Compounds for the treatment of dyslipidemia and related diseases

专利摘要:
H:rslmenvovenNRPorhblDCCRXS506993O).DOC-] 110412013 The present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. HET-X Y
公开号:AU2013204732A1
申请号:U2013204732
申请日:2013-04-12
公开日:2013-05-09
发明作者:Mukul R. Jain；V. V. M. Sairam Kalapatapu；Pankaj Makadia；Harikishore Pingali
申请人:Cadila Healthcare Ltd；
IPC主号:C07D405-06

专利说明:
H:rxslnenvovenTRPoriblDCCaRXS5069930_1.DOC-1 104/2013 -1 COMPOUNDS FOR THE TREATMENT OF DYSLIPIDEMIA AND RELATED DISEASES This application is a divisional of Australian Patent Application No. 2010313068, the entire content of which is incorporated herein by reference. FIELD OF INVENTION The present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers. their pharmaceutically acceptable salts, pharmaceutical compositions containing then, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation The present invention is directed to antagonists of PCSK9 which can be used to treat the diseases mediated through PCSK9 enzyme e.g. dysiipidernia. The compounds of the present invention also lower LDL-c, HEY -- x R 0 BACKGROUND OF THE INVENTION Higher LDL cholesterol levels in the plasma increase cardiovascular risk and reduction in the levels of LDL would decrease CVD risk by a comparable percenage (PNAS, 2009. 106, 9546-9547). Clearance of LDL cholesterol from plasma is through the action of LDL receptors in the liver and LDL receptors are cell surface glycoproteins that bind to apoliporpotein B100 (apoB100) on LDL particles with high affinity and mediate their endocytic uptake (Journal of Biological Chemistry, 2009. 284, 10561-10570). Defect in hepatic cholesterol clearance and elevated levels of plasma LDL cholesterol that result from the mutations cause familial hypercholesterolemia. Such mutations are identified in the human LDL receptor and later in apolipoprotein-B (Nature Structural and Molecular Biology, 2007, 14, 413 419). Recently, mutations within the proprotein convertase subtilisin/kexin type9 (PCSK9) gene were found to represent a third class of mutations associated with autosomal dominant hypercholesterolemia (ADH). Abifadel et al in 2003 discovered PCSK9 as the third gene involved in autosomal dominant hypercholesterolaernia (ADH) (Nature Genetics, 2003, 34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434). Several missense mLta(ions (S127R. D129G, F216L, D374H, D374Y) are associated with hypercholesterolemia and premature atherosclerosis (J Lipid Res. 2008, 49. 1333-1343). Loss-of-function mutations (R46L, L253F, A433T) lead to elevated receptor abundance. enhancing clearance of LDL cholesterol from the circulation and reducing cardiovascular risk (Nature Structural and Molecular Biology, 2007, 14,413-419). PCSK9 belongs to the subtilisin family of serine proteases and its protein structure consists of a prodomain, catalytic domain, and cysteine/histidine rich C 5 terminal domain (Structure, 2007, 1 5, 545-552). Unlike other proprotein convertases, wherein the prodomain is further proteolytically processed to activate the serine protease, the prodomain of secreted PCSK9 remains intact and tightly bound. Within endoplasmic reticulum PCSK9 undergoes autocatalytic process which results in release of -14 kDa prodomain that remains associated with the catalytic/C-terminal domains, 10 wherein the prodomain serves as both a folding chaperon and as an inhibitor of enzymatic activity (Journal of Biological Chemistry, 2009,284, 10561-10570). It is well documented that epidermal growth factor-like repeat A (EGF-A) of LDLR interacts with PCS 9 mainly with residues 367-381. This EGF-A interaction site is located >20 A from the catalytic site of PCSK9. Once EGF-A and PCSK9 interacts 15 they form a PCSK9-LDLR complex that enters endosomal pathway and hence LDLR recycling is prevented leading to LDLR degradation. Detailed molecular mechanisms explaining the association of LDLR and PCS 9 and LDLR degradation is not very clear (Drug News Perspectives, 2008, 21, 323-330). Because of inhibition of LDLR recycling, number of LDL receptors on the cell surface are decreased and this increases 20 plasma LDL levels (PNAS, 2009, 106, 9546-9547). Various approaches for inhibiting PCSK9 are reported, including gene silencing by siRNA or antisense oligonucleotides, mAb disrupting protein-protein interactions or by peptides; all the above-mentioned strategies have shown lowering of LDL cholesterol which may be effective therapy for treating hypercholesterolemia (Biochemical Journal, 25 2009, 419, 577-584; PNAS, 2008, 105. 1 191 5-1 1920; Journal of Lipid Research, 2007, 48, 763-767; PNAS, 2009, 106, 9820-9825). W02004/099173 Al discloses dimethylaminocarbonyl-5glycidyloxy-2-methyl-[1,3] dioxane. W02009/100297 Al discloses an antibody inhibiting the catalytic site of PCSK9. There are many reports mentioning the advantage of having a small molecule inhibitor 30 for PCSK9 (Drug News Perspect 21 (6), July/August 2008, 323-330; PNAS, 106 (24), 9546-9547, 2009; Curr Atheroscler Rep (2010) 12:308-315 etc.). Since then it has been the endeavor of many to discover small molecule inhibitors of PCSK9. Small molecules targeting PCSK9 looked difficult because, LDL-R degradation of PCSK9 is 2 WO 2011/051961 PCT/IN2010/000650 a protein-protein interaction and the process is independent of PCSK9 proteolytic activity (Lou, K.-J. SciBX2(22); doi:10.1038/scibx,2009,895 and respective references therein). In the light of above-mentioned reports, we have hypothesized that small molecule binding to catalytic site of PCSK9 could allosterically effect LDL-R binding 5 to PCSK9. Using in silico docking studies we have designed compounds that can bind to PCSK9 catalytic site. Such molecules as mentioned in the examples have shown SPR binding, in vitro (ELJSA) potency and in vivo efficacy as a proof of concept. SUMMARY OF THE INVENTION The main objective of the present invention is to provide compounds of formula 10 (1) or their pharmaceutically acceptable salts which are modulators of the PCSK9 enzyme. In an embodiment of the present invention is provided a process for the preparation of the compounds of the present invention. In a further embodiment of the present invention is provided process for 15 treatment of diseases mediated by the PCSK9 enzyme by providing therapeutically effective amount of the compounds of formula (I) or their pharmaceutically acceptable salts or their suitable pharmaceutical compositions. In an embodiment is provided a method of identifying small molecules as inhibitors of PCSK9. 20 The above and other embodiments are described hereinafter. DESCRIPTION OF THE FIGURE Figure 1 is a depiction of three dimensional model of PCSK9 docked pose with Example 47. Ligand binding mode is shown with electrostatic surface on the PCSK9 protein. 25 DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisorners, regioisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein HET X Y 0 (I) 0 3 'HET represents an optionally substituted heteroaryl or a heterocyclic group; When the groups 'HET' is substituted, the substituents represents one or more groups selected from hydrogen or optionally substituted groups selected from (Cl-C6) linear or branched alkyl, aryl, heteroaryl, cycloalkyl or a heterocyclyl group In a 5 preferred embodiment, substitution on 'HET are selected from (Cl-C6) linear or branched alkyl, aryl or heteroaryl groups; 'X' represents the groups selected from (CH 2 )n, O(CH2)n, S(CH2)n, SO(CH 2 )n,
SO
2 (CH2). or NR 2
(CH
2 )n wherein R 2 represents H, C(1-6) linear or branched alkyl or a cycloalkyl group, wherein either the alkyl or cycloalkyl group may be further 10 substituted with one or more groups as described hereinafter and n =0 to 3;
'
1 ' represents linear or branched C(1-6) alkyl, or suitable groups selected from cycloalkyl, aryl, groups,; In one embodiment, 'Y' represents NR 3
R
4 wherein R 3 represents C( 1 6) linear or branched alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, 15 heteroarylalkyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy groups, each of which may be further substituted with one or more groups from those described hereinafter and R 4 represents H, C(16 3 linear or branched alkyl, cycloalkyl, cycloalkylalkyi, aryl, heteroaryl, heterocyclyl, arylalkyl, 20 heteroarylalkyl or heterocyclylalkyl groups, each of which may be further substituted with one or more groups from those described hereinafter; O P I Por z In another embodiment,'Y' represents the groups wherein 'P' represents CH 2 , S, SO, SO 2 , o, CO or NR, wherein Rs represents H, C(1-6) linear or branched alkyl or cyclo alkyl groups; 'm' represents integers from I to 3; 'N % N K'oril 25 and 'Z' represents either NR 3
R
4 or the groups or wherein R 3 , R4 and P are as defined earlier; When any of the groups mentioned in the specification is substituted, the substituents at each occurrence may be independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected 30 4 WO 2011/051961 PCT/IN2010/000650 from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyly], heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy. heteroaralkoxy, heterocycloxy, 5 heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylanino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio, heteroarylthio, alkylsulfnyl, cycloalkylsulfinyl, arylsulfinyl, 10 heterocyclylsulfinyl, heteroarylsulfinyl,.alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, alkyisulfonylamino, cycloalkylsulfonylarmino, arylsulfonylamino, heterocyclylsulfonylarnino, heteroarylsulfonylamino. alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclyisulfonyloxy. heteroarylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, is aralkyloxycarbonyl amino, aminocarbonylamino, alkylaminocarbonylarnino, alkoxyamino, hydroxyl amino, sulfinylderivatives, sulfonyl derivatives, sulfonic acid and its derivatives; When the substituents on 'HET' is further substituted, the substituents are selected from halogen, alkyl, haloalkyl, alkoxy, sulfanyl derivative, sulfinyl derivatives, 20 sulfonyl derivatives, sulfonyloxy groups; The term "heterocyclyl" or "heterocyclic" group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen. In a preferred 25 embodiment the helerocyclyl groups are selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidiny4, 4 oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2 oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, 30 benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyriimiidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, WO 2011/051961 PCT/IN2010/000650 benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; The term "heteroaryl" or "heteroaromatic" group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or 5 tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from 0, N or S. In a preferred embodiment the heleroaromatic groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazoly], imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothieny, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrinidinyl, azaquinazolinyl, pyridofuranyl, 10 pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyt, pyridazinyl, triazinyl, benzimidazoly], benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolylI, benzothiazolyl and the like. Preferred 'HET' are selected from aziridinyl, azetidinyl, pyrrolidinyl, is imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2 oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, , oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, difiydrofuran., dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, 20 azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, pyridyl, thienyl, fury], pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, 25 pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyi, benzotriazolyl, phthalazynil, naphthylidinyl. purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl groups. The various groups, radicals and substituents used anywhere in the specification 30 are described in the following paragraphs. 6 WO 2011/051961 PCTINZOIO/000650 - the alkyll" group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, I-amyl, n-pentyl, n hexyl, and the like; 5 - the "alkenyl" group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyt, 4-hexenyl and the like; the "alkenyl" group includes dienes and trienes of straight and branched chains; 10 - the "alkynyl" group used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to six carbon atoms, more preferably thynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, I pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, and the like, The term "alkynyl" includes di- and tri-ynes; is - the "cycloalkyl", or "alicyclic" group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; The terms "bicycloalkyl" means more than one cycloalkyl groups fused together; - the "cycloalkenyl" group used either alone or in combination with other radicals, 20 are preferably selected from cyclopropenyl, I-cyclobutenyl, 2-cylobutenyl, I cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, I-cyclohexenyl, 2-cyclohexenyt, 3-cyclohexenyl and the like; The terms "bicycloalkenyl" means more than one cycloalkenyl groups fused together; - the "alkoxy" group used either alone or in. combination with other radicals, is 25 selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like; - the "cycloalkoxy" group used either alone or in combination with other radicals, is 30 is selected from a cyclic radical containing three to seven carbons, more preferably 7 WO 2011/051961 PCT/IN2010/000650 cyclopropyloxy, cyclobutylxoy, cyclopentyloxy, cyclohexyloxy and the like; The terms "bicycloalkyloxy" means more than one cycloalkyl groups fused together; - the "alkenoxy" group used either alone or in combination with other radicals, is selected from groups containing an alkenyl radical, as defined above, attached to an 5 oxygen atom, more preferably selected from vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like; - the "haloalkyl" group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro (CI-C 6 )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, to fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; - the "haloalkoxy" group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like; 15 - the "perhaloalkoxy" group is selected from a suitable perhaloalkyl radical, as defined above, directly attached to an oxygen- atom, more preferably groups selected from trifluoromethoxy, trifluoroethoxy, and the like; - the "aryl" or "aromatic" group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three 20 rings wherein such rings may be attached together in a pendant manner or may be fused. more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, bipheiyl, and the like; - the "aryloxy" group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly 25 to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like; - the groups "heteroaryloxy", "heteroaralkoxy", "heterocycloxy", "heterocylylalkoxy" are selected from suitable heteroaryl, heteroarylalkyl, 30 heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom; 8 WO 2011/051961 PCT/IN20101000650 - the "acyl" group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, iso-butanoyl. pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted; 5 - the "acyloxy" group used either alone or in combination with other radicals, is selected from a suitable acyl group, as defined above, directly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like; - the "acylamino" group used either alone or in combination with other radicals, is 10 selected from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH 3 CONH, C 2
H
5 CONH,
C
3
H
7 CONH, C4HI 9 CONH, C 6 HSCONH and the like. which may be substituted; - the "mono-substituted amino" group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (Ci Is C 6 )alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n propylamine, n-butylamine, n-pentylamine and the like; - the 'disubstituted amino" group used either alone or in-combination with other radicals, represents an amino group, substituted with two radicals that may be same 20 or different selected from (Ci-C6)alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more preferably the groups are selected from dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like; - the "arylamino" used either alone or in combination with other radicals, represents an aryl group, as defined above, linked through amino having a free valence bond 25 from the nitrogen atom, more preferably the groups are selected from phenylanino, naphthylamino, N-methyl anilino and the like; - the "oxo" or "carbonyl" group used either alone (-C=O) or in combination with other radicals such as alkyl described above, for e.g. "alkylcarbonyl", denotes a carbonyl radical (-C=O-) substituted with an alkyl radical described above such as 30 acyl or alkanoyl; 9 WO 2011/051961 PCT/IN2010/000650 - the "carboxylic acid" group, used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides; the "ester" group used alone or in combination with other radicals, denotes -COO 5 group, and includes carboxylic acid derivatives, more preferably the ester moieties are selected from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, 10 phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroary group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may optionally be substituted; 15 - the "amide" group used alone or in combination with other radicals, represents an aminocarbonyl radical (H 2 N-C=O), wherein the amino group is mono- or di substituted or unsubstituted, more preferably the groups are selected from methyl amide, dimethyl aide, ethyl amide, diethyl amide, and the like; - the "aminocarbonyl" group used either alone or in combination with other radicals, 20 may be selected from 'aminocarbonyl', 'aminocarbonylalkyl', "n alkylaminocarbonyl", "N-arylam inocarbonyl", "N,N-dialkylarninocarbonyl", "N alkyl-N-arylaminocarbonyl", "N-alkyl-N-hydroxyaminocarbonyl", and "N-alkyl N-hydroxyaninocarbonylalkyl", each of them being optionally substituted. The terms "N-alkylaninocabonyl" and "N,N-dialkylaminocarbonyl" denotes 25 aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively, Preferred are "lower alkylaninocarbonyl" having lower alkyl radicals as described above attached to am inocarbonyl radical. The terms "N-arylaminocarbonyl" and "N-alkyl-N arylaminocarbonyl" denote amiocarbonyl radicals substituted, respectively, with 30 one aryl radical, or one alkyl, and one aryl radical. The term "aminocarbonylalkyl" includes alkyl radicals substituted with aminocarbonyl radicals; 10 WO 2011/051961 PCT/IN2010/000650 - the "hydroxyalkyl" group used either alone or in combination with other radicals, is selected from an alkyl group. as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the 5 like; - the "aninoalkyl" group used alone or in combination with other radicals, denotes an amino (-NH 2 ) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term "alkylamino" used herein, alone or in combination with other radicals, denotes an alkyl radical, as 10 defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylarnino; - the "alkoxyalkyl" group used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, 15 methoxyethyl, ethoxyethyl and the like; - the "alkylthio" group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from 20 methylthio, ethylthio, propylthio, butylthio, pentylthio and the- like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted; - the "thioalkyl" group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR', 25 where R' represents hydrogen, alkyl or aryl group, e.g. thiomethyl, nethylthioinethyl, phenylthiornethyl and the like, which may be optionally substituted. - the "arylthio" group used either alone or in combination with other radicals, denotes a comprising an aryl group as defined above, linked through a divalent sulfur atom 30 having a free valence bond from the sulfur atom, more preferably the groups may 11 WO 2011/051961 PCT/IN2010/000650 be selected from phenylthio, naphthylthio, tetrahydronaphthylthio, indanethio, biphenylthio, and the like; - the "heterocyclylthio" group used either alone or in combination with other radicals, denotes a comprising an heterocyclyl group as defined above, linked 5 through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from aziridinylthio, azetidinylthio, pyrrolidinylthio, imidazolidinylthio, piperidinylthio, piperazinyithio, 2 oxopiperidinylthio. 4-oxopiperidinylthio, 2-oxopiperazinylthio, 3 oxopiperazinylthio, morpholinylthio, thiatnorpholinylthio, 2-oxomorpholinylthio, to azepinylthio, diazepinylthio, oxapinylthio, thiazepinylthio, oxazolidinylthio, thiazolidinyhhio, dihydrothiophenethio, dihydropyranthio, dihydrofuranthio, dihydrothiazolethio, benzopyranylthio, benzopyranonylthio, benzodihydrofuranylthio, benzodihydrothienylthio, pyrazolopyrinidonylthio, azaquinazolinoylthio, thienopyrimidonylthio, quinazolonylthio, pyrimidonylthio, t5 benzoxazinylthio, benzoxazinonylthio, benzothiazinylthio, benzothiazinonylthio, thieno piperidinylthio, and the like; - the "heteroarylthio" group used either alone or in combination with other radicals, denotes a comprising an heteroaryl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more 20 preferably the groups may be selected from pyridylthio, thienylthio, furylthio, pyrrolylthio, oxazolylthio, thiazolylthio, isathiazolylthio, imidazolylthio, isoxazolylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, benzofuranylthio, benzothienylthio, indolinylthio. indolylthio, azaindolylthio, azaindolinylthio, pyrazolopyrimidinylthio, azaquinazolinylthio, pyridofuranylthio, 25 pyridothienylthio, thienopyrimidylthio, quinolinylthio, pyrimidinylthio, pyrazolylthio, quinazolinylthio, pyridazinyithio, triazinylthio, benzimidazolylthio, benzotriazolylthio, phthalazynilth lo, naphthylidinylthio, purinylthio, carbazolylthio, phenothiazinylthio, phenoxazinylthio, benzoxazolylthio, benzothiazolylthio and the like; 30 - the "alkoxycarbonylamino" group used alone or in combination with other radicals, . is selected from a suitable alkoxycarbonyl group, as defined above, attached to an WO 2011/051961 PCT/IN2010/000650 amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like; - the "aminocarbonylamino", "alkylaminocarbonylamino", "dialkylaminocarbonylamino" groups used alone or in combination with other s radicals, is a carbonylanino (-CONH 2 ) group, attached to amino(NH2), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above; - the "amidino" group used either alone or in combination with other radicals, represents a -C(=NH)-NH 2 radical; the "alkylamidino" group represents an alkyl radical, as described above, attached to an amidino group; 10 - the "alkoxyanino" group used either alone or in combination with other radicals, represents a suitable alkoxy group as defined above, attached to an amino group; - the "hydroxyamino" group used either alone or in combination with other radicals, represents a -NHOH moiety, and may be optionally substituted with suitable groups selected from those described above; 15 - the "sulfinyl" group or "sulfinyl derivatives" used alone or in combination with other radicals, represents a bivalent group, -SO- or RSO, where R" is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above; - the "sulfonyl" group or "sulfones derivatives" used either alone or in combination 20 with other radicals, with other tern-s such as alkylsulfonyl, represents a divalent radical -SO 2 -, or RSO 2 -, where R, is as defined above. More preferably, the groups may be selected from "alkylsulfonyl" wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like; "arylsulfonyl" wherein 25 an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like; - the "sutfanyl" group or "sulfanyl derivatives" used alone or in combination with other radicals, represents a bivalent group, -S- or RxS, where Rx is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described 30 above; 13 WO 2011/051961 PCT/IN2010/000650 - the "sulfonyloxy" group used either alone or in combination with other radicals, with other terms such as alkylsulfonyloxy, represents a divalent radical -S02-O-, or RNSOO2--, where R, is as defined above. More preferably, the groups may be selected from "alkylsulfonyloxy" wherein suitable alkyl radicals, selected from 5 those defined above, is attached' to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyloxy" wherein an aryl radical, as defined above, is attached to a sulfonyloxy radical, such as phenylsulfonyloxy and the like. Suitable groups and substituents on the groups may be selected from those 10 described anywhere in the specification. Particularly useful compounds may be selected from N-(benzyloxy)-2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-I,3-dioxane-2 carboxamide; N-(benzyloxy)-2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxane-2 is carboxamide; N-(benzyloxy)-2-methyl-5-t-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxane-2 carboxamide; N-hydroxy-2-methyI-5-((5-methyl-2-phenyloxazo1-4-yI)methyl)-1 ,3-dioxane-2 carboxamide; 20 5-c-(3-(9H-carbazol-9-yl)propyl)-N-hydroxy-2-methyl- 1,3-dioxane-2-carboxamide; N-hydroxy-2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)- 1,3-dioxane-2 carboxamide; N-hydroxy-2-methyl-5-t-((5-methyl-2-phenyoxazol-4-yl)methyl)- 1,3-dioxane-2 carboxamide; 25 2-nethyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methy I)-N-((tetrahydro-2H-pyran-4 yl)methyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-t-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 30 yl)methyl)- 1,3-dioxane-2-carboxamide; 14 WO 2011/051961 PCTIN2QIQ/l00650 (2-methyl-5-((5-melhyl-2-phenyloxazolI-4-yI)methyl)-] ,3-dioxan-2 yl)(m orpholi no)methan one, (2-methyl-5-c-((5 -methyl-2-phenyloxazol-4-yI)methyl)- 1 .3-dioxan-2 yl)(m orp holi no)m ethanorie; 5 (2-methyl-5-t+((5 -methyl-2-phenyl oxazo1-4-y I }'fethyl)- I ,3-dioxan-2 yI)(morpholino)mnethanone; (2-mnethyl-5-c-({5-methyl-2-phenyloxazol-4-yI )methyl)- I ,3-diexwi-2-yl)(4 methylpiperazin-] -yI)methanone; (2-methyl-5 -c-((5-methyl-2-phenyloxazol-4-yI)inethyl)- 1,3 -dioxan-2-yI)(piperidin-] 10 y])methanorie; (2-methyl-5-c-((5-mechyl-2-phenyloxazol-4 -yl)methyl)-] ,3-dioxan-2 yl )(thiomorpholino)metharione; (1,1 -dioxidothiom-orphol ino)(2-methyl-5-c-((5-methyl-2-phenyloxazol -4-yI)methyl) I ,3-dioxan-2-yI)methanone; 15 2-mnethyi-5-((5-methyl -2-phenyloxazol-4.yI)methyl)-N-(2-morphol ino-2-oxaethyl)- 1,3 dioxane-2-carboxam ide; 2-methyl-5 -c-((5-rnethyl-2-phenyloxazol-4-yI)m-ethyl)-N-(2-morph olino-2-oxoethyl) I ,3-dioxane-2-carboxamide; 2-methyl -5-z-((5-m ethyl-2-phenyloxazol-4-yi )methyl)-N-(2 -morphalino-2-oxoethyl} 20 1 ,3-dioxane-2-carboxamide; 2 -methyl-5 -c-{(5 -mnethyl -2-pheniyloxazol-4-yI~methyl)-N-(2 -(4-mnethyl p iperaziri- I y) 2-oxoethy )-I ,3-dioxane-2-carboxam ide; 2-methyl-5-c-((5-meti yI-2-phenyloxazol-441l)methyl)-N-{2 -oxo-2-(piperid in- I yI)ethyl)- 1,3-di oxane-2-carboxaniide; 25 2-methyl-5-c-((5-r-nethyl-2-phenyloxazol-4-yl)methyl)-N-(2-oxo-2 thi omorphol inoethyl)- 1,3 -d ioxane-2-carboxam-ide; N-(2-( 1,1 -dioxidothioniorphol ino)-2-oxoechyJ)-2-rnethyl-5-c-((5-methyl-2 phenyl oxazol-4-yI)meihyI)- 1,3 -d ioxane-2-carboxamide; 2-methyl-5-c-((5-methyl-2-pheny Ioxazol-4-yI)mrethyl)-N-(2-oxo-2-(((tetrahydro-2H 30 pyran-4-y])methyl)amino)ethyl)-1I,3-d ioxane-2-6arboxam ide; 15 WO 2011/051961 PCT/1N2010/000650 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-morpholino-3 -oxopropyl) 1,3-dioxane-2-carboxamide; 2-methyl-5 -c-((5 -methyl-2-phenyloxazol-4-yl)methyl)-N-(3 -oxo-3-(((tetrahydro-2H pyran-4-yl)methyl)am ino)propyl)- 1,3-d ioxane-2-carboxamide; 5 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3 -oxo-3 thiomorpholinopropyl)-1,3-dioxane-2-carboxamide; N-(3-(1, I-dioxidothiomorpholino)-3-oxopropyl)-2-methyl-5-c-((5-methyl-2 phenyloxazol-4-yl)methyl)-I1,3-dioxane-2-carboxainide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-oxo-3-(piperidin-I 10 yl)propyl)- I,3-dioxane-2-carboxamide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yI)methyl)-N-(3-(4-methylpiperazin- I -yl) 3-oxopropyl)- Il,3-dioxane-2-carboxarnide; 2-methyl-5-((5-methyl-2-phenyloxazol-4-ylI)methyl)-N-(3-oxo- I -phenylbutan-2-yl) 1,3-dioxane-2-carboxamide; 15 N-benzyloxy-2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)- 1,3-dioxane-2 carboxamide; N-hydroxy-2-mn ethyl-5-(2-(5-methyl-2-phenyloxazol-4-yI)ethyl)- 1,3-dioxane-2 carboxamide; N-hydroxy-2-methyl-5-c-(2-(5 -methyl-2-phenyloxazol-4-yl)ethyl)- 1,3-dioxane-2 20 carboxamide; N-hydroxy-2-methyl-5--(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)- 1,3-dioxane-2 carboxamide; 2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)- 1,3-dioxane-2-carboxamide; 25 2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5--(2-(5-methyl-2-phenyloxazol-4-y)ethyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)- 1,3 -dioxane-2-carboxamide; (2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-1,3-dioxan-2 30 yl)(morpholino)methanone; 16 WO 2011/051961 PCT/IN201O/000650 (2-nethyl-5-c-(2-(5 -meihyl-2-phenyloxazol-4-yl)ethyl)-] 3 -dioxan-2 yI)(morphol i no)methanone; (2-methy 1-5-t-(2-(5 -methyl-2-phenyloxazol-4-yl)ethyl)- 1,3-d ioxan-2 yl)(norphol ino)methanonc; 5 (2-methyl-5-c-(2-(5-nethyl-2-phenyloxazol-4-yl)ethyl)- 1,3-dioxan-2-yl)(4 mcthylpiperazin- I -yl)methanone; (2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-1,3-dioxan-2-y 1)(piperidin-I 1 yl)methanone; (2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)- 1,3-dioxan-2 10 yl)(thiomorpholino)mcthanone; (1,1 -dioxidothionorpholino)(2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yI)ethyl) 1,3-dioxan-2-yl)methanone; 2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-morphol ino-2-oxoethyl)- 1,3 dioxane-2-carboxamide; 15 2-meihyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)etliyl)-N-(2-morpholino-2-oxoethyl) 1,3-dioxanc-2-carboxamide; 2-nethyl-5-1-(2-(5 -methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-morpholino-2-oxoethyl) 1,3-dioxane-2-carboxamide; 2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2-(((tetrahydro-2H 20 pyran-4-yl)methyl)ami no)ethyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-c-(2-(5-methyl-2-plienyloxazol-4-yl)ethyl)-N-(2-(4-methylpiperazin- I -yl) 2-oxoethyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-y1)ethyl)-N-(2-oxo-2 thiomorpholinoethyl)- 1,3-d ioxane-2-carboxamide; 25 2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2-(piperidin-] yl)ethyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(3-oxo-1 -phenylbutan-2-yi) 1,3-dioxane-2-carboxamide; 2-methyl-5-(2-(5-n ethyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2-((3-oxo- I 30 phenyl butan-2-yl)amino)ethyl)-1,3-dioxane-2-carboxanide; )7 WO 2011/051961 PCT1N2010000650 N-benzyloxy-2-methyl-5-((5-rnethyl-2-(p-toyl)oxazol-4-y)methyl)- I ,3-dioxane-2 carhoxam ide; N-benzyloxy-2-methyl-5-c-((5-rnethyl-2-(p-tolyl)oxazol-4-y)methyl)- I ,3-dioxane-2 carboxamide; 5 N-benzyloxy-2-rnethyl-5-r-((5-methyl-2-(p-tolyl)oxazol-4-y)methyl)- I ,3-dioxane-2 carboxamide; N-hydroxy-2-methyl-5-((5-methy I-24(p-tolyl)oxazol-4-yl)methyl)-1I,3-d ioxane-2 carboxarnide; N-hyd roxy-2-mcthyl-5 -c-((5-methyl-2-(p-tolyl)oxazol-4-yl)metliyl)- 1 ,3-d ioxane-2 10 carboxamide; N-hydroxy-2-methyl-5--((5-methyl-2-(p-oly)oxazol-4-ylmethyl)- I ,3-dioxane-2 carboxamide; 2-methyl-5-(5 -met hyl-2-(p-tolyl)oxazo-4-yi )m ethyl)-N.-((tetrahydro-2H-py ran -4 yI)methyl)- 1,3-dioxane-2-carboxamide; 15 2 -merhyl-5 -c-((5-methyi-2-(p-iolyI)oxazol-4-yI)rnethyl)-N-((tetrahydro-2H-pyran-4 yI)rnethyl)- I, 3-d ioxane-2-carboxamidc; 2-methyl-5-r-((5-rnethyl-2-(p-tolyl )oxazol-4-yI)methyl)-N-((tetrahydro-2H-pyran-4 yI)methyl$ I ,3-d ioxane-2-carboxamide; (2-methyl-5-((5-rnethyl-2-(p-tolyl )oxazol-4-yl )methyl)- I ,3-dioxan-2 20 yI)(rnorpholino)rnethanone; (2-methyl-5-c-((5-rnethyl-2-(p-tolyl)oxazol-4-yI)inethyl)- I,3-dioxan-2 yI)(inorphol ino)methanone; (2-metbyl-5-t-((5-methyl-2-(p-tolyl)oxazol -4-yI)methyl )- I,3-dioxan-2 y I)(morpholino)methand'ne; '25 2-methyl-5-((5 -methyl-2-(p-tolyl)oxazol-4-yI)methyl )-N-(2 -morphol ino-2-oxoethy I) I ,3-dioxane-2-carboxamide; 2-mezhyl-5-c-((5-r-nethyl-2-(p-tolyl)oxazol-4-yI)methyl)-N-(2-morphol ino-2-oxoethyl) I ,3-dioxane-2-carboxamidc; 2-rn ethyl -5 -1-((5 -met hyl-2-(p-tolyl)oxazoi -4-yI)methy l)-N-(2 -mnorphol i no-2-oxoechyl ) 30 I ,3-dioxane-2-carboxarnide; WO 2011/951961 PCT/IN2010/000650 N-(benzyloxy)-5-((2-(tert-buty)-5-mehy loxazol-4-yl)methy )-2-methyl- 1,3-dioxane-2 carboxamide; 5-((2-(tert-butyl)-5 -methyloxazol-4-yI)methyl)-N-hydroxy-2-nethyl- 1,3-dioxane-2 carboxamide: 5 (5-((2-(tert-butyl)-5-nethyloxazol-4-yl)methyl)-2-methyl- 1,3-dioxan-2 yl)(morphol ino)m ethanone; 2-methyl-5-c-((5-methyl-2-(5-methylthiophen-2-yl)oxazol-4-yl)methyl)-N ((tetrahydro-2H-pyran-4-yl)n ethyl)-],3-d ioxane-2-carboxam ide; 2-methyl-5-t-((5-methyl-2-(5 -methylthiophen-2-yl)oxazol-4-yl)nethyl)-N-((tetrahydro 10 2H-pyran-4-yl)methyl)- 1,3-dioxane-2-carboxam ide; 2-methyl-5-c-((5-methyl-2-(5-methylthiophen-2-yl)oxazol-4-yl)methyl)- 1,3-dioxan-2 yl)(morphol ino)methanone; 2-methyl -5-t-((5 -methyl-2-(5 -methylthiophen-2-yl)oxazol-4 -yl)methyl)- 1,3 -dioxan-2 yI)(norpholino)methanone; 15 N-benzyloxy-2-methyl-5-c-((5-nethyl-2-(pyridin-4-yl)oxazo-4-yI)methyl)- 1,3 dioxane-2-carboxam ide; N-benzyloxy-2-methyl-5-t-((5-methyl-2-(pyridin-4-yI)oxazol-4-yl)methyl)- 1,3 d ioxane-2-carboxamide; N-hydroxy-2-methyl-5-c-((5-methyl-2-(pyridin-4-yl)oxizol-4-yl)methyl)- 1,3-d ioxane 20 2-carboxamide; N-hydroxy-2-m ethyl-5-i-((5-methyl-2-(pyridin-4-yl)oxazol -4-yl)methyl)- 1,3-dioxane 2-carboxamide; (2-methy I-5-c-((5 -methyi-2-(pyridi n-4-yl)oxazol -4-yl)methy)- 1,3-dioxan-2 yl)(morpholino)methanone; 25 (2-methyl-5-t-((5-methyl-2-(pyrid in-4-yl)oxazol-4-yl)methyl)- 1,3 -dioxan-2 y l)(morpholino)methanone; 2-m eth yl-5-c-((5-methyl-2-(pyridin-4-yl)oxazol-4-yI)methyl)-N-((tetrahydro-2H-pyran 4-yl)methyl)-1 ,3-dioxane-2-carboxam ide; 2-methyl-5 +((5-methyl-2-(pyrid in-4-yl)oxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran 30 4-yl)m ethyl)-1,3-dioxane-2-carboxam ide; 19 WO 201 1/051961 PCTJINZOIO/000650 2-methyl- 5-c-((5 -methyI- 2-(pyridin-4-yI)oxazol -4-y )methyl)-N-(2 -morphoi ino-2 oxoethyl)- I ,3-dioxane-2-carboxamide; 2 -methyI- 5-t-((5-methylI -2-(pyridin-4-y I)oxazol-4-yI)methyl)-N-(2-m orpho lino-2. oxoethyl)- I ,3-dioxane-2-carboxamide; 5 2-m-ethyl- 5-c-((5-methyl-2-(pyridin-4-yl)oxazol-4-yI)methyl)-N-(2-oxo-2-(((tetrahydro 21--pyran-4-yl)rnethy I)amin o)ethyl)- 1 ,3-dioxane-2-carboxamide; 2-methyl -5-t-((5 -methyl-2-(pyridin-4-yI)oxazol-4-yI)methyl)-N-(2-oxo-2-(((tetrahydro 28-pyran-4-yl)methyl)amino)ethyl)- 1 ,3-dioxane-2-carboxamide; N-benzyloxy-2-methyl-5-((4-methyl-2-(4-(tri tluoromethyl)phenyl)thiazol-5-yI)methyl) 0 I ,3-dioxane-2-carboxamide; N-hydroxy-2-rn ethyl -5 -((4-methyl1-2-(4-(tri fl uoromethy1) phenyl)th iazol1-5 -yi)methylI) 1 ,3-dioxane-2-carboxam ide; 1 -(2-methyl-5-((4-m nethyl-2-(4-(trifluoromethyl)pheny I)thiazol-5 -yl)methyl)- 1,3 dioxan-2-yI)-N-((tetrahydro-21--pyran-4-yI)r-nethyimethanamine; 15 (2-methyl-5-((4-methyl-2-(4-(tritluaromethyl)phenyl)thiazol-5-yl)methyl)- I ,3-dioxan 2-yl)(m-orphol ino)methanone; (2-methyl-5-c-((4-r-nethyl-2-(4-(tri fluoromethyl)p henyl)thiazol-5-yI)methy I)- 1,3 dioxan-2-yl )(morpholino)methanone; (2 -met hyl -5-r-((4-m effyi1-2-(4-(tri fluorom ethyl)pheny fth iazoi-5 -yi)methyl)- 1.3 20 dioxan-2-yl)(morphoiino)methanone; 5-c-(3-(9H-carbazol-9-yI)propyl)-N-hydroxy -2-methyl- 1,3-dioxane-2-carboxamide; N-hydroxy-5-c-(3-( I OH -phenothiazin-1I -yI)propyl)-2 -methyl-I ,3-di oxane-2 carboxam ide; N-(benzyloxy)-5-((3-(tert-butyl)- I -(p-tolyl[)-I 1 H-pyrazol- 5-yi)m ethyl)- 2-methyl1- 1,3 25 dioxane-2-carboxarnide; N-(hydroxy)-5-c-((3 -(tert-butyl)- I -(p-tolyi)-] 1 -- pyrazol -5-yl)methylI)-2-methyl- 1,3 d ioxane-2-carboxam ide; N-(hydroxy)-5-t-((3-(tert-butyi) I -(p-tolyl)- I HWpyrazol-5-yI)r-nethyl)-2-mcthyl- 1,3 dioxane-2-carboxamide; 30 5-((3 -(tert-butyl)- I -(p-tolyi)- IH-pyrazol-5-yl)mezhyl)-2-methyl-N-((tetrahydro-2H pyran-4-yI)methyl )- 1,3 -dioxane-2-carboxam-ide; 20 WO 2011/051961 PCT/IN2010/000650 5-((3-(tert-butyl)- 1 -(p-tolyl)- I H-pyrazol-5-yI)metlhyl)-2-methyl-N-(2-oxo-2 (((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)- 1,3-dioxane-2-carboxamide; (5-((3-(tert-butyl)- I -(p-tolyl)- I H-pyrazol-5-yl)methyl)-2-methyl-I,3-di oxan-2 yl)(morpholino)methanone; 5 5-((3-(tert-butyl)-1 -(p-tolyI)- I H-pyrazol-5-yl)methyl)-2-methyl-N-(2-norpholino-2 oxoethyl)- I,3-dioxane-2-carboxamide; (5-((3-(tert-butyl)-I-(p-tolyl)- 1H-pyrazol-5-yl)nethyl)-2-methyl-1,3-dioxan-2-yI)(4 methylpiperazin-I -yl)nethanone; N-(benzyl oxy)-5-c-((2-(4-metlhoxyphenyl)-5 -methyloxazol-4-yI)methyl)-2-methyl- 1,3 10 dioxane-2-carboxam ide; N-(benzyl oxy)-5-+-((2-(4-inethoxyphenyl)-5-methyloxazol-4-yl)m ethyl)-2-methyl- 1,3 d ioxane-2-carboxamide; N-hydroxy-5-c-((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl- 1,3 dioxane-2-carboxamide; 15 N-hydroxy-5-t-((2-(4-methoxyphenyl)-5-nethyloxazol-4-yl)methyl)-2-methyl-1,3 dioxane-2-carboxanide; (5-c-((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl-1,3-dioxan-2 yl)(morpholino)methanone; (5--((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl- 1,3-dioxan-2 20 yi)(morpholino)methanone; 5-c-((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl-N-((tetrahydro-2H pyran-4-yl)methyl)- 1,3-dioxane-2-carboxamide; 5-t-((2-(4-methoxyphenyl)-5-nethyloxazol-4-yl)methyl)-2-methyl-N-((tetrahydro-2H pyran-4-yI)methyl)- 1,3-d ioxane-2-carboxamide; 25 (5-c-((2-(4-nethoxyphenyl)-5-methyloxazol-4-yl)nethyl)-2-methyl- 1,3-dioxan-2-yl)(4 methylpiperazin- I-yl)inethanone; (5-t-((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl- 1,3-dioxan-2-yl)(4 nethylpiperazin-I -yl)methanone; N-(benzyloxy)-2-methyl-5-c-((5-methyl-2-(4-(trifluoronethyl)phenyl)oxazol-4 30 yI)methyl)-1,3-dioxane-2-carboxamide; 21 WO 2011/051961 PCT/IN2010/000650 N-(benzyloxy)-2-methyl-5-t-((5-methyl-2-(4-(trifl uoromethyl)phenyl)oxazol-4 yl)nethyl)- I,3-dioxane-2-carboxamide; N-hydroxy-2-methyl-5-c-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methyl) 1,3-dioxane-2-carboxamide; 5 N-hydroxy-2-methyl-5--((5-methyl-2-(4-(tri fl uoromethyl)phenyl)oxazol-4-yI)m ethyl) 1,3-dioxane-2-carboxamide; (2-methyl-5-c-((5-methyl-2-(4-(trifluorom ethyl)phenyl)oxazol-4-yl)methyl)- 1,3 d ioxan-2-yl)(morphol i nci)methanone; (2-methyl -5 -t-((5-methyl-2-(4-(tri fluoromethyl)phcnyi)oxazol-4-yl)methyl)- 1,3-d ioxan 10 2-yl)(morpholino)methanone; 2-methyl-5-c-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-y )methy l)-N ((tetrahydro-2H-pyran-4-yl)methyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-t-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methyl)-N ((tetrahydro-2H-pyran-4-yl)methyl)- 1,3-dioxane-2-carboxam ide; is The novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. it is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the 20 purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art, It will also be appreciated that one or more of the compounds of the present invention may exist in stercoisomeric and/or diastereomeric forms. Such stereoisomers and/or 25 diastereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be 30 construed to be within the scope of the present invention. 22 WO 2011/051961 PCT/IN2010/000650 Scheme 1: The compounds of general formula (1) wherein all the symbols are as defined earlier, may be prepared by reactions outlined in Scheme I below which comprises COOEt Method A OEi Melhod B OH HET-X-L + H HET-X - 0 HET-X COOEt OEt OH Il lil IV O
R
1
C(O)COOR
6 VI Method C YH + HET-X -C ROH -Method D HET-X 0 R 0R V O O Method E Method H HET- Y Method F ,HET-X YR Ila) 0 0 Method A: Compounds of formula (V wherein 'HET' and X are as defined earlier may be prepared by reacting compounds of general formula (II) where 'L is a suitable leaving group and 'HET' and ' are as defined earlier with diethyl malonate (III) in presence of appropriate base (e.g.NaH, NaOH, KOI, KOt-Bu and the like) in 10an appropriate solvent such as THF, DMF, toluene, dioxane, dimethyl sulfoxide and the like or their suitable mixtures. The reaction may be carried out at the temperatures ranging from 20 *C to the boiling point of the solvent(s) used. The reaction may be carried out in an inert atmosphere. The reaction time may range from 2 hours to 2 days. Method B: Compounds of formula (V) wherein 'HET' and 'X' are as defined earlier may be prepared by the reduction of compounds of general formula (IV) where 'HET' and 'X' are as defined earlier with appropriate reducing agents such as LiAlH4, NaBH4 and the like in an appropriate solvent such as THF, diethyl ether, dioxane, ethanol, methanol, water and the like or their suitable mixtures, The reaction may be 23 WO 2011/051961 PCT/IN2010/000650 carried out at the temperatures ranging from 20 *C to the boiling point of the solvent(s) used. The reaction may be carried out in an inert atmosphere. The reaction time may range from 2 hours to 2 days. Method C: The diol of formula (V) may be converted to dioxane of formula 5 (VII) wherein 'HET', 'X' and R, are as defined earlier and R6 is C(I.
6 ) linear or branched alkyl, cycloalkyl or aryl group as defined earlier, by reacting with appropriate ketoester RiC(O)COOR 6 (VI) in presence of a suitable Lewis acid e.g. boron trifluoride etherate complex and the like. Reaction may be conducted in an appropriate solvent e.g., polar solvents such as acetonitrile or N,N-dimethyl formamide (DMIF); ether 10 solvents such as tetrahydrofuran (THF) or diethyl ether, diisopropyl ether 1,2 dimethoxyethane; halogenated hydrocarbon solvents such as chloroform or dichloromyethane; hydrocarbon solvents such as benzene, toluene, hexane, heptane or mixtures of appropriate solvents selected from those described above. The reaction may be carried out at a temperature in the range -20 *C to reflux temperature of the IS solvent(s) used and the reaction time may range from 1 h to 4 days. Method D: The compound of formula (VII) may be hydrolysed to compound of formula (VIII) where 'HET', Ri and 'X' are as defined earlier using suitable base e.g., NaOH, LiOH, KOH and the like. Reaction may be conducted in suitable solvents such as alcohols like methanol, ethanol, propanol, isopropanol, butanol and the like, 20 THF, water or mixtures thereof. The reaction may be carried out at a temperature in the range 20 "C to reflux temperature of the solvent(s) used and the reaction time may range from I to 48 hours. Method E: Compounds of formula (Ia) where 'HET', Ri, 'X' and 'Y' are as defined earlier may be prepared by coupling of compounds of formula (VIII) and YH 25 using suitable methods available in the literature for standard peptide coupling. Method F: Compounds of formula (I) wherein 'Y' is NR 2
R
3 & where R, is OH and 'HET', R1, R 3 and 'X' are as defined earlier may be prepared by debenzylation of compounds of formula (1a) where 'Y' is NR 2
R
3 wherein R 2 is OBn and 'HET', R 1 , R 3 and 'X' are as defined earlier using suitable methods available in, the literature for 30 deprotection of a benzyl group. 24 WO 2011/051961 PCT/TN2010/000650 Method G: Compounds of formula (I) where 'Y' is NR 2
R
3 wherein R 2 is OH and 'A', R 1 , R 3 and 'X' are as defined earlier may also be prepared from corresponding acid compounds of formula (VIII) using suitable methods available in the literature for conversion of acid to hydroxamic acid. 5 Method H; Compounds of formula (1) where 'Y' is NR 2
R
3 & wherein R 2 is OH and 'A', RI, R 3 and 'X' are as defined earlier may further be prepared from corresponding ester compounds of formula (V11) using suitable methods available in the literature for conversion of an ester to a hydroxamic acid. Scheme 2: The compounds of general formula (Ia) wherein 'HET' represents 10 hetercoaryl or heterocyclyl group which are connected to X through N atom, may also be prepared by reactions outlined in Scheme 2 below. 0 R 1 Method I0 L-X OR Mhd L-X OH + YH oX 0 o0 Ix x Method J HET-X Y MethodK HET + L-X Y o~ 0Y 0 0 (Ila) XII XI Method I: The compound of formula (IX) may be hydrolyzed to compound of formula (X) wherein 'L', 'X', R, and R6 are as defined earlier using suitable base e.g., i5 NaOH, LIOH, KOH and the like, Reaction may be conducted in suitable solvents such as alcohols like methanol, ethanol, propanol, isopropanol, butanol and the like, THF, water or mixtures thereof, The reaction may be carried out at a temperature in the range 20 "C to reflux temperature of the solvent(s) used and the reaction time may range from I to 48 hours. 20 Method J: Compounds of formula (XI) wherein R 1 , 'L, 'X and 'Y' are as defined earlier may be prepared by coupling of compounds of formula (X) and YH using suitable methods available in the literature for standard peptide coupling. Method K; Compounds of formula ([a) wherein 'IHET' represents heteroaryl or heterocyclyl group and R 1 , 'X' and 'Y' are as defined earlier may be prepared by 25 WO 2011/051961 PCT/WN2010/000650 reacting compounds of general formula (XI) wherein RI, ', 'X' and 'Y' are as defined earlier with compounds of general formula (XII) wherein 'HET' represents heteroaryl or heterocyclyl group in presence of appropriate base (e.g ,NaOH, KOH, NaH, KOt-Bu and the like) in an appropriate solvent such as dimethyl sulfoxide, THF, 5 DMF, toluene, dioxane and the like or their suitable mixtures. The reaction may be carried out at the temperatures ranging from 0 "C to the boiling point of the solvent(s) used. The reaction may be carried out in an inert atmosphere. The reaction time may range from 2 hours to 2 days. The compounds of formula (1) or pharmaceutical compositions containing them 10 are useful as PCSK9 ligands suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with dyslipidemia, and related disorders. The pharmaceutical composition is provided by employing conventional 15 techniques. Preferably (he composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (1) according to this invention. The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form 20 thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition. The compounds of the invention or their suitable pharmaceutical compositions 25 are inhibitors of PCSK9 & can be used for the treatment of dyslipidemia and related diseases to an individual in need of such treatment. The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of (he invention as is otherwise described elsewhere in (he specification. 30 '1H NMR spectral data given in the examples videe infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in d scale. Until and otherwise 26 WO 2011/051961 PCTIN2010/000650 mentioned the solvent used for NMR is CDCI3 using tetramethyl silane as the internal standard. Mass (ESI-MS) spectral data in the examples are recorded using a Shimadzu LC-MS 2010-A spectrometer. Example 1 5 N-(benzyloxy)-2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxane-2 carboxamide Step, 1: diethyl 2-((5-methyl-2-phenyloxazol-4-yl)methyl)malonate Diethyl malonate (58 gm, 0.12 moles) was added dropwise to an ice cold suspention of NaH (50%) (8.7 gm, 0.18 moles) in THF (50 ml) at 0-10 "C over a period 10 of 30 min. under nitrogen atmosphere and reaction mixture was stirred at about 25 *C for 30 min. A solution of 4-(chloromethyl)-5-inethyl-2-phenyloxazole (25 gm, 0.12 moles) in THIF (100 ml) was added to the reaction' mixture at 25 *C and reaction mixture was stirred at 25 *C for 18 hours. The reaction mixture was poured into ice cold water and extracted by ethyl acetate. The combined ethyl acetate extract was is washed with water and brine, dried over sodium sulphatetand evapourated in vacuum. Excess diethyl malonate was distilled out under vacuum and the residue was purified by column chromatography (Eluent : 5% to 7% ethyl acetate in hexane) to yield 23 gin required product as thick liquid. 'H NMR: 1.24 (t, J= 7.2 Hz, 6H), 2.34 (s, 3H), 3.07 (d, J=-7.6 Hz, 2H), 3.88 (t, J= 7,6 20 Hz, 1H), 4.15-4.22 (m, 2H), 7.39-7.45 (m, 3), 7,94-7.97 (in, 2H-), ESI/MS m/z : 331.1 (M+H) Yield: 58% Step 2: 2-((5-methyl-2-phenyloxazol-4-yl)methyl)propane-1,3-diol NaBH 4 (21 gm, 0.56 moles) was added in small portions to a solution of the 25 product of step 1 (23 gm, 0.69 moles) in EtOH (80 ml) at 10 *C and the reaction mixture was stirred at 25 "C for 6 hours. The reaction mixture was poured into ice cold water, acidified (2 pH) and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated in vacuum. The residue was triturated in diisopropyl ether to yield 8.0 gm of product as 30 white solid. 27 WO 2011/051961 PCT/IN2010/000650 'H NMR: 2.03-2.11 (m, 1H), 2.36 (s, 3H), 2.66 (d, J 6.8 Hz, 6H), 3.71-3.82 (in, 4H), 7.39-7.44 (m. 3H), 7.94-7.98 (in, 2H). ESI/MS m/z: 247.1 (M+H) Yield: 46% 5 Step 3: methyl 2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxane-2 carboxylate Methyl pyruvate (15.5 ml, 0.17 moles) was added to a solution of the product of step 2 (7.0 gin, 0.028 moles) in CH 3 CN (50 ml) followed by drop wise addition of
BF
3 .Et 2 O (10.68 ml, 0.085 moles) at 25 *C under nitrogen atmosphere and the reaction 10 mixture was stirred at 25 *C for 18 hours. The reaction mixture was poured into ice cold NaHCO 3 solution (300 ml) and extracted by ethyl acetate. The combined ethyl acetate extract was washed with water and brine; dried over sodium sulphate and evapourated in vacuum. The crude product was purified by column chromatography (Eluent : 15% ethyl acetate in hexane) to yield 6,5 gm required product as thick liquid. 15 ESl/MS m/z ' 331.1 (M+H) t Yield: 69% Step 4: 2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxane-2-carboxvlic acid To a solution of the product of step 3 (5.0 gm, 15.10 mmoles) in a mixture of 20 methanol (6 ml), THF (18 ml) and H2O (6 ml) was added a solution of lithium hydroxide (1.27 gm, 30.20 mmoles) in water and the reaction mixture was stirred at ambient temperature for 3 hours. The solvents were evaporated and the residue was dissolved in water, acidified with IN HCI and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried over sodium 25 sulphate and evaporated under reduced pressure to yield 3.5 gm of product as the mixture of cis and trans isomer as white solid. ESI/MS m/z : 317.1 (M+H) Yield: 77% Step 5: N-(benzyloxy)-2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyll-1.3 30 dioxane-2-carboxamide 28 WO 2011/051961 PCT/IN2010/000650 To a solution of the product of step 4 (1.76 gm, 5.6 mmoles) in DMF (10 mL), O-benzyl hydroxylamine hydrochloride (927 mg, 5.8 rnmoles), HOBT (.16 gm, 8.7 mmoles), EDCI (1,28 gm, 6.6 mmoles) and N-ethyl morpholine (2,11 ml, 16.7 mmoles) were added and reaction mixture was srirred at 25 "C for 5 hours under nitrogen 5 atmosphere. The reaction mixture was poured into ice cold water. White solid seperated which was filtered and washed with water & dried over P 2 0s under vacuum to yield 1.7 gm of the desired product as thick liquid. ESI/MS m/z : 445.0 (M+H)* Yield: 86% jo Example 2 N-(benzyloxy)-2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl.)methyl)-1,3-dioxane-2 carboxamide Step 1: 2-methyl-5-t-((5-methyl-2-phenvloxazol-4-vl)methyl)-1,3-dioxane-2-carboxylic acid 15 The product obtained from step 4 of example I was recrystallized using 5% methanol in ethyl acetate (20 ml) at 25 *C to yield 1.76 mg of pure cis isomer as white solid. 'H NMR (DMSO-D 6 ): 1.32 (s, 3H), 2.16-2.24 (im 3H), 2.28 (m, 3H), 3.44 (t, J= 11.2 Hz, 2H), 3.82 (dd, J= 11.4 & 3.4 Hz, 2H), 7.45-7.5 I (m, 3H), 8.87-8.90 (m, 2H). 20 ESI/MS m/z: 31 7.2 (M+H)* Yield: 37% Step 2: N-(benzyloxy)-2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-1.3 dioxane-2-carboxamide To a solution of the product of step 1 (1.76 gm; 5.6 mmoles) in DMF (10 mL), 25 O-benzyl hydroxylamine hydrochloride (927 mg, 5.8 mmoles), HOBT (1.16 gm, 8.7 moless, EOi (1.28 gm, 6.6 mmoles) and N-ethyl morpholine (2.11 ml, 16.7 moles) were added and reaction mixture was srirred at 25 *C for 5 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water. White solid seperated which was filtered and washed with water & dried over P 2 0 5 under vacuum to yield .7 30 gm of the desired product as thick liquid. 29 WO 2011/051961 PCT/IN2010/000650 '14 NMR (DMSO-D 6 ): 1.25 (s, 3H), 2.11-2.15 (m, 3H), 2.28 (s, 3H), 3.30 (t, J = 11.0 Hz, 211), 3.74-3.78 (m, 2H), 4.81 (s, 211), 7.32-7.39 (m, 5H), 7.45-7.49 (m, 311), 7.50 7.89 (m, 2H), 11.45 (s, NH). ESI/MS m/z : 423.2 (M+H) 5 Yield: 45% Example 3 N-(benzyloxy)-2-methyl-5--((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxane-2 carboxam ide Step 1: 2-methyl-5-t-((5-methvl-2-phenyloxazo-4-vl)methyl)-1,3-dioxane-2-carboxvlic 10 acid The mother liquor after the crystallization of cis isomer in step I of example 2 was concentrated under vacuum. The residue was recrystallized using ethyl acetate (30 ml) at 25 C to yield 1.5 gm of pure trans isomer as off white solid. H NMR (DMSO-D 6 ); 1.39 (s, 3H), 1.70-1.74 (m, IH), 2.23 (s, 3H), 2.76 (d, J = 7.6 is Hz, 2H), 3.63 (d, J = 11.2 Hz, 2H), 3.88 (d, J =11.8 & 2.2 Hz, 2H), 7.43-751 (m, 3H), 8.86-8.89 (in, 2H). ESI/MS m/z : 317.0 (M+H4) Yield: 31% Step 2: N-(benzyloxy)-2-methyl-5--((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3 20 dioxane-2-carboxamide To a solution of the product of step 4 (1,50 gm, 4.77 mmoles) in DMF (10 mL). O-benzyl hydroxylamine hydrochloride (927 mg,' 5.8 mmoles), HOBT (1.00 gm, 7.44 mmoles), EDCI (1.10 gin, 5.7 mmoles) and N-ethyl morpholine (1.80 ml, 14.31 mmoles) were added and reaction mixture was srirred at 25 "C for 5 hours under 25 nitrogen atmosphere. The reaction mixture was poured into ice cold water. White solid seperated which was filtered and washed with water & dried over P 2 0 5 under vacuum to yield 1.4 gm of the desired product as thick liquid, H NMR : 1.49 (s, 3H), 1.83-1.89 (in, 1H), 2.34 (s, 3H), 2.78 (d, J = 7.6 Hz, 2H), 3.67 (d, J = 11.2 Hz, 2H), 3.85 (dd, J = 11.8 Hz, 21), 4.99 (s. 2H), 7.34-7.45 (m, 8H), 7.94 30 7.97 (m, 2H), 8.67 (s, NH). ESL/MS m/z : 423.2 (M+H)* 30 WO 2011/051961 PCT/IN2010/000650 Yield: 42% Example 4 N-(Hydroxy)-2-nethyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)- 1,3-dioxane-2 carboxamide 5 To a suspension of 10% palladium on charcoal (150 ng) in methanol (20 mL) was added the product of step 5 (1.7 gm, 4.04 mmoles) followed by addition of ammonium formate (1.27 g, 20.2 mmoles) and the reaction mixture was heated to reflux for 2-5 hours. The reaction mixture was cooled to ambient temperature and the catalyst was filtered off, The filtrate was evaporated and the residue was taken in ethyl 10 acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was recrystallised from a mixture of ethyl acetate and petroleum ether (1:1) (25 ml) to obtain 900 mg of the desired product as white solid. ESI/MS m/z : 333.1 (M+H) 15 Yield: 67% Example 5 N-benzyloxy-5-c-(3-(9H-carbazol-9-yl)propyl)-2-methyl-1,3-dioxane-2-carboxamide Step 1: c-5-(3-chloropropyl)-2-methyl-1,3-dioxane-2-carboxylic acid To a solution of methyl 5-(3 -ch loropropyl)-2-methyl- 1,3 -dioxane-2-carboxylate 20 (5.0 gm, 0.021 moles) in a mixture of methanol (8 ml), THF (24 ml) and H 2 0 (8 ml) was added a solution of lithium hydroxide (1.77 gm, 0.042 moles) in water and the reaction mixture was stirred at ambient temperature for 18 hours. The solvents were evaporated and the residue was dissolved in water, acidified with IN HCI and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried 25 over sodium sulphate and evaporated under reduced pressure to yield 3.91 gm of product as thick liqid. H NMR: 1,20-1.27 (m, 2H), 1,58 (s, 31-), 1.71-1.78 (m, 2H), 2.03-2.09 (m, 11H), 3.47 3.59 (m, 4H), 3.98 (dd, J= 12.2 & 4.6 Hz, 2H), ESI/MS m/z : 222.1 (M+H) 30 Yield: 83% Step 2: N-(benzyloxy)-5-c-(3-ch loropropyl)-2-methyl- 1, 3-dioxane-2-carboxamide 31 WO 2011/051961 PCT/IN2010/000650 To a solution of the product of step 1 (3.91 gm, 0.0176 moles) in DMF (20 mL), 0-benzyl hydroxylamine hydrochloride (2.93 gm, 0.0184 moles), HOBT (3.70 gm, 0.0275 moles), EDCI (4.05 gm, 0.0211 moles) and N-ethyl morpholine (6.2 ml, 0.0528 moles) were added and reaction mixture was stirred at 25 "C for 24 hours under 5 nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted by ethyl acetae, The ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was triturated in hexane to yield 5.3 gm of product as thick liquid. H NMR: 1.12-1.20 (m, 2H), 1.45 (s, 3H), 1.79-1.82 (in, 2H), 1.89-1.94 (in, 1N), 3.27 i (t,j = 11.4 Hz, 2H), 3,45-3,49 (m, 2H), 3.85-3.88 (m, 2H), 5.01 (s, 2H), 7,35-7.41 (m, 5H). ESI/MS m/z: 327.1 (M+H)* Yield: 89% Step 3: N-(benzy loxy)-c-5-(3-(9H-carbazol-9-y I)propyl)-2-methyl- 1,3-dioxan e-2 15 carboxamide To an ice cold suspension of KOH powder (685 mg, 12.23 mmoles) in DMSO (2 ml), a solution of the product of step 2 (1.0 gm, 3.06 mmoles) and 91-carbazole (511 mg, 3.06 mmoles) in DMSO (3 mL) was added dropwise at 0-5 *C under nitrogen atmosphere and reaction mixture was srirred at 25 "C for 2 hours under nitrogen 20 atmosphere. The reaction mixture was poured into ice cold water and extracted by ethyl acetae. The ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by column chromatography (Eluent: 17% ethyl acetate in hexane) to yield 500 mg of product as thick liquid. 25 IH NMR: 1.02-1.04 (m, 2H), 1.39 (s, 3H), 1.79-1.83 (m, 2H), 1.89-1,91 (m, IFH), 3,15 (t, J = 11.6 Hz, 2H), 3.74 (dd, J = 11.8 & 4.2, 2H), 4.28 (t, J = 7.0 Hz, 2H), 4.96 (s, 2H), 7.22-7.26 (m, 2H), 7.34-7.44 (m, 7H), 7.45-7.49 (m, 2H), 8.11 (d, J = 7.6 Hz, 2H), 8.55 (s, NH). ESI/MSm/z: 459.1 (M+H) 30 Yield: 92% 32 WO 2011/051961 PCT/IN2010/000650 The following examples were prepared following the general procedures given in Example 1-5, with suitable modifications, alterations and other process variations which are within the scope of a person skilled in the art. Example 6 5 N-hydroxy-2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)- 1,3-dioxane-2 carboxamide 'H NMR (DMSO-D 6 ): 1.28 (s, 3H), 2.12-2.18 (m, 1IH), 2.20-2.21 (m, 2H), 2.28 (s, 3H), 3.43 (t, 3 = 11.0 Hz, 2H), 3.79-3.83 (dd, J = 12.0 & 4.0 Hz, 2H), 7.47-7.51 (in, 3H), 7.88-7.90 (m, 2H), 8.85 (s, NH), 10.84 (s, OH). 10 ESI/MS m/z: 333.2 (M+H)* Yield: 67% Example'7 N-hydroxy-2-methyl-5-t-((5-methyl-2-phenyloxazol-4-yl)nethyl)-1,3-dioxane-2 carboxamide 15 'H NMR (DMSO-D): 1.36 (s, 3H), 1.74 (m, IH), 2.33 (s, 3H), 2.73 (d, J = 7.6 Hz, 2H), 3.60 (d, J = 11.2 Hz, 2H), 3.84 (d, J = 10.0 Hz, 21-), 7.47-7.51 (m, 31-1), 7.88-7.90 (in, 2H), 8,83 (s, NH), 10.81 (s, OH), ESI/MS m/z : 333.2 (M+H)* Yield: 27% 20 Example 8 2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)-1,3-dioxane-2-carboxamide ESI/MS m/z: 415.1 (M+H)* Yield: 76% 25 Example 9 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)-1,3-dioxane-2-carboxamide "H NMR (DMSO-D 6 ): 1.05-1,15 (in, 2H), 1.27 (s, 3H), 1.45-1.49 (m, 2H), 1.65-1.72 (m, 1IH), 2.13-2.20 (m. 1 H), 2.22 (d, I = 6.8 Hz, 2H), 2.27 (s, 3H), 2.96 (t, J =6.4 Hz, 30 2H), 3.17-3.22 (t, J = 9.6 H, 2H). 3.39 (t. J = 11.2 Hz, 2H), 3.77-3.84 (m, 4H), 7.44 7.51 (m. 3H), 7.86-7.90 (m, 2H), 8.05 (1, NH). 33 WO 2011/051961 PCT/IN2010/000650 ESI/MS m/z : 416.1 (M+H)* Yield: 95% Example 10 2-nethyl-5--((5-methyl-2-phenyloxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 5 yI)methyl)-1,3-dioxane-2-carboxanide ESI/MS m/z : 416.1 (M+H)* Yield: 84% Example 11 (2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxan-2 10 yl)(norpholino)methanone ESI/MS m/z: 387.2 (M+H)' Yield: 41% Example 12 (2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxan-2 15 yl)(morpholino)methanone 'H NMR(DMSO-D 6 ): 1.33 (s, 3H), 2.18-2.25 (m, 3H), 2.28 (s, 3H), 3.51-3.56 (m, 8H), 3.76-3.77 (m, 2H), 3.82 (dd, J = 11.6 & 3.6 Hz, 2H), 7,44-7.51 (m, 3H), 7.87-7.90 (m, 2H). ESI/MS m/z: 409.0 (M+Na)* 20 Yield: 65% Example 13 (2-methyl-5--((5-methyl-2-phenyloxazol-4-y)methyl)l I,3-dioxan-2 yl)(rnorpholino)methanone ESI/MS m/z: 387.2 (M+H) t 25 Yield: 58% Example 14 (2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)nethyl)-1,3-dioxan-2-yI)(4 methylpiperazin- I -yl)methanone 'H NMR; 1.49 (s, 3H), 2.21 (d, J = 7,2 Hz, 2H), 2.28 (s, 3H), 2.30 (s,. 3H), 2.39-2.50 30 (n, 5H), 3.63 (t, J = 11.6 Hz, 2H), 3,72-3,74 (m, 2H), 3.86-3.88 (m, 2H), 3.96 (dd, J = 11.8 & 4.6 Hz. 2H), 7.39-7,45 (m, 3H), 7.95-7.97 (m, 2H). 34 WO 2011/051961 PCT/IN2010/000650 ESI/MS m/z: 400.0 (M+H)* Yield: 48% Example 15 (2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxan-2-yl)(piperidin-I 5 yl)methanone H NMR: 1.49 (s, 3H), 1.53-1.73 (m, 6H), 2.20 (d, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.42 2.51 (m, I H), 3.62-3.68 (m, 4H), 3.78-3.79 (m, 21A), 3.96 (dd, J = 11.8 & 4.6 Hz, 211), 7.38-7.45 (m, 3H), 7.95-7.97 (m, 2H). ESI/MS m/z: 384.9 (M+H)' 10 Yield: 85% Example 16 (2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3-dioxan-2 yl)(thiomorpholino)nethanone 'H NMR: 1.50 (s, 31H), 2,21 (d, J = 7,2 Hz, 2H), 2.28 (s, 3H), 2.43-2.49 (m, I H), 2.66 15 2.68 (in, 4H), 3.63 (t, J = 1 .A Hz, 2H), 3.94-3.95 (n, 2H), 3.97 (dd, J = 11.8 & 4,6 Hz, 2H), 4.10-4.11 (m, 21H), 7.40-7.45 (m, 3H), 7.95-7.97 (m, 2H), ESI/MS im/z: 403.3 (M+H)* Yield: 84% Example 17 20 (1,1 -dioxidothiamorpholino)(2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl) 1,3-dioxan-2-yl)methanone 'H NMR: 1.53 (s, 3H), 2.24 (d, J = 7.2 Hz, 2H), 2.29 (s, 3H), 2.43-2.49 (m, 1H), 3.063.08 (m. 4H), 3.60 (t, J = 11.6 Hz, 2H), 4,05 (dd, J = 11.8 & 4.6 Hz, 2H), 4,19-4.20 (m, 2H), 4.36 (bs, 2H), 7.41-7.46 (m, 3H), 7.94-7,97 (m, 2H). 25 ESI/MS m/z : 434.8 (M+H)' Yield: 74% Example 18 2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(2-inorpholino-2-oxoethyl)- 1,3 dioxane-2-carboxanide 30 ESI/MS m/z: 444.1 (M+H) 4 Yield: 55% 35 WO 2011/051961 PCT/IN2010/000650 Example 19 2-methyl-5-c-((5-nethyl-2-phenyloxazol-4-yl)methyl)-N-(2-morpholino-2-oxoethyl) 1,3-dioxane-2-carboxamide 1H NMR: 1.51 (s, 3H), 2.25 (d, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.38-2.45 (m, 1H), 3.42 s (t, J = 4.8 Hz, 2H), 3.57-3.66 (m, 4H), 3.69-3.72 (in, 411), 4.01 (dd, ) = 12.0 & 4.4 Hz, 2H), 4.13 (d, J = 4.4 Hz, 2H), 7.32-7.33 (in, NH), .7,39-7.44 (m, 3H), 7.94-7.96 (in, 2H), ESUIMS m/z: 444.3 (M+H) t Yield: 84% 10 Example 20 2-methyl-5--((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(2-morpholino-2-oxoethyl) 1,3-dioxane-2-carboxamide ESI/MS m/z: 444.1 (M+H) Yield: 49% 15 Example 21 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(2-(4-methylpiperazin- 1-yl) 2-oxoethyl)- 1,3-dioxane-2-carboxamide 'H NMR: 1.50 (s, 3H), 2.24 (d, J 7.2 Hz, 2H), 2.28 (s, 3H), 2.32 (s, 3H), 2.37-2.44 (in, 511), 3.42 (t. = 5.0 Hz, 2H), 3.56 (t, J = 11.4 Hz, 211), 3.65 (t, J = 5.0 Hz, 2H), 20 4.00 (dd, J - 12.0 & 4.4 Hz, 2H), 4.13 (d, J = 4.0 Hz, 2H), 7.34-7.36 (in, NH), 7.37 7,44 (in, 3H), 7.93-7.96 (in, 2H). ES1/MS in/z: 457.5 (M+H) t Yield: 52% Example 22 25 2-rnethyl-5-c-((5-methyl-2-phenyloxazol-4-yl)m ethyl)-N-(2-oxo-2-(piperid in-] yl)ethyl)- 1,3-dioxane-2-carboxamide 'H NMR: 1.51 (s, 3H), 1.55-1.71 (in, 6H), 2.24 (d, J = 7.6 Hz. 2H), 2.28 (s, 3H), 2.37 2.44 (in, 1H), 3.34 (t. J = 5.4 Hz, 2H), 3.56-3,62 (in, 4H), 4.00 (dd, J= 12.0 & 4.4 Hz, 2H), 4.12 (d, J = 5.2 Hz, 2H), 7.39-7,44 (in, 4H), 7.93-7.96 (m, 2H). 30 ESI/MS in/z : 442.4 (M+H)* Yield: 68% 36 WO 2011/051961 PCT/IN2010/000650 Example 23 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)nethyl)-N-(2-oxo-2 thiomorpholinoethyl)-1,3-dioxane-2-carboxamide H NMR: 1.51 (s, 3H), 2.25 (d, J = 7.6 Hz, 2H), 2.28 (s, 3H), 2.37-2.45 (in, IH), 2.64 5 2.66 (in, 4H), 3.56 (t, J = 11.2 Hz, 2H), 3.68 (t, J = 5.0 Hz, 2H), 3.90 (t, J = 5.0 Hz, 2H), 4.01 (dd, J = 12.0 & 4.4 Hz, 2H), 4.13 (d, J 4.4 Hz, 2H), 7.34 (s, NH), 7.38-7.45 (in, 3H), 7.94-7.97 (in, 2H). ESI/MS n/z : 460.4 (M+H)* Yield: 54% 10 Example 24 N-(2-(I, 1-dioxidothiomorpholino)-2-oxoethyl)-2-methyl-5-c-((5-methyl-2 phenyloxazol-4-yl)methyl)-I 3-dioxane-2-carboxamide 'H NMR: 1.51 (s, 3H), 2,27-2.29 (m, 5H), 2.37-2.43 (in, 1H), 3.07-3.10 (in, 4H), 3.58 (t, J = 11.0 Hz, 2H), 2.942.96 (in, 2H), 4.02 (dd, J = 12.0 & 4.0 Hz, 2H), 4.13-4.14 (in, 15 2H), 4.20 (d, J = 4.8 Hz, 2H), 7.21 (bs, NH), 7.41-7.44 (in, 3H), 7.94-7.96 (in, 2H). ESI/MS m/z: 491.8 (M+H) 4 Yield: 47% Example 25 2-inethyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(2-oxo-2-(((tetrahydro-2H 20 pyran-4-yl)methyl)anino)ethyl)- I,3-dioxane-2-carboxamide 'H NMR: 1.25-1.32 (m, 2H), 1.50 (s, 3H), 1.59-1.63 (in, 2H), 1,71-1.80 (in, I H), 2.26 2.29 (in, 5H), 2.35-2.45 (in, I H), 317 (t, J = 6.4 Hz, 2H), 3.33-3.39 (in, 2H), 3.54 (t, J = 11.0 Hz, 2H), 3.95-4.05 (in, 6H), 6.12 (s, NH), 7.08 (t, J = 5.4 Hz, NH), 7.38-7.45 (m, 3H), 7.94-7.97 (in, 2H). 25 ESI/MS m/z: 427.0 (M+H)* Yield: 53% Example 26 2-methyl-5-c-((5-nethyl-2-phenyloxazol-4-yl)methyl)-N-(3-morpholino-3-oxopropyl) I,3-dioxane-2-carboxamide 30 'H NMR: 1.45 (s, 3H), 2.25 (d, J = 7.2 Hz, 2H), 2.29 (s, 3H), 2.33-2.39 (in IH), 2.54 (t, J = 5.8 Hz, 2H), 3.44 (t, J = 4.8 Hz, 2H), 3.50 (t, J = 11.0 Hz, 2H), 3.62-3.68 (in, 37 WO 2011/051961 PCT/IN2010/00650 8H), 3.98 (dd, J = 12,0 & 4.4 Hz, 2H), 7.13 (t, J = 6,2 Hz, NH), 7.40-7.45 (in, 3H), 7.94-7.96 (m, 2H), ES1/MS m/z: 458.0 (M+H)* Yield: 84% 5 Example 27 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-oxo-3-(((tetrahydro-2H pyran-4-yl)methyl)amino)propyl)-1,3-dioxane-2-carboxamide 'H NMR: 1.25-1.35 (m, 2H), 1.45 (s, 3H), 1.501.51 (m, 2H), 1.69-1.78 (in, IH), 2.25 (d, J = 7.2 Hz, 2H), 2.29 (s, 3H), 2.33-2.39 (m, I H), 2.43 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 10 6.4 Hz, 2H), 3.31 (t, J = 11.8 Hz, 2H), 3.50 (t, J = 10.6 H1z, 2H), 3.59 (q, J = 6.0 Hz, 2H), 3.94-4.02 (in, 4H), 5.82 (bs, NH), 7.06 (t, J = 6.2 Hz, NH), 7.40-7.45 (m, 3H), 7.94-7.96 (m, 2H). ES1/MS m/z : 486.1 (M+H)' Yield: 48% 15 Example 28 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-oxo-3 thiomorpholinopropyl)-1,3-dioxane-2-carboxamide H NMR: 1.45 (s, 3H), 2.24 (d, J = 7.6 Hz, 2H), 2.28 (s, 311), 2.33-2.42 (in, 1H), 2.54 (t, J = 5.8 Hz, 2H), 2.59-2.62 (m. 4H), 3.49 (t, J = 11.2 Hz, 2H), 3.61 (q, J = 6.2 Hz, 20 2H), 3.70-3.75 (m, 2H), 3,85-3,92 (m, 2H), 3.98 (dd. J = 11.8 & 4.2 Hz, 2H), 7.12 (t, J = 6.2 Hz, NH), 7.38-7.45 (m, 3H), 7.94-7.96 (in, 2H). ESI/MS in/z : 473.9 (M+H)* Yield: 82% Example 29 25 N-(3-(1,l -dioxidothiomorpholino)-3-oxopropyl)-2-methyl-5-c-((5-methyl-2 phenyloxazol-4-yl)methyl)-1,3-dioxane-2-carboxamide 11 NMR: 1.45 (s, 3H), 2.28-2.36 (m. 6H), 2.64 (t, J = 6.0 Hz, 2H), 3.05-3.10 (m. 4H), 3.51 (t. J = 10.6 Hz, 2H), 3.61 (q, J = 6.0 Hz 2H), 3.97-4.03 (in, 4H), 4.11-4.12 (m, 2H), 7.01 (t, J = 6.2 Hz, NH), 7.40-7.45 (in, 3H), 7.94-7.96 (in, 2H), 30 ESI/MS m/z: 506,1 (M+H)* Yield: 23% 38 WO 2011/051961 PCT/IN2010/000650 Example 30 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-oxo-3-(piperidin-I yl)propyl)- 1,3-dioxane-2-carboxamide 1 H NMR: 1.45 (s, 3H), 1.50-1,56 (m, 4H), 1.60-1.64 (m, 2H), 2.23 (d, J = 7,2 Hz, 2H), 5 2.28 (s, 3H), 2.32-2.42 (m, 1H), 2.53 (t, J = 5.8 Hz, 2H), 3.36 (t, J = 5.4 Hz, 2H), 3.59 3.65 (m, 411). 3.61 (q, J = 6.0 Hz, 2H), 3.97 (dd, J = 11.8.& 4.2 Hz, 2H), 7.20 (t, J 6.2 Hz, NH), 7.37-7.44 (m, 3H), 7,94-7.97. (m, 2H). ESl/MS m/z: 456.0 (M+H)* Yield: 82% 10 Example 31 2-methyl-5-c-((5-inethyl-2-phenyloxazol-4-yl)nethyl)-N-(3-(4-inethylpiperazin- l-yl) 3-oxopropyl)-1,3-dioxane-2-carboxamide 'H NMR: 1.45 (s, 3H), 2.24 (d, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.32-2.40 (m, 5H),. 2.55 (t, 3 = 5.8 Hz, 2H), 3.45 (t, J = 5.0 Hz, 2H), 3.48-3.55 (m, 2H), 3,61-3.65 15 (m, 4H), 3.98 (dd, J - 12.0 & 4.4 Hz, 21), 7.16 (t, J 6.2 Hz, NH), 7.39-7.45 (M, 3H), 7.93-7.96 (m. 2H). ESI/MS m/z : 471.0 (M+H)* Yield: 63% Example 32 20 2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-oxo-I -phenylbutan-2-y) 1,3-dioxane-2-carboxamide ES1/MS m/z : 463.5 (M+iH)* Yield: 77% Example 33 25 N-benzyloxy-2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-1,3-dioxane-2 carboxamide ESI/MS m/z: 437.2 (M+H)* Yield: 52% Example 34 30 N-hydroxy-2-inethyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-]1,3-dioxane-2 carboxamide 39 WO 2011/051961 PCT/N2010/000650 ESI/MS m/z: 437.2 (M+H) t Yield: 59% Example 35 N-hydroxy-2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yI)ethyl)-,3-dioxane-2 5 carboxamide 'H NMR (CD30D): 1.37-1.44 (in, 5H), 1.96-1.99 (in, 1 H), 2.35 (s, 3H), 2.50 (t, J = 7.6 Hz, 2H), 3.44 (t, J = 11.6 Hz, 2H), 3.91-3.96 (dd, J = 12 & 44 lz. 2H), 7.45-7.49 (in, 3H), 7.93-7.96 (in, 2H). ESJ/MS m/z: 347.0 (M+H) 10 Yield: 62% Example 36 N-hydroxy-2-methyl-5-t-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-1,3-dioxane-2 carboxamide 'H NMR (CD 3 0D): 1.44 (s, 3H), 1.48-1.49 (m, IH), 1.97-2.03 (in, 2H), 2.36 (s, 3H), 15 2.59 (t, J = 7.6 Hz, 2H), 3.80 (d, J = 10.8 Hz, 2H), 3.95-3.98 (dd, J = 11.8 & 3.2 Hz, 2H), 7.46-7.49 (in, 3H), 7.94-7.96 (in, 211). ES1/MS m/z : 346.9 (M+H)* Yield: 41% Example 37 20 2-methyl-5-(2-(5-inethyl-2-phenyloxazol-4-yl)ethyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)-1,3-dioxane-2-carboxamide ES1/MS m/z : 429.3 (M+H)* Yield: 98% Example 38 25 2-nethyl-5-c-(2-(5 -nethyl-2-phenyloxazol-4-yl)ethyl)-N-((tetrahydra-2H-pyran-4 yl)inethyl)- 1,3-dioxane-2-carboxamide 'H NMR: 1.25-1.45 (in, 4H), 1.47 (s, 3H), 1.58-1.62 (in, 2H), 1.74-1.82 (in, IH), 2.01 2.07 (in, 1H), 2.31 (s, 3H), 2.43 (t, J = 7.8 Hz, 21H), 3.22 (t, J = 6.6 Hz, 2H), 3.34-3,41 (m, 2H), 3.42 (t, J = 11.4 Hz, 21H), 3.95 (dd, J = 12.0 & 4.4 Hz, 2H), 6.38 (t, J = 6.2 Hz, 30 NH), 7,38-7.44 (in, 314), 7.94-7.96 (m, 2H). ESI/MS miz : 429.4 (M+H)* 40 WO 2011/051961 PCT/IN2010/000650 Yield: 90% Example 39 2-methyl-5--(2-(5-nethyl-2-phenyloxazol-4-yl)ethyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)- 1,3-dioxane-2-carboxamide 5 ESI/MS m/z: 429.3 (M+H)* Yield: 59% Example 40 (2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-1,3-dioxan-2 yl)(morpholino)methanone 10 ESJ/MS m/z : 401.2 (M+H)* Yield: 98% Example 41 (2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)- 1,3-dioxan-2 yl)(morpholino)rethanone 15 'H NMR: 1.39-1.45 (m, 2H), 1.49 (s, 3H), 2.04-2.12. (m, 1H), 2.31 (s, 3H), 2,42 (t, J = 7.8 Hz, 2H), 3.53 (t, J = 11.6 Hz, 2H), 3.64-3.77 (in, 6H), 3.87-3.89 (in, 2H), 3.94 (dd, J = 11.6 & 4.6 Hz, 2H), 7.37-7.44 (in, 3H), 7.94-7.97 (m, 2H ). ESI/MS m/z: 401.4 (M+H)* Yield: 83% 20 Example 42 (2-methyl-5--(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-1,3-dioxan-2 yI)(morpholino)methanone ESI/MS m/z: 401.3 (M+H)f Yield: 79% 25 Example 43 (2-methyl -5-c-(2-(5-methyl-2-phenyloxazol-4-yI)ethyl)- 1,3-dioxan-2-yl)(4 nethylpiperazin-1-yl)methanone 'H NMR: 1.40-1.46 (m, 2H), 1.50 (s, 3 H), 2.05-2.11 (in, I H), 2.30 (s, 3H). 2.32 (s, 3H), 2.38-2.46 (m, 6H), 3.54 (t, J 1 11.6 Hz, 2H), 3.73-3.75 (m, 2H), 3.88-3.89 (in, 2H), 30 3.95 (dd, J = 12.0 & 4.8 Hz, 2H), 7.39-7.45 (in, 3H), 7.94-7.97 (m, 2H). ESI/MS m/z: 413.9 (M+H)+ 41 WO 2011/051961 PCT/IN2010/000650 Yield: 80% Example 44 (2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-1,3-dioxan-2-yl)(piperidin-I yl)methanone 5 3 H NMR: 1.39 (q, J = 7.0 Hz, 2H), 1.49 (s, 3H), 1.55-1.64 (m, 6H), 2.02-2.11 (m, IH), 2.31 (s, 3H), 2.42 (t, 3 = 7.8 Hz, 2H), 3.55-3.63 (in, 4H), 3.75 (t, J = 5.4 Hz, 2H), 3.93 (dd, J = 11.8 & 4.6 Hz, 2H), 7.37-7.44 (m, 3H), 7.94-7.97 (m, 2H). ESI/MS m/z : 399.0 (M+H) t Yield: 74% 10 Example 45 (2-methyl-5-c-(2-(5-inethyl-2-phenyloxazol-4-yl)ethyl)- 1,3-dioxan-2 yl)(thionorpholino)methanone 1H NMR: 1.39 (q, J = 7.2 Hz, 2H), 1.49 (s, 3H), 2.03-2.12 (m, IH), 2.31 (s, 311), 2.42 (t, I = 7.8 Hz, 2H), 2.62-2.69 (in, 4H), 3.52 (t, J = 11.6 Hz, 2H). 3.93-3.99 (m, 411), 15 4.08-4.12 (m, 2H), 7.37-7.44 (m, 3H), 7.94-7.97 (m, 2H). ESI/MS m/z: 438.9 (M+Na) Yield: 74% Example 46 (1,1 -dioxidothiomorpholino)(2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl) 20 1,3-dioxan-2-yl)methanone H NMR: 1.40 (q, J = 7.2 Hz, 21H), 1.52 (s, 3H), 2,05-2.14 (m, I H), 2.32 (s, 3H), 2.43 (t, J = 7.8 Hz, 2H), 3,04-3.10 (m, 4H), 3.46 (t, J = 11.4 Hz, 2H), 3.99 (dd, J = 11.8 & 4.6 Hz, 2H), 4.19-4.20 (m, 2H), 4.35-4.36 (m, 2H), 7.38-7.47 (m, 3H), 7.94-7.97 (m, 2H), 25 ESI/MS m/z: 449.0 (M+H)7 Yield: 80% Example 47 2-methyl-5-(2-(5-inethyl-2-phenyloxazol-4-yl)ethyl)-N-(2-morpholino-2-oxoethyl)- 1,3 dioxane-2-carboxamide 30 ESI/MS m/z : 459.0 (M+H)* Yield: 75% 42 WO 2011/051961 PCT/N2010/000650 Example 48 2-nethyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-mnorpholino-2-oxoethyl) I,3-dioxane-2-carboxamide 'H NMR: 1.40 (q, J = 7.2 Hz, 2H), 1.50 (s, 311), 2.03-2,09 (m. 1 H), 2.31 (s, 3H), 2.42 5 (t, J = 7.6 Hz, 2H), 3.43-3.46 (m, 2H), 3.48 (t, J = 11.6 Hz, 2H), 3.64-3.67 (in, 2H), 3.70-3.73 (m, 4H), 3.98 (dd, J = 12,0 & 4.4 Hz, 2H), 4.14 (d, J = 4.4 Hz, 2H), 7.38-7.45 (m, 3H), 7.94-7.97 (in, 2H), 7.30 (bs, NH). ES)/MS n/z : 459.1 (M+H)* Yield: 68% 10 Example 49 2-n ethyl-5-t-(2-(5 -methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-inorpholino-2-oxoethyl) 1,3-dioxane-2-carboxamide H NMR: 1.53 (s, 3H), 1.57-1.60 (in, IH), 1.93 (q, J = 7.6 Hz, 2H), 2.32 (s, 3H), 2,52 (t, J = 7,6 Hz, 2H), 3.42 (in, 2H), 3.63 (in, 2H), 3.68 (m, 4H), 3.80 (dd, J = 11.8 & 4.2 15 Hz, 2H), 3.99 (d, J = 11.8 & 3.4 Hz, 2H), 4.11 (d, J = 4.4 Hz, 2H), 7.37-7.44 (m, 3H), 7.95-3.98 (in, 2H). ESI/MS m/z: 458.1 (M+H)* Yield: 7 2% Example 50 20 2-imethyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2-(((tetrahydro-2H pyran-4-yl)methyl)amino)ethyl)-1,3-dioxane-2-carboxamide 1H NMR: 1.25-1,36 (m., 2H), 1.40 (q, J ' 7.2 Hz, 2H), 1,48 (s, 3H), 1.58 (dd, J= 13,0 & 1.6 Hz, 2H), 1.71-1.75 (in, IH), 2,01-2.07 (in, 1 H), 2.31 (s, 3H), 2,42 (t, J = 7.6 Hz. 2H), 3.17 (t, I = 6.0 Hz, 2H), 3,31-3.38 (m, 2H), 3.44 (t, J = 11.4 Hz, 21), 3.94-4.01 25 (in, 6H), 6.29 (bs, NH), 7.08 (t, J = 6.4 Hz, NH), 7.39-7.44 (in, 3H), 7.93-7.96 (in, 2H). ESI/MS m/z: 486.0 (M+H)* Yield: 50% Example 51 2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-(4-methylpiperazin-I-yl) 30 2-oxoethyl)-l I.3-dioxane-2-carboxamide 43 WO 2011/051961 PCT/IN2010/000650 '1- NMR: 1.39 (q, J = 7.4 Hz, 2H), 1.49 (s, 3H), 2.02-2.09 (m, 1 H), 2.30 (s, 3H), 232 (s, 3H), 2.40-2.45 (m, 6H), 3.43 (t, J = 5.0 Hz, 2H), 3.47 (t, J = 11.6 Hz, 2H), 3.65 (t, J = 5.0 Hz, 2H), 3.97 (dd, J = 11.8 & 4.6 Hz, 2H), 4.13 (d, J = 4.4 Hz, 2H), 7.31 (t, J 4.0 Hz, NH), 7.37-7.44 (m, 31). 7.93-7.96 (m, 2H). 5 ESI/MS m/z: 471.0 (M+H)* Yield: 33% Example 52 2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2 thiomorpholinoethyl)-I,3-dioxane-2-carboxamide 10 1 H NMR: 1.39 (q, J = 7.0 Hz, 2H), 1.50 (s, 3H). 2.03-2.08 (m, 1H), 2.31 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H), 2.64-2.67 (m, 4H), 3.47 (t, J = 11,6 Hz, 2H), 3.69 (t, J = 4.8 Hz, 2H), 3.90 (t, J = 5.0 Hz, 211), 3.98 (dd, J = 12.0 & 4.4 Hz, 2H), 4.12 (d, J = 4.4 Hz, 2H), 7.32 (bs, NH), 7.37-7.44 (m, 3H), 7.94-7.96 (m, 2H). ESI/MS m/z: 474.0 (M+H) t 15 Yield: 70% Example 53 2-methyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2-(piperidin-I yl)ethyl)-1,3-dioxane-2-carboxamide H NMR: 1.39 (q, J = 7.2 Hz,'2H), 1.49 (s, 3H),.1.55-1.69 (m, 6H), 2.02-2.08 (m, I H), 20 2.30 (s, 3H), 2.41 (t, J = 7.8 Hz, 2H), 3.34 (t, J = 5.4 Hz, 2H), 3.48 (t, I = 11.6 Hz, 2H), 3.57 (t, J = 5.4 Hz, 2H), 3.97 (dd, J = 12.0 & 4.4 Hz, 21-1), 4.12 (d, J = 4,0 Hz, 2H), 7.37-7.44 (m, 3H), 7.93-7.96 (m, 2H). ESI/MS m/z: 456.0 (M+H)* Yield: 85% 25 Example 54 2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(3-oxo-1 -phenylbutan-2-yl) 1,3-dioxane-2-carboxamide ESI/MS m/z : 477.4 (M+H)+ Yield: 28% 30 44 WO 2011/051961 PCT/IN2010/000650 Example 55 2-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2-((3-oxo- 1 phenylbutan-2-yl)amino)ethyl)-1,3-dioxane-2-carboxamide ESI/MS m/z: 534.1 (M+H)* 5 Yield: 53% Example 56 N-benzyloxy-2-methyl-5-((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-1,3-dioxane-2 carboxamide ESI/MS m/z : 459.1 (M+Na)' 10 Yield: 63% Example 57 N-benzyloxy-2-methyl-5-c-((5-methyl-2-(p-tolyl)oxazol-4-yI)methyl)-1,3-dioxane-2 carboxamide 'H NMR: 1.43 (s, 3H), 2.19 (d, J = 7.2 Hz, 2H), 2.25 (s, 3H), 2.38 (s, 3H), 2.33-2.37 15 (m, I H), 3.46 (t, J = 11.2 Hz, 2H), 3.91 (dd, J = 12 & 4.4 Hz, 2H), 4.98 (s, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.38-7.43 (m, 5H), 7.83 (d, J = 8.0 H1Hz, 2H), 8.68 (s, NH). ESI/MS rn/z: 437.1 (M+H)* Yield: 68% Example 58 20 N-benzyloxy-2-methyl-5--((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-1,3-dioxane-2 carboxamide 'H NMR: 1.49 (s. 3H), 1.84-1.86 (m, I H), 2.32 (s, 3H), 2.38 (s, 3H), 2.78 (d, J = 7.6 Hz, 2H), 3.67 (d, J = 10.8 Hz, 2H), 3.85-3.88 (dd, J = 12 & 2,8 Hz, 2H), 4.99 (s, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.35-7.43 (m, 51), 7.84 (d, J = 8.0 HHz, 2H), 8.65 (s, NH). 25 ESI/MS m/z: 437.1 (M+H)* Yield: 55% Example 59 N-hydroxy-2-methyl-5-((5-methyl-2-(p-tolyI)oxazol-4-yl)inelhyl)-1,3-dioxane-2 carboxamide 30 ESI/MS m/z : 368.9 (M+Na)* Yield: 65% 45 WO 2011/051961 PCT/IN2010/000650 Example 60 N-hydroxy-2-methyl-5-c-((5-methyl-2-(p-toly)oxazo-4-yl)methyl)- 1,3-di oxane-2 carboxamide 1H NMR(DMSO-D 6 ); 1.27 (s, 3H), 2.14-2.19 (m, 3H), 2.26 (s, 3H), 2.33 (s, 3H), 3.41 5 (t, J = 11.2 Hz, 2H), 3.77 (dd, J = 11.2 & 4,4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7,77 (d, J = 8.0 HHz, 2H). ESI/MS m/z: 346.2 (M+H)* Yield: 52% Example 61 10 N-hydroxy-2-methyl-5-t-((5-methyl-2-(p-tolyl)oxazol-4-yI)methyl)-1 .3-dioxane-2 carboxamide 'H NMR: 1.52 (s, 3H),1.94-1.95 (m, lH), 2.34 (s, 3H), 2.40 (s, 3H), 2.78 (d, J = 7.6 Hz, 2H), 3.77 (d, J = 11.2 Hz, 2H), 3.96 (d, J = 10.8 Hz,. 211), 7.22 (d, J = 8.0 Hz, 2H), 7,84 (dd, J = 8.4 & 2.4 Hz, 2H), 8.96 (bs, NH). 15 ESI/MS i/z: 347.0 (M+H)* Yield: 62% Example 62 2-nethyl-5-((5-m ethyl -2-(p-tolyl)oxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)-1,3-dioxane-2-carboxamnide 20 ESI/MS m/z : 429.3 (M+H)* Yield: 55% Example 63 2-methyl-5-c-((5-mnethyl-2-(p-tolyl)oxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 yl)m ethyl)- 1,3-dioxane-2-carboxamide 25 'H NMR: 1.29 -1.40 (in, 2H), 1.49 (s, 3H), 1.54-1.62 (m, 2H), 1.78-1.79 (m. 1H), 2.26 2.27 (m, 5H), 2.36-2.39 (m, 4H), 3.24 (t, J = 6.6 Hz, 2H), 3.37 (t, J = 11.8 Hz, 2H), 3.54 (t, J = 11 Hz, 2H). 3.96-4.03 (in, 4H), 6.45 (t, J = 6.0 Hz, NH), 7,23 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 HHz, 2H). ESl/MS n/z; 429.1 (M+H)+ 30 Yield: 46% 46 WO 2011/051961 PCT/IN2010/000650 Example 64 2-methyl-5-t-((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran-4 yl)methyl)-1,3-dioxane-2-carboxamide 'H NMR: 1.08 -1.16 (m, 2H), 1.35 (s, 3H), 1.48-1.51 (m, 2H), 1.69-1.73 (m, 2H), 2.32 5 (s, 3H), 2.34 (s, 3H), 2.73 (d, J = 8.0 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 3.21 (t, J = 10.8 Hz. 2H), 3.62 (d, J 10.8 Hz, 2H), 3.78-3.84 (m, 4H), 7.29(d, J = 8.0 Hz, 21H), 7.77 (d, J = 8.4 HHz, 2H), 8.07 (t, J = 6.0 Hz, NH). ES1/MS m/z: 429.2 (M+H) 4 Yield: 43% 10 Example 65 (2-methyl-5-((5-methyl-2-(p-tolyl)oxazol-4-yl)inethyl )-1,3-dioxan-2 yl)(morpholino)methanone ESl/MS m/z: 401.2 (M+H)* Yield: 46% 15 Example 66 (2-methyl-5 -c-((5 -methyl-2-(p-tolyl)oxazol-4-yI)methyl)- 1,3-d io xan-2 yl)(morpholino)methanone 'H NMR: 1.33 (s, 3H), 2.20-2.21 ( m, 3H), 2.27 (s, 3H), 2.34 (s, 3H), 3.52-3.56 (m, 8H), 3.76-3.79 (m, 2H), 3.80-3.84 (dd, J = 11.2 Hz & 3.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 20 21H), 7.78 (d, J = 8.0 Hz, 2H). ESI/MS m/z: 401.1 (M+H) t Yield: 80% Example 67 (2-methyl-5--((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-1 ,3-dioxan-2 25 yl)(morpholino)methanone 'H NMR (DMSO-D): 1.41 (s, 3H), 1.75-1.76 (m, I H), 2.32 (s, 3H), 2.33 (s, 3H), 2.73 (d, J = 7.6 Hz, 21-1), 3.50-3.58 (m, 6H), 3.64 (d, J = 10.8 Hz. 2H), 3.77-3.79 (m, 2H), 3.92 (dd, J = 11.6 2.4 Hz, 2H), 7.29 (d, J = 8.4 H z, 2H), 7.77 (d, J = 8.4 Hz, 2H). ESI/MS m/z : 401.1 (M+H)+ 30 Yield: 73% 47 WO 2011/051961 PCT/IN2010/000650 Example 68 2-methyl-5-((5-methyl-2-(p-tolyl)oxazol-4-yi)methyl)-N-(2-morpholino-2-oxoethyl) 1,3-dioxane-2-carboxamide ESI/MS m/z: 458.1 (M+H)* 5 Yield: 67% Example 69 2-methyl-5-c-((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-N-.(2-morpholino-2-oxoethyl) 1,3-dioxane-2-carboxamide 'H NMR (DMSO-Do): 1.30 (s, 3H), 2.14-2.19 (m, 3H), 2.27 (s, 3H), 2.31 (s, 3H), 3.40 io 3.43 (m, 4H), 3.53-3.64 (mn, 6H), 3.79-3.82 (dd, J = 11.8 & 4.4 Hz, 2H), 3.96 (d, J = 5.6 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7,78 (d, J = 8.0, 2H), 7.93 (t, J = 5.6 Hz, NH). ESI/MS mlz: 458.4 (M+H) 4 Yield: 68% Example 70 15 2-methyl-5-t-((5-methyl-2-(p-tolyl)oxazol-4-yl)methy)-N-(2-morpholino-2-oxoethyl) 1,3-dioxane-2-carboxamide ESI/MS m/z: 458.2 (M+H) 4 Yield: 59% Example 71 20 N-(benzyloxy)-5-((2-(tert-butyl)-5-methyloxazol-4-yl)nethyl)-2-methyl-i,3-dioxane-2 carboxamide ESI/MS m/z: 403.2 (M+H) Yield: 54% Example 72 25 5-((2-(tert-butyl)-5-methyloxazol-4-yl)methyl)-N-hydroxy-2-mnethyl-1,3-dioxane-2 carboxamide ESI/MS m/z: 313.3 (M+H) 4 Yield: 50% Example 73 30 (5-((2-(tert-butyl)-5-methyloxazol-4-yl)methyl)-2-methyl-I1,3-dioxan-2 yl)(morpholino)methanone 48 WO 2011/051961 PCT/IN20101000650 ESI/MS m/z : 367.2 (M+H) Yield: 38% Example 74 2-methyl-5-c-((5-methyl-2-(5-methylthiophen-2-yl)oxazol-4-yl)methyl)-N 5 ((tetrahydro-2H-pyran-4-yl)methyl)-1,3-dioxane-2-carboxamide H NMR (DMSO-D 6 ): 1.09-1.15 (m, 2H), 1.27 (s, 3H), 1.46-1.49 (m. 2H), 1.70-1.71 (m, IH), 2.11-2.18 (m, 3H), 2.23 (s, 311), 2.46 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 3.18 3.24 (m, 2H), 3.35 (t, J = 11.2 Hz, 2H), 3.78-3.81 (m, 4H), 6.85 (dd, J = 3.6 & 0.8 Hz, IH), 7.37 (d, J = 3.6 Hz. 1H), 8.03 (t, J =6.0 Hz, NH). 10 ESI/MS m/z: 435.1 (M+H)* Yield: 88% Example 75 2-methyl-5--((5-methyl-2-(5-methylthiophen-2-yl)oxazol-4-yl)methyl)-N-((tetrahydro 2H-pyran-4-yl)methyl)-1,3-dioxane-2-carboxaiide Is 'M NMR: 1.25-1.36 (m, 2H), 1.53 (s, 3H), 1.59-1.62 (m. 2.H), 1.73-1,75 (m, IH), 1.91 1.95 (m, 1H), 2.33 (s, 311), 2.52 (s, 3H). 2.76 (d. J = 7.6 Hz, 2H), 3.21 (t, I = 6.6 Hz, 211), 3.34-3.40 (m, 2H), 3.72-3.75 (dd, J = 11.8 & 2.6 Hz, 2H), 3,93-4.00 (m, 4H), 6.47 (t, J = 6.0 Hz, NH), 6.73 (dd, J = 2.2 & 1.0 Hz, I H), 7.36 (d, J = 3.6 Hz, I H). ESI/MS m/z : 435.1 (M+H)* 20 Yield: 66% Example 76 2-methyl-5-c-((5-methyl-2-(5-nethylthiophen-2-yl)oxazol-4-yl)methyl)- 1,3-dioxan-2 yI)(morpholino)methanone 'H NMR (DMSO-D 6 ): 1.33 (s, 3H), 2.16-2.17 (m, 3H), 2 .24 (s, 3H), 3.27 (s, 311), 3.50 25 3.57 (m, 8H), 3.76-3.82 (m, 4H), 6.85 (dd, J = 3.6 & 0.8 Hz, 1H), 7.37 (d, J = 3.6 Hz, IH). ESI/MS m/z: 407.0 (M-H)* Yield: 92% Example 77 30 2-metlhyl-5--((5-methyl-2-(5 -methylthiophen-2-yl)oxazol-4-yI)methyl)- 1,3 -dioxan-2 yl)(morpholino)methanone 49 WO 2011/051961 PCT/IN2010/000650 'H NMR (DMSO-D 6 ): 1.41 (s, 3H), 1.72-1.73 (in, IH), 2.29 (s, 3H), 2.47 (s, 3H), 2.69 (d, J = 7.6 Hz, 2H), 3.51-3.64 (mn, 8H), 3.77-3.82 (m, 2H), 3.92 (dd, J = 11.6 & 2.4 Hz, 2H), 6.85 (dd, J = 3.6 & 0.8 Hz, 1H), 7.37 (d, J = 3,6 Hz, i H). ESI/MS m/z: 407.0 (M+H) 5 Yield: 75% Example 78 N-benzyloxy-2-.methyl-5-c-((5-methyl-2-(pyridin-4-yl)oxazol-4-yl)methyl)-1,3 dioxane-2-carboxamide 'H NMR: 1.44 (s, 3H), 2.20 (d, I = 7.2 Hz, 2H), 2.29 (s, 3H), 2.31-2.34 (n, IH), 3.45 10 (t, J = 11.2 Hz, 2H), 3.90 (dd, J = 12.0 & 4.4 H4z, 2H), 4.99 (s, 2H), 7.37-7.44 (m, 5H), 7.78 (dd, J = 4.4 & 1.6 Hz, 2H), 8.66 (dd, J = 4,6 & 1.4 Hz, 2H), 8.97 (s, NH). ES£/MS n/z: 423.9 (M+H) t Yield: 75% Example 79 15 N-benzyloxy-2-methyl-5 -t-((5-methyl-2-(pyridin-4-y l)oxazol-4-yl)m ethyl)- 1,3 dioxane-2-carboxamide H NMR: 1.49 (s, 3H), 1.81-1.86 (m, IH), 2.37 (s, 3H), 2.81 (d, J = 7.6 Hz, 2H), 3.66 (d, J = 10.8 Hz, 2H), 3.87-3.90 (m, 2H), 5.00 (s, 2H), 7,33-7,43 (m, 5H), 7.78-7.80 (m, 2H), 8.68 (dd, J = 4.6 & 1.4 Hz, 2H). 20 ESI/MS n/z : 424.0 (M+H) 4 Yield: 75% Example 80 N-hydroxy-2-methyl-5-c-((5-methyl-2-(pyridin-4-yl)oxazol-4-yl)nethyl)-i,3-dioxane 2-carboxamide 25 'H NMR (DMSO-D6): 1.28 (s. 3H), 2.12-2.20 (m, I H), 2.23 (d, J = 7.2 Hz, 2H), 2.32 (s, 3H), 3.41 (t, J = 11.4 Hz, 2H), 3.78 (dd, J = 11.8 & 4.2 Hz, 211), 7.79 (dd, J = 4.4 & 1.6 Hz, 2H), 8.69 (dd, J = 4,4 & 1.6 Hz, 2H), ES1/MS n/z: 333.9 (M+H) 4 Yield: 61% 30 50 WO 2011/051961 PCT/IN2010/000650 Example 81 N-hydroxy-2-methyl-5-t-((5-methyl-2-(pyridin-4-y)oxazol-4-y I)m ethyl)- 1,3-dioxane 2-carboxamide 5 'H NMR (DMSO-D): 1.36 (s, 3H), 1.74-1.75 (m, IH), 2.37 (s, 3H), 2.77 (d, J = 7.6 Hz, 2H), 3.60 (d, J = 10.8 Hz, 2H), 3.84 (dd, J = 11.8 & 2.6 Hz, 2H), 7.78-7.80 (in, 2H), 8.68-8.70 (i, 2H). ESI/MS m/z: 333.9 (M+H)* Yield: 33% 10 Example 82 (2-inethyl-5.-c-((5-netliyl-2-(pyridin-4-yl)oxazol-4-yl)inethyl)- 1,3 -d ioxan-2 yl)(morpholino)methanone 'H NMR (DMSO-D): 1.34 (s, 314). 2.20-2.26 (m, 3H), 2,33 (s, 3H), 3.50-3.57 (m, SH), 3.76-3.77 (m, 2H), 3.82-3.86 (m, 2H), 7.79 (dd, J = 4.6 & 1.8 Hz, 2H), 8.69 (dd, J = 15 4.6 & 1.4 Hz, 2H). ESI/MS m/z: 387.9 (M+H)* Yield: 49% Example 83 (2-methyl-5--((5-methyl-2-(pyridin-4-yl)oxazol-4-yyl)methyl)-1,3-dioxan-2 20 yI)(morpholino)methanone H NMR (DMSO-D 6 ): 1.42 (s, 3H), 1.75-1.78 (m, 1H), 2.37 (s, 3H), 2.78 (d, J = 7.6 Hz, 2H), 3.51-3.58 (in, 6H), 3.63 (d, J = 10.8 Hz, 2H), 3,76-3.78 (m, 2H), 3.93 (dd, J = 11.8 & 2.6 Hz, 2H), 7.78-7.80 (m, 2H), 8.68 (dd, J - 4.6 & 1.4 Hz, 2H). ES1/MS n/z: 387.9 (M+H) 4 25 Yield: 16% Example 84 2-methyl-5-c-((5-neihyl-2-(pyridin-4-yl)oxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran 4-yl)methyl)- 1,3-dioxane-2-carboxamide H NMR: 1.34-1.49 (m, 2H), 1.50 (s, 3H), 1.60-1.63 (in, 2H), 1.76-1.85 (m, IH), 2.2- 30 2.32 (m, 5H), 2.35-2.42 (m, I H), 3.24 (t, J = 6.4 Hz, 2H), 3.35-3.42 (m, 2H), 3.52 (t, J 51 WO 2011/051961 PCT/IN2010/000650 11,0 Hz, 2H), 3.98-4.04 (m, 4H), 6.46 (t, J = 6.0 Hz, NH), 7.80 (dd, J = 4,8 & 1.6 Hz, 2H), 8.70 (dd, J = 4.4 & 1.6 Hz, 2H). ESI/MS m/z: 416.0(M+H) Yield: 38% 5 Example 85 2-methyl-5-t-((5-nethyl-2-(pyridin-4-yl)oxazol-4-yl)methyl)-N-((tetrahydro-2H-pyran 4-yl)methyl)- 1,3-dioxane-2-carboxamide H NMR (DMSO-D 6 ): 1.09-1.13 (m, 2H), 1.35 (s, 3H), 1.48-1.51 (m, 2H), 1.70-1.74 (in, 2H), 2.37 (s, 3H), 2.77 (d, J = 7.6 Hz, 2H), 2.96 (t, J = 6.4 Hz, 2H), 3.18-3.24 (m, 10 2H), 3,61 (d, J = 10.8 Hz, 2H), 3,78-3.84 (in, 4H), 7.80 (dd, J = 4.4 & 1.6 Hz, 2H), 8.04 (t, J = 6.0 Hz, NH), 8.68 (m, 2H). ESI/MS m/z: 416.0 (M+H)* Yield: 27% Example 86 15 2-methyl-5-c-((5-methyl-2-(pyridin-4-yl)oxazol-4-yl)nethyl)-N-(2-morpholino-2 oxoethyl)- l,3-dioxane-2-carboxamide H NMR: 1.51 (s. 3H), 2.27 (d, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.38-2.43 (m, 1H), 3.43 (t, J = 4.8 Hz, 2H), 3.57-3.66 (m, 4H), 3.70-3.72 (m, 4H), 4,01 (dd, J = 12.0 & 4.4 Hz, 2H), 4.14 (d, I = 4.4 Hz, 2H), 7.31-7.33 (t, NH), 7.79 (dd, J = 4.8 & 1.4 Hz, 2H), 8.69 20 (d, J = 4.8 Hz, 2H). ESI/MS m/z: 444.9 (M+H)* Yield: 68% Example 87 2-methyl-5-t-((5-methyl-2-(pyridin-4-yl)oxazol-4-yl)methyl)-N-(2-norpholino-2 25 oxoethyl)-1,3-dioxane-2-carboxamide H NMR: 1.56 (s, 3H), 1,88-1.92 (m, IH), 2.40 (s, 3H), 2.88 (d, J = 7.6 Hz, 2H), 3.42 (t, J = 5.0 Hz, 2H), 3.63-3.65 (m, 2H), 3.69-3.71 (m, 4H), 3.76-3.78 (m. 2H), 4.02 (dd, J = 12.0 & 2.8 Hz, 2H), 4.13 (d, J = 4.4 Hz, 2H), 7.31-7.33 (t, NH), 7.79 (dd, J = 4.8 & 1.6 Hz, 2H), 8.68 (d, J = 6.0 Hz, 2H). 30 ESI/MS m/z: 445.2 (M+H)+ Yield: 63% 52 WO 2011/051961 PCT/IN2010/000650 Example 88 2-methyl-5-c-((5-methyl-2-(pyridin-4-yl)oxazol-4-yl)methyl)-N-(2-oxo-2-(((tetrahydro 2H-pyran-4-yl)nethyl)anino)ethyl)-1,3-dioxane-2-carboxamide H NMR: 1.30-1.37 (m, 2H), 1.51 (s, 3H), 1,59-1:63 (in, 2H), 1.71-1.79 (m, 1 H), 2.28 5 (d, I = 7.6 Hz, 2H), 2.32 (s, 3H), 2.34-2.41 (m, 1H), 3.18 (t, J = 6.4 Hz, 2H), 3.33-3.39 (m, 2H), 3.55 (t, J = 10.8 Hz. 2H), 3.95-4.13 (m, 6H), 6.12 (bs, NH), 7.08 (t, J- 5.4 Hz, NH), 7.79 (d, J = 4.8 & 1.6 Hz, 2H), 8.69 (d, J = 4.8 & 1.6 Hz, 2H). ESI/MS m/z : 473.3 (M+H)* Yield: 53% 10 Example 89 2-methyl-5-+((5-methyl-2-(pyridin-4-yl)oxazol-4-yl)methyl)-N-(2-oxo-2-(((tetrahydro 2H-pyran-4-y)methy)amino)ethyl)-1,3-dioxane-2-carboxamide 'H NMR: 1,27-1.35 (in, 2H), 1.55 (s, 3H), 1.57-1.61 (m, 2H), 1.69-1.77 (m, 1H), 1.92 1.97 (m, 1 H), 2.40 (s, 3H), 2.84 (d, J = 7.6 Hz, 2H), 3.16 (t, J = 6.6 Hz, 2H), 3.31 (t, J =' 15 11.6 Hz, 2H), 3.75-3.78 (m, 2H), 3.94-4.03 (in, 6H), 6.15 (in, NH), 7.08 (m, NH), 7.79 (d, J = 6.0 Hz, 2H), 8.69 (d, J = 3.6 Hz, 2H). ESI/MS m/z : 473.2 (MI+H)* Yield: 63% Example 90 20 N-benzyloxy-2-methyl-5-((4-methyl-2-(4-(irifluoromethyl)phenyl)thiazol-5-y)methyl) 1,3-d ioxane-2-carboxam ide ES1/MS m/z : 507.1 (M+H)' Yield: 50% Example 91 25 N-hydroxy-2-inethyl-5-((4-methyl-2-(4-(trifluoroinethyl)phenyl)thiazol-5-yl)methyl) 1,3-dioxane-2-carboxamide ESI/MS m/z : 416.9 (M+H)* Yield: 70% Example 92 30 1-(2-methyl-5 -((4-methyl-2-(4-(trifluoromethyb)phenyl)thiazo-5-yl)methyl)- 1,3 dioxan-2-yI)-N-((tetrahydro-2H-pyranr-4-yl)methyl)methanamine 53 WO 2011/051961 PCT/N2010/000650 ESI/MS m/z: 499.6 (M+H)* Yield: 99% Example 93 (2-methyl-5-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)-1,3-dioxan s 2-yI)(morpholino)methanone ESI/MS m/z : 471.5 (M+H)+ Yield: 51% Example 94 (2-methyl-5-c-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)-1,3 10 dioxan-2-yl)(norpholino)methanone H NMR: 1.51 (s, 3H), 2.30-2.38 (m, 4H), 2.54 (d, J = 7.2 Hz, 21-1), 3.59-3,67 (m, 4H), 3.73-3.75 (in, 4H), 3.87 (t, J = 4.2 Hz, 2H), 3,95-3.99 (dd, J 12.0 & 4.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H). ESI/MS m/z : 471.0 (M+H) 15 Yield: 36% Example 95 (2-methyl-5-tran-((4 -nethyl-2-(4-(trifluoroinethyl)phenyl)thiazol-5-yl)methyl)-1,3 dioxan-2-yl)(morpholino)methanone 'H NMR: 1.57 (s, 31-1), 1.63-1,67 (m, lH), 2.47 (s. 3H), 3.23 (d, J = 8.0 Hz, 2H), 3.62 20 3.66 (in, 2H), 3.71-3.72 (m, 4H), 3.76-3.79 (dd, J = 12,0 & 4,0 Hz, 2H), 3,88 (t, J = 4.4 Hz, 2H), 4.09-4,12 (m, 2H), 7.66 (d, J = 8.4 Hz, 21-1), 7,98 (d, J = 8.0 Hz, 2H). ESI/MS m/z : 471.1 (M+H)* Yield: 47% Example 96 25 5-c-(3-(9H-carbazol-9-yl)propyl)-N-hydroxy-2-methyl- I,3dioxane-2-carboxamide 'H NMR: 1.06-1, I 1 (m, 2H), 1.46 (s, 3H), 1.80-1.95 (in, 3H), 3.35 (t, J = 11.0 Hz, 2H), 3.8573.88 (m, 2H), 4.27 (t, J = 6,8 H z, 2H), 7.21-7.26 (in, 2H), 7.32 (d, J = 8.4 Hz, 2H). 7.45-7.48 (in, 2H), 8.08-8.10 (in, 2H). ESI/MS m/z : 368.9 (M+H)f 30 Yield: 37% 54 WO 2011/051961 PCT/IN2010/000650 Example 97 N-hydroxy-5-c-(3-( OH-phenothiazin-1 0-yl)propyl)-2-methyl-I,3-dioxane-2 carboxamide H NMR: 1.16-1.19 (m, 2H), 1.48 (s, 3H), 1.72-1.78 (m, 2H). 1.93-1.94 (n, 1H), 3.32 5 (t, J = 11.2 Hz, 2H), 3.81-3.89 (m, 4H), 6.80-6.86 (m, 2H), 6.90 (t, J = 7.6 Hz, 2H), 7.13-7.16 (m, 4H). ESI/MS m/z : 401.0 (M+H)/ Yield: 40% Example 98 10 N-(benzyloxy)-5-((3-(tert-butyl)-I-(p-tolyl)-HI -pyrazol-5-yl)methyl)-2-methyl-1,3 dioxane-2-carboxamide ESI/MS m/z : 478.4 (M+H) 4 Yield: 56% Example 99 15 N-(hydroxy)-5-c-((3-(tert-butyl)-I -(p-toyl)- IH-pyrazol-5-yl)methyl)-2-inethyl-1,3 dioxane-2-carboxamide H NMR: 1.31 (s, 9H), 1.46 (s, 3H), 2.14-2.19 (m, IH), 2.37 (s, 2H), 2.39 (s, 314), 3.35 (t, J = 11.0 Hz, 2H), 3.87 (dd, J = 12.0 & 4.0 Hz, 2H), 6.02 (s, I H), 7.20-7.23 (m, 4H), 7.95 (bs, NH), 8,75 (bs, OH). 20 ESI/MS m/z: 387.9 (M+H) t Yield: 10% Example 100 N-(hydroxy)-5-t-((3-(tert-butyl)-1 -(p-tolyl)-1 H-pyrazol-5-yl)methyl)-2-methyl-1,3 dioxane-2-carboxamide 25 'H NMR: 1.31 (s, 9H), 1.43 (s, 3H), 1.64-1.68 (in, I H), 2.38 (s, 3H), 2.91 (d, 1 = 7.6 Hz, 2H), 3.65 (dd, J = 11.8 Hz, 2H), 3.86 (dd, J = 12.0 & 2,8 Hz, 21-), 6.04 (s, IIH), 7.21-7.29 (m, 4H). ESI/MS m/z: 388.2 (M+H)* Yield: 32% 30 Example 101 55 WO 2011/051961 PCT/IN2010/000650 5-((3-(tert-butyl)- I -(p-tolyl)- I H-pyrazol-5-yl)methyl)-2-methyl-N-((tetrahydro-2H pyran-4-yl)methyl)- I,3-dioxane-2-carboxamide ESI/MS m/z : 470.2 (M+H) t Yield: 90% 5 Example 102 5-((3-(tert-butyl)-1-(p-tolyl)-l H-pyrazol-5-yl)methyl)-2-methyl-N-(2-oxo-2 (((tetrahydro-2H-pyran-4-yl)methyl)anino)ethyl)-1,3-dioxane-2-carboxamide ESI/MS m/z: 527,0 (M+H)* Yield: 33% 10 Example 103 (5-((3-(tert-butyl)-]-(p-tolyl)-1 H-pyrazol-5-yl)nethyl)-2-methyl-1,3-dioxan-2 yl)(morpholino)methanone ESI/MS n/z: 442.4 (M+H)* Yield: 46% 15 Example 104 5-((3-(tert-buty )-l -(p-tolyl)- IH-pyrazol-5-yl)methyl)-2-methyl-N-(2-norpholino-2 oxoethyl)-1,3-dioxane-2-carboxamide ESI/MS m/z : 499.0 (M+H)* Yield: 56% 20 Example 105 (5-((3-(tert-butyl)-I-(p-tolyl)-IH-pyrazol-5-yl)methyl)-2-methyl-1,3-dioxan-2-yl)(4 methylpiperazin- I -yl)methanone ESI/MS m/z : 455.0 (M+H) Yield: 50% 25 Example 106 N-(benzyloxy)-5-c-((2-(4-methoxyphenyl)-5-nethyoxazol-4-yl)methyl )-2-methyl- 1,3 dioxane-2-carboxamide 'H NMR; 1.43 (s, 3H), 2.18 (d, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2,33-2.38 (m, INH), 3.46 (t, J = 11.2 Hz, 2H), 3.84 (s, 3H), 3.90-3.94 (dd, J = 11.8 & 4.8 Hz, 2H), 4.98 (s, 2H), 30 6.92 (d, J = 6,8 Hz, 2H), 7.35-7.43 (m, 5H), 7.87 (d, J = 6.8 Hz, 2H), 8.68 (s, 1 H). ESI/MS m/z: 453.1 (M+H)* 56 WO 2011/051961 PCT/IN2010/000650 Yield: 60% Example 107 N-(benzyloxy)-5-t-((2-(4-methoxyphenyl)-5-methylaxazol-4-yl)methyl)-2-methyl-1,3 d ioxane-2-carboxamide 5 'H NMR: 1.48 (s, 3H), 1.82-1.87 (m, IH), 2.31 (s, 3H), 2.77 (d, J = 7.6 Hz, 2H), 3.66 3.69 (dd, J = 12.2 & 2.0 Hz, 2H), 3.85 (s, 3H), 3.85-3.88 (dd, J = 12.2 & 2.8 Hz, 2H), 4,99 (s, 214) ,6.93 (d, J = 7.2 Hz, 2H), 7.35-7.43 (m, 5H), 7.88 (d, J = 6.8 Hz, 2H), 8.66 (s, NH). ESI/MS m/z: 453.2 (M+H-)+ 10 Yield: 45% Example 108 N-hydroxy-5-c-((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl-1.3 dioxane-2-carboxamide H NMR (DMSO-D 6 ): 1.28 (s, 3H), 1.12-2.18 (m, 3H), 2.26 (s, 31H), 3.41 (t. J = 5.6Hz, 15 2H), 3.78-3.82 (m, 51H), 7.03 (d, J = 6.8 Hz, 2H), 7.82 (d, J = 5.6 Hz, 2H), 8.40 (s, NH), 10.83 (s, OH). ESI/MS m/z: 363,0 (M+H)* Yield: 71% Example 109 20 N-hydroxy-5-t-((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl-1,3 dioxane-2-carboxamide 'H NMR (DMSO-D 6 ): 1.35 (s, 3H), 1.73-1.74 (m. ]H). 2,30 (s. 3H), 2.71 (d, J = 7.6 Hz, 2H), 3.60 (d, J = 10.8 Hz, 2H), 3.79 (s, 3H), 3.83-3.86 (dd, J = 11.6 & 2.4 Hz, 2H), 7.02 (d, J - 7.2 Hz, 2H), 7.81 (d, J = 6.8 Hz, 21H), 8.83 (s, NH), 10.81 (s, OH). 25 ESI/MS m/z; 363.1 (M+H)* Yield: 59% Example 110 (5-c-((2-(4-methoxyphenyl)-5-methyoxazol-4-yl)methyl)-2-methyl-1,3-dioxan-2 yl)(morpholino)methanone 57 WO 2011/051961 PCT/IN2010/000650 'H NMR (DMSO-D 6 ): 1.33 (s, 3H), 2.19 (br S, 3H), 2.26 (s, 3H), 3.49-3.56 (m, 8H), 3.76 (br S, 2H), 3.80 (s, 3H), 3.82 (br S, 2H), 7.03 (d, J = 6.8 Hz, 2H), 7.82 (d, J = 6.8 Hz, 21]). ESI/MS m/z : 417.1 (M+H)7 5 Yield: 84% Example 111 (5-+-((2-(4-nethoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-inethyl-1,3-dioxan-2 yl)(morpholino)nethanone 'H NMR (DMSO-D 6 ): 1.41 (s, 3H), 2.30 (s, 3H), 2.72 (d, J = 7.6 Hz, 2H), 3.51-3.56 io (m, 6H), 3.64 (d, J = 10.8 Hz, 2H). 3.77-3.79 (m, 5H), 3.94 (d, J = 9,2 Hz, 2H), 7.02 (d, J = 6.8 Hz, 2H), 7.81 (d, J = 6.8 Hz, 2H). ESI/MS m/z: 417.1 (M+H)* Yield: 75% Example 112 is 5-c-((2-(4-methoxypheny)-5-methyloxazol-4-yl)methyl)-2-inethyl-N-((tetrahydro-2H pyran-4-yl)methyl)- 1,32dioxane-2-carboxamide 'H NMR (DMSO-D 6 ): 1.08 -1.13 (m, 2H), 1.27 (s, 3H), 1.46-1.49 (n, 21]), 1.69 (m, 1 H), 2.14-2,20 (m, 3H), 2.24 (s, 3H), 2.97 (t, J = 6.6 Hz, 2H), 3.20 (t, J = 11.4 Hz, 2H), 3.41 (t, J = 11 Hz, 21]), 3.77-3.83 (m, 7H), 7.04 (d, J = 6.8 Hz, 2H), 7.81 (d, J = 6.8 Hz, 20 2H), 8.05 (t, J = 6.0 H z, 1H), ESI/MS m/z: 445.2 (M+H)* Yield: 59% Example 113 5-+-((2-(4-nethoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl-N-((tetrahydro-2H 25 pyran-4-yl)methyl)-1,3-dioxane-2-carboxamide HM NMR (DMSO-D 6 ): 1.10 -1.14 (dd, J = 12.4& 4.4 Hz, 2H), 1.36 (s, 3H), 1.49-1.52 (m, 2H), 1.71-1.74 (m, 1 H), 2,32 (s, 3H), 2.72 (d, J = 7.2 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H), 3.22 (t, J = 10.8 Hz, 2H), 3.63 (d, J = 11.2 H z, 2H), 3.81-3.85 (m, 7H), 7.04 (d, J= 8,8 Hz, 21]), 7.81 (d, J = 8.8 Hz, 21]), 8.05 (s, 1 H). 30 ES1/MS m/z: 445.2 (M+H) Yield: 47% 58 WO 2011/051961 PCT/IN2010/000650 Example 114 (5-c-((2-(4-methoxyphenyl)-5-methyloxazol-4-yl)methyl)-2-methyl- 1,3-diaxan-2-yI)(4 methylpiperazin- I-yl)methanone 'H NMR (DMSO-D): 1.32 (s, 3H), 2.15 (s, 3H), 2.19 (s, 3H), 2.25-2.28 (m, 711), 3.50 $ 3.53 (in, 4H), 3.73 (br S, 2H), 3.80 (s, 3H), 3.82 (br S, 2H) , 7.03 (d; J = 7.2 Hz, 2H), 7.82 (d, J = 6.8 Hz, 2H). ESI/MS m/z : 430.3(M+H)* Yield: 95% Example 115 to (5-t-((2-(4-methoxyphenyl)-5-inethyloxazo 1-4-y ])met hyl)-2-methyl- 1,3-dioxan-2-yl)(4 methylpiperazin-l -yl)methanone 'IH NMR (DMSO-D 6 ): 1.40 (s, 3H), 1.74 (br S, I H), 2.20 (br S, 3H), 2.30 (s, 3H), 2.35 (br S, 4H), 2.72 (d, J = 7.6 Hz, 2H), 3.47 (br S, 2H), 3.64 (d, J = 10.8 Hz, 2H), 3.77 3.81 (m, 5H) , 3.90-3.94 (dd, J= 11.8 Hz,21-), 7.03 (d, J = 6.8 Hz, 2H), 7,79-7,82 (m, is 2H). ESI/MS m/z: 430,1 (M+H) t Yield: 89% Example 116 N-(benzyloxy)-2-ri ethyl-5-c-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4 20 yI)methyl)-1.3-dioxane-2-carboxamide H NMR: 1.39 (s, 3H), 2.20 (d, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.32-2.39 (m, 1H), 3.45 (t, J = 10.8 Hz, 2H), 3.91 (dd, J = 11.6 & 4.4 Hz, 2H), 4.99 (s, 21), 7.35-7.44 (n. 5H), 7.66 (d. J = 8.4 Hz. 2H), 8.04 (d, J = 8.0 Hz, 2H), 8.69 (s, NH). ESI/MS m/z: 490.9 (M+H)* 25 Yield: 59% Example 117 N-(benzyloxy)-2-methyl5-t-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4 yI)methyl)-1,3-dioxane-2-carboxanide 'H NMR: 1.49 (s, 3H), 1.82-1.87 (m, 1H), 2.36 (s, 3H), 2.80. (d, J = 8.0 Hz, 2H), 3.66 30 (dd, J = 12.8 & 1.6 Hz, 2H), 3.87 (dd, J = 11.6 & 2.8 Hz, 2H), 5,00 (s, 2H), 7.31-7.43 (m: 5H), 7.67 (d, J = 8.0 Hz, 2H), 8.05 (d. J = 8.0 Hz, 2H). 8.67 (s, NH), 59 WO 2011/051961 PCT/ITN2010/000650 ESI/MS m/z: 490.1 (M+H)* Yield: 58% Example 118 N-hydroxy-2-methyl-5-c-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methyl) 5 1,3-dioxane-2-carboxamide 'H NMR: 1.52 (s, 3H), 2.28 (d, J = 7.6 Hz, 2H), 2.30 (s, 3H), 2.35-2.43 (m, I H), 3.54 (t, J = 11.2 Hz, 2H), 4.01 (dd, J = 11.8 & 4.2 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H). ESI/MS m/z: 401.3 (M+H)* 10 Yield: 52% Example 119 N-hydroxy-2-methyl-5-t-((5-iethyl-2-(4-(tri fluoromethyl)phenyl)oxazol-4-yl)methyl) 1,3-dioxane-2-carboxamide ESI/MS m/z: 401.1 (M+H4)* 15 Yield: 59% Example 120 (2-methyl-5-c-((5-methy 1-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methyl)- 1,3 dioxan-2-yl)(morpholino)methanone H NMR: 1.50 (s, 3H), 2.22 (d, J= 7,2 Hz, 2H), 2.31 (s, 3H), 2.43-2.52 (m, I H), 3.61 20 3.78 (m, 8H), 3.90 (t, J= 4.6 Hz, 2H), 3.91 (dd, J= 12.0 & 4.8 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 8.06 (d, J= 8.0 Hz, 2H). ESI/MS m/z: 455.2 (M+H)* Yield: 60% Example 121 25 (2-methyl-5-t-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methyl)-1,3-dioxan 2-yl)(norpholino)methanone 'H NMR: 1.55 (s, 3H), 1.86-1.90 (n, 1H), 2.40 (s, 3H), 2.90 (d, J = 7.6 Hz, 2H), 3.64 3.67 (m, 2H), 3.71-3.77 (n, 6H), 3.88-3.91 (in, 2H), 4.07-4.1 1 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.0 Hz, 2H) 30 ESI/MS m/z: 455.1 (M+H)* Yield: 90% 60 WO 2011/051961 PCT/IN2010/000650 Example 122 2-methyl-5-c-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methyl)-N ((tetrahydro-2H-pyran-4-yl)methyl)-1.3-dioxane-2-carboxamide 'H NMR: 1.26-1.39 (m, 2H), 1.49 (s, 3H), 1.59-1.62 (m, 2H), 1.75-1.83 (m, 1 H), 2.27 5 (d, J = 7.2 Hz. 2H), 2.30 (s, 3H), 2.34-2.44 (m, 1 H), 3.23 (t, J = 6.6-Hz, 2H), 3.34 (t, J = 11,8 Hz, 2H), 3.52 (t, J = 10.6 Hz, 2H), 3.91-4.04 (m, 4H), 6.43 (t, J'= 6,0 Hz, NH), 7.67 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H) ESI/MS m/z: 483.1 (M+H) Yield: 80% 10 Example 123 2-methyl-5-t-((5-methyl-2-(4-(trifluoronethyl)phenyl)oxazol-4-yl)methyl)-N ((tetrahydro-2H-pyran-4-yl)methyl)- I,3-dioxane-2-carboxanide 'H NMR: 1.25-1.39 (m, 2H), 1.54 (s, 3H), 1,58-1.62 (m, 2H), 1.73-1.83 (m, 1H), 1.92 1.98 (m, I H), 2.39 (s, 3H), 2.82 (d, J = 8.0 Hz, 2H), 3.22 (t, J = 6.4 Hz, 2H), 3.41 (t, J= . 15 11.8 Hz, 2H), 3.75-3.78 (m, 2H), 3.96-4.00 (m, 2H), 6.45 (t, J 6.2 Hz, NH), 7.67 (d, ) = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H) ES/MS m/z: 483.2 (M+H) Yield: 58% In an embodiment is provided a method of identifying small molecules as 20 inhibitors of PCSK9 through in-silico modeling. For identifying molecules which can bind to the PCSK9, an insilico mutant of PCSK9 was generated without prodomain which was subsequently taken for docking simulations, It was surprisingly found that small molecules which bind to the catalytic site as provided below, shows relevant in vitro and in-vivo effects of PCSK9 inhibition. Nomenclature including numbering of 25 amino acids is as per 3BPS crystal structure of PCSK9 obtained from protein databank (www.pdb.org). Amino acid sequence of the catalytic site of PCSK9: ASP 186 THR 187 LYS 222 HIS 224 HIS 226 LEU 230 VAL 252 LEU 253 ASN 254 GLN 256 GLY 257 LYS 258 GLY 259 THR 260 VAL 261 SER 262 THR 264 LEU 287 PRO 288 LEU 289 ALA 290 30 GLY 291 GLY 292 LEU 297 ALA 3,14 ALA 315 ASN 317 PHE 318 TYR 325 SER 326 PRO 327 SER 386 GLN 387 61 WO 2011/051961 PCT/IN2010/000650 In a preferred embodiment, the small molecules which bind to one or more of the amino acids comprising the catalytic triad HIS 226 SER 386 ASP 186 alone or in combination with other amino acids from the catalytic site. Dockin studies: 5 PCSK9 binding molecules were identified using in silico docking studies using PCSK9 protein crystal structure (3BPS) crystallized with EGF-A domain of LDL-R (PNAS, 105 (6), 1820-1825, 2008), pro-domain and CRD obtained from publicly available database protein databank (PDB). Computationally we have generated a mutant of PCSK9 without pro-domain, wherein the active site consists of but not 10 restricted to the following amino acids: . ASP 186 THR 187 LYS 222 HIS 226 LEU 230 VAL 252 LEU 253 ASN 254 GLN 256 GLY 257 LYS 258 GLY 259 THR 260 VAL 261 SER 262 THR 264 LEU 287 PRO 288 LEU 289 ALA 290 GLY 291 GLY 292 LEU 297 ALA 314 ALA 315 ASN 317 PHE 318 TYR 325 SER 326 PRO 327 SER 386 GLN 387 15 PCSK9 protein (3BPS.pdb) was prepared for docking studies using Protein Pr'eparation Wizard tool (Schr6dinger Suite 2010 Protein Preparation Wizard; Epik version 2.1; Schr6dinger, LLC: New York, NY, 2010; Impact version 5.6; Schrodinger, LLC: New York, NY, 2010; Prime version 2.2; Schrodinger, LLC: New York, NY, 2010) implemented in Maestro. All the bond orders were assigned, and the hydrogen atoms 20 were added to the protein as per the standard protocol. Geometry of the compounds to be docked were subsequently optimized using the LigPrep version 2.6 (LigPrep 2.6; Schrodinger, LLC: New York, NY, 2010). Docking studies were carried out for these compounds using Glide version 5.6 (Glide 5.6; Schrodinger, LLC: New York, NY, 2010), the automated docking program implemented in the Schrodinger package. 25 One of the representative examples of the small molecule docked as per the above protocol is provided in figure 1. Docking Results: Example No. G-score H-bonds 1Examl -6.40 Gly 259 C=O...HN of hydroxylamine -6.98 Asp 186 C=0...HO of hydroxyl amine Asp 186 0...HN ofhydroxylamine 62 WO 2011/051961 PCT/IN2010/000650 14 -6.03 Lys 222 NH-L.O=C attached to Piperidine 19 -7.00 Gly 291 NH... of dioxane 37 -6.14 Gly 257 C=O...HN of aide attached to dioxane 40 -5.21 Lys 222 NH,...O=C attached to dioxane 47 -7.35 Lys 222 NH...O=C attached to dioxane The above in-silico results can be further supported by x-ray diffraction of the complex of the compound co-crystallized with the PCSK9 protein. Further support can be obtained by selectively mutating the amino acids in the catalytic site and testing the 5 compounds through Elisa using this mutant protein. Biological studies: The compounds of the present invention lowered LDL, triglyceride and total cholesterol. This was demonstrated by in vitro as well as in ivo animal experiments. A) Demonstration of in vitro efficacy of compounds 10 The PCSK9-LDLR in vitro Binding Assay is a quantitative solid phase binding assay between PCSK9 and recombinant LDLR. Plates were pre-coated with a recombinant LDLR-AB domain, which binds PCSK9. Test compound at different concentration was added to the PCSK9 and added to LDLR immobilized on the wells. The amount of bound PCSK9 is measured by binding it with biotinylated anti-His-tag 15 monoclonal antibody, followed by binding with horseradish peroxidase conjugated streptavidin substrate. The color was quantified by ELISA reader at 450 nM which reflects the relative amount of PCSK9 that binds to LDLR in presence and absence of the inhibitor. EC 50 values were calculated by nonlinear regression analysis using graph pad prism software. Each concentration point represents values in duplicates. Concentration % Inhibition Example No. .(pM) PCSK9 5 25 1 10 30 100 32 10 35 4 100 42 63 WO 2011/051961 PCT/IN2010/000650 5 10 6 10 11 100 22 1 11 7 10 12 100 20 1 18 8 10 23 100 30 10 15 9 100 12 5 20 11 10 30 100 44 10 19 12 100 18 10 41 14 100 5 10 11 15 100 4 16 100 12 17 100 15 1 40 18 100 39 10 23 19 100 25 10 25 22 100 17 10 21 23 100 .22 10 15 25 100 16 64 WO 2011/051961 PCT/IN2010/000650 10 8 29 100 12 1 11 34 10 12 100 15 1 18 35 10 19 100 19 1 10 36 100 24 1 24 37 10 15 100 20 10 14 38 100 21 1 20 40 10 25 100 11 10 12 41 100 19 10 8 43 100 10 10 14 44 100 25 10 11 45 100 18 10 12 46 100 18 1 38 47 10 38 100 42 49 100 17 10 10 100 35 65 WO 2011/051961 PCT/IN2010/000650 10 20 52 100 32 10 21 54 1 100 29 10 23 100 30 5 6 56 10 17 1 26 59 10 27 100 61 1 28 60 10 26 100 70 10 21 100 32 0.1 17 1 21 62 10 14 100 41 1 39 63 10 40 100 51 0.1 20 1 23 64 10 25 100 49 1 11 65 10 26 100 35 1 23 66 10 25 100 31 1 3 67 10 21 100 25 66 WO 2011/051961 PCT/IN2010/000650 5 11 72 110 20 100 25 1 25 73 10 27 100 37 1 4 74 10 15 100 27 1 15 75 10 11 100 20 1 6 76 10 17 100 27 10 14 77 100 16 1 32 80 10 44 100 34 1 7 81 10 12 100 23 1 13 82 10 20 100 42 1 20 83 10 25 100 42 1 25 84 10 29 100 65 1 22 85 10 30 100 44 10 11 86 100 15 67 WO 2011/051961 PCT/IN2010/000650 10 12 87 100 7 10 10 88 100 15 10 7 89 100 10 1 8 91 10 12 100 32 1 11 92 10 26 100 40 1 20 93 10 16 100 49 96 10 10 10 5 99 100 32 10 10 105 .100 40 B) SPR Binding studies: Immobilization protocol: Instrumentation: BIACORE3000 from GE Life Sciences was used and the 5 Interaction analysis was performed at 25 0 C. Buffers: phosphate buffer pH 7,4 supplied by Biacore supplemented with 0.01% dirnethyl sulfoxide (DMSO) was used as running buffer during the assay, Immobilization of Ligand: Sensor chip CM5 was used for analysis, The sensor chip consists of a carboxyrnethyl-modified dextran polymer linked to a gold-covered 10 glass support. The ligand was diluted to 10 micro grain / ml in 10mM sodium acetate, pH5.0 and immobilized to the sensor chip, using amine coupling. Running buffer without DMSO was used during immobilization. The surface was activated by injecting a solution containing 0.2M N-ethyl-N'-dimethyl aminopropyl-carbodiimide (EDC) and 68 WO 2011/051961 PCT/IN2010/000650 50mM N-hydroxy succinimide (NHS). The system was set for Aim for immobilization of about 1000 RU and the surface was blocked by injecting IMehanolarnine at pH 8.5. Then the surface was washed with 50mM NaOH by injecting two 30 second-pulses to remove off non covalently bound ligand and to stabilize the baseline (automated 5 procedure). Activated dextran was used as a reference surface. To ensure highest sensitivity the SPR Detector response was normalized before running the assay. By calibrating the detector at various light intensities under Conditions of total internal reflection (automated procedure). Solvent correction for DMSO was also carried to minimize the error in data. W Assay Design: A binding assay was set up for different compounds at three different concentrations (lOnM, lOOnM and I micro mole), and were injected over the reference and Ligand flow cells at a flow rate of 30 micro liter / min. Each cycle consisted of a 1-min waiting period for monitoring of the baseline stability and 3 minute injection of compound with a 5 minute Undisturbed dissociation phase, and the 15 surface was regenerated with 50 mM NaoH solution. Compound responses in the reference flow cell were subtracted with that of ligand and a solvent correction run was carried in between and the binding potential of the compounds was reported as relative response units (RU). Relative response Example No. (RU) 4 5.13 6 2.65 14 15.81 19 14.1 26 10.3 34 1.95 47 2.64 59 1.36 64 3.48 73 2.4 80 2.64 84 2.23 69 WO 2011/051961 PCT/IN2010/000650 85 17.29 86 14.95 C) Demonstration of in vivo efficacy of compounds i) LDL-C lowering activity in LPS induced dyslipidemia model C57 mice Male C57 mice of 7-10 week age are grouped based on non-fasting LDL-C 5 levels, on next day these mice were administered with Vehicle or test compounds (ip. or oral) and 30 min after compound administration lipolysaccharide (LPS) was administered. After LPS administration all animals were kept on fasting for 24 hours, after that animals were bled and LDL-C was measured. The percent change in LDL-C in test compound group Vs Vehicle group was calculated. 10 Example No % Change in LDL-C 4 -29.4 ± 4.1 8 -33.5 ± 5.4 12 -40 ± 10.0 37 -35.4 ± 8.3 40 -34.1 ± 5.7 63 -9.0 ± 10.0 84 -25.8 1 8.6 91 -37.4 8 8 92 -35.8 ± 10.5 93 -46.0 ± 6,2 ii) Lipid lowering effect in HF-HC diet fed Hamster model In this experiment, Syrian golden hamsters which were kept on high fat -high cholesterol (HF-HC) fructose diet for 2 weeks were divided into various groups based 15 on LDL-C and Total cholesterol levels. The treatment was given by oral gavages once daily for 14 days. The blood was collected by retro-orbital sinus puncture method under light ether anesthesia on day 0 (pretreatment), and day 14 of the treatment for lipid levels measurements. The percent change in LDL-C in compound group Vs Vehicle group was calculated. 20 70 H:rxsnienvovenNRPurtbICCMxS56993]_.DOC-l/041201J -71 % Change Vs Vehicle Control E xample No. ____ ___ _______ LDL-C TG TC HDL-C 4 -24 -35 -27 -25 7 -29.3 -26.7 -29,6 -20,1 34 -38.2 2,2 -32,6 -10.3 iii) LDL-C lowering activity- in high fat diet C57 mice The in-vivo LDL-c lowering for test compound was tested in C57 mice which were kept on high fat diet for 4 weeks and the blood was collected by retro-orbital sinus puncture method under light ether anesthesia on day 0 (pretreatment), animal are grouped based on LDL-C levels, after that 4-6 week treatment with vehicle or test compound orally once a day was given. On completion of treatment on day 28 day and or on day 42 of the treatment the blood was collected for LDL-C levels measurement. The percent change in LDL-C in test compound group Vs Vehicle group was calculated. % Change Vs Vehicle Control Example No LDL-C TG TC HDL-C 4 -24 -35 -14 -5 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

权利要求:
Claims (6)
[1] 1. Compounds of the general formula (1), their tautomeric forms, their stereoisomers, regioisomers, their pharmaceutically acceptable salts, containing them 0X HET-XY (1) 0 wherein 'HET represents an optionally substituted heteroaryl or a heterocyclic group; 'X' represents the groups selected from (CH2)., wherein R2 represents H, (C-Co) linear or branched alkyl or a suitable cycloalkyl group, wherein either the alkyl or cycloalkyl group may be further substituted; n = 0 to 3; 'R 1 ' represents linear or branched (Cr-C-) alkyl, cycloalkyl, aryl, groups; 'Y' represents i) the group NR 3 Rt, wherein 'R3' represents (C-C 6 ) linear or branched alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heterocyclyloxy or heteracyclylalkoxy groups, each of which may be further substituted & 'RI' represents H, C(1.) linear or branched alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl or hetercyclylalkyl groups, each of which may be further substituted; N 'N 0z 1i) the groups or " , wherein 'P' represents CH2, S, SO, S0 2 , 0, CO or NR 5 wherein Rs represents H, (C,-C 6 ) linear or branched alkyl or cyclo- alkyl groups; 'm' represents integers fromiI to 3; N> INN and T' represents either NR 3 R 1 or the groups KA. or R wherein 'R%', 'RI' and 'P are as defined earlier.
[2] 2. The compounds as claimed in claim I wherein the substituents on 'HET' represents one or more groups selected from hydrogen or optionally substituted groups selected from (CI-C,) linear or branched alkyl, aryl, heteroaryl, cycloalkyl or a heterocyclyl group. 5 3. The compounds of claim I wherein the substituents on 'HET' are selected from (CI-C 6 ) linear or branched alkyl, cryl or heteroaryl groups, each of which may be further substituted.
[3] 4. The compounds of claim I wherein when the groups representing 'HET' is further substituted, the substituents are selected from halogen, alkyl, haloalkyl, 10 alkoxy, sulfanyl derivative, sulfinyl derivatives, sulfonyl derivatives, sulfonyloxy groups.
[4] 5. The compounds of formula (I) wherein the groups representing 'HET' is selected from 'HET' are selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2 15 oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2 oxomorpholinyt,- azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, 20 pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiaziny, benzothiazinonyl, thieno piperidinyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, 25 pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl groups.
[5] 6. The compounds of formula (I) selected from 30 N-(benzyloxy)-2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,3 dioxane-2-carboxamide; 73 N-(benzyloxy)-2-niethyl-5-c-((5-methyl-2-phenyloxazol-4-yI)methyl)- 1,3-dioxane 2-carboxamide; N-(benzyloxy)-2-methyl-5-t-((5-methyl-2-phcnyloxazo-4-yI)methyl)- I ,3-dioxane 2-carboxamide; 5 N-hydroxy-2-mczhyl-5-((5-methyl-2-phcnyloxazol-4-yI)mcthyl)- I,3-dioxane-2 carboxamide; 5-c-(3-(91--carbazol-9-yI)propyl)-N-hydroxy-2-methyl- t,3-dioxane-2 carboxamide; N-hydroxy-2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yI)mcthyl)- I ,3-dioxane-2 10 carboxamide; N-hydroxy-2-methyl-5-:-((5-methyl-2-phcnyloxazol-4-yl)methyl)-I ,3-dioxane-2 oarboxamade; 2.methyl-5-((5-methy-2-phenyloxazol4-y)methyl)-N-((tetrahydro-2H--pyranA yl)methyl)-1I,3-dioxane-2-carboxamide; 15 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yi)niethyl)-N4((terrabydro-2H-pyranA yI)methyl)- I ,3-dioxane-2-carboxamide; 2-metbyl-5-t-((5-methyl-2-pbenyloxazol-4-yI)metbyl)-N-((tetrahydro-2H-pyran-4 yI)methyl)- I ,3-dioxane-2-carboxamide; (2-metbyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-I ,3-dioxan-2 20 yl)(morpholino)methanone; (2-methyl-5-c-((5-meihyl-2-phenyloxazol-4-yi)methyl)- 1,3 -dioxan-2 yJ)(morpholino)melhanone; (2-metbyt-5-t-((5-methyl-2-phenyloxazol-4-yl)methyl)- 1,3-dioxan-2 yl)(morpholino)melbanone; 25 (2-methyl-5-c-((5-methyl-2-pbenyloxazol-4-yI)methyl)- I ,3-dioxan-2-yl)(4 methylpiperazin-1 -yI)metbanone; (2-methyl-5-c-((5-methyl-2-phenyloxazolA-yI)methyl)- I ,3-dioxan-2-yI)(piperidin I -yl)methanone; (2-melhyl-5-c-((5-methyt-2-phenyloxazol-4-yl)methyl)- I,3-dioxan-2 30 yI)(thiomorpholino)methanone; (1, 1 -dioxidothiomorpholino)(2-methyl-5-c-((5-methyi-2-phenyloxazol yI)methyl)- 1,3-dioxan-2-yl)methanone; 74 2-mcthyl-5-((5-m ethyl-2-phenyloxa zol-4-yl)methyl)-N-(2-morpholino-2 oxoethyl)-1I,3-dioxane-2-carboxamide; 2-methyl-5-c-((5.znethyl-2-phenyloxazo-4-yl)methyl)-N-(2-morphol ino-2 oxoethyl)- I ,3-dioxane-2-carboxamide; 5 2-meothyl-5-t-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(2-morpholino-2 oxoethyl)- 1,3-dioxane-2-carboxamidc; 2-methyl -5-c-((5-methyl-2 -phenyloxazoi-4-yl)niethyl)-N-(2-(4-methyipiperazin- I yI)-2-oxoethyl)- I ,3-dioxane-2-carboxamide; 2-nishyl-5-c-((5-mcthyl2-phenyloxazol4-yl)mcthyl)-N-(2-oxo-2-(piperidin- I 10 yl)ethyl)-1I,3-dioxane-2-oarboxam ide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(2-oxo-2 thiomnorpholinoethyl)- 1 ,3-dioxane-2-carboxamide; N-(2-(, 1, -dioxidothiomorpholino)-2-oxoethyl)-2-methyl-5-c-((5-methyl-2 phenyloxazol-4-yl)rnethyl)- I ,3-dioxane-2-carboxemide; 15 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(2-oxo-2-(((tetrahydro 2H-pyranA-yl)methyl)amino)ethyl)-1I,3-dioxane-2-carboxamide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-morpholino-3 oxopropyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yI)methyl).N-(3-oxo-J -(((tetrahydro 20 2H-pyran-4-yI)methyl)amino)propyl)- 1,3-dioxane-2-carboxamide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-oxo-3 thiomorpholinopropyl)- 1 ,3-dioxane-2-carboxamide; N-(3-(, I, -dioxidothiomorpholino)-3-oxopropyl)-2-msthyl-5-c-((5-mnethyl-2- phenyloxazol-4-yl)methyl)- 1,3-dioxane-2-carboxamide; 25 2-methyl-5-c-((S-methyl-2-phcnyloxazol-4-yl)methyl)-N-(3-oxo-3-(pipcridin- I yijpropyl)-1 ,3-dioxane-2-carboxamide; 2-methyl-5-c-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-(4-methylpiperazin- I yI)-3-oxo)propyl)-I ,3-dioxane-2-varboxamide; 2-methyl-5-((5-methyl-2-phenyloxazol-4-yl)methyl)-N-(3-oxo- 1 -phenylbutan-2 30 yI)-I ,3-dioxane-2-carboxamide; 75 N-benzyioxy-2-methyi-5 -(2-(5-mcthyI-2-pbcnyloxazoI-4-yletby1)-1I,3-dioxane-2 carboxamide; N-bydroxy.2-methyl-5-(2-(5-metlyl-2-penyoxazo-4-y)CthYl)-l ,3-dioxane-2 carboxaniide; 5 N-hydroxy.2-methyl-5-c-(2-(5-mcthyl-2-phenyoxlzoi4-yI)etbyI)-l ,3-dioxane-2 carboxamide; N-hydwoxy-2-methyI-5-t-2(5-methy-2-phenyoxazo-4-yiethy1)- I ,3-dioxane-2 carhoxamide; 2-inetbyl-5-(2-(5-methyl-2-pheayloxazol4-yl~thy)-N-((ttraydo-2W-pyran-4 10 yl)mctliyl)- 1,3-dioxane-2-carboxamide; 2-mezhyl.5-c-(2-(5-metbyl-2.phenyloxazol-4-yl)ethyi)-N-((tetrahydro-2H-pyran4 yI)metbyl)-1I,3-dioxaae-2-carboxamide; 2-methyl-5-t-(2-(5-methyl-2-pbenyloxazol-4-yl)etbyl)-N-((tetrabydro-2H-pyran4 yI)metbyl)-1I,3-dioxane-2-carboxamide; 15 (2-metbyl-5-(2-(5-mcthyi-2-phenyloxazol4-yl)ethyO- 1,3 -dioxan-2 yi)(morpbolino)methanone; (2-metbyl-5-c-(2-(5-metbyl-2-pbenyloxazol-4-y)ethyl)-1I,3-dioxan-2 yl)(morpholino)methanone; (2-metbyl-5-t-(2-(5-mctbyl-2-pbenyloxazol-4-yI)ethyl)-1I,3-dioxan-2 20 yI)(morpholino)inethanone; (2-metbyl-5-c-(2-(5-methyl-2-phenyloxazol-4-yI)etbyl)- l.3-dioxan-2-yI)(4 methylpiperazin-I -yI)metbanone; (2-inetbyi-5-c-(2-(5-metbyl-2-pbenyloxazol-4-yI)etbyl)-1I,3-dioxan-2-yl)(piperidin I -yl)methaaone;
[6] 25. (2-mcthyl-5-c-(2-(5-metbyl-2-phenyloxazol-4-yletbyl)- I ,3-dioxan-2 yl)(tbiomorpholino)metbanone; (1, 1 -dioxidothiomorphoiino)(2-metbyl-5-c-(2-(5-metiyl-2-pbenyloxazol4 yI)etbyl)-lI,3-dioxan-2-yI)methanone; 2-methyl-5-(2-(5.metbyl-2-phenyloxazol-4-yletbyl)-N-(2-niorpbolino-2 30 oxoethyl)- 1,3 -dioxane-2-carboxamide; 76 2-methyl-5-c-(2-(5-methyl-2-phenyloxazoi-4-yI)eihyi)-N-(2-marpholina-2 oxoethyl)-1I,3-dioxane-2-earhaxam ide; 2-methyl-5-:-(2-(5-cncthyl-2-phenyloxazol-4-yi)ethyl)-N-(2-morpholino-2 oxoethyl)-1I,3-diaxanc-2-earbaxamide; 5 2-methyi-5-c-(2-(5-methyl-2-phenyiaxazalA-y)ethyl)-N-(2-oxo-2-(((tetrahydra 21--pyman-4-yi)methyi)amino)ethyl)- 1,3-diaxane-2-carboxarnide; 2-mcthyl-5-o-(2-(5-niethyl-2-phenyloxazol-4-yI)ethyl)-N-(2-(4-methy Ipiperazin- I yI)-2-oxoethyl)-1 ,3-diaxane-2-carboxamide; 2-mezhyl-5-o-(2-(5-rnethyl-2-phenyloxazol-4-yl)ethyl)-N-(2-axo-2 10 thiamorpholinoethyl)- I ,3-dioxane-2-varboxamide; 2-meffiyf-5-c-(2-(5-methyl-2-phenyloxazol-4-yI)ethyfl-N-(2-oxo-2-(piperidin- I yl)ethyl)-1I,3-dioxane-2-carboxamide; 2-metliyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)-N-(3 -oxo- I -phenylbutan-2 yl)- 1,3-dioxane-2-carhoxamide; 15 2-methyl-5-(2-(5-rncthyl-2-phenyloxazol-4-yl)ethyl)-N-(2-oxo-2-((3-oxo- I1 phenylbutan-2-ylamino)ethyl)- I ,3-dioxane-2-carboxarnide; N-henzyloxy-2-methyl-5 -((5-methyi-2-(p-tolyl)oxazol-4-yI)methyl)- I ,3-dioxane-2 carboxamide; N-benzyloxy-2-methyl-5-c-((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-1I,3-dioxane 20 2-carbcoxamide; N-benzyloxy-2-methyl-5-t-((5-methyl-2-(p-tolyl)oxazal-4-yI)methyl)-1I,3-dioxane 2-carboxamide; N-hydroxy-2-methyl-5-((5-methyl-2-(p-tolyl)oxazol-4-yI)niethy 1)-i ,3-dioxane-2 carboxam ide; 25 N-hydroxy-2-methyl-5-c-((5-methyi-2-(p-tolyl)oxazol-4-yI)methyl)-I ,3-dioxane-2 carboxam ide; N-hydroxy-2-methyl-5-t-((5-methyl-2-(p-tolyl)oxazol-4-yl)methyt)-I ,3-dioxane-2 carboxanmide; 2-methyl-5-((5-methyl-2-(p-tolyl)oxazol-4-yI)methyl)-N-((tetrahydro-2H-pyranA 30 yI)methyi)- 1,3-dioxane-2-carboxamide; 77 2-methyl.5-c-((5-methyl-2-(p-tolyl)oxazol-4-y)methyl)-N-((tetrahydro-2H-pyran 4-yI)methyl)- 1,3-dioxane-2-carboxaniide; 2-mcthyl-5-:-((5-methyl-2-(p-tolyl)oxazol-4-yI)methyl)-N-((tetrahydro-2H-pyran 4-yI)methyl)- 1 ,3-dioxanc-2-earboxamide; 5 (2-nicthyl-5-((5-mcthyl-2-(p-toiyl)oxazol-4-yI)methyl)-I ,3-dioxar-2 yi)(morphalino)methanone; (2-methyl-5-c-((5-methyl-2-(p-talyl)oxazal-4-y)methyi)- I ,3-dioxan-2 y])(morpholino)methanane; (2-methyi-5-t-((5-mcthyl-2-(p-tolyI)oxazol-4-yI)methyt)-1I,3-dioxan-2 10 yI)(morpholina)methanone; 2-methyl-5-((5-nicthyl-2-(p-tolyl)oxazol-4-yI)methyl)-N-(2-marphal ino-2 axoethyl)-] ,3-dioxane-2-oarboxamide; 2-methyl-5-c-((5-methyl-2-(p-tolyl)axazol-4-yI)methyl)-N-(2-morphalino-2 oxoethyl)- I ,3-dioxane-2-carboxamide; 15 2-methyi-5-t-((5-metbyl-2-(p-tolyl)oxazol-4-yI)methyl)-N-(2-morpholino-2 oxoethyl)- 1 ,3-dioxane-2-carboxamide; N-(benzyloxy)-5-((2-(tert-butyl)-5-methyloxazol-4-yI)mnethyl)-2-methyl- 1,3 dioxane-2-carboxaniide; 5-((2-(tent-butyl)-5-methyloxazol-4-y)methyl)-N-hydroxy-2-methyl- I ,3-dioxane 20 2-carboxamide; (5-((2-(tert-butyl)-5-methyloxazol-4-y)methyl)-2-methyi- I ,3-dioxan-2 yl)(morpholino)methanone; 2-mezhyl-5-c-((5-metbyi-2-(5-methylthiophen-2-yI)oxazol-4-yI)methyl)-N ((tetrahydro-2H-pyran-4-yI)methyl)-I13-dioxane-2-carboxamide; 25 2-methyi-5-r-((5-methyl-2-(5-methylthiophcn-2-yI)oxazol-4-yI)methyl)-N ((tetrahydro-2H-pyran-4-yI)methyl)- I ,3-dioxane-2-,carboxamidc; 2-methyl-5 -c-((5-methyl-2-(5-methylthiophen-2 -y)oxazoi -4-yI)methyl)- 1,3 dioxan-2-yl)(morpholino)methanone; 2-methyl-5-t-((5-methyl-2-(5-methylthiophen-2-y)oxazol-4-y)methyl)-1 13 30 dioxan-2-yl)(morpholino)methanone; 78 N-benzyloxy-2-metby-5-c-((5-mcthyl-2-(pyrdin-4-y)oxazo-4-y)methy)-1 ,3 dioxanc-2-carboxamide; N-benzyloxy-2-methyl-5-:-((5-metbyl-2-(pyridin-4-yI)oxazoi-4-yi)methyl)-I .3 5 dioxane-2-oarboxamidc; N-hydroxy-2-metby-5-c-((5-niethyl-2-(pyridin-4-y)oxazo-4-y)methyl)- 1,3 dioxane-2-carboxwnide; N-hydroxy-2-methy-5-t-((5-methy-2-(pyridin4-y)oxazol-4-yI)flethyl)- 1,3 dioxane-2-oarboxamide; 10 (2-methyl-5-c-((5-mnethyl-2-(pyridin4-y)oxazol4-y)methyl)- I ,3-dioxan-2 yl)(morpholino)methanone; (2-metbyl-5-:-((5-methyl-2-(pyridin-4-yI)oxazol-4-yI)methyl)- I ,3-dioxan-2 yi)(morphoiino)mcethanone; 2-miethyl-5-c.((5-methy-2-(pyridin-4-y)oxazol-4-yI)methyl)-N-((tetrahydro-2- 15 pyran-4-yl)metbyl)- I,3-dioxane -2-carboxamidc; 2.methyi-5-t-((5-methyl-2-(pyridin-4-yl)oxazo-4-yl)methyl)-N-((tetrabydro-2H pyran-4-yI)mcthyl)-I,3-dioxane-2-carboxwnide; 2-methyl-5-c-((5-methyl-2-(pyridin-4.y)oxazol-4-yl)methyl)-N-(2-morpholino-2 oxoethy I)- 1,3-dioxane-2-carboxamide; 20 2-methyl-5-t-((5-methyl-2-(pyridin-4-yI)oxazol-4-yJ)metbyl)-N-(2-morphol ino-2 oxoethyl)- 1,3-dioxane -2-carboxamide; 2-methyi-5-c-((5-methyl-2-(pyridin-4-yi)oxazol-4-yI)mecthyl)-N-(2-oxo-2 (((tetrahydra-2H-pyran-4-yi)methyl)amino)ethyl)- 1,3-dioxane-2-varboxamide; 2-methyl-5-t-((5-methyl-2-(pyridin4-y)oxazol-4-y)methy I)-N-(2-oxo-2 25 (((tetrahydro-2H-pyran-4-yI)methyl)aniino)ethyl)- I ,3-dioxane-2-oarboxamnide; N-benzyloxy-2-methyl-5 -((4-methyi-2-(4-(trifluoromethyl)phenyl)thiazol-5 yi)methyl)- I ,3-dioxane-2-carboxamide; N-hydroxy-2-methyl-5-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazo-5 yI)niethyl)-I ,3-dioxane-2-varboxam ide; 30 1 -(2-methyl-5-((4-metbyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yI)methyl)-I .3 dioxan-2-yl)-N-((tetrahydro-2H--pyran-4-yl)methyl)nicthanainine; 7.9 (2-methyI-5-((4-mcthyI-2-(4-(trifluoromehylpheny~hizo-5-YlmethYI)-I .3 dioxan-2-yi)(morphoiino)methanonc; (2-methyI-5-c-((4-mcthy-2-(4-(trifluoroethyI)phny)thizol-5-Yfl2IethyI)- 1,3 5 dioxan-2-yI)(morpholino)mcthanone; (2-methyl-5.t-((4-methyl-2-(4-(triluoromethyl)phnyl)tiazol-5-y)lethy)- 1,3 dioxan-2-yI)(morpholino)methanone; 5-c-(3-(91--carbazol-9-yl)propyi)-N-hydroxy-2-methyl- I ,3-dioxane-2 oarboxamide; 10 N-hydroxy-5-c-(3-( I OI--phenothiazin-1 O-yI)propyl)-2-mcthyl- 1 ,3-dicxane-2 carbaxam ide; N-(benzyloxy)-5-((3-(tert-butyl)-I -(p-tolyl)- I H-pyrazol-5-yI)methyl)-2-methyl 1 ,3-dioxane-2-carboxam ide; N-(hydroxy)-5-c-((3-(tert-butyi)- I-(p-tolyl)-1H-pyrazoi-5-yi)rrethyl)-2-methyl 15 I,3-dioxane-2-carboxamide; N-(hydroxy)-5-t-((3-(tert-butyl)- I-(p-iolyI)- IH-pyrazol-5-yI)methyl)-2-methyl- 1,3 dioxane-2-oarbcxamide; 5-((3-(tert-butyl)- I-(p-tolyl)- IH-pyrazol-5-yI)methyl)-2-mcthyl-N-((tctrahydro 2H-pyran-4-y)mnethyl)- 1,3-dioxane-2-carboxamide; 20 5-((3-(tert-butyl)-1 -(-tolyI)- IH-pyrazol-5-yI)methyl)-2-methyl-N-(2-cxo-2 (((tetrahydro-21--pyran-4-yI)methyl)amino)ethyl)-1,3-dioxane-2-carboxamide; (5-((3-(tert-butyI)- I-(p-tolyl)-1 H-pyrazol-5-yI)methyl)-2-mclhyl-1I,3-dioxan-2 yi)(morphvlino) methanone; 5-((3-(tert-butyI)- I-(p-tolyl)- IH-pyrazol-5-yI)melhyl)-2-methyl-N-(2-rrorpholino 25 2-oxoethyl)-1I,3-dioxane-2-carboxamide; (5-((3-(tert-butyl)-]I-(p-tolyl)-1 1--pyrazol-5-y)methyl)-2-methyl- 1,3-dioxan-2 yI)(4-methylpiperazin- I -yI)methanone; N-(benzyloxy)-5-c-((2-(4-methoxyphenyl)-5-melhyloxazol-4-ylmethyl)-2-mcthyl I ,3-dioxane-2-carboxamide; 30 N-(benzyloxy)-5-t-((2-(4-methoxyphenyl)-5-mlethyloxazol-4-ylmethyl)-2-methyi I ,3-dioxane-2-carboxamide; N-hydroxy-5 -c-((2-(4-methoxyphenyI)-5-methyloxazoI-4-ylmethyI)-2-methy- I ,3 dioxane-2-carboxam ide; 80 N-bydroxy-5-:-((2-(4-methoxypheriyl)-5-methyloxazol-4-yI)methyl)-2-methyl- 1,3 dioxane-2-carboxawidc; (5-c-((2.(4-metboxyphenyl)-5-methytoxazo-4-y)uiethyl)-2-methyl-1I,3 -dioxan-2 5 yI)(morpholino)rnhthanone; (5-i-((2-(4-methoxyphcny)-5-metbyloxazoL-4-yI)methyl)-2-nietbyl-1I,3-dioxan-2 yI)(morphoiino)methanonc; 5-c-((2-(4-mcthoxypheriyl)-5-methyloxazol-4-yI)methyl)-2-methyl-N-((tetrahydro 2H-pyan-4-yl)mctliyl)- 1,3-dioxane-2-carboxarnide; 10 5-i-((2-(4-methoxyphenyl)-5-methyloxazol-4-yI)rnethyl)-2-methyl-N-((tctrahydro 2K-pyran-4-yI)methyl)-I ,3-dioxane-2-carboxamide; (5-c-((2-(4-methoxyphenyl)-5-meihyloxazol-4-yI)methyl)-2-methyl-1I,3-dioxam-2 yI)(4-methylpiperazin- I -yI)methanone; (5-t-((2-(4-methoxyphcny)-5-methyloxazol-4-y)methyl)-2-methyl-1I,3-dioxan-2 15 yIfl4-methylpiperazin- I -yl)rnethanone; N-(benzyloxy)-2-methyl-5-c-((5-nethyl-2-(4-(tri fluoromethyl)phenyloxazol-4 yI)methyQ)-I,3 -dioxane-2-carboxarnide; N-(benzyloxy)-2-rnethyl-5-t-((5-methyl-2-(4-(trifluoromcthyl)phenyl)oxazol-4 yI)methyl)-1 ,3.-dioxane-2-caitoxamide; 20 N-hydroxy-2-mnethyl-5-c-((5-methyl-2-(4-(trifluoromthy)phenyl)oxazoL-4 yI)metliyl)- 1,3-dioxane-2-carboxamide; N-hydroxy-2-methyl-5-t-((5-methyl-2-(4-(trifluoromcthyl)phenyl)oxazol-4 yI)methyQ- 1,3-dioxanc-2-oaatoxamide; (2-methyl-5-c-((5-mcthyl-2-(4-(trifluoromethy)phenyl)oxazoL-4-yI)methyl)- I1,3 25 dioxan-2-yI)Quorpholino)methanone; (2-methyi-5-:-((5-methyl-2-(4-(trifluoromethyl)phnyl)oxazol-4-y)methyl)-1,3 dioxan-2-yI)(morpholino)methanone; 2-methyl-5-c-((5-methyl-2-(4-(zrifluoromethyL)phenyi)oxazol-4-yI)methyl)-N (Qezrehydro-2H-pyran-4-yI)methyl)- I ,3-dioxane-2-carboxamide; 81 2-methyl-5--((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methyl)-N 5 ((tetrahydro-2H-pyran-4-yl)methyl)-1,3-dioxane-2-carboxamide. 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1) as claimed in any of the preceding claims and a pharmaceutically acceptable carrier diluent or excipients. 8. A pharmaceutical composition according to claim 7 which is used for the 10 treatment of dyslipidemia and related diseases. 9. A method of treating disorders caused by dyslipidemia and related diseases comprising administering to a patient in need thereof an effective amount of a compound of formula (1) according to any of the preceding claims or its pharmaceutical composition according to any of the preceding claims. 15 10. The use of a compound of formula (I) or its pharmaceutical composition according to any of the preceding claims for the manufacture of a medicament for the treatment of dyslipidemia and related diseases. I1. A medicine for the treatment of disorders caused by dyslipidemia and related diseases which comprises administering therapeutically effective amount of 20 compound of formula (1) or its pharmaceutical composition as defined in any of the preceding claims to a patient or subject in need thereof. 12. A method of selecting small molecule inhibitors of PCSK9 by identifying molecules which bind to the catalytic site of the PCSK9, and subsequently checking the binding potential of the identified molecules to the PCSK9 25 protein. 13. The method as claimed in claim 12 wherein the molecules bind to one or more of the amino acids comprising the catalytic triad HIS 226 SER 386 ASP 186 alone or in combination with other amino acids from the catalytic site. 14. Small molecules which bind to the catalytic site of the PCSK9, as inhibitors of 30 PCSK9. 15. Small molecules inhibitors of PCSK9 which bind to the catalytic site of the PCSK9'protein. 82

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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WO2004099173A1|2003-05-12|2004-11-18|Theracarb Inc.|Multivalent inhibitors of serum amyloid p component|

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AR070316A1|2008-02-07|2010-03-31|Merck & Co Inc|PCSK9 ANTAGONISTS |

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法律状态:
2016-06-16| MK25| Application lapsed reg. 22.2i(2) - failure to pay acceptance fee|

优先权:

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申请号 | 申请日 | 专利标题

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IN2292/MUM/2009||2009-10-01||

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AU2010313068A|AU2010313068B2|2009-10-01|2010-09-29|Compounds for the treatment of dyslipidemia and related diseases|

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AU2013204732A|AU2013204732B2|2009-10-01|2013-04-12|Compounds for the treatment of dyslipidemia and related diseases|AU2013204732A| AU2013204732B2|2009-10-01|2013-04-12|Compounds for the treatment of dyslipidemia and related diseases|