CN100584842C - Thiazole derivative - Google Patents

Thiazole derivative Download PDF

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CN100584842C
CN100584842C CN200580014266A CN200580014266A CN100584842C CN 100584842 C CN100584842 C CN 100584842C CN 200580014266 A CN200580014266 A CN 200580014266A CN 200580014266 A CN200580014266 A CN 200580014266A CN 100584842 C CN100584842 C CN 100584842C
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CN1956979A (en
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佐藤正和
松永结子
浅沼肇
天田英明
小网武史
高山哲男
薮内哲也
盐泽史康
片贝博典
梅宫广树
池田明子
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Taisho Pharmaceutical Co Ltd
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Abstract

A thiazolylimidazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, and an ALK5 inhibitor, an therapeutic agent for alopecia or a hair growth agent having the above as an active ingredient, wherein: X 1 and X 2 are different from each other and represent a sulfur atom or a carbon atom; R 1 represents a phenyl group; a substituted phenyl group; a phenyl group condensed with a hetero aromatic ring; a pyridyl group; or a pyridyl group condensed with a hetero aromatic ring; R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms, an alkoxy group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms, or a hydroxyalkyl group having 1 to 6 carbon atoms, A represents a group which is represented by the formula (II). The present invention provides an inhibitory substance against ALK5 which is a TGF- type I receptor and provides a hair growth stimulant or a hair growth agent based on its novel activities.

Description

Thiazole derivative
Technical field
The present invention relates to a kind of I receptor activin receptor sample kinases 5 (ALK5) inhibiting compound is arranged TGF-β.The invention still further relates to a kind of hair follicle cell growth stimulant, a kind of hair growth promoter and a kind of educating and send out agent, they all contain the depressant of functions of ALK5 as activeconstituents.
Background technology
Transforming growth factor-beta (TGF-β), activator, BMP etc. are the molecules that belongs to the TGF-beta superfamily.TGF-β has two kinds of different frizzled receptors (I type and II type), all has the serine/threonine kinase district in their cells separately.In case TGF-β and receptors bind, I receptor be by II receptor phosphorylation, thereby be activated, thereby pass the signal along in the nucleus by Smad2/3 approach or TAB1/TAK1 approach.
Obviously, TGF-β has a lot of physiological actions, as everyone knows, one of them is that TGF-β has the proteinic generation by promote constituting extracellular matrix and restrains it and decompose extracellular matrix is built up characteristic (Massague in tissue, Annu Rev Cell Biol 6,597-641 (1990)).Therefore, the activation of the lasting excessive generation of TGF-β and signal transduction system may cause multiple fibrotic disease.For example, with regard to kidney, the fibrosis or the closely related (Okuda etc. of glomerulonephritis that occur in known TGF-β and the ephrosis such as glomerulonephritis or diabetic nephropathy, J Clin Invest 86,453-462 (1990), Border etc., Nature 346,371-374 (1990)).The liver aspect, known TGF-β can impel the generation of the extracellular matrix of nonparenchymal cell, and then causes hepatic fibrosis and liver cirrhosis (Barnard etc., Biochim Biophys Acta1032,79-87 (1990)).In addition, to build up be one of cause of disease of refractory diseases such as relevant pulmonary fibrosis of substantive fibrosis or proliferative vitreoretinopathy to the extracellular matrix that causes of TGF-β superfunction.
According to report, the ALK5 inhibitor can be built up (Grygielko etc. by the extracellular matrix that retardance TGF-β/the Smad signal suppresses to be caused by TGF-β, J Am Soc Nephrol 13 (AbstIss), 5A (F-FC022), therefore 2002), think that this inhibitor can be used as the medicine of relevant various diseases such as the fibrosis of treatment or prevention kidney, liver or lung etc.
On the other hand, known TGF-β has significant inhibition growth effect (Soma etc., J InvestDermatol 111,948-954 (1998)) to various kinds of cell such as epithelial cell, vascular endothelial cell, hemocyte or lymphocytes.As for hair follicle, have and report that the overexpression of TGF-β has caused that the growth of hair follicle cell is prevented/transferred and died, thereby make hair cycle by the anagen become telogen, so TGF-β is obvious and closely related (the Foitzik etc. of development of baldness, FASEB J 14,752-760 (2000)).
But existing research does not throw a flood of light on the growth of hair follicle cell and prevents/transfer to die and mainly caused by the signal pathway of which bar from the TGF-beta receptor.Therefore still do not report and utilize ALK5 inhibitor retardance TGF-β/Smad signal to treat/prevent the effect of baldness.
Though WO00/61576A, WO01/72737A, WO01/62756A, WO02/40468A, WO03/87304A etc. have reported that I receptor activin receptor sample kinases 5 (ALK5) to TGF-β have inhibiting material, do not relate to thiazolyl imidazolium compounds of the present invention.
In addition, though WO99/03837A, WO96/03387A, WO03/62215A, WO01/85723A, WO01/44203A, JP2001163861A, JP07112975A, U.S. Patent No. 6,770,663, WO04/005264A etc. wide coverage with the imidazolium compounds of The compounds of this invention structural similitude, these compounds are to the restraining effect of activin receptor sample kinases 5 (ALK5) report not still.
Summary of the invention
The objective of the invention is provides a kind of hair growth promoter or educates and send out an agent on the basis of the inhibitory substance of the I receptor ALK5 that a kind of TGF-β is provided and new role thereof.
Be based upon the various findings that solve the technical problem and carry out, the contriver finds that the ALK5 inhibitor can suppress the hair follicle cell growth that TGF-β causes and prevent, found that simultaneously certain class can suppress the new compound of ALK5, found that further the preparation above-claimed cpd is to realize intermediate of the present invention.
The invention provides thiazole derivative or its pharmacy acceptable salt of a kind of formula (I) expression:
Figure C20058001426600071
Wherein,
X 1And X 2Different, expression sulphur atom or carbon atom;
R 1The expression phenyl; Be selected from halogen atom, had the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, hydroxyl, have the phenyl alkoxyl group of 7-12 carbon atom and have the phenyl of 1-5 group replacement of the alkylamino of 1-6 carbon atom; With contain at least 1 heteroatomic 5-7 membered aromatic heterocycle or nonaromatic heterocycles condensed phenyl that is selected from nitrogen, oxygen and sulphur; Pyridyl; Quinolyl; Isoquinolyl; Or with contain at least 1 heteroatomic 5-7 membered aromatic heterocycle condensed pyridyl that is selected from nitrogen, oxygen and sulphur;
R 2Expression hydrogen atom, halogen atom, have 1-6 carbon atom alkyl, by the alkyl with 1-6 carbon atom of 1-5 halogen atom replacement, have 1-6 carbon atom alkoxyl group, have the alkyloyl of 1-6 carbon atom or have the hydroxyalkyl of 1-5 carbon atom; With
A is a formula
Figure C20058001426600081
The group of expression, wherein:
R 3The expression hydrogen atom; Hydroxyl; Alkyl with 1-6 carbon atom; Phenylalkyl with 7-12 carbon atom; Or by hydroxyl, have 1-6 carbon atom alkoxyl group, had the phenylalkyl with 7-12 carbon atom of the alkoxyl group replacement with 1-6 carbon atom of alkoxyl group that the alkoxyl group of 1-6 carbon atom replaces or alkylamino replacement with 1-6 carbon atom with 1-6 carbon atom;
R 4The expression phenyl; Quilt is selected from halogen atom, is had the phenyl of 1-5 group replacement of the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, formamyl and cyano group; Hydrogen atom; Alkyl with 1-12 carbon atom; Thiazolinyl with 2-12 carbon atom; Cycloalkyl with 3-7 carbon atom; Had the alkyl that alkoxyl group, the hydroxyl of 1-6 carbon atom, the alkoxyl phenyl alkoxyl group with 8-12 carbon atom, phthalimido, tosyloxy or morpholino replace with 1-12 carbon atom; By the alkyl with 1-6 carbon atom of 1-5 halogen atom replacement; The cycloalkyl that is replaced by the oxo base with 3-9 carbon atom; THP trtrahydropyranyl; The 4-piperidyl; Had the alkyl of 1-6 carbon atom or the piperidyl that tertbutyloxycarbonyl replaces; Hexanaphthene spiral shell-2 '-(1,3-dioxane amyl group) (シ Network ロ ヘ キ サ Application ス ピ ロ-2 '-(1,3-ジ オ キ ソ ラ ニ Le) base); Pyrrolidin-2-one-5-base; Formula-Y 1-Z 1-NR 5-Z 2-Y 2-R 6The group of expression, wherein:
Y 1And Y 2Identical or different, expression singly-bound or have the alkylidene group of 1-12 carbon atom;
R 5Expression hydrogen atom or have the alkyl of 1-12 carbon atom;
Z 1And Z 2Identical or different, the expression singly-bound; Alkylidene group with 1-7 carbon atom;-CO-;-CO 2-;-SO 2-or-OCO-; And
R 6Expression has the cycloalkyl of 3-7 carbon atom; By the alkyl with 1-6 carbon atom of 1-3 halogen atom replacement; Thiazolinyl with 2-6 carbon atom; Alkynyl with 2-6 carbon atom; Amino; Be selected from the amino of 1-2 group replacement of the alkyl with 1-6 carbon atom, cycloalkyl and tertbutyloxycarbonyl with 3-7 carbon atom; Piperidino-(1-position only); Piperidyl; Piperidyl with alkyl replacement of 1-6 carbon atom; Pyrrolidyl; Piperazinyl; Piperazinyl with alkyl replacement of 1-6 carbon atom; Morpholino; Hydroxyl; Alkoxyl group with 1-6 carbon atom; By hydroxyl or had the alkoxyl group that the alkoxyl group of 1-6 carbon atom replaces with 1-6 carbon atom; Trimethylene oxide-2-base; Tetrahydrofuran base; THP trtrahydropyranyl; Hydrogen atom; Phenyl; Phenyl with alkoxyl group replacement of 1-4 carbon atom; Or when being connected, nitrogen-atoms in the said structure formula becomes the group of ring; Or formula-Y 3-CO-R 41The group of expression, wherein:
Y 3Expression singly-bound or have the alkylidene group of 1-7 carbon atom;
R 41The expression hydroxyl; Alkoxyl group with 1-6 carbon atom; Piperidino-(1-position only); Had 1-6 carbon atom alkyl, have the morpholino alkyl of 5-10 carbon atom or have piperazine-1-base that the alkylamino alkyl of 2-14 carbon atom replaces; Or morpholino.
Another aspect of the present invention be a kind of contain above-mentioned thiazolyl imdazole derivatives or its pharmaceutically acceptable salt be the ALK5 inhibitor of activeconstituents.
In addition, another aspect of the present invention is to be useful on the agent of educating that the material that suppresses the relevant ALK5 function of TGF-signal transduction is an activeconstituents a kind of containing, and therefore the invention provides a kind of mechanism of action and is different from traditional novel concept of sending out agent of educating.
In addition, another aspect of the present invention is the intermediate of the compound of a kind of preparation formula (I) expression, and the A in the wherein above-mentioned formula (I) partly is a following radicals,
Figure C20058001426600091
X wherein 3Expression hydrogen atom or halogen atom.
The preferred R of compound of formula of the present invention (I) expression 2For hydrogen atom, halogen atom, have the alkyl of 1-6 carbon atom or the compound of the alkyl that replaced by 1-5 halogen atom with 1-6 carbon atom.R more preferably 2Be the alkyl with 1-6 carbon atom or the compound of trifluoromethyl.More preferably R 2Compound for methyl or trifluoromethyl.
R 1For with contain at least 1 and be selected from the heteroatomic 5-7 fragrant heterocycle of unit of nitrogen, oxygen and sulphur or the compound of nonaromatic heterocycles condensed phenyl is a preferred compound.X 1Be sulphur atom and X 2For the compound of carbon atom also is a preferred compound.
Term used herein " is educated and is sent out agent " though refer to be used to induce the medicine or the accurate medicine of hair tonic, the long head of promotion or anti-loss disease, answers the meaning of this term of broad understanding, should not be limited to certain meaning.For example when the present invention educates an agent as medicine,,, the present invention is not limited only to this but educating the application of sending out agent applicable to improving or preventing alopecia areata or male pattern baldness.
The present invention discloses, and the material that suppresses the ALK5 function can be used as and prevents hypothyroid activator of hair follicle cell or prophylactic agent.
The material that suppresses the ALK5 function is meant the material that suppresses Samd2 and Samd3 generation phosphorylation when TGF-beta receptor outgoing signal, for example compound that claim 1-6 of the present invention exemplified.Because the above-mentioned mechanism of action can suppress the prevent growth result of TGF-β to hair follicle cell (being the hair-keratin founder cell) fully, this material be expected to tradition educate send out agent the symptom that can not improve or prevent produce effect.
In addition, this material and other hair growth promoter or educate to send out and be expected to produce synergistic effect when an agent is used in combination with other effect.
Though according to its character, the present invention educates an agent can carry out administration with different dosage and formulation, in view of the necessity of successive administration, preferred external application or oral this material.The dosage that can not represent all substances with unified numerical value.But for compound 1-202 and 228-249, carry out the outer time spent with lotion, ointment or gelifying agent, its using dosage should reach about 0.0001-10 weight %, preferred 0.001-5 weight %, more preferably 0.001-1 weight %; Perhaps, carry out when oral with powder or capsule, its using dosage should reach about 1-100mg/kg.Can obtain above-mentioned preparation by common preparation technique.
The present invention educates that to send out an agent be not to be defined in certain formulation especially, but with regard to external preparation, contain ALK5 inhibitor (as the arbitrary compound among compound 1-202 and the 228-249) for activeconstituents to educate the preferred form of sending out agent be water-soluble composition.Usually, the various additives of using always in the time of when this type of water-soluble composition of preparation, can using preparation medicine, quasi drug or makeup (wetting Agent for Printing Inks, thickening material, sanitas, antioxidant, spices and tinting material etc.).The present invention educates an agent and can be made into Wo 2008069000 and hair-washing compositions such as shampoo or hair conditioner such as hair medicine, hair oil, hair mousse or hair jelly, perhaps makes ointment etc.
The present invention educates the formulation of sending out agent when being liquid preparation, and ALK5 inhibitor (as the arbitrary compound among compound 1-202 and the 228-249) fully mixes to prepare the medicine of forms such as sterile water solution, non-aqueous solution, suspension, liposome or emulsion with suitable normal saline solutions such as damping fluid, salt solution, Ringer's solution or locke's solution such as pure water, phosphoric acid buffer, ethanol, glycerine and tensio-active agent commonly used.Said preparation is with the form local topical of scalp with liquid preparation.In this case, liquid preparation can directly spread upon on the scalp, also can spray by injection nozzle.
The present invention educates the formulation of sending out agent when being semi-solid preparation, ALK5 inhibitor (as the arbitrary compound among compound 1-202 and the 228-249) can mix with fat, fatty oil, lanolin, Vaseline, paraffin, wax, ointment, resin, plastics, glycols, higher alcohols, glycerine, water, emulsifying agent, suspensoid etc., then with externally applied medicine form local applications such as ointment or cremes.
The present invention educates the formulation of sending out agent when being solid preparation, and ALK5 inhibitor (as the arbitrary compound among compound 1-202 and the 228-249) suitably mixes to prepare externally applied agents such as powder or pulvis with suitable additive.Can or be suspended in the solid preparation that is applied to scalp in the solvent with preparation with the inhibitor dissolving when perhaps, needing.
In addition, for oral medication, ALK5 inhibitor (as the arbitrary compound among compound 1-202 and the 228-249) can mix with pharmaceutically acceptable carrier (vehicle, tackiness agent, disintegrating agent, correctives, perfume compound and emulsifying agent etc.), thinner, solubilizing agent etc., and resulting medicine is prepared into preferred dosage form such as tablet, capsule, granule, powder, syrup, suspensoid, solution by routine techniques.
In the present invention, halogen atom is fluorine atom, chlorine atom, bromine atoms or iodine atom.
Alkyl with 1-6 carbon atom refers to contain the saturated alkyl of the straight or branched of 1-6 carbon atom, comprises for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl and n-hexyl.
Alkoxyl group with 1-6 carbon atom refers to contain the straight or branched alkoxyl group of 1-6 carbon atom, comprises for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy and hexyloxy.
Phenyl alkoxyl group with 7-12 carbon atom refers to contain the phenyl alkoxyl group of 7-12 carbon atom, comprises for example benzyloxy and benzene oxyethyl group.
Alkylamino with 1-6 carbon atom refers to contain the alkyl monosubstituted amino or the dialkyl amido of the straight or branched of 1-6 carbon atom, comprises for example methylamino-, ethylamino and N, the N-dimethylamino.
With contain at least 1 heteroatomic 5-7 membered aromatic heterocycle or nonaromatic heterocycles condensed phenyl that is selected from nitrogen, oxygen and sulphur and comprise for example benzothiazolyl, benzoxazolyl and benzo (1,3) dioxolyl.
With contain at least 1 heteroatomic 5-7 membered aromatic heterocycle condensed pyridyl that is selected from nitrogen, oxygen and sulphur and comprise for example Pyrazolopyridine base, imidazopyridyl and Triazolopyridine base.
Alkyloyl with 1-6 carbon atom refers to contain the straight or branched alkyloyl of 1-6 carbon atom, comprises for example formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, caproyl and valeryl.
Hydroxyalkyl with 1-5 carbon atom refers to contain the straight or branched hydroxyalkyl of 1-5 carbon atom, comprises for example methylol, 1-hydroxyethyl and 2-hydroxyethyl.
Phenylalkyl with 7-12 carbon atom refers to contain the phenylalkyl of 7-12 carbon atom, comprises for example benzyl and styroyl.
Alkyl with 1-12 carbon atom refers to contain the saturated alkyl of the straight or branched of 1-12 carbon atom, comprises for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, 1-ethyl-propyl group, n-hexyl and dodecyl.
Thiazolinyl with 2-12 carbon atom refers to contain the straight or branched thiazolinyl of 2-12 carbon atom, comprises for example vinyl, 1-propenyl, allyl group, pseudoallyl, butenyl, isobutenyl, hexenyl and dodecenyl succinic.
Cycloalkyl with 3-7 carbon atom refers to contain the cycloalkyl of 3-7 carbon atom, comprises for example cyclopropyl, sec.-propyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkoxyl phenyl alkoxyl group with 8-12 carbon atom refers to the phenyl alkoxyl group that contains 8-12 carbon atom that the phenyl ring alkoxy replaces, and comprises for example 4-methoxyl group benzyloxy base and 4-anisole oxyethyl group.
The cycloalkyl with 3-9 carbon atom that is replaced by the oxo base refers to the cycloalkyl that contains 3-9 carbon atom that replaced by the oxo base comprise for example 4-oxo cyclohexyl on ring.
THP trtrahydropyranyl comprises for example 2-THP trtrahydropyranyl, 3-THP trtrahydropyranyl and 4-THP trtrahydropyranyl.
Alkylidene group with 1-12 carbon atom refers to contain the straight or branched alkylidene group of 1-12 carbon atom, comprises for example methylene radical, ethylidene, trimethylene, tetramethylene, pentamethylene, hexamethylene and ten dimethylenes.
Alkylidene group with 1-7 carbon atom refers to contain the straight or branched alkylidene group of 1-7 carbon atom, comprises for example methylene radical, ethylidene, trimethylene, tetramethylene, pentamethylene, hexamethylene and heptamethylene.
Thiazolinyl with 2-6 carbon atom refers to contain the straight or branched thiazolinyl of 2-6 carbon atom, comprises for example vinyl, 1-propenyl, allyl group, pseudoallyl, butenyl, isobutenyl and hexenyl.
Alkynyl with 2-6 carbon atom refers to contain the straight or branched alkynyl of 2-6 carbon atom, comprises for example ethynyl, 1-proyl and 2-propynyl.
Piperidyl comprises for example 2-piperidyl, 3-piperidyl and 4-piperidyl.
Pyrrolidyl comprises for example 2-pyrrolidyl, 3-pyrrolidyl and 4-pyrrolidyl.
Piperazinyl comprises for example 2-piperazinyl and 3-piperazinyl.
Tetrahydrofuran base comprises for example 2-tetrahydrofuran base and 3-tetrahydrofuran base.
Phenyl with alkoxyl group replacement of 1-4 carbon atom comprises for example 4-p-methoxy-phenyl.
Morpholino alkyl with 5-10 carbon atom refers to the straight or branched alkyl that contains 1-6 carbon atom that replaced by morpholino comprise for example morpholino methyl, 1-morpholino ethyl and 2-morpholino ethyl.
Alkylamino alkyl with 2-14 carbon atom refers to be contained the alkylamino of straight or branched of 1-4 carbon atom or the straight or branched alkyl that contains 1-6 carbon atom that dialkyl amido replaces, comprise for example N-methylamino methyl, N-ethylamino methyl, N, N-dimethylaminomethyl and N, the N-dimethyl aminoethyl.
The alkyl with 1-6 carbon atom that is replaced by 1-5 halogen atom refers to be comprised for example chloromethyl, trifluoromethyl and pentafluoroethyl group by the straight or branched alkyl that contains 1-6 carbon atom of 1-5 halogen atom replacement.
In addition, pharmacy acceptable salt is an alkali metal salt, alkaline earth salt, ammonium salt, alkylammonium salt etc., perhaps is inorganic acid salt or organic acid salt.The example of above-mentioned salt comprises sodium salt, sylvite, calcium salt, ammonium salt, aluminium salt, triethyl ammonium salt, acetate, propionic salt, butyrates, formate, trifluoroacetate, maleate, tartrate, Citrate trianion, stearate, succinate, ethyl succinate salt, Lactobionate, gluconate, gluceptate, benzoate, metilsulfate, ethyl sulfonate, the 2-isethionate, benzene sulfonate, tosilate, lauryl sulfate, malate, aspartate, glutaminate, adipate, cysteine salt, N-acetylcystein salt, hydrochloride, hydrobromate, phosphoric acid salt, vitriol, hydriodate, nicotinate, oxalate, picrate, thiocyanate-, undecylate, the salt of acrylic polymers and the salt of carboxyvinyl polymer.
Preferred forms of the present invention
For example, The compounds of this invention can be synthetic by following method.Close at four (triphenylphosphines) catalyzer such as palladium and alkali in the presence of, the compound of formula (a) expression
Figure C20058001426600141
(R wherein 1Definition with aforementioned definition) and the compound of formula (b) expression
Figure C20058001426600142
(X wherein 1, X 2And R 2Definition with aforementioned definition, X represents halogen atom) The compounds of this invention of coupled reaction synthesis type (c) expression takes place in solvent
Figure C20058001426600143
(X wherein 1, X 2, R 1And R 2Definition with aforementioned definition).
In addition, product compound (c) can be by such as contacting Palladous chloride (II) or method oxidation such as contact potassium permanganate etc. in acetone-buffered soln in dimethyl sulfoxide (DMSO), the The compounds of this invention of synthesis type (d) expression
Figure C20058001426600151
(X wherein 1, X 2, R 1And R 2Definition with aforementioned definition).
In addition, the compound of formula (e) expression
R 4-CHO (e)
(R wherein 4Definition with aforementioned definition) with in solvent, the react The compounds of this invention of synthesis type (f) expression of ammonium acetate
Figure C20058001426600152
(X wherein 1, X 2, R 1, R 2And R 4Definition with aforementioned definition).
Perhaps, The compounds of this invention also can be synthetic by the following method that exemplifies.It is the compound of formula (g) expression
Figure C20058001426600153
(R wherein 3Definition with aforementioned definition) and in solvent, the react The compounds of this invention of synthesis type (f) expression of above-mentioned formula (d) compound and ammonium acetate
Figure C20058001426600161
(X wherein 1, X 2, R 1, R 2And R 4Definition with aforementioned definition).
In addition, The compounds of this invention also can be synthetic by the following method that exemplifies.It is the The compounds of this invention of formula (c) expression
Figure C20058001426600162
(X wherein 1, X 2, R 1And R 2Definition with aforementioned definition) can be by in solvent, carrying out the method synthesis type (h) such as hydration reaction or (i) The compounds of this invention of expression with Mercury bisulfate (II) and vitriolization
Figure C20058001426600163
(X wherein 1, X 2, R 1And R 2Definition with aforementioned definition) or the above-mentioned formula (h) and (i) mixture of compound.Formula (h) compound or (i) compound or formula (h) and (i) mixture of compound can further in aqueous hydrochloric acid, obtain the compound of formula (j) or formula (k) expression with methods such as Sodium Nitrite processing
Figure C20058001426600171
(X wherein 1, X 2, R 1And R 2Definition with aforementioned definition) or the above-mentioned formula (j) and (k) mixture of compound, and further in solvent with the compound of formula (e) expression
R 4-CHO (e)
(R wherein 4Definition with aforementioned definition) and ammonium acetate reaction.With (randomly) reduction resulting composition in solvent such as triethyl-phosphite, obtain the The compounds of this invention of formula (f) expression then.
(X wherein 1, X 2, R 1, R 2And R 4Definition with aforementioned definition).
The compounds of this invention also can be used such as following method synthetic.It is the compound of formula (l) expression
R 1-CH 2CO 2H (l)
(R wherein 1Definition with aforementioned definition) by acyl halide and N; the O-dimethyl hydroxylamine reacts in solvent or in the presence of condensing agent (as 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride) and N; the condensation of O-dimethyl hydroxylamine can obtain the compound that formula (m) is represented
Figure C20058001426600181
(R wherein 1Definition with aforementioned definition), alkali such as the compound of formula (n) expression and n-Butyl Lithium react in solvent then
Figure C20058001426600182
(R wherein 2Definition with aforementioned definition, X ' expression halogen atom or hydrogen atom).The gained negatively charged ion can react with above-mentioned formula (m) compound, the The compounds of this invention of synthesis type (o) expression
Figure C20058001426600183
(R wherein 1And R 2Definition with aforementioned definition).Formula (o) compound can be further in solvent by cupric bromide halogenations such as (II), the The compounds of this invention of synthesis type (p) expression
(R wherein 1And R 2Definition with aforementioned definition, X represents halogen atom).Then, the compound of the compound of formula (p) expression and formula (q) expression
Figure C20058001426600192
(R wherein 4Definition with aforementioned definition) in solvent, react the The compounds of this invention of synthesis type (r) expression
Figure C20058001426600193
(R wherein 1, R 2And R 4Definition with aforementioned definition).In addition, in the presence of alkali such as sodium hydride, the compound of the compound of formula (r) expression and formula (s) expression
R 3-X″ (s)
(R wherein 3Definition with aforementioned definition, X " expression halogen atom) in solvent, react, can synthesize then formula (t) or formula (u) expression The compounds of this invention
Figure C20058001426600201
(R wherein 1, R 2, R 3And R 4Definition with aforementioned definition) or the mixture of above-mentioned formula (t) and formula (u) compound.
The compounds of this invention also can be by exchanging the R in the The compounds of this invention that aforesaid method obtains 1, R 2, R 3And R 4Come synthetic.
The example of employed alkali is in the above-mentioned reaction: an alkali metal salt, as yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, methyl-sulphoxide sodium salt, sodium hydride, sodium amide, tertiary butyl potassium; Amines such as triethylamine, Diisopropylamine, tetramethyleneimine and piperidines; Sodium-acetate and Potassium ethanoate.As for reaction solvent, can be used in and be the inert solvent in the reaction process, comprise water; Alcohols such as methyl alcohol, ethanol, Virahol and the trimethyl carbinol; Ethers such as diox and tetrahydrofuran (THF); Dimethyl formamide, methyl-sulphoxide, pyridine, methylene dichloride, chloroform, acetone and acetate.
Embodiment
Now the present invention is elaborated by embodiment and test example.
Embodiment 1
Figure C20058001426600202
Synthesizing of compound 217
In acetonitrile (50ml) solution of 2-iodo-4-methylthiazol (2.50g), add triethylamine (25ml), four (triphenylphosphines) close palladium (642mg) and 5-ethynyl-benzo (1,3) dioxole (1.79g) under refluxad stirred the mixture 4 hours then.After steaming desolventized, the silica gel flash column chromatography purifying gained residue with using ethyl acetate, chloroform and hexane mixed solvent obtained title compound (2.38g).
1H-NMR(300MHz，CDCl 3)δppm：
2.49(3H，d，J＝0.9Hz)，6.01(2H，s)，6.81(1H，d，J＝8.1Hz)，6.91(1H，d，J＝0.9Hz)，7.01(1H，d，J＝1.6Hz)，7.13(1H，dd，J＝8.1，1.6Hz)mp：111.5-112.0℃
Embodiment 2
Synthesizing of compound 203
Figure C20058001426600211
In methyl-sulphoxide (13ml) solution of compound 217 (1.91g), add Palladous chloride (II) (139mg), under 125 ℃, stirred the mixture 3 hours then.This solution dilutes after-filtration through ethyl acetate, and gained solution is water and salt water washing successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Silica gel flash column chromatography purifying gained residue with using ethyl acetate and hexane mixed solvent obtains title compound (960mg).
1H-NMR(300MHz，CDCl 3)δppm：
2.52(3H，d，J＝0.9Hz)，6.09(2H，s)，6.88(1H，d，J＝8.7Hz)，7.40(1H，d，J＝0.9Hz)，7.48-7.54(2H，m)mp：131.5-132.5℃
Embodiment 3
Synthesizing of compound 8
Figure C20058001426600221
In acetate (40ml) solution of compound 203 (893mg) and 4-cyanobenzaldehyde (510mg), add ammonium acetate (1.50g), under refluxad stirred the mixture then 4 hours.After steaming desolventizes, with ammoniacal liquor this solution that neutralizes, with twice of chloroform extraction.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.With methyl alcohol and chloroform recrystallization gained residue, obtain title compound (575mg).
1H NMR(300MHz，DMSO-d6)δppm：
2.36(3H，s)，6.10(2H，s)，7.06(1H，d，J＝7.6Hz)，7.20(1H，s)，7.55(1H，bd，J＝7.6Hz)，7.73(1H，bs)，7.97(2H，d，J＝8.3Hz)，8.26(2H，d，J＝8.3Hz)，13.05(1H，brs)
Embodiment 4
Synthesizing of compound 9
In the trimethyl carbinol (100ml) solution of compound 8 (575mg), add potassium hydroxide (584mg), under refluxad mixture is stirred then and spend the night.After steaming desolventizes, dilute this solution and wash with water with ethyl acetate.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.With recrystallizing methanol gained residue, obtain title compound (556mg).
1H NMR(300MHz，DMSO-d6)δppm：
2.36(3H，s)，6.10(2H，s)，7.05(1H，d，J＝8.1Hz)，7.18(1H，s)，7.42(1H，brs)，7.58(1H，bd，J＝8.1Hz)，7.75(1H，bs)，7.94-8.08(3H，m)，8.15(2H，d，J＝8.2Hz)，12.87(1H，brs)mp：276.0-277.0℃
Embodiment 5
Synthesizing of compound 213
Figure C20058001426600231
(1) at benzo (1,3) add thionyl chloride (39.6g) and 1 dimethyl formamide in toluene (200ml) solution of dioxole-5-base-acetate (30.0g), under 60 ℃, stirred the mixture 2.5 hours then, after desolventizing, steaming obtains unpurified benzo (1,3) dioxole-5-base-Acetyl Chloride 98Min..Under 0 ℃, at N, add sodium hydroxide (20.0g) water (150ml) solution in toluene (200ml) solution of O-dimethyl hydroxylamine (19.5g) hydrochloride, stirred the mixture 3 hours after adding unpurified benzo (1,3) dioxole-5-base-Acetyl Chloride 98Min. again.Reaction mixture obtains unpurified 2-benzo (1,3) dioxole-5-base-N-methoxyl group-N-methylacetamide (35.4g) with the toluene extraction, through anhydrous magnesium sulfate drying after steaming desolventizes.
1H NMR(200MHz，CDCl 3)δppm：
3.19(3H，s)，3.64(3H，s)，3.67(2H，s)，5.82(2H，s)，6.71-6.83(3H，m)
(2) under-70 ℃, in tetrahydrofuran (THF) (150ml) solution of 4-methylthiazol (8.0g), drip hexane (34ml) solution of 2.6M n-Butyl Lithium, stirred the mixture 30 minutes.Splash into tetrahydrofuran (THF) (20ml) solution of 2-benzo (1,3) dioxole-5-base-N-methoxyl group-N-methylacetamide (20.0g) then, stirred the mixture 1 hour.Add saturated aqueous ammonium chloride in this solution after, use ethyl acetate extraction, organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The silica gel flash column chromatography purifying of gained residue through using ethyl acetate and hexane mixed solvent obtains 2-benzo (1,3) dioxole-5-base-1-(4-methylthiazol-2-yl) ethyl ketone (19.3g)
1H NMR(300MHz，CDCl 3)δppm：
2.56(3H，d，J＝0.9Hz)，4.34(2H，s)，5.93(2H，s)，6.76(1H，d，J＝7.8Hz)，6.80(1H，dd，J＝7.8，1.6Hz)，6.86(1H，d，J＝1.6Hz)，7.25(1H，q，J＝0.9Hz)
(3) at 2-benzo (1,3) add cupric bromide (II) (24.7g) in the ethyl acetate (200ml) of dioxole-5-base-1-(4-methylthiazol-2-yl) ethyl ketone (19.3g) and chloroform (200ml) mixing solutions, under refluxad stirred the mixture 3 hours.Steam behind the filter reaction mixture and desolventize.The silica gel flash column chromatography purifying of gained residue through using ethyl acetate and chloroform mixed solvent obtains title compound (8.96g).
1H NMR(300MHz，CDCl 3)δppm：
2.54(3H，d，J＝0.9Hz)，5.95-5.99(2H，m)，6.75(1H，d，J＝8.1Hz)，6.78(1H，s)，7.09(1H，dd，J＝7.9，1.9Hz)，7.21(1H，d，J＝1.9Hz)，7.32(1H，q，J＝0.9Hz)
Embodiment 6
Synthesizing of compound 20
Figure C20058001426600241
In acetonitrile (20ml) solution of compound 213 (1.83g), add 1-acetyl guanidine (1.63g), under refluxad stirred the mixture 16 hours.After steaming desolventizes, dilute water and salt water washing successively behind this solution with chloroform.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.NH silica gel (Chromatorex by FujiSilysia Chemical LTD. produced) the flash column chromatography wash-out of gained residue through using chloroform and hexane mixed solvent.The residue of wash-out obtains title compound (590mg) with ethyl acetate and hexane mixed solvent recrystallization.
1H NMR(300MHz，DMSO-d6)δppm：
2.09(3H，s)，2.34(3H，d，J＝0.9Hz)，6.07(2H，s)，6.98(1H，d，J＝8.2Hz)，7.13(1H，d，J＝0.9Hz)，7.45(1H，dd，J＝8.2，1.7Hz)，7.78(1H，d，J＝1.7Hz)，11.28(1H，bs)，11.76(1H，bs)mp：169.0-173.0℃
Embodiment 7
Synthesizing of compound 19
Figure C20058001426600251
In the methyl alcohol (10ml) of compound 20 (578mg) and water (10ml) mixing solutions, add the vitriol oil (0.58ml), under refluxad stirred the mixture 3 hours.Add potassium hydroxide aqueous solution and make this reaction solution be alkalescence, then with this solution of chloroform extraction three times.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The gained residue is through using the NH silica gel flash column chromatography wash-out of methyl alcohol and chloroform mixed solvent.The residue of wash-out obtains title compound (260mg) with chloroform and hexane mixed solvent recrystallization.
1H NMR(300MHz，CDCl 3)δppm：
2.39(3H，d，J＝0.9Hz)，6.00(2H，s)，6.60(1H，d，J＝0.9Hz)，6.84(1H，d，J＝7.9Hz)，7.15(1H，dd，J＝7.9，1.7Hz)，7.19(1H，d，J＝1.7Hz)mp：205.5-208.0℃
Embodiment 8
Synthesizing of compound 21
In pyridine (0.7ml) solution of compound 19 (70mg), add n-butyl chloride (36 μ l), at room temperature stirred the mixture 2.5 hours.Use the ethyl acetate diluted reaction mixture, use saturated sodium bicarbonate aqueous solution and this mixture of salt water washing then successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The gained residue obtains title compound (84mg) through the NH silica gel chromatography of using chloroform solvent.
1H NMR(300MHz，DMSO-d6)δppm：
0.93(3H，t J＝7.3Hz)，1.63(2H，qt，J＝7.3，7.3Hz)，2.28-2.41(5H，m)，6.07(2H，s)，6.98(1H，d，J＝8.1Hz)，7.12(1H，s)，7.46(1H，brd，J＝8.1Hz)，7.79(1H，brs)，11.25(1H，brs)，11.78(1H，brs)
Embodiment 9
Synthesizing of compound 135
Figure C20058001426600261
In tetrahydrofuran (THF) (55ml) solution of compound 203 (1.50g) and 4-(1,3-dioxy-1,3-xylylenimine-2-yl) butyraldehyde (1.78g), add methyl alcohol (55ml) solution of ammonium acetate (4.20g), under refluxad stirred the mixture 2.5 hours.After steaming desolventizes, use the chloroform diluting soln, wash with saturated aqueous sodium carbonate then.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The gained residue obtains title compound (970mg) through the silica gel flash column chromatography purifying that uses methyl alcohol and chloroform mixed solvent.
1H NMR(300MHz，DMSO-d6)δppm：
2.05-2.10(2H，m)，2.32(3H，d，J＝0.8Hz)，2.70(2H，t，J＝7.7Hz)，3.70(2H，t，J＝6.8Hz)，6.06(2H，s)，6.98(1H，d，J＝8.2Hz)，7.07(1H，d，J＝1.1Hz)，7.46(1H，dd，J＝8.2，1.9Hz)，7.77-7.84(5H，m)，12.19(1H，s)
Embodiment 10
Synthesizing of compound 29
Figure C20058001426600271
In ethanol (50ml) solution of compound 135 (928mg), add a hydrazine hydrate (984mg), under refluxad stirred the mixture 3 hours.After steaming desolventized, the NH silica gel chromatography of gained residue through using methyl alcohol and chloroform mixed solvent obtained title compound (458mg).
1H NMR(200MHz，CDCl 3)δppm：
1.90(2H，tt，J＝6.4，6.4Hz)，2.43(3H，d，J＝0.9Hz)，2.84-3.01(4H，m)，5.99(2H，s)，6.69(1H，d，J＝0.9Hz)，6.84(1H，d，J＝8.1Hz)，7.26(1H，dd J＝8.1，1.7Hz)，7.38(1H，d，J＝1.7Hz)
Embodiment 11
Synthesizing of compound 30
Figure C20058001426600272
In dimethyl formamide (0.8ml) solution of compound 29 (80mg), butyric acid (25mg) and a hydration I-hydroxybenzotriazole (38mg), add 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (54mg), under the room temperature mixture stirring is spent the night.With using saturated sodium bicarbonate aqueous solution and salt water washing behind the ethyl acetate diluted reaction mixture successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The gained residue is through using the NH silica gel column chromatography wash-out of methyl alcohol and chloroform mixed solvent.The residue of wash-out obtains title compound (18mg) with ethyl acetate and hexane mixed solvent recrystallization.
1H NMR(300MHz，CDCl 3)δppm：
0.96(3H，t，J＝7.4Hz)，1.69(2H，qt，J＝7.4，7.4Hz)，1.80-1.94(2H，m)，2.22(2H，t，J＝7.4Hz)，2.45(3H，d，J＝0.9Hz)，2.79(t，J＝6.2Hz)，3.40(2H，td，J＝6.2，5.9Hz)，5.99(2H，s)，6.03(1H，brs)，6.72(1H，s)，6.87(1H，d，J＝8.1Hz)，7.39(1H，brd，J＝8.1Hz)，7.55(1H，brs)mp：134.0-139.0℃
Embodiment 12
Synthesizing of compound 31
In tetrahydrofuran (THF) (2ml) solution of formaldehyde (73mg), add compound 29 (100mg) and acetate (51 μ l), stirred the mixture under the room temperature 30 minutes.In this reaction mixture, add nitrilotriacetic base sodium borohydride (248mg), stirred 16 hours.In reaction mixture, add sodium bicarbonate aqueous solution.With twice in this mixture of ethyl acetate extraction.The organic layer that merges after steam behind the anhydrous magnesium sulfate drying desolventizes.The gained residue obtains title compound (74mg) through the NH silica gel chromatography of using methyl alcohol and chloroform mixed solvent.
1H NMR(200MHz，DMSO-d6)δppm：
1.82(2H，tt，J＝7.7，6.9Hz)，2.15(6H，s)，2.28(2H，t，J＝6.9Hz)，2.35(3H，d，J＝0.9Hz)，2.66(2H，t，J＝7.7Hz)，6.07(2H，s)，6.99(1H，d，J＝8.1Hz)，7.09(1H，d，J＝0.9Hz)，7.46(1H，brd，J＝8.1Hz)，7.75(1H，brs)，12.33(1H，brs)
Embodiment 13
Synthesizing of compound 167
In the tetrahydrofuran (THF) (20ml) of compound 203 (1.50g) and 6-oxo methyl caproate (1.38g) and methyl alcohol (10ml) mixing solutions, add ammonium acetate (4.20g), under refluxad stirred the mixture 4 hours.Steaming desolventizes the back and dilutes this solution with chloroform, washs with saturated aqueous sodium carbonate.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The gained residue obtains title compound (797mg) through the silica gel flash column chromatography purifying that uses methyl alcohol and chloroform mixed solvent.
1H NMR(300MHz，CDCl 3)δppm：
1.67-1.90(4H，m)，2.39(2H，t，J＝6.9Hz)，2.43(3H，d，J＝1.1Hz)，2.81(2H，t，J＝7.2Hz)，3.69(3H，s)，6.00(2H，s)，6.69(1H，bs)，6.86(1H，d，J＝8.1Hz)，7.17-7.37(2H，m)mp：158.0-159.0℃
Embodiment 14
Synthesizing of compound 41
In methyl alcohol (25ml) solution of compound 167 (767mg), add sodium hydroxide (227mg) water (10ml) solution, under refluxad stirred the mixture 1 hour.Neutralize behind this solution with twice of chloroform extraction with the 2N aqueous hydrochloric acid.Organic layer steams to desolventize behind anhydrous magnesium sulfate drying and obtains title compound (790mg).
1H NMR(300MHz，CDCl 3)δppm：
1.82(2H，m)，2.05(2H，m)，2.42(3H，s)，2.53(2H，t，J＝6.8Hz)，3.28(2H，t，J＝7.8Hz)，6.03(2H，s)，6.89(1H，d，J＝0.9Hz)，6.89(1H，d，J＝8.1Hz)，7.14(1H，d，J＝1.7Hz)，7.20(1H，dd，J＝8.1，1.7Hz)
Embodiment 15
Figure C20058001426600301
Synthesizing of compound 42
N at compound 41 (120mg), Tri N-Propyl Amine (21mg) and a hydration I-hydroxybenzotriazole (49mg), add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (69mg) in dinethylformamide (1.2ml) solution, under the room temperature mixture stirring is spent the night.With using saturated sodium bicarbonate aqueous solution and salt water washing behind the ethyl acetate diluted reaction mixture successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The silica gel flash column chromatography purifying of gained residue through using methyl alcohol and chloroform mixed solvent obtains title compound (51mg).
1H NMR(300MHz，CDCl 3)δppm：
0.91(3H，t，J＝7.3Hz)，1.51(2H，qt，J＝7.3，7.3Hz)，1.69-1.91(4H，m)，2.27(2H，t，J＝6.4Hz)，2.44(3H，d，J＝0.9Hz)，2.84(2H，t，J＝6.7Hz)，3.21(2H，td，J＝7.3，6.1Hz)，5.76(1H，brs)，6.00(2H，s)，6.71(1H，d，J＝0.9Hz)，6.86(1H，d，J＝8.1Hz)，7.33(1H，brd，J＝8.1Hz)，7.43(1H，brs)
Embodiment 16
Synthesizing of compound 45
In chloroform (1ml) solution of compound 41 (131mg), add thionyl chloride (0.3ml), under refluxad stirred the mixture 2.5 hours, steam and to desolventize the back and in reaction mixture, add 28% ammoniacal liquor, with twice in this mixture of chloroform extraction.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The silica gel flash column chromatography purifying of gained residue through using methyl alcohol and chloroform mixed solvent obtains title compound (42mg).
1H NMR(300MHz，DMSO-d6)δppm：
1.48-1.75(4H，m)，2.09(2H，t，J＝7.2Hz)，2.34(3H，d，J＝1.0Hz)，2.64(2H，t，J＝7.5Hz)，6.07(2H，s)，6.72(1H，bs)，6.99(1H，d，J＝8.2Hz)，7.09(1H，d，J＝1.0Hz)，7.26(1H，bs)，7.50(1H，dd，J＝8.2，1.7Hz)，7.82(1H，d，J＝1.7Hz)，12.21(1H，brs)
Embodiment 17
Synthesizing of compound 216
Figure C20058001426600312
(1) in triethylamine (260ml) solution of 6-bromo benzothiazole (53.3g), add trimethyl silyl acetylene (106ml), cupric iodide (I) (0.948g) and two (triphenylphosphine) palladium chloride (II) (1.75g), under 80 ℃, stirred the mixture 2.5 hours.Short column (the silica gel of after steaming desolventizes the gained residue being packed into; Hexane: ethyl acetate=2: 1) carry out wash-out.The residue of wash-out obtains colourless powder shape 6-trimethyl silyl ethynyl benzo thiazole (20.0g) (mp:104.5-105.0 ℃) after with hexane-ethyl acetate mixed solvent recrystallization.By with filtrate repeatedly recrystallization (normal hexane-ethyl acetate) obtain secondary crystallization (12.1g), three grades of crystallizations (9.68g) and the level Four crystallization (4.61g) of colourless powder shape.
1H NMR(300MHz，CDCl 3)δppm：
0.27(9H，s)，7.60(1H，dd，J＝8.5，1.6Hz)，8.05(1H，dd，J＝8.5，0.6Hz)，8.09(1H，dd，J＝1.6，0.6Hz)，9.03(1H，s)
Figure C20058001426600321
(2) in methyl alcohol (600ml) solution of 6-trimethyl silyl ethynyl benzo thiazole (45.1g), add salt of wormwood (29.7g), stirred the mixture under the room temperature 1.5 hours.Filtering reacting liquid is successively with methyl alcohol and ethyl acetate washing products therefrom.Concentrated filtrate is used ethyl acetate extraction after adding entry.With salt water washing organic layer, through anhydrous magnesium sulfate drying.Steaming desolventizes the back, and (hexane: ethyl acetate=4: 1 → 1: 1) the purifying residue obtains light yellow solid 6-ethynyl benzo thiazole (mp:47.5-49.0 ℃) with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
3.16(1H，s)，7.63(1H，dd，J＝8.4，1.6Hz)，8.08(1H，dd，J＝8.5，0.6Hz)，8.11(1H，d，J＝1.4Hz)，9.04(1H，s)
Figure C20058001426600331
(3) under nitrogen atmosphere, in acetonitrile (600ml) solution of 6-ethynyl benzo thiazole (29.5g) and 2-iodo-4-methylthiazol, add triethylamine (280ml) and four (triphenylphosphines) close palladium (6.8g).Under nitrogen atmosphere, this solution of reflux 5 hours.Steaming desolventizes the back, and (hexane: ethyl acetate=2: 1 → 1: 1) the purifying residue obtains yellow powder powder title compound (41.2g) (mp:116.0-117.0 ℃) with silica gel column chromatography.
1H NMR(200MHz，CDCl 3)δppm：
2.51(3H，d，J＝0.9Hz)，6.96(1H，d，J＝0.9Hz)，7.71(1H，dd，J＝8.4，1.8Hz)，8.12(1H，d，J＝7.9Hz)，8.20(1H，d，J＝1.8Hz)，9.07(1H，s)
Embodiment 18
Synthesizing of compound 204
Acetone (3.0l)-damping fluid at compound 216 (40.0g) *(1.8l) add potassium permanganate (49.3g) in the mixing solutions, stirred the mixture under the room temperature 30 minutes.Use ice-cooled reaction solution, slowly add Sodium Nitrite (20.7g) back and drip 10% sulfuric acid (210ml).Stirred solution is used the chloroform extraction supernatant liquor after 30 minutes under with ice-cooled condition, and water layer further extracts with chloroform.The organic layer that merges washs after anhydrous magnesium sulfate drying with saturated sodium bicarbonate aqueous solution.Steaming desolventizes the back, and (hexane: ethyl acetate=2: 1 → 1: 1) the purifying residue obtains yellow powder powder title compound (30.1g) (mp:134.5-135.5 ℃) with silica gel column chromatography.
Damping fluid *: sodium bicarbonate (6.8g) and anhydrous magnesium sulfate (68.0g) water-soluble (3.0l).
1H NMR(300MHz，CDCl 3)δppm：
2.51(3H，d，J＝0.8Hz)，7.45(1H，d，J＝0.8Hz)，8.16(1H，dd，J＝8.5，1.7Hz)，8.26(1H，dd，J＝8.5，0.6Hz)，8.64(1H，dd，J＝1.7，0.6Hz)，9.23(1H，s)
Embodiment 19
Synthesizing of compound 16
Figure C20058001426600341
In acetate (8.0ml) solution of compound 204 (200mg) and 4-cyanobenzaldehyde (109mg), add ammonium acetate (321mg), at room temperature stirred 14 hours after under refluxad stirring the mixture 2 hours.Add entry in the reaction solution, with 28% ammoniacal liquor neutralization, with twice of this solution of chloroform extraction.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The gained residue washs with chloroform, leaches crystallization and obtains colourless powder shape title compound (138mg) (mp:295.0-295.5 ℃).
1H NMR(300MHz，DMSO-d6)δppm：
2.34(3H，s)，7.24(1H，s)，8.00(2H，d，J＝8.5Hz)，8.10-8.37(4H，m)，8.86(1H，brs)，9.48(1H，s)，13.33(1H，brs)
Embodiment 20
Synthesizing of compound 50
Figure C20058001426600351
In methyl-sulphoxide (5.2ml) suspension of compound 16 (130mg) and salt of wormwood (148mg), add superoxol (1.56ml), stirred the mixture 1 hour under 100 ℃.Cooling suspension is to room temperature, leaches sedimentary crystallization after adding entry.With silica gel column chromatography (chloroform: methyl alcohol=100: 0 → 90: 10) carry out recrystallization (chloroform-methanol-normal hexane) after the purified crystals and obtain yellow powder powder title compound (75.4mg) (mp:＞300 ℃).
1H NMR(300MHz，DMSO-d6)δppm：
2.34(3H，s)，7.22(1H，s)，7.44(1H，brs)，8.00-8.20(7H，m)，8.87(1H，brs)，9.47(1H，s)，13.15(1H，brs)
Embodiment 21
Figure C20058001426600352
Synthesizing of compound 71
(1) under-70 ℃, in toluene (40ml) solution of t-butoxycarbonyl amino methyl acetate (2.00g), drip toluene (27ml) solution of 1.02M diisobutylaluminium hydride, stirred the mixture 1 hour.In-70 ℃ of downhill reaction liquid, add methyl alcohol (10ml) and carry out quencher, place then and be warming up to room temperature.Reaction solution washs with the 1N aqueous hydrochloric acid with ethyl acetate dilution back.Organic layer salt water washing is steamed behind diatomite filtration, anhydrous magnesium sulfate drying and is desolventized.(hexane: ethyl acetate=60: 40 → 30: 70) purifying obtains colorless oil (2-oxoethyl) t-butyl carbamate (895mg) to residue through silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
1.46(9H，s)，4.05-4.11(2H，m)，5.18(1H，s)，9.66(1H，s)
Figure C20058001426600361
(2) in tetrahydrofuran (THF) (10ml) solution of compound 204 (300mg) and (2-oxoethyl) t-butyl carbamate (294mg), add methyl alcohol (5.0ml) solution of ammonium acetate (811mg), stirred the mixture under the room temperature 2 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution and neutralize, use ethyl acetate extraction then twice.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(hexane: ethyl acetate=40: 60 → 20: 80) purifying obtains faint yellow unbodied title compound (291mg) to residue through silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
1.49(9H，s)，2.44(3H，d，J＝0.9Hz)，4.43(2H，d，J＝6.1Hz)，5.29(1H，brs)，6.76(1H，s)，7.86(1H，dd，J＝8.5，1.8Hz)，8.18(1H，d，J＝8.4Hz)，8.55(1H，brs)，9.04(1H，s)
Embodiment 22
Synthesizing of compound 70
Figure C20058001426600362
In chloroform (10ml) solution of compound 71 (100mg), add 4N hydrochloric acid/diox (1.0ml), stirred the mixture under the room temperature 1.5 hours, and after steaming desolventizes residue was carried out recrystallization (methyl alcohol-diethyl ether) and obtain light brown powder shape title compound (80mg) (mp:229.0-233.0 ℃).
1H NMR(300MHz，DMSO-d6)δppm：
2.37(3H，d，J＝0.9Hz)，4.16-4.25(2H，m)，7.22(1H，d，J＝0.9Hz)，8.08(1H，dd，J＝8.6，1.8Hz)，8.18(1H，d，J＝8.5Hz)，8.60(3H，br)，8.90(1H，d，J＝0.9Hz)，9.47(1H，s)
Embodiment 23
Synthesizing of compound 72
Figure C20058001426600371
In tetrahydrofuran (THF) (70ml) solution of compound 204 (2.00g) and (1,3-dioxo-1,3-indoline-2-yl) acetaldehyde (2.00g), add methyl alcohol (50ml) solution of ammonium acetate (5.40g), stirred the mixture under the room temperature 3.5 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution and neutralize, use ethyl acetate extraction then three times.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Residue is through silica gel column chromatography (hexane: ethyl acetate=40: 60 → 20: 80), methyl alcohol=95: 5) and (chloroform: ethyl acetate=35: 65) purifying is three times, obtains the title compound (1.90g) (mp:250.5-255.0 ℃) of pale yellow powder shape (chloroform:.
1H NMR(300MHz，CDCl 3)δppm：
2.44(3H，d，J＝0.8Hz)，5.08(2H，s)，6.74(1H，brs)，7.71-7.94(6H，m)，8.16(1H，d，J＝8.5Hz)，9.03(1H，s)
Embodiment 24
Synthesizing of compound 105
(1) in ethanol (45ml) suspension of compound 72 (1.88g), adds a hydrazine hydrate (2.12g), stirred the mixture under the room temperature 24 hours.In this reaction solution, add methyl alcohol and chloroform to dissolve precipitation wherein fully.In solution, steam behind the adding NH silica gel and desolventize.(chloroform: methyl alcohol=95: 5) (chloroform: methyl alcohol=90: 10 → chloroform: methyl alcohol: ammonia=100: 10: 1) purifying obtains light yellow unbodied free state compound 70 (761mg) to residue with silica gel column chromatography behind the purifying with the NH silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
2.44(3H，d，J＝1.1Hz)，4.12(2H，s)，6.73(1H，br)，7.87(1H，dd，J＝8.5，1.7Hz)，8.17(1H，dd，J＝8.5，0.5Hz)，8.47(1H，br)，9.03(1H，s)
Figure C20058001426600382
(2) with under ice-cooled, in chloroform (15.0ml) solution of free state compound 70 (600mg) and triethylamine (370mg), drip butyryl chloride (0.21ml).In reaction solution, adding entry after 30 minutes, use twice of chloroform extraction with ice-cooled stirring down.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(ethyl acetate → chloroform: purifying methyl alcohol=90: 10), recrystallization (ethyl acetate → hexane) purifying thing obtains yellow powder shape title compound (441mg) (mp:190.0-191.0 ℃) to residue with silica gel column chromatography.
1H NMR(300MHz，DMSO-d6)δppm：
0.89(3H，t，J＝7.4Hz)，1.47-1.64(2H，m)，2.14(2H，t，J＝7.5Hz)，2.34(3H，s)，4.36(2H，d，J＝5.6Hz)，7.15(1H，d，J＝0.9Hz)，8.08(1H，s)，8.14(1H，d，J＝8.5Hz)，8.34(1H，t，J＝5.1Hz)，8.85(1H，s)，9.43(1H，s)，12.72(1H，s)
Embodiment 25
Synthesizing of compound 88
Figure C20058001426600391
With under ice-cooled,, add compound 72 (100mg) in dinethylformamide (2.0ml) suspension at the N of sodium hydride (13mg), stirred the mixture 10 minutes, in this suspension, add methyl-iodide (0.14ml) down with ice-cooled, stirring 1.5 hours down with ice-cooled.In reaction solution, add salt solution, use chloroform extraction.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.After residue was used silica gel column chromatography (ethyl acetate) purifying, recrystallization (ethyl acetate-hexane) purifying thing obtained colourless powder shape title compound (35mg) (mp:257.0-259.5 ℃).
1H NMR(300MHz，CDCl 3)δppm：
2.28(3H，d，J＝0.9Hz)，3.65(3H，s)，5.06(2H，s)，6.60(1H，d，J＝0.9Hz)，7.56(1H，dd，J＝8.4，1.7Hz)，7.72-7.93(4H，m)，8.11(1H，d，J＝1.6Hz)，8.23(1H，d，J＝8.5Hz)，9.09(1H，s)
Concentrated filtrate obtains colourless unbodied 2-(4-benzothiazole-6-base-1-methyl-5-(4-methylthiazol-2-the yl)-1H-imidazoles-2-ylmethyl) isoindole-1 that following structural formula is represented, 3-diketone (15mg).
1H NMR(300MHz，CDCl 3)δppm：
2.54(3H，d，J＝1.1Hz)，3.87(3H，s)，5.05(2H，s)，6.95(1H，d，J＝0.9Hz)，7.52(1H，dd，J＝8.5，1.7Hz)，7.72-7.93(4H，m)，7.96(1H，dd，J＝8.5，0.6Hz)，8.17(1H，dd，J＝1.7，0.5Hz)，8.93(1H，s)
Figure C20058001426600401
Embodiment 26
Synthesizing of compound 89
In methyl alcohol (5.0ml) suspension of compound 88 (328mg), add a hydrazine hydrate (290mg), stirred the mixture under the room temperature 3 hours.Use twice of chloroform extraction behind the dilute with water reaction solution.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(chloroform: methyl alcohol=90: 10 → chloroform: methyl alcohol: ammonia=100: 10: 1) purifying obtains colourless powder shape title compound (166mg) (mp:183.0-184.5 ℃) to residue with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
2.36(3H，d，J＝0.9Hz)，3.52(3H，s)，4.06(2H，s)，6.61(1H，d，J＝0.9Hz)，7.56(1H，dd，J＝8.5，1.6Hz)，8.10(1H，dd，J＝1.6，0.5Hz)，8.26(1H，dd，J＝8.4，0.5Hz)，9.10(1H，s)
Embodiment 27
Synthesizing of compound 90
Figure C20058001426600411
Under ice-cooled condition, in chloroform (5.0ml) solution of compound 89 (159mg) and triethylamine (101mg), drip butyryl chloride (0.06ml).With ice-cooled down, stirs and in reaction solution, adds entry after 1 hour, twice of usefulness chloroform extraction.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(chloroform: methyl alcohol=9: 1) use NH silica gel column chromatography (ethyl acetate) purifying behind the purifying, recrystallization (ethyl acetate-hexane) purifying thing obtains colourless powder shape title compound (137mg) (mp:212.5-213.5 ℃) to residue with silica gel column chromatography.
1H NMR(300MHz，DMSO-d6)δppm：
0.88(3H，t，J＝7.4Hz)，1.47-1.63(2H，m)，2.09-2.18(5H，m)，3.47(3H，s)，4.46(2H，d，J＝5.8Hz)，7.04(1H，d，J＝0.9Hz)，7.64(1H，dd，J＝8.5，1.7Hz)，8.17(1H，dd，J＝8.5，0.5Hz)，8.34(1H，dd，J＝1.7，0.5Hz)，8.46(1H，brt，J＝5.6Hz)，9.49(1H，s)
Embodiment 28
Synthesizing of compound 95
Figure C20058001426600412
(1), in chloroform (30ml) solution of 2-(methylamino-) ethanol (3.0g) and triethylamine (11.0ml), drips butyryl chloride (4.6ml) with under the ice-cooled condition.After stirring the mixture under ice-cooled 20 minutes, in reaction solution, add entry, twice of chloroform extraction of mixture.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Residue silica gel column chromatography (hexane: ethyl acetate=2: 3 → 1: 4, chloroform then: methyl alcohol=9: 1) obtain light yellow oily N-(hydroxyethyl)-N-methylbutyryl amine (2.8g) behind the purifying.
1H NMR(300MHz，CDCl 3)δppm：
0.91-1.02 (3H, m), 1.58-1.77 (2H, m), 2.26-2.46 (2H, m), 2.96 and 3.07 (3H, 2s), 3.47 and 3.56 (2H, 2t, J=5.7Hz), 3.78 (2H, t, J=5.1Hz)
Figure C20058001426600421
(2) in methylene dichloride (6.0ml) solution of N-(hydroxyethyl)-N-methylbutyryl amine (600mg), add Dess-Martin reagent (1.9g).Stirred the mixture under the room temperature 1.5 hours.Steaming desolventizes and obtains the crystallization of unpurified N-methyl-N-(2-oxoethyl) butyramide crude product.In tetrahydrofuran (THF) (15ml) solution of N-methyl-N-(2-oxoethyl) butyramide and compound 204 (301mg), add methyl alcohol (5.0ml) solution of ammonium acetate (820mg), stirred the mixture under the room temperature 14 hours.With using twice of ethyl acetate extraction behind the saturated sodium bicarbonate aqueous solution neutralization reaction liquid.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Residue is with NH silica gel column chromatography (hexane: ethyl acetate=35: 65 → chloroform: methyl alcohol=95: 5) obtain yellow powder powder title compound (233mg) (mp:175.0-175.5 ℃) through recrystallization (ethyl acetate-hexane) behind the purifying.
1H NMR(300MHz，DMSO-d6)δppm：
0.87-0.98 (3H, m), 1.48-1.67 (2H, m), 2.26-2.44 (5H, m), 2.90 and 3.07 (3H, 2s), 4.63 (2H, s), 7.15 (1H, m), 8.03-8.19 (2H, m), 8.84 (1H, m), 9.44 (1H, d, J=1.2Hz), 12.67 and 12.84 (1H, 2br)
Embodiment 29
Synthesizing of compound 96
℃ (1)-78 under, in toluene (10ml) solution of (2-oxo-pyrrolidine-1-yl) methyl acetate (1.01g), drip toluene (16ml) solution of 1.02M diisobutylaluminium hydride, stirred the mixture 1 hour.In reaction solution, add methyl alcohol under-78 ℃ and carry out quencher, be warming up to room temperature with dilution of 1N aqueous hydrochloric acid and stirring then.With making the filtrate drying behind the diatomite filtration reaction solution.(chloroform: methyl alcohol=95: 5 → 90: 10) purifying obtains colorless oil 2-oxo-pyrrolidine-1-base-acetaldehyde (120mg) to residue with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
2.04-2.20(2H，m)，2.46(2H，t，J＝8.2Hz)，3.47(2H，t，J＝8.2Hz)，4.17(2H，s)，9.61(1H，s)
Figure C20058001426600432
(2) in tetrahydrofuran (THF) (10ml) solution of 2-oxo-pyrrolidine-1-base-acetaldehyde (120mg) and compound 204 (230mg), add toluene (5.0ml) solution of ammonium acetate (640ml), stirred the mixture under the room temperature 1.5 hours.Reaction solution is used in the saturated sodium bicarbonate aqueous solution and twice of chloroform extraction in back.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(ethyl acetate → chloroform: methyl alcohol=90: 10) recrystallization (chloroform-ethyl acetate-hexane) obtains colourless powder shape title compound (161mg) (mp:209.5-210.5 ℃) to residue behind the purifying with the NH silica gel column chromatography.
1H NMR(300MHz，DMSO-d6)δppm：
1.90-2.05(2H，m)，2.25-2.33(2H，m)，2.33(3H，s)，3.43(2H，t，J＝7.2Hz)，4.50(2H，s)，7.15(1H，d，J＝1.1Hz)，8.08(1H，brs)，8.13(1H，d，J＝8.4Hz)，8.81(1H，brs)，9.43(1H，s)，12.82(1H，br)
Embodiment 30
Synthesizing of compound 197
Figure C20058001426600441
(1) with under the ice-cooled condition, at the N of sodium hydride (181mg), Jia Ru oxazolidine in dinethylformamide (5.0ml) suspension-2-ketone (331mg) stirred the mixture 20 minutes.Drip the N of 2-bromine oxethyl methylbenzene (1.11g) down in this suspension with ice-cooled, dinethylformamide (3.0ml) solution at room temperature stirred the mixture 1 hour then.Reaction solution dilutes with ethyl acetate, uses the salt solution washed twice.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(hexane: ethyl acetate=2: 3) purifying obtains colorless oil 3-(2-benzyloxy ethyl) oxazolidine-2-ketone (281mg) to residue with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
3.46-3.52(2H，m)，3.63-3.72(4H，m)，4.25-4.34(2H，m)，4.53(2H，s)，7.27-7.40(5H，m)
Figure C20058001426600442
(2) (add 20% palladium hydroxide (138mg) in methyl alcohol (10ml) solution of 2-benzyloxy ethyl) oxazolidine-2-ketone (278mg), under nitrogen atmosphere and room temperature, stirred the mixture 2 hours at 3-.Reaction solution steams after with diatomite filtration and desolventizes.(chloroform: methyl alcohol=90: 10) purifying obtains colorless oil 3-(2-hydroxyethyl) oxazolidine-2-ketone (144mg) to residue with silica gel column chromatography.
1H NMR(200MHz，CDCl 3)δppm：
2.29(1H，br)，3.39-3.47(2H，m)，3.64-3.77(2H，m)，3.78-3.89(2H，m)，4.30-4.43(2H，m)
Figure C20058001426600451
(3) (add Dess-Martin reagent (516mg) in methylene dichloride (5.0ml) solution of 2-hydroxyethyl) oxazolidine-2-ketone (144mg) at 3-.Stirred the mixture under the room temperature 1 hour.Steaming desolventizes and obtains unpurified (2-Yang Dai oxazolidine-3-yl) acetaldehyde crude product crystallization.In tetrahydrofuran (THF) (10ml) suspension of (2-Yang Dai oxazolidine-3-yl) acetaldehyde and compound 204 (286mg), add methyl alcohol (5.0ml) solution of ammonium acetate (771mg), stirred the mixture for 2 weeks under the room temperature.Reaction solution is used in the saturated sodium bicarbonate aqueous solution and twice of ethyl acetate extraction in back.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Residue is with NH silica gel column chromatography (chloroform → chloroform: methyl alcohol=95: 5) obtain colourless powder shape target (149mg) (mp:232.0-233.0 ℃) through recrystallization (methyl alcohol-ethyl acetate-hexane) behind the purifying.
1H NMR(300MHz，DMSO-d6)δppm：
2.34(3H，s)，3.60-3.68(2H，m)，4.28-4.36(2H，m)，4.49(2H，s)，7.16(1H，d，J＝0.9Hz)，8.08(1H，br)，8.14(1H，d，J＝8.4Hz)，8.83(1H，br)，9.44(1H，s)，12.93(1H，br)
Embodiment 31
Synthesizing of compound 138
Figure C20058001426600461
(45% aqueous solution 2.36g) and add methyl alcohol (40ml) solution of ammonium acetate (5.35g) in tetrahydrofuran (THF) (60ml) solution of compound 204 (2.0g), stirred the mixture under the room temperature 12 hours at glyoxylic acid ethyl ester.Reaction solution is used saturated sodium bicarbonate aqueous solution and salt water washing after diluting with ethyl acetate successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(hexane: ethyl acetate=5: 5 → 3: 7 → 1: 9) (chloroform: purifying methyl alcohol=50: 1) obtains colourless powder shape title compound (1.01g) (mp:238.5-239.0 ℃) by recrystallization (ethyl acetate-hexane) to residue then with the NH silica gel column chromatography behind the purifying with silica gel column chromatography.
1H NMR(300MHz，DMSO-d6)δppm：
1.37(3H，t，J＝7.1Hz)，2.31(3H，s)，4.40(2H，q，J＝6.8Hz)，7.24(1H，s)，8.03(1H，d，J＝8.7Hz)，8.14(1H，d，J＝8.5Hz)，8.74(1H，s)，9.48(1H，s)，14.02(1H，s)
Embodiment 32
Synthesizing of compound 82
Figure C20058001426600462
Under-40 ℃, in tetrahydrofuran (THF) (30ml) suspension of lithium aluminum hydride (134mg), add compound 138 (700mg), stirring the mixture rises to 0 ℃ until temperature, continues to stir 30 minutes down at 0 ℃.Add the 2N aqueous hydrochloric acid in the reaction solution, stirred 5 minutes.Reaction solution is used saturated sodium bicarbonate aqueous solution and salt water washing after diluting with ethyl acetate successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(chloroform: methyl alcohol=20: 1 → 10: 1) purifying and recrystallization (chloroform-methanol-hexane) obtain the Powdered title compound of light orange (309mg) (mp:222.0-223.0 ℃) to residue with silica gel column chromatography.
1H NMR(300MHz，DMSO-d6)δppm：
2.34(3H，d，J＝0.8Hz)，4.53(2H，s)，5.50(1H，brs)，7.15(1H，d，J＝0.9Hz)，8.05-8.18(2H，m)，8.87(1H，brs)，9.43(1H，s)，12.80(1H，br)
Embodiment 33
Synthesizing of compound 198
(7mg) and in toluene (2.0ml) suspension of pyridine (1.0ml) add ethyl isocyanate (57mg) at compound 82 (239mg), cupric chloride (I), under 50 ℃, stirred the mixture 2 hours.Add entry in the solution and use chloroform extraction.Organic layer salt water washing is steamed behind anhydrous magnesium sulfate drying and is desolventized.(chloroform: methyl alcohol=30: 1) recrystallization (ethyl acetate-hexane) obtains colourless powder shape title compound (151mg) (mp:144.0-145.0 ℃) to residue behind the purifying with silica gel column chromatography.
1H NMR(300MHz，DMSO-d6)δppm：
1.04(3H，t，J＝7.2Hz)，2.34(3H，s)，2.99-3.12(2H，m)，5.04(2H，s)，7.18(1H，d，J＝0.8Hz)，7.34(1H，brt，J＝5.7Hz)，8.03-8.20(2H，m)，8.90(1H，brs)，9.45(1H，s)，13.06(1H，brs)
Embodiment 34
Synthesizing of compound 81
Figure C20058001426600481
(1) under nitrogen atmosphere reaches-70 ℃, in toluene (30ml) solution of 5-propyl group dihydrofuran-2-ketone (1.50g), drip toluene (23.4ml) solution of 1.02M diisobutylaluminium hydride, dropwised in 50 minutes.Stirred the mixture under-70 ℃ 1 hour.Add methyl alcohol (3.0ml) in-70 ℃ of downhill reaction liquid and carry out quencher, place then and be warming up to room temperature.Stirred 5 minutes after adding 10% aqueous citric acid solution in the reaction solution.Use the ethyl acetate extraction reaction solution, with salt water washing organic layer.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.(hexane: ethyl acetate=90: 10 → 80: 20) purifying obtains colorless oil 5-propyl group tetrahydrofuran (THF)-2-alcohol (440mg) to residue through silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
0.9-0.98(3H，m)，1.29-2.21(7H，m)，2.45-2.56(1H，m)，3.94-4.26(1H，m)，5.41-5.60(1H，m)
Figure C20058001426600482
(2) in tetrahydrofuran (THF) (25ml) solution of compound 204 (741mg) and 5-propyl group tetrahydrofuran (THF)-2-alcohol (435mg), add methyl alcohol (18ml) solution of ammonium acetate (1.98g), stirred the mixture under the room temperature 13 hours.Water and salt water washing successively after reaction solution dilutes with ethyl acetate.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.With silica gel column chromatography (ethyl acetate → chloroform: purifying residue methyl alcohol=40: 1).The purifying thing is dissolved in methyl alcohol, adds 4N hydrochloric acid/ethyl acetate solution.After steaming desolventizes, obtain colourless powder shape title compound (165mg) by recrystallization (methyl alcohol-ethyl acetate).
1H NMR(300MHz，DMSO-d6)δppm：
0.82-0.96(3H，m)，1.25-1.49(4H，m)，1.70-2.09(2H，m)，2.33-2.48(3H，m)，2.90-3.29(2H，m)，3.51(1H，m)，7.37(1H，s)，7.84(1H，dd，J＝8.5，1.8Hz)，8.29(1H，d，J＝8.5Hz)，8.61(1H，d，J＝1.7Hz)，9.58(1H，s)
Embodiment 35
Synthesizing of compound 201
Figure C20058001426600491
In methylene dichloride (7.0ml) solution of free state compound 81 (342mg), add Dess-Martin reagent (400mg).Stirred the mixture under the room temperature 2 hours.Add entry in the reaction solution and use chloroform extraction.Organic layer, steams then and desolventizes after anhydrous magnesium sulfate drying with the salt water washing.Residue is with silica gel column chromatography (hexane: ethyl acetate=1: 1 → 3: 7 → 1: 9) obtain colourless powder shape title compound (225mg) (mp:145.0-146.0 ℃) through recrystallization (ethyl acetate-hexane) behind the purifying.
1H NMR(300MHz，CDCl 3)δppm：
0.93(3H，t，J＝7.4Hz)，1.58-1.71(2H，m)，2.44(3H，d，J＝0.9Hz)，2.44-2.50(2H，m)，2.95-3.11(4H，m)，6.72(1H，d，J＝0.9Hz)，7.86(1H，dd，J＝8.5，1.8Hz)，8.16(1H，dd，J＝8.5，0.6Hz)，8.48(1H，br)，9.03(1H，s)
Embodiment 36
Synthesizing of compound 73
Figure C20058001426600501
(1) in chloroform (30ml) solution of 2-fourth monoethanolamine (3.00g), drips tert-Butyl dicarbonate (5.87g), stirred the mixture under the room temperature 15 minutes.Steaming desolventizes and obtains colorless oil butyl-(2-hydroxyethyl) t-butyl carbamate (6.10g).
1H NMR(300MHz，CDCl 3)δppm：
0.93(3H，t，J＝7.3Hz)，1.22-1.56(13H，m)，3.22(2H，t，J＝7.3Hz)，3.38(2H，t，J＝5.1Hz)，3.69-3.80(2H，m)
(2) under the room temperature, in methylene dichloride (20ml) solution of butyl-(2-hydroxyethyl) t-butyl carbamate (1.00g), add Dess-Martin reagent (2.15g).Stirred the mixture under the room temperature 15 minutes.Steaming desolventizes the back, and (hexane: ethyl acetate=80: 20 → 75: 25) the purifying residue obtains colorless oil butyl-(2-oxoethyl) t-butyl carbamate (755mg) with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
0.93(3H，t，J＝7.2Hz)，1.20-1.55(13H，m)，3.19-3.36(2H，m)，3.82(1H，s)，3.92(1H，s)，9.58(1H，s)
(3) in tetrahydrofuran (THF) (30ml) solution of compound 204 (750mg) and butyl-(2-oxoethyl) t-butyl carbamate (728mg), add methyl alcohol (20ml) solution of ammonium acetate (2.00g), stirred the mixture under the room temperature 1 hour.Water and salt water washing successively after reaction solution dilutes with ethyl acetate.Organic layer steams behind anhydrous sodium sulfate drying and desolventizes.(hexane: ethyl acetate=80: 20 → 50: 50) the purifying residue obtains colourless unbodied title compound (862mg) with silica gel column chromatography.
1H NMR(300MHz，DMSO-d6)δppm：
0.88(3H，t，J＝7.2Hz)，1.20-1.59(13H，m)，2.34(3H，s)，3.29(2H，brs)，4.46(2H，brs)，7.14(1H，s)，8.02-8.18(2H，m)，8.86(1H，brs)，9.43(1H，s)，12.73(1H，brs)
Embodiment 37
Synthesizing of compound 74
Figure C20058001426600512
Under the room temperature with 10% hydrochloric acid/methyl alcohol (10ml) solution stirring of compound 73 (875mg) 4 hours.In reaction solution, stirred 30 minutes under the room temperature behind adding 4N hydrochloric acid/diox (1.0ml) solution.Steaming desolventizes the back residue and obtains colourless powder shape title compound (730mg) through recrystallization (methyl alcohol-diethyl ether).
1H NMR(300MHz，DMSO-d6)δppm：
0.91(3H，t，J＝7.4Hz)，1.31-1.45(2H，m)，1.62-1.75(2H，m)，2.38(3H，d，J＝1.1Hz)，3.00-3.15(2H，m)，4.32-4.41(2H，m)，7.25(1H，d，J＝0.9Hz)，8.12(1H，dd，J＝8.7，1.8Hz)，8.19(1H，dd，J＝8.7，0.6Hz)，8.94(1H，d，J＝1.2Hz)，9.49(1H，s)，9.69(2H，brs)
Embodiment 38
Synthesizing of compound 78
Figure C20058001426600521
(1) in the solution of piperidin-4-yl methyl alcohol (2.00g) in ethyl acetate (20ml) and tetrahydrofuran (THF) (10ml) mixed solvent, adds tert-Butyl dicarbonate (4.17g), stirred the mixture under the room temperature 22 hours.Steaming desolventizes, and adds ethyl acetate in the residue and uses saturated aqueous ammonium chloride and salt water washing successively.Organic layer steams to desolventize behind anhydrous magnesium sulfate drying and obtains baby pink oily 4-hydroxymethyl piperidine-1-carboxylic acid tert-butyl ester (4.06g).
1H NMR(200MHz，CDCl 3)δppm：1.02-1.82(5H，m)，1.46(9H，s)，2.59-2.81(2H，m)，3.43-3.59(2H，m)，4.02-4.23(2H，m)
Figure C20058001426600522
(2) in methylene dichloride (40ml) solution of 4-hydroxymethyl piperidine-1-carboxylic acid tert-butyl ester (4.00g), add Dess-Martin reagent (7.89g).Stirred the mixture under the room temperature 1.5 hours.Reaction solution is used 1% aqueous sodium hydroxide solution and salt water washing after diluting with ethyl acetate successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes, and (hexane: ethyl acetate=2: 1 → 1: 1) purifying obtains colorless oil 4-formylpiperidine-1-carboxylic acid tert-butyl ester (2.43g) to residue with silica gel column chromatography.
1H NMR(200MHz，CDCl 3)δppm：
1.46(9H，s)，1.38-1.99(4H，m)，2.41(1H，m)，2.83-3.03(2H，m)，3.87-4.08(2H，m)，9.66(1H，s)
Figure C20058001426600531
(3) in tetrahydrofuran (THF) (70ml) solution of compound 204 (2.00g) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (2.22g), add methyl alcohol (35ml) solution of ammonium acetate (5.35g), stirred the mixture under the room temperature 15 hours.Water and salt water washing successively after reaction solution dilutes with ethyl acetate.Organic layer steams behind anhydrous sodium sulfate drying and desolventizes, and (chloroform: methyl alcohol=50: 1 → 20: 1) purifying obtains light yellow unbodied title compound (3.27g) to residue with silica gel column chromatography.
1H NMR(200MHz，CDCl 3)δppm：
1.47(9H，s)，1.67-2.17(4H，m)，2.43(3H，d，J＝0.9Hz)，2.76-3.09(3H，m)，4.13-4.33(2H，m)，6.68(1H，s)，7.85(1H，dd，J＝8.6，1.5Hz)，8.17(1H，d，J＝8.4Hz)，8.30(1H，s)，9.02(1H，s)
Embodiment 39
Synthesizing of compound 77
Figure C20058001426600532
In methyl alcohol (20ml) solution of compound 78 (2.00g), add 4N hydrochloric acid/ethyl acetate solution (10.4ml), stirred the mixture under the room temperature 1 hour, stirred 1.5 hours down at 50 ℃ then.With washing organic layer with saturated sodium bicarbonate aqueous solution behind the chloroform dilute reaction solution.In water layer, add sodium-chlor and make it saturated, use chloroform extraction then.The organic layer that merges steams behind anhydrous magnesium sulfate drying and desolventizes, and residue is with NH silica gel column chromatography (chloroform: methyl alcohol=50: 1 → 20: 1) obtain colourless powder shape title compound (793mg) (mp:199.5-200.5 ℃) through recrystallization (ethyl acetate) behind the purifying.
1H NMR(300MHz，CDCl 3)δppm：
1.76-2.17(4H，m)，2.45(3H，d，J＝0.9Hz)，2.72-2.85(2H，m)，3.02(1H，m)，3.20-3.32(2H，m)，6.68(1H，brs)，7.85(1H，dd，J＝8.5，1.7Hz)，8.17(1H，dd，J＝8.5，0.3Hz)，8.32(1H，br)，9.03(1H，s)
Embodiment 40
Synthesizing of compound 226
Figure C20058001426600541
(1) with after in acetonitrile (20ml) suspension of 2-amino-5-methylthiazol (2.00g), adding nitrite tert-butyl (1.99g) under the ice-cooled condition, slowly adds cupric bromide (II) (4.30g).0 ℃ was stirred this suspension 3 hours down, added 1N hydrochloric acid (100ml) back ethyl acetate (200ml) extracting twice in the reaction solution.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Residue silica gel column chromatography (neutrality; Hexane: ethyl acetate=80: 20) purifying obtains yellow oily 2-bromo-5-methylthiazol (1.31g).
1H NMR(300MHz，CDCl 3)δppm：
2.44(3H，d，J＝1.2Hz)，7.25(1H，d，J＝1.1Hz)
Figure C20058001426600551
℃ (2)-78 under, in tetrahydrofuran (THF) (10ml) solution of 2-bromo-5-methylthiazol (1.00g), drip hexane (2.40ml) solution of 2.59M n-Butyl Lithium, stirred the mixture under the uniform temp 40 minutes.Be added dropwise to tetrahydrofuran (THF) (5ml) solution of iodine (1.55g) under-78 ℃, stirred the mixture under the uniform temp 30 minutes.In reaction solution, add saturated aqueous ammonium chloride (20ml) so that the reaction quencher.Place this solution to room temperature.Add entry (20ml) in this solution and use ethyl acetate (100ml) extracting twice.Organic layer washs after anhydrous magnesium sulfate drying with saturated aqueous sodium thiosulfate (50ml).Steaming desolventizes the back, and (hexane: ethyl acetate=85: 15) the purifying residue obtains brown oily 2-iodo-5-methylthiazol (764mg) with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
(300MHz，CDCl3)δppm：2.47(3H，d，J＝1.2Hz)，7.26(1H，d，J＝1.2Hz)
Figure C20058001426600552
(3) under nitrogen atmosphere, in acetonitrile (10ml) solution of embodiment 17-(2) synthetic 6-ethynyl benzo thiazole (483mg) and 2-iodo-5-methylthiazol (740mg), add triethylamine (15ml) and four (triphenylphosphines) close palladium (179mg).This reaction solution of reflux is 6 hours under nitrogen atmosphere.Steaming desolventizes the back, and (hexane: ethyl acetate=85: 15 → 50: 50) the purifying residue obtains yellow powder shape title compound (601mg) (mp:137.0-140.0 ℃) with silica gel column chromatography.
1H NMR(200MHz，CDCl 3)δppm：
2.53(3H，d，J＝1.1Hz)，7.53(1H，d，J＝1.1Hz)，7.71(1H，dd，J＝8.5，1.6Hz)，8.13(1H，dd，J＝8.5，0.6Hz)，8.20(1H，dd，J＝1.6，0.5Hz)，9.07(1H，s)
Embodiment 41
Synthesizing of compound 227
Figure C20058001426600561
Acetone (45.7ml)-damping fluid at compound 226 (593mg) *(25.5ml) add potassium permanganate (733mg) in the mixing solutions, stirred the mixture under the room temperature 30 minutes.Use ice-cooled reaction solution, slowly add Sodium Nitrite (297mg) back and drip 10% sulfuric acid (3.0ml).In reaction solution, add chloroform (100ml) and water (30ml) after 15 minutes with stirred solution under the ice-cooled condition, use the diatomite filtration reaction solution then.Separating filtrate is used chloroform (100ml) aqueous layer extracted once more.The organic layer that merges steams behind anhydrous magnesium sulfate drying and desolventizes, with silica gel column chromatography (neutrality; Ethyl acetate=65: 35 → 45: 55), (neutrality hexane:; Hexane: ethyl acetate=5: 95) twice purifying residue obtains yellow powder shape title compound (424mg) (mp:154.0-155.0 ℃).
Damping fluid *: sodium bicarbonate (6.8g) and anhydrous magnesium sulfate (68.0g) water-soluble (3.0l).
1H NMR(300MHz，CDCl 3)δppm：
2.65(3H，d，J＝1.1Hz)，7.78(1H，d，J＝1.1Hz)，8.15(1H，dd，J＝8.5，1.7Hz)，8.24(1H，dd，J＝8.5，0.6Hz)，8.63(1H，dd，J＝1.7，0.6Hz)，9.22(1H，s)
Embodiment 42
Synthesizing of compound 228
In tetrahydrofuran (THF) (10ml) solution of compound 227 (414mg), add methyl alcohol (10ml) solution of acetaldehyde (0.15ml) and ammonium acetate (900mg), stirred the mixture under the room temperature 13 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution (70ml) and neutralize, with ethyl acetate (150ml) extracting twice.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes, with silica gel column chromatography (ethyl acetate → chloroform: methyl alcohol=90: 10) obtain colourless powder shape title compound (230mg) (mp:210.0-211.0 ℃) through recrystallization (normal hexane-ethyl acetate) behind the purifying residue.
1H NMR(300MHz，DMSO-d6)δppm：
2.37(3H，s)，2.42(3H，s)，7.44(1H，brs)，8.09-8.15(2H，m)，8.78(1H，br)，9.42(1H，s)，12.53(1H，br)
Embodiment 43
Synthesizing of compound 239
Figure C20058001426600572
(1) at the N of 1-(2-hydroxyethyl)-2-imidazolidone (7.67g), adds imidazoles (9.63g) and TERT-BUTYL DIMETHYL CHLORO SILANE (9.77g) in dinethylformamide (75ml) solution, stirred the mixture under the room temperature 2 hours.Add entry in the reaction solution and, use salt water washing organic layer then with the ethyl acetate dilution.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.With silica gel column chromatography (hexane: ethyl acetate=35: 65 → 0: 100) obtain colorless solid shape 1-[2-(t-butyldimethylsilyloxy base) ethyl behind the purifying residue] imidazolidin-2-one (8.73g) (mp:53.5-57.0 ℃).
1H NMR(200MHz，CDCl 3)δppm：
0.06(6H，s)，0.89(9H，s)，3.30(2H，t，J＝5.3Hz)，3.34-3.46(2H，m)，3.54-3.65(2H，m)，3.74(2H，t，J＝5.3Hz)
(2) add tetrahydrofuran (THF) (10ml) with twice back of hexane wash sodium hydride (393mg).Place ice bath to cool off in container, keep temperature in the container to be lower than under 10 ℃ the condition, in container, drip 1-[2-(t-butyldimethylsilyloxy base) ethyl] tetrahydrofuran (THF) (10ml) solution of imidazolidin-2-one (2.00g).Stir this solution and under uniform temp, drip methyl iodide (766 μ l) after 15 minutes, stirred the mixture under the room temperature 20 minutes.Add water and make the reaction quencher, use the ethyl acetate dilute reaction solution.Use 2N hydrochloric acid, saturated sodium bicarbonate aqueous solution and salt solution cleaning mixture successively.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Residue with silica gel column chromatography (hexane: ethyl acetate=35: 65 → 0: 100, chloroform: methyl alcohol=4: 1) purifying obtain the oily mater mixture ( *)All water layer merging are concentrated, and the gained residue is suspended in the chloroform-methanol mixture, filters this mixture then.Gains steam behind anhydrous magnesium sulfate drying and desolventize.Residue and the oily mater mixture that before obtained ( *) (chloroform: methyl alcohol=9: 1) purifying obtains faint yellow oily 1-(2-hydroxyethyl)-3-Methylimidazole alkane-2-ketone (907mg) through silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
2.80(3H，s)，3.29-3.45(6H，m)，3.74-3.79(2H，m)
Figure C20058001426600582
(3) in chloroform (10ml) solution of 1-(2-hydroxyethyl)-3-Methylimidazole alkane-2-ketone (372mg), add Dess-Martin reagent (1.094g).Stirred the mixture under the room temperature 1.5 hours.In this reaction solution, add methyl alcohol (10ml), compound 204 (400mg) and ammonium acetate (856mg), stirred 2.5 hours under the room temperature.Reaction solution washs with saturated sodium bicarbonate aqueous solution with chloroform dilution back.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.The residue silica gel column chromatography (chloroform: methyl alcohol=20: 1 → 15: 1), (chloroform: acetone=2: 1 → 1: 1) and behind three purifying of NH type silica gel column chromatography (chloroform) obtain colourless powder shape title compound (27mg) (mp:232.0-233.5 ℃) through recrystallization (ethyl acetate-diethyl ether).
1H NMR(200MHz，CDCl 3)δppm：
2.45(3H，d，J＝0.9Hz)，2.83(3H，s)，3.30-3.54(4H，m)，4.47(2H，s)，6.75(1H，s)，7.89(1H，dd，J＝8.6，1.5Hz)，8.12-8.21(1H，m)，9.03(1H，s)
Embodiment 44
Synthesizing of compound 240
(1) adds tetrahydrofuran (THF) (10ml) with twice back of hexane wash sodium hydride (393mg).Place ice bath to cool off in container, keep the interior temperature of container to be lower than under 10 ℃ of conditions, in container, drip tetrahydrofuran (THF) (10ml) solution of embodiment 43-(1) synthetic compound (2.00g).Stir this solution drips tert-Butyl dicarbonate (2.31g) under uniform temp after 5 minutes tetrahydrofuran (THF) (10ml) solution.Stirred 18 hours down at 50 ℃ after stirring the mixture under the room temperature 2 hours.In this reaction mixture, add saturated aqueous ammonium chloride and ethyl acetate successively.Organic layer steams behind salt water washing and anhydrous magnesium sulfate drying and desolventizes.Residue with silica gel column chromatography (hexane: ethyl acetate=2: 1) purifying obtains colourless powder shape 3-[2-(t-butyldimethylsilyloxy base) ethyl]-2-oxo-imidazole alkane-1-carboxylic acid tert-butyl ester (1.54g) (mp:35.5-45.5 ℃).
1H NMR(300MHz，CDCl 3)δppm：
0.05(6H，s)，0.89(9H，s)，1.53(9H，s)，3.35(2H，t，J＝5.2Hz)，3.48-3.55(2H，m)，3.71-3.79(4H，m)
Figure C20058001426600601
(2) at 3-[2-(t-butyldimethylsilyloxy base) ethyl]-add tetrahydrofuran (THF) (4.35ml) solution of the positive tetrabutyl ammonium fluoride of 1.0M in tetrahydrofuran (THF) (15ml) solution of 2-oxo-imidazole alkane-1-carboxylic acid tert-butyl ester (1.50g), stirred the mixture under the room temperature 1 hour.Add methyl alcohol (1ml) in reaction solution, steaming desolventizes.(chloroform: methyl alcohol=20: 1 → 10: 1) purifying obtains colorless oil 3-(2-hydroxyethyl)-2-oxo-imidazole alkane-1-carboxylic acid tert-butyl ester (940mg) to residue with silica gel column chromatography.
1H NMR(200MHz，CDCl 3)δppm：
1.39-1.58(9H，m)，3.27-3.86(8H，m)
Figure C20058001426600602
(3) in chloroform (8ml) solution of 3-(2-hydroxyethyl)-2-oxo-imidazole alkane-1-carboxylic acid tert-butyl ester (800mg), add Dess-Martin reagent (1.47g).Stirred the mixture under the room temperature 1 hour.This mixed reactant dilutes through ethyl acetate, uses diatomite filtration, steams the solvent that removes in the filtrate.In residue, add tetrahydrofuran (THF) (30ml), methyl alcohol (15ml), compound 204 (1.00g) and ammonium acetate (2.14g), stirred 16 hours under the room temperature.Reaction solution washs with saturated sodium bicarbonate aqueous solution with chloroform dilution back.The water layer chloroform extraction.Merge organic layer and behind anhydrous magnesium sulfate drying, steam and desolventize.Residue with silica gel column chromatography (chloroform: methyl alcohol=40: 1 → 20: 1) obtain light yellow unbodied 3-[5-benzothiazole-6-base-4-(4-methylthiazol-2-yl)-1H-imidazoles-2-ylmethyl behind the purifying]-2-oxo-imidazole alkane-1-carboxylic acid tert-butyl ester (983mg).
1H NMR(300MHz，CDCl 3)δppm：
1.49(9H，s)，2.44(3H，d，J＝0.9Hz)，3.50-3.58(2H，m)，3.76-3.84(2H，m)，4.58(2H，s)，6.76(1H，s)，7.88-7.96(1H，m)，8.14(1H，d，J＝8.7Hz)，9.03(1H，s)
Figure C20058001426600611
(4) at 3-[5-benzothiazole-6-base-4-(4-methylthiazol-2-yl)-1H-imidazoles-2-ylmethyl]-add 4N hydrochloric acid/ethyl acetate (4.03ml) in methyl alcohol (8ml) solution of 2-oxo-imidazole alkane-1-carboxylic acid tert-butyl ester (800mg), stirred the mixture under the room temperature 18 hours.Reaction solution washs with saturated sodium bicarbonate aqueous solution with chloroform dilution back.The water layer chloroform extraction.Merge organic layer and behind anhydrous magnesium sulfate drying, steam and desolventize.Residue is with silica gel column chromatography (chloroform: methyl alcohol=20: 1 → 10: 1) obtain the title compound (392mg) (mp:236.0-237.0 ℃) of colourless powder shape behind the purifying through recrystallization (chloroform-ethyl acetate).
1H NMR(300MHz，DMSO-d6)δppm：
2.34(3H，s)，3.23-3.32(2H，m)，3.40-3.48(2H，m)，4.35(2H，s)，6.53(1H，s)，7.16(1H，d，J＝0.9Hz)，8.10-8.17(2H，m)，8.86(1H，brs)，9.44(1H，s)，12.83(1H，brs)
Embodiment 45
Synthesizing of compound 242
Figure C20058001426600621
(1), in water (3ml) solution of chromic oxide (VI), adds sulfuric acid (2.86ml) and water (6ml) successively with under the ice-cooled condition.With ice-cooled remain on condition below 20 ℃ to interior temperature under, in this solution, drip acetone (22ml) solution of 2-methylol trimethylene oxide (1.00g), stirred the mixture under the room temperature 2 hours.Add the 2-propyl alcohol and make the reaction quencher.Reaction solution dilutes with ethyl acetate, uses diatomite filtration.Filtrate is used the salt water washing, twice of ethyl acetate extraction of water layer.Merge organic layer and behind anhydrous magnesium sulfate drying, steam and desolventize.(neutrality, chloroform: methyl alcohol=9: 1 → 4: 1) purifying obtains light yellow oily trimethylene oxide-2-carboxylic acid (83mg) to residue with silica gel column chromatography.
1H NMR(200MHz，CDCl 3)δppm：
2.70-2.90(1H，m)，3.01-3.21(1H，m)，4.68-4.87(2H，m)，5.19(1H，dd，J＝9.2，6.6Hz)
(2) at the N of compound 70 (301mg), trimethylene oxide-2-carboxylic acid (74mg) and a hydration I-hydroxybenzotriazole (118mg), add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (167mg) in dinethylformamide (1.5ml) solution, stirred the mixture under the room temperature 3 hours.Reaction mixture washs with saturated sodium bicarbonate aqueous solution with chloroform dilution back.Twice of chloroform extraction of water layer.Merge organic layer and behind anhydrous magnesium sulfate drying, steam and desolventize.Residue is with silica gel column chromatography (chloroform: methyl alcohol=30: 1 → 15: 1) obtain the title compound (265mg) (mp:224.5-226.5 ℃) of colourless powder shape behind the purifying through recrystallization (chloroform-ethyl acetate).
1H NMR(300MHz，DMSO-d6)δppm：
2.34(3H，s)，2.52-2.63(1H，m)，2.86-3.00(1H，m)，4.38-4.67(4H，m)，4.99(1H，dd，J＝9.0，6.5Hz)，7.15(1H，d，J＝0.9Hz)，8.03-8.17(2H，m)，8.52(1H，t，J＝5.8Hz)，8.87(1H，s)，9.44(1H，s)，12.72(1H，s)
The listed compound of table 1 makes with corresponding material according to the described method of embodiment 1-48.
Embodiment 46
Synthesizing of compound 250
Figure C20058001426600631
(1), progressively adds cupric iodide (I) (1.25g) after in acetonitrile (10ml) solution of 2-amino-4-trifluoromethyl thiazole (1.00g), dripping nitrite tert-butyl (679mg) with under the ice-cooled condition.0 ℃ of following stirred reaction mixture 2 hours adds 1N hydrochloric acid (100ml) and then with ethyl acetate (100ml) extracting twice.In organic layer, steam behind the adding silica gel and desolventize.(hexane: ethyl acetate=80: 20) purifying obtains brown solid shape 2-iodo-4-trifluoromethyl thiazole (747mg) (mp:35.5-36.0 ℃) to residue with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
7.75(1H，q，J＝0.9Hz)
Figure C20058001426600632
(2) under nitrogen atmosphere, add triethylamine (12.5ml) and four (triphenylphosphines) close palladium (151mg) in acetonitrile (8ml) solution of embodiment 17-(2) synthetic 6-ethynyl benzo thiazole (402mg) and 2-iodo-4-trifluoromethyl thiazole (708mg), reflux is 3 hours under nitrogen atmosphere.After steaming desolventized, (hexane: ethyl acetate=85: 15 → 70: 30) purifying obtained yellow powder shape title compound (573mg) (mp:153.0-154.0 ℃) to residue with silica gel column chromatography.
1H NMR(300MHz，CDCl 3)δppm：
7.74(1H，dd，J＝8.5，1.6Hz)，7.81(1H，q，J＝0.9Hz)，8.16(1H，dd，J＝8.5，0.6Hz)，8.24(1H，dd，J＝1.7，0.6Hz)，9.11(1H，s)
Embodiment 47
Synthesizing of compound 251
Figure C20058001426600641
Acetone (35.9ml)-damping fluid at compound 250 (562mg) *(20.0ml) add potassium permanganate (572mg) in the mixing solutions, stirred this mixture 30 minutes under the room temperature.Use ice-cooled reaction mixture, slowly add Sodium Nitrite (234mg) back and drip 10% sulfuric acid (2.4ml).Under ice-cooled condition, stirred this solution 15 minutes, in reaction solution, add chloroform (100ml) and water (30ml) back diatomite filtration gained solution.Separating filtrate, water layer extracts once more with chloroform (100ml).The organic layer that merges steams behind anhydrous magnesium sulfate drying and desolventizes.Residue silica gel column chromatography (neutrality; Hexane: ethyl acetate=50: 50) purifying obtains yellow powder shape title compound (113mg) (mp:163.5-164.5 ℃).
Damping fluid *: sodium bicarbonate (6.8g) and anhydrous magnesium sulfate (68.0g) water-soluble (3.0l).
1H NMR(300MHz，CDCl 3)δppm：
8.14-8.32(3H，m)，8.69(1H，m)，9.27(1H，s)
Embodiment 48
Synthesizing of compound 244
Figure C20058001426600651
Methyl alcohol (3ml) solution that adds acetaldehyde (0.15ml) and ammonium acetate (194mg) in tetrahydrofuran (THF) (5ml) solution of compound 251 (107mg) stirred this mixture 3.5 hours under the room temperature.In reaction mixture, add sodium bicarbonate aqueous solution (50ml) and neutralize, with ethyl acetate (100ml) extracting twice.Organic layer steams behind anhydrous magnesium sulfate drying and desolventizes.Residue with silica gel column chromatography (hexane: ethyl acetate=30: 70 → 1: 99) and recrystallization (normal hexane-ethyl acetate) purifying obtain colourless powder shape title compound (25mg) (mp:190.5-192.0 ℃).
1H NMR(300MHz，DMSO-d6)δppm：
2.40(3H，s)，8.03(1H，dd，J＝8.6，1.5Hz)，8.15(1H，d，J＝8.6Hz)，8.34(1H，s)，8.89(1H，brs)，9.45(1H，s)，12.78(1H，br)
Table 1
Figure C20058001426600661
Figure C20058001426600671
Figure C20058001426600681
Figure C20058001426600701
Figure C20058001426600711
Figure C20058001426600721
Figure C20058001426600731
Figure C20058001426600751
Figure C20058001426600761
Figure C20058001426600771
Figure C20058001426600781
Figure C20058001426600791
Figure C20058001426600801
Figure C20058001426600811
Figure C20058001426600821
Figure C20058001426600831
Figure C20058001426600841
Figure C20058001426600851
Figure C20058001426600861
Figure C20058001426600871
Figure C20058001426600881
Figure C20058001426600891
Figure C20058001426600901
Test example 1 (the Smad2/3 phosphorylation suppresses activity test)
Inoculation A549 cell spends the night with Ham ' the s F-12 culture medium culturing of having added 10%FBS on flat board.Replace this substratum with the same medium that contains or do not contain described compound, hatch again after 2 hours that to add final concentration be the TGF-β 1 of 1ng/ml, continued to hatch 1 hour.Hatch the recession that finishes and remove substratum, with using RIPA solution lysing cell behind the PBS cleaning cell.Make cell lysate solution produce immunoprecipitation with anti-Smad2/3 antibody, carry out the test of Western trace then.As primary antibody, the anti-rabbit igg antibody of HRP mark as detection reagent, is measured luminous quantity with Limi-Imager F1 (Roche Diagnostics) with ECL Western trace detection reagent as secondary antibody with the anti-phosphorylation Serine of rabbit antibody.
According to aforesaid method, measure the inhibition activity that each compound anti-TGF-beta 1 stimulates caused Smad2/3 phosphorylation, calculate the IC50 value.
Test-results is as shown in table 2.
Table 2
Compound number IC50 (nM) Compound number IC50 (nM)
Compound 50 80 Compound 129 107
Compound 52 24 Compound 171 89
Compound 57 45 Compound 175 126
Compound 68 31 Compound 176 77
Compound 80 89 Compound 186 38
Compound 81 52 Compound 191 31
Compound 83 99 Compound 197 92
Compound 87 38 Compound 198 93
Compound 105 32 Compound 199 70
Compound 124 67 Compound 201 42
Test example 2 (hair follicle cell proliferation test)
According to people's such as Arase method (Arase etc., J Dermatol sci 2,66-70 (1991)), from the people sends out, separate hair follicle cell and use KGM-1 (Clonetics) to cultivate.
Hair follicle cell is inoculated on 24 orifice plates, and the substratum that contains or do not contain described compound after the overnight incubation with another is replaced substratum, hatches that to add final concentration after 2 hours be the TGF-β 1 of 0.1ng/ml again, continues to hatch 72 hours.Finish preceding 2 hours of cultivation, with 1/10 amount adding Alamar blue reagent in substratum of substratum, (Ex:544nm is Em:590nm) to determine the quantity of viable cell for the fluorescence intensity of mensuration substratum.Fig. 1 shows and only to give TGF-β 1 and to give TGF-β 1 simultaneously and the viable cell quantity during described compound that supposing not add the viable cell quantity of TGF-β 1 culturing cell after 72 hours is 100%.
Industrial applicibility
The compounds of this invention has the I receptor ALK5 of TGF-β and suppresses active, can be used as the medicine of the multiple disease relevant with the I receptor ALK5 of TGF-β such as treatment or prevention baldness or nephrosis etc.

Claims (11)

1. formula
Figure C2005800142660002C1
A kind of thiazole derivative or its pharmacy acceptable salt of expression, wherein
X 1It is sulphur atom;
X 2It is carbon atom;
R 1The expression phenyl; Be selected from halogen atom, had the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, hydroxyl, have the phenyl alkoxyl group of 7-12 carbon atom and have the phenyl of 1-5 group replacement of the alkylamino of 1-6 carbon atom; With contain at least 1 heteroatomic 5-7 membered aromatic heterocycle or nonaromatic heterocycles condensed phenyl that is selected from nitrogen, oxygen and sulphur; Pyridyl; Quinolyl; Isoquinolyl; Or with contain at least 1 heteroatomic 5-7 membered aromatic heterocycle condensed pyridyl that is selected from nitrogen, oxygen and sulphur;
R 2Expression hydrogen atom, halogen atom, have 1-6 carbon atom alkyl, by the alkyl with 1-6 carbon atom of 1-5 halogen atom replacement, have 1-6 carbon atom alkoxyl group, have the alkyloyl of 1-6 carbon atom or have the hydroxyalkyl of 1-5 carbon atom; With
A is a formula
Figure C2005800142660002C2
Or
Figure C2005800142660002C3
The group of expression, wherein:
R 3The expression hydrogen atom; Hydroxyl; Alkyl with 1-6 carbon atom; Phenylalkyl with 7-12 carbon atom; Or by hydroxyl, have 1-6 carbon atom alkoxyl group, had the phenylalkyl with 7-12 carbon atom of the alkoxyl group replacement with 1-6 carbon atom of alkoxyl group that the alkoxyl group of 1-6 carbon atom replaces or alkylamino replacement with 1-6 carbon atom with 1-6 carbon atom;
R 4The expression phenyl; Quilt is selected from halogen atom, is had the phenyl of 1-5 group replacement of the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, formamyl and cyano group; Hydrogen atom; Alkyl with 1-12 carbon atom; Thiazolinyl with 2-12 carbon atom; Cycloalkyl with 3-7 carbon atom; Had the alkyl that alkoxyl group, the hydroxyl of 1-6 carbon atom, the alkoxyl phenyl alkoxyl group with 8-12 carbon atom, phthalimido, tosyloxy or morpholino replace with 1-12 carbon atom; By the alkyl with 1-6 carbon atom of 1-5 halogen atom replacement; The cycloalkyl that is replaced by the oxo base with 3-9 carbon atom; THP trtrahydropyranyl; The 4-piperidyl; Had the alkyl of 1-6 carbon atom or the piperidyl that tertbutyloxycarbonyl replaces; Hexanaphthene spiral shell-2 '-(1,3-dioxane amyl group); Pyrrolidin-2-one-5-base; Formula-Y 1-Z 1-NR 5-Z 2-Y 2-R 6The group of expression, wherein:
Y 1And Y 2Identical or different, expression singly-bound or have the alkylidene group of 1-12 carbon atom;
R 5Expression hydrogen atom or have the alkyl of 1-12 carbon atom;
Z 1And Z 2Identical or different, the expression singly-bound; Alkylidene group with 1-7 carbon atom;-CO-;-CO 2-;-SO 2-or-OCO-; And
R 6Expression has the cycloalkyl of 3-7 carbon atom; By the alkyl with 1-6 carbon atom of 1-3 halogen atom replacement; Thiazolinyl with 2-6 carbon atom; Alkynyl with 2-6 carbon atom; Amino; Be selected from the amino of 1-2 group replacement of the alkyl with 1-6 carbon atom, cycloalkyl and tertbutyloxycarbonyl with 3-7 carbon atom; Piperidino-(1-position only); Piperidyl; Piperidyl with alkyl replacement of 1-6 carbon atom; Pyrrolidyl; Piperazinyl; Piperazinyl with alkyl replacement of 1-6 carbon atom; Morpholino; Hydroxyl; Alkoxyl group with 1-6 carbon atom; By hydroxyl or have the alkoxyl group that the alkoxyl group of 1-6 carbon atom replaces with 1-6 carbon atom; Trimethylene oxide-2-base; Tetrahydrofuran base; THP trtrahydropyranyl; Hydrogen atom; Phenyl; Phenyl with alkoxyl group replacement of 1-4 carbon atom; Or when being connected, nitrogen-atoms in the said structure formula becomes the group of ring; Or by structural formula-Y 3-CO-R 41The group of expression, wherein:
Y 3Expression singly-bound or have the alkylidene group of 1-7 carbon atom;
R 41The expression hydroxyl; Alkoxyl group with 1-6 carbon atom; Piperidino-(1-position only); Had 1-6 carbon atom alkyl, have the morpholino alkyl of 5-10 carbon atom or have piperazine-1-base that the alkylamino alkyl of 2-14 carbon atom replaces; Or morpholino.
2. thiazole derivative according to claim 1 or its pharmacy acceptable salt, wherein R 2Be hydrogen atom, halogen atom, have the alkyl of 1-6 carbon atom or a alkyl that is replaced by 1-5 halogen atom with 1-6 carbon atom.
3. thiazole derivative according to claim 1 or its pharmacy acceptable salt, wherein R 2Be alkyl or trifluoromethyl with 1-6 carbon atom.
4. thiazole derivative according to claim 1 or its pharmacy acceptable salt, wherein R 2Be methyl or trifluoromethyl.
5. according to the described thiazole derivative of arbitrary claim or its pharmacy acceptable salt, wherein R among the claim 1-4 1Be and contain at least 1 heteroatomic 5-7 membered aromatic heterocycle or nonaromatic heterocycles condensed phenyl that is selected from nitrogen, oxygen and sulphur.
6. one kind being the ALK5 inhibitor of activeconstituents according to the described thiazole derivative of arbitrary claim or its pharmacy acceptable salt among the claim 1-5.
According to the described thiazole derivative of arbitrary claim or its pharmacy acceptable salt among the claim 1-5 in preparation as the curative of glomerulonephritis, diabetic nephropathy, hepatic fibrosis, liver cirrhosis, pulmonary fibrosis, proliferative vitreoretinopathy or baldness or educate purposes in the medicine of sending out agent.
8. purposes according to claim 7, wherein curative or educate and send out agent as externally applied agent.
9. to breed stimulant as the hair follicle of activeconstituents according to the described thiazole derivative of arbitrary claim or its pharmacy acceptable salt among the claim 1-5.
With according to the described thiazole derivative of arbitrary claim or its pharmacy acceptable salt among the claim 1-5 as the hair growth promoter of activeconstituents or educate and send out an agent.
11. formula
Figure C2005800142660004C1
Thiazole derivative or its pharmacy acceptable salt of expression, wherein:
X 1It is sulphur atom;
X 2It is carbon atom;
R 1The expression phenyl; Be selected from halogen atom, had the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, hydroxyl, have the phenyl alkoxyl group of 7-12 carbon atom and have the phenyl of 1-5 group replacement of the alkylamino of 1-6 carbon atom; With contain at least 1 heteroatomic 5-7 membered aromatic heterocycle or nonaromatic heterocycles condensed phenyl that is selected from nitrogen, oxygen and sulphur; Pyridyl; Quinolyl; Isoquinolyl; Or with contain at least 1 heteroatomic 5-7 membered aromatic heterocycle condensed pyridyl that is selected from nitrogen, oxygen and sulphur;
R 2Expression hydrogen atom, halogen atom, have 1-6 carbon atom alkyl, by the alkyl with 1-6 carbon atom of 1-5 halogen atom replacement, have 1-6 carbon atom alkoxyl group, have the alkyloyl of 1-6 carbon atom or have the hydroxyalkyl of 1-5 carbon atom; With
A 1Be formula
Figure C2005800142660005C1
Or
Figure C2005800142660005C2
The group of expression, wherein X 3Expression hydrogen atom, halogen atom or have the alkyl of 1-6 carbon atom.
CN200580014266A 2004-03-05 2005-03-04 Thiazole derivative Expired - Fee Related CN100584842C (en)

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