Compounds for the treatment of dyslipidemia and related diseases

Invention field

The invention relates to the general formula (I) compounds, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salt, pharmaceutical compositions containing them, methods for their preparation, the use of these compounds in the medicine and in the use of the preparation of the intermediates.

The invention relates to PCSK9 of the antagonist, it can be used for the treatment of the PCSK9 enzyme-mediated disease, such as dyslipidemia. The compounds of this invention also reduce LDL-c.

Background of the invention

LDL cholesterol content in blood plasma is relatively high will increase the risk of cardiovascular, reducing the level of LDL in order to reasonably percentage reduce the risk of CVD (PNAS, 2009, 106, 9546-9547). The removal of LDL cholesterol in blood plasma is the role of the LDL receptor in the liver, LDL receptor is a cell surface glycoprotein, the LDL particles with high affinity of the apolipoprotein (apoliporpotein) B   100 (apoB100) binding, and their the butcher swallows mediated uptake (Journal   of   Biological   Chemistry, 2009, 284, 10561-10570). The liver caused by mutations removing defects and plasma LDL cholesterol cholesterol levels result in familial hypercholesterolemia. Such a mutation in the human LDL receptor identification, in after identifying the apolipo B (Nature   Structural   and   Molecular Biology, 2007, 14,413-419). Recently, found that the original protein (proprotein) convertase subtilisin/kexin   9-type (PCSK9) represents the mutation of the gene in the 3rd euchromosome dominace hypercholesterolemia (ADH) related mutation. In Abifadel 2003 as found in a 3rd PCSK9 of the gene is involved in alcoholemia euchromosome dominace gao Dan (autosomal   dominant hypercholesterolemia, ADH) of gene 3rd (Nature   Genetics, 2003, 34, 154-156, Trends   in   Biochemical   Sciences, 2008, 33,426-434). Some of the missense mutation (S127R, D129G, F216L, D374H, D374Y) with hypercholesterolemia and early maturity atherosclerosis (premature   atherosclerosis) relevant (J   Lipid   Res. 2008, 49, 1333-1343). Function mutant loses the nature (R46L, L253F, A433T) caused by receptor abundance to rise, the increase in LDL cholesterol from circulation of the cleaning and reduce the cardiovascular risk (Nature Structural   and   Molecular   Biology, 2007, 14,413-419).

PCSK9 belongs to the serine proteinase class of bacillus subtilis protease family, its protein structure (prodomain) by the original domain, catalytic domain and cysteine/histidine enriched C a terminal domain (Structure, 2007, 15,545-552). And the other of the original protein convertase (its CENTA domain is further proteolytic processing to activate the serine protease) different, secreted PCSK9 of the original domain to remain intact and are tightly combined. Within the endoplasmic reticulum, PCSK9 self-catalytic process, and results in the release of the same catalytic/C-terminal domain combined -14kDa the original domain, wherein the original domain at the same time serve as the folding chaperone protein (folding   chaperon) and enzyme activity inhibitor (Journal   of   Biological   Chemistry, 2009, 284, 10561-10570).

Conclusively epidermal growth of the LDLR factor type repetitive sequence with A(EGF-A) PCSK9 Interac, primarily with the residue 367-381 interaction. The interaction site EGF-A PCSK9 located at catalytic sites> 20 Is. Once EGF-A and PCSK9 role each other, they forming PCSK9-LDLR complex, endosome into the path, and therefore prevent the LDLR re-circulation, leading to degradation of LDLR. Explanation with LDLR PCSK9 LDLR degradation and the detailed molecular mechanism also is not very clear (Drug   News   Perspectives, 2008, 21,323-330). The inhibit recirculation of LDLR, on the surface of a cell the number of LDL receptors, this improves the level of plasma LDL (PNAS, 2009, 106, 9546-9547).

PCSK9 reported that inhibit the various methods, including through the siRNA or antisense oligonucleotide gene silencing, mAb fracture protein-protein interactions or attached via peptide; all of the above-mentioned strategies are shown to reduce LDL cholesterol, it may be an effective therapy for treating hypercholesterolemia (Biochemical   Journal, 2009,419,577-584; PNAS, 2008, 105, 11915-11920; Journal   of   Lipid   Research, 2007, 48,763-767; PNAS, 2009,106, 9820-9825).

Referred to the many reports PCSK9 of has the advantages of small molecule inhibitors (Drug   News Perspect   21 (6), July/August   2008,323-330; PNAS, 106 (24), 9546-9547, 2009 ; Curr   Atheroscler   Rep (2010) 12 : 308-315; and the like). Subsequently, after many efforts discovered PCSK9 of small molecule inhibitors. Targeting PCSK9 small molecule appears to be quite difficult, because PCSK9 LDL-R degradation is a kind of protein-protein interactions, the process and PCSK9 protein to a cracking activity (Lou, K.-J.SciBX   2 (22); doi: 10.1038/scibx. 2009 . 895 and the reference literature). According to the above-mentioned report, we assume that the PCSK9 combination of a catalytic site of the small molecules can be allosterically to affect (allosterically) with LDL-R PCSK9 binding. Butt joint by computer simulation (in   silico   docking) research, we design the PCSK9 can be combined with a compound of a catalytic site. Such a molecule (such as embodiment the) display as a combination of SPR view of the evidence, in vivo efficacy in vitro effectiveness and (ELISA).

Invention SUMMARY

The main purpose of the invention is of formula (I) compounds or their pharmaceutically acceptable salt, as PCSK9 modulators of the enzyme.

In the present invention in one embodiment, provides a method for preparing the compounds of this invention.

The invention in another embodiment, provides by providing a therapeutically effective amount of formula (I) compound or a pharmaceutically acceptable salt or their appropriate PCSK9 to a pharmaceutical composition for the treatment of diseases mediated by the enzyme method.

In one embodiment, provides a method of identifying as PCSK9 small molecule inhibitors of the method.

The above-mentioned and the other in some embodiments described below.

Description of drawings

Figure 1 to embodiment 47 PCSK9 of the abutting posture (  pose docked) map of the three-dimensional model. Display ligand binding mode and PCSK9 the static electricity on the surface of the protein.

Invention details

Therefore, the present invention relates to the general formula (I) compounds, their tautomeric forms, their stereoisomers, regional isomer, pharmaceutically acceptable salts of them and pharmaceutical compositions containing them,

Wherein

'HET' represents optionally substituted heteroaryl or heterocyclyl;

When the group of "HET" is when substituted, the substituent on behalf of one or more selected from the group of the following: hydrogen or is selected from (C1-C6) straight-chain or branched alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl optionally substituted group. In a preferred embodiment, the 'HET' substituent on (C₁-C₆) straight-chain or branched alkyl, aryl or heteroaryl;

'X' represents a group selected from the following group : (CH₂)_n, O (CH₂)_n, S (CH₂)_n, SO (CH₂)_n, SO₂ (CH₂)_n or NR₂ (CH₂)_n, wherein R₂ representative H, C_(1-6) straight-chain or branched chain alkyl or cycloalkyl, wherein the alkyl or cycloalkyl may be further substituted by one or more of substituted with a group such as are described below, and n=0 to 3;

'R₁' represents straight-chain or branched C_(1-6) alkyl, or is selected from cycloalkyl, aryl the appropriate group;

In one embodiment, the representative 'Y' NR₃ R₄, wherein R₃ representative C_(1-6) straight-chain or branched alkyl, cycloalkyl, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl, aryl-alkyl, heteroaryl-alkyl, heterocyclyl-alkyl, hydroxy, alkoxy, naphthenic propoxycyclohexyl, naphthenic alkoxy, aryloxy, arylalkoxy, Heteraryloxy, heteroaryl alkoxy, heterocyclic yloxy or Teterocyclyloxy, each can further be one or more selected from the group described below those group substituted, R₄ representative H, C_(1-6) straight-chain or branched alkyl, cycloalkyl, cycloalkyl alkyl, aryl, heteroaryl, heterocyclyl, aryl-alkyl, heteroaryl-alkyl or heterocyclic-based alkyl, their respective can further be one or more selected from group substituted from those described below;

In another embodiment, 'Y' represents a group

Wherein the representative 'P' CH₂, S, SO, SO₂, O, CO or NR₅, wherein R₅ representative H, C_(1-6) straight-chain or branched chain alkyl or cycloalkyl; the representative 'm' 1 to 3 of the integer;

'Z' representative NR₃ R₄ or group Wherein R₃, R₄ and P as previously defined.

When stated in the specification of any group is substituted, the substituent can be in each occurrence independently selected from the group consisting of hydroxy, oxo base (oxo), halogen, thiol, nitro, amino, cyano, formyl, or a substituted or unsubstituted group selected from the group consisting of the following: amidino, alkyl, halogenated alkyl, fully halogenated alkyl, alkoxy, alkyl halide propoxycyclohexyl, the halo-phenoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, double-ring alkyl, double-cycloalkenyl, alkoxy, alkene oxygen radical , naphthenic oxy, aryl, aryloxy, aralkyl, aralkyloxy, heterocyclyl, heteroaryl, heterocyclyl-alkyl, heteroarylalkyl, heteroaryl propoxycyclohexyl, Heteraromatic alkoxy, heterocyclic oxy, Teterocyclyloxy, acyl Teterocyclyloxy, acyl, acyloxy, acylamino, mono-substituted or di-substituted amino, aryl amino, arylalkyl amino, carboxylic acid and its derivative if ester and amide, carbonyl amino, hydroxy alkyl, amino alkyl, alkoxy alkyl, aryloxy alkyl, aralkyloxy alkyl, alkyl thio, thio alkyl (thioalkyl), cycloalkyl thio, aryl thio, heterocyclic base sulfenyl , heteroaryl thio, alkyl sulphinyl, naphthenic methylene sulfonyl, aryl sulfonyl, sulfonyl heterocyclic methylene, hetero aryl sulfonyl, alkyl sulfonyl, cycloalkyl sulfonyl, aryl sulfonyl, heterocyclyl sulfonyl, heteroaryl sulfonyl, alkyl sulfonyl amino, cycloalkyl sulfonyl amino, aryl sulfonyl amino, heterocycle base sulfuryl amino, heteroaryl sulfonyl amino, alkyl sulfonyloxy, naphthenic sulfonate acyloxy, aryl sulfonyloxy, heterocyclic sulfonate acyloxy, hetero aryl sulfonyloxy, alkoxy carbonyl amino, aryloxy carbonyl amino, aralkyloxy-carbonyl amino, amino carbonyl amino, alkyl amino carbonyl amino, alkoxy amino, hydroxy amino, sulfinyl derivatives, sulfonyl derivative, sulfonic acid and its derivatives;

When the 'HET' of the substituent is further substituted, the substituent is selected from halogen, alkyl, halogenated alkyl, alkoxy, alkyl (sulfanyl) derivatives sulfur, sulfinyl (sulfinyl) derivatives, sulfonyl derivatives, sulfonyloxy;

Alone or used in combination with other group terms "heterocyclic radical" or "heterocyclic" is selected from the appropriate saturated, partially saturated or unsaturated aromatic or non-aromatic monocyclic, bicyclic or tricyclic group, which comprises one or more selected from the group consisting of nitrogen, sulfur heteroatom. In a preferred embodiment, said heterocyclic group is selected from ethylenimine base , nitrogen heterocyclic butyl , pyrrolidinyl, imidazole alkyl, piperidinyl, piperazinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo-piperazine, 3-oxo-piperazinyl, morpholinyl, thiophosphoro morpholinyl, 2-oxo-morpholinyl, aza Yl (aziridinyl), two nitrogen mixed Zhuo Ji , oxa Yl (oxapinyl), thia azatropy Yl (thiazepinyl), [...] , thiazole alkyl, carbamylaspartic thiopheneglyoxylic, dihydropyrane, dihydrofuran, dihydro thiazole, benzopyranyl, benzopyrones yl, benzo carbamylaspartic furyl, benzene and dihydro thienyl, pyrazolopyrimidine keto, nitrogen [...] , thiopheneglyoxylic hepyramine, quinazolone base , pyrimidine keto, styrene-acrylic Benzoxazinyl, benzo [...] , benzothiazinyl, BENZOTHIAZINE keto, thiophene and piperidinyl, and the like;

Alone or used in combination with other group the term "heteroaryl (heteroaryl)" or "heteroaryl (heteroaromatic)" is selected from the appropriate single or condensed single, double or tricyclic aromatic heterocyclic radical, containing one or more selected from O, or S N the hetero-atom. In a preferred embodiment, the hetero aryl group is selected from the group consisting of pyridyl, thienyl, furyl, pyrrolyl, Oxazolyl, thiazolyl, isothiazolyl, imidazolyl, heteroploid Oxazolyl, Oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indoline based (indolinyl), indolyl, aza-indolyl, aza-indoline based, pyrazole pyrimidinyl, nitrogen [...] , pyridine and furyl, pyridine and thienyl, thiophene and pyrimidinyl, quinolyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, [...] (phthalazynil), (naphthylidinyl) naphthyridine base , purinyl, carbazolyl, [...] , order Benzoxazinyl, benzo Azoly, benzothiazolyl, and the like.

Preferably selected from the 'HET' ethylenimine base , nitrogen heterocyclic butyl , pyrrolidinyl, imidazole alkyl, piperidinyl, piperazinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo-piperazine, 3-oxo-piperazinyl, morpholinyl (morpholinyl), thio morpholinyl, 2-oxo-morpholinyl, aza Yl, diazepine Yl, oxa Yl (oxapinyl), thia azatropy Yl (thiazepinyl), [...] , thiazole alkyl, carbamylaspartic thiopheneglyoxylic, dihydropyrane, dihydrofuran, dihydro thiazole, benzopyranyl, benzopyrones yl, benzo carbamylaspartic furyl, benzene and dihydro thienyl, pyrazolopyrimidine keto, nitrogen [...] , thiophene and pyrimidine keto, quinazolone base , pyrimidine keto, benzo Benzoxazinyl, benzo [...] , benzothiazinyl, BENZOTHIAZINE keto, thiophene and piperidinyl, pyridyl, thienyl, furyl, pyrrolyl, Oxazolyl, thiazolyl, isothiazolyl, imidazolyl, heteroploid Oxazolyl, Oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indoline based, indolyl, aza-indolyl, aza-indoline based (azaindolinyl), pyrazole pyrimidinyl, nitrogen [...] , pyridine and furyl, pyridine and thienyl, thiophene and pyrimidinyl, quinolyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, [...] (phthalazynil), (naphthylidinyl) naphthyridine base , purinyl, carbazolyl, [...] , order Benzoxazinyl, benzo Azoly, benzothiazolyl.

Any place in this specification the use of the various groups and substituted the base is even described in the following paragraphs.

-alone or used in combination with other group comprises "alkyl" of 1 to 6 carbon atoms of straight-chain or branched, is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, ert-amyl , positive pentylimidazolium, nhexyl, etc.;

-alone or the combined use with other group "alkenyl" selected from the group comprising 2 to 6 carbon groups, preferably selected from the group consisting of vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexene group base and so on ; the "alkenyl" includes straight-chain and branched diene and hexatrienes;

-alone or the combined use with other group "alkynyl" selected from the group comprising 2 to 6 carbon atoms of straight-chain or branched chain group of, (thynyl) is more preferably ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- propylacetylene base , 2- propylacetylene base , 3- propylacetylene base , 4- propylacetylene base , 1- methyl propyl-acetylene base , and the like. The term "alkynyl" includes the diyne and three alkyne ;

-alone or the combined use with other group "cycloalkyl" or "having an alicyclic group" selected from the group comprising 3 to 6 carbon atoms of the cyclic group, more preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; the term "bicyclic alkyl" means more than one fused together cycloalkyl;

-alone or the combined use with other group is preferably selected from the "cycloalkenyl" cyclo propene base , 1- cyclobutene base , 2- cyclobutene base , 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, and the like; the term "double-cycloalkenyl" means more than one fused together the cycloalkenyl;

-alone or used in combination with other groups selected from the group comprising "alkoxy" is directly connected with an oxygen atom of the alkyl group as defined above, more preferably selected from the group consisting of methoxy, ethoxy, are propoxy, isopropoxy, is butoxy, tert-butoxy, isobuoxy, pentyloxy, hexyloxy, etc.;

-alone or the combined use with other group "naphthenic propoxycyclohexyl" selected from the group comprising 3 to 7 carbon atom of the cyclic group, preferably cyclopropyloxy, link butoxy , cyclopentyloxy, cyclohexyloxy, and the like; the term "double-naphthenic propoxycyclohexyl" means more than one fused together cycloalkyl;

-alone or used in combination with other groups selected from the group comprising " alkene oxygen radical " is connected with an oxygen atom of the alkenyl group as defined above, more preferably selected from the group consisting of ethylene oxy, allyloxy, butene propoxycyclohexyl, pentene propoxycyclohexyl, enyl propoxycyclohexyl, etc.;

"Halogenated alkyl" group is selected from a properly by one or more halogen-substituted by an alkyl group as defined above; such as the halogenated alkyl, more preferably the whole fluorocholine (C₁-C₆) alkyl, for instance fluorine methyl, difluoromethyl, trifluoromethyl, fluoro ethyl, di ethyl, trifluoro ethyl, or shan Lumulti-halogen substituted methyl, ethyl, propyl, butyl, pentyl or hexyl;

"Alkyl halide propoxycyclohexyl" directly connected with an oxygen atom group is selected from as defined above of the appropriate halogenated alkyl, more preferably selected from fluoro methoxy , chloro- methoxy , fluoro ethoxy group , chloropivaloyl ethoxy, and the like;

"Full alkyl halide propoxycyclohexyl" directly connected with an oxygen atom group is selected from as defined above of the appropriate full halogenated alkyl, more preferably, is selected from trifluoromethoxy, trifluoroethoxy, group;

Alone or the combined use with other group "aryl" or "aryl" selected from the group comprising 1, 2 or 3 aromatic system the appropriate link , wherein the rings are connected together (pendant) can be overhung manner or may be fused, more preferably, the group is selected from a phenyl, naphthyl, four hydrogen naphthyls , indanyl, biphenyl, etc.;

Alone or used in combination with other groups selected from the group comprising "aryloxy" is directly connected with an oxygen atom of the aryl group as defined above, more preferably, in order to be selected from phenoxy, naphthoxy, tetralin propoxycyclohexyl, biphenyl propoxycyclohexyl the group;

Group "heteroaryl oxy", "Heteraromatic alkoxy", "heterocyclic oxy", "Teterocyclyloxy" with an oxygen atom are selected from the group as defined above with the appropriate heteroaryl, heteroaryl alkyl, heterocyclyl, heterocyclyl-alkyl;

Alone or the combined use with other group "acyl" selected from the group comprising 1 to 8 carbon atoms per group, more preferably selected from can be substituted formyl, acetyl, propionyl, butyryl, isobutyric acyl, fifth heavenly stem acyl group , oneself acyl group , age acyl group , benzoyl, etc.;

Alone or with other group of combined use with an oxygen atom "acyloxy" of selected from the group as defined above is directly connected with the appropriate acyl group, more preferably, such a group is selected from a acetoxy, c acyloxy, ding acyloxy , isobutyric acyloxy, acyloxy benzoate;

Alone or used in combination with other group is selected from "acylamino" is defined as before the appropriate acyl group, more preferably, such a group is selected from a can be substituted CH₃ CONH, C₂ H₅ CONH, C₃ H₇ CONH, C₄ H₉ CONH, C₆ H₅ CONH, etc.;

Alone or the combined use with other group "mono-substituted amino" by a representative as defined before (C₁-C₆) alkyl, substituted alkyl, aryl, substituted aryl or aryl alkyl group substituted amino, more preferably, such a group is selected from the group consisting of methylamine, ethylamine, propylamine, butylamine, pentylamine, is;

Alone or the combined use with other group "disubstituted amino" group represent the two can be the same or different selected from the group consisting of as previously defined (C₁-C₆) alkyl, substituted alkyl, aryl, substituted aryl or aryl alkyl group substituted amino, more preferably, such a group is selected from a dimethylamino, methylethylamino, diethyl-amino, phenyl methyl amino;

Alone or used in combination with other groups of the representatives of the "arylamino" is an aryl group as defined above of, its has the free valence bond from the nitrogen atom, more preferably, the group is selected from a phenyl amino, naphthyl amino, -methylaniline N base and so on ;

Separate (-C=O-) or with other groups (such as the above-mentioned alkyl) combination of " oxo base " or "carbonyl", for example "alkyl carbonyl", represented by the above-mentioned alkyl substituted carbonyl (-C=O-), such as the acyl or alkanoyl;

Alone or the combined use with other group "carboxylic acid" said-COOH group, comprises a carboxylic acid derivative if ester and amide;

Alone or the combined use with other group "ester" said-COO-group, comprises a carboxylic acid derivative, more preferably, the ester portion is selected from the group consisting of alkoxy carbonyl, such as methoxy carbonyl group, ethoxy carbonyl, etc., which may be optionally substituted; aryloxy carbonyl, such as phenoxy carbonyl, naphthoxy carbonyl, etc., which may be optionally substituted; carbonyl aralkyloxy, such as benzyloxy carbonyl, phenelzine oxy carbonyl, such as carbonyl naphthalene methoxy , its may be optionally substituted; Heteroaryloxy carbonyl, Heteraromatic alkoxy carbonyl, wherein the hetero aryl group such as defined on, its may be optionally substituted; heterocyclic oxy carbonyl, wherein the heterocyclic ring of the variables are defined prior to, its may be optionally substituted;

Alone or the combined use with other group "amide" amino carbonyl group representative (H₂ N-C=O-), wherein the amino group is in mono-substituted or substituted or not substituted, more preferably, the group is selected from a formamide, dimethyl amide, acetamide, diethyl amide, etc.;

Alone or with other group of combined use can be selected from the "aminocarbonyl" "aminocarbonyl", "amino-carbonyl alkyl", "N-alkyl amino carbonyl", "N-aryl amino carbonyl", "N, N-dialkyl amino carbonyl", "N-alkyl-N-aryl amino carbonyl", "N-alkyl-N-hydroxy amino carbonyl" and "N-alkyl-N-hydroxy amino carbonyl alkyl", each of which is optionally substituted. Terminology "N-alkyl amino carbonyl" and "N, N-dialkyl amino carbonyl" has already been said that respectively and two one alkyl substituted alkyl amino carbonyl group as defined above. Preferred is connected with amino carbonyl lower alkyl group as defined above to the "lower alkyl amino carbonyl". Terminology "N-aryl amino carbonyl" and "N-alkyl-N-aryl amino carbonyl" are respectively expressed by a aryl or a alkyl and one aryl-substituted amino carbonyl group. The term "amino-carbonyl alkyl" includes being amino carbonyl substituted alkyl;

Alone or used in combination with other group of selected "hydroxy alkyl" by one or more hydroxyl-substituted alkyl as defined above, more preferably, the group is selected from a hydroxy methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxy hexyl, etc.;

Alone or with other group of combined use with said "amino alkyl" is as defined above for alkyl amino (-NH₂) part, which may be substituted, such as mono-substituted or di-substituted amino alkyl. Herein alone or in combined use with other group terms "alkylamino" is a representation of the amino alkyl as defined above, which may be substituted, such as mono-substituted and di-substituted alkyl amino;

Alone or the combined use with other group "alkoxy alkyl" group as defined above that is connected with the of the alkyl group of the alkoxy as defined above, more preferably, the group can be selected from methoxy methyl, ethoxy methyl, methoxy ethyl, such as ethoxy ethyl;

Alone or the combined use with other group "alkylthio" represents straight-chain or branched or cyclic monovalent substituent, containing the same through the divalent sulfur atom is alkyl as defined above, having a sulfur atom the divalent radical may free valence bond from the sulfur atom, more preferably, the group can be selected from methylthio, ethylthio, third sulfenyl , ding Liuji , such as fifth heavenly stem sulfenyl , or is selected from cyclopropane sulfenyl , link Ding Liuji , cyclopentane sulfenyl , cyclohexanone sulfur base and so on cyclic alkylthio, which can be optionally substituted;

Alone or used in combination with other groups of said "thio-alkyl" general formula-SR 'is connected with the group of the above-mentioned alkyl, wherein R' stands for hydrogen, alkyl or aryl, e.g. thiomethyl, methyl thio methyl, phenyl thiophosphoro methyl, and the like, which can be optionally substituted;

Alone or used in combination with other groups of said "arylthio" group with the divalent sulfur atom is aryl as defined above, having a sulfur atom the divalent radical may free valence bond from the sulfur atom, more preferably, the group can be selected from phenylthio, naphthalene sulfenyl , tetralin base sulfenyl , [...] , biphenyl sulfur base and so on ;

Alone or used in combination with other groups of said "heterocyclic base sulfenyl " with divalent sulfur atom of the heterocyclic group as defined above, having a sulfur atom the divalent radical may free valence bond from the sulfur atom, more preferably, the group can be selected from aziridine base sulfenyl (aziridinylthio), azetidine base sulfenyl (azetidinylthio), pyrrole alkyl thio, imidazole alkyl thio, piperidine base sulfenyl , piperazine base sulfenyl , 2-oxo-piperidine base sulfenyl , 4-oxo-piperidine base sulfenyl , 2-Oxodiethylenediamine base sulfenyl , 3-Oxodiethylenediamine base sulfenyl , morpholinyl thio, thiophosphoro morpholinyl thio, 2-oxo-morpholinyl thio, aza base sulfenyl , diazepine base sulfenyl , oxapinylthio, thia base sulfenyl (thiazepinylthio), Thio [...] , thiazole alkyl thio, carbamylaspartic thiopheneglyoxylic thio, dihydro pyrane sulfenyl , dihydrofuran thio, dihydro thiazole thio, benzopyranyl thio, benzopyrones base sulfenyl , benzo-dihydrofuran base sulfenyl , benzene and dihydro thiopheneglyoxylic base sulfenyl , pyrazolopyrimidine keto sulfenyl , aza quinolinemethyl keto sulfenyl , thiophene and pyrimidine keto sulfenyl , quinazolonylthio, pyrimidine keto sulfenyl , benzo [...] , benzo [...] , BENZOTHIAZINE base sulfenyl , BENZOTHIAZINE keto sulfenyl , such as thiophene-piperidine base sulfenyl ;

Alone or used in combination with other groups of said "heteroaryl thio" with divalent sulfur atom of the heteroaryl as defined above, having a sulfur atom the divalent radical may free valence bond from the sulfur atom, more preferably, the group can be selected from pyridine base sulfenyl , thiopheneglyoxylic base sulfenyl , furan base sulfenyl , pyrrolizinone base sulfenyl , [...] , thiazole base sulfenyl , Isothizole base sulfenyl , imidazolyl thio, heteroploid [...] , Oxadiazole base sulfenyl , thiadiazole base sulfenyl , triazole base sulfenyl , tetrazole base sulfenyl , benzofuranyl thio, benzothiophene base sulfenyl , indoline based thio, indole base sulfenyl , aza indole base sulfenyl , aza-indoline based thio, pyrazolopyrimidine base sulfenyl , nitrogen [...] , pyridine and furan base sulfenyl , pyrido thiophene base sulfenyl , and pyrimidine base sulfenyl of thiophene, quinoline base sulfenyl , pyrimidine base sulfenyl , pyrazolyl sulfenyl , [...] , [...] , triazine base sulfenyl , benzimidazolyl thio, benzotriazole base sulfenyl , [...] (phthalazynilthio), (naphthylidinylthio) naphthyridine base sulfenyl , purine base sulfenyl , diphenylenimine base sulfenyl , [...] thio, order [...] , benzo [...] , such as benzothiazole base sulfenyl ;

Alone or the combined use with other group "alkoxycarbonylamino" is selected from the group of the amino group as defined above is connected with a suitable alkoxy carbonyl, more preferably methoxy carbonyl amino, ethoxy carbonyl amino;

Alone or the combined use with other group "amino carbonyl amino", "alkyl amino carbonyl amino", "dialkyl amino carbonyl amino" are respectively and amino (NH₂), alkyl amino or dialkyl amino carbonyl amino connected (-CONH₂) group, wherein alkyl is defined as above;

Alone or used in combination with the other group of the representative "amidino"-C (=NH)-NH₂ group; the representative "alkyl amidino" as described above with the amidino is alkyl;

Alone or used in combination with the other group of the representative "Alkyloxyamino" is as defined above with the amino group of the appropriate alkoxy;

Alone or used in combination with other group "hydroxy amino" group of representative-NHOH part, and can be optionally selected from the above-mentioned those replaced by the appropriate group;

Alone or the combined use with other group "sulfinyl" or "sulfinyl derivative" represents a divalent group-SO-or R_x SO-, wherein R_x to those of the above-mentioned selected from the group consisting of optionally substituted alkyl, aryl, heteroaryl, heterocyclic radical;

Alone or the combined use with other group "sulfonyl" group or a "sulfone derivatives" and other terms such as alkylsulfonyl represents bivalent perssad-SO₂-or R_x SO₂-, wherein R_x defined as above. More preferably, the group can be selected from "alkyl sulfonyl", which is selected from the above-mentioned those appropriate connected to the sulfonyl is alkyl, such as methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, and the like; also can be selected from "arylsulfonyl", wherein aryl is defined as above is connected to the sulfonyl is, for example, phenyl sulfonyl, etc.;

Alone or the combined use with other group "sulfanyl" group or a "sulfur alkyl derivatives" represents a divalent group-S-or R_x S-, wherein R_x is optionally substituted is selected from the above-mentioned those alkyl, aryl, heteroaryl, heterocyclic radical;

Alone or the combined use with other group "sulfonyl propoxycyclohexyl" (such as an alkyl sulfonyl oxy) representative-SO₂-O-or R_x SO₂-O-, wherein R_x defined as above. More preferably, the group can be selected from "alkyl sulfonyl oxy", which is selected from the above-mentioned those appropriate connected to the sulfonyl is alkyl, for example methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, etc., also can be selected from "aryl sulfonyl oxy", wherein aryl is as defined above to the sulfonyl propoxycyclohexyl is, for example, phenyl sulfonyl propoxycyclohexyl, and the like.

The group of the appropriate group and substituents can be selected from any place in the specification from those described.

Particularly useful compounds can be selected from

N-(benzyloxy)-2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-(benzyloxy)-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-(benzyloxy)-2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

5-c-(3-(9H-carbazole-9-yl) propyl)-N-hydroxy-2-methyl -1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

(2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (4-methyl piperazin-1-yl) methanone;

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (piperidin-1-yl) methanone;

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (thiophosphoro morpholinyl) methanone;

(1, 1-sulfur dioxide generation morpholinyl) (2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) methanone;

2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-(4-methyl piperazin-1-yl)-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-oxo-2-(piperidin-1-yl) ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-oxo-2-thio morpholinyl ethyl)-1, 3-II Menthane-2-carboxamide;

N-(2-(1, 1-sulfur dioxide generation morpholinyl)-2-oxo-ethyl)-2-methyl-5-c-( (5-methyl-2-phenyl-oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-morpholino-3-oxo-propyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-3-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) propyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-3-thio morpholinyl n-propyl)-1, 3-II Menthane-2-carboxamide;

N-(3-(1, 1-sulfur dioxide generation morpholinyl)-3-oxo-propyl)-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-3-(piperidin-1-yl) propyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-(4-methyl piperazin-1-yl)-3-oxo-propyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-1- benzyl Ding -2-yl)-1, 3-II Menthane-2-carboxamide;

N-benzyloxy-2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

(2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (4-methyl pyrazine-1-yl) methanone;

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (piperidin-1-yl) methanone;

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (thiophosphoro morpholinyl) methanone;

(1, 1-sulfur dioxide generation morpholinyl) (2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) methanone;

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-(4-methyl piperazin-1-yl)-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-oxo-2-thio morpholinyl ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-oxo-2-(piperidin-1-yl) ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(3-oxo-1- benzyl Ding -2-yl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-ethoxy-2-( (3-oxo-1- benzyl Ding -2-yl) amino) ethyl)-1, 3-II Menthane-2-carboxamide;

N-benzyloxy-2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-benzyloxy-2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-benzyloxy-2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

(2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

N-(benzyloxy)-5-( (2-(tert-butyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

5-( (2-(tert-butyl)-5-methyl Oxazol-4-yl) methyl)-N-hydroxy-2-methyl -1, 3-II Menthane-2-carboxamide;

(5-( (2-(tert-butyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone;

2-methyl-5-c-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

2-methyl-5-t-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

N-benzyloxy-2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-benzyloxy-2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

(2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide;

2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide;

N-benzyloxy-2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-carboxamide;

1-(2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl)-N-( (tetrahydro -2H-pyran-4-yl) methyl) armor alkylamine ;

(2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-c-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-t-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

5-c-(3-(9H-carbazole-9-yl) propyl)-N-hydroxy-2-methyl -1, 3-II Menthane-2-carboxamide;

N-hydroxy-5-c-(3-(10H-phenothiazine -10-yl) propyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

N-(benzyloxy)-5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

N-(hydroxy)-5-c-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

N-(hydroxy)-5-t-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide;

(5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone;

5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide;

(5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (4-methyl pyrazine-1-yl) methanone;

N-(benzyloxy)-5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

N-(benzyloxy)-5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

N-hydroxy-5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

N-hydroxy-5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide;

(5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone;

5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

(5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (4-methyl pyrazine-1-yl) methanone;

(5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (4-methyl piperazin-1-yl) methanone;

N-(benzyloxy)-2-methyl-5-c-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-(benzyloxy)-2-methyl-5-t-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-c-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

N-hydroxy-2-methyl-5-t-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide;

(2-methyl-5-c-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

(2-methyl-5-t-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone;

2-methyl-5-c-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-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-II Menthane-2-carboxamide.

Such as the following can be used is shown and described in this section of the reaction and technology for preparing the novel compounds of the present invention. By the reaction of the reagent and the raw material and is suitable for realizing the conversion is carried out in a solvent. The technicians of this field should be understood, in order to optimize the compounds of the invention the purpose of the form, shown in the nature of the synthesis steps can be changed and the order of. It should also be understood, in order to facilitate the synthesis, can make use of the technology known to those skilled in the art to one or more reactants to protect and deprotected. It should also be understood, the present invention of one or more types of compounds can be in a three-dimensional heterogeneous and/or non-stereo isomeric form. Such stereomeride and/or non-stereo isomer and optical antimer of them is treated as within the scope of the present invention. Also it should be understood, can be based on compounds of the specific group on one or more of these compounds into their salts and other derivatives, the technical personnel in the field can be easily understood. In these circumstances, such a salt and/or other derivatives should also be considered within the scope of the present invention.

Programme 1: can by following scheme 1 of the reaction to prepare the general formula (I) compound (wherein all symbols are as previously defined), the programme includes

Method A: can be in a suitable solvent (such as THF, DMF, toluene, b Alkanes, dimethyl sulfoxide or its appropriate mixture) in, in a suitable base (such as NaH, NaOH, KOH, such as KOt-Bu) the presence of, by the general formula (II) compound (wherein 'L' for appropriate leaving group, 'HET' and 'X' as previously defined) with malonic acid diethyl ester (III) reaction of compound of formula (IV) (wherein 'HET' and 'X' as previously defined). The reaction can be in the 20 to [...] the temperature of the boiling point of the solvent used for the. The reaction can be carried out in the inert atmosphere. The reaction time of 2 hours to 2 days.

Method B: can be through in a suitable solvent (such as THF, diethyl ether, b Alkanes, ethanol, methanol-water or a mixture of its appropriate) in, with a suitable reducing agent (such as LiAlH₄, NaBH₄, etc.) the compounds of the formula (IV) (wherein 'HET' and 'X' as previously defined) also the original formula (V) compound (wherein 'HET' and 'X' as previously defined). The reaction can be in the 20 to [...] the temperature of the boiling point of the solvent used for the. The reaction can be carried out in the inert atmosphere. The reaction time of 2 hours to 2 days.

Method C: can be through the appropriate Lewis acid (for example boron trifluoride ether complex, and the like) in the presence of, and the appropriate keto-ester R₁ C (O) COOR₆ (VI) reaction, to the formula (V) of the totally integrated (VII) conversion of diol Alkanes (wherein 'HET' , 'X' and R₁ as previously defined, R₆ is before the defined C_(1-6) straight-chain or branched alkyl, cyclic alkyl or aryl group). For example, the reaction can be carried out in a suitable solvent: polar solvent, such as acetonitrile or N, N-dimethyl formamide (DMF); ether solvent, such as tetrahydrofuran or ethyl ether (THF), diisopropylether, 1, 2-dimethoxy ethane; halogenated hydrocarbon solvent, such as chloroform or dichloromethane; hydrocarbon solvent, such as benzene, toluene, hexane, heptane or is selected from those mentioned above, of a mixture of a suitable solvent. The reaction can be the in -20 [...] to the reflux temperature of the solvent used to the temperature of, the reaction time can be 1 hour to 4 days.

Method D: can be using a suitable alkali (e.g., NaOH, LiOH, KOH, etc.), the hydrolysis of the compound of the formula (VII) compounds of totally integrated (VIII), wherein 'HET' , R₁ and 'X' as previously defined. The reaction can be carried out in a suitable solvent, such as alcohols (such as methanol, ethanol, propanol, isopropanol, butanol, etc.), THF, water or a mixture thereof. The reaction can be in the 20 [...] to the reflux temperature of the solvent used to the temperature of, the reaction time can be 1 to 48 hours.

Method E: can be used can be obtained in the literature of the appropriate standard method for peptide, the compounds of the formula (VIII) by YH coupling to formula (1a) compounds, wherein 'HET' , R₁, 'X' and 'Y' as previously defined.

Method F: can be used can be obtained in the literature the appropriate the phenmethyl escapes protection method, the compound of formula (Ia) (wherein 'Y' to NR₂ R₃, and wherein R₂ to OBn, 'HET' , R₁, R₃ and 'X' as previously defined) to escapes the phenmethyl formula (I) compound, wherein the 'Y' NR₂ R₃, and wherein R₂ to OH, 'HET' , R₁, R₃ and 'X' as previously defined.

Method G: can be obtained in the literature can be used a suitable acid is transformed into hydroxamic acid (hydroxamic   acid) method, the corresponding acid by formula (VIII) a compound of formula (I) compound, wherein the 'Y' NR₂ R₃, wherein R₂ to OH, 'A' , R₁, R₃ and 'X' as previously defined.

Method H: can be used can be obtained in the literature of the appropriate ester transformation into hydroxamic acid method, by formula (VII) to the corresponding ester compound of formula (I) compound, wherein the 'Y' NR₂ R₃, and wherein R₂ to OH, 'A' , R₁, R₃ and 'X' as previously defined.

Programme 2: compound of formula (Ia) (wherein 'HET' representatives through N atoms and X is heteroaryl or heterocyclyl) can also by the following scheme 2 preparation of the reaction.

Method I: can be using a suitable alkali (e.g., NaOH, LiOH, KOH, and the like), totally integrated hydrolysis of the compound of the formula (IX) (X) compound, wherein the 'L' , 'X' , R₁ and R₆ as previously defined. The reaction can be carried out in a suitable solvent, the solvent such as alcohols (such as methanol, ethanol, propanol, isopropanol, butanol, etc.), THF, water or a mixture thereof. The reaction can be in the 20 [...] to the reflux temperature of the solvent used to the temperature of, the reaction time can be 1 to 48 hours.

Method J: can be used can be obtained in the literature of the appropriate standard method for peptide, through the formula (X) to the compound of formula (XI) with the compound coupling YH, wherein R₁, 'L' 'X' and 'Y' as previously defined.

Method K: can be in a suitable solvent (such as dimethyl sulfoxide, THF, DMF, toluene, b alkane and so on or its appropriate mixture) in, in a suitable alkali (e.g., NaOH, KOH, NaH, such as KOt-Bu) the presence of, the compound represented by the general formula (XI) (wherein R₁, 'L' , 'X' and 'Y' as previously defined) the compound of the general formula (XII) (wherein 'HET' representative hetero aryl group or a heterocyclic group) by reaction of the compounds of formula (Ia), wherein 'HET' representative heteroaryl or heterocyclic base, R₁, 'X' and 'Y' as previously defined. The reaction can be in the 0 to [...] the temperature of the boiling point of the solvent used for the. The reaction can be carried out in the inert atmosphere. The reaction time of 2 hours to 2 days.

Formula (I) compound or pharmaceutical composition containing the same can be used as the suitable for humans and other warm-blooded animals PCSK9 ligand, it is able to be through oral, topical or gastronintestinal edministration administered for the treatment of dyslipidemia associated with various diseases disorders and related disorders.

Through the use of conventional method provides pharmaceutical compositions. Preferably, said composition comprising an effective amount of the active component (that is, according to the present invention of formula (I) compound) in the unit dosage form.

And the pharmaceutical composition the active ingredient in unit dosage form (that is, the invention of the formula (I) compound) can be used according to specific amount of the application method, and specific compounds of the effectiveness of the desired concentration and extensively change or adjustment. Usually, the amount of active ingredient by weight of the composition will be 0.5% to 90%.

The compounds of this invention or their appropriate pharmaceutical composition is PCSK9 inhibitors, and can be used for the treatment of an individual in need of this treatment the dyslipidaemic and related diseases.

The adoption of the following embodiment is given of the present invention is of a more detailed explanation, the embodiment in the manner of the note for example, it cannot be regarded as its limitations as to the rest of the specification in the scope of the present invention is described.

In the embodiment given in (see below) the¹ HNMR spectrum data using 400MHz spectrometer (Bruker   AVANCE-400) recording, and to report scaling δ. Unless otherwise indicated, otherwise the NMR solvent is CDCl₃, adopts four methyl silane as an internal standard. In an embodiment of the mass spectrum data using Shimadzu   LC-MS (ESI-MS)   2010-A spectrometer recording.

Embodiment 1

N-(benzyloxy)-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

Step 1:2-( (5-methyl-2-phenylOxazol-4-yl) methyl) malonic acid diethyl ester

In the 0-10 [...] , under the nitrogen atmosphere, after 30 minutes to the ice-cold NaH (50%) (8.7g, 0 . 18 molar) in THF (50 milliliter) adds by drops third in suspension of the second acid diethyl ester (58g, 0.12 mol), and the reaction mixture at about 25 the stirring [...] 30 minutes. In the 25 [...] , the 4-(chloromethyl)-5-methyl-2-phenyl Azole (25g, 0.12 mol) THF of (100 milliliter) in solution is added to the reaction mixture, and the reaction mixture in the 25 [...] stirring 18 hours. The reaction mixture is in the dumping of the ice-cold water, extracted with ethyl acetate. The combined ethyl acetate extract water and the salt water wash, the sodium sulfate drying, and vacuum evaporation. The excessive malonic acid diethyla ester vacuum the distillation of wines, and the residue by column chromatography (eluant: in hexane in the 5% to 7% of ethyl acetate) purification, get 23g is the necessary product of the viscous liquid.

¹ H   NMR: 1.24 (t, J=7.2Hz, 6H), 2.34 (s, 3H), 3.07 (d, J=7.6Hz, 2H), 3.88 (t, J=7.6Hz, 1H), 4.15-4.22 (m, 2H), 7.39-7.45 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 331.1(M+H)⁺

Yield: 58%

Steps 2:2-( (5-methyl-2-phenylOxazol-4-yl) methyl) propane -1, 3-diol

In the 10 [...] , will be in small batches NaBH₄ (21g, 0.56 mol) is added to the step 1 the product (23 g, 0 . 69 mol) in EtOH (80 milliliter) in solution, and the reaction mixture in the 25 [...] stirring 6 hours. The reaction mixture is in the dumping of the ice-cold water, acidified (pH   2), and ethyl acetate extraction. The combined ethyl acetate extract water and the salt water wash, the sodium sulfate drying, and vacuum evaporation. Selectivity in the grinding residue, to obtain 8.0g is white solid product.

¹ H   NMR: 2.03-2.11 (m, 1H), 2.36 (s, 3H), 2.66 (d, J=6.8Hz, 6H), 3.71-3.82 (m, 4H), 7.39-7.44 (m, 3H), 7.94-7.98 (m, 2H).

ESI/MS   m/z: 247.1(M+H)⁺

Yield: 46%

Steps 3:2-methyl-5-( (5-methyl-2-phenylOxazol-4-yl) methyl)-1, 3-IIMenthane-2-carboxylic acid methyl ester

Under a nitrogen atmosphere, in the 25 [...] , the pyruvic acid methyl ester (15.5 milliliter, 0 . 17 mol) is added to the step 2 the product (7.0g, 0 . 028 mol) of CH₃ CN (50 milliliter) solution, then dropwise BF₃. Et₂ O (10.68 milliliter, 0 . 085 mol), and the reaction mixture in the 25 [...] stirring 18 hours. The reaction mixture is decanted to the ice-cold NaHCO₃ solution (300 milliliter) in, and using ethyl acetate extraction. The combined ethyl acetate extract water and the salt water wash, the sodium sulfate drying, and vacuum evaporation. The crude product by column chromatography (eluant: in hexane in the 15% ethyl acetate) purification, is 6.5g is the necessary product of the viscous liquid.

ESI/MS   m/z: 331.1(M+H)⁺

Yield: 69%

Steps 4:2-methyl-5-( (5-methyl-2-phenylOxazol-4-yl) methyl)-1, 3-IIMenthane-2-carboxylic acid

To step 3 the product (5.0g, 15 . 10 mmol) in methanol (6 milliliter), THF (18 milliliter) and H₂ O (6 milliliter) into a solution of a mixture of lithium hydroxide (1.27g, 30 . 20 mmol) aqueous solution, and stirring under the environmental temperature 3 hours. Evaporation of the solvent, the residue is dissolved in water, using 1N   HCl dyeworks, and using ethyl acetate extraction. The combined ethyl acetate extract water and the salt water wash, the sodium sulfate drying, and evaporation under reduced pressure, to obtain 3.5g is white solid of the product mixture of cis and trans isomers.

ESI/MS   m/z: 317.1(M+H)⁺

Yield: 77%

Steps 5:N-(benzyloxy)-2-methyl-5-( (5-methyl-2-phenylOxazol-4-yl) methyl)-1, 3-IIMenthane-2-carboxamide

To the step 4 the product (1.76g, 5.6 mmol) of DMF (10 milliliter) adding solution of O-benzyl hydroxylamine hydrochloride (927 milligram, 5.8 mmol), HOBT (1.16g, 8.7 mmol), EDCI (1.28g, 6.6 mmol) and N-ethyl morpholine (2.11 milliliter, 16.7 mmol), under nitrogen atmosphere and the 25 the stirring the reaction mixture [...] 5 hours. Pouring the reaction mixture into ice-cold water. Filtering and separating the white solid, wash with water, and in the vacuum through P₂ O₅ drying, obtain 1.7g is the necessary product of the viscous liquid.

ESI/MS   m/z: 445.0(M+H)⁺

Yield: 86%

Embodiment 2

N-(benzyloxy)-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

Step 1:2-methyl-5-t-( (5-methyl-2-phenylOxazol-4-yl) methyl)-1, 3-IIMenthane-2-carbencillin acid

To be obtained from example 1 step 4 the product of 25 the use under [...] in ethyl acetate (20 milliliter) of the in 5% methanol is recrystallized, get 1.76 milligram is white solid pure cis isomer.

¹ H   NMR (DMSO-D₆): 1.32 (s, 3H), 2.16-2.24 (m, 3H), 2.28 (m, 3H), 3.44 (t, J=11.2Hz, 2H), 3.82 (dd, J=11.4 and 3.4Hz, 2H), 7.45-7.51 (m, 3H), 8.87-8.90 (m, 2H).

ESI/MS   m/z: 317.2(M+H)⁺

Yield: 37%

Steps 2:N-(benzyloxy)-2-methyl-5-c-( (5-methyl-2-phenylOxazol-4-yl) methyl)-1, 3-IIMenthane-2-carboxamide

To the step 1 the product (1.76g, 5.6 mmol) of DMF (10 milliliter) adding solution of O-benzyl hydroxylamine hydrochloride (927 milligram, 5.8 mmol), HOBT (1.16g, 8.7 mmol), EDCI (1.28g, 6.6 mmol) and N-ethyl morpholine (2.11 milliliter, 16.7 mmol), and in the reaction mixture under nitrogen atmosphere in the 25 the stirring [...] 5 hours. Pouring the reaction mixture into ice-cold water. Filtering and separating the white solid, wash with water, and in the vacuum through P₂ O₅ drying, obtain 1.7g is the necessary product of the viscous liquid.

¹ H   NMR (DMSO-D₆): 1.25 (s, 3H), 2.11-2.15 (m, 3H), 2.28 (s, 3H), 3.30 (t, J=11.0Hz, 2H), 3.74-3.78 (m, 2H), 4.81 (s, 2H), 7.32-7.39 (m, 5H), 7.45-7.49 (m, 3H), 7.50-7.89 (m, 2H), 11.45 (s, NH).

ESI/MS   m/z: 423.2(M+H)⁺

Yield: 45%

Embodiment 3

N-(benzyloxy)-2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

Step 1:2-methyl-5-t-( (5-methyl-2-phenylOxazol-4-yl) methyl)-1, 3-IIMenthane-2-carbencillin acid

In the implementation of the example 2 step 1 after crystallization in cis-isomer of the, vacuum concentrating the mother liquor. In the 25 [...] , using ethyl acetate (30 milliliter) recrystallize the residue, to obtain 1.5g is gray solid pure trans isomer.

¹ H   NMR (DMSO-D₆): 1.39 (s, 3H), 1.70-1.74 (m, 1H), 2.23 (s, 3H), 2.76 (d, J=7.6Hz, 2H), 3.63 (d, J=11.2Hz, 2H), 3.88 (d, J=11.8 & 2.2 Hz, 2H), 7.43-7.51 (m, 3H), 8.86-8.89 (m, 2H).

ESI/MS   m/z: 317.0(M+H)⁺

Yield: 31%

Steps 2:N-(benzyloxy)-2-methyl-5-t-( (5-methyl-2-phenylOxazol-4-yl) methyl)-1, 3-IIMenthane-2-carboxamide

To the step 4 the product (1.50g, 4 . 77 mmol) of DMF (10 milliliter) solution by adding O-benzyl hydroxylamine hydrochloride (927 milligram, 5.8 mmol), HOBT (1.00g, 7 . 44 mmol), EDCI (1.10g, 5.7 millimoles) and N-ethyl morpholine (1.80 milliliter, 14 . 31 mmol), and in the reaction mixture under nitrogen atmosphere in the 25 the stirring [...] 5 hours. Pouring the reaction mixture into ice-cold water. Filtering and separating the white solid, wash with water, and in the vacuum through P₂ O₅ drying, to obtain 1.4 g of a viscous liquid the required product.

¹ H   NMR: 1.49 (s, 3H), 1.83-1.89 (m, 1H), 2.34 (s, 3H), 2.78 (d, J=7.6 Hz, 2H), 3.67 (d, J=11.2Hz, 2H), 3.85 (dd, J=11.8Hz, 2H), 4.99 (s, 2H), 7.34-7.45 (m, 8H), 7.94-7.97 (m, 2H), 8.67 (s, NH).

ESI/MS   m/z: 423.2(M+H)⁺

Yield: 42%

Embodiment 4

N-(hydroxy)-2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

To 10% of the palladium-carbon (150 milligram) in methanol (20 milliliter) is added to the suspension in step 5 product (1.7g, 4 . 04 mmol), then add formic acid ammonium (1.27g, 20.2 mmol), and the reaction mixture is heated reflux 2-5 hours. Cooling the reaction mixture to the ambient temperature, and filtering out catalyst. Evaporating the filtrate, collected in the residue in ethyl acetate, and washed with water. The organic phase is dried by sodium sulfate, and vacuum evaporation. The product from ethyl acetate and petroleum ether (the 1 [...] 1) mixture (25 milliliter) recrystallizing, get 900 milligram a desired product in a white solid.

ESI/MS   m/z: 333.1(M+H)⁺

Yield: 67%

Embodiment 5

N-benzyloxy-5-c-(3-(9H-carbazole-9-yl) propyl)-2-methyl -1, 3-II Menthane-2-carboxamide

Step 1:c-5-(3-chloro-propyl)-2-methyl -1, 3-IIMenthane-2-carboxylic acid

To 5-(3-chloro-propyl)-2-methyl -1, 3-II Menthane-2-carboxylic acid methyl ester (5.0g, 0 . 021 mol) in methanol (8 milliliter), THF (24 milliliter) and H₂ O (8 milliliter) in the mixture is added to a solution of lithium hydroxide (1.77g, 0 . 042 mole) aqueous solution, and the ambient temperature the reaction mixture stirring 18 hours. Evaporation of the solvent, the residue is dissolved in water, using 1N   HCl dyeworks, and using ethyl acetate extraction. The ethyl acetate extract water and the salt water washing, drying with sodium sulfate, evaporated under reduced pressure, to obtain 3.91g the product of a viscous liquid.

¹ H   NMR: 1.20-1.27 (m, 2H), 1.58 (s, 3H), 1.71-1.78 (m, 2H), 2.03-2.09 (m, 1H), 3.47-3.59 (m, 4H), 3.98 (dd, J=12.2 and 4.6Hz, 2H).

ESI/MS   m/z: 222.1(M+H)⁺

Yield: 83%

Steps 2:N-(benzyloxy)-5-c-(3-chloro-propyl)-2-methyl -1, 3-IIMenthane-2-carboxamide

To the step 1 the product (3.91g, 0 . 0176 mol) of DMF (20 milliliter) adding solution of O-benzyl hydroxylamine hydrochloride (2.93g, 0 . 0184 mol), HOBT (3.70g, 0 . 0275 mol), EDCI (4.05g, 0 . 0211 mol) and N-ethyl morpholine (6.2 milliliter, 0 . 0528 mol), and in the reaction mixture under nitrogen atmosphere the 25 [...] stirring 24 hours. The reaction mixture is in the dumping of the ice-cold water, extracted with ethyl acetate. The ethyl acetate extract water and the salt water wash, the sodium sulfate drying, and decompression evaporation. In the grinding of the crude product in hexane, to obtain 5.3g the product of a viscous liquid.

¹ H   NMR: 1.12-1.20 (m, 2H), 1.45 (s, 3H), 1.79-1.82 (m, 2H), 1.89-1.94 (m, 1H), 3.27 (t, j=11.4Hz, 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%

Steps 3:N-(benzyloxy)-c-5-(3-(9H-carbazole-9-yl) propyl)-2-methyl -1, 3-IIMenthane-2-carboxamide

In the 0-5 [...] , under the nitrogen atmosphere, to the KOH powder (685 milligram, 12 . 23 mmol) in DMSO (2 milliliter) in ice-cold suspension of adding dropwisely step 2 product (1.0g, 3 . 06 mmol) and 9H-carbazole (511 milligram, 3 . 06 mmol) in DMSO (3 milliliter) the solution, and in the reaction mixture under nitrogen atmosphere the 25 [...] stirring 2 hours. The reaction mixture is in the dumping of the ice-cold water, extracted with ethyl acetate. The ethyl acetate extract water and the salt water wash, the sodium sulfate drying, and decompression evaporation. The crude product by column chromatography (eluant: in hexane in the 17% ethyl acetate) purification, be 500 milligram is the product of the viscous liquid.

¹ H   NMR: 1.02-1.04 (m, 2H), 1.39 (s, 3H), 1.79-1.83 (m, 2H), 1.89-1.91 (m, 1H), 3.15 (t, J=11.6Hz, 2H), 3.74 (dd, J=11.8 and 4.2, 2H), 4.28 (t, J=7.0Hz, 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=7.6Hz, 2H), 8.55 (s, NH).

ESI/MS   m/z: 459.1(M+H)⁺

Yield: 92%

In the embodiment in accordance with the 1-5 given in the general method, the technical personnel in this field within the scope of the adjustment of the appropriate, changes and other process change, preparing the following embodiment.

Embodiment 6

N-hydroxy-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.28 (s, 3H), 2.12-2.18 (m, 1H), 2.20-2.21 (m, 2H), 2.28 (s, 3H), 3.43 (t, J=11.0Hz, 2H), 3.79-3.83 (dd, J=12.0 and 4.0 Hz, 2H), 7.47-7.51 (m, 3H), 7.88-7.90 (m, 2H), 8.85 (s, NH), 10.84 (s, OH).

ESI/MS   m/z: 333.2(M+H)⁺

Yield: 67%

Embodiment 7

N-hydroxy-2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.36 (s, 3H), 1.74 (m, 1H), 2.33 (s, 3H), 2.73 (d, J=7.6Hz, 2H), 3.60 (d, J=11.2Hz, 2H), 3.84 (d, J=10.0Hz, 2H), 7.47-7.51 (m, 3H), 7.88-7.90 (m, 2H), 8.83 (s, NH), 10.81 (s, OH).

ESI/MS   m/z: 333.2(M+H)⁺

Yield: 27%

Embodiment 8

2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 415.1(M+H)⁺

Yield: 76%

Embodiment 9

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.05-1.15 (m, 2H), 1.27 (s, 3H), 1.45-1.49 (m, 2H), 1.65-1.72 (m, 1H), 2.13-2.20 (m, 1H), 2.22 (d, J=6.8Hz, 2H), 2.27 (s, 3H), 2.96 (t, J=6.4Hz, 2H), 3.17-3.22 (t, J=9.6H, 2H), 3.39 (t, J=11.2Hz, 2H), 3.77-3.84 (m, 4H), 7.44-7.51 (m, 3H), 7.86-7.90 (m, 2H), 8.05 (t, NH).

ESI/MS   m/z: 416.1(M+H)⁺

Yield: 95%

Embodiment 10

2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 416.1(M+H)⁺

Yield: 84%

Embodiment 11

(2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 387.2(M+H)⁺

Yield: 41%

Embodiment 12

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 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 and 3.6Hz, 2H), 7.44-7.51 (m, 3H), 7.87-7.90 (m, 2H).

ESI/MS   m/z: 409.0(M+Na)⁺

Yield: 65%

Embodiment 13

(2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 387.2(M+H)⁺

Yield: 58%

Embodiment 14

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (4-methyl pyrazine-1-yl) methanone

¹ H   NMR: 1.49 (s, 3H), 2.21 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.39-2.50 (m, 5H), 3.63 (t, J=11.6Hz, 2H), 3.72-3.74 (m, 2H), 3.86-3.88 (m, 2H), 3.96 (dd, J=11.8 and 4.6Hz, 2H), 7.39-7.45 (m, 3H), 7.95-7.97 (m, 2H).

ESI/MS   m/z: 400.0(M+H)⁺

Yield: 48%

Embodiment 15

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (piperidin-1-yl) methanone

¹ H   NMR: 1.49 (s, 3H), 1.53-1.73 (m, 6H), 2.20 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 2.42-2.51 (m, 1H), 3.62-3.68 (m, 4H), 3.78-3.79 (m, 2H), 3.96 (dd, J=11.8 and 4.6Hz, 2H), 7.38-7.45 (m, 3H), 7.95-7.97 (m, 2H).

ESI/MS   m/z: 384.9(M+H)⁺

Yield: 85%

Embodiment 16

(2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (thiophosphoro morpholinyl) methanone

¹ H   NMR: 1.50 (s, 3H), 2.21 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 2.43-2.49 (m, 1H), 2.66-2.68 (m, 4H), 3.63 (t, J=11.4Hz, 2H), 3.94-3.95 (m, 2H), 3.97 (dd, J=11.8 and 4.6Hz, 2H), 4.10-4.11 (m, 2H), 7.40-7.45 (m, 3H), 7.95-7.97 (m, 2H).

ESI/MS   m/z: 403.3(M+H)⁺

Yield: 84%

Embodiment 17

(1, 1-sulfur dioxide generation morpholinyl) (2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) methanone

¹ H   NMR: 1.53 (s, 3H), 2.24 (d, J=7.2Hz, 2H), 2.29 (s, 3H), 2.43-2.49 (m, 1H), 3.063.08 (m, 4H), 3.60 (t, J=11.6Hz, 2H), 4.05 (dd, J=11.8 and 4.6Hz, 2H), 4.19-4.20 (m, 2H), 4.36 (bs, 2H), 7.41-7.46 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 434.8(M+H)⁺

Yield: 74%

Embodiment 18

2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 444.1(M+H)⁺

Yield: 55%

Embodiment 19

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.51 (s, 3H), 2.25 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 2.38-2.45 (m, 1H), 3.42 (t, J=4.8Hz, 2H), 3.57-3.66 (m, 4H), 3.69-3.72 (m, 4H), 4.01 (dd, J=12.0 and 4.4Hz, 2H), 4.13 (d, J=4.4Hz, 2H), 7.32-7.33 (m, NH), 7.39-7.44 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 444.3(M+H)⁺

Yield: 84%

Embodiment 20

2-methyl-5-t-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 444.1(M+H)⁺

Yield: 49%

Embodiment 21

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-(4-methyl pyrazine-1-yl)-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.50 (s, 3H), 2.24 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 2.32 (s, 3H), 2.37-2.44 (m, 5H), 3.42 (t, J=5.0Hz, 2H), 3.56 (t, J=11.4Hz, 2H), 3.65 (t, J=5.0Hz, 2H), 4.00 (dd, J=12.0 and 4.4Hz, 2H), 4.13 (d, J=4.0 Hz, 2H), 7.34-7.36 (m, NH), 7.37-7.44 (m, 3H), 7.93-7.96 (m, 2H).

ESI/MS   m/z: 457.5(M+H)⁺

Yield: 52%

Embodiment 22

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-ethoxy-2-(piperidin-1-yl) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.51 (s, 3H), 1.55-1.71 (m, 6H), 2.24 (d, J=7.6Hz, 2H), 2.28 (s, 3H), 2.37-2.44 (m, 1H), 3.34 (t, J=5.4Hz, 2H), 3.56-3.62 (m, 4H), 4.00 (dd, J=12.0 & 4.4Hz, 2H), 4.12 (d, J=5.2Hz, 2H), 7.39-7.44 (m, 4H), 7.93-7.96 (m, 2H).

ESI/MS   m/z: 442.4(M+H)⁺

Yield: 68%

Embodiment 23

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-oxo-2-thio morpholinyl ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.51 (s, 3H), 2.25 (d, J=7.6Hz, 2H), 2.28 (s, 3H), 2.37-2.45 (m, 1H), 2.64-2.66 (m, 4H), 3.56 (t, J=11.2Hz, 2H), 3.68 (t, J=5.0Hz, 2H), 3.90 (t, J=5.0Hz, 2H), 4.01 (dd, J=12.0 & 4.4Hz, 2H), 4.13 (d, J=4.4Hz, 2H), 7.34 (s, NH), 7.38-7.45 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 460.4(M+H)⁺

Yield: 54%

Embodiment 24

N-(2-(1, 1-sulfur dioxide generation morpholinyl)-2-oxo-ethyl)-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.51 (s, 3H), 2.27-2.29 (m, 5H), 2.37-2.43 (m, 1H), 3.07-3.10 (m, 4H), 3.58 (t, J=11.0Hz, 2H), 2.942.96 (m, 2H), 4.02 (dd, J=12.0 & 4.0Hz, 2H), 4.13-4.14 (m, 2H), 4.20 (d, J=4.8Hz, 2H), 7.21 (bs, NH), 7.41-7.44 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 491.8(M+H)⁺

Yield: 47%

Embodiment 25

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.25-1.32 (m, 2H), 1.50 (s, 3H), 1.59-1.63 (m, 2H), 1.71-1.80 (m, 1H), 2.26-2.29 (m, 5H), 2.35-2.45 (m, 1H), 3.17 (t, J=6.4Hz, 2H), 3.33-3.39 (m, 2H), 3.54 (t, J=11.0Hz, 2H), 3.95-4.05 (m, 6H), 6.12 (s, NH), 7.08 (t, J=5.4Hz, NH), 7.38-7.45 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 427.0(M+H)⁺

Yield: 53%

Embodiment 26

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-morpholino-3-oxo-propyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.45 (s, 3H), 2.25 (d, J=7.2Hz, 2H), 2.29 (s, 3H), 2.33-2.39 (m, 1H), 2.54 (t, J=5.8Hz, 2H), 3.44 (t, J=4.8Hz, 2H), 3.50 (t, J=11.0 Hz, 2H), 3.62-3.68 (m, 8H), 3.98 (dd, J=12.0 & 4.4Hz, 2H), 7.13 (t, J=6.2Hz, NH), 7.40-7.45 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 458.0(M+H)⁺

Yield: 84%

Embodiment 27

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-3-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) propyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.25-1.35 (m, 2H), 1.45 (s, 3H), 1.501.51 (m, 2H), 1.69-1.78 (m, 1H), 2.25 (d, J=7.2Hz, 2H), 2.29 (s, 3H), 2.33-2.39 (m, 1H), 2.43 (t, J=6.0Hz, 2H), 3.14 (t, J=6.4Hz, 2H), 3.31 (t, J=11.8Hz, 2H), 3.50 (t, J=10.6Hz, 2H), 3.59 (q, J=6.0Hz, 2H), 3.94-4.02 (m, 4H), 5.82 (bs, NH), 7.06 (t, J=6.2Hz, NH), 7.40-7.45 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 486.1(M+H)⁺

Yield: 48%

Embodiment 28

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-3-thio morpholinyl n-propyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.45 (s, 3H), 2.24 (d, J=7.6Hz, 2H), 2.28 (s, 3H), 2.33-2.42 (m, 1H), 2.54 (t, J=5.8Hz, 2H), 2.59-2.62 (m, 4H), 3.49 (t, J=11.2Hz, 2H), 3.61 (q, J=6.2Hz, 2H), 3.70-3.75 (m, 2H), 3.85-3.92 (m, 2H), 3.98 (dd, J=11.8 & 4.2Hz, 2H), 7.12 (t, J=6.2Hz, NH), 7.38-7.45 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 473.9(M+H)⁺

Yield: 82%

Embodiment 29

N-(3-(1, 1-sulfur dioxide generation morpholinyl)-3-oxo-propyl)-2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.45 (s, 3H), 2.28-2.36 (m, 6H), 2.64 (t, J=6.0Hz, 2H), 3.05-3.10 (m, 4H), 3.51 (t, J=10.6Hz, 2H), 3.61 (q, J=6.0Hz, 2H), 3.97-4.03 (m, 4H), 4.11-4.12 (m, 2H), 7.01 (t, J=6.2Hz, NH), 7.40-7.45 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 506.1(M+H)⁺

Yield: 23%

Embodiment 30

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-3-(piperidin-1-yl) propyl)-1, 3-II Menthane-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=7.2Hz, 2H), 2.28 (s, 3H), 2.32-2.42 (m, 1H), 2.53 (t, J=5.8Hz, 2H), 3.36 (t, J=5.4Hz, 2H), 3.59-3.65 (m, 4H), 3.61 (q, J=6.0Hz, 2H), 3.97 (dd, J=11.8 & 4.2Hz, 2H), 7.20 (t, J=6.2Hz, NH), 7.37-7.44 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 456.0(M+H)⁺

Yield: 82%

Embodiment 31

2-methyl-5-c-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-(4-methyl pyrazine-1-yl)-3-oxo-propyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.45 (s, 3H), 2.24 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.32-2.40 (m, 5H), 2.55 (t, J=5.8Hz, 2H), 3.45 (t, J=5.0Hz, 2H), 3.48-3.55 (m, 2H), 3.61-3.65 (m, 4H), 3.98 (dd, J=12.0 & 4.4Hz, 2H), 7.16 (t, J=6.2Hz, NH), 7.39-7.45 (m, 3H), 7.93-7.96 (m, 2H).

ESI/MS   m/z: 471.0(M+H)⁺

Yield: 63%

Embodiment 32

2-methyl-5-( (5-methyl-2-phenyl Oxazol-4-yl) methyl)-N-(3-oxo-1- benzyl Ding -2-yl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 463.5(M+H)⁺

Yield: 77%

Embodiment 33

N-benzyloxy-2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 437.2(M+H)⁺

Yield: 52%

Embodiment 34

N-hydroxy-2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 437.2(M+H)⁺

Yield: 59%

Embodiment 35

N-hydroxy-2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (CD₃ OD): 1.37-1.44 (m, 5H), 1.96-1.99 (m, 1H), 2.35 (s, 3H), 2.50 (t, J=7.6Hz, 2H), 3.44 (t, J=11.6Hz, 2H), 3.91-3.96 (dd, J=12 & 4.4Hz, 2H), 7.45-7.49 (m, 3H), 7.93-7.96 (m, 2H).

ESI/MS   m/z: 347.0(M+H)⁺

Yield: 62%

Embodiment 36

N-hydroxy-2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (CD₃ OD): 1.44 (s, 3H), 1.48-1.49 (m, 1H), 1.97-2.03 (m, 2H), 2.36 (s, 3H), 2.59 (t, J=7.6Hz, 2H), 3.80 (d, J=10.8Hz, 2H), 3.95-3.98 (dd, J=11.8 & 3.2Hz, 2H), 7.46-7.49 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 346.9(M+H)⁺

Yield: 41%

Embodiment 37

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 429.3(M+H)⁺

Yield: 98%

Embodiment 38

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.25-1.45 (m, 4H), 1.47 (s, 3H), 1.58-1.62 (m, 2H), 1.74-1.82 (m, 1H), 2.01-2.07 (m, 1H), 2.31 (s, 3H), 2.43 (t, J=7.8Hz, 2H), 3.22 (t, J=6.6Hz, 2H), 3.34-3.41 (m, 2H), 3.42 (t, J=11.4Hz, 2H), 3.95 (dd, J=12.0 & 4.4Hz, 2H), 6.38 (t, J=6.2Hz, NH), 7.38-7.44 (m, 3H), 7.94-7.96 (m, 2H).

ESI/MS   m/z: 429.4(M+H)⁺

Yield: 90%

Embodiment 39

2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 429.3(M+H)⁺

Yield: 59%

Embodiment 40

(2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 401.2(M+H)⁺

Yield: 98%

Embodiment 41

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ 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=7.8Hz, 2H), 3.53 (t, J=11.6Hz, 2H), 3.64-3.77 (m, 6H), 3.87-3.89 (m, 2H), 3.94 (dd, J=11.6 and 4.6Hz, 2H), 7.37-7.44 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 401.4(M+H)⁺

Yield: 83%

Embodiment 42

(2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 401.3(M+H)⁺

Yield: 79%

Embodiment 43

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (4-methyl piperazin-1-yl) methanone

¹ H   NMR: 1.40-1.46 (m, 2H), 1.50 (s, 3H), 2.05-2.11 (m, 1H), 2.30 (s, 3H), 2.32 (s, 3H), 2.38-2.46 (m, 6H), 3.54 (t, J=11.6Hz, 2H), 3.73-3.75 (m, 2H), 3.88-3.89 (m, 2H), 3.95 (dd, J=12.0 and 4.8Hz, 2H), 7.39-7.45 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 413.9(M+H)⁺

Yield: 80%

Embodiment 44

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (piperidin-1-yl) methanone

¹ H   NMR: 1.39 (q, J=7.0Hz, 2H), 1.49 (s, 3H), 1.55-1.64 (m, 6H), 2.02-2.11 (m, 1H), 2.31 (s, 3H), 2.42 (t, J=7.8Hz, 2H), 3.55-3.63 (m, 4H), 3.75 (t, J=5.4Hz, 2H), 3.93 (dd, J=11.8 and 4.6Hz, 2H), 7.37-7.44 (m, 3H), 7.94-7.97 (m, 2H).

ESI/MS   m/z: 399.0(M+H)⁺

Yield: 74%

Embodiment 45

(2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) (thiophosphoro morpholinyl) methanone

¹ H   NMR: 1.39 (q, J=7.2Hz, 2H), 1.49 (s, 3H), 2.03-2.12 (m, 1H), 2.31 (s, 3H), 2.42 (t, J=7.8Hz, 2H), 2.62-2.69 (m, 4H), 3.52 (t, J=11.6Hz, 2H), 3.93-3.99 (m, 4H), 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%

Embodiment 46

(1, 1-sulfur dioxide generation morpholinyl) (2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-1, 3-II Menthane-2-yl) methanone

¹ H   NMR: 1.40 (q, J=7.2Hz, 2H), 1.52 (s, 3H), 2.05-2.14 (m, 1H), 2.32 (s, 3H), 2.43 (t, J=7.8Hz, 2H), 3.04-3.10 (m, 4H), 3.46 (t, J=11.4Hz, 2H), 3.99 (dd, J=11.8 and 4.6Hz, 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).

ESI/MS   m/z: 449.0(M+H)⁺

Yield: 80%

Embodiment 47

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 459.0(M+H)⁺

Yield: 75%

Embodiment 48

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.40 (q, J=7.2Hz, 2H), 1.50 (s, 3H), 2.03-2.09 (m, 1H), 2.31 (s, 3H), 2.42 (t, J=7.6Hz, 2H), 3.43-3.46 (m, 2H), 3.48 (t, J=11.6Hz, 2H), 3.64-3.67 (m, 2H), 3.70-3.73 (m, 4H), 3.98 (dd, J=12.0 and 4.4Hz, 2H), 4.14 (d, J=4.4Hz, 2H), 7.38-7.45 (m, 3H), 7.94-7.97 (m, 2H), 7.30 (bs, NH).

ESI/MS   m/z: 459.1(M+H)⁺

Yield: 68%

Embodiment 49

2-methyl-5-t-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.53 (s, 3H), 1.57-1.60 (m, 1H), 1.93 (q, J=7.6Hz, 2H), 2.32 (s, 3H), 2.52 (t, J=7.6Hz, 2H), 3.42 (m, 2H), 3.63 (m, 2H), 3.68 (m, 4H), 3.80 (dd, J=11.8 and 4.2Hz, 2H), 3.99 (d, J=11.8 and 3.4Hz, 2H), 4.11 (d, J=4.4Hz, 2H), 7.37-7.44 (m, 3H), 7.95-3.98 (m, 2H).

ESI/MS   m/z: 458.1(M+H)⁺

Yield: 72%

Embodiment 50

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.25-1.36 (m, 2H), 1.40 (q, J=7.2Hz, 2H), 1.48 (s, 3H), 1.58 (dd, J=13.0 and 1.6Hz, 2H), 1.71-1.75 (m, 1H), 2.01-2.07 (m, 1H), 2.31 (s, 3H), 2.42 (t, J=7.6Hz, 2H), 3.17 (t, J=6.0Hz, 2H), 3.31-3.38 (m, 2H), 3.44 (t, J=11.4Hz, 2H), 3.94-4.01 (m, 6H), 6.29 (bs, NH), 7.08 (t, J=6.4Hz, NH), 7.39-7.44 (m, 3H), 7.93-7.96 (m, 2H).

ESI/MS   m/z: 486.0(M+H)⁺

Yield: 50%

Embodiment 51

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-(4-methyl piperazin-1-yl)-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.39 (q, J=7.4Hz, 2H), 1.49 (s, 3H), 2.02-2.09 (m, 1H), 2.30 (s, 3H), 2.32 (s, 3H), 2.40-2.45 (m, 6H), 3.43 (t, J=5.0Hz, 2H), 3.47 (t, J=11.6Hz, 2H), 3.65 (t, J=5.0Hz, 2H), 3.97 (dd, J=11.8 and 4.6Hz, 2H), 4.13 (d, J=4.4Hz, 2H), 7.31 (t, J=4.0Hz, NH), 7.37-7.44 (m, 3H), 7.93-7.96 (m, 2H).

ESI/MS   m/z: 471.0(M+H)⁺

Yield: 33%

Embodiment 52

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-oxo-2-thio morpholinyl ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.39 (q, J=7.0Hz, 2H), 1.50 (s, 3H), 2.03-2.08 (m, 1H), 2.31 (s, 3H), 2.41 (t, J=7.6Hz, 2H), 2.64-2.67 (m, 4H), 3.47 (t, J=11.6Hz, 2H), 3.69 (t, J=4.8Hz, 2H), 3.90 (t, J=5.0Hz, 2H), 3.98 (dd, J=12.0 and 4.4Hz, 2H), 4.12 (d, J=4.4Hz, 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)⁺

Yield: 70%

Embodiment 53

2-methyl-5-c-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-oxo-2-(piperidin-1-yl) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.39 (q, J=7.2Hz, 2H), 1.49 (s, 3H), 1.55-1.69 (m, 6H), 2.02-2.08 (m, 1H), 2.30 (s, 3H), 2.41 (t, J=7.8Hz, 2H), 3.34 (t, J=5.4Hz, 2H), 3.48 (t, J=11.6Hz, 2H), 3.57 (t, J=5.4Hz, 2H), 3.97 (dd, J=12.0 and 4.4Hz, 2H), 4.12 (d, J=4.0Hz, 2H), 7.37-7.44 (m, 3H), 7.93-7.96 (m, 2H).

ESI/MS   m/z: 456.0(M+H)⁺

Yield: 85%

Embodiment 54

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(3-oxo-1- benzyl Ding -2-yl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 477.4(M+H)⁺

Yield: 28%

Embodiment 55

2-methyl-5-(2-(5-methyl-2-phenyl Oxazol-4-yl) ethyl)-N-(2-oxo-2-( (3-oxo-1- benzyl Ding -2-yl) amino) ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 534.1(M+H)⁺

Yield: 53%

Embodiment 56

N-benzyloxy-2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 459.1(M+Na)⁺

Yield: 63%

Embodiment 57

N-benzyloxy-2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.43 (s, 3H), 2.19 (d, J=7.2Hz, 2H), 2.25 (s, 3H), 2.38 (s, 3H), 2.33-2.37 (m, 1H), 3.46 (t, J=11.2Hz, 2H), 3.91 (dd, J=12 and 4.4Hz, 2H), 4.98 (s, 2H), 7.21 (d, J=8.0Hz, 2H), 7.38-7.43 (m, 5H), 7.83 (d, J=8.0HHz, 2H), 8.68 (s, NH).

ESI/MS   m/z: 437.1(M+H)⁺

Yield: 68%

Embodiment 58

N-benzyloxy-2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.49 (s, 3H), 1.84-1.86 (m, 1H), 2.32 (s, 3H), 2.38 (s, 3H), 2.78 (d, J=7.6Hz, 2H), 3.67 (d, J=10.8Hz, 2H), 3.85-3.88 (dd, J=12 and 2.8Hz, 2H), 4.99 (s, 2H), 7.22 (d, J=8.0Hz, 2H), 7.35-7.43 (m, 5H), 7.84 (d, J=8.0HHz, 2H), 8.65 (s, NH).

ESI/MS   m/z: 437.1(M+H)⁺

Yield: 55%

Embodiment 59

N-hydroxy-2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 368.9(M+Na)⁺

Yield: 65%

Embodiment 60

N-hydroxy-2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.27 (s, 3H), 2.14-2.19 (m, 3H), 2.26 (s, 3H), 2.33 (s, 3H), 3.41 (t, J=11.2Hz, 2H), 3.77 (dd, J=11.2 and 4.4Hz, 2H), 7.29 (d, J=8.0Hz, 2H), 7.77 (d, J=8.0HHz, 2H).

ESI/MS   m/z: 346.2(M+H)⁺

Yield: 52%

Embodiment 61

N-hydroxy-2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.52 (s, 3H), 1.94-1.95 (m, 1H), 2.34 (s, 3H), 2.40 (s, 3H), 2.78 (d, J=7.6Hz, 2H), 3.77 (d, J=11.2Hz, 2H), 3.96 (d, J=10.8Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.84 (dd, J=8.4 and 2.4Hz, 2H), 8.96 (bs, NH).

ESI/MS   m/z: 347.0(M+H)⁺

Yield: 62%

Embodiment 62

2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 429.3(M+H)⁺

Yield: 55%

Embodiment 63

2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.29-1.40 (m, 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=6.6Hz, 2H), 3.37 (t, J=11.8Hz, 2H), 3.54 (t, J=11Hz, 2H), 3.96-4.03 (m, 4H), 6.45 (t, J=6.0Hz, NH), 7.23 (d, J=8.0Hz, 2H), 7.84 (d, J=8.0HHz, 2H).

ESI/MS   m/z: 429.1(M+H)⁺

Yield: 46%

Embodiment 64

2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ 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 (s, 3H), 2.34 (s, 3H), 2.73 (d, J=8.0Hz, 2H), 2.97 (t, J=6.6Hz, 2H), 3.21 (t, J=10.8Hz, 2H), 3.62 (d, J=10.8Hz, 2H), 3.78-3.84 (m, 4H), 7.29 (d, J=8.0Hz, 2H), 7.77 (d, J=8.4HHz, 2H), 8.07 (t, J=6.0Hz, NH).

ESI/MS   m/z: 429.2(M+H)⁺

Yield: 43%

Embodiment 65

(2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 401.2(M+H)⁺

Yield: 46%

Embodiment 66

(2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ 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=11.2Hz and 3.2 Hz, 2H), 7.29 (d, J=8.0Hz, 2H), 7.78 (d, J=8.0Hz, 2H).

ESI/MS   m/z: 401.1(M+H)⁺

Yield: 80%

Embodiment 67

(2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 1.41 (s, 3H), 1.75-1.76 (m, 1H), 2.32 (s, 3H), 2.33 (s, 3H), 2.73 (d, J=7.6Hz, 2H), 3.50-3.58 (m, 6H), 3.64 (d, J=10.8 Hz, 2H), 3.77-3.79 (m, 2H), 3.92 (dd, J=11.62.4Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4Hz, 2H).

ESI/MS   m/z: 401.1(M+H)⁺

Yield: 73%

Embodiment 68

2-methyl-5-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 458.1(M+H)⁺

Yield: 67%

Embodiment 69

2-methyl-5-c-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.30 (s, 3H), 2.14-2.19 (m, 3H), 2.27 (s, 3H), 2.31 (s, 3H), 3.40-3.43 (m, 4H), 3.53-3.64 (m, 6H), 3.79-3.82 (dd, J=11.8 and 4.4Hz, 2H), 3.96 (d, J=5.6Hz, 2H), 7.29 (d, J=8.0Hz, 2H), 7.78 (d, J=8.0, 2H), 7.93 (t, J=5.6Hz, NH).

ESI/MS   m/z: 458.4(M+H)⁺

Yield: 68%

Embodiment 70

2-methyl-5-t-( (5-methyl-2-(P-tolyl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 458.2(M+H)⁺

Yield: 59%

Embodiment 71

N-(benzyloxy)-5-( (2-(tert-butyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 403.2(M+H)⁺

Yield: 54%

Embodiment 72

5-( (2-(tert-butyl)-5-methyl Oxazol-4-yl) methyl)-N-hydroxy-2-methyl -1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 313.3(M+H)⁺

Yield: 50%

Embodiment 73

(5-( (2-(tert-butyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 367.2(M+H)⁺

Yield: 38%

Example 74

2-methyl-5-c-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.09-1.15 (m, 2H), 1.27 (s, 3H), 1.46-1.49 (m, 2H), 1.70-1.71 (m, 1H), 2.11-2.18 (m, 3H), 2.23 (s, 3H), 2.46 (s, 3H), 2.96 (t, J=6.4Hz, 2H), 3.18-3.24 (m, 2H), 3.35 (t, J=11.2Hz, 2H), 3.78-3.81 (m, 4H), 6.85 (dd, J=3.6 and 0.8Hz, 1H), 7.37 (d, J=3.6Hz, 1H), 8.03 (t, J=6.0Hz, NH).

ESI/MS   m/z: 435.1(M+H)⁺

Yield: 88%

Example 75

2-methyl-5-t-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.25-1.36 (m, 2H), 1.53 (s, 3H), 1.59-1.62 (m, 2H), 1.73-1.75 (m, 1H), 1.91-1.95 (m, 1H), 2.33 (s, 3H), 2.52 (s, 3H), 2.76 (d, J=7.6Hz, 2H), 3.21 (t, J=6.6Hz, 2H), 3.34-3.40 (m, 2H), 3.72-3.75 (dd, J=11.8 and 2.6Hz, 2H), 3.93-4.00 (m, 4H), 6.47 (t, J=6.0Hz, NH), 6.73 (dd, J=2.2 and 1.0Hz, 1H), 7.36 (d, J=3.6Hz, 1H).

ESI/MS   m/z: 435.1(M+H)⁺

Yield: 66%

Example 76

2-methyl-5-c-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 1.33 (s, 3H), 2.16-2.17 (m, 3H), 2.24 (s, 3H), 3.27 (s, 3H), 3.50-3.57 (m, 8H), 3.76-3.82 (m, 4H), 6.85 (dd, J=3.6 and 0.8Hz, 1H), 7.37 (d, J=3.6Hz, 1H).

ESI/MS   m/z: 407.0(M+H)⁺

Yield: 92%

Example 77

2-methyl-5-t-( (5-methyl-2-(5-methyl-thiophene-2-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 1.41 (s, 3H), 1.72-1.73 (m, 1H), 2.29 (s, 3H), 2.47 (s, 3H), 2.69 (d, J=7.6Hz, 2H), 3.51-3.64 (m, 8H), 3.77-3.82 (m, 2H), 3.92 (dd, J=11.6 and 2.4Hz, 2H), 6.85 (dd, J=3.6 and 0.8Hz, 1H), 7.37 (d, J=3.6Hz, 1H).

ESI/MS   m/z: 407.0(M+H)⁺

Yield: 75%

Example 78

N-benzyloxy-2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.44 (s, 3H), 2.20 (d, J=7.2Hz, 2H), 2.29 (s, 3H), 2.31-2.34 (m, 1H), 3.45 (t, J=11.2Hz, 2H), 3.90 (dd, J=12.0 and 4.4Hz, 2H), 4.99 (s, 2H), 7.37-7.44 (m, 5H), 7.78 (dd, J=4.4 and 1.6Hz, 2H), 8.66 (dd, J=4.6 and 1.4Hz, 2H), 8.97 (s, NH).

ESI/MS   m/z: 423.9(M+H)⁺

Yield: 75%

Example 79

N-benzyloxy-2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.49 (s, 3H), 1.81-1.86 (m, 1H), 2.37 (s, 3H), 2.81 (d, J=7.6 Hz, 2H), 3.66 (d, J=10.8Hz, 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 and 1.4Hz, 2H).

ESI/MS   m/z: 424.0(M+H)⁺

Yield: 75%

Example 80

N-hydroxy-2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.28 (s, 3H), 2.12-2.20 (m, 1H), 2.23 (d, J=7.2 Hz, 2H), 2.32 (s, 3H), 3.41 (t, J=11.4Hz, 2H), 3.78 (dd, J=11.8 and 4.2 Hz, 2H), 7.79 (dd, J=4.4 and 1.6Hz, 2H), 8.69 (dd, J=4.4 and 1.6Hz, 2H).

ESI/MS   m/z: 333.9(M+H)⁺

Yield: 61%

Example 81

N-hydroxy-2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.36 (s, 3H), 1.74-1.75 (m, 1H), 2.37 (s, 3H), 2.77 (d, J=7.6Hz, 2H), 3.60 (d, J=10.8Hz, 2H), 3.84 (dd, J=11.8 and 2.6 Hz, 2H), 7.78-7.80 (m, 2H), 8.68-8.70 (m, 2H).

ESI/MS   m/z: 333.9(M+H)⁺

Yield: 33%

Example 82

(2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 1.34 (s, 3H), 2.20-2.26 (m, 3H), 2.33 (s, 3H), 3.50-3.57 (m, 8H), 3.76-3.77 (m, 2H), 3.82-3.86 (m, 2H), 7.79 (dd, J=4.6 and 1.8Hz, 2H), 8.69 (dd, J=4.6 and 1.4Hz, 2H).

ESI/MS   m/z: 387.9(M+H)⁺

Yield: 49%

Example 83

(2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 1.42 (s, 3H), 1.75-1.78 (m, 1H), 2.37 (s, 3H), 2.78 (d, J=7.6Hz, 2H), 3.51-3.58 (m, 6H), 3.63 (d, J=10.8Hz, 2H), 3.76-3.78 (m, 2H), 3.93 (dd, J=11.8 and 2.6Hz, 2H), 7.78-7.80 (m, 2H), 8.68 (dd, J=4.6 and 1.4Hz, 2H).

ESI/MS   m/z: 387.9(M+H)⁺

Yield: 16%

Example 84

2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.34-1.49 (m, 2H), 1.50 (s, 3H), 1.60-1.63 (m, 2H), 1.76-1.85 (m, 1H), 2.2--2.32 (m, 5H), 2.35-2.42 (m, 1H), 3.24 (t, J=6.4Hz, 2H), 3.35-3.42 (m, 2H), 3.52 (t, J=11.0Hz, 2H), 3.98-4.04 (m, 4H), 6.46 (t, J=6.0Hz, NH), 7.80 (dd, J=4.8 and 1.6Hz, 2H), 8.70 (dd, J=4.4 and 1.6 Hz, 2H).

ESI/MS   m/z: 416.0(M+H)⁺

Yield: 38%

Example 85

2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.09-1.13 (m, 2H), 1.35 (s, 3H), 1.48-1.51 (m, 2H), 1.70-1.74 (m, 2H), 2.37 (s, 3H), 2.77 (d, J=7.6Hz, 2H), 2.96 (t, J=6.4Hz, 2H), 3.18-3.24 (m, 2H), 3.61 (d, J=10.8Hz, 2H), 3.78-3.84 (m, 4H), 7.80 (dd, J=4.4 and 1.6Hz, 2H), 8.04 (t, J=6.0Hz, NH), 8.68 (m, 2H).

ESI/MS   m/z: 416.0(M+H)⁺

Yield: 27%

Example 86

2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.51 (s, 3H), 2.27 (d, J=7.2Hz, 2H), 2.31 (s, 3H), 2.38-2.43 (m, 1H), 3.43 (t, J=4.8Hz, 2H), 3.57-3.66 (m, 4H), 3.70-3.72 (m, 4H), 4.01 (dd, J=12.0 and 4.4Hz, 2H), 4.14 (d, J=4.4Hz, 2H), 7.31-7.33 (t, NH), 7.79 (dd, J=4.8 and 1.4Hz, 2H), 8.69 (d, J=4.8Hz, 2H).

ESI/MS   m/z: 444.9(M+H)⁺

Yield: 68%

Example 87

2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.56 (s, 3H), 1.88-1.92 (m, 1H), 2.40 (s, 3H), 2.88 (d, J=7.6 Hz, 2H), 3.42 (t, J=5.0Hz, 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 and 2.8Hz, 2H), 4.13 (d, J=4.4Hz, 2H), 7.31-7.33 (t, NH), 7.79 (dd, J=4.8 and 1.6Hz, 2H), 8.68 (d, J=6.0Hz, 2H).

ESI/MS   m/z: 445.2(M+H)⁺

Yield: 63%

Example 88

2-methyl-5-c-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.30-1.37 (m, 2H), 1.51 (s, 3H), 1.59-1.63 (m, 2H), 1.71-1.79 (m, 1H), 2.28 (d, J=7.6Hz, 2H), 2.32 (s, 3H), 2.34-2.41 (m, 1H), 3.18 (t, J=6.4Hz, 2H), 3.33-3.39 (m, 2H), 3.55 (t, J=10.8Hz, 2H), 3.95-4.13 (m, 6H), 6.12 (bs, NH), 7.08 (t, J=5.4Hz, NH), 7.79 (d, J=4.8 and 1.6Hz, 2H), 8.69 (d, J=4.8 and 1.6Hz, 2H).

ESI/MS   m/z: 473.3(M+H)⁺

Yield: 53%

Example 89

2-methyl-5-t-( (5-methyl-2-(pyridine-4-yl) Oxazol-4-yl) methyl)-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.27-1.35 (m, 2H), 1.55 (s, 3H), 1.57-1.61 (m, 2H), 1.69-1.77 (m, 1H), 1.92-1.97 (m, 1H), 2.40 (s, 3H), 2.84 (d, J=7.6Hz, 2H), 3.16 (t, J=6.6Hz, 2H), 3.31 (t, J=11.6Hz, 2H), 3.75-3.78 (m, 2H), 3.94-4.03 (m, 6H), 6.15 (m, NH), 7.08 (m, NH), 7.79 (d, J=6.0Hz, 2H), 8.69 (d, J=3.6 Hz, 2H).

ESI/MS   m/z: 473.2(M+H)⁺

Yield: 63%

Example 90

N-benzyloxy-2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 507.1(M+H)⁺

Yield: 50%

Example 91

N-hydroxy-2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 416.9(M+H)⁺

Yield: 70%

Example 92

1-(2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl)-N-( (tetrahydro -2H-pyran-4-yl) methyl) methylamine

ESI/MS   m/z: 499.6(M+H)⁺

Yield: 99%

Example 93

(2-methyl-5-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 471.5(M+H)⁺

Yield: 51%

Example 94

(2-methyl-5-c-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR: 1.51 (s, 3H), 2.30-2.38 (m, 4H), 2.54 (d, J=7.2Hz, 2H), 3.59-3.67 (m, 4H), 3.73-3.75 (m, 4H), 3.87 (t, J=4.2Hz, 2H), 3.95-3.99 (dd, J=12.0 and 4.4Hz, 2H), 7.66 (d, J=8.0Hz, 2H), 7.97 (d, J=8.0Hz, 2H).

ESI/MS   m/z: 471.0(M+H)⁺

Yield: 36%

Example 95

(2-methyl-5-trans-( (4-methyl-2-(4-(trifluoromethyl) phenyl) thiazole-5-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR: 1.57 (s, 3H), 1.63-1.67 (m, 1H), 2.47 (s, 3H), 3.23 (d, J=8.0 Hz, 2H), 3.62-3.66 (m, 2H), 3.71-3.72 (m, 4H), 3.76-3.79 (dd, J=12.0 and 4.0Hz, 2H), 3.88 (t, J=4.4Hz, 2H), 4.09-4.12 (m, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.0Hz, 2H).

ESI/MS   m/z: 471.1(M+H)⁺

Yield: 47%

Example 96

5-c-(3-(9H-carbazole-9-yl) propyl)-N-hydroxy-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.06-1.11 (m, 2H), 1.46 (s, 3H), 1.80-1.95 (m, 3H), 3.35 (t, J=11.0Hz, 2H), 3.85-3.88 (m, 2H), 4.27 (t, J=6.8Hz, 2H), 7.21-7.26 (m, 2H), 7.32 (d, J=8.4Hz, 2H), 7.45-7.48 (m, 2H), 8.08-8.10 (m, 2H).

ESI/MS   m/z: 368.9(M+H)⁺

Yield: 37%

Example 97

N-hydroxy-5-c-(3-(10H-phenothiazine -10-yl) propyl)-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.16-1.19 (m, 2H), 1.48 (s, 3H), 1.72-1.78 (m, 2H), 1.93-1.94 (m, 1H), 3.32 (t, J=11.2Hz, 2H), 3.81-3.89 (m, 4H), 6.80-6.86 (m, 2H), 6.90 (t, J=7.6Hz, 2H), 7.13-7.16 (m, 4H).

ESI/MS   m/z: 401.0(M+H)⁺

Yield: 40%

Example 98

N-(benzyloxy)-5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 478.4(M+H)⁺

Yield: 56%

Example 99

N-(hydroxy)-5-c-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.31 (s, 9H), 1.46 (s, 3H), 2.14-2.19 (m, 1H), 2.37 (s, 2H), 2.39 (s, 3H), 3.35 (t, J=11.0Hz, 2H), 3.87 (dd, J=12.0 and 4.0Hz, 2H), 6.02 (s, 1H), 7.20-7.23 (m, 4H), 7.95 (bs, NH), 8.75 (bs, OH).

ESI/MS   m/z: 387.9(M+H)⁺

Yield: 10%

Embodiment 100

N-(hydroxy)-5-t-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.31 (s, 9H), 1.43 (s, 3H), 1.64-1.68 (m, 1H), 2.38 (s, 3H), 2.91 (d, J=7.6Hz, 2H), 3.65 (dd, J=11.8Hz, 2H), 3.86 (dd, J=12.0 and 2.8Hz, 2H), 6.04 (s, 1H), 7.21-7.29 (m, 4H).

ESI/MS   m/z: 388.2(M+H)⁺

Yield: 32%

Example 101

5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 470.2(M+H)⁺

Yield: 90%

Example 102

5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl-N-(2-oxo-2-( ((tetrahydro -2H-pyran-4-yl) methyl) amino) ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 527.0(M+H)⁺

Yield: 33%

Example 103

(5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone

ESI/MS   m/z: 442.4(M+H)⁺

Yield: 46%

Example 104

5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl-N-(2-morpholinyl-2-oxo-ethyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 499.0(M+H)⁺

Yield: 56%

Example 105

(5-( (3-(tert-butyl)-1-(P-tolyl)-1H-pyrazol-5-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (4-methyl piperazin-1-yl) methanone

ESI/MS   m/z: 455.0(M+H)⁺

Yield: 50%

Example 106

N-(benzyloxy)-5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.43 (s, 3H), 2.18 (d, J=7.2Hz, 2H), 2.24 (s, 3H), 2.33-2.38 (m, 1H), 3.46 (t, J=11.2Hz, 2H), 3.84 (s, 3H), 3.90-3.94 (dd, J=11.8 and 4.8Hz, 2H), 4.98 (s, 2H), 6.92 (d, J=6.8Hz, 2H), 7.35-7.43 (m, 5H), 7.87 (d, J=6.8Hz, 2H), 8.68 (s, 1H).

ESI/MS   m/z: 453.1(M+H)⁺

Yield: 60%

Example 107

N-(benzyloxy)-5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.48 (s, 3H), 1.82-1.87 (m, 1H), 2.31 (s, 3H), 2.77 (d, J=7.6 Hz, 2H), 3.66-3.69 (dd, J=12.2 and 2.0Hz, 2H), 3.85 (s, 3H), 3.85-3.88 (dd, J=12.2 and 2.8Hz, 2H), 4.99 (s, 2H), 6.93 (d, J=7.2Hz, 2H), 7.35-7.43 (m, 5H), 7.88 (d, J=6.8Hz, 2H), 8.66 (s, NH).

ESI/MS   m/z: 453.2(M+H)⁺

Yield: 45%

Example 108

N-hydroxy-5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D⁶): 1.28 (s, 3H), 1.12-2.18 (m, 3H), 2.26 (s, 3H), 3.41 (t, J=5.6Hz, 2H), 3.78-3.82 (m, 5H), 7.03 (d, J=6.8Hz, 2H), 7.82 (d, J=5.6Hz, 2H), 8.40 (s, NH), 10.83 (s, OH).

ESI/MS   m/z: 363.0(M+H)⁺

Yield: 71%

Example 109

N-hydroxy-5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.35 (s, 3H), 1.73-1.74 (m, 1H), 2.30 (s, 3H), 2.71 (d, J=7.6Hz, 2H), 3.60 (d, J=10.8Hz, 2H), 3.79 (s, 3H), 3.83-3.86 (dd, J=11.6 and 2.4Hz, 2H), 7.02 (d, J=7.2Hz, 2H), 7.81 (d, J=6.8Hz, 2H), 8.83 (s, NH), 10.81 (s, OH).

ESI/MS   m/z: 363.1(M+H)⁺

Yield: 59%

Embodiment 110

(5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 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=6.8Hz, 2H), 7.82 (d, J=6.8Hz, 2H).

ESI/MS   m/z: 417.1(M+H)⁺

Yield: 84%

Example 111

(5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR (DMSO-D₆): 1.41 (s, 3H), 2.30 (s, 3H), 2.72 (d, J=7.6Hz, 2H), 3.51-3.56 (m, 6H), 3.64 (d, J=10.8Hz, 2H), 3.77-3.79 (m, 5H), 3.94 (d, J=9.2Hz, 2H), 7.02 (d, J=6.8Hz, 2H), 7.81 (d, J=6.8Hz, 2H).

ESI/MS   m/z: 417.1(M+H)⁺

Yield: 75%

Example 112

5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.08-1.13 (m, 2H), 1.27 (s, 3H), 1.46-1.49 (m, 2H), 1.69 (m, 1H), 2.14-2.20 (m, 3H), 2.24 (s, 3H), 2.97 (t, J=6.6Hz, 2H), 3.20 (t, J=11.4Hz, 2H), 3.41 (t, J=11Hz, 2H), 3.77-3.83 (m, 7H), 7.04 (d, J=6.8Hz, 2H), 7.81 (d, J=6.8Hz, 2H), 8.05 (t, J=6.0Hz, 1H).

ESI/MS   m/z: 445.2(M+H)⁺

Yield: 59%

Example 113

5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR (DMSO-D₆): 1.10-1.14 (dd, J=12.4 and 4.4Hz, 2H), 1.36 (s, 3H), 1.49-1.52 (m, 2H), 1.71-1.74 (m, 1H), 2.32 (s, 3H), 2.72 (d, J=7.2 Hz, 2H), 2.99 (t, J=6.4Hz, 2H), 3.22 (t, J=10.8Hz, 2H), 3.63 (d, J=11.2 Hz, 2H), 3.81-3.85 (m, 7H), 7.04 (d, J=8.8Hz, 2H), 7.81 (d, J=8.8Hz, 2H), 8.05 (s, 1H).

ESI/MS   m/z: 445.2(M+H)⁺

Yield: 47%

Example 114

(5-c-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (4-methyl piperazin-1-yl) methanone

¹ H   NMR (DMSO-D₆): 1.32 (s, 3H), 2.15 (s, 3H), 2.19 (s, 3H), 2.25-2.28 (m, 7H), 3.50-3.53 (m, 4H), 3.73 (br   S, 2H), 3.80 (s, 3H), 3.82 (br   S, 2H), 7.03 (d, J=7.2Hz, 2H), 7.82 (d, J=6.8Hz, 2H).

ESI/MS   m/z: 430.3(M+H)⁺

Yield: 95%

Example 115

(5-t-( (2-(4-methoxyphenyl)-5-methyl Oxazol-4-yl) methyl)-2-methyl -1, 3-II Menthane-2-yl) (4-methyl piperazin-1-yl) methanone

¹ H   NMR (DMSO-D₆): 1.40 (s, 3H), 1.74 (br   S, 1H), 2.20 (br   S, 3H), 2.30 (s, 3H), 2.35 (br   S, 4H), 2.72 (d, J=7.6Hz, 2H), 3.47 (br   S, 2H), 3.64 (d, J=10.8Hz, 2H), 3.77-3.81 (m, 5H), 3.90-3.94 (dd, J=11.8 Hz, 2H), 7.03 (d, J=6.8Hz, 2H), 7.79-7.82 (m, 2H).

ESI/MS   m/z: 430.1(M+H)⁺

Yield: 89%

Example 116

N-(benzyloxy)-2-methyl-5-c-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.39 (s, 3H), 2.20 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 2.32-2.39 (m, 1H), 3.45 (t, J=10.8Hz, 2H), 3.91 (dd, J=11.6 and 4.4Hz, 2H), 4.99 (s, 2H), 7.35-7.44 (meter 5H), 7.66 (d, J=8.4Hz, 2H), 8.04 (d, J=8.0Hz, 2H), 8.69 (s, NH).

ESI/MS   m/z: 490.9(M+H)⁺

Yield: 59%

Example 117

N-(benzyloxy)-2-methyl-5-t-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ 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 (dd, J=12.8 and 1.6Hz, 2H), 3.87 (dd, J=11.6 and 2.8Hz, 2H), 5.00 (s, 2H), 7.31-7.43 (meter 5H), 7.67 (d, J=8.0Hz, 2H), 8.05 (d, J=8.0Hz, 2H), 8.67 (s, NH).

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)-1, 3-II Menthane-2-carboxamide

¹ H   NMR: 1.52 (s, 3H), 2.28 (d, J=7.6Hz, 2H), 2.30 (s, 3H), 2.35-2.43 (m, 1H), 3.54 (t, J=11.2Hz, 2H), 4.01 (dd, J=11.8 and 4.2Hz, 2H), 7.67 (d, J=8.0Hz, 2H), 8.05 (d, J=8.0Hz, 2H).

ESI/MS   m/z: 401.3(M+H)⁺

Yield: 52%

Example 119

N-hydroxy-2-methyl-5-t-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

ESI/MS   m/z: 401.1(M+H)⁺

Yield: 59%

Example 120

(2-methyl-5-c-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR: 1.50 (s, 3H), 2.22 (d, J=7.2Hz, 2H), 2.31 (s, 3H), 2.43-2.52 (m, 1H), 3.61-3.78 (m, 8H), 3.90 (t, J=4.6Hz, 2H), 3.91 (dd, J=12.0 and 4.8Hz, 2H), 7.68 (d, J=8.4Hz, 2H), 8.06 (d, J=8.0Hz, 2H).

ESI/MS   m/z: 455.2(M+H)⁺

Yield: 60%

Example 121

(2-methyl-5-t-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-1, 3-II Menthane-2-yl) (morpholinyl) methanone

¹ H   NMR: 1.55 (s, 3H), 1.86-1.90 (m, 1H), 2.40 (s, 3H), 2.90 (d, J=7.6 Hz, 2H), 3.64-3.67 (m, 2H), 3.71-3.77 (m, 6H), 3.88-3.91 (m, 2H), 4.07-4.11 (m, 2H), 7.67 (d, J=8.4Hz, 2H), 8.06 (d, J=8.0Hz, 2H)

ESI/MS   m/z: 455.1(M+H)⁺

Yield: 90%

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-II Menthane-2-carboxamide

¹ H   NMR: 1.26-1.39 (m, 2H), 1.49 (s, 3H), 1.59-1.62 (m, 2H), 1.75-1.83 (m, 1H), 2.27 (d, J=7.2Hz, 2H), 2.30 (s, 3H), 2.34-2.44 (m, 1H), 3.23 (t, J=6.6Hz, 2H), 3.34 (t, J=11.8Hz, 2H), 3.52 (t, J=10.6Hz, 2H), 3.97-4.04 (m, 4H), 6.43 (t, J=6.0Hz, NH), 7.67 (d, J=8.4Hz, 2H), 8.05 (d, J=8.4Hz, 2H)

ESI/MS   m/z: 483.1(M+H)⁺

Yield: 80%

Example 123

2-methyl-5-t-( (5-methyl-2-(4-(trifluoromethyl) phenyl) Oxazol-4-yl) methyl)-N-( (tetrahydro -2H-pyran-4-yl) methyl)-1, 3-II Menthane-2-carboxamide

¹ 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, 1H), 2.39 (s, 3H), 2.82 (d, J=8.0Hz, 2H), 3.22 (t, J=6.4Hz, 2H), 3.41 (t, J=11.8Hz, 2H), 3.75-3.78 (m, 2H), 3.96-4.00 (m, 2H), 6.45 (t, J=6.2Hz, NH), 7.67 (d, J=8.4Hz, 2H), 8.05 (d, J=8.4Hz, 2H)

ESI/MS   m/z: 483.2(M+H)⁺

Yield: 58%

In one embodiment, provides a model identification by the computer as a biological (in-silico) PCSK9 small molecule inhibitors of the method. And in order to identify PCSK9 bound molecules, produced PCSK9 without the original domain of mutant insilico, its subsequent analog (docking) used to butt-joint. Unexpectedly discovered that, catalytic site are as follows provided with small molecule of combining the display the relevant in vitro and in vivo PCSK9 inhibit function. The amino acid number according to the name is obtained from a protein database (www.pdb.org) PCSK9 the 3BPS made of a crystal structure.

PCSK9 the amino acid sequence of the catalytic site:

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

GLY   291   GLY   292   LEU   297   ALA   314   ALA   315   ASN   317   PHE   318   TYR   325   SER   326   PRO   327   SER

386   GLN   387

In a preferred embodiment, the molecule bind one or more of the amino acid, the amino acid to include the single catalytic triplex HIS   226   SER   386   ASP   186 with the catalytic site or the other the combination of amino acids.

Butt joint research:

The docking study in   silico, using PCSK9 protein crystal structure (3BPS) identified PCSK9 binding molecule, the stated PCSK9 is to adopt the structure of protein crystal of LDL-R EGF-A domain (PNAS, 105 (6), 1820-1825,2008), the original domain and the crystalline CRD, can be obtained from the public, the database-protein database (PDB). Through the computer, we produce PCSK9 without the original domain of the mutant, wherein the active site is composed of the following amino acid composition, but are not limited 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

In order to use the implementation of the Maestro   Preparation Protein   Wizard tool( Suite   2010Protein   Wizard   Preparation; Epik   version   2.1; 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) preparing the PCSK9 protein (3BPS. pdb) research for the butt joint. According to the standard programmes, bond order to all of the home, in the hydrogen atom is added to the protein. Furthermore, using LigPrep   2.6 Edition (LigPrep   2.6; Schrodinger, LLC: New   York, NY, 2010) of the to-end joint optimization of the geometric structure of the compound. Using Glide   5.6 Edition (Glide   5.6; Schrodinger, LLC: New   York, NY, 2010) docking studies on these compounds, a software package to Schrodinger automated docking program.

In accordance with the above-mentioned scheme of one example of the representation of small molecules provided in the Figure 1 in.

Butt results:

The above-mentioned computer biological results can further obtain the compound with PCSK9 protein co-crystallization of the complex the support of the X-ray diffraction. Through the further support of amino acid in a catalytic site selective mutation and through the use of the mutant protein Elisa obtained to the test compound.

Biological research:

The compounds of this invention reduce the LDL, triglycerides and total cholesterol. In vitro and this has been confirmed in vivo animal experiments.

A) confirmed the efficacy of compounds in vitro

PCSK9-LDLR PCSK9 in vitro binding assay is quantitative between the recombinant LDLR solid phase binding assay. PCSK9 by binding domain of recombinant LDLR-AB pre-the board. The different concentrations of test compound are added to PCSK9 in, added to and is fixed in the hole in the LDLR. By first with the biotinylated anti-His-tag monoclonal antibody binding, then and horseradish peroxidase conjugated streptavidin substrate binding, PCSK9 to measure the binding of the quantity. Using ELISA reader at 450 nanometer quantitative color, its reflected and does not exist in the presence of inhibitors of the binding of the LDLR PCSK9 the relative amounts of the. Using graph   pad prism software, through the non-linear regression analysis and calculation EC₅₀ value. Each concentration point representative of the value of the time.

B) SPR binding studies:

Fixed programme:

Instrument: from the use of GE BIACORE3000   Life   Sciences, in 25 the analysis interaction [...].

Buffer solution: during the trial period, of use provide Biacore supplemented with 0.01% dimethyl sulfoxide (DMSO) phosphate buffer (pH   7.4) as the running buffer.

Ligand fixed: using a sensor chip CM5 for analysis. The sensor chip by the combination of the glass support jin Gai carboxymethyl-modified dextran polymer. The ligands in 10 mm sodium acetate (pH5.0) for dilution to 10 micrograms/ml, and using amine coupling is fixed on the sensor chip. In the fixed period, the operation of the buffer containing DMSO. By injecting containing 0.2M   N-ethyl-N '-dimethyl amino propyl-carbodiimide (EDC) and 50 mm   N-hydroxy succinimide (NHS) activating the surface of the solution. Set as the system used for fixing Aim contractual 1000 RU, and through injection pH   8.5 with 1M ethanolamine closed surface. Furthermore, through into two 30 second pulse of 50 mm   NaOH wash surface, in order to remove non-covalently bound ligand and stable baseline (automated process). Using the activated dextran is used as the reference surface. In order to ensure maximum sensitivity, before determining the start, the total internal reflection condition (automated process) to different light intensity calibration detector to the SPR normalized detector response. Also conducted to the DMSO solvent correction, in order to make the data error is minimized.

Assay design: for different compound, designed in three different concentrations (10 nanometer, and 100 nanometer the 1  M) of the binding assay, and the light in the pool and ligand infusion flow, velocity of flow is 30 micro-liters/minute. Each cycle from 1 minutes waiting time (used for monitoring the stability of the base line) and 3 minutes compound injection time and 5 minutes a disturbance not from the ruled some regions, and the surface with 50 mm NaoH solution regeneration. From a reference flow cell in the response of the compound in the ligand is subtracted in response to the flow in the pool, solvent during the correcting operation, potential combination of compounds (RU) relative to the response units report to.

C) confirmed the effectiveness of the compound in vivo

I) in the LPS-induced dyslipidaemic model C57 LDL-C activity in the mouse

The level based on must fasts LDL-C 7-10 of age male C57 mouse packet, 2nd day the carrier or administered to these MICE of the test compound (intraperitoneally (i.p.) or oral), and the compound administered 30 minutes after the administration of lipopolysaccharide (LPS). After the administration of LPS, maintain jejunitas all the animals 24 hours, the RAT is measured after LDL-C to the animal. Compared with the carriers of the test compound group is calculated in percentage change of LDL-C.

Ii) diet HF-HC in the supply in the hamster model;

In this experiment, total cholesterol levels and LDL-C-based, will maintain a high-fat, high-cholesterol diet fructose (HF-HC) 2 weeks of Syrian Golden hamster classico in different groups. To oral the tube raises the law , once per day, a total of 14 days. In section 0 days (pretreatment), under the light b etherizations, by collecting blood mummification after eye socket, Dou , and the processing section 14 days measuring lipid levels. Computerized compound comparatives carriers LDL-C changes in percentage.

Iii) in a high-fat diet C57 LDL-C reduction in the activity of the mouse

While keeping high fat diet 4 week C57 mouse of the test compound in vivo testing of the effects of reducing LDL-c, in section 0 days (before processing), under the light b etherizations, the mummification after eye socket, Dou collecting blood, the animal grouping based on LDL-C level, thereafter, oral administration of a carrier or test compound processing 4-6 week, once-a-day. After the completion of the processing, in paragraph 28 days or section 42 days, collecting blood level measurement LDL-C. Calculates the contrast of the test compound group LDL-C change percentage in the carriers.