BR112015023454B1 - HALOGENATED OXAZOLIDINONE DERIVATIVES, THEIR PREPARATION PROCESS, PHARMACEUTICAL COMPOSITION, AND THEIR USE - Google Patents

Abstract

INHIBITORS, THEIR PHARMACEUTICAL COMPOSITION, THEIR PREPARATION PROCESS AND THEIR USE. The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein R1, R2, R3, R4 and R5 are as defined herein , as glutaminyl cyclase inhibitors (QC, EC 2,3,2,5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (5-oxo-prolyl, pGlu*) under ammonia release and the intramolecular cyclization of N-terminal glutamate residues to pyroglutamic acid under water release.

Description

Field of Invention

[001] The invention relates to halogenated oxazolidinone derivatives with improved pharmacokinetic properties as glutaminyl cyclase inhibitors (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (5-oxo-prolyl, pGlu*) under ammonia release and the intramolecular cyclization of N-terminal glutamate residues to pyroglutamic acid under water release.

Background of the Invention

[002] Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (pGlu*) releasing ammonia. QC was first isolated by Messer from the latex of the tropical plant Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). 24 years later, a corresponding enzymatic activity was observed in animal pituitaries (Busby, W. H. J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl Acad Sci USA 84, 3628-3632 ). For mammalian QC, conversion of Gln to pGlu by QC can be shown for the precursors of TRH and GnRH (Busby, W. H. J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl Acad Sci U S A 84, 3628-3632). Furthermore, early localization experiments of QC revealed colocalization with its putative catalysis products in bovine pituitary, also enhancing the suggested function in peptide hormone synthesis (Bockers, T. M. et al. 1995 J Neuroendocrinol 7, 445-453). In contrast, the physiological function of plant QC is less evident. In the case of the C. papaya enzyme, a role in the plant's defense against pathogenic microorganisms has been suggested (El Moussaoui, A. et al. 2001 Cell Mol Life Sci 58, 556-570). Putative QCs from other plants have been identified by sequence comparisons recently (Dahl, S. W. et al. 2000 Protein Expr Purif 20, 27-36). The physiological function of these enzymes, however, is still ambiguous.

[003] Known QCs from plants and animals show an extrinsic specificity for L-Glutamine in the N-terminal position of the substrates, and their compounding has been observed to obey the Michaelis-Menten equation (Pohl, T. et al. 1991 Proc Natl Acad Sci U S A 88, 10059-10063; Consalvo, A. P. et al. 1988 Anal Biochem 175, 131-138; Gololobov, M. Y. et al. 1996 Biol Chem Hoppe Seyler 377, 395-398). A comparison of the primary structures of the C. papaya QCs and that of the highly conserved mammalian QC, however, did not reveal any sequence homology (Dahl, S. W. et al. 2000 Protein Expr Purif 20, 27-36). Whereas plant QCs appear to belong to a new enzyme family (Dahl, S. W. et al. 2000 Protein Expr Purif 20, 27-36), mammalian QCs have been found to have pronounced sequence homology to bacterial aminopeptidases (Bateman, R. C. et al. 2001 Biochemistry 40, 11246-11250), leading to the conclusion that plant and animal QCs have different evolutionary origins.

[004] Recently, it has been shown that recombinant human QC as well as QC activity from brain extracts catalyze N-terminal glutaminyl as well as glutamate cyclization. More impressive is the finding that cyclase-catalyzed conversion of Glu1 is favored around pH 6.0 while conversion of Gln1 to pGlu derivatives occurs at an optimal pH around 8.0. Since the formation of pGlu-Aβ-related peptides can be suppressed by inhibiting recombinant human QC and the QC activity of pig pituitary extracts, the CQ enzyme is a target in the development of drugs for the treatment of pGlu-Aβ-related peptides. Alzheimer's.

[005] QC inhibitors are described in WO 2004/098625, WO 2004/098591, WO 2005/039548, WO 2005/075436, WO 2008/055945, WO 2008/055947, WO 2008/055950, WO2 008/065141, WO 2008 /110523, WO 2008/128981, WO 2008/128982, WO 2008/128983, WO 2008/128984, WO 2008/128985, WO 2008/128986, WO 2008/128987, WO 2010/0 26212, WO 2011/029920, WO 2011 /107530, WO 2011/110613, WO 2011/131748 and WO 2012/123563, in which WO 2011/029920 describes among other things, oxazolidinone derivatives as glutaminyl cyclase inhibitors.

[006] EP 02 011 349.4 describes polynucleotides encoding insect glutaminyl cyclase, as well as polypeptides encoded in this way and their use in methods of evaluating agents that reduce glutaminyl cyclase activity. Such agents are useful as pesticides.

Definitions

[007] The terms "ki" or "KI" and "KD" are binding constants, which describe the binding of an inhibitor to, and the subsequent release of, an enzyme. Another measurement is the "IC50" value, which reflects the inhibitor concentration, which at a given substrate concentration results in 50% enzyme activity.

[008] The term "DP IV inhibitor" or "dipeptidyl peptidase IV inhibitor" is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of DP IV or DP IV-like enzymes.

[009] "DP IV activity" is defined as the catalytic activity of dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. These enzymes are post-proline (to a lesser extent post-alanine, post-serine, or post-glycine) cleaving serine proteases found in various tissues of the mammalian body including the kidney, liver, and intestine, where they remove terminal dipeptides. N of biologically active peptides with a high specificity when proline or alanine form residues that are adjacent to the N-terminal amino acid in their sequence.

[0010] The term "PEP inhibitor" or "prolyl endopeptidase inhibitor" is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP).

[0011] "PEP activity" is defined as the catalytic activity of an endoprotease that is capable of hydrolyzing proline post-bonds in peptides or proteins, where the proline is at amino acid position 3 or higher counted from the N terminus of a peptide or protein substrate.

[0012] The term "QC" as used herein comprises glutaminyl cyclase (QC) and QC-like enzymes. QC and QC-like enzymes have identical or similar enzymatic activity, also defined as QC activity. In this regard, QC-like enzymes may fundamentally differ in their molecular structure from QC. Examples of QC-like enzymes are the glutaminyl-peptide cyclotransferase-like proteins (QPCTLs) of human (GenBank NM_017659), mouse (GenBank BC058181), Macaca fascicularis (GenBank AB168255), Macaca mulatta (GenBank XM_001110995), Canis familiaris (GenBank XM_541552 ), Rattus norvegicus (GenBank XM_001066591), Mus musculus (GenBank BC058181) and Bos taurus (GenBank BT026254).

[0013] The term "QC activity" as used herein is defined as intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (pGlu*) or of N-terminal L-homoglutamine or L-β-homoglutamine to a cyclic pyrohomoglutamine derivative ammonia release. See, therefore, schemes 1 and 2. Scheme 1: Glutamine cyclization by QC

[0014] Caption: peptide Scheme 2: Cyclization of L-homoglutamine by QC

[0015] Caption: peptide

[0016] The term "EC" as used herein comprises the activity of QC and QC-like enzymes such as glutamate cyclase (EC), also defined as EC activity.

[0017] The term "EC activity" as used here is defined as intramolecular cyclization of N-terminal glutamate residues to pyroglutamic acid (pGlu*) by QC. See therefore Scheme 3. Scheme 3: N-terminal cyclization of uncharged glutamyl peptides by QC (EC)

[0018] The term "QC inhibitor" "glutaminyl cyclase inhibitor" is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of glutaminyl cyclase (QC) or its glutamyl cyclase activity (EC ).

QC inhibition power

[0019] In light of the correlation with QC inhibition, in preferred embodiments, the object method and medical use utilizes an agent with an IC50 for QC inhibition of 10 μM or less, more preferably 1 μM or less, even more preferably of 0.1 μM or less or 0.01 μM or less, or more preferably 0.001 μM or less. Indeed, inhibitors with Ki values in the lower micromolar, preferably the nanomolar and even more preferably the picomolar range are contemplated. Thus, while the active agents are described here, for convenience, as "QC inhibitors", it will be understood that such nomenclature is not intended to limit the object of the invention to a particular mechanism of action.

Molecular weight of QC inhibitors

[0020] In general, the QC inhibitors of the subject method or medical use will be small molecules, for example, with molecular weights of 500 g/mole or less, 400 g/mole or less, preferably 350 g/mole or less, and even more preferably 300 g/mole or less and further preferably 250 g/mole or less.

[0021] The term "subject" as used herein refers to an animal, preferably a mammal, more preferably a human, that has been the object of treatment, observation or experiment.

[0022] The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that induces the biological or medical response in a tissue, animal or human system being sought by a researcher, veterinarian, physician or other clinical, which includes relief of symptoms of the disease or disorder being treated.

[0023] As used herein, the term "pharmaceutically acceptable" encompasses both human and veterinary use: for example, the term "pharmaceutically acceptable" encompasses a veterinary acceptable compound or a compound acceptable in human medicine and medical care.

[0024] Throughout the description and the claims the expression "alkyl", unless specifically limited, denotes a C1-12 alkyl group, a suitable C1-8 alkyl group, e.g. C1-6 alkyl group, e.g. C1-4 alkyl group. Alkyl groups can be straight or branched chain. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. , n-pentyl), hexyl (e.g. n-hexyl), heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl). The expression "alc", for example in the expressions "alkoxy", "haloalkyl" and "thioalkyl" should be interpreted in accordance with the definition of "alkyl". Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g. n -heptoxy) and octoxy (e.g. n-octoxy). Exemplary thioalkyl groups include methylthio-. Exemplary haloalkyl groups include fluoroalkyl, for example, CF3, fluoroethyl, fluropropyl, fluorobutyl, difluoroethyl, difluoropropyl and difluorobutyl.

[0025] The expression "alkylene" denotes a chain of formula - (CH2)n- where n is an integer for example, 2-5, unless specifically limited.

[0026] The expression "cycloalkyl", unless specifically limited, denotes a C3-10 cycloalkyl group (i.e., carbon atoms of 3 to 10 rings), a more suitable C3-8 cycloalkyl group, e.g. C3-6 cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A more suitable number of ring carbon atoms is three to six, for example five.

[0027] The expression "heterocyclyl", unless specifically limited, denotes a C3-10 heterocyclyl group (i.e., carbon atoms from 3 to 10 rings), a more suitable C3-8 heterocyclyl group, e.g. C3-6 heterocyclyl. A more suitable number of ring carbon atoms is three to six, for example five. Unless specifically limited, one or more (e.g. 1, 2 or 3) carbon atoms in the heterocyclyl ring are replaced by heteroatoms selected from N, S and O. A specific example of a heterocyclyl group is a cycloalkyl group (e.g. , cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O. Exemplary heterocyclyl groups containing a heteroatom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two heteroatoms include morpholine and piperazine. Another specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) in which one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms. selected from N, S and O. An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).

[0028] The term "halogen" or "halo" comprises fluorine (F), chlorine (Cl) and bromine (Br).

[0029] When benzimidazolyl is shown as benzimidazol-5-yl, which is represented as: The person skilled in the art will appreciate that benzimidazol-6-yl, which is represented as:

[0030] It is an equivalent structure. As used herein, both forms of benzimidazolyl are encompassed by the term "benzimidazol-5-yl".

Stereoisomers:

[0031] All possible stereoisomers of the claimed compounds are included in the present invention.

[0032] Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where compounds have two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof fall within the scope of the present invention.

Preparation and isolation of stereoisomers:

[0033] Where the processes for preparing the compounds according to the invention give rise to a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. Compounds can be prepared in racemic form, or individual enantiomers can be prepared by enantiospecific synthesis or by resolution. Compounds can, for example, be resolved into their component enantiomers by standard techniques, such as formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-acid. tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. Compounds can also be resolved by formation of diastereomeric amides or esters, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, compounds can be resolved using a chiral HPLC column. Pharmaceutically acceptable salts:

[0034] In view of the close relationship between free compounds and compounds in the form of their salts or solvates, whenever a compound is referred to in this context, a corresponding salt, solvate or polymorph is also intended, provided that such is possible or appropriate under the circumstances.

[0035] Salts and solvates of the compounds of Formula (I) and physiologically functional derivatives thereof that are suitable for use in medicine are those in which the associated counterion or solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.

[0036] Suitable salts according to the invention include those formed with both organic and inorganic bases or acids. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic , glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (e.g., p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic, or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (e.g., cinnamic substituted by phenyl, methyl, methoxy or halo, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (e.g. 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (e.g. naphthalene-2-acrylic), benzoic , 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (e.g. 1,4-benzenediacrylic), isethionic, perchloric, propionic, glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic acids, saccharinic and trifluoroacetic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, and salts with organic bases such as dicyclohexylamine and N-methyl-D- glucamine.

[0037] All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be encompassed by the scope of this invention.

Polymorph Crystal Forms:

[0038] Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. Furthermore, some of the compounds may form solvates with water (i.e. hydrates) or common organic olvents, and such solvates are also intended to be encompassed within the scope of this invention. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

Prodrugs:

[0039] The present invention also includes within its scope pharmaceuticals from the compounds of this invention. In general, such drugs will be functional derivatives of compounds that are readily convertible in vivo to the desired therapeutically active compound. Thus, in these cases, the treatment methods of the present invention, the term "administer" shall encompass the treatment of the various disorders described with drug versions of one or more of the claimed compounds, but which convert to the compound specified above in vivo after administration. to the individual. Conventional procedures for the selection and preparation of suitable drug derivatives are described, for example, in "Design of Drugs", ed. H. Bundgaard, Elsevier, 1985.

Protection groups:

[0040] During any of the processes for preparing the compounds of the present invention, it may be necessary and/or desirable to protect reactive or sensitive groups on any of the molecules in question. This can be activated by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, fully incorporated herein by reference. Protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0041] A protecting group or protective group is introduced into the molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Protecting groups are, for example, alcohol protecting groups, amine protecting groups, carbonyl protecting groups, carboxylic acid protecting groups and phosphate protecting groups.

[0042] Examples for alcohol protecting groups are acetyl (Ac), benzoyl (Bz), benzyl (Bn, Bnl), β-methoxyethoxymethyl ether (MEM), mimethoxytrityl [bis-(4-methoxyphenyl)phenylmethyl, DMT] , methoxymethyl ether (MOM), methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), trityl (triphenylmethyl, Tr ), silyl ethers (such as trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBDMS), tert-butyldimethylsilyloxymethyl ether (TOM), and triisopropylsilyl ether (TIPS)); methyl ethers and ethoxyethyl ethers (EE).

[0043] Suitable amine protecting groups are selected from carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz ), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), and other sulfonamides (Nosila & Nps).

[0044] Suitable carbonyl protecting groups are selected from acetals and ketals, acylals and dithines.

[0045] Suitable carboxylic acid protecting groups are selected from methyl esters, benzyl esters, tert-butyl esters, silyl esters, orthoesters, and oxazoline.

[0046] Examples for phosphate protecting groups are 2-cyanoethyl and methyl (Me)

[0047] As used herein, the term "composition" is intended to encompass a product comprising the claimed compounds in therapeutically effective amounts, as well as any product that results, directly or indirectly, from combinations of the claimed compounds.

Vehicles and Additives for galenic formulations:

[0048] Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable vehicles and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; For solid oral preparations such as, for example, powders, capsules, gel capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.

[0049] Carriers, which may be added to the mixture, include inert and necessary pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorings, sweeteners, preservatives, coatings, disintegrating agents, coloring agents and coloring.

[0050] Soluble polymers as targetable drug carriers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention can be coupled to a class of biodegradable polymers useful in activating controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and amphipathic block copolymers or cross-linked hydrogels.

[0051] Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate. sodium, sodium acetate, sodium chloride and the like.

[0052] Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Summary of the invention

[0053] Glutaminyl cyclase inhibitors are known in the art. WO 2011/029920 describes, among other things, glutaminyl cyclase inhibitors comprising an oxazolidinone moiety. However, for use in medicine, that is, the prevention and therapy of diseases, there is a need for other compounds, which have improved pharmacokinetic properties in order to reduce dose levels and therefore reduce unwanted side effects and prevent adverse events after administration to a individual. In particular, for the treatment or prevention of diseases of the central nervous system (CNS), for example, neurodegenerative diseases such as mild cognitive impairment, Alzheimer's disease, neurodegeneration in Down syndrome or familial Alzheimer's disease, there is a need for new compounds , which show increased levels and increased half-life in the CNS, e.g., the brain and CSF.

[0054] Therefore, this was the problem of the present invention to provide new compounds with improved pharmacokinetic properties, in particular for the treatment of CNS-related diseases.

[0055] This problem was solved by the present invention by providing compounds of Formula (I).

[0056] According to the invention, a compound of Formula (I) is provided: or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein:

[0057] R1 represents alkyl, -O-alkyl, heterocyclyl or cycloalkyl;

[0058] R2 and R3 independently represent hydrogen, halogen or CN;

[0059] R4 and R5 independently represent hydrogen or halogen;

[0060] wherein at least one of R2, R3, R4 and R5 is halogen or CN; It is

[0061] in which the alkyl, -O-alkyl, heterocyclyl or cycloalkyl groups above are replaced by one or more halogen.

Detailed Description of the Invention

[0062] Surprisingly, it was observed by the inventors that the fluorination of compounds, which comprise an oxazolidinone residue, results in glutaminyl cyclase inhibitors, which have multiple advantages compared to the glutaminyl cyclase inhibitors existing in the prior art. Due to fluorination, the inhibitor constants such as the Ki value of the compounds are markedly improved, preferably reduced several times, more preferably reduced between about 10 times and about 100 times compared to the prior art oxazolidinone compounds.

[0063] Most surprisingly, due to fluorination, the compounds of the present invention show a markedly prolonged half-life in the brain and CSF as well as improved brain levels (shown by improved AUC values), a steady-state distribution ratio of barrier permeation improved brain blood flow of compounds between brain tissue and plasma shown by improvement (logBB values).

[0064] Particularly, advantageous compounds according to the present invention have been obtained, when both are fluorinated: (i) the phenyl ring, that is, at least one of R2, R3, R4 and R5 is fluorine, and (ii) the substituent in position R1.

[0065] In a particular embodiment of the invention, a compound of Formula (I) is provided: or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein:

[0066] R1 represents alkyl, -O-alkyl, heterocyclyl or cycloalkyl;

[0067] R2 and R3 independently represent hydrogen, fluorine or CN;

[0068] R4 and R5 independently represent hydrogen or fluorine;

[0069] wherein at least one of R2, R3, R4 and R5 is fluorine or CN;

[0070] and

[0071] in which the alkyl, -O- alkyl, heterocyclyl or cycloalkyl groups above are replaced by one or more fluorine.

[0072] When alkyl, cycloalkyl and heterocyclyl are substituted, they are typically substituted by 1 or 2 substituents (e.g. 2 substituents). Typically the substituents are both halogen. Most typically, the halogen substituents are fluorine.

[0073] When phenyl is substituted, it is typically substituted by 1, 2 or 3 (e.g. 1 or 2) halogen substituents. Most typically, the halogen substituents are fluorine.

[0074] When R1 represents alkyl, examples include straight or branched chain C1-C12 alkyl groups. A suitable alkyl is a C1-8 alkyl, more suitable a C2-6 alkyl, most suitable a C3-4 alkyl. The aforementioned alkyl groups are replaced by one or more halogen substituents, typically 1 or 2 halogen substituents. Most suitable, the halogen substituents are fluorine.

[0075] When R1 represents -O-alkyl, examples include straight-chain or branched-O-alkyl groups O-C1-8. A suitable -O-alkyl is an -O-C1-12 alkyl, more suitable an -O-C2-6 alkyl, most suitable an -O-C3-4 alkyl. The aforementioned O-alkyl groups are substituted by one or more halogen substituents, typically by 1 or 2 halogen substituents. Most suitable, the halogen substituents are fluorine.

[0076] When R1 represents heterocyclyl, examples include monocyclic (e.g. 5 and 6 membered) and bicyclic (e.g. 9 and 10 membered, particularly 9 membered) heterocyclyl rings, especially rings containing nitrogen atoms (e.g. 1 or 2 nitrogen atoms). Suitable, the heterocyclyl is a 5- and 6-membered heterocyclic ring, most suitable a 5-membered heterocyclic ring. Examples of heterocyclyl rings include pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, dioxolane, thiazolidine, and isoxazolidine. The aforementioned heterocyclyl groups are substituted by one or more halogen substituents typically by 1 or 2 halogen substituents. Most suitable, the halogen substituents are fluorine.

[0077] When R1 represents cycloalkyl, examples include a C3-10 cycloalkyl group (i.e., carbon atoms from 3 to 10 rings), more suitable a C3-8 cycloalkyl group, for example, a C3-6 cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A more suitable number of ring carbon atoms is three to six, e.g. five or six. The aforementioned cycloalkyl groups are substituted by one or more halogen substituents typically by 1 or 2 halogen substituents. Most suitable, the halogen substituents are fluorine.

[0078] When R1 is -O-alkyl, R1 preferably represents -O-C2-6alkyl substituted by one or more halogen, such as fluorine.

[0079] More appropriately, R1 represents -O-C3-4alkyl, substituted by one or more halogen, such as fluorine.

[0080] Preferably, R1 represents difluoropropoxy or difluorobutoxy.

[0081] More preferably, R1 represents 2,2-difluoropropoxy, 3,3-difluoropropoxy or 3,3-difluorobutoxy.

[0082] When R1 is heterocyclyl, R1 preferably represents pyrrolidinyl substituted by one or more halogen, such as fluorine.

[0083] More preferably, R1 is difluoropyrrolidinyl.

[0084] More preferably, R1 is 3,3-difluoropyrrolidin-1-yl.

[0085] When R1 is cycloalkyl, R1 preferably represents cyclohexyl substituted by one or more halogen, such as fluorine.

[0086] More preferably, R1 is difluorocyclohexyl.

[0087] More preferably, R1 is 4,4-difluorocyclohexyl.

[0088] When R1 is alkyl, R1 preferably represents C2-4alkyl substituted by one or more halogen, such as fluorine.

[0089] Preferably, R1 represents C3-4alkyl substituted by one or more halogen, such as fluorine.

[0090] More preferably, R1 is difluorobutyl.

[0091] More preferably, R1 is 3,3-difluorobutyl.

[0092] Especially preferred, according to the invention, are compounds of Formula (I), in which R1 is -O-alkyl.

[0093] Also preferred, according to the present invention, are compounds, in which the phenyl ring in the compound of Formula (I) is replaced by at least one halogen or CN, that is, at least one of R2, R3, R4 and R5 is halogen or CN.

[0094] In one embodiment, R2 and R5 are halogen such as fluorine, and R3 and R4 are hydrogen.

[0095] In another embodiment, R2 is halogen such as fluorine, and R3, R4 and R5 are hydrogen.

[0096] In another embodiment, R3 and R4 are halogen such as fluorine, and R2 and R5 are hydrogen.

[0097] In another embodiment, R3 is halogen such as fluorine, and R2, R4 and R5 are hydrogen.

[0098] In yet another embodiment, R2 and R3 are halogen, such as fluorine, and R4 and R5 are hydrogen.

[0099] In another embodiment, R2 is CN and R3, R4 and R5 are hydrogen.

[00100] In another embodiment, R3 is CN and R2, R4 and R5 are hydrogen.

[00101] Preferred, according to the present invention, are compounds of Formula (I), in which at least one of R2, R3, R4 and R5 is halogen. More preferably, at least one of R2, R3, R4 and R5 is fluorine.

[00102] Still preferably, R3 is fluorine and R2, R4 and R5 are hydrogen; or

[00103] R2 and R3 are fluorine and R4 and R5 are hydrogen.

[00104] More preferably, R1 is 2,2-difluoropropoxy, R3 is fluorine, and R2, R4 and R5 are hydrogen; or R1 is 3,3-difluoropropoxy, R2 and R3 are fluorine, and R4 and R5 are hydrogen.

Law Suit

[00105] According to another aspect of the invention, a process is provided for the preparation of a compound of Formula (I) comprising:

[00106] (a) prepare a compound of Formula (I) from a compound of Formula (II): on what

[00107] R2, R3, R4 and R5 and are as defined above for compounds of Formula (I); R6 is alkyl and R7 and R8 are halogen, such as fluorine.

[00108] The process typically involves reacting a compound of Formula (II) with formamidine acetate in the presence of a suitable solvent such as acetonitrile. A non-limiting example of the Process (a) methodology is described in Method K here.

[00109] (b) prepare a compound of Formula (I) from a compound of Formula (III): on what

[00110] R2, R3, R4 and R5 are as defined above for compounds of Formula (I) and R9 is cycloalkyl or heterocyclyl and R10 and R11 are halogen, such as fluorine.

[00111] Process (b) typically involves reacting a compound of Formula (III) with formamidine acetate in the presence of a suitable solvent such as acetonitrile. A non-limiting example of the Process (b) methodology is described in Methods R and U here.

[00112] (c) prepare a compound of Formula (I) from a compound of Formula (IV): wherein R12 comprises suitable reactant reaction, such as diethylaminosulfur trifluoride, which can be employed in the presence of a suitable solvent such as dichloromethane. A non-limiting example of the Process (c) methodology is described in method V here.

[00113] (d) prepare a compound of Formula (I) from a compound of Formula (V): wherein R1, R2 and R4 are as defined above for compounds of Formula (I), R13 is alkyl and R14 and R15 are halogen such as fluorine.

[00114] The process typically involves reacting a compound of Formula (V) with formamidine acetate in the presence of a suitable solvent, such as acetonitrile. A non-limiting example of the Process (d) methodology is described in the AA method here.

[00115] Compounds of Formula (I) and intermediate compounds can also be prepared using techniques analogous to those known to a skilled person, or described here.

[00116] New intermediates are claimed as an aspect of the present invention.

Therapeutic uses

[00117] Physiological substrates of QC (EC) in mammals are, for example, amyloid beta-peptides (3-40), (3-42), (11-40 and (11-42), ABri, ADan, Gastrin , Neurotensin, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, Fractalkine, Orexin A, [Gln3]-glucagon(3-29), [Gln5]- substance P(5-11) and the peptide QYNAD. For further details see Table 1. The compounds and/or combinations according to the present invention and pharmaceutical compositions comprising at least one QC inhibitor (CE) are useful for treating conditions that can be treated by modulating QYNAD activity. QC.Table 1: Amino acid sequence of physiologically active peptides with an N-terminal glutamine residue, which are prone to be cyclized to the final pGlu.

[00118] Glutamate is found at positions 3, 11 and 22 of the amyloid β-peptide. Among them the mutation of glutamic acid (E) to glutamine (Q) at position 22 (corresponding to amyloid precursor protein APP 693, Swissprot P05067) was described as the so-called Dutch-type cerebroarterial amyloidosis mutation.

[00119] β-amyloid peptides with a pyroglutamic acid residue at position 3, 11 and/or 22 have been described to be more cytotoxic and hydrophobic than β-amyloid peptides 1-40 (42/43) (Saido T.C. 2000 Medical Hypotheses 54(3): 427-429).

[00120] Multiple N-terminal variations, e.g., Abeta(3-40), Abeta(3-42), Abeta(11-40), and Abeta(11-42) can be generated by the precursor protein cleavage enzyme of amyloid from the β-site enzyme β-secretase (BACE) at different sites (Huse J.T. et al. 2002 J. Biol. Chem. 277 (18): 16278-16284), and/or by aminopeptidase or dipeptidylaminopeptidase processing of the peptides life-size Abeta(1-40) and Abeta(1-42). In all cases, the cyclization of the then occurring glutamic acid residue at the N terminus is catalyzed by QC.

[00121] Transepithelial transduction cells, particularly the gastrin (G) cell, coordinate the secretion of gastric acid with the arrival of food in the stomach. Recent work has shown that multiple active products are generated from the gastrin precursor, and that there are multiple control points in gastrin biosynthesis. Precursors and biosynthetic intermediates (progastrin and gastrins-Gly) are putative growth factors; Its products, the amidated gastrins, regulate epithelial cell proliferation, the differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like cells (ECL), and the expression of genes associated with histamine synthesis and storage in ECL cells. , as well as precisely stimulating acid secretion. Gastrin also stimulates the production of members of the epidermal growth factor (EGF) family, which in turn inhibits parietal cell function but stimulates the growth of surface epithelial cells. Plasma gastrin concentrations are elevated in individuals with Helicobacter pylori, who are known to be at increased risk of duodenal ulcer disease and gastric cancer (Dockray, G.J. 1999 J Physiol 15 315-324).

[00122] The peptide hormone gastrin, released from antral G cells, is known to stimulate the synthesis and release of histamine from ECL cells in the oxyntic mucosa via CCK-2 receptors. Mobilized histamine induces acid secretion by binding to H(2) receptors located on parietal cells. Recent studies suggest that gastrin, in both its fully amidated and less processed forms (progastrin and glycine-extended gastrin), is also a growth factor for the gastrointestinal tract. It has been established that the greatest trophic effect of amidated gastrin is towards the oxyntic mucosa of the stomach, where it causes increased proliferation of gastrin stem cells and ECL cells, resulting in increased parietal cell mass and ECL. On the other hand, the major trophic target of less processed gastrin (e.g., glycine-extended gastrin) appears to be the colonic mucosa (Koh, T.J. and Chen, D. 2000 Regul Pept 9337-44).

[00123] Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be inappropriately regulated in this disorder. Clinical studies in which cerebrospinal fluid (CSF) NT concentrations were measured revealed a subgroup of schizophrenic patients with decreased CSF NT concentrations that are restored by effective antipsychotic drug treatment. Considerable evidence also exists consistent with the involvement of NT systems in the mechanism of action of antipsychotic drugs. The behavioral and biochemical effects of centrally administered NT are remarkably similar to those of systemically administered antipsychotic drugs, and antipsychotic drugs increase NT neurotransmission. This concatenation of observations led to the hypothesis that NT functions as an endogenous antipsychotic. Furthermore typical and atypical antipsychotic drugs differentially alter NT neurotransmission in nigrostriatal and mesolimbic dopamine terminal regions, and these effects are predictive of side effect risk and efficacy, respectively (Binder, E. B. et al. 2001 Biol Psychiatry 50 856-872 ).

[00124] Fertilization-promoting peptide (FPP), a tripeptide related to thyrotropin-releasing hormone (TRH), is found in seminal plasma. Recent evidence obtained in vitro and in vivo has shown that FPP plays an important role in regulating sperm fertility. Specifically, FPP initially stimulates non-fertilizing (incapacitated) sperm to "change in" and become fertile more quickly, but then interrupts capacitation so that sperm do not undergo spontaneous acrosome loss and therefore do not lose potential. of fertilization. These responses are mimicked, and actually enhanced, by adenosine, known to regulate the adenylyl cyclase (AC)/cAMP signal transduction reaction series. Both FPP and adenosine have been shown to stimulate cAMP production in incapacitated cells but inhibit it in capacitated cells, with FPP receptors somehow interacting with adenosine receptors and G proteins to achieve AC regulation. These events affect the tyrosine phosphorylation state of several proteins, some being important in the initial "activation", others possibly being involved in the acrosome reaction itself. Calcitonin and angiotensin II, also found in seminal plasma, have similar effects in vitro on incapacitated sperm and can increase responses to FPP. These molecules have similar effects in vivo, affecting fertility by stimulating and then maintaining fertilization potential. Reductions in the availability of FPP, adenosine, calcitonin, and angiotensin II or defects in their receptors contribute to male infertility (Fraser, L. R. and Adeoya-Osiguwa, S. A. 2001 Vitam Horm 63, 1-28).

[00125] CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and fractalkine play an important role in pathophysiological conditions, such as suppression of myeloid progenitor cell proliferation, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humoral and cell-mediated responses, leukocyte adhesion and migration processes in the endothelium, inflammatory bowel disease, restenosis, pulmonary fibrosis, pulmonary hypertension, liver fibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling, heart failure, arteriopathy after organ transplants and vein graft failure.

[00126] Several studies highlight in particular the crucial role of MCP-1 for the development of atherosclerosis (Gu, L., et al., (1998) Mol.Cell 2, 275-281; Gosling, J., et al. , (1999) J Clin.Invest 103, 773778); rheumatoid arthritis (Gong, J. H., et al., (1997) J Exp.Med 186, 131-137; Ogata, H., et al., (1997) J Pathol. 182, 106-114); pancreatitis (Bhatia, M., et al., (2005) Am.J Physiol Gastrointest.Liver Physiol 288, G1259-G1265); Alzheimer's disease (Yamamoto, M., et al., (2005) Am.J Pathol. 166, 1475-1485); pulmonary fibrosis (Inoshima, I., et al., (2004) Am.J Physiol Lung Cell Mol.Physiol 286, L1038-L1044); renal fibrosis (Wada, T., et al., (2004) J Am.Soc.Nephrol. 15, 940-948), and graft rejection (Saiura, A., et al., (2004) Arterioscler. Thromb. Vasc. Biol. 24, 1886-1890). Furthermore, MCP-1 may also play a role in gestosis (Katabuchi, H., et al., (2003) Med Electron Microsc. 36, 253-262), as a paracrine factor in tumor development (Ohta, M. , et al., (2003) Int.J Oncol. 22, 773-778; Li, S., et al., (2005) J Exp.Med 202, 617-624), neuropathic pain (White, F. A., et al., (2005) Proc. Natl. Acad.Sci.U.S.A) and AIDS (Park, I. W., Wang, J. F., and Groopman, J. E. (2001) Blood 97, 352-358; Coll, B., et al., (2006) Cytokine 34, 51-55).

[00127] MCP-1 levels are increased in CSF of AD patients and patients showing mild cognitive impairment (MCI) (Galimberti, D., et al., (2006) Arch.Neurol. 63, 538-543). Furthermore, MCP-1 shows an increased level in serum of patients with MCI and early AD (Clerici, F., et al., (2006) Neurobiol. Aging 27, 1763-1768).

[00128] Several cytotoxic T lymphocyte peptide-based vaccines against hepatitis B, human immunodeficiency virus and melanoma have recently been studied in clinical trials. An interesting melanoma candidate alone or in combination with other tumor antigens is the ALS decapeptide. This peptide is an immunodominant peptide analogue of Melan-A/MART-1 antigen, with an N-terminal glutamic acid. It has been reported that the amino group and gamma carboxylic group of glutamic acids, as well as the amino group and gamma carboxamide group of glutamines, readily condense to form pyroglutamic derivatives. To overcome this stability problem, several peptides of pharmaceutical interest were developed with pyroglutamic acid instead of N-terminal glutamine or glutamic acid, without loss of pharmacological properties. Unfortunately compared to ELA, the pyroglutamic acid derivative (PyrELA) and also the N-terminal acetyl-buffered derivative (AcELA) did not elicit cytotoxic T lymphocyte (CTL)y activity. Despite the apparent minor modifications introduced in PyrELA and AcELA, these two derivatives probably have lower affinity than ELA for the specific class I major histocompatibility complex. Consequently, in order to conserve full ELA activity, the formation of PyrELA must be avoided (Beck A. et al. 2001, J Pept Res 57(6):528-38.).

[00129] Orexin A is a neuropeptide that plays a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiological responses of these complementary homeostatic functions. It also plays a role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids.

[00130] Recently, increased levels of the pentapeptide QYNAD were identified in the cerebrospinal fluid (CSF) of patients suffering from multiple sclerosis or Guillain-Barré syndrome compared to healthy individuals (Brinkmeier H. et al. 2000, Nature Medicine 6, 808-811) . There is enormous controversy in the literature surrounding the mechanism of action of the pentapeptide Gln-Tyr-Asn-Ala-Asp (QYNAD), especially its effectiveness in interacting with and blocking sodium channels resulting in the promotion of axonal dysfunction, which is involved in diseases inflammatory autoimmune diseases of the central nervous system. However, recently, it has been demonstrated that not QYNAD, but its cyclized pyroglutamated form, pEYNAD, is the active form, which blocks sodium channels resulting in the promotion of axonal dysfunction. Sodium channels are expressed at high density in myelinated axons and play an obligatory role in conducting action potentials along axons within the mammalian brain and spinal column. Therefore, it is speculated that they are involved in several aspects of the pathophysiology of inflammatory autoimmune diseases, especially multiple sclerosis, Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

[00131] Furthermore, QYNAD is a substrate of the enzyme glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in the brain of mammals, especially in the human brain. Glutaminyl cyclase effectively catalyzes the formation of pEYNAD from its precursor QYNAD.

[00132] Accordingly, the present invention provides the use of the compounds of Formula (I) for the preparation of a medicament for the prevention or alleviation or treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, British Disease Familial, Familial Danish Dementia, neurodegeneration in Down syndrome, Huntington's disease, Kennedy's disease, ulcer disease, duodenal cancer with or without Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter infections pylori, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, host inflammatory responses, cancer, malignant metastasis, melanoma, psoriasis, rheumatoid arthritis, atherosclerosis, pancreatitis, restenosis, impaired cell-mediated humoral and immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance or impaired regulation of body fluids, multiple sclerosis, Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

[00133] Furthermore, by administering a compound according to the present invention to a mammal it may be possible to stimulate the proliferation of myeloid progenitor cells.

[00134] Furthermore, administration of a QC inhibitor according to the present invention can lead to suppression of male fertility.

[00135] In a preferred embodiment, the present invention provides the use of QC activity (CE) inhibitors in combination with other agents, especially for the treatment of neuronal diseases, atherosclerosis and multiple sclerosis.

[00136] The present invention also provides a method of treating the aforementioned diseases, comprising administering a therapeutically active amount of at least one compound of Formula (I) to a mammal, preferably a human.

[00137] More preferably, said method and corresponding uses are for the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Disease, Familial Danish Dementia, neurodegeneration in Down Syndrome, Parkinson's disease and Huntington's Chorea, comprising administering a therapeutically effective amount of at least one compound of Formula (I) to a mammal, preferably a human.

[00138] Still preferably, the present invention provides a treatment method and corresponding uses for the treatment of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.

Pharmaceutical Combinations

[00139] In a preferred embodiment, the present invention provides a composition, preferably a pharmaceutical composition, comprising at least one QC inhibitor optionally in combination with at least one other agent selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, inhibitors amyloid protein deposition, amyloid beta synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

[00140] More preferably, said QC inhibitor is a compound of Formula (I) of the present invention.

[00141] More specifically, the aforementioned agent is selected from the group consisting of beta-amyloid antibodies, vaccines, cysteine protease inhibitors, PEP inhibitors, LiCl, acetylcholinesterase (AChE) inhibitors, PIMT enhancers, beta secretase inhibitors , gamma secretase inhibitors, aminopeptidase inhibitors, preferably dipeptidyl peptidase inhibitors. More preferably DP IV inhibitors; neutral endopeptidase inhibitors, phosphodiesterase-4 (PDE-4) inhibitors, TNFalpha inhibitors, M1 muscarinic receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents, antagonists of MCP-1 or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridin-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284 ), SH636, Diferin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix metalloproteinase inhibitors (e.g., BB 76163), interferon-tau (trophoblastin), and SAIK-MS.

[00142] Furthermore, the other agent may be, for example, an anti-anxiety or anti-depressant agent selected from the group consisting of

[00143] (a) Benzodiazepines, for example, alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, fludiazepam, loflazepate, lorazepam, methaqualone, oxazepam, prazepam, tranxene,

[00144] (b) Selective serotonin reuptake inhibitors (SSRI's), for example, citalopram, fluoxetine, fluvoxamine, escitalopram, sertraline, paroxetine,

[00145] (c) Tricyclic antidepressants, for example, amitriptyline, clomipramine, desipramine, doxepin, imipramine

[00146] (d) Monoamine oxidase (MAO) inhibitors,

[00147] (e) Azapirones, for example, buspirone, tandopsirone,

[00148] (f) Serotonin-norepinephrine reuptake inhibitors (SNRI's), for example, venlafaxine, duloxetine,

[00149] (g) Mirtazapine,

[00150] (h) Norepinephrine reuptake inhibitors (NRI's), for example, reboxetine,

[00151] (i) Bupropion,

[00152] (j) Nefazodone,

[00153] (k) beta-blockers,

[00154] (l) NPY receptor ligands: NPY agonists or antagonists.

[00155] In another embodiment, the other agent may be, for example, an anti-multiple sclerosis drug selected from the group consisting of

[00156] Dihydroorotate dehydrogenase inhibitors, for example, SC-12267, teriflunomide, MNA-715, HMR-1279 (syn. A HMR-1715,MNA-279),

[00157] Autoimmune suppressant, for example, laquinimod,

[00158] paclitaxel,

[00159] antibodies, for example, AGT-1, anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) monoclonal antibody, Nogo receptor modulators, ABT-874, alemtuzumab (CAMPATH), anti-OX40 antibody, CNTO-1275, DN-1921, natalizumab (syn. A AN- 100226, Antegren, VLA-4 Mab), daclizumab (syn. A Zenepax, Ro-34-7375, SMART anti-Tac), J-695, priliximab ( syn. Centara, CEN-000029, cM-T412), MRA, Dantes, anti-IL-12 antibody,

[00160] peptide nucleic acid (PNA) preparations, for example, reticulose,

[00161] alpha interferon, for example, Alfaferona, human alpha interferon (syn. A Omniferon, Alpha Leukoferon),

[00162] interferon beta, for example, Frone, interferon beta-1a such as Avonex, Betron (Rebif), interferon beta analogues, interferon beta-transferrin fusion protein, recombinant interferon beta-1b such as Betaseron,

[00163] interferon tau,

[00164] peptides, for example, AT-008, AnergiX.MS, Immunokine (alpha-Immunokine-NNSO3), cyclic peptides such as ZD-7349,

[00165] therapeutic enzymes, for example, soluble CD8 (sCD8),

[00166] multiple sclerosis-specific autoantigen-encoding plasmid and cytokine-encoding plasmid, for example, BHT-3009;

[00167] TNF-alpha inhibitor, for example, BLX-1002, thalidomide, SH-636,

[00168] TNF antagonists, for example, solimastat, lenercept (syn. A RO-45-2081, Tenefuse), onercept (sTNFR1), CC-1069,

[00169] TNF alpha, e.g. etanercept (syn. Enbrel, TNR-001)

[00170] CD28 antagonists, for example, abatacept,

[00171] Lck tyrosine kinase inhibitors,

[00172] cathepsin K inhibitors,

[00173] analogues of the neuron-targeting membrane transport protein taurine and the plant-derived calpain inhibitor leupeptin, e.g., Neurodur,

[00174] chemokine receptor-1 (CCR1) antagonist, e.g., BX-471,

[00175] CCR2 antagonists,

[00176] AMPA receptor antagonists, for example, ER-167288-01 and ER-099487, E-2007, talampanel,

[00177] potassium channel blockers, for example, fampridine,

[00178] small molecule tosyl-proline-phenylalanine antagonists of the VLA-4/VCAM interaction, e.g., TBC-3342,

[00179] cell adhesion molecule inhibitors, for example, TBC-772,

[00180] antisense oligonucleotides, for example, EN-101,

[00181] free immunoglobulin light chain (IgLC) antagonists binding to mast cell receptors, e.g., F-991,

[00182] apoptosis-inducing antigens, for example, Apogen MS,

[00183] Alpha-2 adrenoceptor agonist, for example, tizanidine (syn.A Zanaflex, Ternelin, Sirdalvo, Sirdalud, Mionidine),

[00184] Copolymer of L-tyrosine, L-lysine, L-glutamic acid and L-alanine, for example, glatiramer acetate (syn. Copaxone, COP-1, copolymer-1),

[00185] Topoisomerase II modulators, for example, mitoxantrone hydrochloride,

[00186] Adenosine deaminase inhibitor, for example, cladribine (syn. Leustatin, Mylinax, RWJ-26251),

[00187] interleukin-10, for example, ilodecacin (syn. Tenovil, Sch-52000, CSIF),

[00188] interleukin-12 antagonists, for example, lysophilin (syn.A CT-1501R, LSF, lysophilin),

[00189] Ethanamino, for example, SRI-62-834 (syn. A CRC-8605, NSC-614383),

[00190] immunomodulators, for example, SAIK-MS, PNU-156804, alpha-fetoprotein peptide (AFP), IPDS,

[00191] retinoid receptor agonists, for example, adapalene (syn. A Differin, CD-271),

[00192] TGF-beta, for example, GDF-1 (growth and differentiation factor 1),

[00193] TGF-beta-2, for example, BetaKine,

[00194] MMP inhibitors, for example, glycomed,

[00195] Phosphodiesterase 4 (PDE4) inhibitors, for example, RPR-122818,

[00196] Purine nucleoside phosphorylase inhibitors, for example, 9-(3-pyridylmethyl)-9-deazaguanine, peldesine (syn. BCX-34, TO-200),

[00197] Alpha-4/beta-1 integrin antagonists, for example, ISIS-104278,

[00198] Alpha-4 antisense integrin (CD49d), for example, ISIS-17044, ISIS-27104,

[00199] Cytokine-inducing agents, e.g., nucleosides, ICN-17261,

[00200] Cytokine inhibitors,

[00201] Heat shock protein vaccines, e.g. HSPPC-96,

[00202] Neuregulin growth factors, for example, GGF-2 (syn. neuregulin, glial growth factor 2),

[00203] Cathepsin S inhibitors,

[00204] Bropyrimine analogues, for example, PNU-56169, PNU-63693,

[00205] Monocyte chemoattractant protein 1 inhibitors, for example, benzimidazoles such as MCP-1 inhibitors, LKS-1456, PD-064036, PD-064126, PD-084486, PD-172084, PD-172386.

[00206] Furthermore, the present invention provides pharmaceutical compositions, for example, for parenteral, enteral or oral administration, comprising at least one QC inhibitor, optionally in combination with at least one of the other agents mentioned above.

[00207] These combinations provide a particularly beneficial effect. Such combinations are, therefore, shown to be effective and useful for the treatment of the above-mentioned diseases. Accordingly, the invention provides a method for treating these conditions.

[00208] The method comprises either co-administration of at least one QC inhibitor and at least one of the other agents or sequential administration thereof.

[00209] Co-administration includes the administration of a formulation, which comprises at least one QC inhibitor and at least one of the other agents or the essentially simultaneous administration of separate formulations of each agent.

[00210] Beta-amyloid antibodies and compositions containing them are described, for example, in WO/2009/065054, WO/2009/056490, WO/2009/053696, WO/2009/033743, WO/2007/113172, WO/2007/022416, WO 2006/137354, WO 2006/118959, WO 2006/103116, WO 2006/095041, WO 2006/081171, WO 2006/066233, WO 2006/066171, WO 2006/066089, WO 2006/066049 , WO 2006/055178, WO 2006/046644, WO 2006/039470, WO 2006/036291, WO 2006/026408, WO 2006/016644, WO 2006/014638, WO 2006/014478, WO 2006/008661, WO 2005/123775 , WO 2005/120571, WO 2005/105998, WO 2005/081872, WO 2005/080435, WO 2005/028511, WO 2005/025616, WO 2005/025516, WO 2005/023858, WO 2005/018424, WO 2005/011599 , WO 2005/000193, WO 2004/108895, WO 2004/098631, WO 2004/080419, WO 2004/071408, WO 2004/069182, WO 2004/067561, WO 2004/044204, WO 2004/032868, WO 2004/031400 , WO 2004/029630, WO 2004/029629, WO 2004/024770, WO 2004/024090, WO 2003/104437, WO 2003/089460, WO 2003/086310, WO 2003/077858, WO 2003/074081, WO 2003/070760 , WO 2003/063760, WO 2003/055514, WO 2003/051374, WO 2003/048204, WO 2003/045128, WO 2003/040183, WO 2003/039467, WO 2003/016466, WO 2003/015691, WO 2003/014162 , WO 2003/012141, WO 2002/088307, WO 2002/088306, WO 2002/074240, WO 2002/046237, WO 2002/046222, WO 2002/041842, WO 2001/062801, WO 2001/012598, WO 2000/077178 , WO 2000/072880, WO 2000/063250, WO 1999/060024, WO 1999/027944, WO 1998/044955, WO 1996/025435, WO 1994/017197, WO 1990/014840, WO 1990/012871, WO 1990/012870 , WO 1989/006242.

[00211] Beta-amyloid antibodies can be selected from, for example, polyclonal, monoclonal, chimeric or humanized antibodies. Furthermore, said antibodies may be useful for developing active and passive therapies, i.e., vaccines and monoclonal antibodies.

[00212] Suitable examples of beta-amyloid antibodies are ACU-5A5, huC091 (Acumen/Merck); PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (Pfizer Inc)); Ablynx/Boehringer Ingelheim nanobody therapeutics; beta-amyloid-specific humanized monoclonal antibodies from Intellect Neurosciences/IBL; m266, m266.2 (Eli Lilly &Co.); AAB-02 (Elan); bapineuzumab (Elan); BAN-2401 (Bioarctic Neuroscience AB); ABP-102 (Abiogen Pharma SpA); BA-27, BC-05 (Takeda); R-1450 (Roche); ESBA-212 (ESBATech AG); AZD-3102 (AstraZeneca) and beta-amyloid antibodies from Mindset BioPharmaceuticals Inc.

[00213] Antibodies that recognize the N terminus of the Aβ peptide are especially preferred. A suitable antibody that recognizes the Aβ-N terminus is, for example, Acl-24 (AC Immune SA).

[00214] Monoclonal antibodies against beta-amyloid peptide are described in WO 2007/068412, WO/2008/156621 and WO/2010/012004. Respective chimeric and humanized antibodies are described in WO 2008/011348 and WO/2008/060364. Vaccine composition for treating an amyloid-associated disease is described in WO/2002/096937, WO/2005/014041, WO 2007/068411, WO/2007/097251, WO/2009/029272, WO/2009/054537, WO/ 2009/090650 WO/2009/095857, WO/2010/016912, WO/2010/011947, WO/2010/011999, WO/2010/044464.

[00215] Vaccines suitable for treating a disease associated with amyloid are, for example, Affitopes AD-01 and AD-02 (GlaxoSmithKline), ACC-01 and ACC-02 (Elan/Wyeth), CAD-106 (Novartis / Cytos Biotechnology),

[00216] Suitable cysteine protease inhibitors are cathepsin B inhibitors. Cathepsin B inhibitors and compositions containing such inhibitors are described, for example, in WO/2008/077109, WO/2007/038772, WO 2006/060473, WO 2006/ 042103, WO 2006/039807, WO 2006/021413, WO 2006/021409, WO 2005/097103, WO 2005/007199, WO2004/084830, WO 2004/078908, WO 2004/02 6851, WO 2002/094881, WO 2002/027418 , WO 2002/021509, WO 1998/046559, WO 1996/021655.

[00217] Examples of suitable PIMT enhancers are 10-aminoaliphatyl-dibenz[b,f] oxepins described in WO 98/15647 and WO 03/057204, respectively. Also useful according to the present invention are the modulators of PIMT activity described in WO 2004/039773.

[00218] Beta secretase inhibitors and compositions containing such inhibitors are described, for example, in WO/2010/094242, WO/2010/058333, WO/2010/021680, WO/2009/108550, WO/2009/042694, WO /2008/054698, WO/2007/051333, WO/2007/021793, WO/2007/019080, WO/2007/019078, WO/2007/011810, WO03/059346, WO2006/099352, WO2006/0 78576, WO2006/060109 , WO2006/057983, WO2006/057945, WO2006/055434, WO2006/044497, WO2006/034296, WO2006/034277, WO2006/029850, WO2006/026204, WO2006/0 14944, WO2006/014762, WO2006/002004, US 7,109,217, WO2005/ 113484, WO2005/103043, WO2005/103020, WO2005/065195, WO2005/051914, WO2005/044830, WO2005/032471, WO2005/018545, WO2005/004803, WO 2005/004802, WO2004/062625, WO2004/043916, WO2004/013098, WO03/099202, WO03/043987, WO03/039454, US 6,562,783, WO02/098849 and WO02/096897.

[00219] Suitable examples of beta secretase inhibitors, for the purpose of the present invention, are WY-25105 (Wyeth); Posiphen, (+)-phenserine (TorreyPines/NIH); LSN-2434074, LY-2070275, LY-2070273, LY-2070102 (Eli Lilly &Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312, PNU-38773, PNU-90530 (Elan/Pfizer); KMI-370, KMI-358, kmi-008 (Kyoto University); OM-99-2, OM-003 (Athenagen Inc.); AZ-12304146 (AstraZeneca/Astex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 (De Novo Pharmaceuticals Ltd.), and CT-21166 (CoMentis Inc.).

[00220] Gamma secretase inhibitors and compositions containing such inhibitors are described, for example, in WO/2010/090954, WO/2009/011851, WO/2009/008980, WO/2008/147800, WO/2007/084595, WO2005 /008250, WO2006/004880, US 7,122,675, US 7,030,239, US 6,992,081, US 6,982,264, WO2005/097768, WO2005/028440, WO2004/101562, US 6,756.51 1, US 6,683,091, WO03/066592, WO03/014075, WO03/013527, WO02 /36555, WO01/53255, US 7,109,217, US 7,101,895, US 7,049,296, US 7,034,182, US 6,984,626, WO2005/040126, WO2005/030731, WO2005/014553, US 6,890,956, EP 1334085, EP 1263774, WO2004/101538, WO2004/00958 , WO2004/089911, WO2004/073630, WO2004/069826, WO2004/039370, WO2004/031139, WO2004/031137, US 6,713,276, US 6,686,449, WO03/091278, US 6,649,196, US 6,448,229, WO01/77144 and WO01/66564.

[00221] Gamma secretase inhibitors suitable for the purpose of the present invention are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, L-852631, L-852646 (Merck & Co. Inc.); LY-450139, LY-411575, AN-37124 (Eli Lilly &Co.); BMS-299897, BMS-433796 (Bristol-Myers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT-0206, EHT-206 (ExonHit Therapeutics SA); NGX-555 (TorreyPines Therapeutics Inc.) and Semagacestat (Eli Lilly).

[00222] DP IV inhibitors and compositions containing such inhibitors are described, for example, in US6,011,155; US6,107,317;US6,110,949; US6,124,305; US6,172,081; WO99/61431, WO99/67278, WO99/67279, DE19834591, WO97/40832, WO95/15309, WO98/19998, WO00/07617, WO99/38501, WO99/46272, WO99/38501, WO 01/68603, WO01/40180, WO01/81337, WO01/81304, WO01/55105, WO02/02560, WO01/34594, WO02/38541, WO02/083128, WO03/072556, WO03/002593, WO03/000250, WO03/000 180, WO03/000181, EP1258476, WO03/002553, WO03/002531, WO03/002530, WO03/004496, WO03/004498, WO03/024942, WO03/024965, WO03/033524, WO03/035057, WO03/035067, WO 03/037327, WO03/040174, WO03/ 045977, WO03/055881, WO03/057144, WO03/057666, WO03/068748, WO03/068757, WO03/082817, WO03/101449, WO03/101958, WO03/104229, WO03/7 4500, WO2004/007446, WO2004/007468, WO2004/018467, WO2004/018468, WO2004/018469, WO2004/026822, WO2004/032836, WO2004/033455, WO2004/037169, WO2004/041795, WO2004/043 940, WO2004/048352, WO2004/050022, WO2004/052850, WO2004/ 058266, WO2004/064778, WO2004/069162, WO2004/071454, WO2004/076433, WO2004/076434, WO2004/087053, WO2004/089362, WO2004/099185, WO 2004/103276, WO2004/103993, WO2004/108730, WO2004/110436, WO2004/111041, WO2004/112701, WO2005/000846, WO2005/000848, WO2005/011581, WO2005/016911, WO2005/023762, WO2005/025554, WO2005/026 148, WO2005/030751, WO2005/033106, WO2005/037828, WO2005/ 040095, WO2005/044195, WO2005/047297, WO2005/051950, WO2005/056003, WO2005/056013, WO2005/058849, WO2005/075426, WO2005/082348, WO 2005/085246, WO2005/087235, WO2005/095339, WO2005/095343, WO2005/095381, WO2005/108382, WO2005/113510, WO2005/116014, WO2005/116029, WO2005/118555, WO2005/120494, WO2005/121089, WO2005/121 131, WO2005/123685, WO2006/995613; WO2006/009886; WO2006/013104; WO2006/017292; WO2006/019965; WO2006/020017; WO2006/023750; WO2006/039325; WO2006/041976; WO2006/047248; WO2006/058064; WO2006/058628; WO2006/066747; WO2006/066770 and WO2006/068978.

[00223] Suitable DP IV inhibitors for the purpose of the present invention are, for example, Sitagliptin, des-fluorositagliptin (Merck & Co. Inc.); vildagliptin, DPP-728, SDZ-272-070 (Novartis); ABT-279, ABT-341 (Abbott Laboratories); denagliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322 (Takeda San Diego Inc.); talabostat (Point Therapeutics Inc.); Ro-0730699, R-1499, R-1438 (Roche Holding AG); FE-999011 (Ferring Pharmaceuticals); TS-021 (Taisho Pharmaceutical Co. Ltd.); GRC-8200 (Glenmark Pharmaceuticals Ltd.); ALS-2-0426 (Alantos Pharmaceuticals Holding Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi Pharma Corp.); DP-893, CP-86753401 (Pfizer Inc.); TSL-225, TMC-2A (Tanabe Seiyaku Co. Ltd.); PHX-1149 (Phenomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.); PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 (ActivX Biosciences Inc.); sulfostine (Zaidan Hojin); KR-62436 (Korea Research Institute of Chemical Technology); P32/98 (Probiodrug AG); BI-A, BI-B (Boehringer Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. Ltd.); and NNC-72-2138 (Novo Nordisk A/S).

[00224] Other preferred DP IV inhibitors are

[00225] (i) dipeptide-like compounds, described in WO 99/61431, for example, N-valyl prolyl, O-benzoyl hydroxylamine, alanyl pyrrolidine, isoleucyl thiazolidine such as L-allo-isoleucyl thiazolidine, L-threo-isoleucyl pyrrolidine and salts thereof, especially fumaric salts, and L-allo-isoleucyl pyrrolidine and salts thereof;

[00226] (ii) peptide structures, described in WO 03/002593, for example, tripeptides;

[00227] (iii) peptidyl ketones, described in WO 03/033524;

[00228] (vi) substituted aminoketones, described in WO03/040174;

[00229] (v) Topically active DP IV inhibitors, described in WO 01/14318;

[00230] (vi) prodrugs of DP IV inhibitors, described in WO 99/67278 and WO 99/67279; It is

[00231] (v) Glutaminyl-based DP IV inhibitors, described in WO 03/072556 and WO 2004/099134.

[00232] Amyloid beta synthesis inhibitors suitable for the purpose of the present invention are, for example, Bisnorcymserine (Axonyx Inc.); (R)-flurbiprofen (MCP-7869; Flurizan) (Myriad Genetics); nitroflurbiprofen (NicOx); BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466 (BTG plc.), RQ-00000009 (RaQualia Pharma Inc).

[00233] Amyloid protein deposition inhibitors suitable for the purpose of the present invention are, for example, SP-233 (Samaritan Pharmaceuticals); AZD-103 (Ellipsis Neurotherapeutics Inc.); AAB-001 (Bapineuzumab), AAB-002, ACC-001 (Elan Corp plc.); Colostrinin (ReGen Therapeutics plc.); Tramiprosate (Neurochem); AdPEDI-(amyloid-beta1-6)11) (Vaxin Inc.); MPI-127585, MPI-423948 (Mayo Foundation); SP-08 (Georgetown University); ACU-5A5 (Acumen/Merck); Transthyretin (State University of New York); PTI-777, DP-74, DP 68, Exebril (ProteoTech Inc.); m266 (Eli Lilly &Co.); EGb-761 (Dr. Willmar Schwabe GmbH); SPI-014 (Satori Pharmaceuticals Inc.); ALS-633, ALS-499 (Advanced Life Sciences Inc.); AGT-160 (ArmaGen Technologies Inc.); TAK-070 (Takeda Pharmaceutical Co. Ltd.); CHF-5022, CHF-5074, CHF-5096 and CHF-5105 (Chiesi Farmaceutici SpA.), SEN-1176 and SEN-1329 (Senexis Ltd.), AGT-160 (ArmaGen Technologies), Davunetida (Allon Therapeutics), ELND -005 (Elan Corp/Transition Therapeutics) and nilvadipine (Archer Pharmaceuticals).

[00234] PDE-4 inhibitors suitable for the purpose of the present invention are, for example, Doxofilina (Instituto Biologico Chemioterapica ABC SpA.); idudilast, tipelukast, ibudilast eye drops (Kyorin Pharmaceutical Co. Ltd.); theophylline (Elan Corp.); cilomilst (GlaxoSmithKline plc.); Atopik (Barrier Therapeutics Inc.); tofimilast, CI-1044, PD-189659, CP-220629, PDE 4d BHN Inhibitor (Pfizer Inc.); arofilin, LAS-37779 (Almirall Prodesfarma SA.); roflumilast, hydroxypumafentrine (Altana AG), tectomilast (Otska Pharmaceutical Co. Ltd.); tipelukast, ibudilast (Kyorin Pharmaceutical), CC-10004 (Celgene Corp.); HT-0712, IPL-4088 (Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917 (Memory Pharmaceuticals Corp.); oglemilast, GRC-4039 (Glenmark Pharmaceuticals Ltd.); AWD-12-281, ELB-353, ELB-526 (Elbion AG); EHT-0202 (ExonHit Therapeutics SA.); ND-1251 (Neuro3d SA.); 4AZA-PDE4 (4 AZA Bioscience NV.); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottapharm SpA.); GP-0203, NCS-613 (Centre National de la Recherche Scientifique); KF-19514 (Kyowa Hakko Kogyo Co. Ltd.); ONO-6126 (Ono Pharmaceutical Co. Ltd.); OS-0217 (Dainippon Pharmaceutical Co. Ltd.); IBFB-130011, IBFB-150007, IBFB-130020, IBFB-140301 (IBFB Pharma GmbH); IC-485 (ICOS Corp.); RBx-14016 and RBx-11082 (Ranbaxy Laboratories Ltd.). A preferred PDE-4 inhibitor is Rolipram.

[00235] MAO inhibitors and compositions containing such inhibitors are described, for example, in WO2006/091988, WO2005/007614, WO2004/089351, WO01/26656, WO01/12176, WO99/57120, WO99/57119, WO99/13878 , WO98/40102, WO98/01157, WO96/20946, WO94/07890 and WO92/21333.

[00236] MAO inhibitors suitable for the purpose of the present invention are, for example, Linezolid (Pharmacia Corp.); RWJ-416457 (RW Johnson Pharmaceutical Research Institute); budipine (Altana AG); GPX-325 (BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine; indantadol (Chiesi Farmaceutici SpA.); moclobemide (Roche Holding AG); SL-25.1131 (Sanofi-Synthelabo); CX-1370 (Burroughs Wellcome Co.); CX-157 (Krenitsky Pharmaceuticals Inc.); deoxypeganine (HF Arzneimittelforschung GmbH & Co. KG); bifemelan (Mitsubishi-Tokyo Pharmaceuticals Inc.); RS-1636 (Sankyo Co. Ltd.); esuprone (BASF AG); rasagiline (Teva Pharmaceutical Industries Ltd.); ladostigil (Hebrew University of Jerusalem); safinamide (Pfizer), NW-1048 (Newron Pharmaceuticals SpA.), EVT-302 (Evotec),

[00237] Histamine H3 antagonists suitable for the purpose of the present invention are, for example, ABT-239, ABT-834 (Abbott Laboratories); 3874-H1 (Aventis Pharma); UCL-2173 (Berlin Free University), UCL-1470 (BioProjet, Societe Civile de Recherche); DWP-302 (Daewoong Pharmaceutical Co Ltd); GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.); cipralysant, GT-2203 (Gliatech Inc.); Cyproxyphan (INSERM), 1S,2S-2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (Hokkaido University); JNJ-17216498, JNJ-5207852 (Johnson &Johnson); NNC-0038-0000-1049 (Novo Nordisk A/S); and Sch-79687 (Schering-Plough).

[00238] PEP inhibitors and compositions containing such inhibitors are described, for example, in JP 01042465, JP 03031298, JP 04208299, WO 00/71144, US 5,847,155; JP 09040693, JP 10077300, JP 05331072, JP 05015314, WO 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP 01068396, EP 0709373, US 5.96 5,556, US 5,756,763, US 6,121,311, JP 63264454, JP 64000069, JP 63162672, EP 0268190, EP 0277588, EP 0275482, US 4,977,180, US 5,091,406, US 4,983,624, US 5,112,847, US 5,100,904, US 5,254,550, US 5,262,43 1, US 5,340,832, US 4,956. 380, EP 0303434, JP 03056486, JP 01143897, JP 1226880, EP 0280956, US 4,857,537, EP 0461677, EP 0345428, JP 02275858, US 5,506,256, JP 061 92298, EP 0618193, JP 03255080, EP 0468469, US 5,118 811, JP 05025125, WO 9313065, JP 05201970, WO 9412474, EP 0670309, EP 0451547, JP 06339390, US 5,073,549, US 4,999,349, EP 0268281, US 4. 743,616, EP 0232849, EP 0224272, JP 62114978 , JP 62114957, US 4,757,083, US 4,810,721, US 5,198,458, US 4,826,870, EP 0201742, EP 0201741, US 4,873,342, EP 0172458, JP 61037764, EP 0201 743, US 4,772,587, EP 0372484, US 5,028,604, WO 91/18877, JP 04009367, JP 04235162, US 5,407,950, WO 95/01352, JP 01250370, JP 02207070, US 5,221,752, EP 0468339, JP 0 4211648, WO 99/46272, WO 2006/058720 and PCT/EP2006/061428.

[00239] Suitable prolyl endopeptidase inhibitors for the purpose of the present invention are, for example, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Benzothiazol (Probiodrug), Z-321 (Zeria Pharmaceutical Co Ltd.); ONO-1603 (Ono Pharmaceutical Co Ltd); JTP-4819 (Japan Tobacco Inc.) and S-17092 (Servier).

[00240] Other suitable compounds that can be used according to the present invention in combination with QC inhibitors are NPY, an NPY mimetic or an agonist or antagonist of NPY or the NPY receptor ligand.

[00241] Preferred according to the present invention are NPY receptor antagonists.

[00242] Suitable ligands or antagonists of NPY receptors are compounds derived from 3a, 4,5,9b-tetrahydro-1h-benz[e]indol-2-ylamine as described in WO 00/68197.

[00243] NPY receptor antagonists that may be mentioned include those described in European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378; International patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; WO 00/30674, US Patent Nos. 5,552,411, 5,663,192 and 5,567,714; 6,114,336, Japanese patent application JP 09157253; International patent applications WO 94/00486, WO 93/12139, WO 95/00161 and WO 99/15498; US Patent No. 5,328,899; German patent application DE 393 97 97; European patent applications EP 355 794 and EP 355 793; and Japanese patent applications JP 06116284 and JP 07267988. Preferred NPY antagonists include those compounds that are specifically described in these patent documents. More preferred compounds include non-peptide and amino acid based NPY antagonists. Non-peptide and amino acid-based NPY antagonists that may be mentioned include those described in European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378; International patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; US patent Nos. 5,552,411, 5,663,192 and 5,567,714; and Japanese patent application JP 09157253. Non-peptide and amino acid-based NPY antagonists include those compounds that are specifically described in these patent documents.

[00244] Particularly preferred compounds include amino acid-based NPY antagonists. Amino acid-based compounds that may be mentioned include those described in international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 97/19914 or preferably, WO 99/15498. Preferred amino acid-based NPY antagonists include those that are specifically described in these patent documents, e.g., BIBP3226 and especially (R)-N2-(diphenylacetyl)-(R)-N-[1-(4- hydroxy-phenyl)ethyl]arginine amide (Example 4 of international patent application WO 99/15498).

[00245] M1 receptor agonists and compositions containing such inhibitors are described, for example, in WO2004/087158, WO91/10664.

[00246] M1 receptor antagonists suitable for the purpose of the present invention are for example, CDD-0102 (Cognitive Pharmaceuticals); Cevimelina (Evoxac) (Snow Brand Milk Products Co. Ltd.); NGX-267 (TorreyPines Therapeutics); sabcomelina (GlaxoSmithKline); alvamelina (H Lundbeck A/S); LY-593093 (Eli Lilly &Co.); VRTX-3 (Vertex Pharmaceuticals Inc.); WAY-132983 (Wyeth), CI-101 7/ (PD-151832) (Pfizer Inc.) and MCD-386 (Mitridion Inc.), .

[00247] Acetylcholinesterase inhibitors and compositions containing such inhibitors are described, for example, in WO2006/071274, WO2006/070394, WO2006/040688, WO2005/092009, WO2005/079789, WO2005/039580, WO2005/02 7975, WO2004/084884 , WO2004/037234, WO2004/032929, WO03/101458, WO03/091220, WO03/082820, WO03/020289, WO02/32412, WO01/85145, WO01/78728, WO01/66096, WO00/02549, WO01/00215, WO00 /15205, WO00/23057, WO00/33840, WO00/30446, WO00/23057, WO00/15205, WO00/09483, WO00/07600, WO00/02549, WO99/47131, WO99/07359, WO98/ 30243, WO97/38993 , WO97/13754, WO94/29255, WO94/20476, WO94/19356, WO93/03034 and WO92/19238.

[00248] Suitable acetylcholinesterase inhibitors for the purpose of the present invention are, for example, Donepezil (Eisai Co. Ltd.); rivastigmine (Novartis AG); (-)-phenserine (TorreyPines Therapeutics); ladotigila (Hebrew University of Jerusalem); huperzine A (Mayo Foundation); galantamine (Johnson &Johnson); Memoquina (Universita di Bologna); SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 (Sankyo Co. Ltd.); physostigmine (Forest Laboratories Inc.); NP-0361 (Neuropharma SA); ZT-1 (Debiopharm); tacrine (Warner-Lambert Co.); metrifonate (Bayer Corp.), INM-176 (WhanIn), huperzine A (Neuro-Hitech/Xel Pharmaceutical), mimopezil (Debiopharm), and Dimebon (Medivation/Pfizer).

[00249] NMDA receptor antagonists and compositions containing such inhibitors are described, for example, in WO2006/094674, WO2006/058236, WO2006/058059, WO2006/010965, WO2005/000216, WO2005/102390, WO2005/07 9779, WO2005 /079756, WO2005/072705, WO2005/070429, WO2005/055996, WO2005/035522, WO2005/009421, WO2005/000216, WO2004/092189, WO2004/039371, WO 2004/028522, WO2004/009062, WO03/010159, WO02/072542 , WO02/34718, WO01/98262, WO01/94321, WO01/92204, WO01/81295, WO01/32640, WO01/10833, WO01/10831, WO00/56711, WO00/29023, WO00/00197 , WO99/53922, WO99 /48891, WO99/45963, WO99/01416, WO99/07413, WO99/01416, WO98/50075, WO98/50044, WO98/10757, WO98/05337, WO97/32873, WO97/23216, WO97/ 23215, WO97/23214 , WO96/14318, WO96/08485, WO95/31986, WO95/26352, WO95/26350, WO95/26349, WO95/26342, WO95/12594, WO95/02602, WO95/02601, WO94/20109 , WO94/13641, WO94 /09016 and WO93/25534.

[00250] NMDA receptor antagonists suitable for the purpose of the present invention are for example, Memantine (Merz & Co. GmbH); topiramate (Johnson &Johnson); AVP-923 (Neurodex) (Center for Neurologic Study); EN-3231 (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dexanabinol (HU-211; Sinabidol; PA-50211) (Pharmos); EpiCept NP-1 (Dalhousie University); indantadol (V3381; CNP-3381) (Vernalis); perzinfotel (EAA-090, WAY-126090, EAA- 129) (Wyeth); RGH-896 (Gedeon Richter Ltd.); traxoprodil (CP-101606), besonprodil (PD-196860, CI-1041) (Pfizer Inc.); CGX-1007 (Cognetix Inc.); delucemin (NPS-1506) (NPS Pharmaceuticals Inc.); EVT-101 (Roche Holding AG); acamprosate (Synchroneuron LLC.); CR-3991, CR-2249, CR-3394 (Rottapharm SpA.); AV-101 (4-Cl-kynurenine (4-Cl-KYN)), 7-chloro-kynurenic acid (7-Cl-KYNA) (VistaGen); NPS-1407 (NPS Pharmaceuticals Inc.); YT-1006 (Yaupon Therapeutics Inc.); ED-1812 (Sosei R&D Ltd.); himantane (N-2-(adamantyl)-hexamethylenimine hydrochloride) (RAMS); Lancicemina (AR-R-15896) (AstraZeneca); EVT-102, Ro-25-6981 and Ro-63-1908 (Hoffmann-La Roche AG / Evotec), neramexane (Merz).

[00251] Furthermore, the present invention relates to combination therapies useful for treating atherosclerosis, restenosis or arthritis, administering a QC inhibitor in combination with another therapeutic agent selected from the group consisting of angiotensin-converting enzyme inhibitors ( ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high-density lipoprotein (HDL)-increasing compounds; renin inhibitors; IL-6 inhibitors; anti-inflammatory corticosteroids; antiproliferative agents; nitric oxide donors; extracellular matrix synthesis inhibitors; growth factor or cytokine signal transduction inhibitors; MCP-1 antagonists and tyrosine kinase inhibitors that provide beneficial or synergistic therapeutic effects over each monotherapy component alone.

[00252] Angiotensin II receptor blockers are understood to be those active agents that bind to the AT1 receptor subtype of angiotensin II receptor, but do not result in activation of the receptor. As a consequence of AT1 receptor blockade, these antagonists can, for example, be employed as antihypertensive agents.

[00253] Suitable angiotensin II receptor blockers that can be used in the combination of the present invention include AT1 receptor antagonists having different structural aspects, preferred are those with non-peptide structures. For example, mention should be made of compounds that are selected from the group consisting of valsartan (EP 443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP 403159), irbesartan (EP 454511), olmesartan (EP 503785), tasosartan (EP 539086), telmisartan (EP 522314), the compound with the designation E-41 77 of the formula the compound with the designation SC-52458 of the following formula and the compound with the compound designation ZD-8731 of the formula or, in each case, a pharmaceutically acceptable salt thereof.

[00254] Preferred AT1 receptor antagonists are those agents that have been approved and reached the market, the most preferred is valsartan, or a pharmaceutically acceptable salt thereof.

[00255] Interrupting the enzymatic degradation of angiotensin to angiotensin II with ACE inhibitors is a successful variant for regulating blood pressure and thus also makes available a therapeutic method for treating hypertension.

[00256] A suitable ACE inhibitor to be used in the combination of the present invention is, for example, a compound selected from the group consisting of alacepril, benazepril, benazeprilate; captopril, ceronapril, cilazapril, delapril, enalapril, enaprilate, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril and trandolapril, or in each case, a pharmaceutically acceptable salt thereof.

[00257] Preferred ACE inhibitors are those agents that have been marketed, the most preferred are benazepril and enalapril.

[00258] A diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylchlothiazide, and chlorthalidone. The most preferred diuretic is hydrochlorothiazide. A diuretic further comprises a low potassium diuretic such as amiloride or triametherin, or a pharmaceutically acceptable salt thereof.

[00259] The class of CCBs essentially comprises dihydropyridines (DHPs) and non-DHPs, such as diltiazem-type and verapamil-type CCBs.

[00260] A CCB useful in said combination is preferably a representative DHP selected from the group consisting of amlodipine, felodipine, riosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, and is preferably a representative non-DHP selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, galopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All of these CCBs are used therapeutically, for example, as antihypertensive, antiangina pectoris or antiarrhythmic drugs.

[00261] Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil or, for example, depending on the specific CCB, a pharmaceutically acceptable salt thereof. Especially preferred as DHP are amlodipine or a pharmaceutically acceptable salt thereof, especially the besylate. An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt thereof, especially the hydrochloride thereof.

[00262] Beta-blockers suitable for use in the present invention include beta-adrenergic blocking agents (beta-blockers), which compete with epinephrine for beta-adrenergic receptors and interfere with the action of epinephrine. Preferably, beta-blockers are selective for the beta-adrenergic receptor compared to alpha-adrenergic receptors, and therefore do not have a significant alpha-blocking effect. Suitable beta-blockers include compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol. Where the beta-blocker is an acid or base or otherwise capable of forming pharmaceutically acceptable salts or prodrugs, these forms are to be considered covered herein, and it is understood that the compounds may be administered in free form or in the form of a salt. pharmaceutically acceptable thereof or a prodrug, such as a physiologically acceptable and hydrolyzable ester. For example, metoprolol is suitably administered as its tartrate salt, propranolol is suitably administered as its hydrochloride salt, and so on.

[00263] Platelet aggregation inhibitors include PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol) and aspirin.

[00264] Cholesterol absorption modulators include ZETIA® (ezetimibe) and KT6-971 (Kotobuki Pharmaceutical Co. Japan).

[00265] HMG-Co-A reductase inhibitors (also called beta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors or statins) are understood to be those active agents that can be used to lower levels of lipids including cholesterol in the blood.

[00266] The class of HMG-Co-A reductase inhibitors comprises compounds having different structural aspects. For example, mention may be made of compounds, which are selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or in each case, a pharmaceutically acceptable salt thereof.

[00267] Preferred HMG-Co-A reductase inhibitors are those agents, which have been commercialized, the most preferred being atorvastatin, pitavastatin or simvastatin, or a pharmaceutically acceptable salt thereof.

[00268] HDL-increasing compounds include, but are not limited to, cholesterol ester transfer protein (CETP) inhibitors. Examples of CETP inhibitors include JTT7O5 described in Example 26 of U.S. Patent No. 6,426,365 issued July 30, 2002, and pharmaceutically acceptable salts thereof.

[00269] Inhibition of interleukin-6-mediated inflammation can be achieved indirectly by regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the signal transduction reaction series using the interleukin-6 inhibitor/antibody, inhibitor/ interleukin-6 receptor antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor/antibody, tyrosine kinase inhibitors/antibodies, serine/threonine kinase inhibitors/antibodies, (MAP) gp130 kinase inhibitors/antibodies mitogen-activated protein, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, nuclear factor kappaB (NF-KB) inhibitors/antibodies, IKB kinase (IKK) inhibitors/antibodies, activating protein-1 (AP) inhibitors/antibodies -1), inhibitors/antibodies of STAT transcription factors, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, PPAR gamma activators/ligands and/or PPAR beta/delta or a functional fragment thereof.

[00270] A suitable anti-inflammatory corticosteroid is dexamethasone.

[00271] Suitable antiproliferative agents are cladribine, rapamycin, vincristine and taxol.

[00272] A suitable inhibitor of extracellular matrix synthesis is halofuginone.

[00273] A suitable growth factor or cytokine signal transduction inhibitor is, for example, the ras inhibitor R115777.

[00274] A suitable tyrosine kinase inhibitor is tyrphostin.

[00275] Suitable renin inhibitors are described, for example, in WO 2006/116435. A preferred renin inhibitor is aliskiren, preferably in the form of the hemi-fumarate salt thereof.

[00276] MCP-1 antagonists can, for example, be selected from anti-MCP-1 antibodies, preferably monoclonal or humanized monoclonal antibodies, MCP-1 expression inhibitors, CCR2 antagonists, TNF-alpha inhibitors, of VCAM-1 gene expression and anti-C5a monoclonal antibodies.

[00277] MCP-1 antagonists and compositions containing such inhibitors are described, for example, in WO02/070509, WO02/081463, WO02/060900, US2006/670364, US2006/677365, WO2006/097624, US2006/316449, WO200 4/ 056727, WO03/053368, WO00/198289, WO00/157226, WO00/046195, WO00/046196, WO00/046199, WO00/046198, WO00/046197, WO99/046991, WO99/0 07351, WO98/006703, WO97/012615, WO2005/105133, WO03/037376, WO2006/125202, WO2006/085961, WO2004/024921, WO2006/074265.

[00278] Suitable MCP-1 antagonists are, for example, C243 (Telik Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis AG); CC-11006 (Celgene Corp.); SSR-150106 (Sanofi-Aventis); MLN-1202 (Millenium Pharmaceuticals Inc.); AGI-1067, AGIX-4207, AGI-1096 (AtherioGenics Inc.); PRS-211095, PRS-211092 (Pharmos Corp.); anti-C5a monoclonal antibodies, e.g., neutrozumab (G2 Therapies Ltd.); AZD-6942 (AstraZeneca plc.); 2-mercaptoimidazoles (Johnson &Johnson); TEI-E00526, TEI-6122 (Deltagen); RS-504393 (Roche Holding AG); SB-282241, SB-380732, ADR-7 (GlaxoSmithKline); anti-MCP-1 monoclonal antibodies (Johnson & Johnson).

[00279] Combinations of QC inhibitors with MCP-1 antagonists may be useful for the treatment of inflammatory diseases in general, including neurodegenerative diseases.

[00280] Combinations of QC inhibitors with MCP-1 antagonists are preferred for the treatment of Alzheimer's disease.

[00281] More preferably, the QC inhibitor is combined with one or more compounds selected from the following group:

[00282] PF-4360365, m266, bapineuzumab, R-1450, Posiphen, (+)-phenserine, MK-0752, LY-450139, E-2012, (R)-flurbiprofen, AZD-103, AAB-001 (Bapineuzumab ), Tramiprosate, EGb-761, TAK-070, Doxophylline, Theophylline, Cilomilast, Tofimilast, Roflumilast, Tetomilast, Tipelukast, Ibudilast, HT-0712, MEM-1414, Oglemilast, Linezolid, Budipine, Isocarboxazid, Phenelzine, Tranylcypromine, Indantadol, moclobemide, rasagiline, ladostigil, safinamide, ABT-239, ABT-834, GSK-189254A, Ciproxiphane, JNJ-17216498, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Benzothiazol, Z-321, ONO-1603, JTP-4819, S-17092, BIBP3226; (R)-N2-(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl) ethyl] arginine amide, Cevimeline, sabcomelin, (PD-151832), Donepezil, rivastigmine, (-)-phenserine, ladostigil , galantamine, tacrine, metrifonate, memantine, topiramate, AVP-923, EN-3231, neramexane, valsartan, benazepril, enalapril, hydrochlorothiazide, amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil, amlodipine, acebutolol , atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol), aspirin, ZETIA® ( ezetimibe) and KT6-971, statins, atorvastatin, pitavastatin or simvastatin; dexamethasone, cladribine, rapamycin, vincristine, taxol, aliskiren, C243, ABN-912, SSR-150106, MLN-1202 and betaferone.

[00283] In particular, the following combinations are considered:

[00284] (a) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with Atorvastatin for the treatment and/or prevention of atherosclerosis,

[00285] (b) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with immunosuppressive agents, preferably rapamycin for the prevention and/or treatment of restenosis,

[00286] (c) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with immunosuppressive agents, preferably paclitaxel for the prevention and/or treatment of restenosis,

[00287] (d) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with AChE inhibitors, preferably Donepezil, for the prevention and/or treatment of Alzheimer's disease,

[00288] (e) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with interferons, preferably Aronex, for the prevention and/or treatment of multiple sclerosis,

[00289] (f) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with interferons, preferably betaferon, for the prevention and/or treatment of multiple sclerosis,

[00290] (g) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with interferons, preferably Rebif, for the prevention and/or treatment of multiple sclerosis

[00291] (h) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with Copaxone, for the prevention and/or treatment of multiple sclerosis,

[00292] (i) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with dexamethasone, for the prevention and/or treatment of restenosis,

[00293] (j) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with dexamethasone, for the prevention and/or treatment of atherosclerosis,

[00294] (k) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with dexamethasone, for the prevention and/or treatment of rheumatoid arthritis,

[00295] (l) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with HMG-Co-A-reductase inhibitors, for the prevention and/or treatment of restenosis, in which the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin,

[00296] (m) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with HMG-Co-A reductase inhibitors, for the prevention and/or treatment of atherosclerosis in which the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin,

[00297] (n) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with HMG-Co-A reductase inhibitors, for the prevention and/or treatment of rheumatoid arthritis in which the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin , pravastatin, rosuvastatin and simvastatin,

[00298] (o) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with amyloid-beta antibodies for the prevention and/or treatment of mild cognitive impairment, in which the amyloid-beta antibody is Acl-24,

[00299] (p) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with amyloid-beta antibodies for the prevention and/or treatment of Alzheimer's disease, wherein the amyloid-beta antibody is Acl-24,

[00300] (q) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with amyloid-beta antibodies for the prevention and/or treatment of neurodegeneration in Down Syndrome, in which the amyloid-beta antibody is Acl-24,

[00301] (r) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with beta-secretase inhibitors for the prevention and/or treatment of mild cognitive impairment, wherein the beta-secretase inhibitor is selected from WY-25105, GW-840736X and CTS-21166,

[00302] (s) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with beta-secretase inhibitors for the prevention and/or treatment of Alzheimer's disease, wherein the beta-secretase inhibitor is selected from WY-25105, GW-840736X and CTS-21166,

[00303] (t) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with beta-secretase inhibitors for the prevention and/or treatment of neurodegeneration in Down Syndrome, wherein the beta-secretase inhibitor is selected from WY-25105, GW-840736X and CTS-21166,

[00304] (u) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with gamma-secretase inhibitors for the prevention and/or treatment of mild cognitive impairment, wherein the gamma-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124,

[00305] (v) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with gamma-secretase inhibitors for the prevention and/or treatment of Alzheimer's disease, wherein the gamma-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124,

[00306] (w) a QC inhibitor, preferably a QC inhibitor of Formula (I), more preferably a QC inhibitor selected from any of examples 1-3, 5-15, 17-21, 23-26, 28-30, in combination with gamma-secretase inhibitors for the prevention and/or treatment of neurodegeneration in Down Syndrome, wherein the gamma-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124.

[00307] Such combination therapy is in particular useful for AD, FAD, FDD and neurodegeneration in Down Syndrome as well as atherosclerosis, rheumatoid arthritis, restenosis and pancreatitis.

[00308] Such combination therapies may result in a better therapeutic effect (less proliferation, as well as less inflammation, a stimulus for proliferation) than would occur with either agent alone.

[00309] With regard to the specific combination of QC inhibitors and other compounds, reference is made in particular to WO 2004/098625 in this regard, which is incorporated herein by reference.

Pharmaceutical compositions

[00310] To prepare the pharmaceutical compositions of this invention, at least one compound of Formula (I) optionally in combination with at least one of the other agents mentioned above can be used as the active ingredient(s). The active ingredient(s) are intimately admixed with a pharmaceutical carrier in accordance with conventional pharmaceutical compounding techniques, which carrier may have a wide variety of forms depending on the form of preparation desired for administration, e.g. example, oral or parenteral, such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; For solid oral preparations such as, for example, powders, capsules, gel capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets can be sugar-coated or enteric-coated by standard techniques. For parenterals, the vehicle will usually comprise sterile water, although other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.

[00311] Injectable suspensions can also be prepared, in which case appropriate liquid vehicles, suspending agents and the like can be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoon and the like, an amount of the active ingredient(s) necessary to release an effective amount as above. described. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoon and the like, from about 0.03 mg to 100 mg/kg (preferred 0.1 - 30 mg /kg) and can be administered at a dosage of about 0.1 - 300 mg/kg per day (preferred 1 - 50 mg/kg per day) of each active ingredient or combination thereof. The dosages, however, can be varied depending on the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of daily administration or post-periodic dosing may be employed.

[00312] Preferably, these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, dosed aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, intranasal, subline or rectal parenteral administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-a-week or once-a-month administration; for example, an insoluble salt of the active compound, such as the decanoate salt, can be adapted to provide a depot preparation for intramuscular injection. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tablet making ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate. , dicalcium phosphate or gums, and other pharmaceutical diluents, for example, water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be easily subdivided into equally effective dosage forms, such as tablets, pills and capsules. This preformulation composition is then divided into unit dosage forms of the type described above, containing from 0.1 to about 500 mg of each active ingredient or combinations thereof of the present invention.

[00313] Tablets or pills of a composition of the present invention may be coated or otherwise compounded to provide a dosage form providing the advantage of prolonged action. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or have its release delayed. A variety of material can be used for such enteric layers or coatings, such materials including various polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[00314] This liquid form in which the compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

[00315] The pharmaceutical composition can contain between about 0.01 mg and 100 mg, preferably about 5 to 50 mg, of each compound, and can be constituted in any form suitable for the selected mode of administration. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavors, sweeteners, preservatives, pigments, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate-release, controlled-release, and extended-release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs. , emulsions, and suspensions. Useful forms for parenteral administration include sterile solutions, emulsions and suspensions.

[00316] Advantageously, compounds of the present invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times a day. Furthermore, compounds for the present invention can be administered in intranasal form through topical use of suitable intranasal vehicles, or through transdermal patches well known to those skilled in the art. To be administered in the form of a transdermal delivery system, dosage administration will, in effect, be continuous rather than intermittent, throughout the dosage regimen.

[00317] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a non-toxic, oral, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water and the like. Furthermore, when desired or necessary, suitable binders, desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate , sodium acetate, sodium chloride and the like. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

[00318] Liquid forms in suitable flavored suspending agents or dispersants, such as synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations that usually contain suitable preservatives are employed when intravenous administration is desired.

[00319] The compounds or combinations of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[00320] Compounds or combinations of the present invention can also be released by using monoclonal antibodies as individual vehicles to which the compound molecules are coupled. The compounds of the present invention can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention can be coupled to a class of biodegradable polymers useful in obtaining controlled release of a drug, for example, polyacetic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogel copolymers. amphipathic or reticulated blocks.

[00321] Compounds or combinations of this invention can be administered in any of the aforementioned compositions, and in accordance with dosage regimens established in the art, whenever treatment of the disorders in question is required.

[00322] The daily dosage of the products can be varied in a range of 0.01 to 1,000 mg per mammal per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25, 0, 50.0, 100, 150, 200, 250 and 500 milligrams of each active ingredient or combinations thereof for symptomatic dosage adjustment to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of about 0.1 mg/kg to about 300 mg/kg of body weight per day. Preferably, the range is about 1 to about 50 mg/kg. kg of body weight per day. The compounds or combinations can be administered on a 1 to 4 times per day regimen.

[00323] The ideal dosages to be administered can be easily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the intensity of the preparation, the mode of administration, and the advancement of the disease condition. Additionally, factors associated with the particular patient being treated, including the patient's age, weight, diet and administration time, will result in the need to adjust dosages.

[00324] In another aspect, the invention also provides a process for preparing a pharmaceutical composition comprising at least one compound of Formula (I), optionally in combination with at least one of the other agents mentioned above and a pharmaceutically acceptable carrier.

[00325] The compositions are preferably in unit dosage form in an amount appropriate to the relevant daily dosage.

[00326] Suitable dosages, including especially unit dosages, of the compounds of the present invention include the known dosages, including unit doses for these compounds, as described or referred to in the reference text, such as the British and North American Pharmacopoeias, Remington's Pharmaceutical Sciences ( Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see 31st Edition, page 341 and pages cited here) or the publications mentioned above.Examples

[00327] The invention also relates to racemates and restereoisomers of the compounds of the present invention: General Summary Description: Method A: Example 1 - 3 Step 1:

[00328] A mixture of the corresponding fluorine-substituted 4-hydroxybenzonitrile (1 equivalent), the corresponding 4-Chloro-2-butanol (3 equivalents) and potassium carbonate (2 equivalents) in acetonitrile was refluxed for 20 h. The reaction mass was cooled to room temperature and then filtered. The filtrate was partitioned with water and ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the crude intermediates MA-S1.Step 2:

[00329] 2-Iodoxy benzoic acid (9 equivalents) was added to a solution of MA-S1 (crude, 1 equivalent) in dichloromethane and dimethyl sulfoxide and stirred for 18 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash layers were washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to yield crude intermediates MA-S2, which were purified by column chromatography.Step 3:

[00330] Diethylamino sulfurtrifluoride (4 equivalents) was added to a solution of MA-S3 (1 equivalent) in dichloromethane at 0°C. The reaction mass was warmed to room temperature and then stirred for 35 h. The reaction was quenched in ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed successively with aqueous sodium bicarbonate, water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the crude intermediates MA-S3.Method B: Example 5 – 9 Step 1:

[00331] A mixture of the corresponding 4-hydroxy benzonitrile (1 equivalent), chlorine acetone (1.5 equivalents) and potassium carbonate (2 equivalents) in acetonitrile was refluxed for 12 h. The reaction mass was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the crude intermediate MB-S1.Step 2:

[00332] Diethylamino sulfurtrifluoride (2 equivalents) was added to a solution of MB-S1 (1 equivalent) in dichloromethane at 0°C and then the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the crude intermediate MB-S2.Method C: Example 1 - 3, 5 – 9 Step 1:

[00333] Diisobutylaluminiumhydride (DIBAL) (1.5 M; 2 equivalents) was added slowly to a solution of the corresponding intermediate MA-S3 or MB-S2 (1 equivalent) in dry and cooled tetrahydrofuran (-30 ° C) over 15 min. The reaction mass was warmed to room temperature and stirred for another 2 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed successively with saline water; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate MC-S1, which was purified by column chromatography on silica gel.Step 2:

[00334] N-Butyl lithium (n-BuLi) in hexane (2.5 M; 2 equivalents) was added to a stirred solution of methyl triphenyl phosphonium bromide (2 equivalents) in tetrahydrofuran at -50°C and was stirred again for 30 min at 0 to 5°C. The reaction mixture was cooled and a solution of the corresponding intermediate MC-S1 (1 equivalent) in tetrahydrofuran was added dropwise to the reaction at -50 ° C. The reaction mixture was warmed to room temperature and stirred for another 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate MC-S2. Purification was done by column chromatography on silica gel.Method D: Example 10 – 13 Legend: alkyl, toluene Step 1:

[00335] A mixture of the corresponding 4-bromo phenol (1 equivalent), the corresponding alkyl chlorine (2 equivalents) and potassium carbonate (3 equivalents) in acetonitrile was refluxed for 24 h. The reaction mass was cooled to room temperature and filtered. The filtrate was partitioned between water and ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the crude intermediate MD-S1, subsequently used for the next step without purification.Step 2:

[00336] 2-Iodoxy benzoic acid (3 equivalents) was added to a solution of MD-S1 (1 equivalent) in dichloromethane and dimethyl sulfoxide and the mixture stirred for 16 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash portion were washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain crude intermediates. Purification by silica gel column chromatography provided the pure compounds MD-S2.Step 3:

[00337] Diethylamino sulfurtrifluoride (4 equivalents) was added to a solution of MD-S2 (1 equivalent) in dichloromethane at 0°C. The reaction was warmed to room temperature and the mixture was stirred for 48 h. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification was done by column chromatography on silica gel to provide the compound MD-S3.Step 4:

[00338] The solution of MD-S3 (1 equivalent) and tri-n-butyl vinyltin (1.3 equivalents) in toluene was purged with argon gas for 5 min. Tetracis-(triphenylphosphine)-palladium (0.2 equivalents) was added and the mixture was continuously purged for an additional 5 min. The reaction mixture was heated in a sealed tube at 110°C for 8 h. The mixture was filtered through celite and washed with ethyl acetate. The combined filtrate and wash portion were concentrated in vacuo to obtain the crude intermediate. Purification by silica gel column chromatography finally provided the pure intermediate MD-S4.Method E: Example 14

[00339] Caption: ether

[00340] The description was provided in Example 14 Method F: Example 15 Caption: toluene

[00341] The description was provided in Example 15 Method G: Example 4 and 16

[00342] Caption: alkyl Step 1:

[00343] Thionyl chloride (2 equivalents) was added dropwise to a suspension of (S)-4-hydroxy phenyl glycine (1 equivalent) in methanol at 0°C. The mixture was slowly heated to reflux and maintained there for 15 h. The solvent was evaporated in vacuum and the residue was co-distilled twice with petroleum ether. Vacuum drying provided MG-S1.Step 2:

[00344] Aqueous potassium carbonate (2 equivalents in water) and boc anhydride (1.2 equivalents) were added successively to a suspension of MG-S1 (1 equivalent) in 1,4-dioxane at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched in water and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. The compound was suspended in petroleum ether, stirred for 30 min, filtered and dried in vacuum at MG-S2.Step 3:

[00345] Triphenyl phosphine (1.5 equivalents) and the corresponding benzylalkyl alcohol (1.1 equivalents) were added successively to a stirred solution of MG-S2 (1 equivalent) in dry tetrahydrofuran at room temperature. Diethyl azodicarboxylate (1.5 equivalents) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by silica gel column chromatography provided MG-S3.Step 4:

[00346] The solution of MG-S3 (1 equivalent) in methanol was hydrogenated over Pd/C in a Parr apparatus. The reaction mass was filtered through celite and washed with methanol. The combined filtrate and wash portion were concentrated under reduced pressure to obtain MG-S4.Step 5:

[00347] Iodoxy benzoic acid (4 equivalents) was added to a solution of MG-S4 (1 equivalent) in a mixture of dichloromethane and dimethyl sulfoxide, and a solution was stirred for 20 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash portion were washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by silica gel column chromatography provided MG-S5.Step 6:

[00348] Diethylamino sulfurtrifluoride (2 equivalents) was added to a solution of MG-S5 (1 equivalent) in dichloromethane at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain MG-S6.Step 7:

[00349] Sodium borohydride (4 equivalents) was added in two equal batches (over 15 min) to a solution of MG-S6 (1 equivalent), to a mixture of tetrahydrofuran and methanol at room temperature. Due to the exothermic reaction the temperature rose to ~50°C. After completion of the addition the reaction mixture was stirred for 1 h. Ethyl acetate was added and the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain MG-S7, later used without any purification. Method H: Example 17

[00350] Caption: Niquel Raney

[00351] The description was provided in Example 17 Method J: Example 1 - 3, 5 – 15 Step 1:

[00352] Hypochlorite t-Butyl hypochlorite (3 equivalents) was added to a stirred solution of Nt-Butoxycarbonyl-amide (Boc-NH2) (3 equivalents) in 1-propanol and 0.4 N aqueous sodium hydroxide at 15° C and stirred for 15 min. A solution of 1,4-phthalazinediyl hydrokinine diether ((DHQ)2PHAL, 0.05 equivalents) in 1-propanol was added followed by a solution of the corresponding intermediate MC-S2, MD-S4, ME-S5 or MF-S3 (1 equivalent) in 1-propanol. Finally potassium osmatodihydrate (0.04 equivalents) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediates MJ-S1. Purification was carried out by column chromatography on silica gel.Method K: Example 1 – 17

[00353] Legend: type, dioxane, alkyl Step 1:

[00354] Type 1: potassium t-butoxide (3 equivalents) was added to a solution of the corresponding intermediate MG-S7, MH-S9 or MJ-S1 (1 equivalent) in tetrahydrofuran at 0°C. The reaction mass was warmed to room temperature and stirred for 2 h. The reaction was acidified with acetic acid (pH~6) and extracted with ethyl acetate. The separated organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum provided the intermediates MK-S1.

[00355] Type 2: thionylchloride (8 equivalents) was added dropwise to a solution of the corresponding intermediate MG-S7, MH-S9 or MJ-S1 (1 equivalent) in tetrahydrofuran at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was evaporated under vacuum and the remaining mass was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain MK-S1.Step 2:

[00356] A mixture of the corresponding intermediate MK-S1 (1 equivalent), 1,2-diamino-4-bromobenzene (1 equivalent) and cesium fluoride (2 equivalents) in 1,4-dioxane was purged with argon gas for 10 min. Copper iodide (0.5 equivalents) was added and the reaction mixture was purged for an additional 10 min. Finally 1,2-diaminocyclohexane (0.05 equivalents) was added and again the reaction mixture was purged for another 10 min. The reaction mass was stirred at 110 to 115°C in a sealed tube for 20 h. The reaction was cooled to room temperature, filtered through celite, washed with dioxin and concentrated under reduced pressure to obtain the crude intermediates MK-S2. The compound was purified by column chromatography.Step 3:

[00357] Formamidine acetate (3 equivalents) was added to a solution of the corresponding intermediate MK-S2 (1 equivalent) in acetonitrile and refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude compound Examples 1 - 17. The products were either purified by washing with diethyl ether, filtered and dried or purified by Preparative HPLC or equivalent methods. Method L: Example 18 – 20

[00358] Legend: toluene Step 1:

[00359] Potassium iodide (2 equivalents), N,N-diisopropylethylamine (2 equivalents), 1,4-dibromo-2-butanol (2 equivalents) were added successively to a stirred solution of the corresponding 4-bromoaniline (1 equivalent) in toluene. The reaction mass was stirred at 90°C for 18 h. The reaction mass was filtered and washed with ethyl acetate. The filtrate was washed successively with water, saline; dried over anhydrous sodium sulfate, evaporated in vacuum. Purification by silica gel column chromatography provided the intermediate ML-S1.Step 2:

[00360] The solution of ML-S1 (1 equivalent) and copper cyanide (1.5 equivalents) in N,N-dimethylformamide was stirred at 150°C for 20 h. The reaction mass was evaporated in vacuum, then stirred in ammonium chloride solution, filtered and washed with dichloromethane. The filtrate was washed with water; dried over anhydrous sodium sulfate and evaporated in vacuum. Purification by column chromatography on silica gel gave ML-S2.Step 3:

[00361] Oxalyl chloride (2 equivalents) was added to a stirred solution of dimethyl sulfoxide (4 equivalents) in dichloromethane at -78°C and the mixture was stirred for 1 h. A solution of ML-S2 (1 equivalents) in dichloromethane was added dropwise at -78°C and the solution was stirred for 1 h at the same temperature. Triethyl amine (5 equivalents) was added and the mixture was warmed to room temperature for 40 min. The reaction mixture was quenched with ice water and extracted with dichloromethane. The separated organic layer was washed with brine; dried over anhydrous sodium sulfate and evaporated in vacuum to obtain the crude intermediate ML-S3, subsequently used without any purification.Step 4:

[00362] Diethylamino sulfurtrifluoride (2 equivalents) was added to a solution of ML-S3 (1 equivalent) in dichloromethane at 0°C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, bicarbonate, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the crude intermediate ML-S4, subsequently used without any purification.Step 5:

[00363] Diisobutyl aluminum hydride in toluene (1.5 M, 2 equivalents) was added to a solution of ML-S4 (1 equivalent) in tetrahydrofuran at -70°C and the mixture slowly heated to 0°C. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed with saline; dried over anhydrous sodium sulfate and evaporated in vacuum. Purification by column chromatography over neutral alumina gave ML-S5.Method M: Example 21 – 22 Step 1:

[00364] (R)-3-Hydroxypyrrolidine (1.5 equivalents) was added to a stirred solution of the corresponding 4-fluorobenzonitrile (1 equivalent) and potassium carbonate (1 equivalent) in dimethylformamide and the mixture was stirred overnight at 80°C. The reaction mass was filtered, washed with ethyl acetate and the filtrate was evaporated in vacuum. The residue was partitioned between water and ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography over neutral alumina gave MN-S1.Step 2: Type 1:

[00365] Periodinane Dess-martin (2 equivalents) was added to a solution of MM-S1 (1 equivalent) and the mixture was stirred for 15 h. The reaction mass was filtered through celite and washed with dichloromethane. The filtrate was washed with water, brine; dried over anhydrous sodium sulfate and concentrated to obtain MM-S2, later used without any purification. Type 2:

[00366] Oxalyl chloride (2 equivalents) was added to a stirred solution of dry dimethylsulfoxide (4 equivalents) in dichloromethane at -78°C and stirred for 1 h at the same temperature. A solution of MM-S1 (1 equivalent) in dichloromethane was added dropwise at -78°C and the solution was stirred for 2 h at the same temperature. Triethylamine (5 equivalents) was added and the mixture was stirred for 30 min at room temperature. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography over neutral alumina gave MM-S2.Step 3:

[00367] Diethylamino sulfurtrifluoride (2.1 equivalents) was added to a solution of MM-S2 (1 equivalent) in dichloromethane at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was quenched with ice water and the separated organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain MM-S3, later used without any purification.Step 4:

[00368] Diisobutyl aluminum hydride (DIBAL) in toluene (1 M; 2 equivalents) was slowly added to a stirred solution of MM-S3 (1 equivalent) in tetrahydrofuran at -10°C. The reaction mixture was stirred for 6 h at room temperature. The reaction was quenched with ammonium chloride solution, filtered and the filtrate was extracted into ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the intermediate MM-S4.Method N: Example 18 – 22 Step 1:

[00369] N-Butyl lithium in hexane (2.2M; 2 equivalents) was added to a stirred solution of methyl-triphenyl-phosphoniobromide (2 equivalents) in tetrahydrofuran at -30°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of the corresponding intermediate ML-S5 or MM-S4 (1 equivalent) in tetrahydrofuran was added dropwise at -30°C. The temperature was warmed to room temperature and the mixture stirred for 2 h. The reaction was quenched with acetic acid and the pH value was adjusted to pH~5. A solution was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel gave MN-S1.Method O: Example 23

[00370] Caption: toluene

[00371] The description method was provided in Example 23. Method P: Example 24

[00372] The description method was provided in Example 24. Method Q: Example 23 – 24

[00373] Legend: toluene Step 1:

[00374] Oxalyl chloride (2 equivalents) was added to a solution of dimethylsulfoxide (4 equivalents) in dichloromethane at -78°C and the mixture was stirred for 30 min. A solution of the corresponding intermediate MO-S1 or MP-S1 (2.45g, 9.21mmol) in dichloromethane was slowly added over 10 min and the mixture was stirred for 1 h at -78°C. Triethylamine (5 equivalents) was added and the mixture was stirred at room temperature for 30 min. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain MQ-S1, later used without any purification.Step 2:

[00375] Diethylamino sulfurtrifluoride (2 equivalents) was added to a solution of MQ-S1 (1 equivalent) in dichloromethane at 0°C. The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with aqueous sodium bicarbonate, water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by silica gel column chromatography provided MQ-S2.Step 3:

[00376] The solution of MQ-S2 (1.1g, 3.85mmol) and tri-n-butyl vinyl tin (1.3 equivalents) in toluene was purged with argon gas for 5 min. Tetracis-(triphenylphosphine)-palladium (0.02 equivalents) was added and the mixture was continuously purged for an additional 5 min. The reaction mixture was heated in a sealed tube at 110°C for 8 h. The reaction mass was filtered through celite and washed with ethyl acetate. The combined filtrate and wash portion were concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel gave MQ-S3. Method R: Example 18 – 24

[00377] Caption: dioxane Step 1:

[00378] T-Butyl hypochlorite (3 equivalents) was added to a stirred solution of t-butyl carbanate (3 equivalents) in 1-propanol and 0.4N aqueous sodium hydroxide at 15°C and the mixture was stirred for 15 min. A solution of 1,4-phthalazinediyl hydrokinine diether ((DHQ)2PHAL, 0.05 equivalents) in 1-propanol was added, followed by a solution of the corresponding intermediate MN-S1 or MQ-S1 (1 equivalent) in 1- propanol. Finally potassium osmatodihydrate (0.04 equivalents) was added and the reaction mixture was stirred for another 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography provided MR-S1.Step 2:

[00379] Potassium-t-butoxide (2 equivalents) was added to a stirred solution of MR-S1 (1 equivalent) in tetrahydrofuranate 0°C and the mixture was stirred for 1 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain MR-S2, subsequently used without any purification.Step 3:

[00380] A mixture of MR-S2 (1 equivalent), 4-Bromo-1,2-diaminobenzene (1.1 equivalents) and cesium fluoride (2 equivalents) in 1,4-dioxane were purged with argon gas for 10 min in a sealed tube. Copper iodide (0.15 equivalents) and 1,2-diaminocyclohexane (0.15 equivalents) were added and the mixture was continuously purged for a further 10 min. The sealed tube was heated for 18 h at 110-115°C. The mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina provided MR-S3.Step 4:

[00381] Formamidine acetate (2 equivalent) was added to a solution of MR-S3 (1 equivalent) in acetonitrile and the mixture was refluxed for 1 h. The solvent was evaporated in vacuum and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was triturated with diethyl ether and dried to obtain Example 18 - 24. Method S: Example 25

[00382] The description method was provided in Example 25. Method T: Example 26

[00383] Caption: imidazole, dioxane, pyridine

[00384] The description method was provided in Example 26. Method U: Example 25 – 26

[00385] Caption: dioxane Step 1:

[00386] 2-Iodoxybenzoic acid (3 equivalents) was added to a solution of MS-S6 or MT-S8 (1 equivalent) in dichloromethane: dimethyl sulfoxide (3:1) and the mixture was stirred for 8 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash portion were washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. purification by column chromatography on silica provided MU-S1.Step 2:

[00387] N-Butyl lithium (2.2 M; 2 equivalents) was added to a stirred solution of triphenylphosphonium methylbromide (2 equivalents) in tetrahydrofuran at -30 ° C and the mixture was stirred for 30 min at 0 to 5°C. A solution of MU-S1 (1 equivalent) in tetrahydrofuran was added dropwise at -30°C. The temperature was warmed to room temperature and the reaction mixture was stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography provided MU-S2.Step 3:

[00388] T-Butylhypochlorite (3.1 equivalents) was added to a stirred solution of t-butyl carbanate (3 equivalents in 1-propanol and 0.4N aqueous sodium hydroxide at 15°C and the mixture was stirred for 15 min. A solution of 1,4-phthalazinediyl hydrokinine diether ((DHQ)2PHAL, 0.05 equivalents) in 1-propanol was added, followed by a solution of MU-S2 (1 equivalent) in 1-propanol. Finally Potassium osmatodihydrate (0.4 equivalents) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfate solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate.Purification by silica gel column chromatography gave MU-S3.Step 4:

[00389] Potassium-t-butoxide (3 equivalents) was added in 2 portions to a stirred solution of MU-S3 (1 equivalent) in tetrahydrofuran over 15 min at 0°C, and the mixture was stirred for 2 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain MU-S4, subsequently used without any purification.Step 5:

[00390] A mixture of MU-S4 (1 equivalent), 4-Bromo-1,2-diaminobenzene (1 equivalent) and cesium fluoride (2 equivalents) in 1,4-dioxane was purged with argon gas for 30 min . Copper iodide (0.38 equivalents) and 1,2-diaminocyclohexane (0.38 equivalents) were added and the mixture was continuously purged for a further 10 min. The reaction was heated in a sealed tube for 16 h at 105 to 110°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina provided MU-S5.Step 6:

[00391] Formamidine acetate (3 equivalents) was added to a solution of MU-S5 (1 equivalent) in acetonitrile and the mixture was refluxed for 2 h. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by column chromatography on ???? neutral provided Example 25 - 26.Method V: Example 27

[00392] Legend: toluene, dioxane, 18-crown-6

[00393] The description method was provided in Example 27. Method W: Example 28

[00394] Caption: toluene

[00395] The description method was provided in Example 28. Method X: Example 29

[00396] Caption: toluene

[00397] The description method was provided in Example 29. Method Y: Example 28 – 29 Step 1:

[00398] Sodium acetate (2 equivalents) and hydroxylamine hydrochloride (2 equivalents) were added successively to a solution of the corresponding intermediate MW-S5 or MX-S3 (1 equivalent) in absolute ethanol and the mixture was refluxed for 1 h. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain MY-S1, subsequently used without any purification.Step 2:

[00399] The solution of MY-S1 (1 equivalent) in absolute ethanol was hydrogenated over 10% Pd-C in a Parr apparatus. The reaction mass was filtered through celite and washed with ethanol. The combined filtrate and wash portion were concentrated under reduced pressure to obtain MY-S2, subsequently used without any purification.Step 3:

[00400] A sufficient amount (large excess) of trifluoroacetic acid was added to a solution of MY-S2 (1 equivalent) in dichloromethane at 0°C and the mixture was stirred for 3 h at room temperature. The solvent was evaporated in vacuum, the remaining mass was dissolved in hydrochloric acid (6N) and washed with 40% ethyl acetate in petroleum ether. The aqueous layer was basified with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain MY-S3, later used without any purification.Step 4:

[00401] Triethyl amine (3 equivalents) and Di-tertbutyl dicarbonate (1.1 equivalents) were added successively to a solution of MY-S3 (1 equivalent) in dichloromethane and the mixture was stirred for 20 h at room temperature. Water was added and the mixture was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by silica gel column chromatography provided MY-S4. Step 5:

[00402] Diethylamino sulfurtrifluoride (3 equivalents) was added to a solution of MY-S4 (1 equivalent) in dichloromethane at 0°C and the mixture was stirred for 52 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated to obtain the crude intermediate. Purification by silica gel column chromatography provided MY-S5.Step 6:

[00403] Sodium borohydride (2 equivalents) was slowly added to a solution of MY-S5 (1 equivalent) in methanol at room temperature. The reaction mass was stirred for 1 h. Ethyl acetate was added and the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain MY-S6, later used without any purification. Method Z: Example 30

[00404] Legend: acetone, pyridine

[00405] The description method was provided in Example 30. AA Method: Example 28 – 30

[00406] Caption: dioxane; example

[00407] Step 1:

[00408] Potassium T-butoxide (2.5 equivalents) was slowly added to a stirred solution of the corresponding intermediate MY-S6 or MZ-S14 (1 equivalent) in tetrahydrofuran at 0°C and the mixture was stirred for 3 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain MAA-S1, subsequently used without any purification.

[00409] Step 2:

[00410] A mixture of MAA-S1 (1 equivalent), 4-Bromo-1,2-diaminobenzene (1 equivalent) and cesium fluoride (2 equivalents) in 1-4dioxane was purged with argon gas for 30 min. Copper iodide (0.2 equivalents) and 1,2-diaminocyclohexane (0.3 equivalents) were added and the mixture was continuously purged for an additional 10 min. The reaction was heated in a sealed tube for 20 h at 105 to 110°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina provided MAA-S2.

[00411] Step 3:

[00412] Formamidine acetate (3 equivalents) was added to a solution of MAA-S2 (1 equivalent) in acetonitrile and the mixture was refluxed for 1 h. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was triturated with diethyl ether and dried to obtain Example 28 - 30. Examples: Example 1: (S)-3-(1H-benzo[d ]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy)-2,3-difluorophenyl)-oxazolidin-2-one

[00413] Step 1 (MA-S1):

[00414] A mixture of 2,3-Difluoro 4-hydroxybenzonitrile (9.0g, 58 mmol), 4-Chloro-2-butanol (18.87 g, 174 mmol) and potassium carbonate (16.04 g, 116 mmol)) in acetonitrile (200 mL) was refluxed for 20 h. The reaction mass was cooled to room temperature, filtered. The filtrate was partitioned with water and ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 18 g (crude) as a yellow liquid.

[00415] Step 2 (MA-S2):

[00416] 2-Iodoxy benzoic acid (89.12 g, 318 mmol) was added to a solution of MA-S1 (7.6 g crude, 36.3 mmol) in dichloromethane (50 mL), dimethyl sulfoxide (50 mL ) and stirred for 18 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and washing solution were again washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude MA-S2, which was purified by silica gel column chromatography (60 at 120 mesh) using 20% ethyl acetate in petroleum ether as eluent to provide 12 g (91%) of 299b as a pale yellow solid.

[00417] Step 3 (MA-S3):

[00418] Diethylamino sulfurtrifluoride (19.7 mL, 142 mmol) was added to a solution of MA-S2 (8 g, 35 mmol) in dichloromethane (160 mL) at 0°C. The reaction mass was warmed to room temperature and stirred for 35 h. The reaction was quenched in ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (1x50 mL). The combined organic layer was washed successively with aq sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude 9.6 g of MA-S3.

[00419] Step 4 (MC-S1):

[00420] DIBAL (1.5 M; 52.3 mL, 78 mmol) was added slowly to a solution of MA-S3 (9.6 g, 39 mmol) in dry tetrahydrofuran (120 mL) at -30°C about 15 min. The reaction mass was warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed successively with saline water; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude MC-S1 which was purified by column chromatography on silica gel (100-200 mesh) using 8-10% ethyl acetate in petroleum ether as eluent to give 5.96g (98%) MC-S1 as yellow liquid.

[00421] Step 5 (MC-S2):

[00422] N-Butyl lithium in hexane (2.5 M; 19.06 mL, 46 mmol) was added to a stirred solution of methyl triphenyl phosphonium bromide (17.02 g, 46 mmol) in tetrahydrofuran (100 mL) at -50°C and stirred again for 30 min at 0 to 5°C. A solution of MC-S1 (5.96 g, 23 mmol) in tetrahydrofuran (50 mL) was added dropwise to the reaction mixture at -50 °C. The reaction temperature was warmed to room temperature and stirred again for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude MC-S2. Purification by silica gel column chromatography (60 to 120 mesh) using 5% ethyl acetate in petroleum ether as eluent provided 4.8 g (99%) of MC-S2 as pale yellow liquid.

[00423] Step 6 (MJ-S1):

[00424] T-Butyl hypochlorite (2.07 mL, 18.21 mmol) was added to a stirred solution of t-butyl carbanate (2.12 g, 18.14 mmol) in 1-propanol (24 mL) and hydroxide of 0.4 N aqueous sodium (0.738 g in 46 mL water) at 15°C and stirred for 15 min. A solution of (DHQ)2PHAL (236 mg, 0.3 mmol) in 1-propanol (24 mL) was added, followed by the addition of a solution of MC-S2 (1.5 g, 6 mmol) in 1-propanol (24 mL). Finally potassium osmatodihydrate (89 mg, 0.24 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude. Another similar batch was maintained and purification of both by silica gel column chromatography (60 to 120 mesh) using 18 to 20% ethyl acetate in petroleum ether as eluent provided 2.6 g (56%) of MJ-S1 as a yellow solid.

[00425] Step 7 (MK-S1):

[00426] Potassium T-butoxide (1.7 g, 15.6 mmol) was added to a solution of MJ-S1 (2.0 g, 5.2 mmol) in tetrahydrofuran (35 mL) at a temperature from 0°C. The reaction mass was warmed to room temperature and stirred for 2 h. The reaction mass was acidified with acetic acid (pH~6) and extracted with ethyl acetate. The separated organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo gave 1.15 g of MK-S1 as oil.

[00427] Step 8 (MK-S2):

[00428] A mixture of MK-S1 (1.15 g, 3.7 mmol), 1,2-diamino-4-bromobenzene (588 mg, 3.7 mmol) and cesium fluoride (1.1 g, 7 .5 mmol) in 1,4-dioxane (20 mL) was purged with argon gas for 10 min. To this, copper iodide (355 mg, 1.8 mmol) was added and the reaction mixture was continuously purged for another 10 min. Finally 1,2-diaminocyclohexane (21 mg, 0.18 mmol) was added to the reaction and purging was continued again for 10 min. The reaction mass was then stirred at 110 to 115 ° C in a sealed tube for 20 h. The reaction mixture was cooled to room temperature, filtered through celite, washed with dioxin, and concentrated under reduced pressure to obtain the crude intermediate MK-S2. The compound was purified by column chromatography over neutral alumina using 1.5% methanol in chloroform as eluent to obtain 890 mg (57%) as a brown gummy solid.

[00429] Step 9 (Example 1):

[00430] Formamidine acetate (680 mg, 6.3 mmol) was added to a solution of MK-S2 (890 mg, 2.1 mmol) in acetonitrile (20 mL) and refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude. The crude product was purified by washing with diethyl ether, filtered and dried to obtain 240mg (27%) of PQPL-299 as a pale brown solid.

[00431] Melting range: 222 to 223°C; 1H-NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1H); 7.61 to 7.43 (m, 2H); 7.29 to 7.17 (m, 2H); 7.00 (t, 1H); 5.92 to 5.88 (m, 1H); 4.84 (t, 1H); 4.31 (q, 1H); 4.16 (t, 2H); 2.41 to 2.30 (m, 2H); 1.64 (t, 3H); MS=424.1(M+1); HPLC~98.03%:chiral HPLC~99.92%. Example 2: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2-fluorophenyl)oxazolidin-2-one

[00432] Step 1 (MA-S1):

[00433] A mixture of 2-Fluoro-4-hydroxy benzonitrile (10.0 g, 72.8 mmol), 3-Chloropropanol (8.4 g, 87.6 mmol) and potassium carbonate (20 g, 146 mmol )) in acetonitrile (100 mL) was refluxed for 24 h. The reaction mass was cooled to room temperature, filtered. The filtrate was partitioned with water and ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 12 g of MS-S1 as the crude intermediate, again used without purification.

[00434] Step 2 (MA-S2):

[00435] Periodinane Dess-martin (13 g, 30.76 mmol) was added to a solution of MA-S1 (6 g, 30.76 mmol) in dichloromethane (60 mL) and stirred for 3 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and washings were washed successively with saturated sodium bicarbonate solution, water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by trituration with petroleum ether provided 6 g of MS-S2 as a solid.

[00436] Step 3 (MA-S3):

[00437] Diethylamino sulfurtrifluoride (17 mL, 124.34 mmol) was added to a solution of MS-S2 (12 g, 62.16 mmol) in dichloromethane (100 mL) at 0°C. The reaction mass was warmed to room temperature and stirred for 3 h. The reaction was quenched in ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 6.2 g of MS-S3 as a crude intermediate, again used for the next step without purification.

[00438] Step 4 (MC-S1):

[00439] DIBAL (1.5 M in THF; 37.2 mL, 55.81 mmol) was added slowly to a solution of MS-S3 (6 g, 27.90 mmol) in dry tetrahydrofuran (100 mL) at -30°C about 15 min. The reaction mass was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed successively with saline water; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was purified by silica gel column chromatography (60 to 120 mesh) using 10% ethyl acetate in petroleum ether as eluent to give 5 g of MC-S1 as a pale brown liquid.

[00440] Step 5 (MC-S2):

[00441] N-Butyl lithium (2.4 M; 15.3 mL, 36.70 mmol) was added to a stirred solution of methyl triphenyl phosphonium bromide (13.1 g, 36.70 mmol) in tetrahydrofuran (50 mL) at -30°C and then the solution stirred for 30 min at 0 to 5°C. A solution of MC-S1 (4 g, 18.34 mmol) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at -30 °C. The temperature of the reaction mass was warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 5% ethyl acetate in petroleum ether as eluent provided 3.4 g of MC-S2 as a pale yellow liquid.

[00442] Step 6 (MJ-S1):

[00443] T-Butyl hypochlorite (5.38 mL, 47.3 mmol) was added to a stirred solution of t-butylcarbamate (5.52 g, 47.20 mmol) in 1-propanol (32 mL) and sodium hydroxide. 0.4 N aqueous sodium (1.98 g in 120 mL water) at 15°C and stirred for 15 min. A solution of (DHQ)2PHAL (612 mg, 0.78 mmol) in 1-propanol (32 mL) was added, followed by a solution of MC-S2 (3.4 g, 15.60 mmol) in 1-propanol (32 mL). Finally potassium osmate dihydrate (230 mg, 0.62 mmol) was added and the reaction mixture was stirred for another 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 25% ethyl acetate in petroleum ether as eluent provided 1.7 g of MJ-S1 as a brown solid.

[00444] Step 7 (MK-S1):

[00445] Thionylchloride (2.7 mL, 36.67 mmol) was added dropwise to a solution of MJ-S1 (1.6 g, 4.58 mmol) in tetrahydrofuran (20 mL) at 0°C . The reaction mass was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1.15 g of MK-S1 as an off-white solid.

[00446] Step 8 (MK-S2):

[00447] A mixture of MK-S1 (1.1 g, 4.0 mmol), 1,2-diamino-4-bromobenzene (1.12 g, 6.0 mmol) and cesium fluoride (1.2 g , 8 mmol) in 1,4-dioxane (30 mL) was purged with argon gas for 10 min. To this mixture copper iodide (380 mg, 2 mmol) was added and the solution was purged again for another 10 min. Finally 1,2-diaminocyclohexane (230 mg, 2 mmol) was added and the reaction mixture was continuously purged for another 10 min. The reaction mass was stirred at 110 to 115°C in a sealed tube for 18 h. The reaction was cooled to room temperature, filtered through a celite pad, washed with dioxin and concentrated under reduced pressure to obtain the crude intermediate. The crude compound was purified by column chromatography over neutral alumina using 2% methanol in chloroform as eluent to obtain 900 mg of MK-S2 as a brown solid.

[00448] Step 9 (Example 2):

[00449] Formamidine acetate (740 mg, 7.1 mmol) was added to a solution of MK-S2 (900 mg, 2.36 mmol) in acetonitrile (20 mL) and refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification was done by washing with diethyl ether, filtered and dried to give 500 mg of Example 2 as a pale brown solid.

[00450] Melting range: 199 to 204°C; 1H-NMR (DMSO-d6): δ 12.2 (s, 1H); 8.17 (s, 1H); 7.57 (d, 1H); 7.49 (d, 1H); 7.34 (t, 1H); 7.22 (d, 1H); 6.84 (dd, 1H); 6.74 (dd, 1H); 6.17 (bt, 1H); 5.85 (q, 1H); 4.83 (t, 1H); 4.24 (q, 1H); 4.07 to 4.03 (m, 2H); 2.27 to 2.23 (m, 2H); MS=392.0 (M+1); HPLC~98.63%;Chiral HPLC~99.86%.Example 3: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy) -2- fluorophenyl)oxazolidin-2-one

[00451] Step 1 (MA-S1):

[00452] A mixture of 2-Fluoro-4-Hydroxy benzonitrile (10.0 g, 72.99 mmol), 4-Chloro-2-butanol (16 mL, 145.98 mmol) and potassium carbonate (30 g, 218.97 mmol)) in acetonitrile (200 mL) was refluxed for 24 h. The reaction mass was cooled to room temperature and filtered. The filtrate was partitioned with water and ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 18 g of MA-S1 as the crude intermediate, supplied as a brown liquid.

[00453] Step 2 (MA-S2):

[00454] 2-Iodoxy benzoic acid (80 g, 287.07 mmol) was added to a solution of MA-S1 (15 g, 71.77 mmol) in dichloromethane (100 mL) and dimethyl sulfoxide (100 mL) and stirred for 22 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and washings were washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by trituration with petroleum ether provided 13 g of MA-S2 as an off-white solid.

[00455] Step 3 (MA-S3):

[00456] Diethylamino sulfurtrifluoride (21 mL, 154.58 mmol) was added to a solution of MA-S2 (8 g, 38.64 mmol) in dichloromethane (120 mL) at 0°C. The reaction was warmed to room temperature and stirred for 48 h. The reaction was quenched in ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (1x200 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 7 g of MA-S3 as the crude intermediate, again used for the next step.

[00457] Step 4 (MC-S1):

[00458] DIBAL (1.5 M; 61 mL, 61 mmol) was added slowly to a solution of MA-S3 (7.0 g, 30.56 mmol) in dry tetrahydrofuran (120 mL) at -30° C about 15 min. The reaction mass was warmed to room temperature and stirred again for 2 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed successively with saline water; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was purified by silica gel column chromatography (60 to 120 mesh) using 5 to 7% ethyl acetate in petroleum ether as eluent to obtain 6.0 g of MC-S1 as a pale brown liquid.

[00459] Step 5 (MC-S2):

[00460] N-Butyl lithium in hexane (2.5 M; 25 mL, 62.11 mmol) was added to a stirred solution of methyl triphenyl phosphonium bromide (27 g, 77.58 mmol) in tetrahydrofuran (80 mL) at -30°C and then a solution was stirred for 30 min at 0-5°C. A solution of MC-S1 (6.0 g, 25.862 mmol) in tetrahydrofuran (40 mL) was added dropwise to the reaction mixture at -30 ° C. The temperature was warmed to room temperature and the reaction mixture was stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 2% ethyl acetate in petroleum ether as eluent provided 4.5 g of MC-S2 as a pale yellow liquid.

[00461] Step 6 (MJ-S1):

[00462] T-Butyl hypochlorite (2.2 mL, 19.56 mmol) was added to a stirred solution of t-butyl carbanate (2.28 g, 19.56 mmol) in 1-propanol (26 mL) and hydroxide of 0.4 N aqueous sodium (1.16 g in 73 mL water) at 15°C and stirred for 15 min. A solution of (DHQ)2PHAL (254 mg, 0.32 mmol) in 1-propanol (26 mL) was added followed by a solution of MC-S2 (1.5 g, 6.5 mmol) in 1-propanol ( 26 mL). Finally potassium osmatodihydrate (95 mg, 0.26 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 18 to 20% ethyl acetate in petroleum ether as eluent provided 600 mg of MJ-S1 as an off-white solid.

[00463] Step 7 (MK-S1):

[00464] Potassium T-butoxide (920 mg, 8.265 mmol) was added to a solution of MJ-S1 (1.2 g, 3.3 mmol) in tetrahydrofuran (30 mL) at 0°C. The reaction mass was warmed to room temperature and stirred for 2 h. The reaction mixture was acidified with acetic acid (pH~6) and extracted with ethyl acetate. The separated organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo provided 800 mg of MK-S1 as an off-white solid.

[00465] Step 8 (MK-S2):

[00466] A mixture of MK-S1 (800 mg, 2.76 mmol), 1,2-diamino-4-bromobenzene (517 mg, 2.76 mmol) and cesium fluoride (840 mg, 5.53 mmol) in 1,4-dioxane (30 mL) was purged with argon gas for 10 min. Copper iodide (103 mg, 0.544 mmol) was added and the reaction mixture was purged again for another 10 min. Finally 1,2-diaminocyclohexane (350 mg, 0.3 mmol) was added and the reaction mixture was continuously purged for the next 10 min. The reaction mass was then stirred at 110 to 115 ° C in a sealed tube for 18 h. The reaction was cooled to room temperature, filtered through celite, washed with dioxin and concentrated under reduced pressure to obtain the crude intermediate. The compound was purified by column chromatography over neutral alumina using 2% methanol in chloroform as eluent to obtain 400 mg of MK-S2 as a brown solid.

[00467] Step 9 (Example 3):

[00468] Formamidine acetate (315 mg, 3.0 mmol) was added to a solution of MK-S2 (400 mg, 1.0 mmol) in acetonitrile (10 mL) and refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude. The crude product was purified by washing with diethyl ether, filtered and dried to obtain 200 mg of Example 3 as a pale brown solid.

[00469] Melting range: 199 to 200°C; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, 1H); 7.58 to 7.42 (m, 2H); 7.35 to 7.15 (m, 2H); 6.86 to 6.81 (m, 1H); 6.75 to 6.71 (m, 1H); 5.85 (t, 1H); 4.83 (t, 1H); 4.24 (q, 1H); 4.08 (t, 2H); 2.39 to 2.26 (m, 2H); 1.63 (t, 3H); MS=406.1(M+1); HPLC~95.71%:Chiral HPLC~99.01%.Example 4: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy) phenyl)oxazolidin-2-one

[00470] Step 1 (MG-S1):

[00471] Thionyl chloride (17.5 mL, 0.239 mol) was added to a suspension of (S)-4-hydroxy phenyl glycine (20 g, 0.120 mol) in methanol (100 mL) at 0°C dropwise . The mixture was slowly heated to reflux and maintained there for 15 h. The solvent was evaporated in vacuum and the residue was co-distilled twice with petroleum ether. Vacuum drying provided 25.2 g (96.55%) of MG-S1 as a white solid.

[00472] Step 2 (MG-S2):

[00473] Aqueous potassium carbonate (31.8 g, 0.230 mol in 100 mL water) and boc anhydride (31.65 mL, 0.138 mol) were added successively to a suspension of MG-S1 (25.0 g, 0.115 mol) in 1,4-dioxane (200 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched in water and extracted with ethyl acetate (2x100 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. The compound was suspended in petroleum ether, stirred for 30 min, filtered and dried under vacuum to obtain 28.9 g (89.43%) of MG-S2 as a white solid.

[00474] Step 3 (MG-S3):

[00475] Triphenyl phosphine (2.09 g, 8.01 mmol) and 3-Benzyloxy-1-propanol (1.01, 6.40 mmol) were added successively to a stirred solution of MG-S3 (1.5 g , 5.34 mmol) in dry tetrahydrofuran (30 mL) at room temperature. Diethylazo dicarboxylate (50 mL, 0.319 mol) was added dropwise and the reaction mass was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 20% ethyl acetate in petroleum ether as the eluent provided 1.8 g (78.98%) of MG-S3 as a colorless thick liquid. .

[00476] Step 4 (MG-S4):

[00477] The solution of MG-S3 (1.8 g, 4.21 mmol) in methanol (50 mL) was hydrogenated over Pd/C (10%; 450 mg) at 5.62 kg/cm2 (80 psi) for 2 h in a Parr apparatus. The reaction mass was filtered through celite and washed with methanol. The combined filtrate and wash portion were concentrated under reduced pressure to obtain 1.3 g (91.10%) of MG-S4 as an off-white solid.

[00478] Step 5 (MG-S5):

[00479] Benzoic Iodoxy Acid (3.63 g, 12.98 mmol) was added to a solution of MG-S4 (1.1 g, 3.24 mmol) in dichloromethane and dimethyl sulfoxide (30 mL: 1 mL) and the mixture was stirred for 20 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash portion was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 25% ethyl acetate in petroleum ether as the eluent provided 730 mg (66.91%) of MG-S5 as a yellow syrup.

[00480] Step 6 (MG-S6):

[00481] Diethylamino sulfur trifluoride (0.56 mL, 4.27 mmol) was added to a solution of MG-S5 (720 mg, 2.14 mmol) in dichloromethane (20 mL) at 0°C. The reaction mass was warmed to room temperature and stirred for 2 h. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (1x30 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 700 mg (91.14%) of MG-S6 as a yellow syrup.

[00482] Step 7 (MG-S7):

[00483] Sodium borohydride (295 mg, 7.80 mmol) was added in two equal batches (over 15 min) to a solution of MG-S6 (700 mg, 1.95 mmol) in tetrahydrofuran mixture ( 10 mL) and methanol (4 mL) at room temperature. Due to the exothermic reaction the temperature rose to ~50°C. After complete addition, the reaction mass was stirred for 15 h. Ethyl acetate was added and the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 600 mg (93.02%) of MG-S7 as an off-white solid.

[00484] Step 8 (MK-S1):

[00485] Thionyl chloride (1.06 mL, 14.50 mmol) was added to a solution of MG-S7 (600 mg, 1.81 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 4 h. The solvent was evaporated in vacuum and co-distilled twice with toluene to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1% methanol in chloroform as the eluent provided 305 mg (65.59%) of MK-S1 as an off-white solid.

[00486] Step 9 (MK-S2):

[00487] A mixture of MK-S1 (300 mg, 1.17 mmol), 1,2-diamino-4-bromobenzene (218 mg, 1.17 mmol), cesium fluoride (356 mg, 2.34 mmol) and Copper iodide (34 mg, 0.1755 mmol) in 1,4-dioxane (10 mL) was purged with argon gas for 15 min. 1,2-diaminocyclohexane (20 mg, 0.1755 mmol) was added and the reaction mixture was continuously purged for an additional 10 min. The reaction mass was stirred at 110 to 115°C in a sealed tube for 18 h. The reaction mixture was filtered through celite, washed with dioxane and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 2% methanol in chloroform as the eluent provided 310 mg (72.99%) of MK-S2 as a brown solid.

[00488] Step 10 (Example 4):

[00489] Formamidine acetate (258 mg, 2.48 mmol) was added to a solution of MK-S2 (300 mg, 0.83 mmol) in acetonitrile (10 mL) and the mixture was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was purified by column chromatography over neutral alumina and using 2 to 3% methanol in chloroform as the eluent to obtain 200 mg (64.60% ) of Example 14 as a pale brown solid.

[00490] Melting range: 198 to 200°C; 1H-NMR (400MHz, DMSO-d6): δ 12.41 (s, 1H); 8.16 (s, 1H); 7.57 (d, 1H); 7.47 (bs, 1H); 7.33 to 7.24 (m, 3H); 6.89 (d, 2H); 6.33 to 6.03 (m, 1H); 5.69 to 5.66 (m, 1H); 4.80 (t, 1H); 4.14 to 4.01 (m, 3H); 2.32-2.18 (m, 2H); MS=374.1 (M+1); HPLC~97.75%; Chiral HPLC ~97.87%; Example 5: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-3-fluorophenyl)oxazolidin-2-one

[00491] Step 1 (MB-S1):

[00492] A mixture of 3-fluoro-4-hydroxy benzonitrile (4.0 g, 29.17 mmol), chlorine acetone (3.5 mL, 43.76 mmol) and potassium carbonate (8.06 g, 58 .3 mmol)) in acetonitrile (50 mL) was refluxed for 2 h. The reaction was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 5.0 g (89.3%) of the crude intermediate MB-S1 as a brown solid.

[00493] Step 2 (MB-S2):

[00494] Diethylamino sulfurtrifluoride (7.1 mL, 51.8 mmol) was added to a solution of MB-S1 (5.0 g, 25.9 mmol) in dichloromethane (50 mL) at 0°C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 5.1 g (91.7%) of the crude intermediate MB-S2 as a brown liquid.

[00495] Step 3 (MC-S1):

[00496] DIBAL in toluene (1.5 M; 23.25 mL, 34.88 mmol) was slowly added to a solution of MB-S2 (5.0 g, 23.25 mmol) in dry tetrahydrofuran (70 mL) at -30°C over 15 min. The reaction mass was warmed to room temperature and the solution was stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed successively with saline water; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was purified by silica gel column chromatography (60 to 120 mesh) using 9 to 10% ethyl acetate in petroleum ether as eluent to obtain 3.8 g (75.09%) of MC-S1 as a pale yellow liquid.

[00497] Step 4 (MC-S2):

[00498] N-Butyl lithium in hexane (2.5 M; 112.8 mL, 32.11 mmol) was added to a stirred solution of methyl triphenyl phosphonium bromide (11.46 g, 32.11 mmol) in tetra -hydrofuran (40 ml) at -30°C and a solution was stirred for 30 min at 0 to 5°C. A solution of MC-S1 (3.5 g, 16.05 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture at -30 °C. The temperature was warmed to room temperature and the reaction mixture was stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent provided 2.5 g (72.25%) of MC-S2 as a pale yellow liquid. .

[00499] Step 5 (MJ-S1):

[00500] T-Butyl hypochlorite (3.96 mL, 34.83 mmol) was added to a stirred solution of t-butyl carbanate (4.06 g, 34.72 mmol) in 1-propanol (57.8 mL) and 0.4N aqueous sodium hydroxide (1.41 g in 88 ml water) at 15°C and the mixture was stirred for 15 min. A solution of (DHQ)2PHAL (450 mg, 0.578 mmol) in 1-propanol (57.8 mL) was added, followed by a solution of MC-S2 (2.5 g, 11.57 mmol) in 1-propanol (57.8 mL). Finally potassium osmatodihydrate (170 mg, 0.462 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 20 to 22% ethyl acetate in petroleum ether as the eluent provided 900 mg of MJ-S1 as a white solid.

[00501] Step 6 (MK-S1):

[00502] To a stirred solution of Potassium-t-butoxide (866 mg, 7.73 mmol) in tetrahydrofuran (10 mL) was added a solution of MJ-S1 (900 mg, 2.57 mmol) in tetrahydrofuran (10 mL) hydrofuran (10 mL) at 0°C and the mixture was stirred for 3 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 670 mg of MK-S1 as a yellow solid.

[00503] Step 7 (MK-S2):

[00504] A mixture of MK-S1 (650 mg, 2.36 mmol), 4-bromo-1,2-diamino benzene (236 mg, 2.36 mmol) and cesium fluoride (718 mg, 4.72 mmol ) in 1,4-dioxane (20 mL) was purged with argon gas for 15 min. Copper iodide (67.36 mg, 0.354 mmol) and 1,2-diaminocyclohexane (40.4 mg, 0.354 mmol) were added and purging was continued for an additional 10 min. The reaction mixture was heated in a sealed tube for 20 h at 110-115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2 to 3% methanol in chloroform as the eluent provided 450 mg of MK-S2 as a brown solid.

[00505] Step 8 (Example 5):

[00506] Formamidine acetate (328 mg, 3.15 mmol) was added to a solution of MK-S2 (400 mg, 1.05 mmol) in acetonitrile (15 mL) and a solution was refluxed for 2 h. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was purified by washing with diethyl ether, filtered and dried to provide 220 mg (53.65%) of Example 5 as a pale brown solid.

[00507] Melting range: 224 to 227°C; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H); 7.59(s, 1H); 7.50 (bs, 1H); 7.16 (t, 3H); 5.70 (t, 1H); 4.80 (t, 1H); 4.29 (t, 2H); 4.15 (t, 1H); 1.67 (t, 3H); MS=392.1 (M+1); HPLC~97.00%: Chiral HPLC~97.20%.Example 6: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy) -2,3-difluorophenyl)oxazolidin-2-one

[00508] Step 1 (MB-S1):

[00509] A mixture of 2,3-difluoro-4-hydroxy benzonitrile (4.5 g, 29.01 mmol), chlorine acetone (3.5 mL, 43.52 mmol) and potassium carbonate (8.02 g , 58.02 mmol) in acetonitrile (100 mL) was refluxed for 2 h. The reaction was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 5.6 g (91.8%) of the crude intermediate MB-S1 as a brown solid.

[00510] Step 2 (MB-S2):

[00511] Diethylamino sulfurtrifluoride (7.3 mL, 53.08 mmol) was added to a solution of MB-S1 (5.6 g, 26.54 mmol) in dichloromethane (60 mL) at 0°C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 5.6 g (90.77%) of the crude intermediate MB-S2 as a brown liquid.

[00512] Step 3 (MC-S1):

[00513] DIBAL in THF (1 M; 48 mL, 48 mmol) was added slowly to a solution of MB-S2 (5.6 g, 24.03 mmol) in dry tetrahydrofuran (100 mL) at -30° C about 15 min. The reaction mixture was warmed to room temperature and stirred again for 2 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed successively with saline water; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 10 to 12% ethyl acetate in petroleum ether as eluent provided 4.6 g (81.13%) of MC-S1 as a pale yellow liquid .

[00514] Step 4 (MC-S2):

[00515] N-Butyl lithium in hexane (2.1 M; 18.56 mL, 38.98 mmol) was added to a stirred solution of methyl triphenyl phosphonium bromide (13.92 g, 38.98 mmol) in tetra -hydrofuran (100 ml) at -30°C and a solution was stirred for 30 min at 0 to 5°C. A solution of MC-S1 (4.6 g, 19.49 mmol) in tetrahydrofuran (40 mL) was added dropwise at -30°C. The temperature was warmed to room temperature and the mixture was stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 2% ethyl acetate in petroleum ether as eluent provided 2.5 g (54.82%) of MC-S2 as a pale yellow liquid.

[00516] Step 5 (MJ-S1):

[00517] T-Butyl hypochlorite (3.65 mL, 32.14 mmol) was added to a stirred solution of t-butyl carbanate (3.75 g, 32.05 mmol) in 1-propanol (42.5 mL) and 0.4N aqueous sodium hydroxide (1.302 g in 81 mL water) at 15°C and stirred for 15 min. A solution of (DHQ)2PHAL (416 mg, 0.534 mmol) in 1-propanol (42.5 mL) was added, followed by a solution of MC-S2 (2.5 g, 10.68 mmol) in 1-propanol (42.5 mL). Finally potassium osmatodihydrate (157 mg, 0.427 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 22 to 25% ethyl acetate in petroleum ether as eluent provided 600 mg of MJ-S1 as a white solid.

[00518] Step 6 (MK-S1):

[00519] Potassium-t-butoxide (550 mg, 4.90 mmol) was added to a stirred solution of MJ-S1 (600 mg, 1.63 mmol) in tetrahydrofuran (20 mL) at 0°C and the The mixture was stirred for 3 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 370 mg of MK-S1 as a yellow solid.

[00520] Step 7 (MK-S2):

[00521] A mixture of MK-S1 (370 mg, 1.26 mmol), 4-Bromo-1,2-diamino benzene (236 mg, 1.26 mmol) and cesium fluoride (383 mg, 2.52 mmol ) in 1,4-dioxane (15 mL) was purged with argon gas for 30 min. Copper iodide (36 mg, 0.19 mmol) and 1,2-diaminocyclohexane (22 mg, 0.19 mmol) were added and purging was continued for a further 10 min. The reaction mixture was heated in a sealed tube for 18 h at 110 to 115°C. The resulting mass was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2 to 3% methanol in chloroform as the eluent provided 310 mg of MK-S2 as a brown semisolid.

[00522] Step 8 (Example 6):

[00523] Formamidine acetate (260 mg, 2.48 mmol) was added to a solution of MK-S2 (300 mg, 0.83 mmol) in acetonitrile (15 mL) and the mixture was refluxed for 2 h. The solvent was evaporated in vacuum and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by column chromatography over neutral alumina and using 2.5 to 3% methanol in dichloromethane as the eluent provided 120 mg (38.71%) of Example 6 as a pale brown solid.

[00524] Melting range: 235 to 237°C; 1H-NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1H); 7.61 to 7.43 (m, 2H); 7.30 to 7.17 (m, 2H); 7.03 (t, 1H); 5.94 to 5.89 (m, 1H); 4.88 (t, 1H); 4.37-4.30 (m, 3H); 1.67 (t, 3H); MS=410.1 (M+1); HPLC~96.30%:Chiral HPLC~98.75%.Example 7: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy) -2- fluorophenyl)oxazolidin-2-one

[00525] Step 1 (MB-S1):

[00526] A mixture of 2-fluoro-4-hydroxy benzonitrile (1 g, 7.29 mmol), chlorine acetone (0.88 mL, 10.94 mmol) and potassium carbonate (2.0 g, 14.58 mmol) in acetonitrile (10 mL) was refluxed for 12 h. The reaction was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 1.25 g (85.8%) of the crude intermediate MB-S1 as a brown solid, again used for the next step.

[00527] Step 2 (MB-S2):

[00528] Diethylamino sulfurtrifluoride (1.36 mL, 10.36 mmol) was added to a solution of MB-S1 (1.0 g, 5.18 mmol) in dichloromethane (10 mL) at 0°C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 1.0 g (86.2%) of the crude intermediate MB-S2 as a brown liquid.

[00529] Step 3 (MC-S1):

[00530] DIBAL in THF (1 M; 9.3 mL, 9.3 mmol) was added slowly to a solution of MB-S2 (1.0 g, 4.65 mmol) in dry tetrahydrofuran (10 mL) at -30°C for 5 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate (3x25 mL). The filtrate was washed successively with water - saline; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 10% ethyl acetate in petroleum ether as eluent provided 520 mg (51.4%) of MC-S1 as a colorless liquid.

[00531] Step 4 (MC-S2):

[00532] N-Butyl lithium in hexane (2.5 M; 7.3 mL, 18.34 mmol) was added to a stirred solution of methyl triphenyl phosphonium bromide (6.5 g, 18.34 mmol) in tetra -hydrofuran (20 ml) at -50°C and a solution was stirred again for 30 min at 0 to 5°C. A solution of MC-S1 (2.0g, 9.17 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture at -30°C. The temperature of the reaction mass was warmed to room temperature and stirred for another 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by silica gel column chromatography (60 to 120 mesh) using 1% ethyl acetate in petroleum ether as eluent provided 1.2 g (60.6%) of MC-S2 as a colorless liquid.

[00533] Step 5 (MJ-S1):

[00534] T-Butyl hypochlorite (2.5 mL, 22.27 mmol) was added to a stirred solution of t-butyl carbanate (2.59 g, 22.20 mmol) in 1-propanol (29 mL) and hydroxide of 0.4 N aqueous sodium (900 mg in 55 mL water) at 15°C and stirred for 15 min. A solution of (DHQ)2PHAL (288 mg, 0.37 mmol) in 1-propanol (29 mL) was added, followed by a solution of MC-S2 (1.6 g, 7.4 mmol) in 1-propanol (29 mL). Finally potassium osmatodihydrate (108 mg, 0.296 mmol) was added and the reaction mixture was stirred again for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over 60 to 120 mesh silica using 22 to 25% ethyl acetate in petroleum ether as eluent provided 1.0 g (40%) of MJ-S1 as a white solid.

[00535] Step 6 (MK-S1):

[00536] Potassium-t-butoxide (640 mg, 5.73 mmol) was added to a stirred solution of MJ-S1 (1.0 g, 2.86 mmol) in tetrahydrofuran (15 mL) at 0°C and the mixture was stirred for 3 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 600 mg (76.9%) of MKS1 as a colorless liquid.

[00537] Step 7 (MK-S2):

[00538] A mixture of MK-S1 (600 mg, 2.18 mmol), 4-Bromo-1,2-diamino benzene (407 mg, 2.18 mmol) and cesium fluoride (662 mg, 4.36 mmol ) in 1,4-dioxane (15 mL) was purged with argon gas for 10 min. Copper iodide (62 mg, 0.327 mmol) and 1,2-diaminocyclohexane (37 mg, 0.327 mmol) were added and purging was continued for a further 10 min. The reaction mixture was heated in a sealed tube for 18 h at 110 to 115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina using 2-3% methanol in chloroform as the eluent provided 350 mg (42.1%) of MK-S2 as a solid brown color.

[00539] Step 8 (Example 7):

[00540] Formamidine acetate (300 mg, 2.89 mmol) was added to a solution of MK-S2 (350 mg, 0.964 mmol) in acetonitrile (10 mL) and the mixture was refluxed for 2 h. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was triturated with diethyl ether and dried to obtain 190 mg (53%) of Example 5 as an off-white solid.

[00541] Melting range: 205 to 209°C; 1H-NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H); 7.57 (d, 1H); 7.48 (d, 1H); 7.36 (t, 1H); 7.20 (q, 1H); 6.90 (dd, 1H); 6.80 (dd, 1H); 5.83 (q, 1H); 4.84 (t, 1H); 4.27 to 4.20 (m, 3H); 1.66 (t, 3H); MS=392.1 (M+1); HPLC~98.40%:Chiral HPLC~98.43%. Example 8: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-3,5-difluorophenyl)oxazolidin-2-one

[00542] Step 1 (MB-S1):

[00543] A mixture of 3,5-difluoro-4-hydroxy benzonitrile (4.3 g, 27.77 mmol), chlorine acetone (3.3 mL, 41.66 mmol) and potassium carbonate (7.6 g , 55.55 mmol) in acetonitrile (40 mL) was refluxed for 2 h. The reaction mass was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 3.8 g (65.5%) of MB-S1 as a brown liquid, again used for the next step.

[00544] Step 2 (MB-S2):

[00545] Diethylamino sulfurtrifluoride (5.0 mL, 37.91 mmol) was added to a solution of MB-S1 (4.0 g, 18.95 mmol) in dichloromethane (40 mL) at 0°C and the mixture was stirred for 4 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 5.0 g of crude intermediate MB-S2 as a brown liquid, again used for the next step.

[00546] Step 3 (MC-S1):

[00547] DIBAL in toluene (1.5 M; 29 mL, 42.91 mmol) was slowly added to a solution of MB-S2 (5.0 g, 21.45 mmol) in dry tetrahydrofuran (100 mL) at -30°C about 15 min. The mixture was warmed to room temperature and the solution was stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed successively with water-saline solution; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. purification by column chromatography on silica gel (60 to 120 mesh) and using 4 to 8% ethyl acetate in petroleum ether as the eluent provided 3.0 g (60%) of MC-S1 to an oil.

[00548] Step 4 (MC-S2):

[00549] N-Butyl lithium in hexane (2.5 M; 10.2 mL, 25.42 mmol) was added to a stirred solution of methyl triphenyl phosphonium bromide (9.0 g, 25.42 mmol) in tetra -hydrofuran (30 ml) at -30°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of MC-S1 (3.0 g, 12.78 mmol) in tetrahydrofuran (40 mL) was added dropwise to the mixture at -30°C. The temperature was warmed to room temperature and a solution was stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent provided 2.0 g (64.4%) of MC-S2 to an oil.

[00550] Step 5 (MJ-S1):

[00551] T-Butyl hypochlorite (2.92 mL, 35.72 mmol) was added to a stirred solution of t-butyl carbamate (3.98 g, 25.64 mmol) in 1-propanol (34 mL) and hydroxide of 0.4N aqueous sodium (65 mL) at 15°C and the mixture was stirred for 15 min. A solution of (DHQ)2PHAL (332 mg, 0.43 mmol) in 1-propanol (34 mL) was added, followed by a solution of MC-S2 (2.0 g, 8.54 mmol) in 1-propanol (34 mL). Finally potassium osmatodihydrate (125 mg, 0.4272 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 22 to 25% ethyl acetate in petroleum ether as the eluent provided 1.3 g (40%) of MJ-S1 as a white solid.

[00552] Step 6 (MK-S1):

[00553] Potassium-t-butoxide (764 mg, 6.824 mmol) was added to a stirred solution of MJ-S1 (1.3 g, 3.412 mmol) in tetrahydrofuran (20 mL) at 0°C and the mixture was stirred for 3 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 800 mg (76%) of MK-S1 as a gummy yellow solid.

[00554] Step 7 (MK-S2):

[00555] A mixture of MK-S1 (760 mg, 2.59 mmol), 4-bromo-1,2-diamino benzene (485 mg, 2.59 mmol) and cesium fluoride (789 mg, 5.19 mmol ) in 1,4-dioxane (60 mL) was purged with argon gas for 30 min. Copper iodide (98.7 mg, 0.51 mmol) and 1,2-diaminocyclohexane (50 mg, 0.51 mmol) were added and purging continued for an additional 10 min. The reaction mixture was heated in a sealed tube for 18 h at 110 to 115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2 to 3% methanol in chloroform as the eluent provided 500 mg (53%) of MK-S2 as a yellowish brown solid.

[00556] Step 8 (Example 8):

[00557] Formamidine acetate (391 mg, 3.75 mmol) was added to a solution of MK-S2 (500 mg, 1.25 mmol) in acetonitrile (50 mL) and the mixture was refluxed for 2 h. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was triturated with diethyl ether and dried to obtain 300 mg (58.5%) of Example 8 as a yellow solid.

[00558] Melting range: 205 to 207°C; 1H-NMR (400 MHz, DMSO-d6): δ 12.50 (bs, 1H); 8.18 (s, 1H); 7.63 (s, 1H); 7.51 (d, 1H); 7.28 (m, 3H); 5.75 (t, 1H); 4.81 (t, 1H); 4.31(t, 2H); 4.15 (q, 1H); 1.66 (t, 3H); MS=410.1 (M+1); HPLC~98.42%;Chiral HPLC~95.03%.Example 10: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy) -3- fluorophenyl)oxazolidin-2-one

[00559] Step 1 (MD-S1):

[00560] A mixture of 4-bromo-2-fluorophenol (8.0 g, 41.8 mmol), 4-chloro-2-butanol (9.0 g, 83.75 mmol) and potassium carbonate ( 17.3 g, 125.6 mmol) in acetonitrile (100 ml), was refluxed for 24 hours. The reaction mass was cooled to room temperature and filtered. The filtrate was partitioned with water and ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 8.0 g of MD-S1 as the crude intermediate MD-S1, subsequently used for the next step without purification.

[00561] Step 2 (MD-S2):

[00562] 2-lodoxy benzoic acid (25.5 g, 91.25 mmol) was added to a solution of MD-S1 (8.0 g, 30.4 mmol) in dichloromethane (100 ml), and dimethyl sulfoxide (50 ml), and the mixture was stirred for 16 hours at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash portion were washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 7-8% ethyl acetate in petroleum ether as the eluent provided 5.0 g (63% in two steps) of MD-S2 as a light brown liquid.

[00563] Step 3 (MD-S3):

[00564] Diethylamino Sulfurtrifluoride (10.7 ml, 76.6 mmol) was added to a solution of MD-S2 (5.0 g, 19.1 mmol) in dichloromethane (100 ml), at 0°C. The reaction mixture was warmed to room temperature and stirred for 48 hours. The reaction was quenched with ice water and the organic layer was separated. The aqueous phase was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification was done by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent to obtain 4.0 g (74%) of MD-S3 as an brown liquid.

[00565] Step 4 (MD-S4):

[00566] A solution of MD-S3 (4.0 g, 14.1 mmol) and tri-n-butyl vinyltin (5.18 ml, 17.6 mmol) in toluene (60 ml) was purged with hydrogen gas. argon for 5 min. Tetracis-(triphenylphosphine)-palladium (326 mg, 0.28 mmol) was added and the mixture was continuously purged for an additional 5 minutes. The reaction mass was heated in a sealed tube at 110 °C for 8 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The combined filtrate and wash portion were concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using petroleum ether as the eluent provided 3.0 g (92%) of MD-S4 as a colorless liquid.

[00567] Step 5 (MJ-Sl):

[00568] t-Butylhypochlorite (4.46 ml, 39.2 mmol) was added to a stirred solution of t-butylcarbamate (4.5 g, 39.1 mmol) in 1-propanol (52 ml), and sodium hydroxide 0.4 N aqueous sodium (1.6 g in 100 ml of water) at 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (500 mg, 0.6 mmol) in 1-propanol (52 ml) was added, followed by a solution of MD-S4 (3.0 g, 13.0 mmol) in 1- propanol (52 ml). Finally potassium osmatedihydrate (240 mg, 0.6 mmol) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with saturated sodium sulfate solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound. Purification by column chromatography on silica gel (60 to 120 mesh) and using 18 to 20% ethyl acetate in petroleum ether as the eluent provided 1.2 g (25%) of intermediate MJ-S1 as a solid brown.

[00569] Step 6(MK-Sl):

[00570] Potassium t-butoxide (550 mg, 4.9 mmol) was added in portions to a solution of MJ-S1 (1.2 g, 3.3 mmol) in tetrahydrofuran (60 ml), at 0 °C. The reaction was warmed to room temperature and the mixture was stirred for 2 hours. The reaction was acidified with acetic acid (pH~6) and extracted with ethyl acetate. The separated organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum provided 700 mg (73%) of MK-S1 as a non-white solid, subsequently used without any purification.

[00571] Step 7 (MK-S2):

[00572] A mixture of MK-S1 (700 g, 2.4 mmol), 1,2-diamino-4-bromobenzene (380 mg, 2.4 mmol) and cesium fluoride (718 g, 4.8 mmol) in 1,4-dioxan (30 ml), was purged with argon gas for 10 min. Copper iodide (69 mg, 0.36 mmol) was added and the reaction mixture was continuously purged for an additional 10 minutes. Finally 1,2-diaminocyclohexane (41 mg, 0.36 mmol) was added and the reaction was purged again for 10 minutes. The reaction mass was stirred at 110 to 115°C in a sealed tube for 18 hours. The reaction mixture was cooled to room temperature, filtered through celite, washed with dioxin and concentrated under reduced pressure to obtain the crude compound. Purification was done by column chromatography over neutral alumina using 2% methanol in chloroform as eluent to obtain 500 mg (51%) of MK-S2 as a brown solid.

[00573] Step 8 (Example 10):

[00574] Formamidine acetate (394 mg, 3.7 mmol) was added to a solution of MK-S2 (500 mg, 1.2 mmol) in acetonitrile (20 mL) and the mixture was refluxed for 2 hours. The solution was concentrated under reduced pressure and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification was by washing with diethyl ether, filtered and dried to obtain 350 mg (68%) of Example 10 as a light brown solid. Melting range: 206.7 to 213.7 °C; 1H-NMR (400 MHz, DMSO-d6): δ 12.2 (d, 1 H); 8.17 (d, 1 H); 7.58 (d, 1H); 7.53 (dd, 1 H); 7.34 (t, 2H); 7.29-7.11 (m, 3H); 5.69 (t, 1H); 4.80 (t, 1H); 4.17-4.11 (m, 3H); 2.40-2.29 (m, 2H); 1.64 (t, 3H); MS = 406.0 (M+1); HPLC ~ 97.19%: Chiral HPLC ~ 99.62%. Example 11: (S) -3- (1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy) -2,3-difluorophenyl)oxazolidin- 2-one

[00575] Step 1 (MD-S1):

[00576] A mixture of 4-Bromo-2,3-difluorophenol (2 g, 9.57 mmol), 3-chloro-1-propanol (1.0 mL, 11.48 mmol) and potassium carbonate (2 .64 g, 19.14 mmol) in acetonitrile (20 mL) was stirred at 80°C for 40 hours. The reaction mass was filtered and washed with ethyl acetate. The combined filtrate and wash portion was concentrated in vacuo to obtain 2.5 g of MD-S1 (98.42%) as a non-white solid.

[00577] Step 2 (MD-S2):

[00578] Periodinane Dess-martin (4.47 g, 10.30 mmol) was added to a solution of MD-S1 (2.5 g, 9.36 mmol) in dichloromethane (40 mL) at 0 ° C and the The mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuum and the resulting mass was suspended in diethyl ether, and the reaction mixture was stirred for 15 minutes and then filtered. The filtrate was successively washed with water, saline; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 2.4 g (96.42%) of MD-S2 as a colorless syrup.

[00579] Step 3 (MD-S3):

[00580] Diethylamino Sulfurtrifluoride (2.36 ml, 9.02 mmol) was added to a solution of MD-S2 (2.4 g, 9.02 mmol) in dichloromethane (30 ml), at 0°C and at The mixture was stirred at room temperature for 3 hours. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude intermediate 10. Purification by column chromatography on silica gel (60 to 120 mesh) and using 5% ethyl acetate in petroleum ether as the eluent provided 1.5 g (57.96%) of MD-S3 as a colorless syrup. .

[00581] Step 4 (MD-S4):

[00582] A solution of MD-S3 (1.5 g, 5.23 mmol) and tri-n-butyl vinyltin (1.92 ml, 6.53 mmol) in toluene (50 ml) was purged with hydrogen gas. argon for 5 min. Tetracis-(triphenylphosphine)-palladium (121 mg, 0.1 mmol) was added and continuously purged for another 5 minutes. The reaction mass was heated in a sealed tube at 110°C for 8 hours. The reaction mass was filtered over celite and washed with ethyl acetate. The combined filtrate and wash portion were concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent provided 1.2 g (98.36%) of MD-S4 as a colorless liquid .

[00583] Step 5 (MJ-Sl):

[00584] t-Butyl hypochlorite (1.76 ml, 15.44 mmol) was added to a stirred solution of t-butylcarbamate (1.8 g, 15.38 mmol) in 1-propanol (20.5 ml) , and 0.4N aqueous sodium hydroxide (626 mg in 39 mL of water) at 10°C to 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (200 mg, 0.26 mmol) in 1-propanol (20.5 ml) was added, followed by a solution of MD-S4 (1.2 g, 5.13 mmol) in 1-propanol (20.5 ml). Finally, potassium osmatedihydrate (75 mg, 0.20 mmol) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 25-30% ethyl acetate in petroleum ether as the eluent provided 710 mg (37.76%) of MJ-S1 as a white solid.

[00585] Step 6 (MK-Sl):

[00586] Thionylchloride (1.1 ml, 15.26 mmol) was added to a solution of MJ-S1 (700 mg, 1.91 mmol) in tetrahydrofuran (20 ml), at 0°C. The reaction was warmed to room temperature and the solution was stirred for 3 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between ice-cold saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 480 mg (85.87%) of MK-S1 as a not entirely white solid.

[00587] Step 7 (MK-S2):

[00588] A mixture of MK-S1 (480 mg, 1.64 mmol), 4-bromo-1,2-diaminobenzene (370 mg, 1.96 mmol) and cesium fluoride (500 mg, 3.28 mmol) in 1,4-dioxane (20 ml), it was purged with argon gas for 15 min. Copper iodide (47 mg, 0.24 mmol) and 1,2-diaminocyclohexane (27 mg, 0.24 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction mixture was stirred in a sealed tube for 20 hours at 110 to 115 ° C. The resulting mass was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina using 1-2% methanol and dichloromethane as the eluent provided 480 mg (73.40%) of MK-S2 as a brown solid.

[00589] Step 8 (Example 11):

[00590] Formamidine acetate (375 mg, 3.61 mmol) was added to a solution of MK-S2 (480 mg, 1.20 mmol) in acetonitrile (10 ml), and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by trituration with 8:2 (diethyl ether: ethyl acetate) provided 350 mg of Example 11 as a light brown solid.

[00591] Melting range: 222 to 225.5 °C; 1H-NMR (400 MHz, DMS0-d6): δ 12.22 (s, 1 H); 8.18 (s, 1H); 7.60 (s, 1 H); 7.49 (bs, 1H); 7,297.19 (m, 2H); 6.99 (t, 1H); 6.26 (bt, 1H); 5.88 (t, 1H); 4.87 (t, 1 H); 4.33 (q, 1H); 4.16 (t, 2H); 2.29-2.16 (m, 2H); MS = 410.0 (M+1); HPLC ~ 99.78%: Chiral HPLC ~ 99.82%. Example 12: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-3-fluorophenyl)oxazolidin-2-one

[00592] Step 1 (MD-S1):

[00593] A mixture of 4-Bromo-2-fluorophenol (5.0 g, 26.17 mmol), 3-chloro-1-propanol (2.8 g, 31.41 mmol), and potassium carbonate (7 .23 g, 52.34 mmol) in acetonitrile (50 mL) was heated at 85°C for 12 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 6.0 g of the crude intermediate MD-S1 as a colorless liquid, subsequently used without purification.

[00594] Step 2 (MD-S2):

[00595] Periodinane Dess-martin (11.50 g, 26.50 mmol) was added to a solution of MD-S1 (6.0 g, 24.09 mmol) in dichloromethane (60 mL) at 0 ° C and the The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite, washed with dichloromethane and the solvent was evaporated under reduced pressure to obtain 4.5 g of the crude intermediate as a colorless oil.

[00596] Step 3 (MD-S3):

[00597] Diethylamino Sulfurtrifluoride (6.1570 g, 36.43 mmol) was added to a solution of MD-S2 (4.5 g, 18.21 mmol) in dichloromethane (40 mL) at °C and the mixture was stirred for 3 hours at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 10% ethyl acetate in petroleum ether as the eluent provided 3.3 g of MD-S3 as a colorless oil.

[00598] Step 4 (MD-S4):

[00599] A solution of MD-S3 (2.8 g, 10.48 mmol) and tri-n-butyl vinyltin (3.84 mL, 13.10 mmol) in toluene (30 mL) was purged with argon gas for 5 minutes. Tetracis-(triphenylphosphine)-palladium (242 mg, 0.1 mmol) was added and the mixture was continuously purged for another 5 minutes. The reaction mass was heated in a sealed tube at 110 °C for 8 hours. The reaction mass was filtered over celite and washed with ethyl acetate. The combined filtrate and wash portion was concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent provided 1.2 g (98.36%) of MD-S4 as a colorless liquid .

[00600] Step 5 (MJ-Sl):

[00601] t-Butyl hypochlorite (2.14 mL, 18.81 mmol) was added to a stirred solution of t-butylcarbamate (2.193 g, 18.75 mmol) in 1-propanol (25 mL) and sodium hydroxide 0.4 N aqueous solution (48 ml) at 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (235 mg, 0.312 mmol) in 1-propanol (25 mL) was added, followed by a solution of MD-S4 (1.35 g, 6.25 mmol) in 1-propanol (25 mL). Finally, potassium osmatedihydrate (92 mg, 0.25 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 17% ethyl acetate in petroleum ether as the eluent provided 1.1 g of MJ-S1 as a non-white solid.

[00602] Step 6(MK-Sl):

[00603] Thionylchloride (0.84 mL, 11.44 mmol) was added dropwise to a solution of MJ-S1 (1.0 g, 2.873 mmol) in tetrahydrofuran (25 mL) at 0°C . The reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was evaporated and the remaining mass was diluted with water. Saturated sodium hydrogen carbonate solution was added (50 mL) and the mixture was extracted with chloroform (2x100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 900 mg of MK-S1 as a non-white solid, subsequently used without purification.

[00604] Step 7 (MK-S2):

[00605] A mixture of MK-S1 (900 mg, 3.2727 mmol), 1,2-diamino-4-bromobenzene (1.22 g, 6.5454 mmol) and cesium fluoride (995 mg, 6.5454 mmol) in 1,4-dioxane (10 mL) was purged with argon gas for 20 minutes. Copper iodide (93 mg, 0.490 mmol) and 1,2-diaminocyclohexane (55 mg, 0.490 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction mass was stirred at 110°C in a sealed tube for 18 hours. The resulting mixture was filtered through a celite pad, washed with dioxane and concentrated under reduced pressure to obtain the crude intermediate. The compound was purified by column chromatography over neutral alumina and using 2% methanol in chloroform as the eluent to obtain 600 mg of MK-S2 as a brown solid.

[00606] Step 8 (Example 12):

[00607] Formamidine acetate (515 mg, 4.958 mmol) was added to a solution of MK-S2 (600 mg, 1.652 mmol) in acetonitrile (20 ml), and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. The crude compound was successively washed with 2% methanol in diethyl ether and filtered to obtain 300 mg of Example 12 as a not entirely white solid. Melting range: 198.5 to 201.7°C; 1H-NMR (400 MHz, DMSO-d6): δ 12.2 (d, 1 H); 8.16 (s, 1H); 7.58-7.09 (m, 5H); 6.17 (bt, 1 H); 5.68 (t, 1H); 4.80 (t, 1 H); 4.14 (q, 3H); 2.50-2.21 (m, 2H); MS = 392.0 (M+1); HPLC ~ 99.52%: Chiral HPLC ~ 98.71%.Example 13: (S)-3-(1H-benzo[d]imidazol-6-yl)-4-(4-(3,3-difluoropropoxy) -3,5-difluorophenyl)oxazolidin-2-one

[00608] Step (MD-Sl):

[00609] A mixture of 4-bromo-1,6-difluorophenol (8 g, 38.10 mmol), 3-chloro-1-propanol (4.82 ml, 57.14 mmol) and potassium carbonate (10. 53 g, 76.2 mmol) in dimethyl formamide (70 ml), was heated at 80°C for 6 hours. The reaction mass was filtered and washed with diethyl ether. Water was added to the filtrate and extracted with diethyl ether. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 8 g of the crude intermediate MD-S1 as a brown liquid, subsequently used without any purification.

[00610] Step 2 (MD-S2):

[00611] Periodinane Dess-martin (12.95 g, 29.85 mmol) was added to a solution of MD-S1 (8 g, 29.85 mmol) in dichloromethane (80 ml) at °C and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated in vacuo and the resulting mass was suspended in diethyl ether, stirred for 15 minutes and filtered. The filtrate was successively washed with water, saline; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 5% ethyl acetate in petroleum ether as the eluent provided 5 g (62.97%) of MD-S2 as a pale yellow solid.

[00612] Step 3 (MD-S3):

[00613] Diethylamino sulfur trifluoride (4.92 mL, 37.60 mmol) was added to a solution of MD-S2 (5 g, 18.80 mmol) in dichloromethane (100 mL) at °C and the mixture was stirred at room temperature for 20 hours. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 3% ethyl acetate in petroleum ether as the eluent provided 3.3 g (61.17%) of MD-S3 as a yellow solid pale.

[00614] Step 4 (MD-S4):

[00615] A solution of MD-S3 (1.5 g, 5.23 mmol) and tri-n-butylvinyltin (1.92 mL, 6.53 mmol) in toluene (60 mL) was purged with argon gas for 5 minutes. Tetracis-(triphenylphosphine)-palladium (121 mg, 0.1 mmol) was added and the mixture was continuously purged for an additional 5 minutes. The reaction mass was heated in a sealed tube at 110 °C for 8 hours. The reaction mass was filtered over celite and washed with ethyl acetate. The combined filtrate and wash portion were concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using petroleum ether as the eluent provided 1.2 g (98.36%) of MD-S4 as a colorless liquid.

[00616] Step 5 (MJ-S1):

[00617] t-Butylhypochlorite (1.9 mL, 16.70 mmol) was added to a stirred solution of t-butyl carbamate (1.95 g, 16.67 mmol) in 1-propanol (22 mL) and hydroxide of 0.4N aqueous sodium (677 mg in 42 mL of water) at 10°C to 15°C and the mixtures were stirred for 15 minutes. A solution of (DHQ)2PHAL (216 mg, 0.28 mmol) in 1-propanol (22 mL) was added followed by a solution of MD-S4 (1.3 g, 5.55 mmol) in 1-propanol ( 22 mL). Finally, potassium osmatedihydrate (82 mg, 0.22 mmol) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 18 to 22% ethyl acetate in petroleum ether as the eluent provided 700 mg (34.38%) of MJ-S1 as a white solid. .

[00618] Step 6 (MK-S1):

[00619] Thionyl chloride (1.03 mL, 14.17 mmol) was added to a solution of MJ-S1 (650 mg, 1.77 mmol) in tetrahydrofuran (30 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 2 hours. The solvent was evaporated in vacuum and the resulting mass was divided between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 400 mg (77.22%) of MK-S1 as a light yellow solid.

[00620] Step 7 (MK-S2):

[00621] A mixture of MK-S1 (400 mg, 1.36 mmol), 4-bromo-1,2-diaminobenzene (306 mg, 1.64 mmol) and cesium fluoride (413 mg, 2.72 mmol) in 1,4-dioxane (20 mL) was purged with argon gas for 15 minutes. Copper iodide (39 mg, 0.20 mmol) and 1,2-diaminocyclohexane (23 mg, 0.20 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction mixture was heated in a sealed tube for 20 hours at 110 to 115°C. The mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 1-1.5% methanol in dichloromethane as the eluent provided 400 mg (73.80%) of MK-S2 as a brown sticky liquid.

[00622] Step 8 (Example 13):

[00623] Formamidine acetate (312 mg, 3.00 mmol) was added to a solution of MK-S2 (400 mg, 1.00 mmol) in acetonitrile (10 mL) and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by trituration with 8:2 (diethyl ether: ethyl acetate) provided 310 mg of Example 13 as a light brown solid.

[00624] Melting range: 207 to 209.4 °C; 1H-NMR (400 MHz, DMS0-d6): δ 8.19 (s, 1 H); 7.63 (d, 1H); 7.50 (d, 1 H); 7.29-7.24 (m, 3H); 6.37-5.99 (m, 1H); 5.76 (t, 1H); 4.81 (t, 1 H); 4.18-4.13 (m, 3H); 2,292.16 (m, 2H); MS = 410.0 (M+1); HPLC ~ 99.11%: Chiral HPLC ~ 99.96%.Example 14: (S)-5-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)- 2-(2,2-difluoropropoxy) benzonitrile

[00625] Step 1 (ME-S1):

[00626] Triethiamine (18.5 mL, 135 mmol) was added to a solution of hydroxyacetone (5.0 g, 67.49 mmol) in dichloromethane (80 mL) at 0 °C. Benzoyl chloride (7.84 mL, 67.49 mmol) was added dropwise over 15 minutes and DMAP (200 mg) was added. The reaction mass was warmed to room temperature and stirred for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 8% ethyl acetate in petroleum ether as the eluent provided 8 g of ME-S1 as a colorless liquid.

[00627] Step 2 (ME-S2):

[00628] Diethylamino Sulfurtrifluoride (5.9 mL, 44.94 mmol) was added to a solution of ME-S1 (4.0 g, 22.47 mmol) in dichloromethane (40 mL) at 0°C and the solution was stirred at room temperature for 18 hours. The reaction was quenched with ice water and the mixture was extracted with dichloromethane. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 4.0 g of ME-S2 as a brown liquid.

[00629] Step 3 (ME-S3):

[00630] A solution of ME-S2 (4 g, 20.0 mmol) in diethyl ether (80 mL) was heated at 60 °C for 4 hours. The reaction mass was cooled to room temperature and extracted with diethyl ether. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated under mild reduced pressure at room temperature to provide 4 g of ether containing ME-S3.

[00631] Step 4 (ME-S4):

[00632] A solution of crude ME-S3 (3.8 g, 39.58 mmol) in Dimethyl formamide (5 mL) was added to a suspension of sodium hydride (60%; 1.3 g, 32.5 mmol ) in dry dimethylformamide (20 mL) at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mass was cooled again to 0°C and a solution of 5-bromo-2-fluorobenzonitrile (2.36 g, 11.8 mmol) in dimethylformamide (5 mL) was added. The reaction mass was warmed to room temperature and stirred for 30 minutes, quenched with saturated ammonium chloride solution and extracted with diethyl ether. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 8% ethyl acetate in petroleum ether as the eluent provided 2.5 g (69.4%) of ME-S4 as a sticky liquid. yellow.

[00633] Step 5 (ME-S5):

[00634] A mixture of ME-S4 (1 g, 3.62 mmol), potassium vinyl trifluoroborate (490 mg, 3.62 mmol), triphenyl phosphine (57 mg, 0.22 mmol) and cesium carbonate ( 3.56 g, 10.86 mmol) in tetrahydrofuran (40 mL) and water (4 mL) was purged with argon gas for 5 minutes. Palladium chloride (13 mg, 0.07 mmol) was added and the mixture was continuously purged for another 5 minutes. The reaction was heated in a sealed tube for 18 hours. The reaction mass was filtered over celite and washed with ethyl acetate. Water was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 4-5% ethyl acetate in petroleum ether as the eluent provided 600 mg (74.35%) of ME-S5 as a yellow solid pale.

[00635] Step 6 (MJ-S1):

[00636] t-Butyl hypochlorite (0.92 mL, 8.09 mmol) was added to a stirred solution of t-butyl carbamate (945 mg, 8.07 mmol) in 1-propanol (11 mL) and hydroxide of 0.4N aqueous sodium (330 mg in 16.5 mL of water) at 10 to 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (105 mg, 0.13 mmol) in 1-propanol (11 mL) was added, followed by a solution of ME-S5 (600 mg, 2.69 mmol) in 1-propanol (11 mL). Finally, potassium osmate dihydrate (40 mg, 0.11 mmol) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 32% ethyl acetate in petroleum ether as the eluent provided 480 mg (50.16%) of MJ-S1 as a white solid.

[00637] Step 7 (MK-Sl):

[00638] Potassium-t-butoxide (450 mg, 4.04 mmol) was added to a stirred solution of MJ-S1 (480 mg, 1.35 mmol) in tetrahydrofuran (10 ml), at 0°C and the mixture was stirred for 2 hours at room temperature. The reaction was neutralized with 10% acetic acid and the mass extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 350 mg of MK-S1 as a not entirely white solid.

[00639] Step 8 (MK-S2):

[00640] A mixture of MK-S1 (340 mg, 1.20 mmol), 4-bromo-1,2-diaminobenzene (2 mg, 1.20 mmol) and cesium fluoride (3 mg, 2.40 mmol) in 1,4-dioxane (15 ml), it was purged with argon gas for 15 minutes. Copper iodide (34 mg, 0.18 mmol) and 1,2-diaminocyclohexane (21 mg, 0.18 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction mixture was heated in a sealed tube for 18 hours at 110 to 115°C. The reaction mass was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 3% methanol in dichloromethane as the eluent provided 300 mg (64.3%) of MK-S2 as a brown solid.

[00641] Step 9 (Example 14):

[00642] Formamidine acetate (300 mg, 0.75 mmol) was added to a solution of MK-S2 (300 mg, 0.75 mmol) in acetonitrile (5 ml), and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by preparative TLC using 4.5% methanol in dichloromethane as the eluent provided 110 mg of Example 14 with a purity of -91.87% measured by LCMS. Further purification using preparative HPLC was done under consideration of the following conditions: Column: Sun fire C-18 (250*30mm*10μ); Mobile phase: A: acetonitrile; B: 10 mM ammonium acetate (50:50); flow rate: 38 mL/min; diluent: ACN+MeOH+mobile phase; Method: Gradient; Temp °C column: Ambient. The fractions were evaporated in vacuum and the resulting residue was partitioned between water and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 80 mg (28%) of Example 14 as a white solid.

[00643] Melting range: 155.6 to 158 °C; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, 1 H); 7.89 (s, 1H); 7.76-7.70 (m, 1H); 7.59 (d, 1H); 7.54-7.42 (m, 1 H); 7.23-7.15 (m, 2H); 4.82 (t, 1H); 4.41 (t, 2H); 4.17 (t, 1 H); 1.70 (t, 3H); MS = 399.0 (M+1); HPLC ~ 99.72%; Chiral HPLC ~ 97.92%. Example 15: (S)-2-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-5-(2,2-difluoropropoxy) benzonitrile

[00644] Step 1 (MF-S1):

[00645] A mixture of 2-bromo-5-hydroxybenzonitrile (12 g, 60.61 mmol), chloroacetone (5.85 mL, 72.73 mmol) and potassium carbonate (16.75 g, 121 mmol)) in Acetonitrile (100 mL) was refluxed for 2 hours. The reaction mass was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to provide the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 15 to 20% ethyl acetate in petroleum ether as the eluent provided 6.75 g (43.86%) of MF-S1 as an solid not completely white.

[00646] Step 2 (MF-S2):

[00647] Diethylamino Sulfurtrifluoride (6.9 mL, 52.75 mmol) was added to a solution of MF-S1 (6.7 g, 26.38 mmol) in dichloromethane (80 mL) at °C and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 6% ethyl acetate in petroleum ether as the eluent provided 4 g (54.94%) of MF-S2 as a white solid.

[00648] Step 3 (MF-S3):

[00649] A solution of MF-S2 (1.5 g, 5.43 mmol) and tri-n-butyl vinyltin (2 mL, 6.79 mmol) in toluene (50 mL) was purged with argon gas for 5 minutes. Tetracis-(triphenylphosphine)-palladium (125 mg, 0.11 mmol) was added and the mixture was continuously purged for an additional 5 minutes. The reaction mass was heated in a sealed tube at 110°C for 8 hours. The reaction mass was filtered over celite, washed with ethyl acetate and the filtrate was concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) 5 and using 3% ethyl acetate in petroleum ether as the eluent provided 1.2 g (99.17%) of MF-S3 as a liquid colorless.

[00650] Step 4 (MJ-Sl):

[00651] t-Butyl hypochlorite (1.84 ml, 16.19 mmol) was added to a stirred solution of t-butyl carbamate (1.89 g, 16.14 mmol) in 1-propanol (21.5 ml), and 0.4N aqueous sodium hydroxide (656 mg in 41 ml of water) at 10 to 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (210 mg, 0.27 mmol) in 1-propanol (21.5 ml) was added, followed by a solution of MF-S3 (1.2 g, 5.38 mmol) in 1-propanol (21.5 ml). Finally, potassium osmate dihydrate (80 mg, 0.21 mmol) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 25% ethyl acetate in petroleum ether as the eluent provided 900 mg (47.12%) of MJ-S1 as a white solid.

[00652] Step 5 (MK-Sl):

[00653] Thionyl chloride (1.3 ml, 17.98 mmol) was added to a solution of MJ-S1 (800 mg, 2.25 mmol) in tetrahydrofuran (20 ml), at 0°C. The reaction mass was warmed to room temperature and stirred for 5 hours. The solvent was evaporated in vacuum and the resulting mass was divided between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 450 mg (70.98%) of MK-S1 as a not entirely white solid.

[00654] Step 6 (MK-S2):

[00655] A mixture of MK-S1 (500 mg, 1.77 mmol), 4-bromo-1,2-diaminobenzene (400 mg, 2.13 mmol) and cesium fluoride (540 mg, 3.54 mmol) in 1,4-dioxane (20 ml), it was purged with argon gas for 15 minutes. Copper iodide (50 mg, 0.26 mmol) and 1,2-diaminocyclohexane (30 mg, 0.26 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction mixture was heated in a sealed tube for 20 hours at 110 to 115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 1% methanol in dichloromethane as the eluent provided 500 mg (72.89%) of MK-S2 as a light brown solid.

[00656] Step 7 (Example 15):

[00657] Formamidine acetate (536 mg, 5.15 mmol) was added to a solution of MK-S2 (500 mg, 1.29 mmol) in acetonitrile (10 mL) and the mixture was refluxed for 1.5 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by trituration with 8:2 (diethyl ether: dichloromethane) provided 300 mg (58.48%) of Example 15 as a brown solid.

[00658] Melting range: 137.9 to 140.0 °C; 1H-NMR (400 MHz,DMSO-d6): δ 8.18 (s, 1 H); 7.64-7.58 (m, 2H); 7.49 (d, 2H); 7.33-7.20 (m, 32); 5.95 (t, 1H); 4.92 (t, 1H); 4.31 (t, 3H); 1.67 (t, 3H); MS = 399.0 (M+1); HPLC ~ 98.91%; Chiral HPLC ~ 98.62%.Example 16: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(4,4-difluorobutoxy)phenyl)oxazolidin-2-one

[00659] Step 1 (MG-S1):

[00660] Thionyl chloride (17.5 mL, 0.239 mol) was added to a suspension of (S)-4-hydroxy phenyl glycine (20 g, 0.120 mol) in methanol (100 mL) at °C dropwise. The mixture was slowly heated to reflux and held for 15 hours. The solvent was evaporated in vacuo and the residue was co-distilled twice with petroleum ether. Vacuum drying provided 25.2 g (96.55%) of MG-S1 as a white solid.

[00661] Step 2 (MG-S2):

[00662] Aqueous potassium carbonate (31.8 g, 0.230 mol in 100 mL of water) and boc anhydride (31.65 mL, 0.138 mol) were added successively to a suspension of MG-S1 (25.0 g, 0.115 mol) in 1,4-dioxane (200 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched in water and extracted with ethyl acetate (2x100 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. The compound was suspended in petroleum ether, stirred for 30 minutes, filtered and dried under vacuum to obtain 28.9 g (89.43%) of MG-S2 as a white solid.

[00663] Step 3 (MG-S3):

[00664] Triphenyl phosphine (1.39 g, 5.33 mmol) and 4-benzyl-oxy-1-butanol (0.70 g, 3.91 mmol) were added successively to a stirred solution of MG-S2 (1 .0 g, 3.55 mmol) in dry tetrahydrofuran (30 mL) at room temperature. Diethyl azodicarboxylate (950 mg, 5.3 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 6% ethyl acetate in petroleum ether as the eluent provided 1.1 g (70.06%) of MG-S3 as a thick liquid colorless.

[00665] Step 4 (MG-S4):

[00666] A solution of MG-S3 (1.1 g, 2.481 mmol) in methanol (50 mL) was hydrogenated over Pd/C (10%; 150 mg) at 5.62 kg/cm2 (80 psi) for 2 hours in a Parr apparatus. The reaction mass was filtered through celite and washed with methanol. The combined filtrate and wash portion were concentrated under reduced pressure to obtain 800 mg (91.32%) of MG-S4 as a non-white solid.

[00667] Step 5 (MG-S5):

[00668] Iodoxy benzoic acid (2.535 g, 9.053 mmol) was added to a solution of MG-S4 (800 mg, 2.264 mmol) in dichloromethane (20 mL) and dimethyl sulfoxide (3 mL) and the mixture was stirred for 20 hours at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and washing portion were successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 20% ethyl acetate in petroleum ether as the eluent provided 780 mg (98.11%) of MG-S5 as a yellow syrup.

[00669] Step 6 (MG-S6):

[00670] Diethylamino sulfurtrifluoride (0.58 mL, 4.44 mmol) was added to a solution of MG-S5 (780 mg, 2.22 mmol) in dichloromethane (20 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer is extracted with dichloromethane (1x30 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 600 mg (72.90%) of MG-S6 as a yellow syrup.

[00671] Step 7 (MG-S7):

[00672] Sodium borohydride (243 mg, 6.42 mmol) was added in two equal batches (over 15 minutes) to a solution of MG-S6 (600 mg, 1.60 mmol) in a mixture of tetrahydrofuran (10 mL) and methanol (4 mL) at room temperature. Due to the exothermic reaction, the temperature rose to ~50°C. After completion of the addition, the reaction mixture was stirred for 1 hour. Ethyl acetate was added and the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to provide 400 mg (72.20%) of MG-S7 as a non-white solid, subsequently used without any purification.

[00673] Step 8 (MK-S1):

[00674] Potassium t-butoxide (390 mg, 3.478 mmol) was added to a solution of MG-S7 (400 mg, 1.159 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mass was acidified (pH~6). Ethyl acetate was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and the volatiles were evaporated in vacuum, co-distilled twice with toluene to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1% methanol in chloroform as the eluent provided 250 mg (79.61%) of MK-S1 as a non-white solid.

[00675] Step 9 (MK-S2):

[00676] A mixture of MK-S1 (250 mg, 0.92 mmol), 1,2-diamino-4-bromobenzene (175 mg, 0.92 mmol), cesium fluoride (152 mg, 1.845 mmol) and iodide of copper (30 mg, 0.138 mmol) in 1,4-dioxane (10 mL) was purged with argon gas for 15 minutes. 1,2-diaminocyclohexane (20 mg, 0.17 mmol) was added and the mixture was continuously purged for another 10 minutes. The reaction mixture was stirred at 110 to 115°C in a sealed tube for 18 hours. The reaction mass was filtered through celite, washed with dioxane and concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2% methanol in chloroform as the eluent provided 200 mg (57.47%) of MK-S2 as a brown solid.

[00677] Step 10 (Example 16):

[00678] Formamidine acetate (206 mg, 1.98 mmol) was added to a solution of MK-S2 (200 mg, 0.66 mmol) in acetonitrile (10 ml), and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain the crude product, which was purified by preparative HPLC using the following conditions: Column: X Bridge C18 (30x250 mm) 5 μ; Mobile phase: 0.01 M ammonium acetate (Aq): CH3CN; flow rate: 35 mL/minute; diluents used: ACN+MeOH+THF. The corresponding fractions were concentrated in vacuum and divided between water and chloroform. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 55 mg of Example 16 as a solid. Melting range: 187 to 191 °C; 1H-NMR (400 MHz, DMSO-d6): δ 12.42 (s, 1 H); 8.16 (s, 1H); 7.56 20 (s, 1 H); 7.46 (bs, 1 H); 7.31 (d, 2H); 7.23 (bs, 1H); 6.87 (d, 2H); 6.27-5.97 (m, 2H); 5.67 (t, 1H); 4.80 (t, 1 H); 4.13 (q, 1H); 3.92 (t, 2H); 1.95-1.72 (m, 4H); MS = 386.0 (M+1);

[00679] HPLC~96.46%; Chiral HPLC ~ 92.72%. Example 17: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-2,6-difluorophenyl)oxazolidin-2-one

[00680] Step 1 (MH-S1):

[00681] Benzyl bromide (10.11 ml, 84.61 mmol) was added to the stirred solution of 3,5-difluorophenol (10 g, 76.92 mmol) and potassium carbonate (21.22 g, 153.84 mmol) in N,N-dimethylformamide (100 ml). The reaction mixture was heated to 85°C and stirred for 12 hours. The reaction mixture was filtered, washed with diethyl ether. The filtrate was washed with water, brine; dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain 12.6 g (74.55%) of MH-S1 as a yellow liquid.

[00682] Step 2 (MH-S2):

[00683] N-Butyl lithium (2.4 M; 18.9 mL, 45.45 mmol) was added to a solution of MH-S1 (10.0 g, 45.46 mmol) in dry tetrahydrofuran (70 mL) at 0°C and the mixture was stirred for 1 hour at the same temperature. The mixture was added to a solution of diethyl oxalate (9.17 ml, 90.90 mmol) in tetrahydrofuran (30 ml) at -78°C for 15 minutes. The reaction mass was warmed to room temperature and stirred for 15 minutes. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica (60 to 120 mesh) and using 4% ethyl acetate in petroleum ether as the eluent provided 7.3 g (50.34%) of MH-S2 as a yellow liquid.

[00684] Step 3 (MH-S3):

[00685] Sodium acetate (3.74 g, 45.62 mmol) and hydroxylamine hydrochloride (3.16 g, 45.62 mmol) were added successively to a solution of MH-S2 (7.3 g, 22. 81 mmol) in absolute ethanol (70 mL) and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 7.6 g (99.47%) of the crude intermediate MH-S3 as a yellow liquid, subsequently used without any purification.

[00686] Step 4 (MH-S4):

[00687] A solution of MH-S3 (7.6 g, 22.68 mmol) in absolute ethanol (150 mL) was employed during hydrogenation using 10% Pd-C in a Parr apparatus (5.62 kg/cm2 (80 psi)) for 12 hours. The reaction mass was filtered through celite and washed with ethanol. The combined filtrate and wash portion was concentrated under reduced pressure to obtain 5.2 g (94.03%) of crude intermediate MH-S4 as a light brown syrup, subsequently used without any purification.

[00688] Step 5 (MH-S5):

[00689] MH-S4 (5.2 g, 2.12 mmol) in ethanol (70 mL) was hydrogenated over Raney Nickel (5.0 g) in a Parr operator. The reaction mixture was stirred for 48 hours at 5.62 kg/cm2 (80 psi). The mixture was filtered through celite and washed with ethanol. The filtrate was concentrated under reduced pressure to obtain 4.8 g (97.95%) of MH-S5 as the crude intermediate, which was subsequently used without further purification.

[00690] Step 6 (MH-S6):

[00691] Triethylamine (5.8 ml, 41.54 mmol) and di-tert-butyl bicarbonate (4.7 ml, 20.77 mmol) were added successively to a solution of MH-S5 (4.8 g, 20.77 mmol) in dichloromethane (50 ml), and the mixture was stirred for 20 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 30% ethyl acetate in petroleum ether as the eluent provided 2.8 g (40.75%) of MH-S6 as a viscous solid .

[00692] Step 7 (MH-S7):

[00693] A mixture of MH-S6 (2.8 g, 8.45 mmol), chloroacetone (0.84 ml, 10.15 mmol) and potassium carbonate (2.3 g, 16.91 mmol) in acetonitrile (30 ml), was refluxed for 5 hours. The reaction mass was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 2.4 g (70.79%) of MH-S7 as a viscous solid.

[00694] Step 8 (MH-S8):

[00695] Diethylamino Sulfurtrifluoride (1.6 ml, 11.97 mmol) was added to a solution of MH-S7 (2.4 g, 5.98 mmol) in dichloromethane (30 ml), at 0 ° C and the The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was successively washed with saturated sodium bicarbonate solution, water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 15% ethyl acetate in petroleum ether as the eluent provided 1.7 g (69.67%) of MH-S8 as a viscous solid .

[00696] Step 9 (MH-S9):

[00697] MH-S8 (1.5 g, 3.66 mmol) in tetrahydrofuran (15 ml) was added to the stirred solution of lithium aluminum hydride (420 mg, 10.98 mmol) in tetrahydrofuran (10 ml), at 0 °C. The reaction mixture was warmed to room temperature, quenched with saturated sodium sulfate solution, filtered and washed with ethyl acetate solution. The aqueous and organic layers were separated and the organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 20% ethyl acetate in petroleum ether as the eluent provided 800 mg (59.70%) of MH-S9 as a viscous solid.

[00698] Step 10 (MK-S1):

[00699] Thionyl chloride (0.8 ml, 10.21 mmol) was added dropwise to a stirred solution of MH-S9 (750 mg, 2.04 mmol) in tetrahydrofuran (15 ml), at 0°C. The reaction mixture was warmed to room temperature and stirred for 5 hours. The solvent was evaporated under reduced pressure. The resulting mass was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Washing with petroleum ether and later drying purified the remaining mass, which provided 450 mg (75.25%) of MK-S1.

[00700] Step 11 (MK-S2):

[00701] A mixture of MK-S1 (450 mg, 1.53 mmol), 4-Bromo-1,2-diaminobenzene (430 mg, 2.30 mmol) and cesium fluoride (465 mg, 3.06 mmol) in 1,4-dioxane (20 ml), it was purged with argon gas for 30 minutes. Copper iodide (44 mg, 0.23 mmol) and 1,2-diaminocyclohexane (26 mg, 0.23 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction mixture was heated in a sealed tube for 16 hours at 105 to 110°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 1.5 to 2% methanol in dichloromethane as the eluent provided 450 mg (73.52%) of MK-S2 as a brown solid.

[00702] Step 12 (Example 17):

[00703] Formamidine acetate (352 mg, 3.38 mmol) was added to a solution of MK-S2 (450 mg, 1.12 mmol) in acetonitrile (10 ml), and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by column chromatography over neutral alumina and using 2 to 2.5% methanol in dichloromethane as the eluent provided 360 mg of Example 17, which was triturated with n-pentane and then dried to obtain 310 mg of Example 17 as a light yellow solid. Melting range: 122.2 to 126.8 °C; 1H-NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1 H); 7.54 (s, 2H); 7.18 (s, 1 H); 6.80 (d, 2H); 6.00 (q, 1 H); 4.84 (t, 1H); 4.38 (t, 1H); 4.25 (t, 2H); 1.65 (t, 3H); 5 MS = 410.1 (M+1); HPLC ~ 99.19%; Chiral HPLC ~ 99.21%.Example 18: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-2- fluorophenyl)-oxazolidin-2-one

[00704] Step 1 (ML-S1):

[00705] Potassium iodide (5.24 g, 31.57 mmol), N,N-diisopropylethylamine (4.08 g, 31.57 mmol) and 1,4-dibromo-2-butanol (7.32 g, 31.57 mmol) were added successively to the stirred solution of 4-bromo-3-fluoroaniline (3 g, 15.78 mmol) in toluene (25 mL). The reaction mixture was stirred at 90°C for 18 hours. The reaction mass was filtered and washed with ethyl acetate. The filtrate was successively washed with water, saline; dried over anhydrous sodium sulfate and evaporated in vacuum. Purified by column chromatography on silica gel and using 20% ethyl acetate in petroleum ether as the eluent provided 2 g (48.8%) of ML-S1 as a brown solid.

[00706] Step 2 (ML-S2):

[00707] A solution of ML-S1 (2 g, 7.69 mmol) and cuprous cyanide (1.03 g, 11.44 mmol) in N,N-dimethylformamide (20 mL) was heated to 150°C for 20 hours. The reaction mass was evaporated in vacuum, after which it was stirred in ammonium chloride solution, filtered and washed with dichloromethane. The filtrate was washed with water; dried over anhydrous sodium sulfate and evaporated in vacuum. Purification by column chromatography on silica gel and using 30% ethyl acetate in petroleum ether as the eluent provided 950 mg (60.1%) of ML-S2 as a yellow solid.

[00708] Step 3 (ML-S3):

[00709] Oxalyl chloride (1.18 g, 9.29 mmol) was added to the stirred solution of dimethylsulfoxide (1.44 g, 18.43 mmol) in dichloromethane (15 mL) at -78°C and the mixture stirred for 1 hour. A solution of ML-S2 (950 mg, 4.61 mmol) in dichloromethane (20 mL) was added dropwise at -78 ° C and the reaction mixture was stirred for 1 hour at the same temperature. Triethyl amine (2.32 g, 22.97 mmol) was added and the mixture was warmed to room temperature over the next 40 minutes. The reaction was quenched with ice water and extracted with dichloromethane. The separated organic layer was washed with brine; dried over anhydrous sodium sulfate and evaporated in vacuum to obtain 900 mg (95.74%) of ML-S3 as a yellow solid.

[00710] Step 4 (ML-S4):

[00711] Diethylamino sulfurtrifluoride (1.42 g, 8.82 mmol) was added to a solution of ML-S3 (900 mg, 4.41 mmol) in dichloromethane (10 mL) at °C and the mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, bicarbonate, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 900 mg of crude intermediate ML-S4 as a brown liquid.

[00712] Step 5 (ML-S5):

[00713] Diisobutyl aluminum hydride in toluene (1.5 M, 5.3 mL, 7.96 mmol) was added to a solution of ML-S4 (900 mg, 3.98 mmol) in tetrahydrofuran (10 mL) at -70°C and the mixture was slowly warmed to 0°C. Subsequently, the reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed with brine; dried over anhydrous sodium sulfate and the solvent was evaporated in vacuum. Purification by column chromatography over neutral alumina and using 15% ethyl acetate in petroleum ether as the eluent provided 580 mg (63.6%) of ML-S5 as a pale yellow solid.

[00714] Step 6 (MN-Sl):

[00715] N-Butyl lithium in hexane (2.2 M; 2.3 mL, 5.06 mmol) was added to a stirred solution of methyl-triphenylphosphoniobromide (1.8 g, 5.06 mmol) in tetrahydrofuran (10 mL) at -50°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of ML-S5 (580 mg, 2.53 mmol) in tetrahydrofuran (10 mL) was added dropwise at -30 °C. The temperature was warmed to room temperature and the reaction mixture was stirred for 2 hours. The reaction was quenched with acetic acid and the PH value was adjusted to pH~5. a solution was extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 1% ethyl acetate in petroleum ether as the eluent provided 330 mg (57.5%) of MN-S1 as a pale yellow solid.

[00716] Step 7(MR-Sl):

[00717] t-Butyl hypochlorite (0.49 mL, 4.37 mmol) was added to a stirred solution of t-butyl carbamate (510 mg, 4.35 mmol) in 1-propanol (5.8 mL) and 0.4N aqueous sodium hydroxide (11.08 mL) at 15°C and the mixture was then stirred for 15 minutes. A solution of (DHQ)2PHAL 5 (56.62 mg, 0.07 mmol) in 1-propanol (5.8 mL) was added, followed by a solution of MN-S1 (330 mg, 1.45 mmol) in 1-propanol (5.8 mL). Finally potassium osmatedihydrate (21.4 mg, 0.058 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 15% ethyl acetate in petroleum ether as the eluent provided 280 mg (53.53%) of MR-S1 as a white solid.

[00718] Step 8 (MR-S2):

[00719] Potassium-t-butoxide (186.6 mg, 1.67 mmol) was added to a stirred solution of MR-S1 (280 mg, 0.83 mmol) in tetrahydrofuran (10 mL) at 0°C and the mixture was stirred for 1 h at room temperature. The reaction mixture was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 180 mg (81%) of intermediate MR-S2 as a light yellow solid.

[00720] Step 9 (MR-S3):

[00721] A mixture of MR-S1 (180 mg, 0.63 mmol), 4-Bromo-1,2-diaminobenzene (117.7 mg, 0.67 mmol) cesium efluorethyl (191 mg, 1.26 mmol ) in 1,4-dioxane (10 mL) was purged with argon gas for 10 min in a sealed tube. Copper iodide (18 mg, 0.09 mmol) and 1,2-diaminocyclohexane (10.8 mg, 0.09 mmol) were added and the mixture was continuously purged for a further 10 minutes. The sealed tube was heated for 18 hours at 110 to 115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2 to 3% methanol in chloroform as the eluent provided 150 mg (60.97%) of MR-S3 as a brown solid.

[00722] Step 10 (Example 18):

[00723] Formamidine acetate (107 mg, 0.765 mmol) was added to a solution of MR-S3 (150 mg, 0.38 mmol) in acetonitrile (5 ml), and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was triturated with diethyl ether and dried to obtain 80 mg (52.3%) of example 18 as a solid.

[00724] Melting range: 273 to 278 °C; 1H-NMR (400 MHz, DMSO-d6): δ 8.16 (d, 1 H); 7.54 to 7.28 (m, 2H); 7.27 to 7.14 (m, 2H); 6.39 to 6.31 (m, 2H); 5.79 (t, 1H); 4.81 (t, 1 H); 4.21 (q, 1H); 3.16 (t, 2H); 3.39 (t, 2H); 2.51 to 2.27 (fused with DMSO, 2H); MS = 403.1 (M+1); HPLC ~ 98.19%; Chiral HPLC ~ 99.44%. Example 19: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-2,3-difluorophoxazolidin-2-one Step 1 (ML-S1):

[00725] Diisopropyl ethylamine (1.6 ml, 9.6 mmol) and potassium iodide (1.5 g, 9.6 mmol) were added to a solution of 4-bromo-2,3-difluoroaniline (1.0 g, 4.80 mmol) in toluene (15 ml), and the mixture was stirred for 10 min at room temperature. 1,4-dibromo-2-butanol (1.1 ml, 9.6 mmol) was added and the reaction mixture was stirred at 90 ° C for 24 hours. The reaction mass was filtered and washed with ethyl acetate. The filtrate was successively washed with water, saline; dried over anhydrous sodium sulfate and evaporated in vacuum. Purification by column chromatography on silica gel (60 to 120 mesh) and using 15% ethyl acetate in petroleum ether as the eluent provided 500 mg (38.46%) of ML-S1 as a brown solid Of course.

[00726] Step 2 (ML-S2):

[00727] Copper cyanide (962 mg, 10.75 mmol) was added to a solution of ML-S1 (2.5 g, 8.96 mmol) in dimethyl formamide (20 ml), and the mixture was stirred at 155 at 160°C for 12 hours. The reaction mass was cooled to room temperature, filtered and the solvent was evaporated under reduced pressure. The resulting mass was dissolved in ethyl acetate (100 ml), and washed with water and saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 25% ethyl acetate in petroleum ether as the eluent provided 1.0 g (50%) of ML-S2 as a brown solid pale.

[00728] Step 3 (ML-S3):

[00729] Oxalyl chloride (0.92 mL, 10.66 mmol) was added to a stirred solution of dry dimethyl sulfoxide (1.52 mL, 21.30 mmol) in dichloromethane (10 mL) at -78'C and the mixture was stirred for 1 h at the same temperature. A solution of ML-S2 (1.2g, 5.33 mmol) in dichloromethane (5 mL) was added dropwise at -78°C and the mixture was stirred for 1 h at the same temperature. Triethyl amine (3.5 mL, 26.65 mmol) was added and the mixture was subsequently stirred for 30 min at room temperature. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using ethyl acetate in petroleum ether as the eluent provided 750 mg (63%) of ML-S3 as a solid.

[00730] Step 4 (ML-S4):

[00731] Diethylamino sulfurtrifluoride (0.82 mL, 6.27 mmol) was added to a solution of ML-S3 (700 mg, 3.13 mmol) in dichloromethane (10 mL) at 0°C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine and saturated sodium hydrogen carbonate; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 700 mg (92%) of ML-S4 as a brown liquid.

[00732] Step 5 (ML-S5):

[00733] DIBAL in toluene (1.5 M; 3.8 mL, 5.71 mmol) was added slowly over 5 min to a solution of ML-S4 (700 mg, 2.85 mmol) in dry tetrahydrofuran ( 10 mL) at -30°C. The reaction mass was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate (3x25 mL). The filtrate was successively washed with saline water; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 20% ethyl acetate in petroleum ether as the eluent provided 370 mg (52.4%) of ML-S5 as a colorless liquid.

[00734] Step 6(MN-Sl):

[00735] N-Butyl lithium in hexane (2.2 M; 1.35 mL, 2.99 mmol) was added to a stirred solution of (1.07 g, 2.99 mmol) in tetrahydrofuran (10 mL ) at -50°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of ML-S5 (370 mg, 1.49 mmol) in tetrahydrofuran (10 mL) was added dropwise at -30°C. The temperature was warmed to room temperature and the mixture was stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 5% ethyl acetate in petroleum ether as the eluent provided 250 mg (68.11%) of MN-S1 as a colorless liquid.

[00736] Step 7(MR-Sl):

[00737] t-Butyl hypochlorite (0.34 mL, 3.07 mmol) was added to a stirred solution of t-butyl carbamate (358 mg, 3.06 mmol) in 1-propanol (4 mL) and hydroxide of 0.4 N aqueous sodium (124 mg in 7.7 mL of water) at 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (39 mg, 0.051 mmol) in 1-propanol (4 mL) was added, followed by a solution of MN-S1 (250 mg, 1.02 mmol) in 1-propanol (4 mL) . Finally potassium osmatedihydrate (15 mg, 0.04 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and the use of 22 to 25% ethyl acetate in petroleum ether as the eluent provided 250 mg (64.9%) of MR-S1 as a solid white.

[00738] Step 8 (MR-S2):

[00739] Potassium-t-butoxide (148 mg, 1.32 mmol) was added to a stirred solution of MR-S1 (250 mg, 0.66 mmol) in tetrahydrofuran (10 mL) at 0°C and the The mixture was stirred for 1 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 175 mg (87%) of MR-S2 as a yellow solid.

[00740] Step 9 (MR-S3):

[00741] A mixture of MR-S2 (175 mg, 0.575 mmol), 4-Bromo-1,2-diaminobenzene (107 mg, 0.575 mmol) and cesium fluoride (174 mg, 1.15 mmol) in 1.4 -dioxane (10 mL) was purged with argon gas for 10 minutes. Copper iodide (16 mg, 0.086 mmol) and 1,2-diaminocyclohexane (10 mg, 0.086 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction was heated in a sealed tube for 24 hours at 110 to 115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 1.5% methanol in chloroform as the eluent provided 190 mg (80.5%) of MR-S3 as a brown solid.

[00742] Step 10 (Example 19):

[00743] Formamidine acetate (145 mg, 1.39 mmol) was added to a solution of MR-S3 (190 mg, 0.464 mmol) in acetonitrile (10 mL) and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was triturated with diethyl ether and dried to obtain 130 mg (67%) of Example 19 as a not quite pale brown solid. Melting range: 236 to 244 °C; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, 1 H); 7.58-7.43 (m, 2H); 7.29 to 7.16 (m, 1 H); 7.10 to 7.03 (m, 1 H); 6.52 (t, 1H); 5.85 (q, 1H); 4.83 (t, 1H); 4.27 (q, 1H); 3.73 (t, 2H); 3.50 (t, 2H); 2.51 to 2.36 (fused with DMSO, 2H); MS = 421.1 (M+1); HPLC ~ 98.86%; Chiral HPLC ~ 99.94%.Example 20: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3!3-difluoropyrrolidin-1-yl)-2, 6-difluorophenyl)oxazolidin-2-one

[00744] Step 1 (ML-S1):

[00745] Potassium iodide (4.7 g, 28.8 mmol), N,N-diisopropylethylamine (3.7 g, 28.8 mmol) and 1,4-dibromo-2-butanol (6.6 g, 28.8 mmol) were added successively to the stirred solution of 4-bromo-2,6-difluoroaniline (3 g, 14.4 mmol) in toluene (30 mL) and the mixture was stirred at 90°C for 18 hours. The reaction mass was filtered, washed with ethyl acetate and the filtrate was successively washed with water, saline solution; dried over anhydrous sodium sulfate and evaporated in vacuum to provide the crude intermediate compound. Purification by column chromatography on silica gel and using 20% ethyl acetate in petroleum ether as the eluent provided 2 g (49.9%) of ML-S1 as a brown solid.

[00746] Step 2 (ML-S2):

[00747] A solution of ML-S1 (2 g, 7.19 mmol) and Copper Cyanide (1.28 g, 14.3 mmol) in N,N-dimethylformamide (20 mL) was heated to 150°C for 20 hours. The reaction mass was evaporated in vacuum and the residue was stirred in ammonium chloride solution, filtered and washed with dichloromethane. The filtrate was washed with water; dried over anhydrous sodium sulfate and evaporated in vacuum to provide the crude intermediate. Purification by column chromatography on silica gel and using 30% ethyl acetate in petroleum ether as the eluent provided 950 mg (57%) of ML-S2 as a yellow solid.

[00748] Step 3 (ML-S3):

[00749] Oxalyl chloride (2.7 mL, 31.2 mmol) was added to a stirred solution of dimethyl sulfoxide (4.4 mL, 62.5 mmol) in dichloromethane (15 mL) at -78oC and the mixture was stirred for 1 h at -78°C. A solution of ML-S2 (3.5 mg, 15.6 mmol) in dichloromethane (50 mL) was slowly added and the mixture was stirred for 1 h at the same temperature. Triethyl amine (10.8 mL, 78.0 mmol) was added and the reaction was slowly warmed to room temperature and then stirred for 1 hour. The mixture was partitioned between water and dichloromethane. The separated organic layer was washed with brine; dried over anhydrous sodium sulfate and evaporated in vacuo to give 2.0 g (57.8%) ML-S3 as a yellow solid.

[00750] Step 4 (ML-S4):

[00751] Diethylamino sulfurtrifluoride (3.8 g, 22.5 mmol) was added to a solution of ML-S3 (2.0 g, 9.0 mmol) in dichloromethane (30 mL) at 0°C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, bicarbonate, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 1.8 g (81.8%) of ML-S4 as a brown liquid, subsequently used without any purification.

[00752] Step 5 (ML-S5):

[00753] Diisobutyl aluminum hydride (1.5 M, 7.3 mL, 11.0 mmol) was added to a solution of ML-S4 (1.8 g, 7.3 mmol) in tetrahydrofuran (20 mL) until -20°C and the mixture was slowly warmed to 0°. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate. The filtrate was washed with saline; dried over anhydrous sodium sulfate and evaporated in vacuum to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 12% ethyl acetate in petroleum ether as the eluent provided 1.0 g (55.0%) of ML-S5 as a yellow solid Of course.

[00754] Step 6(MN-Sl):

[00755] N-Butyl lithium in hexane (2.2 M; 3.6 mL, 8.0 mmol) was added to a stirred solution of methyl triphenylphosphoniobromide (2.8 g, 8.0 mmol) in tetrahydrofuran ( 20 mL) at -30°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of ML-S5 (1.0 g, 4.0 mmol) in tetrahydrofuran (10 mL) was added dropwise at -30°C. The reaction mass was slowly warmed to room temperature and stirred for 2 h at this temperature. The reaction was quenched with acetic acid and the PH value was adjusted to pH~5. The mass was filtered and washed with ethyl acetate. The filtrate was successively washed with water, saline; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 1% ethyl acetate in petroleum ether as the eluent provided 800 mg (82%) of MN-S1 as a non-white solid.

[00756] Step 7(MR-Sl):

[00757] T-Butyl hypochlorite (1.11 mL, 9.8 mmol) was added to a stirred solution of t-butyl carbamate (1.14 g, 9.78 mmol) in 1-propanol (13 mL) and 0.4N aqueous sodium hydroxide (25 mL) at 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (127 mg, 0.05 mmol) in 1-propanol (13 mL) was added, followed by a solution of MN-S1 (800 mg, 3.26 mmol) in 1-propanol (13 mL). Finally potassium osmatedihydrate (48 mg, 0.04 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfate solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 18% ethyl acetate in petroleum ether as the eluent provided 700 mg (57%) of MR-S1 as a non-white solid.

[00758] Step 8 (MR-S2):

[00759] Potassium-t-butoxide (620 mg, 5.5 mmol) was added to a stirred solution of MR-S1 (700 mg, 1.8 mmol) in tetrahydrofuran (20 mL) at 0°C and the The mixture was stirred for 1 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 24 to 26% ethyl acetate in petroleum ether as the eluent provided 90 mg (16%) of MR-S2 as a not entirely white solid. .

[00760] Step 9 (MR-S3):

[00761] A mixture of MR-S2 (90 mg, 0.29 mmol), 4-Bromo-1,2-diaminobenzene (50 mg, 0.29 mmol) and cesium fluoride (87 mg, 0.59 mmol) in 1,4-dioxane (5 mL) was purged with argon gas for 10 min in a sealed tube. Copper iodide (7.44 mg, 0.04 mmol) and 1,2-diaminocyclohexane (4.6 mg, 0.04 mmol) were added and the mixture was continuously purged for a further 10 minutes. The sealed tube was heated for 18 hours at 110 to 115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2 to 3% methanol in chloroform as the eluent provided 100 mg (82%) of MR-S3 as a brown solid.

[00762] Step 10 (Example 20):

[00763] Formamidine acetate (76 mg, 0.72 mmol) was added to a stirred solution of MR-S3 (100 mg, 0.24 mmol) in acetonitrile (5 mL) and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification was done by preparative HPLC using the following conditions:

[00764] Column: Packed C-18 (250*25mm*10 μ); Mobile phase: A: acetonitrile; B: 10 mM ammonium acetate (50:50); flow rate: 25 mL/min; diluents used: ACN+MeOH+mobile phase; method:gradient; ambient temperature °C: ambient. The resulting fractions were evaporated in vacuum and the resulting mass was partitioned between water and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 50 mg of Example 20 as a brown solid. 1H-NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1 H); 7.50 (d, 2H); 7.19 (d, 1H); 6.24 (d, 2H); 5.96 to 5.91 (m, 1 H); 4.83 (t, 1H); 4.31 (q, 1H); 3.62 (t, 2H); 3.39 (t, 2H); 2.50 to 2.40 (fused with DMSO, 2H); MS = 421.0 (M+1); HPLC ~ 99.08%; Chiral HPLC ~84.18%. Example 21: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-3-fluorophenyl)oxazolidin-2-one

[00765] Step 1 (MM-S1):

[00766] Potassium carbonate (22 g, 79.13 mmol) was added to a solution of hydroxypyrrolidone 3-hydrochloride (9.6 g, 79.12 mmol) in diemethylformamide (60 ml), and the mixture was stirred for 15 minutes. 3,4-Difluorobenzonitrile (10 g, 71.94 mmol) was added and the mixture was stirred at 90°C for 9 hours. The reaction was cooled to room temperature and then quenched with ice water. The resulting mass was filtered and washed with water, petroleum ether and dried in vacuum to provide 10 g (67.5%) of MM-S1 as a non-white solid.

[00767] Step 2 (MM-S2):

[00768] Periodinane Dess-martin (41.2 g, 97.08 mmol) was added to a solution of MM-S1 (10 g, 48.5 mmol) and the mixture was stirred for 15 hours. The reaction mass was filtered through celite and washed with dichloromethane. The filtrate was washed with water, brine; dried over anhydrous sodium sulfate and concentrated to obtain 3.2 g (32%) of MM-S2 as a not entirely white solid.

[00769] Step 3 (MM-S3):

[00770] Diethylamino sulfurtrifluoride (3.85 ml, 29.41 mmol) was added to a solution of MM-S2 (3.0 g, 14.70 mmol) in dichloromethane (30 ml), at 0°C and at The mixture was stirred for 4 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, bicarbonate, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 2.8 g (84.3%) of MM-S3 as a brown liquid.

[00771] Step 4 (MM-S4):

[00772] DIBAL in toluene (16.5 ml, 24.77 mmol) was added to a solution of MM-S3 (2.8 g, 12.38 mmol) in tetrahydrofuran (30 ml), at -70° C and the mixture was slowly heated to 0°C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The salts were filtered and the remaining mass was washed with ethyl acetate. The organic layer was separated from the filtrate and washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 5% ethyl acetate in petroleum ether as the eluent provided 1.5 g (53%) of MM-S4 as a pale yellow solid.

[00773] Step 5 (MN-Sl):

[00774] N-Butyllithium in hexane (2.5M; 5.24mL, 13.10mmol) was added to a stirred solution of triphenylphosphonium methylbromide (4.67g, 13.10mmol) in tetrahydrofuran (40mL) at -30°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of MM-S4 (1.5 g, 6.55 mmol) in tetrahydrofuran (10 mL) was added dropwise at -30°C. The temperature was warmed to room temperature and the mixture was stirred for 1 hour. The reaction was quenched with acetic acid and the PH value was adjusted to pH~5. The mixture was extracted with ethyl acetate (3x25 mL). The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 1% ethyl acetate in petroleum ether as the eluent provided 1.2 g (81%) of MN-S1 as a light yellow solid.

[00775] Step 6 (MR-Sl):

[00776] t-Butyl hypochlorite (0.98 mL, 8.59 mmol) was added to a stirred solution of t-butyl carbamate (1 g, 2.86 mmol) in 1-propanol (11.5 mL) and 0.4N aqueous sodium hydroxide (349 mg in 22 mL of water) at 15°C and the mixture was stirred for 15 minutes. A solution of DHQ2PHAL (111 mg, 0.143 mmol) in 1-propanol (11.5 mL) was added, followed by a solution of MN-S1 (650 mg, 2.86 mmol) in 1-propanol (11.5 mL ). Finally potassium osmatedihydrate (42 mg, 0.114 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60-120 mesh) and using 20% ethyl acetate in petroleum ether as the eluent provided 400 mg (38.8%) of MR-S1 as a white solid.

[00777] Step 7 (MR-S2):

[00778] Potassium-t-butoxide (497 mg, 4.44 mmol) was added to a stirred solution of MR-S1 (800 mg, 2.22 mmol) in tetrahydrofuran (10 mL) at 0°C and the mixture was stirred for 1 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 490 mg (76.5%) of MR-S2 as a light yellow solid.

[00779] Step 8 (MR-S3):

[00780] A mixture of MR-S2 (490 mg, 1.70 mmol), 4-Bromo-1,2-diaminobenzene (318 mg, 1.70 mmol) and cesium fluoride (517 mg, 3.40 mmol) in 1,4-dioxane (10 mL) was purged with argon gas for 10 min in a sealed tube. Copper iodide (48 mg, 0.255 mmol) and 1,2-5 diaminocyclohexane (29 mg, 0.255 mmol) were added and the mixture was continuously purged for a further 10 minutes. The sealed tube was heated for 18 hours at 110 to 115°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2 to 3% methanol in chloroform as the eluent 10 provided 220 mg (31.2%) of MR-S3 as a brown solid.

[00781] Step 9 (Example 21):

[00782] Formamidine acetate (110 mg, 100.12 mmol) was added to a solution of MR-S3 (200 mg, 50.6 mmol) in acetonitrile (5 mL) and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was triturated with diethyl ether and dried to obtain 125 mg of Example 21 as a light brown solid.

[00783] Melting range: 265 to 269 °C; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1 H); 7.58 (d, 1H); 7.48 (d, 1H); 7.25-7.18 (m, 2H); 7.09 (d, 1 H); 6.72 (t, 1 H); 5.65 (q, 1H); 4.78 (t, 1H); 4.13 (q, 1H); 3.66 (t, 2H); 3.45 (t, 2H); 2.50 to 2.35 (m, 2H); MS = 403.1 (M+1); HPLC ~ 96.84%; Chiral HPLO99.40%.Example 22:3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)oxazolidin-2-one

[00784] Step 1 (MM-S1):

[00785] (R)-3-Hydroxy pyrrolidine (1.6 g, 18.30 mmol) was added to the stirred solution of 4-fluorobenzonitrile (1.5 g, 12.19 mmol) and potassium carbonate (1.68 g, 12.19 mmol) in dimethylformamide (20 mL) and the mixture was stirred overnight at 80°C. The reaction mass was filtered, washed with ethyl acetate and the filtrate was evaporated in vacuum. The mass was divided between water and ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using ethyl acetate in petroleum ether as the eluent provided 1.9 g of MM-S1 as a solid.

[00786] Step 2 (MM-S2):

[00787] Oxalylchloride (1.18 ml, 13.90 mmol) was added to a stirred solution of dry dimethylsulfoxide (1.87 ml, 27.80 mmol) in dichloromethane (20 ml), at -78°C and the mixture was stirred for 1 h at the same temperature. A solution of MM-S1 (1.1 g, 6.95 mmol) in dichloromethane was added dropwise at -78°C and the mixture was subsequently stirred for 2 h at the same temperature. Triethylamine (4.83 ml, 34.75 mmol) was added and the mixture was stirred for 30 min at room temperature. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using ethyl acetate in petroleum ether as the eluent provided 930 mg of MM-S2 as a solid.

[00788] Step 3 (MM-S3):

[00789] Diethylamino sulfurtrifluoride (1.95 ml, 13.44 mmol) was added to a solution of MM-S2 (930 mg, 6.4 mmol) in dichloromethane (20 ml), at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with ice water and the separated organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 900 mg of MM-S3 as a solid.

[00790] Step 4 (MM-S4):

[00791] Diisobutyl aluminum hydride in toluene (1 M; 12.5 ml, 12.50 mmol) was slowly added to a stirred solution of MN-S4 (1.3 g, 6.25 mmol) in tetrahydrofuran at -10 °C. The reaction mass was stirred for 6 h at room temperature. The reaction was quenched with ammonium chloride solution, filtered, and the filtrate was extracted into ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 900 mg of MN-S4 as a yellow liquid.

[00792] Step 5(MN-Sl):

[00793] N-Butyl lithium in hexane (2 M; 1.4 ml, 2.8 mmol) was added to a stirred solution of triphenylphosphonium methylbromide (1 g, 2.82 mmol) in tetrahydrofuran (20 ml) , at 0 °C and a solution stirred for 1 hour. A solution of MN-S4 (300 mg, 1.42 mmol) in tetrahydrofuran (10 ml) was added dropwise at -10°C and the solution was stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The organic layer was washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 5% ethyl acetate in petroleum ether as the eluent provided 150 mg of MN-S1 as a yellow liquid.

[00794] Step 6(MR-Sl):

[00795] Tert-Butyl hypochloride (1.24 mL, 11.56 mmol) was added to a stirred solution of t-butyl carbamate (1.33 g, 11.41 mmol) in 1-propanol (25 mL) and 0.4N aqueous sodium hydroxide (326 mg in 24 mL of water) at 0°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (140 mg, 0.0189 mmol) in 1-propanol (25 mL) was added, followed by MN-S1 (6 mg, 3.79 mmol) in 1-propanol (25 mL). Finally potassium phosphate dihydrate (5.5 mg, 0.0151 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 40% ethyl acetate in petroleum ether as the eluent provided 500 mg of MR-S1 as a white solid.

[00796] Step 7 (MR-S2):

[00797] Potassium-t-butoxide (327 mg, 2.92 mmol) was added to a stirred solution of MR-S1 (500 mg, 1.46 mmol) in tetrahydrofuran (50 mL) at 0°C and the The mixture was stirred for 8 h at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting mass was extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and evaporated to obtain the crude intermediate. Purification by column over neutral alumina and using 30% ethyl acetate in petroleum ether as the eluent provided 200 mg of MR-S2 as a yellow solid.

[00798] Step 8 (MR-S3):

[00799] A mixture of MR-S2 (200 mg, 0.543 mmol), 4-bromo-1,2-diaminobenzene (108 mg, 0.597 mmol), cesium fluoride (165 mg, 1.08 mmol) and copper iodide (51 mg, 0.271 mmol) in 1,4-30 dioxane (10 mL) was purged with argon gas for 30 minutes. 1,2-diaminocyclohexane (9.2 mg, 0.08 mmol) was added and the mixture was continuously purged for a further 10 minutes. The reaction was stirred for 36 hours at 110 to 115°C in a sealed tube. The reaction mixture was filtered through celite, washed with dioxane and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1% methanol in chloroform as the eluent provided 80 mg of MR-S3 as a brown solid.

[00800] Step 9 (Example 22):

[00801] MR-S3 (80 mg, 0.213 mmol) was stirred in formic acid (5 mL) for 2 h at 80 to 90 ° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was successively washed with saturated bicarbonate solution, brine; The combined organic layers were concentrated under reduced pressure to obtain the crude product. Purification by preparative TLC and using 4% methanol in chloroform as the eluent provided 30 mg of Example 22 as a yellow solid.

[00802] Melting range: 245 to 250 °C; 1H-NMR (400 MHz, DMSO-d6): δ 12.40 (d, 1 H); 8.13(d, 1H); 7.52 to 7.13 (m, 5H); 6.51 (t, 2H); 5.57 (t, 1 H); 4.76 (t, 1H); 4.09 (t, 1 H); 3.61 to 3.33 (DMSO moisture melt, 4 H); 2.48 to 2.40 (fused with DMSO, 2H); MS = 383.0 (M-1); HPLC ~ 92.07%.Example 23: (S)-2-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-5-(3,3-difluoropyrrolidin -1-yl)benzonitrile

[00803] Step 1 (MO-S1):

[00804] Potassium iodide (5.22 g, 31.47 mmol), N,N-Diisopropyl ethylamine (5.4 mL, 31.47 mmol) and 1,4-dibromo-2-butanol (3.7 mL, 31.47mmol) were added successively to a stirred solution of 5-Amino-2-bromobenzonitrile (3.1 g, 15.74 mmol) in toluene (50 mL). The reaction mixture was stirred at 90°C for 20 hours. The reaction mass was filtered, washed with ethyl acetate and the filtrate was successively washed with water, saline solution; dried over anhydrous sodium sulfate and evaporated in vacuum to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 24 to 25% ethyl acetate in petroleum ether as the eluent provided 2.45 g (58.47%) of MO-S1 as an brown solid.

[00805] Step 2 (MQ-Sl):

[00806] Oxalyl chloride (1.61 mL, 18.42 mmol) was added to a solution of dimethyl sulfoxide (2.62 30 mL, 36.84 mmol) in dichloromethane (50 mL) at -78°C and a solution was stirred for 30 minutes. A solution of MO-S1 (2.45 g, 9.21 mmol) in dichloromethane (20 mL) was slowly added over 10 min and the mixture was stirred for 1 h at -78 oC. Triethylamine (6.42 mL, 46.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 2.4 g (98.76%) of MQ-S1 as a brown solid.

[00807] Step 3 (MQ-S2):

[00808] Diethylamino sulfurtrifluoride (2.2 mL, 16.67 mmol) was added to a solution of MQ-S1 (2.4 g, 8.33 mmol) in dichloromethane (50 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was successively washed with aqueous sodium bicarbonate, water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 3% ethyl acetate in petroleum ether as the eluent afforded 1.8 g (75.63%) of MQ-S2 as a solid. completely white.

[00809] Step 4 (MQ-S3):

[00810] A solution of MQ-S2 (1.1 g, 3.85 mmol) and tri-n-butylvinyltin (1.4 mL, 4.81 mmol) in toluene (60 mL) was purged with hydrogen gas. argon for 5 minutes. Tetracis-(tri-phenyl-phosphine)-palladium (89 mg, 0.08 mmol) was added and the mixture was continuously purged for an additional 5 minutes. The reaction mass was heated in a sealed tube at 110 °C for 8 hours. The reaction mass was filtered over celite and washed with ethyl acetate. The combined filtrate and wash portion was concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent provided 900 mg (100%) of MQ-S3 as a colorless syrup.

[00811] Step 5 (MR-Sl):

[00812] T-Butylhypochlorite (1.32 mL, 11.59 mmol) was added to a stirred solution of t-butyl carbamate (1.35 g, 11.54 mmol) in 1-propanol (15.4 mL) and 0.4N aqueous sodium hydroxide (470 mg in 29.4 mL of water) at 10 to 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (150 mg, 0.19 mmol) in 1-propanol (15.4 mL) was added, followed by a solution of MQ-S3 (900 mg, 3.85 mmol) in 1-propanol (15.4 mL). Finally potassium osmatedihydrate (57 mg, 0.15 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 25 to 26% ethyl acetate in petroleum ether as the eluent provided 510 mg (36.1%) of MR-S1 as a white solid .

[00813] Step 6 (MR-S2):

[00814] Thionyl chloride (0.8 ml, 10.90 mmol) was added to a solution of MR-S1 (500 mg, 1.36 mmol) in tetrahydrofuran (20 ml), at 0 °C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The solvent was evaporated in vacuum and the resulting mass was divided between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate, which was triturated with petroleum ether and dried to obtain 390 mg (97.99%) of MR-S2 as a light yellow solid.

[00815] Step 7 (MR-S3):

[00816] A mixture of MR-S2 (390 mg, 1.33 mmol), 4-Bromo-1,2-diaminobenzene (300 mg, 1.60 mmol) and cesium fluoride (404 mg, 2.66 mmol) in 1,4-dioxane (15 ml), it was purged with argon gas for 15 minutes. Copper iodide (38 mg, 0.20 mmol) and 1,2-diaminocyclohexane (23 mg, 0.20 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction mixture was heated in a sealed tube for 18 hours at 110 to 115°C. The reaction mass was filtered through celite, washed with dichloromethane and the filtrate was concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1 to 2% methanol in dichloromethane as the eluent provided 360 mg (67.84%) of MR-S3 as a light brown solid.

[00817] Step 8 (Example 23):

[00818] Formamidine acetate (365 mg, 3.51 mmol) was added to a solution of MR-S3 (350 mg, 0.88 mmol) in acetonitrile (10 ml), and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by trituration with diethyl ether:dichloromethane:ethyl acetate (8:1:1) provided 200 mg (55.40%) of Example 23 as a brown solid. Melting range: 156.2 to 159.8 °C; 1H-NMR (400 MHz, DMSO-d6): δ 7.97 (s, 1 H); 7.65 (s, 1H); 7.55 (d, 1H); 7.35 (d, 1H); 7.26 (fused with CDCI3, 1 H); 6.65 (d, 2H); 5.81 (t, 1H); 4.91 (t, 1 H); 4.26 (q, 1H); 3.60(t, 2H); 3.48 (t, 2H); 2.53 to 2.43 (m, 2H); MS = 410.0 (M+1); HPLC ~ 97.77%; Chiral HPLC ~ 98.59%.Example 24: (S)-5-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-2-(3,3- difluoropyrrolidin-1-yl)benzonitrile

[00819] Step 1 (MP-S1):

[00820] Potassium carbonate (2.07 g, 15 mmol) was added to a solution of 3-hydroxypyrrolidine hydrochloride (0.617 g, 5 mmol) in dimethylformamide (20 mL), followed by 2-flouro-5-bromo- benzonitrile (1 g, 5 mmol) and the mixture was stirred in a sealed tube at 90° for 20 hours. The reaction mass was cooled to room temperature and the solvent was evaporated under vacuum. The remaining mass was dissolved in ethyl acetate, washed with water, saline; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 1.3 g of MP-S1 as the red gummy liquid.

[00821] Step 2 (MQ-Sl):

[00822] Dry dimethylsulfoxide (1.39 mL, 20 mmol) was added dropwise to a stirred solution of Oxalylchloride (0.84 mL, 10 mol) in dichloromethane (30 mL) at -78°C and the mixture was stirred for 20 min at the same temperature. A solution of MP-S1 (1.31 g, 4.9 mmol) in diclomethane (20 mL) was added and the reaction mixture was stirred for 1 h at -78 oC. Triethylamine (3.25 mL, 25 mmol) was added and the mixture was stirred for 15 min at -78°C, then at room temperature and further stirred for 45 minutes. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane and the combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1.34 g of MQ-S2 as an orange solid.

[00823] Step 3 (MQ-S2):

[00824] Diethylamino sulfurtrifluoride (1.24 mL, 4.6 mmol) was added to a solution of MQ-S1 (8 g, 35 mmol) in dichloromethane (23 mL) at 0 °C. The reaction mass was warmed to room temperature and stirred for 90 minutes. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was successively washed with aqueous sodium bicarbonate, water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 0 to 5% ethyl acetate in petroleum ether as the eluent provided 960 mg of MQ-S2 as a white solid.

[00825] Step 4 (MQ-S3):

[00826] A mixture of MQ-S2 (0.84 g, 2.9 mmol), tri-n-butylvinyltin (1.1 mL, 3.62 mmol) in toluene was purged for 5 min using argon gas. Tetracis(triphenylphosphine) palladium (0.067 g, 0.02 mmol) was added and the mixture was continuously purged for 5 min. The mixture was then refluxed for 8 hours. The reaction mixture was filtered over a celite pad, washed with ethyl acetate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 0 to 2% ethyl acetate in petroleum ether as the eluent provided 700 mg of MQ-S3 as a colorless liquid.

[00827] Step 5(MR-Sl):

[00828] T-Butylhypochlorite (1.023 mL, 8.99 mmol) was added to a stirred solution of t-butyl carbamate (1.049 g, 8.97 mmol) in 1-propanol (12 mL) and aqueous sodium hydroxide at 0.4 N (0.364 g in 22.8 mL of water) at 15°C and the mixture was stirred for 15 min. A solution of (DHQ)2PHAL (116 mg, 0.14 mmol) in 1-propanol (12 mL) was added and the mixture was stirred for 5 minutes. A solution of MQ-S3 (0.7 g, 2.99 mmol) in 1-propanol (12 mL) was added and the mixture was stirred for 5 minutes. Finally potassium osmatedihydrate (44 mg, 0.11 mmol) was added and the reaction mixture was stirred for 5 min at 15°C, warmed to room temperature and then stirred for 5 minutes. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Another similar batch was maintained and purification of both batches by column chromatography on silica gel (60 to 120 mesh) and using 0 to 28% ethyl acetate in petroleum ether as the eluent provided 380 mg of MR-S1 as a yellow liquid.

[00829] Step 6 (MR-S2):

[00830] A solution of MR-S1 (0.4 g, 1.08 mmol) in tetrahydrofuran (10 mL) was added to a solution of potassium t-butoxide (0.4 g, 1.08 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was acidified with acetic acid and the PH value was adjusted to pH~6. The mixture was extracted with ethyl acetate and the separated organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 346 mg of MR-S2 as a brown gummy solid.

[00831] Step 7 (MR-S3):

[00832] A mixture of MR-S2 (0.406 g, 1.38 mmol), 1,2-diamino-4-bromobenzene (261 mg, 1.38 mmol) and cesium fluoride (0.409 g, 2.7 mmol) in 1,4-dioxane (25 ml), it was purged with argon gas for 10 minutes. Copper iodide (131 mg, 0.69 mmol) was added and the reaction mixture was continuously purged for an additional 10 minutes. Finally 1,2-diaminocyclohexane (0.02 ml, 0.17 mmol) was added and the mixture was purged again for 10 minutes. The reaction mass was stirred at 110 to 115qC in a sealed tube for 14 hours. The reaction mixture was cooled to room temperature, filtered through celite, washed with 10% methanol in dichloromethane and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 0 to 1.6% methanol in chloroform as the eluent provided 269 mg of MR-S3 as a brown gummy solid.

[00833] Step 8 (Example 24):

[00834] Formamidine acetate (350 mg, 3 mmol) was added to a solution of MR-S3 (269 mg, 0.67 mmol) in acetonitrile (15 ml), and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification was done by preparative HPLC using the following conditions: Column: Packed C-18 (250*25mm*10 μ); Mobile phase: A: acetonitrile; B: 10 mM ammonium acetate (50:50); flow rate: 25 mL/min; diluent used: ACN+MeOH+mobile phase; method: gradient. The corresponding fractions were evaporated in vacuum and the resulting mass was divided between water and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 69 mg of Example 24 as a brown solid.

[00835] 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1 H); 7.64 to 7.47(m, 4H); 7.24 (d, 1H); 6.79 (d, 1H); 5.68 (t, 1H); 4.78 (t, 1H); 4.14 (t, 1H); 3.90 (t, 2H); 3.70 (t, 2H); 2.50 to 2.43 (fused with DMSO, 2H); MS = 410.0 (M+1); HPLC ~ 98.07%; Chiral HPLC ~ 94.81%. Example 25: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(4,4-difluorocyclohexyl)-2-fluorophenyl)oxazolidin-2-one

[00836] Step 1 (MS-S1):

[00837] 3-Fluoro-1-bromobenzene (1 mL, 11.6 mmol) was added to a mixture of magnesium (1.2 g, 48.0 mmol) and a small amount (tip of a spatula) of iodine in dry tetrahydrofuran (20 mL) under organic atmosphere. After the color changed from bluish to colorless remaining 3-fluoro-1-bromobenzene (3.3 mL, 38.4 mmol) was added and the mixture was stirred for 2 h at 50°C. 1,4-cyclohexane monoethylene ketal (7.2 g, 50 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate and the separated organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 15% ethyl acetate in petroleum ether as the eluent provided 4.0 g (50%) of MS-S1 as a white solid.

[00838] Step 2 (MS-S2):

[00839] A mixture of MS-S1 (4.0 g, 15.8 mmol) and trifluoroacetic acid (40 mL) was stirred at 80oC for 1 hour. The mixture was evaporated in vacuum, subsequently basified with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 4 g of intermediate MS-S2 as a yellow liquid, subsequently used without any purification.

[00840] Step 3 (MS-S3):

[00841] A solution of MS-S2 (4 g, 21.0 mmol) in absolute ethanol (100 mL) was hydrogenated over 10% Pd-C in a Parr apparatus (4.92 kg/cm2 (70 psi)) for 5 hours. The reaction mass was filtered through celite and washed with ethanol. The combined filtrate and wash portion was concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 7% ethyl acetate in petroleum ether as the eluent provided 2.7 g (66%) of MS-S3 as a colorless liquid.

[00842] Step 4 (MS-S4):

[00843] Oxalyl chloride (7.1 g, 56.2 mmol) and aluminum chloride (7.5 g, 56.2 mmol) were successively added to a solution of MS-S3 (2.7 g, 14.0 mmol) in dichloromethane (60 mL) at -30°C and the mixture was stirred for 2 h at room temperature. Methanol (20 ml) was added at -30°C and the reaction mixture was warmed to room temperature and stirred for 12 h at this temperature. The reaction was quenched with ice water, basified with saturated sodium bicarbonate and extracted with dichloromethane. The separated organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by column chromatography on silica gel (60 to 120 mesh) and using 15% ethyl acetate in petroleum ether as the eluent provided 4.0 g (50%) of MS-S4 as a not entirely white solid. .

[00844] Step 5 (MS-S5):

[00845] Diethylamino sulfurtrifluoride (3.35 ml, 24.1 mmol) was added to a solution of MS-S4 (2.0 g, 8.0 mmol) in dichloromethane (30 ml), at 0°C and at The mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 2 g, (91%) of MS-S5 as a colorless oil, subsequently used without any purification.

[00846] Step 6 (MS-S6):

[00847] A solution of MS-S5 (2 g, 7.3 mmol) in tetrahydrofuran (20 ml) was added to the suspension of lithium aluminum hydride in hexane (279 mg, 7.3 mmol) at 0 °C and the mixture was stirred for 1 h at room temperature. The reaction was quenched with saturated sodium sulfate solution and filtered. The filtrate was partitioned between water and ethyl acetate. The separated organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to provide 2 g of MS-S6 as a colorless liquid, subsequently used without any purification.

[00848] Step 7(MU-Sl):

[00849] 2-lodoxybenzoic acid (6.8 g, 24.5 mmol) was added to a solution of MS-S6 (2 g, 8.1 mmol) in dichloromethane (30 ml), and dimethyl sulfoxide (10 ml), and the mixture was stirred for 8 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash portion was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent provided 1.0 g (50%) of MU-S1 as a pale yellow solid.

[00850] Step 8 (MU-S2):

[00851] N-Butyl lithium (2.2 M; 3.7 ml, 8.2 mmol) was added to a stirred solution of triphenylphosphonium methylbromide (2.95 g, 8.2 mmol) in tetrahydrofuran (10 ml), at -30°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of MU-S1 (1.0 g, 4.1 mmol) in tetrahydrofuran (10 ml) was added dropwise at -30°C. The temperature was warmed to room temperature and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 1% ethyl acetate in petroleum ether as the eluent provided 800 mg (80%) of MU-S2 as a pale yellow solid.

[00852] Step 9 (MU-S3):

[00853] T-Butylhypochlorite (1.14 ml, 10.0 mmol) was added to a stirred solution of t-butyl carbamate (1.17 g, 9.8 mmol) in 1-propanol (13.2 ml) , and 0.4N aqueous sodium hydroxide (406 mg in 25.4 mL of water) at 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (128 mg, 0.16 mmol) in 1-propanol (13.2 ml) was added followed by a solution of MU-S2 (800 mg, 3.2 mmol) in 1-propanol (13.2 mL). Finally potassium osmatedihydrate (49 mg, 0.12 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfate solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 18 to 20% ethyl acetate in petroleum ether as the eluent provided 500 mg (40%) of MU-S3 as a white solid.

[00854] Step 10 (MU-S4):

[00855] Potassium-t-butoxide (450 mg, 4.0 mmol) was added in 2 portions to a stirred solution of MUSS (500 mg, 1.3 mmol) in tetrahydrofuran (20 ml), at 0°C over 15 min and the mixture was stirred for 2 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 300 mg (75%) of MU-S4 as a brown solid.

[00856] Step 11 (MU-S5):

[00857] A mixture of MU-S4 (300 mg, 1.0 mmol), 4-Bromo-1,2-diaminobenzene (157 mg, 1.0 mmol) and cesium fluoride (297 mg, 2.0 mmol) in 1,4-dioxane (40 mL) was purged with argon gas for 30 minutes. Copper iodide (28 mg, 0.38 mmol) and 1,2-diaminocyclohexane (17 mg, 0.385 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction was heated in a sealed tube for 16 h at 105 to 110°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1.5 to 2% methanol in dichloromethane as the eluent provided 200 mg (49%) of MU-S5 as a brown solid.

[00858] Step 12 (Example 25):

[00859] Formamidine acetate (150 mg, 1.48 mmol) was added to a solution of MU-S5 (200 mg, 0.49 mmol) in acetonitrile (20 mL) and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by column chromatography over neutral alumina and using 2 to 2.5% methanol in dichloromethane as the eluent to provide 100 mg (49%) of Example 25 as a non-white solid. Melting range: 251.9 to 253.7°C; 1H-NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1 H); 8.17 (s, 1H); 7.62 (d, 1H); 7.48 (d, 1H); 7.37 to 7.25 (m, 2H); 7.11 to 7.03 (m, 2H); 5.91 (q, 1H); 4.84 (t, 1H); 4.24 (q, 1H); 2.61 (t, 1H); 2.04 to 1.77 (m, 6H); 1.63 to 1.54 (m, 2H); MS = 416.08 (M+1); HPLC ~ 96.71%. Example 26: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(4,4-difluorocyclohexyl)-3-fluorophenyl)oxazolidin-2-one

[00860] Step 1 MT-S1):

[00861] Boranomethyl sulfide in ether (5.0 M; 38.3 mL, 191.8 mmol) was added to a solution of 4-bromo-3-fluorobenzoic acid (21.0 g, 95.9 mmol) in dried tetrahydrofuran (250 mL) at 0°C and the reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate, and the combined organic layers were washed with water, brine; dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum to obtain 18 g (91.6%) of MT-51 as a colorless liquid, subsequently used without any purification.

[00862] Step 2 (MT-S2):

[00863] Tert-butylmethylsilyl chloride (16.5 g, 105.3 mmol) and imidazole (11.95 g, 175.6 mmol) were added to a solution of MT-51 (18 g, 87.8 mmol) in dimethylformamide (200 ml) at -10°C and the reaction mixture was stirred at room temperature for 48 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under vacuum to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2 to 5% ethyl acetate in petroleum ether as the eluent provided 20 g (71.4%) of MT-S2 as a colorless liquid .

[00864] Step 3 (MT-S3):

[00865] N-Butyl lithium in hexane (2.2 M; 56.6 ml, 125.4 mmol) was added to a solution of MT-52 (20 g, 62.7 mmol) in dry tetrahydrofuran (200 ml), at -78°C and the mixture was stirred for 30 minutes. A solution of 1,4-cyclohexane monoethylene ketal (9.8 g, 62.7 mmol) in dry tetrahydrofuran (50 ml) at -78°C was added and the temperature was warmed to 0°C. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and the combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under vacuum to obtain 18 g of the crude intermediate MT-S3 as an oily yellow liquid, subsequently used without any purification.

[00866] Step 4 (MT-S4):

[00867] A mixture of MT-S3 (15.0 g, 37.87 mmol), 6N HCl (100 ml) in 1,4-dioxane (100 ml) was stirred at 80°C for 3 hours. The reaction was cooled to room temperature and the solvent was vaporized under vacuum. The remaining mass was diluted with water, extracted with ethyl acetate and the combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under vacuum to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 27% ethyl acetate in petroleum ether as the eluent provided 4 g of MT-S4 as an oily yellow liquid.

[00868] Step 5 (MT-S5):

[00869] To a solution of MT-S4 (4.0 g, 18.18 mmol) in dichloromethane (40 ml), pyridine (7.32 ml, 90.9 mmol) was added at 0°C and the mixture was stirred for 10 minutes. Acetyl chloride (1.93 ml, 27.27 mmol) was added and the reaction mixture was stirred for 2 h at room temperature. The reaction was cooled to 0oC and then quenched with 2N hydrochloric acid. The organic layer was separated, washed with water, brine; dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under vacuum to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 15% ethyl acetate in petroleum ether as the eluent provided 2 g (42%) of MT-S5 as an oily yellow liquid.

[00870] Step 6 (MT-S6):

[00871] A solution of MT-S5 (2 g, 7.63 mmol) in absolute ethanol (40 ml) was hydrogenated over 10% Pd-C in a Parr apparatus 2.81 kg/cm2 (40 psi) for 3 hours. The reaction mass was filtered through celite and washed with ethanol. The combined filtrates were concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 15% ethyl acetate in petroleum ether as the eluent afforded 1.7 g of MT-S6 (84.5%) as a solid. completely white.

[00872] Step 7 (MT-S7):

[00873] Diethylamino sulfurtrifluoride (2.65 ml, 19.3 mmol) was added to a solution of MT-S6 (1.7 g, 6.4 mmol) in dichloromethane (30 ml), at 0°C and at The mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 4% ethyl acetate in petroleum ether as the eluent provided 1.5 g (81%) of MT-S7 as a brown oily liquid.

[00874] Step 8 (MT-S8):

[00875] Lithium hydroxide monohydride (758.5 mg, 15.73 mmol) was added to a solution of MT-S7 (1.5 g, 5.24 mmol) in tetrahydrofuran: water (1 ml: 1 .20 ml) at room temperature and the mixture was stirred for 5 hours. The organic solvent was evaporated under vacuum. The resulting aqueous layer was cooled to 0°C and acidified with 1N hydrochloric acid and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 1.2 g (93%) of MT-S8 as a yellow liquid, subsequently used without any purification.

[00876] Step 9 (MU-Sl):

[00877] 2-lodoxy benzoic acid (4.13 mg, 14.75 mmol) was added to a solution of MT-S8 (1.2 g, 4.9 mmol) in dichloromethane (30 mL) and dimethyl sulfoxide (4 mL ) and the mixture was stirred for 5 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrates were successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 5% ethyl acetate in petroleum ether as the eluent provided 900 mg (75.6%) of MU-S1 as a yellow solid.

[00878] Step 10 (MU-S2):

[00879] N-Butyllithium (2.2 M; 3.4 mL, 7.44 mmol) was added to a stirred solution of triphenylphosphonium methylbromide (2.65 g, 7.44 mmol) in tetrahydrofuran (10 mL ) at -60°C and the mixture was stirred for 30 min at 0 to 5°C. A solution of MU-S1 (900 mg, 3.72 mmol) in tetrahydrofuran (10 mL) was added dropwise at -30oC. The mass temperature was warmed to room temperature and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2% ethyl acetate in petroleum ether as the eluent provided 680 mg (75.7%) of MU-S2 as a pale yellow solid.

[00880] Step 11 (MU-S3):

[00881] T-Butylhypochlorite (97 mL, 8.52 mmol) was added to a stirred solution of t-butyl carbamate (994.5 mg, 8.5 mmol) in 1-propanol (11.2 mL) and hydroxide of 0.4N aqueous sodium (345.7 mg in 21.3 mL of water, 8.64 mmol) at 10 to 15°C and the mixture was stirred for 15 minutes. A solution of (DHQ)2PHAL (110.03 mg, 0.14 mmol) in 1-propanol (11.2 mL) was added, followed by a solution of MU-S2 (680 mg, 2.8 mmol) in 1 -propanol (11.2 mL). Finally potassium osmatedihydrate (41.7 mg, 0.11 mmol) was added and the reaction mixture was stirred for 15 min at room temperature. The reaction was quenched with saturated sodium sulfite solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (100 to 200 mesh) and using 16 to 20% ethyl acetate in petroleum ether as the eluent afforded 500 mg (47.6%) of MU-S3 as a solid. completely white.

[00882] Step 12 (MU-S4):

[00883] Potassium T-butoxide (450 mg, 4.02 mmol) was slowly added in 2 batches over 15 min to a stirred solution of MU-S3 (500 mg, 1.34 mmol) in tetrahydrofuran (20 ml ), at 0°C and a solution was stirred for 3 h at room temperature. The reaction mixture was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 300 mg (75%) of MU-S4 as a yellow solid, subsequently used without any purification.

[00884] Step 13(MU-S5):

[00885] A mixture of MU-S4 (300 mg, 1.0 mmol), 4-Bromo-1,2-diaminobenzene (187 mg, 1.0 mmol) and cesium fluoride (305 mg, 2.0 mmol) in 1,4-dioxane (40 ml), it was purged with argon gas for 30 minutes. Copper iodide (28.6 mg, 0.15 mmol) and 1,2-diaminocyclohexane (17 mg, 0.15 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction was heated in a sealed tube for 24 h at 105 to 110°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1.3 to 2% methanol in chloroform as the eluent provided 200 mg (49%) of MU-S5 as a brown solid.

[00886] Step 14 (Example 26):

[00887] Formamidine acetate (154.07 mg, 1.48 mol) was added to a solution of MU-S5 (200 mg, 0.49 mmol) in acetonitrile (20 ml), and the mixture was refluxed for 2 hours . The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by washing with ether and evaporation of the solvent under vacuum provided 130 mg (63%) of Example 26 as an off-white solid.

[00888] Melting range: 270 to 273.5 °C; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1 H); 7.61 (d, 1H); 7.56 to 7.43 (m, 1 H); 7.36 to 7.21 (m, 3H); 5.75 (q, 1H); 4.80 (t, 1 H); 4.15 (q, 1 H); 2.89 (t, 1H); 2.04 to 1.60 (m, 8H); MS = 416.2 (M+1); HPLC ~ 99.16%: Chiral HPLC ~ 99.60%. Example 27: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(4,4-difluorocyclohexyl)phenyl)oxazolidin-2-one

[00889] Step 1 (MV-S1):

[00890] sodium borohydride (0.54 g, 14.36 mmol) was added to a solution of 4-phenylcyclohexanone (5.0 g, 28.73 mmol) in ethanol (50 ml), at room temperature and a solution was stirred for 30 minutes. The organic solvent was evaporated, ammonium chloride solution was added and the mixture was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and the solvent was evaporated to obtain 5.0 g of MV-S1 as a white solid, subsequently used without any purification.

[00891] Step 2 (MV-S2):

[00892] Tetrabutylammonium hydrogen sulfate (1.42 g, 4.21 mmol) and dimethyl sulfate (14.15 g, 112.35 mmol) were added to a solution of MV-S1 (5.0 g, 28.08 mmol) in aqueous sodium hydroxide (50%):toluene (1:1; 100 ml), and the mixture was stirred at 80°C for 48 hours. The reaction mixture was diluted with water, acidified by hydrochloric acid (10%) and extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and the solvent was evaporated to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 2 to 4% ethyl acetate in petroleum ether as the eluent provided 4.0 g of MV-S3 as a colorless oil.

[00893] Step 3 (MV-S3):

[00894] Ethylchlorine oxalate (7.16 ml, 63.15 mmol) and aluminum chloride (8.42 g, 63.15 mmol) were added to a solution of MV-S2 (2.0 g, 13.33 mmol) in dichloromethane (60 ml) at -20°C. The mixture was stirred for 1 h, warmed to room temperature and then stirred for 2 hours. The reaction was quenched with saturated sodium hydrogen carbonate solution at 0oC, filtered and washed with excess ethyl acetate (200 ml). The organic layer was separated, washed with water, brine; dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 3.0 g MV-S3 as a brown liquid, subsequently used without any purification.

[00895] Step 4 (MV-S4):

[00896] Hydroxylamine hydrochloride (1.44 g, 20.68 mmol) and sodium acetate (1.69 g, 20.68 mmol) were added to a solution of MV-S3 (2.5 g, 10 mmol) in ethanol (30 ml), and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to obtain the crude intermediate. The mass was suspended in water and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and evaporated to obtain 3.1 g of MV-S4 as a colorless liquid, subsequently used without further purification.

[00897] Step 5 (MV-S5):

[00898] MV-S4 (3.1g, 10.16 mmol) in absolute ethanol was hydrogenated over 10% Pd-C (0.62g, 20%) in a Parr apparatus (5.62 kg/cm2 (80 psi) ) at room temperature for 12 hours. The reaction mixture was filtered through celite and the solvent was evaporated to obtain 3.0 g of MV-S5 as a colorless liquid, subsequently used without any purification.

[00899] Step 6 (MV-S6):

[00900] Boc anhydride (2.23 g, 10.3 mmol) was added to a solution of MV-S5 (3.0 g, 10.30 mmol) and Triethylamine (1.6 mL, 12.37 mmol) in dichloromethane (30 mL), and the mixture was stirred for 12 h at room temperature. The reaction mixture was washed with water (30 mL) and extracted with dichloromethane (3x50 mL). The combined organic layer was washed with brine (20 ml); dried over anhydrous sodium sulfate and the solvent was evaporated to obtain 2.9 g of MV-S6 as a brown oil, subsequently used without any purification.

[00901] Step 7 (MV-S7):

[00902] Sodium borohydride (0.82 g, 21.48 mmol) was added to a solution of MV-S6 (2.1 g, 5.37 mmol) in ethanol (30 mL) at room temperature and the mixture was stirred at 50oC for 3 hours. The solvent was evaporated under reduced pressure and saturated ammonium hydrochloride solution (25 mL) was added. The mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine; the solvent was evaporated to provide 1.5 g of MV-S7 as a gummy mass, subsequently used without any purification.

[00903] Step 8 (MV-S8):

[00904] Thionyl chloride (2.5 mL, 34.38 mmol) was added to a solution of MV-S7 (1.5 g, 4.29 mmol) in tetrahydrofuran (20 mL) at 0°C. The reaction mixture was warmed to room temperature and then stirred for 12 hours. The solvent was evaporated and saturated sodium hydrogen carbonate solution (10 mL) was added. The mixture was extracted with chloroform (3x25 mL) and the combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1.0 g of MV-S8 as a non-white solid, subsequently used without further purification.

[00905] Step 9 (MV-S9):

[00906] A mixture of MV-S8 (1 g, 3.63 mmol), 1,2-diamino4-bromobenzene (0.74 g, 3.99 mmol), cesium fluoride (1.1 g, 7.26 mmol) and copper iodide (0.1 g, 0.54 mmol) in 1,4-dioxane (15 mL) was purged with argon gas for 15 minutes. 1,2-diaminocyclohexane (61 mg, 0.22 mmol) was added and the reaction mixture was continuously purged for an additional 15 minutes. The reaction mixture was stirred in a sealed tube for 24 h at 120 °C. The reaction mixture was filtered through celite, washed with dioxane and the solvent was evaporated under reduced pressure. Purification by column chromatography over neutral alumina and using 3% methanol in chloroform as the eluent provided 1 g of MV-S9 as a light brown solid.

[00907] Step 10 (MV-Sl0):

[00908] A solution of MV-S9 (1.1 g, 2.62 mmol) in formic acid (10 mL) was stirred for 1 h at 90°C. The reaction mixture was concentrated under reduced pressure and the resulting mass was basified with saturated sodium bicarbonate solution and extracted with chloroform. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude intermediate. The mass was triturated with n-pentane and dried to obtain 1 g of MV-S10.

[00909] Step 11 (MV-S11):

[00910] A solution of 18-crown-6-ether (4.46 g, 16.87 mmol) saturated with potassium iodide in dry dichloromethane (30 mL) was added to a solution of MV-S10 (1.1 g , 2.81 mmol) in dichloromethane (10 mL). The mixture was cooled to -30°C, boron tribromide (0.8 mL, 8.43 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with sodium bicarbonate solution, diluted with water and extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and evaporated to obtain the crude intermediate. Purification over neutral alumina and using 3 to 4% methanol in chloroform as the eluent provided 450 mg of MV-S11.

[00911] Step 12(MV-Sl2):

[00912] A solution of MV-S11 (0.4 g, 1.06 mmol) in dichloromethane (20 mL) was added to the suspension of 2-lodoxybenzoic acid (0.89 g, 3.18 mmol) in dimethyl sulfoxide (7 mL) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, washed with saturated sodium bicarbonate solution, water, saline; dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to obtain 300 mg of MV-S12 as a not entirely white solid. Purification by preparative TLC and using 4% methanol in chloroform as the eluent provided 50 mg of MV-S12 as a non-white solid.

[00913] Step 13 (Example 27):

[00914] Diethylaminosulfur trifluoride (0.25 g, 0.31 ml, 1.6 mmol) was added to a solution of MV-S12 (0.15 g, 0.4 mmol) in dichloromethane (5 ml), at 0°C and the mixture was refluxed for 48 hours. The reaction mixture was quenched with ice, basified with saturated bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and evaporated to provide 140 mg of the crude compound as a brown solid. Purification was done by preparative HPLC using the following conditions: Column: Zodiacsil 220x50 mm 10μ, Mobile phase: 0.01% ammonium carbonate in methanol T/%B: 0/50, 3/50, 20/90; flow rate: 20 mL/min, UV: 210nm, diluents used: methanol, acetonitrile. The corresponding fractions were concentrated under reduced pressure and partitioned between water and chloroform. The separated organic layer was washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 20 mg of Example 27 as a light brown solid.

[00915] 1H-NMR (400 MHz, CDCI3): δ 7.98 (s, 1 H), 7.70 (s, 1 H), 7.52 (s, 1 H), 7.21 to 7, 1 (Fused with CDCI3, 4 H), 5.45-5.41 (q, 1 H), 4.81 (t, 1 H), 4.25-4.22 (q, 1 H), 2, 53 (d, 1 H), 2.17 to 2.02 (m, 2 H), 1.86 to 1.25 (m, 7H): MS = 398.1 (M+1); HPLC ~ 98.36%.Example 28:(S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3!3-difluorobutyl)-2,3-difluorophenyl)oxazolidin -2-one

[00916] Step 1 (MW-S1):

[00917] Sodium borohydride (5.3 g, 140.84 mmol) was slowly added in 3 equal portions (over 25 min) to a solution of 2,3-difluorobenzaldehyde (20 g, 140.84 mmol) in methanol ( 200 ml), at 0°C. Due to the exothermic reaction the temperature rose to -50°C. The reaction mixture was stirred for 1h and the solvent was evaporated under reduced pressure. ethyl acetate and then saturated ammonium chloride solution were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 20 g of MW-S1 as a colorless liquid, subsequently used without any purification.

[00918] Step 2 (MW-S2):

[00919] Phosphorus tribomide (6.7 ml, 69.44 mmol) was added dropwise over 15 min to a solution of MW-S1 (20 g, 138.88 mmol) in diethyl ether (250 ml), at -10°C. The reaction mixture was stirred for 1 hour. The reaction was quenched with saturated sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 20 g of MW-S2 as a light brown liquid, subsequently used without any purification.

[00920] Step 3 (MW-S3):

[00921] A mixture of MW-S3 (20 g, 96.618 mmol), 2,4-pentadione (9.6 ml, 96.618 mmol) and potassium carbonate (13.32 g, 96.618 mmol) in methanol (150 ml) , was refluxed for 20 hours. The solvent was filtered and evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 8 to 9% ethyl acetate in petroleum ether as the eluent provided 14 g of MW-S3 as a pale yellow liquid.

[00922] Step 4 (MW-S4):

[00923] A solution of MW-S3 (14 g, 76.086 mmol), ethylene glycol (11.8 ml, 190.21 mmol) and p-toluenesulfonic acid (2.1 g, 11.413 mmol) in toluene (200 ml) , was refluxed under Dean-Stark conditions for 3 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 6 to 8% ethyl acetate in petroleum ether as the eluent provided 14.0 g (86.75%) of MW-S4 as a solid pale yellow.

[00924] Step 5 (MW-S5):

[00925] N-Butyl lithium in hexane (2.5 M; 20.9 ml, 52.16 mmol) was added to a solution of MW-S4 (10.0 g, 43.47 mmol) in dry tetrahydrofuran (80 mL) at -78°C and the mixture was stirred for 1 h at the same temperature. The mass was slowly added to a solution of diethyl oxalate (9.53 g, 65.21 mmol) in tetrahydrofuran (60 mL) at -78°C over 15 minutes. The reaction mixture was stirred for 1 h, thereby raising the temperature to -60oC. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 14 g of MW-S5 as a yellow syrup, subsequently used without any purification.

[00926] Step 6 (MY-Sl):

[00927] Sodium acetate (7.97 g, 84.84 mmol) and Hydroxylamine hydrochloride (5.85 g, 84.85 mmol) were added successively to a solution of MW-S5 (14 g, 42.42 mmol ) in absolute ethanol (120 mL) and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 14 g of MY-S1 as a yellow syrup.

[00928] Step 7 (MY-S2):

[00929] A solution of MY-S1 (14 g, 40.57 mmol) in absolute ethanol (200 mL) was hydrogenated over 10% Pd-C in a Parr apparatus (5.62 kg/cm2 (80 psi)) for 20 hours. The reaction mass was filtered through celite and washed with ethanol. The combined filtrate and wash portion was concentrated under reduced pressure to obtain 14.0 g of MY-S2 as a pale brown syrup.

[00930] Step 8 (MY-S3):

[00931] Trifluoroacetic acid (150 mL) was added to a solution of MY-S2 (12.0 g, 36.25 mmol) in diclomethane (50 mL) at 0°C and the mixture was stirred for 3 h at room temperature . The solvent was evaporated in vacuum, the remaining mass was dissolved in hydrochloric acid (6N) and washed with 40% ethyl acetate in petroleum ether. The aqueous layer was basified with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 6.01 g of MY-S3 as a yellow liquid.

[00932] Step 9 (MY-S4):

[00933] Triethyl amine (8.9 mL, 63.15 mmol) and Di-tert-butyl dicarbonate (5 mL, 23.15 mmol) were added successively to a solution of MY-S3 (6.0 g, 21.052 mmol ) in dichloromethane (100 mL) and the mixture was stirred for 20 h at room temperature. Water was added and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 20% ethyl acetate in petroleum ether as the eluent provided 3.5 g of MY-S4 as a yellow sticky liquid.

[00934] Step 10 (MY-S5):

[00935] Diethylamino sulfurtrifluoride (1.6 ml, 11.75 mmol) was added to a solution of MY-S4 (1.50 g, 3.896 mmol) in dichloromethane (30 ml) at 0°C and the mixture was stirred for 52 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 10% ethyl acetate in petroleum ether as the eluent provided 800 mg of MY-S5 as a colorless oil.

[00936] Step 11 (MY-S6):

[00937] Sodium borohydride (150 mg, 3.93 mmol) was slowly added in 3 equal batches (about 15 min) to a solution of MY-S5 (80 mg, 1.965 mmol) in methanol (10 ml), at temperature environment. Due to the exothermic reaction the temperature rose to -50oC. The reaction mass was stirred for 1 hour. Ethyl acetate was added and the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 700 mg of MY-S6 as a white solid.

[00938] Step 12 (MAA-Sl):

[00939] Potassium T-butoxide (540 mg, 4.807 mmol) was added in 4 batches to a stirred solution of MY-S6 (700 mg, 1.92 mmol) in tetrahydrofuran (25 ml), at 0°C over 15 min and the mixture was stirred for 3 h at room temperature. The reaction was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 400 mg of MAA-S1 as a white solid.

[00940] Step 13 (MAA-S2):

[00941] A mixture of MAA-S1 (400 mg, 1.38 mmol), 4-Bromo-1,2-diaminobenzene (257 mg, 1.38 mmol) and cesium fluoride (417 mg, 2.75 mmol) in 1-4dioxane (20 ml), it was purged with argon gas for 30 minutes. Copper iodide (52 mg, 0.27 mmol) and 1,2-diaminocyclohexane (45 mg, 0.38 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction was heated in a sealed tube for 20 h at 105 to 110°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 1.5-2% methanol in dichloromethane as the eluent provided 250 mg of MAA-S2 as a brown solid.

[00942] Step 14 (Example 28):

[00943] Formamidine acetate (196 mg, 1.88 mmol) was added to a solution of MAA-S2 (250 mg, 0.63 mmol) in acetonitrile (20 ml), and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was triturated with diethyl ether and dried to obtain 150 mg of Example 28 as an off-white solid. Melting range: 191.8 to 196.3 °C; 1H-NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1 H); 8.19 (s, 1H); 7.62 (d, 1H); 7.57 to 7.44 (m, 1 H); 7.33 to 7.09 (m, 3H); 5.91 (q, 1H); 4.86 (t, 1H); 4.30 (q, 1H); 2.71 (t, 2H); 2.18 to 2.05 (m, 2H); 1.59 (t, 3H); MS =408.1 (M+1); HPLC ~ 97.51%. Example 29: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)-3-fluorophenyl)oxazolidin-2-one

[00944] Step 1 (MX-S1):

[00945] A mixture of 4-Bromo-2-Fluorobenzyl bromide (20 g, 74.65 mmol), 2,4-Pentadione (7.68 ml, 74.65 mmol) and potassium carbonate (10.32 g, 74.65 mmol) in methanol (200 ml), was refluxed for 16 hours. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 8 to 9% ethyl acetate in petroleum ether as the eluent provided 12 g (65.50%) of MX-S1 as a yellow solid pale.

[00946] Step 2 (MX-S2):

[00947] A solution of MX-S1 (10.75 g, 43.88 mmol), ethylene glycol (6.1 ml, 109.69 mmol) and p-toluenesulfonic acid (1.25 g, 6.55 mmol) in toluene (100 ml), it was refluxed under Dean-Stark conditions for 3 hours. The solvent was evaporated in vacuum and the resulting residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 6 to 8% ethyl acetate in petroleum ether as the eluent provided 11.0 g 10 (86.75%) of MX-S2 as a pale yellow solid.

[00948] Step 3 (MX-S3):

[00949] N-Butyllithium in hexane (2.2 M; 9.44 ml, 20.76 mmol) was added to a solution of MX-S2 (6.0 g, 20.76 mmol) in dry tetrahydrofuran ( 120 ml), at -78°C and the mixture was stirred for 1 h at the same temperature. The mixture was added to a solution of diethyl oxalate (5.53 g, 37.37 mmol) in tetrahydrofuran (120 ml) at -78°C over 15 minutes. The reaction mass was stirred for 1 h, when the temperature rose to -60°C. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 6.5g of MX-S3 as a yellow syrup, subsequently used without any purification.

[00950] Step 4 (MY-Sl):

[00951] Sodium acetate (3.44 g, 41.93 mmol) and Hydroxylamine Hydrochloride (2.91 g, 41.93 mmol) were added successively to a solution of MX-S3 (6.5 g, 20. 97 mmol) in absolute ethanol (65 ml), and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting residue was partitioned between water and ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 6.5 g of MY-S1 as a yellow syrup.

[00952] Step 5 (MY-S2):

[00953] A solution of MY-S1 (6.5 g, 20.0 mmol) in absolute ethanol (150 ml) was hydrogenated over 10% Pd-C in a Parr apparatus (5.62 kg/cm2 (80 psi )) for 20 hours. The reaction mass was filtered through celite and washed with ethanol. The combined filtrate and wash portion was concentrated under reduced pressure to obtain 6.0 g MY-S2 as a pale brown syrup.

[00954] Step 6 (MY-S3):

[00955] Trifluoroacetic acid (50 mL) was added to a solution of MY-S2 (5.0 g, 16.08 mmol) in dichloromethane (50 mL) at 0°C and the mixture was stirred for 30 min at room temperature . The solvent was evaporated in vacuum, and the remaining mass was dissolved in hydrochloric acid (6N) and washed with 50% ethyl acetate in petroleum ether. The aqueous layer was basified with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 2.01 g (42.93%) of MY-S3 as a yellow liquid.

[00956] Step 7 (MY-S4):

[00957] Triethyl amine (2.09 mL, 14.95 mmol) and Di-tert-butyl dicarbonate (2.06 mL, 8.99 mmol) were added successively to a solution of MY-S3 (2.0 g, 7 .49 mmol) in dichloromethane (50 mL) and the mixture was stirred for 20 h at room temperature. Water was added and the mixture was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 20% ethyl acetate in petroleum ether as the eluent provided 2.0 g (72.73%) of MY-S4 as a sticky liquid. yellow.

[00958] Step 8 (MY-S5):

[00959] Diethylamino sulfurtrifluoride (2.14 mL, 16.35 mmol) was added to a solution of MY-S4 (2.0 g, 5.45 mmol) in dichloromethane (30 mL) at 0°C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1.4 g (66.04%) of MY-S5 as a colorless oil.

[00960] Step 9 (MY-S6):

[00961] Sodium borohydride (680 mg, 18.00 mmol) was slowly added in 3 equal batches (over 15 min) to a solution of MY-S5 (1.4 g, 3.60 mmol) in methanol (30 mL ) at room temperature. Due to the exothermic reaction the temperature rose to -50 oC. The reaction mixture was stirred for 1 hour. Ethyl acetate was added and the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1.1 g (88%) of MY-S6 as a white solid.

[00962] Step 10 (MAA-Sl):

[00963] Potassium T-butoxide (1.06 g, 9.51 mmol) was slowly added in 4 batches (over 15 min) to a stirred solution of MY-S6 (1.1 g, 3.17 mmol) in tetrahydrofuran (40 ml) at 0°C and the mixture was stirred for 2h at room temperature. The reaction mixture was neutralized with 10% acetic acid and extracted with ethyl acetate. The combined organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1% methanol in diclomethane as the eluent provided 700 mg (80.92%) of MAA-S1 as a white solid.

[00964] Step 11 (MAA-S2):

[00965] A mixture of MAA-S1 (700 mg, 2.56 mmol), 4-Bromo-1,2-diaminobenzene (480 mg, 2.56 mmol) and cesium fluoride (780 mg, 5.12 mmol) in 1,4-dioxane (40 ml), it was purged with argon gas for 30 minutes. Copper iodide (75 mg, 0.38 mmol) and 1,2-diaminocyclohexane (45 mg, 0.38 mmol) were added and the mixture was continuously purged for a further 10 minutes. The reaction was heated in a sealed tube for 16 h at 105 to 110°C. The reaction mixture was filtered through celite, washed with dioxane and the filtrate was concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1.5 to 2% methanol in dichloromethane as the eluent provided 600 mg (61.85%) of MAA-S2 as a brown solid.

[00966] Step 12 (Example 29):

[00967] Formamidine acetate (495 mg, 1.58 mmol) was added to a solution of MAA-S2 (600 mg, 1.58 mmol) in acetonitrile (20 ml), and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuum and the resulting mass was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Purification by column chromatography over neutral alumina and using 2 to 2.5% methanol in dichloromethane as the eluent provided 370 mg of product which was triturated with diethyl ether and dried to obtain 350 mg (56.91%) of Example 29 as a not entirely white solid.

[00968] Melting range: 163.9 to 170.2 °C; 1H-NMR (400 MHz,DMSO-d6): δ 12.47 (s, 1 H); 8.17 (s, 1H); 7.61 (d, 1H); 7.48 (s, 1H); 7.32 to 7.16 (m, 4H); 5.74 (q, 1H); 4.82 (t, 1 H); 4.14 (q, 1H); 2.67 (t, 2H); 2.11 to 2.05 (m, 2H); 1.59 (t, 3H); MS = 390.1.1 (M+1); HPLC ~ 98.50%. Example 30: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)-2-fluorophenyl)oxazolidin-2-one

[00969] Step 1 (MZ-S1):

[00970] 3-Fluorocinnamic acid (20 g, 121.9 mmol) was hydrogenated with 10% Pd-C (2 g) in ethanol under hydrogen pressure (4.92 kg/cm2 (70 psi)) for 2 h. The reaction mass was filtered through celite and washed with ethanol. The filtrate was concentrated under reduced pressure to obtain 19.5 g (97%) of MZ-S1 as a non-white solid, subsequently used without further purification.

[00971] Step 2 (MZ-S2):

[00972] N,N-Carbonyl diimidazole (22.83 g, 14.09 mmol) ethriethylamine (16 mL, 11.7 mmol) was added to a solution of MZ-S1 (19.5 g, 11.7 mmol) in tetrahydrofuran (150 ml) and the mixture was refluxed for 1 hour. The reaction was cooled to room temperature and the suspension of N,O-dimethyl hydroxylamine hydrochloride (13.8 g, 14.09 mmol) and triethylamine (16 mL, 11.7 mmol) in tetrahydrofuran (100 mL) was added. The reaction mixture was stirred for 1 h at room temperature. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 27 g of MZ-S2, subsequently used without any purification.

[00973] Step 3 (MZ-S3):

[00974] A solution of methyl magnesium bromide (64.5 mL, 142.10 mmol) was added to a solution of MZ-S2 (27 g, 129.18 mmol) in diethyl ether (160 mL) at 0° C and the mixture was stirred for 4 h at room temperature. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 10% ethyl acetate in petroleum ether as the eluent provided 10.2 g of MZ-S3.

[00975] Step 4 (MZ-S4):

[00976] Sodium borohydride (8 g, 48.19 mmol) was added to a solution of MZ-S3 (8 g, 48.19 mmol) in methanol (80 mL). The reaction mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure and the remaining mass was separated between water and ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate to obtain 8g of MZ-S4 as a solid, subsequently used without any purification.

[00977] Step 5 (MZ-S5):

[00978] Pyridine (7.4 g, 94.04 mmol) was added to a solution of MZ-S4 (7.9 g, 47.02 mmol) in dichloromethane (100 ml) at 0°C and the mixture was stirred for 10 minutes. Acetyl chloride (4.4 g, 56.42 mmol) was added and the mixture was stirred again at room temperature for 1 hour. Water was added and the mixture was extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 8.3 g (84.6%) of MZ-S5 as a solid, subsequently used without any purification.

[00979] Step 6 (MZ-S6):

[00980] Ethyloxalyl chloride (17.3 ml, 152.3 mmol) was added to a solution of MZ-S5 (8 g, 38.09 mmol) in dichloromethane (120 ml), at - 20°C. Aluminum chloride (20.32 g, 152.3 mmol) was added in portions at the same temperature and the mixture was stirred for 1 h at -20°C. The reaction was slowly warmed to room temperature and then stirred for 5 hours. The reaction was quenched with saturated bicarbonate solution and extracted with dichloromethane. The mixture was filtered and the separated organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 5% ethyl acetate in petroleum ether as the eluent provided 3.7 g (32%) of MZ-S6 as a solid.

[00981] Step 7 (MZ-S7):

[00982] A mixture of MZ-S6 (3.5 g, 11.62 mmol), sodium acetate (1.90 g, 23.25 mmol) and hydroxylamine hydrochloride (1.61 g, 23.25 mmol) in ethanol (25 ml), it was refluxed for 2 hours. The reaction mass was filtered and the filtrate was directly taken to the next step without isolation.

[00983] Step 8 (MZ-S8):

[00984] MZ-S7 (3.5 g, 11.11 mmol) in absolute ethanol (50 ml), was hydrogenated with 10% Pd-C (150 mg) in a Parr apparatus (5.62 kg/cm2 (80 psi)) for 15 hours. The mixture was filtered through ethanol-washed celite. The filtrate was concentrated under reduced pressure to obtain 3 g of MZ-S8, which was subsequently used without further purification.

[00985] Step 9 (MZ-S9):

[00986] Triethylamine (2.7 mL, 20.06 mmol) and di-tert-butyl dicarbonate (2.6 mL, 12.04 mmol) were added successively to a solution of MZ-S9 (3 g, 10.03 mmol) in dichloromethane (25 mL) at room temperature and the mixture was stirred for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 5% ethyl acetate in petroleum ether as the eluent provided 2.8 g of MZ-S9 as an oily liquid.

[00987] Step 10(MZ-Sl0):

[00988] To the stirred solution of MZ-S9 (2.8 g, 6.81 mmol) in tetrahydrofuran (10 mL) and water (20 mL) water, lithium hydroxide (1.1 g, 27.25 mmol ) was added and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure. Water (5 mL) was added and the mixture was neutralized with acetic acid and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.2 g of MZ-S10, which was subsequently used without further purification.

[00989] Step 11 (MZ-S11):

[00990] Methyl iodide (1.83 g, 12.90 mmol) was added to a solution of MZ-S10 (2.2 g, 6.45 mmol) and potassium carbonate (1.07 g, 7.74 mmol ) in acetone (20 mL) and the mixture was stirred for 3 h at room temperature. The solvent was evaporated under reduced pressure and ethyl acetate was added. The organic layer was filtered, washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2 g of MZ-S11 as a solid, subsequently used without further purification.

[00991] Step 12(MZ-Sl2):

[00992] Lodoxybenzoic acid (6.3 g, 22.53 mmol) was added to a solution of MZ-S11 (2 g, 5.63 mmol) in diclomethane (20 mL) and dimethyl sulfoxide (5 mL) and the mixture was stirred for 60 h at room temperature. The reaction mass was filtered and washed with dichloromethane. The combined filtrate and wash portion was successively washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude intermediate. Purification by column chromatography on silica gel and using 20% ethyl acetate in petroleum ether as the eluent provided 1.8 g of MZ-S12 as an oily liquid.

[00993] Step 13 (MZ-Sl3):

[00994] Diethylamino sulfurtrifluoride (1.9 ml, 14.52 mmol) was added to a solution of MZ-S12 (1.7 g, 4.84 mmol) in dichloromethane (10 ml), at 0°C. The reaction was warmed to room temperature and stirred for 72 hours. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was successively washed with water, saturated sodium bicarbonate solution, brine; dried over anhydrous sodium sulfate and evaporated in vacuum to obtain the crude intermediate. Purification by column chromatography on silica gel (60 to 120 mesh) and using 10% ethyl acetate in petroleum ether as the eluent provided 800 mg of MZ-S13 as a brown liquid.

[00995] Step 14(MZ-Sl4):

[00996] Sodium borohydride (122 mg, 3.21 mmol) was added to a solution of MZ-S13 (800 mg, 2.14 mmol) in methanol (50 ml). The mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure and ethyl acetate was added. The organic layer was successively washed with water, brine; dried over anhydrous sodium sulfate to obtain 720 mg of MZ-S14 as a white solid, subsequently used without any purification.

[00997] Step 16 (MAA-Sl):

[00998] A solution of MZ-S14 (720 mg, 2.08 mmol) in tetrahydrofuran (80 ml) was added to the suspension of potassium t-butoxide (467 mg, 4.17 mmol) in tetrahydrofuran (2 ml) at 0°C and the mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure, dichloromethane was added and the mixture was acidified with acetic acid to adjust the pH value to pH~6. The mixture was washed with dichloromethane and the combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and evaporated to obtain the crude intermediate. Purification by column chromatography over neutral alumina and using 1% methanol in diclomethane as the eluent provided 420 mg of MAA-S1 as a solid.

[00999] Step 17 (MAA-S2):

[001000] A mixture of MAA-S1 (420 mg, 1.61 mol), 4-bromo-1,2-diaminobenzene (302 mg, 1.61 35 mmol), cesium fluoride (491 mg, 3.23 mmol ) and copper iodide (46 mg, 0.24 mmol) in 1,4-dioxane (20 ml) was purged with argon gas for 15 min in a sealed tube. 1,2-diaminocyclohexane (52.5 mg, 0.44 mmol) was added and the mixture was continuously purged for a further 10 minutes. The reaction was heated for 20 hours at 110 to 115°C. The reaction mixture was filtered, washed with dioxane and concentrated under reduced pressure to provide the crude intermediate. Purification by column chromatography over neutral alumina and using 2% methanol in chloroform as the eluent provided 300 mg of MAA-S2 as a brown solid.

[001001] Step 18 (Example 30):

[001002] A mixture of MAA-S2 (300 mg, 0.817 mmol), formamidine acetate (170 mg, 1.634 mmol) in acetonitrile (10 ml) was stirred for 2 h at 80 to 90oC. The reaction mixture was evaporated, water was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. Diethyl ether (10 ml) and methanol (2 ml) were added and the mixture was stirred for 10 minutes. The mixture was filtered and remaining solid was dried to obtain 135 mg of Example 30 as a brown solid. Melting range: 151.2 to 155.5; 1H-NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1 H); 8.17 (s, 1 H); 7.60 (d, 1H); 7.48 (bs, 1H); 7.34 (t, 1H); 7.25 (bs, 1H); 7.11 (d, 1H); 7.03 (d, 1H); 5.91 (q, 1H); 4.85 (t, 1H); 4.25 (q, 1 H); 2.68-2.64 (m, 2H); 2,172.05 (m, 2H); 1.58 (t, 3H); MS = 390.2 (M+1); HPLC ~ 99.41%. Activity Assessment Fluorometric Assays

[001003] All measurements were performed with a BioAssay HTS-7000Plus Reader for microplates (Perkin Elmer) at 30°C. QC activity was assessed fluorometrically using H-Gln-βNA. Samples consisted of 0.2 mM fluorogenic substrate, 0.25 U of pyroglutamyl aminopeptidase (Unizyme, H0rsholm, Denmark) in 0.2 M Tris/HCl, pH 8.0 containing 20 mM EDTA and an appropriately diluted aliquot of QC in a final volume of 250 μL. Excitation/emission wavelengths were 410 nm. Assay reactions were initiated by the addition of glutaminyl cyclase. QC activity was determined from a standard curve of β-naphthylamine under assay conditions. One unit is defined as the amount of QC catalyzing the formation of 1 μmol pGlu-βNA of H-Gln-βNA per minute under the conditions described.

[001004] In a second fluorometric assay, QC was the activity determined using H-Gln-AMC as substrate. Reactions were performed at 30 °C using the NOVOStar microplate reader (BMG labtechnologies). Samples consisted of varying concentrations of the fluorogenic substrate, 0.1 U pyroglutamyl aminopeptidase (Qiagen) in 0.05 M Tris/HCl, pH 8.0 containing 5 mM EDTA, and an appropriately diluted aliquot of in a final volume of 250 μL. Excitation/emission lengths were 380/460 nm. Assay reactions were initiated by the addition of glutaminyl cyclase. QC activity was determined from a standard curve of 7-amino-4-methylcoumarin under assay conditions. Kinetic data were evaluated using GraFit software.

QC spectrophotometric assay

[001005] This new assay was used to determine the kinetic parameters for most QC substrates. QC activity was analyzed spectrophotometrically using a continuous method, which was derived by adaptation of a previous batch assay (Bateman, R. C. J. 1989 J Neurosci Methods 30, 23-28) using glutamate dehydrogenase as the helper Enzyme. Samples consisted of the respective QC substrate, 0.3 mM NADH, 14 mM a-ketoglutaric acid, and 30 U/mL glutamate dehydrogenase in a final volume of 250 μL. Reactions were initiated by adding QC and followed by monitoring the decrease in absorbance at 340 nm for 8 to 15 minutes.

[001006] Initial velocities were evaluated and enzyme activity was determined from an ammonia standard curve under test conditions. All samples were evaluated at 30°C, using either the SPECTRAFluor Plus or Sunrise microplate readers (both from TECAN). Kinetic data were evaluated using GraFit software.

Inhibitor Assay

[001007] For inhibitor testing, the sample composition was the same as described above, except for the putative inhibitor compound added. For a rapid QC inhibition test, samples contained 4 mM of the respective inhibitor and a substrate concentration at 1 KM. For detailed investigations of inhibition and determination of Ki values, the influence of the inhibitor on the auxiliary enzymes was first investigated. In all cases, there was no influence on any of the detected enzymes, thus enabling reliable determination of QC inhibition. The inhibition constant was evaluated by fitting the set of progress curves to the general equation for competitive inhibition using GraFit software. The inhibitory assay was performed at two different pH levels, pH 6.0 and pH 8.0: The respective pH value in the test solution was adjusted using conventional methods.

Pharmacokinetic parameters Methods

[001008] Three mice (CD-1 lineage) were orally administered 30 mg/kg of each test compound dissolved in 0.8% Metocel. Samples were taken at time points of 10 min, 0.5, 1, 2, 4, and 8 hours after test compound administration for plasma and brain collection.

Blood collection

[001009] The mice were anesthetized with Isoflurane. Approximately 200 μL of each blood sample was collected via cardiac puncture for terminal bleeding into K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma sample within 15 minutes.

[001010] CSF collection: The animals were euthanized with pure CO2 inhalation. A midline incision was made in the neck. The muscle under the skin was cut to expose the cisterna magna. The cisterna magna was penetrated with the tip of a capillary and CSF was collected via capillary action.

Brain Harvest

[001011] After CSF collection, a perfusion with 7x volume of whole mouse blood (approximately 15 ml) of ice-cold PBS (pH 7.4) was conducted via cardiac puncture before brain collection. A midline incision was made in the animal's scalp. The brain was removed and rinsed with cold saline. The brain was placed in a screw-top tube and weighed. Brain samples were homogenized for 2 minutes with 3 volumes (v/w) of PBS (pH 7.4) and then analyzed with LC-MS/MS. Brain concentration was corrected with a dilution factor of 4 following:

[001012] Brain concentration = conc. Brain homogenate x 4, assuming 1 g of wet brain tissue equals 1 ml.

[001013] Plasma, brain and CSF samples were stored at approximately -80°C until analysis.

Sample preparation

[001014] For plasma samples: A 20 μL aliquot of sample was added with 200 μ of IS (Diclofenac, 200 ng/mL) in ACN, the mixture was vortexed for 2 minutes and centrifuged at 12,000 rpm for 5 minutes. 1μL of supernatant was injected for LC-MS/MS analysis.

[001015] For diluted plasma samples: A 4 μL aliquot of sample was added with 16 μL of empty plasma, mixed well, added with 200 μL of IS (Diclofenac, 200 ng/ml) in ACN.

[001016] For brain samples: brain tissue was homogenized for 2 minutes with 3 volumes (v/w) of PBS. A 20 μL aliquot of sample was added with 200 μL of IS (Diclofenac, 200 ng/ml) in ACN, the mixture was vortexed for 2 minutes and centrifuged at 12000 rpm for 5 min. 1 μL of supernatant was injected for LC-MS/MS analysis.

[001017] For CSF samples: The CSF sample was added with corresponding to 20 times the volume of IS (Diclofenac, 200 ng/ml) in ACN, the mixture was vortexed for 2 min. 3 μL of supernatant was injected for LC-MS/MS analysis.

[001018] Tmax, T1/2, AUC and logBB values were calculated using conventional methods. Results

Analytical methods HPLC

[001019] Method [A]: The analytical HPLC system consisted of a Merck-Hitachi device (model LaChrom®) using a LUNA® RP 18 (5 μm), analytical column (length: 125 mm, diameter: 4 mm), and a diode array detector (DAD) with À = 214 nm as the reported wavelength. Compounds were analyzed using a gradient at a flow rate of 1 mL/min; so the eluent (A) was acetonitrile, eluent (B) was water, both containing 0.1% (v/v) trifluoroacetic acid, applying the following gradient:: 0 min - 5 min → 5% (A), 5 min - 17 min → 5 - 15% (A), 15 min - 27 min → 15 - 95% (A) 27 min - 30 min → 95% (A), Method [B]: 0 min - 15 min → 5 - 60 % (A), 15 min - 20 min → 60 - 95 % (A), 20 min -23 min → 95 % (A), Method [C]: 0 min - 20 min → 5 - 60 % (A), 20 min - 25 min → 60 – 95 % (A). 25 min - 30 min → 95% (A).

[001020] Method [B]: The analytical HPLC system consisted of an Agilent MSD 1100 using a Waters SunFire RP 18 (2.5 μm), analytical column (length: 50 mm, diameter: 2.1 mm), and a diode array detector (DAD) with À = 254 nm as the reported wavelength. Compounds were analyzed using a gradient at a flow rate of 0.6 mL/min; Therefore, the eluent (A) was acetonitrile, eluent (B) was water and eluent (C) 2% formic acid in acetonitrile applying the following gradient:

[001021] The purities of all reported compounds were determined by the percentage of peak area at 214 nm.

Mass Spectrometry, NMR spectroscopy:

[001022] ESI Mass spectra were obtained with a SCIEX API 365 spectrometer (Perkin Elmer) using positive ionization mode.

[001023] 1H NMR spectra (500 MHz) were recorded on a BRUKER AC 500. The solvent was DMSO-D6, unless otherwise specified. Chemical shifts are expressed as parts per million (ppm) downstream of tetramethylsilane. The separation patterns were designated as follows: s (singlet), d (doublet), dd (doublet doublet), t (triplet), m (multiplet), and br (broad signal).

MALDI-TOF mass spectrometry

[001024] Matrix-assisted laser deabsorption/ionization mass spectrometry was performed using the Hewlett-Packard G2025 LD-TOF System with a linear time-of-flight analyzer. The instrument was equipped with a 337 nm nitrogen laser, a potential acceleration source (5 kV) and a 1.0 m flight tube. The detector was operated in positive ion mode and signals were recorded and filtered using a LeCroy 9350M digital storage oscilloscope connected to a personal computer. Samples (5 μL) were mixed with equal volumes of matrix solution. For the matrix solution DHAP/DAHC was used, prepared by resolving 30 mg of 2',6'-dihydroxyacetophenone (Aldrich) and 44 mg of diammonium hydrogen citrate (Fluka) in 1 mL of acetonitrile/0.1% TFA in water (1/1, v/v). A small volume (® 1 μL) of the analyzed-matrix mixture was transferred to the tip of a probe and immediately evaporated in a vacuum chamber (Hewlett-Packard Sample Prep Accessory G2024A) to ensure rapid and homogeneous crystallization.

[001025] During long-term testing of Glu1 cyclization, Aβ-derived peptides were incubated in 100 μL 0.1 M sodium acetate buffer, pH 5.2 or 0.1 M Bis-Tris buffer, pH 6 .5 to 30°C. Peptides were applied at concentrations of 0.5 mM [Aβ(3-11)a] or 0.15 mM [Aβ(3-21)a], and 0.2 U QC is added every 24 hours. In the case of Aβ(3-21)a, the assays contained 1% DMSO. At different times, samples are removed from the test tube, peptides extracted using ZipTips (Millipore) according to manufacturer's recommendations, mixed with matrix solution (1:1 v/v) and subsequently mass spectra recorded. Negative controls either contain no QC or heat-deactivated enzyme. For inhibitor studies the sample composition was the same as described above, with the exception of the added inhibitory compound (5 mM or 2 mM of a test compound of the invention).

[001026] The compounds and combinations of the invention may have the advantage that they are, for example, more potent, more selective, have fewer side effects, have better formulation properties and stability, have better pharmacokinetic properties, are more bioavailable, are capable of crossing the blood-brain barrier and are more effective in the mammalian brain, are more compatible or effective in combination with other drugs or are more easily synthesized than other prior art compounds.

[001027] Throughout the specification and the claims that follow, unless the context otherwise requires, the word "comprise", and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a established integer, step, group of integers or group of steps, but not to the exclusion of any other integer, step, group of integers or groups of steps.

[001028] All patents and patent applications mentioned throughout the specification of the present invention are hereby incorporated in their entirety by reference.

[001029] The invention encompasses all combinations of preferred and more preferred groups and modalities of groups mentioned above. Abbreviations ACN acetonitrile CDI N,N-carbonyl diimidazole (DHQ)2PHAL 1,4-phthalazinediyl hydrokinine diether DAD diode array detector DAST diethylamino sulfurtrifluoride DEAD diethyl azodicarboxylate DCM dichlormethane DEA diethylamine DHAP/DAHC dihydroxyacetone/dihydro phosphate -5-azacytidine DIBAL diisobutylaluminium hydride DIPEA N,N-diisopropylethylamine DMS dimethylsulfate DMSO dimethylsulfoxide EDTA ethylenediamine-N,N,N',N'-tetraacetic acid EtOH ethanol HPLC high performance liquid chromatography IBX 2-iodoxy benzoic acid KOtBu potassium t-butoxide LD-TOF laser desorption time-of-flight mass spectrometry MeI methyl iodide MS mass spectrometry NaOAc sodium acetate n-BuLi n-butyl lithium NMR nuclear magnetic resonance PTSA p-toluenesulfonic acid PPh3 triphenyl phosphine (PPh3)4Pd tetracis-(triphenylphosphine)-palladium PPh3CH3Br triphenyl phosphonium methyl bromide TBDMSCl tert-butylmethylsilyl chloride t-BuoCl t-butyl hypochlorite TEA triethylamine TBAHS tetrabutylammonium hydrogen sulfate TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TPP triphenylphosphine

Claims (18)

1. Compound, characterized by the fact that it presents Formula I: or a pharmaceutically acceptable salt or polymorph thereof, including all tautomers thereof, in which: R1 represents C1-12alkyl, -O-C1-12alkyl, C3-10heterocyclyl, with 1, 2 or 3 carbon atoms in the ring of heterocyclyl are substituted by heteroatoms selected from N, S and O; or C3-10cycloalkyl; R2 and R3 independently represent hydrogen, halogen or CN; R4 and R5 independently represent hydrogen or halogen; wherein at least one of R2, R3, R4 and R5 is halogen or CN; and the groups being C1-12alkyl, -O- C1-12alkyl, C3- 10heterocyclyl, with 1, 2 or 3 carbon atoms in the heterocyclyl ring being replaced by heteroatoms selected from N, S and O; or C3-10cycloalkyl above are substituted by two fluorines. 2. Compound, according to claim 1, characterized by the fact that it has Formula I: or a pharmaceutically acceptable salt or polymorph thereof, including all tautomers thereof, in which: R1 represents C1-12alkyl, -O-C1-12alkyl, C3-10heterocyclyl, with 1, 2 or 3 carbon atoms in the ring of heterocyclyl are substituted by heteroatoms selected from N, S and O; or C3-10cycloalkyl; R2 and R3 independently represent hydrogen, fluorine or CN; R4 and R5 independently represent hydrogen or fluorine; wherein at least one of R2, R3, R4 and R5 is fluorine or CN; and the groups being C1-12alkyl, -O- C1-12alkyl, C3- 10heterocyclyl, with 1, 2 or 3 carbon atoms in the heterocyclyl ring being replaced by heteroatoms selected from N, S and O; or C3-10cycloalkyl above are substituted by two fluorines. 3. Compound according to claim 1 or 2, characterized by the fact that R1 represents -O-C2-6alkyl substituted by two fluores. 4. Compound according to claim 1, characterized by the fact that R1 represents pyrrolidinyl substituted by two fluores. 5. Compound according to claim 1, characterized by the fact that R1 represents cyclohexyl substituted by two fluores. 6. Compound according to claim 1, characterized by the fact that R1 represents -C2-6 alkyl substituted by two fluores. 7. Compound according to claim 1, characterized in that R1 is selected from difluoropropoxy, such as 2,2-difluoropropoxy or 3,3-difluoropropoxy; difluorobutoxy, such as 3,3-difluorobutoxy; difluoropyrrolidinyl such as 3,3-difluoropyrrolidin-1-yl, difluorocyclohexyl such as 4,4-difluorocyclohexyl, and difluorobutyl such as 3,3-difluorobutyl. 8. Compound according to any one of claims 1 to 7, characterized by the fact that: R2 and R5 are halogen such as fluorine, and R3 and R4 are hydrogen; or where R2 is halogen such as fluorine, and R3, R4 and R5 are hydrogen; or where R3 and R4 are halogen such as fluorine, and R2 and R5 are hydrogen; or where R3 is a halogen such as fluorine, and R2, R4 and R5 are hydrogens; or where R2 and R3 are halogens, such as fluorine, and R4 and R5 are hydrogen; or where R2 is CN and R3, R4 and R5 are hydrogens; or where R3 is CN and R2, R4 and R5 are hydrogens. 9. Compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or polymorph thereof, including all tautomers, characterized in that the compound of Formula I is a compound selected from the group consisting of: 1) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy)-2,3-difluorophenyl)-oxazolidin-2-one 2) ( S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2-fluorophenyl)oxazolidin-2-one 3) (S)-3-( 1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy)-2-fluorophenyl)oxazolidin-2-one 5) (S)-3-(1H-benzo[d] imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-3-fluorophenyl)oxazolidin-2-one 6) (S)-3-(1H-benzo[d]imidazol-5-yl) -4-(4-(2,2-difluoropropoxy)-2,3-difluorophenyl)oxazolidin-2-one 7) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-( 4-(2,2-difluoropropoxy)-2-fluorophenyl)oxazolidin-2-one 8) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2 - difluoropropoxy)-3,5-difluorophenyl)oxazolidin-2-one 10) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy)- 3-fluorophenyl)oxazolidin-2-one 11) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2,3-difluorophenyl) oxazolidin-2-one 12) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-3-fluorophenyl)oxazolidin-2-one 13 ) S)-3-(1H-benzo[d]imidazol-6-yl)-4-(4-(3,3-difluoropropoxy)-3,5-difluorophenyl)oxazolidin-2-one 14) (S)- 5-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-2-(2,2-difluoropropoxy) benzonitrile 15) (S)-2-(3-( 1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-5-(2,2-difluoropropoxy) benzonitrile 17) (S)-3-(1H-benzo[d]imidazol-5 -yl)-4-(4-(2,2-difluoropropoxy)-2,6-difluorophenyl)oxazolidin-2-one 18) (S)-3-(1H-benzo[d]imidazol-5-yl)- 4-(4-(3,3-difluoropyrrolidin-1-yl)-2-fluorophenyl)-oxazolidin-2-one 19) (S)-3-(1H-benzo[d]imidazol-5-yl)-4 -(4-(3,3-difluoropyrrolidin-1-yl)-2,3-difluorophenyl)-oxazolidin-2-one 20) (S)-3-(1H-benzo[d]imidazol-5-yl)- 4-(4-(3,3-difluoropyrrolidin-1-yl)-2,6-difluorophenyl) oxazolidin-2-one 21) (S)-3-(1H-benzo[d]imidazol-5-yl)- 4-(4-(3,3-difluoropyrrolidin-1-yl)-3-fluorophenyl) oxazolidin-2-one 23) (S)-2-(3-(1H-benzo[d]imidazol-5-yl) -2-oxooxazolidin-4-yl)-5-(3,3-difluoropyrrolidin-1-yl)benzonitrile 24) (S)-5-(3-(1H-benzo[d]imidazol-5-yl)-2 -oxooxazolidin-4-yl)-2-(3,3-difluoropyrrolidin-1-yl)benzonitrile 25) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-( 4,4-difluorocyclohexyl)-2-fluorophenyl)oxazolidin-2-one 26) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(4,4- difluorocyclohexyl)-3-fluorophenyl)oxazolidin-2-one 28) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)- 2 ,3-difluorophenyl)oxazolidin-2-one 29) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)- 3-fluorophenyl)oxazolidin -2-one 30) (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)- 2-fluorophenyl)oxazolidin-2-one 10. Compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or polymorph thereof, including all tautomers, characterized by the fact that the compound of Formula I is (S)-3-(1H-benzo [d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-2-fluorophenyl)oxazolidin-2-one. 11. Compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or polymorph thereof, including all tautomers, characterized by the fact that the compound of Formula I is (S)-3-(1H-benzo [d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2,3-difluorophenyl)oxazolidin-2-one. 12. Compound according to any one of claims 1 to 11, characterized by the fact that it is for use as a medicine. 13. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 9, optionally in combination with one or more therapeutically acceptable diluents or carriers. 14. Pharmaceutical composition according to claim 13, characterized in that it further comprises at least one compound, selected from the group consisting of neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, amyloid beta synthesis inhibitors, antidepressants , anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs. 15. Pharmaceutical composition according to claim 13 or 14, characterized by the fact that it further comprises at least one compound selected from the group consisting of PEP inhibitors, LiCI, inhibitors of DP IV or DP IV type enzyme inhibitors, inhibitors of acetylcholinesterase (ACE), PIMT enhancers, beta secretase inhibitors, gamma secretase inhibitors, neutral endopeptidase inhibitors, phosphodiesterase-4 (PDE-4) inhibitors, TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists , sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents, or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fanpridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix metalloproteinase inhibitors, interferon-tau (trophoblastin) and SAIK-MS. 16. Compound according to any one of claims 1 to 9, or pharmaceutical composition according to any one of claims 13 to 15, characterized in that it is for use in the treatment of a disease selected from the group consisting of disease Kennedy, duodenal cancer with or without Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, inflammatory host responses, cancer, malignant metastasis , melanoma, psoriasis, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes on the endothelium, impaired food intake, impaired sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance or impaired regulation of body fluids, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, Huntington's disease, rheumatoid arthritis, atherosclerosis , pancreatitis and restenosis. 17. Process for preparing a compound of Formula (I), as defined in any one of claims 1 to 9, characterized in that it comprises: (a) preparing a compound of Formula (I) from a compound of Formula (II): reacting a compound of Formula (I) with formamidine acetate, in the presence of a suitable solvent such as acetonitrile, in which R2, R3, R4 and R5 are as defined above for compounds of Formula (I); R6 is C1-12alkyl; and R7 and R8 are fluorine; or (b) preparing a compound of Formula (I) from a compound of Formula (III): reacting a compound of Formula (II) with formamidine acetate in the presence of a suitable solvent such as acetonitrile, in which R2, R3, R4 and R5 are as defined above for compounds of Formula (I), R9 is C3-10 cycloalkyl or C3-10heterocyclyl, with 1, 2 or 3 carbon atoms in the heterocyclyl ring being replaced by heteroatoms selected from N, S and O; and R10 and R11 are fluorine; or (c) preparing a compound of Formula (I) from a compound of Formula (IV): reacting a compound of Formula (IV) with a typical agent such as diethylaminosulfur trifluoride employed in the presence of a suitable solvent such as dichloromethane; in which R12 is C3-10cycloalkyl; or (d) preparing a compound of Formula (I) from a compound of Formula (V): reacting a compound of Formula (V) with formamidine acetate, in the presence of a suitable solvent, such as acetonitrile; in which R1, R2 and R4 are as defined above for compounds of Formula (I), R13 is C1-12alkyl; and R14 and R15 are halogen such as fluorine. 18. Use of a compound, as defined in any one of claims 1 to 9, or of a pharmaceutical composition, as defined in any one of claims 13 to 15, characterized by the fact that it is for manufacturing a composition or medicament to treat or prevent a disease selected from the group consisting of Kennedy disease, ulcer disease, duodenal cancer with or without Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions , schizophrenia, infertility, neoplasia, host inflammatory responses, cancer, malignant metastasis, melanoma, psoriasis, impaired cell-mediated humoral and immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wake regulation impaired homeostatic energy metabolism, impaired autonomic function, impaired hormonal balance or impaired regulation of body fluids, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia ,neurodegeneration in Down Syndrome, Huntington's disease, rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.