(4-ethoxy-benzyl)-5,5-
385.76
0.73



dimethyl-oxazolidin-4-one


81
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-
428.09
0.86



dimethyl-phenyl)-5,5-dimethyl-oxazolidin-4-one


82
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-
436.07
0.83



difluoro-phenyl)-5,5-dimethyl-oxazolidin-4-one


83
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2-
443.31
0.86



methoxy-6-methyl-phenyl)-5,5-dimethyl-oxazolidin-



4-one


84
2-(2-Fluoro-6-methoxy-phenyl)-5,5-dimethyl-3-(4-
422.20
0.82



phenoxy-benzyl)-oxazolidin-4-one


85
2-(2-Chloro-6-methoxy-phenyl)-5,5-dimethyl-3-(4-
438.19
0.83



phenoxy-benzyl)-oxazolidin-4-one


86
2-(2-Methoxy-6-trifluoromethyl-phenyl)-5,5-
472.25
0.85



dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one


87
3-Biphenyl-4-ylmethyl-2-(2,6-dimethoxy-phenyl)-
417.77
0.81



5,5-dimethyl-oxazolidin-4-one


88
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-
442.17
0.81



trifluoromethylsulfanyl-benzyl)-oxazolidin-4-one


89
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(6-
435.24
0.73



phenoxy-pyridin-3-ylmethyl)-oxazolidin-4-one









Example 90
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(5-phenoxy-pyridin-2-ylmethyl)-oxazolidin-4-one
This compound has been prepared according to method A above using 2-chloromethyl-5-phenoxy-pyridine hydrochloride (prepared using the methods given in Kawasuji T. et al, Bioorganic & Medicinal Chemistry 2006, 14, 8430-8445 and WO2007/099317) as halide. LC-MS: tR=0.72 min; [M+H]+=435.16.
A.3 Preparation of Examples (Method B)
A.3.1 Preparation of 2-(2,6-dimethoxy-phenyl)-3-(4-hydroxy-benzyl)-5,5-dimethyl-oxazolidin-4-one
This compound has been prepared according to method A above using (4-bromomethyl-phenoxy)-tert-butyl-diphenyl-silane (prepared using the methods given in Petit G. R. et al, Journal of Medicinal Chemistry 2002, 45, 12, 2534-2542) as halide. LC-MS: tR=0.58 min; [M+H]+=358.20.
A.3.2 Preparation of Examples (Method B)
The examples given in table 2 have been prepared from 2-(2,6-dimethoxy-phenyl)-3-(4-hydroxy-benzyl)-5,5-dimethyl-oxazolidin-4-one via Ullmann reaction with an appropriate heteroaryl halide derivatives of formula R15-L1 in the presence of CuCl, 2,2,6,6-tetramethyl-heptane-3,5-dione and a base such as Cs2CO3 in an aprotic solvent such as NMP (WO2006/0173049).










TABLE 2





Example
Name
[M + H]+
tR







91
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-
435.28
0.73



3-[4-(pyridin-2-yloxy)-benzyl]-



oxazolidin-4-one


92
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-
436.31
0.72



3-[4-(pyrazin-2-yloxy)-benzyl]-



oxazolidin-4-one


93
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-
449.71
0.64



3-[4-(6-methyl-pyridazin-3-yloxy)-



benzyl]-oxazolidin-4-one


94
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-
441.18
0.73



3-[4-(thiazol-2-yloxy)-benzyl]-



oxazolidin-4-one


95
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-
436.24
0.68



3-[4-(pyrimidin-2-yloxy)-benzyl]-



oxazolidin-4-one









A.4 Preparation of Examples (Method C)
A.4.1 Preparation of 2-(2-hydroxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one
A.4.1.1. Preparation of 2-(2-benzyloxy-6-methoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one
A mixture of commercially available 2-hydroxyisobutyramide (638.5 mg, 3 eq), 2-benzyloxy-6-methoxy-benzaldehyde (500 mg) (Katritzky A. R. et al ARKIVOC 2001, 2, 3, 3-12) is heated at 240° C. for 5 min using microwave irradiation (Lecolier S. et al Chimica Therapeutica 1969, 4,6, 437-445). The crude oil is poured into water and extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 1/1 to 1/0) gives the title compound as a yellow solid (0.41 g, 61%); LC-MS: tR=0.65 min; [M+H]+=328.22.
A.4.1.2. Preparation of 2-(2-hydroxy-6-methoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one
To a cold (0° C.) solution of 2-(2-benzyloxy-6-methoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one (410 mg) in dry DMF (5 mL) is added portionwise NaH 90% (45 mg, 1.5 eq). The reaction mixture is stirred for 15 min at 0° C. and then commercially available 1-(bromomethyl)-4-phenoxybenzene (395 mg, 1.2 eq) is added and the reaction mixture is stirred at RT for 1 h. The reaction mixture is poured into water, extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 0/1 to 4/6) gives 2-(2-benzyloxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one as a colorless oil (0.495 g, 77%); LC-MS: tR=0.88 min; [M+H]+=510.33.
Hydrogenation of this intermediate over Pd(OH)2 at normal pressure in EtOH gives the title compound as a white solid (388 mg, 93%); LC-MS: tR=0.75 min; [M+H]+=420.17.
A.4.2. Preparation of Examples (Method C)
To a mixture of 2-(2-hydroxy-6-methoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one (0.05 mmol), Cs2CO3 (0.065 mmol) in dry DMF (0.1 mL) is added dropwise the appropriate halide alkylating agent (0.1 mmol) (e.g. 1-bromo-3-hydroxy-propane, 2-methoxy-ethylbromide, 2-bromopropane, ethylbromide) in dry DMF (0.1 mL). The reaction mixture is stirred at 90° C. for 30 min. The products are directly purified by prep. HPLC to provide the final compound.
The Examples given in table 3 were synthesized according to method C above:










TABLE 3





Example
Name
[M + H]+
tR







96
2-(2-Isopropoxy-6-methoxy-phenyl)-
462.24
1.04



5,5-dimethyl-3-(4-phenoxy-benzyl)-



oxazolidin-4-one


97
2-(2-Ethoxy-6-methoxy-phenyl)-5,5-
448.19
1.01



dimethyl-3-(4-phenoxy-benzyl)-



oxazolidin-4-one


98
2-[2-Methoxy-6-(2-methoxy-ethoxy)-
478.16
0.97



phenyl]-5,5-dimethyl-3-(4-phenoxy-



benzyl)-oxazolidin-4-one


99
2-[2-(3-Hydroxy-propoxy)-6-methoxy-
478.15
0.90



phenyl]-5,5-dimethyl-3-(4-phenoxy-



benzyl)-oxazolidin-4-one









II-Biological Assays

In Vitro Assay

The orexin receptor antagonistic activity of the compounds of formula (I) is determined in accordance with the following experimental method.
Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 μg/ml G418, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% heat inactivated fetal calf serum (FCS). The cells are seeded at 20′000 cells/well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37° C. in 5% CO2.
Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH:water (1:1), diluted in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g/l and 20 mM HEPES for use in the assay at a final concentration of 3 nM.
Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g/l and 20 mM HEPES. On the day of the assay, 50 μl of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, NaHCO3: 0.375 g/l, 5 mM probenecid (Sigma) and 3 μM of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well. The 384-well cell-plates are incubated for 50 min at 37° C. in 5% CO2 followed by equilibration at rt for 30-120 min before measurement.
Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists are added to the plate in a volume of 10 μl/well, incubated for 10 min and finally 10 μl/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 3 nM orexin-A with vehicle in place of antagonist. For each antagonist, the IC50 value (the concentration of compound needed to inhibit 50% of the agonistic response) is determined and normalized using the obtained IC50 value of a on-plate reference compound. Optimized conditions were achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values of the compounds may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art.
Antagonistic activities of exemplified compounds are displayed in Table 1.















TABLE 1






OX1 IC50
OX2 IC50

OX1 IC50
OX2 IC50

OX1 IC50
OX2 IC50


Ex.
(nM)
(nM)
Ex.
(nM)
(nM)
Ex.
(nM)
(nM)























18
8794 
 26
1
6487
263
13
>10000
290


37
162
477
2
>10000
223
14
>10000
169


40
198
 29
3
9991
230
15
>10000
359


47
1184 
 68
4
>10000
705
16
590
3813


50
 28*
 58*
5
>10000
462
17
9370
627


51
220
 25
6
>10000
55
19
9598
586


57
   5*2
  151*2
7
6806
74
20
>10000
262


61
 29
160
8
9167
584
21
>10000
696


67
  25*2
  322*2
9
8736
79
22
>10000
839


70
 65
1298 
10
8409
693
23
1844
787


76
114
193
11
5408
385
24
>10000
363


80
139
1937 
12
4044
590
68
2936
508


25
>10000   
199
38
1382
730
53
47
65


26
>10000   
652
39
4105
795
54
1710
81


27
>10000   
353
41
542
681
55
178
108


28
8021 
661
42
1489
376
56
164
111


29
>10000   
696
43
553
349
58
25
133


30
3045 
844
44
1758
467
59
2134
150


31
7596 
634
45
1738
870
60
3242
159


32
>10000   
413
46
788
1522
62
2867
193


33
>10000   
225
47
1184
68
63
260
216


34
6474 
298
48
1352
99
64
411
222


35
2889 
618
49
2991
113
65
6325
243


36
1340 
632
52
726
41
66
421
266


69
187
928
82
336
110
92
1212
3059


71
150
1664 
83
133
69
93
1198
8331


72
188
2267 
84
421
46
95
2990
7262


73
581
 86
85
204
37
96
10
120


74
1208 
 95
86
2177
65
97
25
62


75
1763 
123
87
64
1086
98
345
366


77
114
484
88
120
298
99
80
150


78
472
620
89
139
212
81
920
88


79
830
864
90
413
236
91
110
443





Ex. = Compound of Example


*geomean from n = 5 values


*2geomean from n = 2 values

## Claims

1. A compound of formula (I)



wherein
Y represents CH2, CHR1, or CR1R2; wherein
R1 and R2 independently represent (C1-4)alkyl;

R3 represents Ar1 or Ar3—Z—Ar2—* wherein the asterisk indicates the bond that is attached to the rest of the molecule; wherein
Ar1 represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C1-3)fluoroalkyl-thio-, and (C3-6) cycloalkyl-(C1-4)alkoxy;
Ar2 represents phenyl or 5- to 6-membered heteroaryl;
Z represents a bond, O, or —CH2—O—* wherein the asterisk indicates the bond that is attached to Ar2;
Ar3 represents phenyl or 5- to 6-membered heteroaryl wherein the phenyl or 5- to 6-membered heteroaryl is independently unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3) fluoroalkoxy; and

R4 represents aryl or heteroaryl, wherein the aryl or heteroaryl is independently mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C14alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy; wherein, in the specific case wherein said aryl or heteroaryl is a bicyclic ring, the aryl or heteroaryl may also be unsubstituted;
with the exception of the following compounds:
2-(2-bromophenyl)-3-[(4-methoxyphenyl)methyl]-4-oxazolidinone;
2-(2-bromophenyl)-3-{[4-(trifluoromethyl)phenyl]methyl}-4-oxazolidinone;
2-(2-bromophenyl)-3-(phenylmethyl)-4-oxazolidinone; and
2-(4-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]-5-methyl-4-oxazolidinone;
in a free or a pharmaceutically acceptable salt.

2. The compound according to claim 1; wherein Y represents CHR1, or CR1R2;
in a free or a pharmaceutically acceptable salt.

3. The compound according to claim 1; wherein
Ar1 represents aryl which is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C1-3)fluoroalkyl-thio-, and (C3-6)cycloalkyl-(C1-4)alkoxy; or
Ar1 represents heteroaryl which is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy and (C1-3)fluoroalkyl;

in a free or a pharmaceutically acceptable salt.

4. The compound according to claim 1; wherein, in case Ar1 represents aryl, said aryl is
phenyl which is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C1-3)fluoroalkyl-thio-, and (C3-6)cycloalkyl-(C1-4)alkoxy; or
naphthyl which is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; or
a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 to 2 oxygen atoms which is unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of methyl, methoxy, and halogen;

in a free or a pharmaceutically acceptable salt.

5. The compound according to claim 1; wherein Z represents a O; in a free or a pharmaceutically acceptable salt.

6. The compound according to claim 1; wherein
Ar3 represents phenyl which is unsubstituted, or mono-, di-, or tri-substituted wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; or
Ar3 represents 5- to 6-membered heteroaryl which is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy;

in a free or a pharmaceutically acceptable salt.

7. The compound according to claim 1; wherein R3 represents
phenyl which is mono-, or di-substituted, wherein one substituent is (C1-4)alkoxy, or (C1-3)fluoroalkoxy in position 4 of said phenyl and the other (if present) is selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; or
Ar3—Z—Ar2—* wherein the asterisk indicates the bond that is attached to the rest of the molecule; wherein
Ar2 represents phenyl or 6-membered heteroaryl which are substituted by Z and the rest of the molecule in a para arrangement,
Z represents O, and
Ar3 represents phenyl or 5- to 6-membered heteroaryl wherein the phenyl or 5- to 6-membered heteroaryl is independently unsubstituted or mono-substituted, wherein the substituent is independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy;


in a free or a pharmaceutically acceptable salt.

8. The compound according to claim 1; wherein
R4 represents aryl which is mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy; wherein, in the specific case wherein said aryl is a bicyclic ring, the aryl may also be unsubstituted; or
R4 represents heteroaryl which is mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4) alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy; wherein, in the specific case wherein said heteroaryl is a bicyclic ring, the heteroaryl may also be unsubstituted;

in a free or a pharmaceutically acceptable salt.

9. The compound according to claim 1; wherein, in case R4 represents aryl, said aryl is
phenyl which is mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, hydroxy-(C1-4)alkoxy, and (C1-4)alkoxy-(C1-4)alkoxy; or
naphthyl which is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; or
a phenyl ring fused to a 5- or 6-membered saturated or partially unsaturated non-aromatic ring optionally containing 1 to 2 oxygen atoms which is unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from the group consisting of methyl, methoxy, and halogen;

in a free or a pharmaceutically acceptable salt.

10. A compound of formula (II)



wherein
Y1 represents CH2, CH(CH3) or CH(CH3)2;




R13 represents
wherein
R15 represents (C1-4)alkyl or (C1-3)fluoroalkyl;
V1, V2 and V4 are CH, and V3 is CR17, wherein optionally one or two of V1, V2, V3 and V4 may also be N; and
R17 is hydrogen or halogen; or

R15 represents phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or 5- to 6-membered heteroaryl is independently unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; and
one or two of V1, V2, V3 and V4 are CH or N and the remaining are CH; and

R14 represents a group selected from the group consisting of:




wherein
W1 represents CH and W2 represents CR17 or N, or
W1 represents N and W2 represents CH;

R16 represents methyl, (C1-3)alkoxy, halogen, (C1-2)fluoroalkoxy, or trifluoromethyl;
R17 represents hydrogen, methyl or fluoro; and
n represents the integer 1 or 2;


in a free or a pharmaceutically acceptable salt.

11. The compound according to claim 1 selected from the group consisting of:
3-(4-Chloro-3-trifluoromethyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(2-methyl-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(4-trifluoromethyl-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(3-methoxy-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(3-trifluoromethyl-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(3-trifluoromethoxy-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(4-fluoro-3-methyl-benzyl)-oxazolidin-4-one;
3-(3-Chloro-4-fluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
3-(3-Chloro-2-fluoro-5-trifluoromethyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(2-methyl-3-trifluoromethyl-benzyl)-oxazolidin-4-one;
3-(2-Chloro-5-trifluoromethyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(2-fluoro-5-trifluoromethyl-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(4-fluoro-3-trifluoromethyl-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(3-fluoro-4-trifluoromethyl-benzyl)-oxazolidin-4-one;
3-(2-Chloro-3,6-difluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
3-(4-Chloro-3-fluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
3-(4-Chloro-2-fluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(2-fluoro-benzyl)-oxazolidin-4-one;
3-(4-Chloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(2-fluoro-4-trifluoromethyl-benzyl)-oxazolidin-4-one;
3-(2,6-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(3-methyl-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(4-fluoro-benzyl)-oxazolidin-4-one;
3-(3,4-Difluoro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(4-methoxy-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-phenyl)-3-(2-methyl-5-trifluoromethyl-benzyl)-oxazolidin-4-one;
3-(3,4-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
3-(2,4-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
3-(3-Chloro-4-methyl-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-trifluoromethyl-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(2-trifluoromethoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(3-trifluoromethoxy-benzyl)-oxazolidin-4-one;
3-(3-Chloro-4-fluoro-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
3-(3-Chloro-2-fluoro-5-trifluoromethyl-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-fluoro-3-trifluoromethyl-benzyl)-oxazolidin-4-one;
3-(4-Chloro-3-fluoro-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(2,4,6-trimethyl-benzyl)-oxazolidin-4-one;
3-(2,4-Dichloro-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
3-(3-Chloro-4-methyl-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(2,6-dimethyl-benzyl)-oxazolidin-4-one;
3-(2-Chloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
3-(2,5-Dichloro-benzyl)-2-(2-ethoxy-phenyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
3-(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-naphthalen-2-ylmethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-propoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-trifluoromethoxy-benzyl)-(R)-5-methyl-oxazolidin-4-one;
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-naphthalen-2-ylmethyl-oxazolidin-4-one;
3-(3-Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-(S)-5-methyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
3 -Benzothiazol-2-ylmethyl-2-(2,6-dimethoxy-phenyl)-(R)-5-methyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-(R)-5-methyl-3-(4-trifluoromethoxy-benzyl)-oxazolidin-4-one;
3 -Benzothiazol-2-ylmethyl-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
3-(4-Cyclopropylmethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-(S)-5-methyl-3-naphthalen-2-ylmethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(3-fluoro-4-trifluoromethoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
3 -Benzooxazol-2-ylmethyl-2-(2,6-dimethoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one;
3 -(4-Difluoromethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-5 ,5 -dimethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5 ,5 -dimethyl-3 -(1-methyl-1H-benzoimidazol-2-ylmethyl)-oxazolidin-4-one;
3 -Benzo [1,3]dioxol-5 -ylmethyl-2-(2,6-dimethoxy-phenyl)-5 ,5 -dimethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-methoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
(R)-2-(2,6-Dimethoxy-phenyl)-5-methyl-3-(4-propoxy-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-(R)-5-methyl-oxazolidin-4-one;
3 -(4-Cyclopropylmethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-(R)-5 -methyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-isopropoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-propoxy-benzyl)-oxazolidin-4-one;
3 -(4-Cyclopropylmethoxy-benzyl)-2-(2,6-dimethoxy-phenyl)-5 ,5 -dimethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-ethoxy-benzyl)-(R)-5-methyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-3-(4-ethoxy-benzyl)-5,5-dimethyl-oxazolidin-4-one;
3 -(3 -Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-dimethyl-phenyl)-5 ,5 -dimethyl-oxazolidin-4-one;
3 -(3 -Chloro-4-trifluoromethoxy-benzyl)-2-(2,6-difluoro-phenyl)-5 ,5 -dimethyl-oxazolidin-4-one;
3 -(3 -Chloro-4-trifluoromethoxy-benzyl)-2-(2-methoxy-6-methyl-phenyl)-5 ,5 -dimethyl-oxazolidin-4-one;
2-(2-Fluoro-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
2-(2-Chloro-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
2-(2-Methoxy-6-trifluoromethyl-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
3 -Biphenyl-4-ylmethyl-2-(2,6-dimethoxy-phenyl)-5 ,5 -dimethyl-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanyl-benzyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-(6-phenoxy-pyridin-3-ylmethyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5 ,5 -dimethyl-3 -(5-phenoxy-pyridin-2-ylmethyl)-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(pyridin-2-yloxy)-benzyl]-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(pyrazin-2-yloxy)-benzyl]-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5 ,5-dimethyl-3-[4-(6-methyl-pyridazin-3-yloxy)-benzyl]-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(thiazol-2-yloxy)-benzyl]-oxazolidin-4-one;
2-(2,6-Dimethoxy-phenyl)-5,5-dimethyl-3-[4-(pyrimidin-2-yloxy)-benzyl]-oxazolidin-4-one;
2-(2-Isopropoxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
2-(2-Ethoxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
2-[2-Methoxy-6-(2-methoxy-ethoxy)-phenyl]-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one; and
2-[2-(3-Hydroxy-propoxy)-6-methoxy-phenyl]-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one;
in a free or a pharmaceutically acceptable salt.

12. The pharmaceutical composition containing, as active principle, the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

13. A method for the treatment of a disease or disorder wherein the compound of claim 1 is administered to a patient in need therof, wherein said disease or disorder is an insomnia.

14. A method for the treatment of a disease or disorder wherein the compound of claim 10 is administered to a patient in need thereof, wherein said disease or disorder is an insomnia.

15. A pharmaceutical composition comprising a compound according to claim 10, in a free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier.