CN1444584A - N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases - Google Patents

N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl] carboxamide inhibitors of cyclin dependent kinases Download PDF

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CN1444584A
CN1444584A CN01813367A CN01813367A CN1444584A CN 1444584 A CN1444584 A CN 1444584A CN 01813367 A CN01813367 A CN 01813367A CN 01813367 A CN01813367 A CN 01813367A CN 1444584 A CN1444584 A CN 1444584A
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hydrochloride
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trifluoroacetate
acceptable salt
pharmacy acceptable
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CN100457753C (en
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R·N·米斯拉
H·-Y·肖
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Bristol Myers Squibb Co
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Abstract

The present invention describes compounds of formula (I): and enantiomers, diastereomers and pharmaceutically acceptable salts thereof. The formula (I) compounds are protein kinase inhibitors and are useful in the treatment of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer's disease, chemotherapy-induced alopecia, and cardiovascular disease.

Description

The kinase whose N-[5-[[[5-alkyl-2-oxazolyl of cyclin dependent] methyl] sulfo-]-the 2-thiazolyl] carboxamide inhibitors
The present invention relates to formula I compound and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt:
Figure A0181336700111
Wherein: R is an alkyl; R 1It is hydrogen or alkyl; X is NR 2Or CHNR 2R 3R 2And R 3Independently be the cycloalkyl of alkyl, cycloalkyl or the replacement of hydrogen, alkyl, replacement separately; And n is 0,1,2 or 3.
Formula I compound especially can be used as effectively, kinases inhibitor, can be used for treating proliferative disease, for example cancer, inflammation and sacroiliitis.They also can be used for treating the alopecia and the cardiovascular disorder of Alzheimer disease, chemotherapy induction.
The method of the invention provides formula I compound, using the medicinal compositions of these compounds and use these compounds.
Below list the definition of the various terms that are used to illustrate The compounds of this invention.When specification sheets uses these terms (unless they are having qualification in addition in concrete example) separately or as the part than macoradical in full, these definition are applicable to described term.
Unless otherwise indicated, term " alkyl " or " alk " refer to contain 1 to 12, and preferred 1-6 is individual, more preferably unit price alkane (hydrocarbon) the deutero-group of 1-4 carbon atom.Optional straight chain, side chain or the cyclic saturated hydrocarbyl of alkyl group for replacing.When replacing, at any available tie point, can be with maximum four substituting groups (as the R of definition 4) the substituted alkyl group.When saying that described alkyl group is replaced by an alkyl group, can exchange with " branched alkyl group " and use.Unsubstituted these examples of groups comprise methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.Substituent example can include, but are not limited to one or more following groups: halogeno-group (as F, Cl, Br or I), haloalkyl are (as CCl 3Or CF 3), alkoxyl group, alkylthio, hydroxyl, carboxyl, alkyl-carbonyl, carbalkoxy, alkyl-carbonyl oxygen base, amino, formamyl, urea, amidino groups or thiol.
Cycloalkyl does not have a class alkyl of alternating double bond or the two keys of resonance for containing 3 to 15 carbon atoms between carbon atom.It can comprise 1-4 ring.Unsubstituted these examples of groups comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.Substituent example comprises one or more following groups: halogeno-group, alkyl, alkoxyl group, alkyl hydroxy, amino, nitro, cyano group, thiol and/or alkylthio.
The logical respectively peroxide bridge of term used herein " alkoxyl group " or " alkylthio " expression (O-) or sulfide linkage (S-) the aforesaid alkyl group of Lian Jieing.
The alkoxy base that term used herein " carbalkoxy " expression connects by carbonyl.Carbalkoxy is expressed from the next :-C (O) OR 5, R wherein 5Be straight or branched C 1-6Alkyl.
Term " alkyl-carbonyl " refers to the alkyl by the carbonyl connection.
Term used herein " alkyl-carbonyl oxygen base " refers to the alkyl-carbonyl that logical peroxide bridge connects.
Phrase used herein " The compounds of this invention " system refers to compound and pharmacy acceptable salt and the solvate (comprising hydrate) in the formula I scope.Salify, solvation and become the method for hydrate to know in this area.The present invention also comprises the stereoisomer mixture of The compounds of this invention.Steric isomer includes, but are not limited to the racemic modification that enantiomorph, diastereomer and wherein said compound have one or more chiral centre.Estimate all steric isomers of The compounds of this invention or exist with mixture or with pure or pure basically form.The definition of The compounds of this invention comprises all possible steric isomer and composition thereof.Especially comprise racemic modification form and isolating optical isomer form with given activity.Described racemic modification can pass through physical method, splits as fractional crystallization, separation or the crystallization of non-enantiomer derivative or by the chiral column chromatographic separation.Single optical isomer can be used racemic modification, by common method, as with optical activity acid salify, crystallization obtains then.Estimate all configurational isomers of The compounds of this invention or exist with mixture or with pure or pure substantially form.The definition of The compounds of this invention comprises the cis and the trans-isomer(ide) of cis (Z) and trans (E) alkene isomer and cycloalkyl or heterocycloalkyl ring especially.
In addition, the present invention also comprises and pharmaceutically is not suitable for but can be used for the salt of the formula I compound of others (as isolated or purified formula I compound).
Define compound of the present invention by chemical structure and/or chemical name herein.When specifying a certain compound with chemical structure and chemical name simultaneously, and when this chemical structure and chemical name conflict, this compound structure has decisive role to compound itself.
Phrase used herein " pharmacy acceptable salt " includes, but are not limited to the acidity that can exist or the salt of basic group in The compounds of this invention.The example of these pharmacy acceptable salts includes, but are not limited to hydrochloride, hydrobromate, dihydrochloride, vitriol, trifluoroacetate, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and iodate and composition thereof.Comprise also and other organic or inorganic acid that as the salt that hydroxyl methylsulfonic acid, acetate, Phenylsulfonic acid, toluenesulphonic acids form, perhaps various other salt are as nitrate, phosphoric acid salt, borate, benzoate, ascorbate salt, salicylate etc.In addition, can with basic metal, as sodium, potassium and lithium; Alkaline-earth metal is as calcium and magnesium; Organic bases is as dicyclohexylamine, tributylamine and pyridine etc.; Amino acid forms the pharmacy acceptable salt of formula I compound as arginine, Methionin etc.
The salt of The compounds of this invention comprises its solvate, racemic modification and all stereoisomer forms thereof, comprises enantiomorph and diastereomer (for example, D-tartrate and L-tartrate).
Term used herein " solvate " is meant The compounds of this invention and the salt thereof that also comprises by one or more solvent molecule of non-covalent intermolecular forces bonded stoichiometry or nonstoichiometry amount.Acceptable solvent when preferred solvent is volatility, non-toxicity and/or trace administration of human.When described solvent was water, this solvate was called " hydrate ".
Formula I compound can be by adopting the method preparation that proposes among WO 99/65884 and the WO 99/24416, and two patents all are attached to herein as a reference.Perhaps, the universal method preparation I compound shown in the available following option A, the synthetic method of the big class of this option A formula XIV compound.This starting compound can have been bought or can be by the known method preparation of those of ordinary skills.Term used in the option A is as follows: R 7, R 8And R 10It independently is hydrogen or alkyl; R is alkyl, aryl or heteroaryl; R 9Be hydrogen, alkyl, aryl or heteroaryl; R 1And R 11Independently be hydrogen, alkyl, aryl, heteroaryl, halogeno-group, hydroxyl or alkoxyl group; R 12Be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, CONR 13R 14, COR 15Or COOR 16R 13, R 14, R 15And R 16Independently be hydrogen, alkyl or aryl; R is the integer of 0-5; S is the integer of 0-5;
L is suitable leavings group, as halogeno-group or sulfonate radical (R 6SO 2O -, CF 3SO 2O -Deng, R wherein 6Be alkyl, cycloalkyl or aryl);
M is hydrogen, Li, Na, K, Cs or quaternary ammonium ion, as (R 6) 4N or comprise the ring alkylidene group tetramine (as vulkacit H) quaternary ammonium ion;
Q is hydroxyl, halogeno-group or acyloxy (R 6COO -, R 6OCOO -Deng);
Y is O, S, NH, N-alkyl, N-aryl or N-acyl group;
Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2, N-alkyl, N-aryl or N-acyl group; With
P is nitrogen-protecting group (Boc, Cbz, R 3Si etc.).When functional group is called as " protected ", be meant that this group is to prevent that in protective position the modified forms of uncomfortable side reaction from existing with a kind of.Consider from those skilled in the art's level; and with reference to the standard textbook that is attached to herein as a reference; Greene as the 3rd edition (1999); T.W.; Protective Groups inOrganic Synthesis is easy to identify the due care base of the compound that relates in this method from this specification sheets.
Present method relates generally to the reaction that α-Lu Daitong II (can buy or can be easily synthetic by the method known) and trinitride reaction generate α-azido-ketone III.III obtains alpha-amino group ketone IV with the reductive agent reduction.
Another kind of more favourable selection is by making α-Lu Daitong II and ring alkylidene group four ammoniums (as vulkacit H etc.) reaction, quaternary ammonium salt III ' that will obtain, new hydrolysis then, preparation alpha-amino group ketone IV.This reaction provides the desired midbody compound IV of yield fine (more than 90%).
Then, in the presence of alkali, make alpha-amino group ketone IV and alpha-halogen acyl halide V reaction, perhaps make alpha-amino group ketone IV and alpha-halogen acid coupling, generate corresponding acid amides VI.Subsequently, VI and dewatering agent carry out ring-closure reaction, generate 2-oxazolyl alkyl halide VII.When using conventional dewatering agent, as three oxyhalogen phosphorus (as POCl 3) time, owing to form a large amount of hydrochloric acid and phosphoric acid, product separation difficulty.Therefore, this method of the present invention is preferably utilized Burgess reagent, and this reagent can obtain yield preferably, and can isolate product easily, safely from water.
Then 2-oxazolyl alkyl halide VII is handled with sulfur-bearing regent VIII or VIII ', generate new key intermediate compound 2-oxazolyl alkyl sulfur compounds IX.IX and 5-halo-thiazolamine X coupling obtains 5-(2-oxazolyl alkylthio)-thiazolamine XI.XI and azacycloalkyl acid derivative XII coupling obtain Thizaolyl amide XIII, but latter's deprotection (is under the situation of protecting group such as Boc at P) generates 5-(2-oxazolyl alkylthio)-2-azacycloalkanoyl aminothiazoles XIV.Option A
Figure A0181336700161
As shown in option A, the preparation process of 5-(2-oxazolyl alkylthio)-2-azacycloalkanoyl aminothiazoles and analogue thereof comprises following conversion:
Step (a) is included in appropriate solvent or the solvent mixture, makes the ketone II (as α-Lu Daitong) of alpha-substitution and trinitride reaction generate α-azido-ketone III; Perhaps, better is (a ') in appropriate solvent or solvent mixture, make the ketone II (as α-Lu Daitong) and ring alkylidene group four ammoniums (as vulkacit H) reaction of alpha-substitution, obtain new quaternary ammonium salt III '.
This α-Lu Daitong comprises alpha-halogen aliphatic series and alpha-halogen aromatic ketone.Preferred α-Lu Daitong is the alpha-halogen Pinacolone, most preferably alpha-brominated Pinacolone.Sulfonate radical is as RSO 2O -(wherein R is alkyl, aryl or heteroaryl), CF 3SO 2O -Deng the halogeno-group that can replace alpha-position.This trinitride comprises metal azide and quaternary ammonium trinitride.Preferable alloy trinitride, most preferably sodiumazide.Appropriate solvent comprises as hydrocarbon, ether, acid amides (as dimethyl formamide), ketone equal solvent or its mixture, and reaction (a) and (a ') be preferred ketone solvent, as acetone.
Step (b) is included in appropriate solvent or the solvent mixture, make the α-azido-ketone III and the reductive agent reaction that obtain in the step (a) obtain alpha-amino group ketone IV, perhaps, better is (b ') in appropriate solvent or solvent mixture, makes the quaternary ammonium salt III ' that obtains in the step (a ') obtain alpha-amino group ketone IV with acid-respons.
Reductive agent in the reaction (b) is included in the hydrogen under transition-metal catalyst such as palladium, trialkyl or triaryl phosphine (as the triphenyl phosphine) existence.Hydrogen under preferred transition-metal catalyst exists, most preferably hydrogen and activated carbon-palladium.The appropriate solvent of reaction in (b) comprise as hydrocarbon, ether, pure equal solvent or its mixture, and preferred alcohols solvent wherein is as methyl alcohol.Perhaps, this reduction reaction can be carried out in the presence of acidic medium (ethanolic soln of example hydrochloric acid), obtains separable alpha-amino group ketone acid salt for acid salt or unhindered amina form.
Acid in the reaction (b ') includes but not limited to protonic acid, as HCl, HBr, HI, H 2SO 4, H 3PO 4Deng, wherein preferred HCl.Appropriate solvent in the reaction (b ') comprises as hydrocarbon, ether, pure equal solvent or its mixture, and preferred alcohols solvent wherein is as ethanol.Described alpha-amino group ketone product can be separated into salt or free alkali form.
Step (c) is included in alkali and exists down; and in appropriate solvent or solvent mixture; make the alpha-amino group ketone IV that obtains among step (b) or (b ') or acyl derivative V (as the alpha-halogen acyl halide) reaction (acidylate) of its acid salt and alpha-substitution, obtain acid amides VI.
Alpha-halogen acyl halide V comprises that alpha-alkyl or aryl replace or unsubstituted alpha-halogen acyl halide, the wherein preferred latter.Most preferred alpha-halogen acyl halide is the alpha-chloro Acetyl Chloride 98Min..Used alkali includes but not limited to aromatics and aliphatic organic amine in the reaction, the wherein preferred latter.Most preferred alkali is triethylamine.Appropriate solvent comprises that as aprotic solvent or its mixtures such as hydrocarbon, halohydrocarbon, ether, esters wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.Perhaps, available alpha-substitution acid substitution alpha-substitution acyl derivative adopts coupling agent then, carries out this reaction as water-soluble diimine (as carbodiimide), haloformate, thionyl halide etc.In arbitrary reaction, sulfonate radical such as RSO 2O -(wherein R is alkyl, aryl or heteroaryl), CF 3SO 2O -Halogeno-group Deng the alpha-position that can replace alpha-halogen acyl halide or illustrational alpha-halogen acid reaction.
Step (d) relates in appropriate solvent or solvent mixture, makes the acid amides VI and the dewatering agent reaction that obtain in the step (c), obtains the 2-oxazolyl alkyl derivative VII of cyclisation, as 2-oxazolyl alkyl halide.
Beneficially utilize hydroxide (methoxycarbonyl sulfamyl) three second ammoniums (Burgess reagent) to carry out this reaction as dewatering agent.Appropriate solvent comprises hydrocarbon, halohydrocarbon, ether etc. or its mixture.Most preferably in tetrahydrofuran (THF), utilize Burgess reagent.Suitable dewatering agent also includes, but are not limited to other alkali, acid, acid anhydrides etc., as the vitriol oil, Tripyrophosphoric acid etc.Though be not easy to use, described dewatering agent can be three oxyhalogen phosphorus, as tribromo oxygen phosphorus or phosphorus oxychloride, it can use separately or with solvent (as toluene).
Step (e) relates in appropriate solvent or solvent mixture, makes the 2-oxazolyl alkyl derivative VII and sulfur-bearing regent VIII or the VIII ' reaction that obtain in the step (d), generates new key intermediate compound 2-oxazolyl alkyl sulfur compounds IX.
Sulfur-bearing regent comprises that N-replaces or unsubstituted thiocarbamide, thioic acid sulfoacid or salt (as thioacetic acid or its salt), xanthogenic acid or salt (as xanthogenic acid sylvite).Preferred unsubstituted thiocarbamide.Appropriate solvent comprises hydrocarbon, halohydrocarbon, ether, ester, acid amides, alcohol etc. or its mixture, and preferred alcohols solvent wherein is as methyl alcohol or ethanol.
Step (f) relates in the presence of alkali, in appropriate solvent or solvent mixture, makes the 2-oxazolyl alkyl sulfur compounds IX and the 5-halo-thiazolamine X reaction that obtain in the step (e), generates 5-(2-oxazolyl alkylthio)-thiazolamine XI.
5-halo-thiazolamine comprises that 4-N-replaces or unsubstituted 5-halo-thiazolamine, wherein preferred 5-bromo-thiazolamine.Suitable alkali includes, but are not limited to the aqueous solution of metal hydroxides, metal alkoxide, metal carbonate and amine such as ammonium hydroxide.Preferred sodium hydroxide.Appropriate solvent comprises that as hydrocarbon, halohydrocarbon, ether, ester, acid amides, pure equal solvent or its mixture wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.
Step (g) relates in the presence of coupling agent, in appropriate solvent or solvent mixture, makes 5-(2-oxazolyl the alkylthio)-thiazolamine XI and the azacycloalkyl acid derivative XII reaction that obtain in the step (f), obtains Thizaolyl amide XIII.
Described azacycloalkyl acid derivative comprises the derivative of N-protected, as the different piperidine carboxylic acid of N-protected or the nipecotic acid of N-protected.Preferred nitrogen-protecting group is Boc, Cbz, silicon derivative etc., wherein Boc most preferably.Described coupling agent includes, but are not limited to water-soluble carbodiimide, haloformate etc., and preferred carbodiimide is as the alkyl carbodiimide.Appropriate solvent comprises that as hydrocarbon, halohydrocarbon, ether, ester, acid amides equal solvent or its mixture wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.
Step (h) relates in appropriate solvent or solvent mixture, makes the reaction of the Thizaolyl amide XIII that obtains in the step (g) and deprotection agent, obtains required 5-(2-oxazolyl alkylthio)-2-azacycloalkanoyl aminothiazoles XIV (R wherein 11Be hydrogen).
Character according to protecting group (P) is selected deprotection agent.For the Boc protecting group, preferred deprotection agent is acid, and example hydrochloric acid or trifluoroacetic acid, the appropriate solvent of this deprotection reaction comprise that as hydrocarbon, halohydrocarbon, ether, ester, acid amides equal solvent or its mixture wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.
The more detailed synthesis method of formula I compound among the following scheme 1-5.Starting compound can have been bought or can be according to the known method preparation of those of ordinary skills.Use following term below among the scheme 1-5:
L is suitable leavings group, as halogeno-group or sulfonate radical (as Br, Cl, I, R 6SO 2O -, CF 3SO 2O -, R wherein 6Be alkyl, cycloalkyl, heteroaryl or aryl);
M is hydrogen, Li, Na, K, Cs or quaternary ammonium ion, as (R 6) 4N or comprise the ring alkylidene group tetramine (as vulkacit H) quaternary ammonium ion;
Q is hydroxyl, halogeno-group or acyloxy (R 6COO -, R 6OCOO -Deng);
Y is O, S, NH, N-alkyl, N-aryl or N-acyl group; With
Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2, N-alkyl, N-aryl or N-acyl group.Scheme 1 provides the synthesis method of formula 11 compounds.
Scheme 1: the synthesis method of formula 11 compounds
At first, step (a) relates in appropriate solvent or solvent mixture, makes the ketone 2 (as α-Lu Daitong) and trinitride reaction of suitable alpha-substitution, generates α-azido-ketone 3; Perhaps, better is (a ') in appropriate solvent or solvent mixture, make ketone 2 and ring alkylidene group four ammoniums (as vulkacit H) reaction, obtain quaternary ammonium salt 3 '.
Suitable α-Lu Daitong 2 comprises alpha-halogen aliphatic series and alpha-halogen aromatic ketone.Preferred α-Lu Daitong is the alpha-halogen Pinacolone, most preferably alpha-brominated Pinacolone.Sulfonate radical such as R 6SO 2O -(wherein as above definition, R 6Be alkyl, cycloalkyl, heteroaryl or aryl), CF 3SO 2O -Deng the halogeno-group that can replace alpha-position (as L).This trinitride comprises metal azide and quaternary ammonium trinitride.Preferable alloy trinitride, most preferably sodiumazide.Appropriate solvent comprises hydrocarbon, ether, acid amides (as dimethyl formamide), ketone equal solvent or its mixture, and reaction (a) and (a ') be preferred ketone solvent, as acetone.
Step (b) is included in appropriate solvent or the solvent mixture, make the α-azido-ketone 3 and reductive agent reaction that obtain in the step (a), obtain alpha-amino group ketone 4, perhaps, better is (b ') in appropriate solvent or solvent mixture, make the quaternary ammonium salt 3 ' and the acid-respons that obtain in the step (a '), obtain alpha-amino group ketone 4.
Reductive agent in the reaction (b) is included in the hydrogen under transition-metal catalyst such as palladium, trialkyl or triaryl phosphine (as the triphenyl phosphine) existence.Hydrogen under preferred transition-metal catalyst exists, most preferably hydrogen and activated carbon-palladium.The appropriate solvent of reaction in (b) comprises hydrocarbon, ether, alcohol etc. or its mixture, and preferred alcohols solvent wherein is as methyl alcohol.Perhaps, this reduction reaction can be carried out in the presence of acidic medium (ethanolic soln of example hydrochloric acid), obtains separable alpha-amino group ketone acid salt for acid salt or unhindered amina form.
The suitable acid of using in the reaction (b ') includes, but are not limited to HCl, HBr, HI, H 2SO 4, H 3PO 4Deng, wherein preferred HCl.Appropriate solvent in the reaction (b ') comprises hydrocarbon, ether, alcohol etc. or its mixture, and preferred alcohols solvent wherein is as ethanol.Described alpha-amino group ketone product is separable to be acid salt or free alkali form.
Step (c) is included in alkali and exists down; and in appropriate solvent or solvent mixture; make acyl derivative 5 (as the alpha-halogen acyl halide, i.e. Q and the L=halogeno-group) reaction (acidylate) of the alpha-amino group ketone 4 that obtains among step (b) or (b ') or its acid salt and alpha-substitution, obtain acid amides 6.
Alpha-halogen acyl halide 5 comprises alkyl or aryl-alpha-halogen acyl halide (replacement or unsubstituted), the wherein preferred latter.Most preferred alpha-halogen acyl halide is the alpha-chloro Acetyl Chloride 98Min..Used alkali includes, but are not limited to aromatics and aliphatic organic amine in the reaction, the wherein preferred latter.Most preferred alkali is triethylamine.Appropriate solvent comprises aprotic solvent, and as hydrocarbon, halohydrocarbon, ether, ester etc. or its mixture, wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.Perhaps, available alpha-substitution acid (Q=OH) replaces the alpha-substitution acyl derivative, adopts coupling agent then, carries out this reaction as water-soluble diimine (as carbodiimide), haloformate, thionyl halide etc.In arbitrary reaction, sulfonate radical is as R 6SO 2O -(R wherein 6Be alkyl, cycloalkyl, aryl or heteroaryl), CF 3SO 2O -The halogeno-group that can replace the alpha-position (being group L) of compound 5.
Step (d) relates in appropriate solvent or solvent mixture, makes the acid amides 6 and dewatering agent reaction that obtain in the step (c), obtains the 2-oxazolyl alkyl derivative 7 of cyclisation, as 2-oxazolyl alkyl halide (being that L is a halogeno-group).
Beneficially utilize hydroxide (methoxycarbonyl sulfamyl) three second ammoniums (Burgess reagent) to carry out this reaction as dewatering agent.Appropriate solvent comprises hydrocarbon, halohydrocarbon, ether etc. or its mixture.Most preferably in tetrahydrofuran (THF), utilize Burgess reagent.Suitable dewatering agent also includes, but are not limited to other alkali, acid, acid anhydrides etc., as the vitriol oil, Tripyrophosphoric acid etc.Though be not easy to use, described dewatering agent can be three oxyhalogen phosphorus, as tribromo oxygen phosphorus or phosphorus oxychloride, it can use separately or with solvent (as toluene).
Step (e) is included in appropriate solvent or the solvent mixture, makes the 2-oxazolyl alkyl derivative 7 and sulfur-bearing regent 8 or 8 ' reaction that obtain in the step (d), generates 2-oxazolyl alkyl sulfur compounds 9.
Sulfur-bearing regent comprises that N-replaces or unsubstituted thiocarbamide, thioic acid sulfoacid or salt (as thioacetic acid or its salt), xanthogenic acid or salt (as xanthogenic acid sylvite).Preferred unsubstituted thiocarbamide.Appropriate solvent comprises hydrocarbon, halohydrocarbon, ether, ester, acid amides, alcohol etc. or its mixture, and preferred alcohols solvent wherein is as methyl alcohol or ethanol.
Step (f) illustrates in the presence of alkali, and in appropriate solvent or solvent mixture, make the 2-oxazolyl alkyl sulfur compounds 9 and thiazolamine 10 (preferred L is a halogeno-group) reaction that obtain in the step (e), generate 5-(2-oxazolyl alkylthio)-thiazolamine 11.
Described thiazolamine 10 comprises that 4-N-replaces or unsubstituted 5-halo-thiazolamine, wherein preferred 5-bromo-thiazolamine.Suitable alkali includes, but are not limited to the aqueous solution of metal hydroxides, metal alkoxide, metal carbonate and amine such as ammonium hydroxide.Preferred sodium hydroxide.Appropriate solvent comprises hydrocarbon, halohydrocarbon, ether, ester, acid amides, alcohol etc. or its mixture, and wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.
Scheme 2 has provided in the presence of coupling agent, by the carboxylic acid reaction of amine 11 with formula 12, the universal method of synthetic compound of formula i.Suitable coupling agent includes, but are not limited to water-soluble carbodiimide, haloformate etc., preferred carbodiimide, and as the alkyl carbodiimide, the mixture of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and alkali for example.
Scheme 2
Figure A0181336700231
Following scheme 3 illustrates that wherein X is NR 2And R 2It is the synthesis method of the formula I compound of H.At first, in the presence of coupling agent, make the carboxylic acid reaction of the N-protected of the amine of formula 11 and formula 13, form the compound of the N-protected of formula 14.With compound 14 deprotections, obtain formula I compound then.Suitable coupling agent includes, but are not limited to water-soluble carbodiimide, haloformate etc., preferred carbodiimide, and as the alkyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and alkali for example.
Scheme 3
Figure A0181336700241
In above scheme, P is that nitrogen-protecting group is (as Boc, Cbz, R 3Si etc.).When functional group is called " protected ", be meant that this group is to prevent that in protective position the modified forms of uncomfortable side reaction from existing with a kind of.Consider from those skilled in the art's level; and with reference to the standard textbook that is attached to herein as a reference; Greene as the 3rd edition (1999); T.W.; Protective Groups in Organic Synthesis is easy to identify the due care base of the compound that relates in this method from this specification sheets.Preferred nitrogen-protecting group is Boc, Cbz, silicon derivative, wherein Boc most preferably.Appropriate solvent comprises hydrocarbon, halohydrocarbon, ether, ester, acid amides etc. or its mixture, and wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.Character according to protecting group (P) is selected deprotection agent.For the Boc protecting group, preferred deprotection agent is acid, and example hydrochloric acid or trifluoroacetic acid, the appropriate solvent of this deprotection reaction comprise that as hydrocarbon, halohydrocarbon, ether, ester, acid amides equal solvent or its mixture wherein preferred halogenated hydrocarbon solvent is as methylene dichloride.
Following scheme 4 illustrates that wherein X is NR 2And R 2Be 2, the synthesis method of the formula I compound of 3-dihydroxypropyl, it is by in the presence of reductive agent (as sodium triacetoxy borohydride) and alcohol (as methyl alcohol), and making wherein, X is NR 2And R 2The formula I compound and the Glycerose reaction that are H are carried out.
Scheme 4
Following scheme 5 illustrates that wherein X is NR 2And R 2Be the synthesis method of the formula I compound of 2-hydroxyethyl, X is NR by making wherein for it 2And R 2Be the formula I compound of H and 2-(bromine oxethyl) the trialkyl silane reaction of formula 15, generate intermediate 16, use acid (as hydrofluoric acid) that intermediate 16 deprotections are carried out then.
Scheme 5
Preferred formula I compound is following compound, and wherein: R is an alkyl; R 1Be hydrogen; X is NR 2Or CHNR 2R 3And R 2And R 3It independently is the alkyl or cycloalkyl of hydrogen, alkyl, replacement; And n is 2.
First group of preferred compound of the present invention is formula Ia compound and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt:
Figure A0181336700271
R wherein 2It is the alkyl or cycloalkyl of hydrogen, alkyl, replacement.
Second group of preferred compound of the present invention is formula Ib compound and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt: R wherein 2It is the alkyl or cycloalkyl of hydrogen, alkyl, replacement.
The 3rd group of preferred compound of the present invention is formula Ic compound and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt:
Figure A0181336700273
R wherein 2And R 3Each independently is the alkyl or cycloalkyl of hydrogen, alkyl, replacement.
In another embodiment, formula I compound includes, but are not limited to compound listed in the following table 1 and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt.
Table 1: The compounds of this invention
Figure A0181336700281
The preferably salt of above compound is hydrochloride, hydrobromate, dihydrochloride, vitriol, trifluoroacetate, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and iodate or its mixture.
The present invention also comprises the method based on the The compounds of this invention pharmacological properties.The compounds of this invention has pharmacological property; Especially, formula I compound is a kinases inhibitor, the kinases of protein kinase such as cyclin dependent (cdks), for example cdc2 (cdk1), cdk2, cdk3, cdk4, cdk5, cdk6, cdk7 and cdk8.Therefore, the present invention comprises the purposes of The compounds of this invention in treatment, prevention and/or control cancer, inflammation or inflammatory diseases, sacroiliitis, Alzheimer disease and cardiovascular disorder.In a more particular embodiment, the present invention also comprises the purposes of The compounds of this invention in treatment, prevention and/or control proliferative disease or its symptom.The present invention also comprises the purposes of The compounds of this invention in treatment or prevention part and systemic fungal infection.
More particularly, formula I compound is used for the treatment of various cancers, includes, but is not limited to:
-cancer comprises bladder cancer, breast cancer, colorectal carcinoma, kidney, liver cancer, lung cancer, ovum
Nest cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma;
The hemopoietic tumour of-lymphatic system, comprise acute lymphoblastic leukemia,
B-cell lymphoma and Burkett lymphoma;
The hemopoietic tumour of-myeloid lineage comprises acute and chronic lymphocytic leukemia
With the promyelocyte leukemia;
-come from mesochymal tumour, comprise fibrosarcoma and rhabdosarcoma; And
-other tumour, comprise melanoma, spermocytoma, teratoma, osteosarcoma,
Neuroblastoma and neurospongioma.
Be not subjected to any theoretical limit, because the keying action of cdks in regulating hyperplasia, usually inhibitor can play a role as the reversible cytostatics, it is any lysis of feature that described cytostatics can be used for treating with unusual hyperplasia, as the restenosis after neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, revascularization or the vascular surgery, hypertrophic cicatrix formation, inflammatory bowel, transplant rejection, vasculogenesis and endotoxin shock.
The present invention also comprises the purposes of The compounds of this invention in treatment Alzheimer disease, because nearest discovery prompting cdk5 relevant with the phosphorylation of Protein tau (J.Biochem, 117,741-749 (1995)).
The present invention comprises that also The compounds of this invention is as other protein kinase, purposes as the inhibitor of protein kinase C, her2, raf1, MEK1, map kinase, EGF acceptor, pdgf receptor, IGF acceptor, PI3 kinases, wee1 kinases, Src, Ab1, VEGF and lck, therefore, can treat effectively and other protein kinase diseases associated.
The present invention comprises that also The compounds of this invention brings out or suppresses apoptosis, promptly a kind of purposes of critical physiological process of cell death in normal development and stable state.The change of apoptosis approach can cause multiple human body diseases.Formula I compound is as the conditioning agent of apoptosis, can be used for treating the human body diseases of multiple in apoptosis, distort (abberation), comprise that cancer (especially, but be not limited to follicular lymphoma, the p53 cancer of suddenling change, mammary gland, the hormone-dependent tumor of prostate gland and ovary and lesion precancerous (as the familial adenomatous polyp), virus infection (comprises, but be not limited to simplexvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune disorder (comprises, but be not limited to systemic lupus, lupus erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel, autoimmune diabetes), neurodegenerative disorders (comprises, but be not limited to the Alzheimer disease, the dementia relevant with AIDS, the Parkinson disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellum degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, the local asphyxia damage relevant with myocardial infarction, apoplexy and reperfusion injury, heart disorder, atherosclerosis, the hepatopathy that toxin brings out or alcohol brings out, hemopathy (comprises, but be not limited to chronic anaemia and aplastic anemia), the degenerative disorders of flesh and Skeletal system (including, but are not limited to osteoporosis and sacroiliitis), to acetylsalicylic acid sinusitis paranasal sinusitis hypersensitive (rhinosinusitis), cystic fibrosis of the pancreas, multiple sclerosis, ephrosis and cancer pain.
In another embodiment, the present invention includes the method that suppresses cdk in the cell.More particularly, the present invention includes by one or more The compounds of this invention of Mammals that needs this inhibition and treat or prevention and cdk regulate the method for diseases associated.
The present invention includes Mammals, especially people's treatment.
In addition, The compounds of this invention can be used for treating the alopecia of chemotherapy induction, the thrombopenia of chemotherapy induction, the oligoleukocythemia or the mucocitis of chemotherapy induction.In the alopecia of treatment chemotherapy induction, preferably with medicament forms as gel, solution, dispersion liquid or paste, the local The compounds of this invention that uses.
The compounds of this invention can with known anti-cancer therapies (as radiation therapy) or with cytostatics and cytotoxic agent combined utilization (before,, afterwards, comprise the circulation medication), these cytostatics and cytotoxic agent include, but are not limited to microtubule stabilizer, microtubule cracking agent, alkylating agent, metabolic antagonist, epidophyllotoxin, antitumor enzyme, topoisomerase enzyme inhibitor, Procarbazine, mitoxantrone, platinum coordination complex, biological respinse modifier, growth inhibitor, hormone/hormone antagonist therapeutical agent, hemopoieticgrowth factor etc.
Can comprise with the classification that formula I compound of the present invention is united the carcinostatic agent of use, but be not limited to anthracycline class medicine, Changchun flower drugs, mitomycin, bleomycin class, cytotoxicity ucleosides, taxane class, epothilone class, discodermolide, pteridine class medicine, diynenes, aromatics enzyme (aromatase) inhibitor and podophyllotoxin.The concrete member of these classifications comprises; taxol for example; docetaxel; 7-O-methylthiomethyl taxol (United States Patent (USP) 5; 646; open in 176); 3 '-tertiary butyl-3 '-N-tertbutyloxycarbonyl-4-deacetylation-3 '-Tuo phenyl-3 '-N-takes off benzoyl-4-O-methoxycarbonyl-taxol (USSN 60/179 that on February 3rd, 2000 submitted to; open in 965, it is attached among the present invention as a reference); C-4 methyl carbonic taxol (open among the WO 94/14787); epothilone A; epothilone B; epothilone C; epothilone D; desoxyepothilone A; desoxyepothilone B; [1S-[1R *, 3R *(E), 7R *, 10S *, 11R *, 12R *, 16S *]]-7,11-dihydroxyl-8,8,10,12,16-pentamethyl--3-[1-methyl-2-(2-methyl-4-thiazolyl) vinyl]-4-azepine-17-oxabicyclo [14.1.0] heptadecane-5,9-diketone (open among the WO 99/02514), [1S-[1R *, 3R *(E), 7R *, 10S *, 11R *, 12R *, 16S *]]-3-[2-[2-(amino methyl)-4-thiazolyl]-the 1-methyl ethylene]-7,11-dihydroxyl-8,8,10,12,16-pentamethyl--4,17-two oxa-dicyclo [14.1.0] heptadecanes-5,9-diketone (the USSN 09/506 that on February 17th, 2000 submitted to, open in 481, it is attached among the present invention as a reference), Dx, Carubicin, daunorubicin, aminopterin, methotrexate, methopterin-A, dichioromethotrexate, ametycin, porfiromycin, 5 FU 5 fluorouracil, Ismipur, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivative are as Etoposide, phosphoric acid Etoposide or teniposide, melphalan, vinealeucoblastine(VLB), vincristine(VCR), leurosidine, vindesine, leurosine etc.Can include, but are not limited to other useful carcinostatic agent that compound of the present invention is united use estramustine, cis-platinum, carboplatin, endoxan, bleomycin, tamoxifen, ifosfamide, melphalan, altretamine, plug for group, cytosine arabinoside, idatrexate, trimetrexate, Dacarbazine, altheine enzyme, camptothecine, CPT-11, holder pool for may, ara-C, bicalutamide, flutamide, Leuprolide, pyrido benzindole derivative, Interferon, rabbit, interleukin etc.In addition, The compounds of this invention can with as U.S.6, those farnesyl protein transferase inhibitors described in 011,029; Anti-angiogenic agent (as angiostatin and endostatin); Kinase inhibitor (as the her2 specific antibody); And p53 trans-activation conditioning agent is united use.
When being formulated as fixed dosage, this mixed preparation is used the The compounds of this invention of the following stated dosage range and the forms of pharmacologically active agents in other approval dosage range.When being unsuitable for making mixed preparation, can use formula I compound and known carcinostatic agent or cytotoxic agent in turn with any order.
The present invention also provides the medicinal compositions that comprises The compounds of this invention and pharmaceutically acceptable carrier.It should be noted that in the content of medicinal compositions of the present invention, The compounds of this invention or formula I compound refer to free alkali, enantiomorph, diastereomer, solvate and pharmacy acceptable salt.The example of these pharmacy acceptable salts includes, but are not limited to mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.Also comprise the salt that forms with other organic and mineral acid such as hydroxyl methylsulfonic acid, acetate, Phenylsulfonic acid, toluenesulphonic acids, and various other salt, as nitrate, phosphoric acid salt, borate, benzoate, ascorbate salt, salicylate etc.These salt comprise racemic modification form and enantiomorph and diastereomer (as D-tartrate and L-tartrate).In addition, can with basic metal, as sodium, potassium and lithium; Alkaline-earth metal is as calcium and magnesium; Organic bases is as dicyclohexylamine, tributylamine and pyridine etc.; Amino acid forms the pharmacy acceptable salt of formula I compound as arginine, Methionin etc.
Medicinal compositions of the present invention also comprises one or more pharmaceutically acceptable other carrier, vehicle or thinner, includes but not limited to the component as alum, stablizer, antiseptic-germicide, buffer reagent, tinting material, correctives etc.Compound of the present invention and composition can oral or parenterai administrations, comprise intravenously, intramuscular, intraperitoneal, subcutaneous, rectum and topical routes.
For oral application, can give compound of the present invention and composition with for example tablet or Capsule form or with solution or suspension agent form.For the tablet of oral application, carrier commonly used comprises lactose and W-Gum, generally can add lubricant such as Magnesium Stearate.When with the capsule form oral administration, useful carrier comprises lactose and W-Gum.When with water-soluble suspensoid oral administration, generally add emulsifying agent and/or suspension agent.In addition, can in oral compositions, add sweeting agent and/or correctives.For intramuscular, intraperitoneal, subcutaneous and intravenous administration, adopt the sterile solution of described active ingredient usually, and should suitably regulate and cushion the pH of described solution.For intravenous administration, ooze for making described preparation etc., should control the total concn of solute.
Per daily dose during the The compounds of this invention administration of human generally determines that by the doctor in charge its dosage generally changes according to the severity of patient's age, body weight, route of administration and individual reaction and patient's symptom.The about 0.001-100mg of amount preferred every day of every kg body weight of the formula I compound of the present invention of administration of human, more preferably from about 0.01-50mg, most preferably from about 0.1-20mg.
Cdc2/ cell periodic protein B 1 kinase assays
Be attached in the histone h1 by monitoring 32P measures cdc2/ cell periodic protein B 1 kinase whose activity.This reactant is expressed the baculovirus of GST-cdc2, baculovirus, 1 μ g histone HI (BoehringerMannheim), the 0.2 μ Ci that 75ng expresses GST-cell periodic protein B 1 by 50ng 32The kinase buffer liquid of P γ-ATP and 25 μ MATP (50mM Tris, pH8.0,10mM MgCl 2, 1mM EGTA, 0.5mM DTT) form.Hatched this reactant 30 minutes at 30 ℃, making final concentration by adding then is that 15% cold trichoroacetic acid(TCA) (TCA) stops hatching, and hatches on ice 20 minutes.With a Packard Filtermate Universal harvesting device with this reactant collect the single filter plate of GF/C (unifilter plates) (Packard) on, and on a Packard Topcount 96 hole liquid scintillation counters to filter thing counting (Marshak, D.R., Vanderberg, M.T., Bae, Y.S., Yu, I.J., J.of CellularBiochemistry, 45,391-400 (1991) merges to herein by reference).
Cdk2/ cyclin E kinase assays
Be attached in the retinoblastoma protein by monitoring 32P measures the kinase whose activity of cdk2/ cyclin E.This reactant is expressed the bacteriogenic GST-retinoblastoma protein of baculovirus, 500ng (aa776-928), the 0.2 μ Ci of GST-cdk2/ cyclin E by 2.5ng 32The kinase buffer liquid of P γ-ATP and 25 μ MATP (50mM Hepes, pH8.0,10mM MgCl 2, 5mM EGTA, 2mM DTT) form.Hatched this reactant 30 minutes at 30 ℃, making final concentration by adding then is that 15% cold trichoroacetic acid(TCA) (TCA) stops hatching and hatching 20 minutes on ice.With a Packard Filtermate Universal harvesting device this reactant is collected on the single filter plate of GF/C (Packard), and on a PackardTopCount 96 hole liquid scintillation counters, the filter thing is counted.
Cdk4/ cyclin D1 kinase activity
Be attached in the retinoblastoma protein by monitoring 32P measures the kinase whose activity of cdk4/ cyclin D1.This reactant is expressed the baculovirus of GST-cdk4, the bacteriogenic GST-retinoblastoma protein of cyclin D1,500ng (aa 776-928), the 0.2 μ Ci that the 282ng bacterial expression is the S-mark by 165ng 32The kinase buffer liquid of P γ-ATP and 25 μ MATP (50mM Hepes, pH8.0,10mM MgCl 2, 5mM EGTA, 2mM DTT) form.Hatched this reactant 1 hour at 30 ℃, making final concentration by adding then is that 15% cold trichoroacetic acid(TCA) (TCA) stops hatching and hatching 20 minutes on ice.With a Packard Filtermate Universal harvesting device this reactant is collected on the single filter plate of GF/C (Packard), and on a Packard TopCount 96 hole liquid scintillation counters, the filter thing is counted (Coleman, K.G., Wautlet, B.S., Morissey, D, Mulheron, J.G., Sedman, S., Brinkley, P., Price, S., Wedster, K.R. (1997) .Identification ofCDK4 Sequences involved in cyclin D, and p16 binding.J.Biol.Chem. 272, 30:18869-18874 is attached to herein by reference).
For being easier to understand the present invention, mainly particular compound of the present invention is described with following embodiment.Scope of the present invention is not subjected to the qualification of these embodiment, but scope of the present invention comprises all themes that define in the claim.Embodiment 1:5-[5-(tertiary butyl)-2-oxazolyl methyl sulfo-]-2-(azacycloalkanoyl) amino-
The preparation of thiazole hydrochloride A. the preparation of α-azido--Pinacolone
Figure A0181336700352
In 1.785L acetone, (1eq) (93.9g, 1.4444mol 1.3eq) mix with sodiumazide for 199.07g, 1.1115mol with alpha-brominated-Pinacolone.Under the room temperature, reaction solution was stirred 27.5 hours.The slurry that obtains is filtered, with acetone (3 * 150mL) washings.The filtrate vacuum concentration is obtained 154.3g (98.4%) title compound.HPLC:83.85%, 2.57 minutes (Phenomenex Inc., Torrance, CA, 5 μ m C18 posts, 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).B. the preparation of bromination α-hexamethylene tetraammonia base-Pinacolone
Figure A0181336700353
In 2L acetone, (1eq) (154.21g, 1.1mol 1.1eq) mix, then at room temperature, logical N with vulkacit H for 179g, 1mol with alpha-brominated-Pinacolone 2Reaction solution was stirred 26 hours down.The slurry that obtains is filtered, and (spend the night 50 ℃ of following vacuum-dryings, obtains the title compound that 330g (100%) contains 7% vulkacit H by 3 * 50mL) washings with ether for filter cake.HPLC R.T.=0.17 minute (Phenomenex Inc., 5 μ m C18 posts, 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).C. the preparation of alpha-amino group-Pinacolone hydrochloride
Figure A0181336700361
In 4.2L methyl alcohol, (128.5g, 0.911mol) Pd/C with dense HCl of 77.1mL and 15.42g 10% mixes with α-azido--Pinacolone.Under hydrogen, reaction mixture was stirred 1.5 hours.Remove by filter catalyzer.Solvent distillation obtains wet solid.(2 * 500mL) azeotropic are removed residuary water with Virahol.Add t-butyl methyl ether (300mL), the slurry that obtains is stirred, filter, (3 * 100mL) washings, drying obtains 131.0g (95.5%) title compound with t-butyl methyl ether.D. the preparation of alpha-amino group-Pinacolone hydrochloride
In 2L ethanol, (1eq) (439mL, 5.26mol 4.2eq) mix with the 12N HCl aqueous solution for 400g, 1.254mol with bromination α-hexamethylene tetraammonia base-Pinacolone.Under 75 ℃, reaction solution was stirred 1 hour, be cooled to room temperature then, the slurry that obtains is filtered, vacuum concentrated filtrate adds Virahol.Again this solution is filtered.Adding the 1.2L ether again is precipitated out required material from solution.Filtration product, (2 * 300mL) washings are spent the night 50 ℃ of following vacuum-dryings, obtain 184.1g (97%) title compound with ether.E. the preparation of α-N-(2-chloro acetylamino)-Pinacolone
At-5 ℃, logical N 2Down, (130.96g, 0.8637mol 1eq) are dissolved in 3.025L CH with the title compound of part D 2Cl 2In.(301mL, 2.16mol 2.5eq), then add chloro-acetyl chloride (75.7mL, 0.450mol, 175mL CH 1.1eq) to add triethylamine 2Cl 2Solution.Under-5 ℃ to-10 ℃, the slurry that obtains was stirred 2 hours.Add entry (1.575L), then add the dense HCl of 175mL.Organic phase is used the HCl solution washing of 1.75L 10% for the second time, use the 500mL water washing then.Organic phase is through Na 2SO 4Drying, vacuum concentration obtain 155.26g (93.8%) title compound.HPLC R.T.=2.27 minute (Phenomenex Inc., 5 μ m C18 posts, 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).F.5-the preparation of (tertiary butyl)-2-oxazolyl methyl chloride
Figure A0181336700372
At logical N 2Down, (1eq) (262mL, 2.8109mol 3eq) mix with phosphorus oxychloride for 180.13g, 0.9398mol with the title compound of part E.Under 105 ℃, with reactant heating 1 hour, then mixture is cooled to room temperature, ice quencher with 1.3kg.(1L 2 * 500mL) extracts then with ethyl acetate with water.With the saturated NaHCO of organic extract liquid 3The aqueous solution (strip for several times with ethyl acetate again by 4 * 1L) washings.Merge organic phase, use saturated NaHCO in turn 3The aqueous solution (500mL) and the saturated NaCl aqueous solution (300mL) washing are through MgSO 4Drying, vacuum concentration obtains brown oil.Under 100 ℃, high vacuum,, obtain 155.92g (96%) title compound with this crude product distillation.HPLC R.T.=3.62 minute (Phenomenex Inc., 5 μ m C18 posts, 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).
Perhaps; title compound (10.0g with part E; 52.17mmol; 50mL tetrahydrofuran (THF) (THF) solution 1eq) and hydroxide (methoxycarbonyl sulfamyl)-three second ammonium (Burgess reagent; 105.70mmol; 2.03eq, in 100mL THF, produce on the spot by 9.2mL chloro sulfonyl isocyanate, 4.4mL methyl alcohol and 14.8mL triethylamine) mix.With reaction solution be heated to 45 ℃ following 1.5 hours.After being cooled to room temperature, with reaction solution water (50mL) quencher.Separate organic layer, use saturated NaHCO 3(2 * 50mL) and water (50mL) washing, through MgSO 4Drying is filtered by little silica gel plug.Removing desolvates obtains oily matter, and it is dissolved in the mixture of 15mL heptane and 90mL t-butyl methyl ether, use then 0.2N HCl (2 * 25mL), saturated brine (25mL) washing, dry (MgSO 4).Filter and remove to desolvate and obtain the 10.9g title compound.G.5-the preparation of (tertiary butyl)-2-oxazolyl methylthiourea hydrochloride
Figure A0181336700381
At logical N 2Down, (1.02eq) (0.76g, 9.98mmol 1eq) mix in the 10mL straight alcohol with thiocarbamide for 1.77g, 10.2mmol with the title compound of part F.Reaction solution was heated 1.5 hours under refluxing.Mixture is cooled to room temperature and vacuum concentration.The crude product that obtains is ground with t-butyl methyl ether, obtain 2.32g (93%) title compound.HPLC R.T.=2.05 minute (Phenomenex Inc., 5 μ m C18 posts, 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring); 1H NMR (d 6-DMSO): δ 9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H), 1.24 (s, 9H).H.5-[5-(tertiary butyl)-2-oxazolyl methyl sulfo-]-preparation of thiazolamine
With the title compound of part G (1.25g, 5mmol, 1eq) join NaOH (3.0g, 75mmol, 15eq), (50mg, 0.086mmol is in mixed solution 0.017eq) for water (10mL), toluene (10mL) and sulfuric acid TBuA.(1.70g, 5mmol 1eq), at room temperature stir reactant 14.5 hours to add 5-bromo-thiazolamine hydrobromate.This mixed solution dilute with water is also used ethyl acetate extraction 2 times, and (4 * 10mL) extractions are through MgSO with the organic extract liquid water 4Drying, vacuum concentration obtain 1.1g (82%) title compound.HPLC 86.3%, 2.75 minute (Phenomenex Inc., 5 μ m C18 posts, 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out that contains 0.2% phosphoric acid 4 minutes, 4mL/ minute, in the 220nm monitoring); 1H NMR (CDCl 3): δ 6.97 (s, 1H), 6.59 (s, 1H), 5.40 (br s, 2H), 3.89 (s, 2H), 1.27 (s, 9H).I.5-[5-(tertiary butyl)-2-oxazolyl methyl sulfo-]-the 2-[(N-tertbutyloxycarbonyl)-azacycloalkanoyl] preparation of aminothiazole
Figure A0181336700392
(9.6g 35.6mmol) is dissolved in N, dinethylformamide (36mL) and CH with the title compound of section H 2Cl 2(100mL), to wherein adding 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (13.8g, 72mmol, 2eq), N-tertbutyloxycarbonyl-nitrogen heterocyclic alkanoic acid (12.6g, 55mmol, 1.5eq) and 4-(dimethylamino) pyridine (2g, 16mmol, 0.45eq).After at room temperature stirring 3.5 hours, it is muddy that this clarifying reaction mixture becomes.Add entry (300mL) and ethyl acetate (200mL), remove by filter the precipitation that obtains.Filtrate is used ethyl acetate extraction, and organic extract liquid is through MgSO 4Drying, vacuum concentration obtains yellow solid.Itself and the precipitation that is obtained by filtration are merged.Described solid was seethed with excitement 20 minutes in the mixed solution of ethanol, acetone and water, filter, with the washing of ethanol/water mixed solution, drying obtains 16.6g (97%) title compound.J.5-[5-(tertiary butyl)-2-oxazolyl methyl sulfo-]-preparation of 2-(azacycloalkanoyl) amino-thiazolyl-hydrochloride
Figure A0181336700401
The title compound (16.6g) of part I is dissolved in the CH of 150mL 2Cl 2In, be added dropwise to trifluoroacetic acid (30mL), under the room temperature mixed solution was stirred 2 hours.With this reaction solution vacuum concentration, water (300mL) dilution is cooled off in ice, makes with sodium hydroxide to be alkalescence, with the solid filtering that obtains, with ethanol, water and recrystallizing methanol, obtains 11.2g (83%) title compound, is yellow solid.By in the methanol solution of this material of 7g, adding the 18mL 1N HCl aqueous solution, can obtain the hydrochloride of white solid.MS:381[M+H] +HPLC:100%, 3.12 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 2:(±)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiophene
The azoles base]-preparation of 3-piperidyl urea A. (±)-N-tertbutyloxycarbonyl-nipecotic acid
(1.3g, 10mmol 1eq) mix with 10mL diox, 2mL acetonitrile, 10mL water and the 10mL 1N NaOH aqueous solution (1eq) with nipecotic acid.(3.3g, 15mmol 1.5eq), under the room temperature spend the night the reaction mixture stirring to add tert-Butyl dicarbonate.The reaction mixture vacuum concentration to remove organic solvent, is added 10% aqueous citric acid solution.(3 * 100mL) extract with ethyl acetate with this mixed solution.Organic extract liquid is through Na 2SO 4Drying, by filtered through silica gel, vacuum concentration.Crude product with ethyl acetate and hexane recrystallization, is obtained 2.2g (96%) (±)-N-tertbutyloxycarbonyl-nipecotic acid, be white solid.B. (±)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-(N-tertbutyloxycarbonyl)-3-piperidyl urea
With 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (383mg, 2mmol, 2eq) join 2-amino-5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-] thiazole (270mg, 1mmol, 1eq), N-tertbutyloxycarbonyl-nipecotic acid (344mg, 1.5mmol, 1.5eq), 4-(dimethylamino) pyridine (61mg, 0.5mmol, 0.5eq), N, dinethylformamide (1mL) and CH 2Cl 2In the mixed solution (6ml).Under the room temperature reaction mixture was stirred 1.3 hours.(0.28mL, 2mmol 2eq), stir reaction mixture 1 hour to add triethylamine.Add N-tertbutyloxycarbonyl-nipecotic acid (340mg), triethylamine (0.28mL) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (380mg) again.After 1 hour, do not find further to change.Add 4-(dimethylamino) pyridine, N again, dinethylformamide, triethylamine and raw material acid under the room temperature are spent the night the reactant stirring.With the saturated NaHCO of the dark solution that obtains 3CH is used in aqueous solution dilution 2Cl 2Extraction.With the organic extract liquid drying, vacuum concentration, through the flash chromatography on silica gel purifying, hexane solution gradient elution with the 50-100% ethyl acetate, obtain (±)-N-[5-[[[5-(1 of 397mg (83%), the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-(N-tertbutyloxycarbonyl)-3-piperidyl urea, be yellow glass shape solid.C. (±)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 3-piperidyl urea
Figure A0181336700421
With (±)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-(355mg, 0.74mmol 1eq) are dissolved in the CH of 3mL to (N-tertbutyloxycarbonyl)-3-piperidyl urea 2Cl 2In.Add trifluoroacetic acid (3mL), under the room temperature mixed solution was stirred 20 minutes.With this reaction mixture vacuum concentration, use saturated NaHCO 3Aqueous solution neutralization.With the mixed solution ethyl acetate extraction that obtains.Organic extract liquid is through Na 2SO 4Drying, vacuum concentration is used re-crystallizing in ethyl acetate, obtains (±)-N-[5-[[[5-(1, the 1-the dimethyl ethyl)-2-oxazolyl of 142mg (50%)] methyl] sulfo-]-the 2-thiazolyl]-the 3-piperidyl urea, be white solid.MS:381[M+H] +HPLC:100%, 3.15 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 3:(±)-1-(2, the 3-dihydroxypropyl)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazole
Base] methyl] sulfo-]-preparation of 2-thiazolyl 1-4-piperidyl urea
With N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea (66mg, 0.17mmol, 1eq) with Glycerose (69mg, 0.77mmol, 4.5eq), sodium triacetoxy borohydride (163mg, 0.77mmol, 4.5eq) and 1,2-ethylene dichloride (4mL) mixes.Under the room temperature suspension that obtains was stirred 4 hours.Add methyl alcohol (1mL), under the room temperature reaction mixture stirring is spent the night, vacuum concentration, through preparation HPLC purifying, obtain (±)-1-(2 of 69mg (59%), the 3-dihydroxypropyl)-and N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea, be white solid.MS:455[M+H] +HPLC:100%, 3.06 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 4:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] the sulfo-1,2-thiazole
Base]-preparation of 1-(1-methylethyl)-4-piperidyl urea A.1-(1-methylethyl)-4-piperidine ethyl formate
Figure A0181336700441
With different piperidine ethyl formate (3.2g, 20mmol, 1eq) with acetone (5.8g, 100mmol, 5eq), (2.5eq) and 1,2-ethylene dichloride (200mL) mixes sodium triacetoxy borohydride for 10.5g, 50mmol.Under the room temperature reaction mixture was stirred 72 hours.Add saturated NaHCO 3The aqueous solution is then with this mixed solution CH 2Cl 2Extraction.With the organic extract liquid drying, filter by silicagel pad, vacuum concentration obtains 1-(1-the methylethyl)-4-piperidine ethyl formate of 3.72g (93%), is colourless liquid.B.1-(1-methylethyl)-4-piperidine carboxylic acid
Figure A0181336700442
In 70mL water and 44mL alcoholic acid mixed solution, (1eq) (10.4g, 33mmol 1.8eq) mix with hydrated barta eight hydrates for 3.6g, 18mmol with 1-(1-methylethyl)-4-piperidine ethyl formate.Mixed solution was heated 1.3 hours down at 60 ℃.With the reaction mixture vacuum concentration, with the dilution of 70mL water.Gradation adds volatile salt, and (6.9g, 87mmol 4.8eq), under the room temperature spend the night the reaction mixture stirring.Mixed solution by diatomite filtration, is concentrated, and lyophilize obtains 1-(1-the methylethyl)-4-piperidine carboxylic acid of 3.1g (100%), is white solid.C.N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-1-(1-methylethyl)-4-piperidyl urea
With 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.0g, 5.2mmol, 2eq) join 2-amino-5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-] thiazole (0.7g, 2.6mmol, 1eq), 1-(1-methylethyl)-4-piperidine carboxylic acid (0.78g, 3.9mmol, 1.5eq), 4-(dimethylamino) pyridine (0.16g, 1.3mmol, 0.5eq), N, dinethylformamide (2.6mL) and CH 2Cl 2In the mixed solution (7.8ml).Under the room temperature reaction mixture was stirred 1 hour, with the dilution of 30ml water, with ethyl acetate (2 * 70mL) extractions.Organic extract liquid is through Na 2SO 4Drying, vacuum concentration is through the flash chromatography on silica gel purifying, with the ethyl acetate solution gradient elution of 5-10% triethylamine.With product second alcohol and water recrystallization, obtain N-[5-[[[5-(1, the 1-the dimethyl ethyl)-2-oxazolyl of 0.93g (85%)] methyl] sulfo-]-the 2-thiazolyl]-1-(1-methylethyl)-4-piperidyl urea, be yellow solid.MS:423[M+H] +HPLC:100%, 3.15 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 5:1-cyclopropyl-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-
The 2-thiazolyl]-preparation of 4-piperidyl urea A.1-cyclopropyl-4-piperidine carboxylic acid
Figure A0181336700462
(1eq) (100mL methanol solution 5eq) mixes for 8.7g, 50mmol with ((1-oxyethyl group cyclopropyl) oxygen base) trimethyl silane for 1.57g, 10mmol with different piperidine ethyl formate.Add acetate (5.7mL, 100mmol, 10eq) and molecular sieve.After following 30 minutes of the room temperature, add sodium triacetoxy borohydride (2.5g, 40mmol, 4eq), with reaction mixture 65 ℃ of following heated overnight.With this reaction mixture cooling, add Na 2CO 3(20g).Under the room temperature this mixed solution was stirred 2 hours, pass through diatomite filtration.With this diatomite methanol wash.Merging filtrate, vacuum concentration, dilute with water is used ethyl acetate extraction.With the organic extract liquid drying, filter by silicagel pad, vacuum concentration obtains the 2.4g colourless liquid.In 38mL water and 24mL alcoholic acid mixed solution, with product and hydrated barta eight hydrates (5.7g, 18mmol, 1.8eq) merging.Mixed solution was heated 1 hour down at 60 ℃.With the reaction mixture vacuum concentration, with the dilution of 38mL water.Gradation adds volatile salt (3.8g), under the room temperature reaction solution is stirred 2 hours.Mixture by diatomite filtration, is washed with water.Filtrate is washed with ethyl acetate.Concentrate water, obtain 1-cyclopropyl-4-piperidine carboxylic acid of 1.56g (92%), be the water absorbability white solid.B.1-cyclopropyl-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea
With 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.0g, 5.2mmol, 2eq) join 2-amino-5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-] thiazole (0.7g, 2.6mmol, 1eq), 1-cyclopropyl-4-piperidine carboxylic acid (0.77g, 3.9mmol, 1.5eq), 4-(dimethylamino) pyridine (0.16g, 1.3mmol, 0.5eq), N, dinethylformamide (2.6mL) and CH 2Cl 2In the mixed solution (7.8ml).Under the room temperature reaction mixture was stirred 1 hour, water (30ml) dilution is with ethyl acetate (2 * 70mL) extractions.The organic extract liquid that merges is through anhydrous sodium sulfate drying, and vacuum concentration is through the flash chromatography on silica gel purifying, with the ethyl acetate solution gradient elution of 0-10% triethylamine.With product ethyl acetate and hexane crystallization, obtain 1-cyclopropyl-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl of 0.7g (65%)] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea, be white crystal.MS:421[M+H] +HPLC:100%, 3.13 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 6:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-preparation of 1-(2-hydroxyethyl)-4-piperidyl urea
Figure A0181336700472
A.N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-1-(2-dimethyl tertiary butyl silyl oxygen base ethyl)-4-piperidyl urea
With N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-(1.4g, 3.68mmol 1eq) are dissolved in the N of 30ml, in the tetrahydrofuran (THF) of dinethylformamide and 100ml to the 4-piperidyl urea.Add 2-(bromine oxethyl)-tertiary butyl dimethylsilane (0.79mL, 3.68mmol, 1eq) and NaHCO 3, under 50 ℃, reaction mixture was stirred 23 hours.Add 2-(bromine oxethyl)-tertiary butyl dimethylsilane (0.9mL) again, under 50 ℃, reaction mixture was stirred 22 hours, cooling, vacuum concentration, water (25mL) dilution.The aqueous mixture that obtains is extracted with ethyl acetate (50mL).Organic extract liquid is through Na 2SO 4Dry, vacuum concentration, through the flash chromatography on silica gel purifying, ethyl acetate solution gradient elution with the 0-5% triethylamine, obtain the N-[5-[[[5-(1 of 1.7g (84%), the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-1-(2-dimethyl-tertiary butyl silyl oxygen base ethyl)-4-piperidyl urea, be yellow solid.MS:539[M+H] +HPLC:98%, 4.01 minutes (YMC S5ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).B.N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidyl urea
Figure A0181336700482
With N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-1-(2-dimethyl-tertiary butyl silyl oxygen base ethyl)-4-piperidyl urea (1.45g, 2.7mmol, 1eq) be dissolved in the acetonitrile of 100ml, (48% aqueous solution 2.5mL) mixes with the HF aqueous solution.Under the room temperature reaction mixture was stirred 4 hours.Add the 2.5ml HF aqueous solution again, reaction mixture is stirred spend the night.Add ethyl acetate (100mL) and saturated NaHCO 3The aqueous solution (50mL).Add solid NaHCO again 3, make mixed solution be alkalescence.(2 * 50mL) extract with ethyl acetate with mixed solution.Organic extract liquid is through Na 2SO 4Drying is filtered vacuum concentration by silicagel pad.With white solid ethanol and the water crystallization that obtains, obtain N-[5-[[[5-(1, the 1-the dimethyl ethyl)-2-oxazolyl of 1.6g (59%)] methyl] sulfo-]-the 2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidyl urea, be white solid.MS:425[M+H] +HPLC:100%, 3.05 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 7:(R)-and N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiophene
The azoles base]-preparation of 3-piperidine formyl amine hydrochlorate A. (R)-and (S)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-(N-tertbutyloxycarbonyl)-3-piperidyl urea
Figure A0181336700501
With 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (3.8g, 20mmol, 2eq) join 2-amino-5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-] thiazole (2.7g, 10mmol, 1eq), N-tertbutyloxycarbonyl-nipecotic acid (3.4g, 1.5mmol, 1.5eq), N, dinethylformamide (10mL) and CH 2Cl 2In the mixed solution (30ml).Under the room temperature reaction mixture was stirred 4 hours.The dark solution that vacuum concentration obtains, water (90ml) dilution is with ethyl acetate (100mL, 2 * 75mL) extractions then.Organic extract liquid is through Na 2CO 3Drying, vacuum concentration through the flash chromatography on silica gel purifying, with the hexane solution gradient elution of 50-100% ethyl acetate, obtains the yellow solid of 3.8g (79%).Through chirality HPLC (Chiral Pak AD 5 * 50cm20 μ: elutriant 10% (aqueous isopropanol of 0.1% triethylamine) hexane solution; 45mL/ minute, detect at 254nm, load the 5ml aqueous isopropanol of 300mg) enantiomer separation, obtain two kinds of optically pure isomers: 1.65g R isomer and 1.65g S isomer.B. (R)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-3-piperidine formyl amine hydrochlorate
(1.65g, 3.43mmol 1eq) are dissolved in the CH of 10ml with (R) isomer of part A 2Cl 2In.Add trifluoroacetic acid (6mL), under the room temperature with this mixed solution stirred for several hour.With the reaction mixture vacuum concentration, use saturated NaHCO 3Aqueous solution neutralization.The mixed solution and the ethyl acetate that obtain were stirred 1 hour.Organic extract liquid is through Na 2SO 4Drying, vacuum concentration obtains yellow solid.This solid is dissolved in the methyl alcohol, adds the 1N HCl aqueous solution of 1eq.With the solution lyophilize that obtains, obtain (R)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl of 1g (77%)] methyl] sulfo-]-the 2-thiazolyl]-3-piperidine formyl amine hydrochlorate, be yellow solid.MS:381[M+H] +HPLC:100%, 3.14 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 8:(S)-and N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-preparation of 3-piperidine formyl amine hydrochlorate
Figure A0181336700512
(1.65g, 3.43mmol 1eq) are dissolved in the CH of 10ml with (S) isomer of embodiment 7 part A 2Cl 2In.Add trifluoroacetic acid (6mL), under the room temperature with this mixed solution stirred for several hour.With the reaction solution vacuum concentration, use saturated NaHCO 3Aqueous solution neutralization.The mixed solution and the ethyl acetate that obtain were stirred 1 hour.Organic extract liquid is through Na 2SO 4Drying, vacuum concentration obtains yellow solid.This solid is dissolved in the methyl alcohol, adds the 1N HCl aqueous solution of 1eq.With the solution lyophilize that obtains, obtain (S)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl of 0.918g (70%)] methyl] sulfo-]-the 2-thiazolyl]-3-piperidine formyl amine hydrochlorate, be yellow solid.MS:381[M+H] +HPLC:100%, 3.15 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 9: cis-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulphur
Generation]-the 2-thiazolyl] cyclohexyl carboxamide hydrochloride and trans-4-amino-N-[5-
[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-2-thiazolyl] hexamethylene
The preparation of base carboxamide hydrochloride
Figure A0181336700521
A.4-(t-butoxycarbonyl amino) naphthenic acid
Figure A0181336700522
Under the room temperature, adding total amount in the solution of 2.86g (20mmol) 4-aminocyclohexane formic acid in the acetonitrile of the NaOH of the 40mL 0.5M aqueous solution, 20mL De diox and 4mL is the tBOC acid anhydrides of 6.5g (30mmol).After 20 hours, add the aqueous citric acid solution of 100mL ethyl acetate and 100mL10%.Separate the water layer that forms, with the ethyl acetate extraction of three parts of 50mL.Merge organic phase, dry (sodium sulfate), vacuum concentration obtains crude product 4-(t-butoxycarbonyl amino) naphthenic acid of 6.0g (125%), is colorless oil, and it places after fixing.B.4-(t-butoxycarbonyl amino)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl methane amide
Under the room temperature, to 5g crude product 4-(t-butoxycarbonyl amino) naphthenic acid and 3.50g (13mmol) 2-amino-5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-] thiazole is at 13mLN, dinethylformamide and 36mL CH 2Cl 2In solution in add 5.0g (26mmol) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride.The reaction mixture stirring is spent the night, with the dilution of 100ml water.Separate water layer, with the ethyl acetate extraction of two parts of 150mL.With the organic phase drying (sodium sulfate) that merges, filter by silicagel pad.Vacuum concentrated filtrate obtains orange solids.With crude product recrystallization (95% ethanol), obtain 4-(t-butoxycarbonyl amino)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl methane amide, be yellow solid.And, obtain other 4-(t-butoxycarbonyl amino)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl with the mother liquor vacuum concentration] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl methane amide, be brown solid.C: cis-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] cyclohexyl carboxamide hydrochloride and trans-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl carboxamide hydrochloride
Figure A0181336700541
Under the room temperature, to 4-(t-butoxycarbonyl amino)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] add the 5ml trifluoroacetic acid in the suspension of cyclohexyl methane amide (being derived from part B mother liquor) in the 15mL methylene dichloride.Reaction mixture was stirred 2 hours, and vacuum concentration is to remove volatile matter then.With the residue dilute with water, with the alkalization of the NaOH aqueous solution, then with the aqueous solution ethyl acetate extraction that obtains.Organic extract liquid drying (sodium sulfate) with merging obtains crude product cis/trans product.This crude product is through flash chromatography purifying (Merck silica gel, 25 * 3cm, 1: 9 Isopropylamine/ethyl acetate, 1: 2: 7 methyl alcohol/Isopropylamine/ethyl acetate then), and obtaining cis-isomeride and 0.50g that 0.74g is a yellow solid is the trans-isomer(ide) of brown solid.This cis-isomeride is dissolved in the methyl alcohol, adds the 0.34mL 5N HCl aqueous solution then.With this solution for vacuum concentration, with ether washing, dilute with water, lyophilize obtains the cis that 0.80g is a yellow solid-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl carboxamide hydrochloride.MS:395[M+H] +HPLC-HI:98%, 3.17 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).This trans-isomer(ide) is dissolved in the methyl alcohol, adds the 0.24mL 5N HCl aqueous solution then.With this solution for vacuum concentration, with ether washing, dilute with water, lyophilize obtains trans-4-amino-N-[5-[[[5-that 0.54g is an orange solids (1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl carboxamide hydrochloride.MS:395[M+H] +HPLC-HI:96%, 3.22 minutes (YMC S5 ODS post 4.6 * 50mm, with the 10-90% methanol aqueous solution wash-out 4 minutes that contains 0.2% phosphoric acid, 4mL/ minute, in the 220nm monitoring).Embodiment 10:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea one hydrochloride
Figure A0181336700551
In ice bath refrigerative 40mL ethanol solution, be added dropwise to Acetyl Chloride 98Min. (0.28mL, 3.9mmol).Reaction mixture is warmed to room temperature with 30 minutes, then under agitation, disposable adding N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-(1.50g, 3.94mmol 1eq), obtain thick slurry to the 4-piperidyl urea.Add entry (about 4mL) to homogeneous phase, vacuum concentration obtains the crude product light yellow solid.With this crude product recrystallization (the EtOH aqueous solution), obtain title compound (70%), be white solid, mp 256-258 ℃.C 17H 24N 4O 2S 2The analytical calculation value of HCl: C, 48.96; H, 6.04; N, 13.43; S, 15.38; Cl, 8.50.Measured value: C, 48.69; H, 5.99; N, 13.24; S, 15.27; Cl, 8.31.Embodiment 11:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea one hydrobromate
Figure A0181336700561
In the EtOH of 1M HBr (0.5mL) solution, add N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-(190mg, 0.5mmol 1eq), are cooled to-40 ℃ and spend the night the 4-piperidyl urea then.Collect the solid precipitation that forms with Buchner funnel, use absolute ethanol washing,, obtain title compound (72%), be tenderly white toner end, mp 235-237 ℃ then 100 ℃ of following vacuum-dryings.C 17H 24N 4O 2S 2The analytical calculation value of HBr: C, 44.24; H, 5.46; N, 12.14; S, 13.89; Br, 17.31.Measured value: C, 44.16; H, 5.40; N, 12.12; S, 13.91; Br, 17.70.Embodiment 12:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea 0.5-L-tartrate
Figure A0181336700562
To N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea (1.75g, 4.6mmol) the warm solution of anhydrous EtOH (70mL) in add L-tartrate (345mg, 2.3mmol, anhydrous EtOH (5ml) solution 0.5eq).Begin to form precipitation after several minutes.Under the room temperature this mixed solution was placed 4 hours, collected solid precipitation with Buchner funnel then, use absolute ethanol washing,, obtain title compound (94%), be pale yellow crystals, mp 234-236 ℃ 85 ℃ of following vacuum-dryings 24 hours.C 17H 24N 4O 2S 20.5-L-tartaric analytical calculation value: C, 50.09; H, 5.97; N, 12.29; S, 14.07.Measured value: C, 49.85; H, 5.90; N, 12.12; S, 13.75.Embodiment 13:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea 0.5-D-tartrate
To N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea (1.00g, 2.63mmol) the warm solution of anhydrous EtOH (40mL) in add D-tartrate (198mg, 1.32mmol, anhydrous EtOH (4ml) solution 0.5eq).Begin to form precipitation after several minutes.Under the room temperature this mixed solution was placed 18 hours, collected solid precipitation with Buchner funnel then, use absolute ethanol washing,, obtain title compound (73%), be white solid, mp 232-233 ℃ 65 ℃ of following vacuum-dryings 6 hours.C 17H 24N 4O 2S 20.5-D-tartaric analytical calculation value: C, 50.09; H, 5.97; N, 12.29; S, 14.07.Measured value: C, 49.75; H, 5.81; N, 12.04; S, 13.37.Embodiment 14:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea 0.5-fumarate
Figure A0181336700572
To N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea (1.75g, 4.6mmol) the warm solution of anhydrous EtOH (100mL) in add fumaric acid (276mg, 2.3mmol, anhydrous EtOH (5ml) solution 0.5eq).Begin to form precipitation after 10 minutes.Under the room temperature this mixed solution was placed 2 hours, placed 16 hours down at 5 ℃ then.Collect the solid precipitation that forms with Buchner funnel, use absolute ethanol washing,, obtain title compound (84%), be white solid, mp 206-207 ℃ 65 ℃ of following vacuum-dryings 24 hours.C 17H 24N 4O 2S 20.5 the analytical calculation value of fumaric acid: C, 52.04; H, 5.98; N, 12.77; S, 14.62.Measured value: C, 51.74; H, 5.76; N, 12.57; S, 14.19.Recrystallization (the 95%EtOH aqueous solution) obtains comprising the title compound of 1 mole of EtOH (83%), is big clear crystal, mp 212-214 ℃.C 17H 24N 4O 2S 20.5 the analytical calculation value of fumaric acid EtOH: C, 52.05; H, 6.66; N, 11.56; S, 13.23.Measured value: C, 52.03; H, 6.06; N, 11.50; S, 12.99.Embodiment 15:N-[5-[[[5-1, the 1-dimethyl ethyl)-the 2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea 0.5-succinate
Figure A0181336700581
To N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea (50mg, 0.13mmol) the warm solution of anhydrous EtOH (2mL) in add succsinic acid (7.7mg, 0.065mmol, anhydrous EtOH (0.25ml) solution 0.5eq).Begin to form precipitation after 10 minutes.Under the room temperature this mixed solution was placed 1 hour, used the Buchner funnel collecting precipitation then, use absolute ethanol washing,, obtain title compound (70%), be white solid, mp 190-192 ℃ 100 ℃ of following vacuum-dryings 24 hours.C 17H 24N 4O 2S 20.5 succsinic acid 0.46H 2The analytical calculation value of O: C, 50.96; H, 6.28; N, 12.51; S, 14.32.Measured value: C, 50.96; H, 6.20; N, 12.49; S, 14.23.Embodiment 16:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] the sulfo-1,2-thiazole
Base 1-4-piperidyl urea 0.5-vitriol
To N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea (50mg, 0.13mmol) the warm solution of anhydrous EtOH (2mL) in add the 1M aqueous sulfuric acid (0.065mL, 0.065mmol, 0.5eq).Almost form precipitation immediately.With this mixed solution be cooled to 5 ℃ 2 hours, use the Buchner funnel collecting precipitation then, use absolute ethanol washing, 100 ℃ of following vacuum-dryings 24 hours, obtain title compound (79%), be white solid, mp 256-258 ℃.C 17H 24N 4O 2S 20.5H 2SO 40.68H 2The analytical calculation value of O: C, 46.22; H, 6.01; N, 12.68; S, 18.14.Measured value: C, 46.21; H, 5.95; N, 12.71; S, 18.23.Embodiment 17:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea 0.5-Citrate trianion
To N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea (50mg, add in the warm solution of anhydrous EtOH (2mL) 0.13mmol) citric acid solution (8.3mg, 0.043mmol, 0.33eq).With this solution be cooled to 5 ℃ 18 hours, use the Buchner funnel collecting precipitation then, use absolute ethanol washing, 100 ℃ of following vacuum-dryings 24 hours, obtain title compound (68%), be white solid, mp 214-216 ℃.C 17H 24N 4O 2S 20.5 citric acid 0.10H 2The analytical calculation value of O: C, 50.21; H, 5.94; N, 11.71; S, 13.40.Measured value: C, 50.21; H, 6.01; N, 11.83; S, 13.44.Embodiment 18:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea mesylate
To N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea (100mg, add in Virahol 0.26mmol) (0.75mL) slurry methylsulfonic acid (0.017mL, 0.26mmol, 1eq).This slurry is heated to 70 ℃ to obtain settled solution, adds methyl tertiary butyl ether (1.5mL) then.Form precipitation in 15 minutes.Under 55 ℃, the mixed solution that obtains was stirred 2 hours, at room temperature stirred then 14 hours.Filter and collect the precipitation that forms,, obtain title compound (85%), be colourless powder, 105 ℃ of mp 50 ℃ of following vacuum-dryings 14 hours.C 17H 24N 4O 2S 2MSAH 2The analytical calculation value of O: C, 43.70; H, 6.11; N, 11.32; S, 19.44.Measured value: C, 43.53; H, 6.14; N, 11.15; S, 19.15.Embodiment 19:N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazole
Base]-4-piperidyl urea 0.5-D, L MALIC ACID salt
Figure A0181336700602
Under 70 ℃, to N-[5-[[[5-(1, the 1-dimethyl ethyl)-and the 2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea (100mg, 0.26mmol) Virahol (0.80mL) solution in slowly add D, L MALIC ACID (35mmg, 0.13mmol, Virahol 0.5eq) (0.3mL) solution.Form precipitation immediately.Under 55 ℃, the mixture that obtains was stirred 2 hours, at room temperature stirred then 14 hours.Filter collecting precipitation,, obtain title compound (75%), be colourless powder, 216 ℃ of mp 50 ℃ of following vacuum-dryings 14 hours.C 17H 24N 4O 2S 20.5-C 4H 6O 5H 2The analytical calculation value of O: C, 50.98; H, 6.08; N, 12.51; S, 14.32.Measured value: C, 50.55; H, 6.17; N, 12.29; S, 14.05.

Claims (59)

1. the compound of a formula I and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt: Wherein: R is an alkyl; R 1It is hydrogen or alkyl; X is NR 2Or CHNR 2R 3R 2And R 3Independently be the cycloalkyl of alkyl, cycloalkyl or the replacement of hydrogen, alkyl, replacement separately; And n is 0,1,2 or 3.
2. the compound of claim 1, wherein: R is an alkyl; R 1Be hydrogen; X is NR 2Or CHNR 2R 3R 2And R 3Independently be the alkyl or cycloalkyl of hydrogen, alkyl, replacement separately; And n is 2.
3. the compound of the claim 1 of formula Ia and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt:
Figure A0181336700031
R wherein 2It is the alkyl or cycloalkyl of hydrogen, alkyl, replacement.
4. the compound of the claim 1 of formula Ib and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt: R wherein 2It is the alkyl or cycloalkyl of hydrogen, alkyl, replacement.
5. the compound of the claim 1 of formula Ic and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt:
Figure A0181336700033
R wherein 2And R 3Independently be the alkyl or cycloalkyl of hydrogen, alkyl, replacement separately.
6. be selected from compound and its enantiomorph, diastereomer, solvate and the pharmacy acceptable salt of the claim 1 of following compounds:
N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea;
(±)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 3-piperidyl urea;
(±)-1-(2, the 3-dihydroxypropyl)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea;
N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-1-(1-methylethyl)-4-piperidyl urea;
1-cyclopropyl-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 4-piperidyl urea;
N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidyl urea;
(R)-and N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 3-piperidyl urea;
(S)-and N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-the 3-piperidyl urea;
Cis-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl methane amide; With
Trans-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] the cyclohexyl methane amide.
(7.N-[5-[[[5-1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-4-piperidyl urea and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt.
8. (±)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-3-piperidyl urea and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt.
9. (R)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-3-piperidyl urea and pharmacy acceptable salt thereof.
10. (S)-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl]-3-piperidyl urea and pharmacy acceptable salt thereof.
11. cis-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] cyclohexyl methane amide and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt.
12. trans-4-amino-N-[5-[[[5-(1, the 1-dimethyl ethyl)-2-oxazolyl] methyl] sulfo-]-the 2-thiazolyl] cyclohexyl methane amide and its enantiomorph, diastereomer, solvate and pharmacy acceptable salt.
13. a medicinal compositions, it comprises the compound and the pharmaceutically acceptable carrier of claim 1.
14. a medicinal compositions, it comprises compound and the pharmaceutically acceptable carrier and the carcinostatic agent of the claim 1 that is formulated as fixed dosage.
15. a medicinal compositions, it comprises compound and the pharmaceutically acceptable carrier and the p53 trans-activation conditioning agent of the claim 1 that is formulated as fixed dosage.
16. a method of regulating apoptosis, this method comprise that the Mammals that needs this adjusting effectively regulates the compound of claim 1 of the amount of apoptosis.
17. the kinase whose method of arrestin, this method comprise the compound of the claim 1 of the kinase whose amount of the effective arrestin of the Mammals that needs this inhibition.
18. a kinase whose method that suppresses cyclin dependent, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the kinase whose amount of cyclin dependent.
19. a method that suppresses cdc2 (cdk1), this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdc2.
20. a method that suppresses cdk2, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdk2.
21. a method that suppresses cdk3, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdk3.
22. a method that suppresses cdk4, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdk4.
23. a method that suppresses cdk5, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdk5.
24. a method that suppresses cdk6, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdk6.
25. a method that suppresses cdk7, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdk7.
26. a method that suppresses cdk8, this method comprise that the Mammals that needs this inhibition effectively suppresses the compound of claim 1 of the amount of cdk8.
27. a method for the treatment of proliferative disease, this method comprise the composition of the claim 13 of the Mammals treatment significant quantity that needs this treatment.
28. a treatment method for cancer, this method comprise the composition of the claim 13 of the Mammals treatment significant quantity that needs this treatment.
29. a method for the treatment of inflammation, inflammatory bowel or transplant rejection, this method comprise the composition of the claim 13 of the Mammals treatment significant quantity that needs this treatment.
30. the method for a treatment of arthritis, this method comprise the composition of the claim 13 of the Mammals treatment significant quantity that needs this treatment.
31. a method for the treatment of proliferative disease, this method comprise the composition of the claim 14 of the Mammals treatment significant quantity that needs this treatment.
32. a treatment method for cancer, this method comprise the composition of the claim 14 of the Mammals treatment significant quantity that needs this treatment.
33. a method for the treatment of proliferative disease, this method comprise the composition of the claim 15 of the Mammals treatment significant quantity that needs this treatment.
34. a treatment method for cancer, this method comprise the composition of the claim 15 of the Mammals treatment significant quantity that needs this treatment.
35. the method for the disease that a treatment is relevant with the kinases of cyclin dependent, this method comprises the compound of at least a claim 1 that needs the patient of this treatment significant quantity.
36. treat the alopecia of chemotherapy induction, the thrombopenia of chemotherapy induction, the oligoleukocythemia of chemotherapy induction or the method for mucocitis for one kind, this method comprises the compound of the claim 1 of the Mammals treatment significant quantity that needs this treatment.
37. the compound of claim 1, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
38. the compound of claim 2, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
39. the compound of claim 3, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
40. the compound of claim 4, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
41. the compound of claim 5, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
42. the compound of claim 6, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
43. the compound of claim 7, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
44. the compound of claim 8, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
45. the compound of claim 9, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
46. the compound of claim 10, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
47. the compound of claim 11, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
48. the compound of claim 12, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
49. the medicinal compositions of claim 13, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
50. the medicinal compositions of claim 14, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
51. the medicinal compositions of claim 15, wherein said pharmacy acceptable salt are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
52. the method for claim 17, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
53. the method for claim 18, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
54. the method for claim 20, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
55. the method for claim 27, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
56. the method for claim 28, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
57. the method for claim 31, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
58. the method for claim 32, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
59. the method for claim 36, the described pharmacy acceptable salt of wherein said compound are selected from mixture, tartrate, fumarate, succinate, maleate, Citrate trianion, mesylate, bromate and the iodate of hydrochloride, dihydrochloride, vitriol, trifluoroacetate, trifluoroacetate and hydrochloride.
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