CN109912576A - Cyclic annular or loop coil Diamines pyrimidine-hydroxamic acid and application thereof - Google Patents

Cyclic annular or loop coil Diamines pyrimidine-hydroxamic acid and application thereof Download PDF

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CN109912576A
CN109912576A CN201910212087.1A CN201910212087A CN109912576A CN 109912576 A CN109912576 A CN 109912576A CN 201910212087 A CN201910212087 A CN 201910212087A CN 109912576 A CN109912576 A CN 109912576A
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pyrimidine
formulas
preparation
methyl
hydroxamic acid
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CN109912576B (en
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李剑
江陆斌
李若曦
黄正辉
汤同柯
凌大正
王熳炯
朱进
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East China University of Science and Technology
Institut Pasteur of Shanghai of CAS
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East China University of Science and Technology
Institut Pasteur of Shanghai of CAS
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Abstract

The present invention relates to a kind of pyrimidine-hydroxamic acid compounds and application thereof.Pyrimidine-the hydroxamic acid compound is compound or its pharmaceutically acceptable salt shown in Formulas I.Pyrimidine-hydroxamic acid compound provided by the invention has inhibition of histone deacetylase (HDAC) activity, can be used for anti-malaria medicaments.In Formulas I, R is hydrogen or C4~C16Saturated or unsaturated, substituted or non-substituted carbocylic radical or carbon heterocyclic base；N is 0 or 1；L is a kind of in following groups:Wherein, the substituent group of the substituted carbocylic radical or carbon heterocyclic base is selected from: C1~C3Alkyl, C1~C3It is one or more kinds of in alkoxy, halogen or cyano；The hetero atom of the carbon heterocyclic base is selected from: a kind of in oxygen, sulphur or nitrogen, hetero atom number is 1 or 2.

Description

Cyclic annular or loop coil Diamines pyrimidine-hydroxamic acid and application thereof
Technical field
The present invention relates to a kind of pyrimidine-hydroxamic acid compounds and application thereof；Specifically, being related to a kind of cyclic annular or spiral shell Ring Diamines pyrimidine-hydroxamic acid and application thereof
Background technique
Malaria (Malaria) is a kind of unicellular parasite of entitled plasmodium (Plasmodium) of organism infection and draws The communicable disease risen.Plasmodium species are various, and the plasmodium for parasitizing the mankind has 6 kinds, i.e. plasmodium falciparum (Plasmodium Falciparum), Plasmodium vivax (Plasmodium vivax), malariae (Plasmodium malariae), two kinds Plasmodium ovale (Plasmodium ovale) and Plasmodium knowlesi (Plasmodium knowlesi).P.falciparum is Clinically cause to endanger maximum helminth, because it is that unique one kind can cause severe complication and can lead to dead malaria Protozoon；Although P.vivax causes serious complication unlike P.falciparum, geographical distribution is extensive and can lead to disease Disease recurrent exerbation；And the malaria as caused by P.malariae and P.ovale is not common.
Resistance problems are always the major obstacles of malaria control.The wreaking havoc of drug resistance relies on people for a long time natural (quinine) or artificial synthesized (chloroquine, Mefloquine, primary amine quinoline etc.) aminoquinolines drug or antibiotics (sulfadoxine, Pyrimethamine etc.) curative effect have a greatly reduced quality.Qinghaosu and qinghaosu conjoint therapy (artemisinin Combinationtherapy, ACT) predicament that changes antimalarial medication, become the core force of contemporary malaria treatment.Unfortunate It is the resistance to ACT therapy occurred in Cambodia area before 10 years.The malaria of qinghaosu tolerance in recent years is in Southeast Asia river bank public affairs River valley wide-scale distribution, or even have the risk for being disseminated to Africa.Tradition antimalarial agent is mainly concentrated through prevention malarial pigment at present It generates, interference folic acid synthesis, breaks mitochondrial electron transport chain and DNA and egg are generated and then caused using low price iron induced radical White matter alkylation etc. plays drug effect.As time goes by, the resistance that the drug of traditional mechanism faces threatens increasing.Therefore, Antimalarial agent novel targets are found, in particular for the key link in plasmodium life cycle, developing has different from existing The antimalarial agent of the novel mechanism of chemotherapeutics, the resistance problems got worse for solution are significant.
Histon deacetylase (HDAC) (histone deacetylase, HDAC) can be catalyzed lysine in histone, arginine The deacetylation of residue, to adjust the structure of cyto-chromatin, transcription and gene expression.There are five types of P.falciparum HDAC, wherein 3 kinds are respectively I class (PfHDAC1) and II class (PfHDAC2/3) HDAC, remaining 2 kinds are then Group III HDAC (PfSir2A/2B).Research shows that PfHDAC1 participates in histone and nonhistones posttranslational modification, to influence the table of gene Up to as a result, the significance of existence to plasmodium is great；PfHDAC3 is most important to vegetative phase P.falciparum existence and growth, And it plays a role in transcriptional control；PfSir2A and PfSir2B is adjusted gene expression, maintains telomere length, and influences The expression of PfEMP1 albumen, and PfEMP1 variation can help plasmodium to escape host immune killing when invading human body.1996 Darkin-Ratray reports that cyclic peptide hdac inhibitor apicidin has antimalarial active (IC50=200nM), henceforth pass through Effort in more than 20 years is crossed, multiple seminars further investigate the hdac inhibitors antimalarial curative effects such as romidepsin, vorinostat, or Structure of modification is carried out to develop noval chemical compound using known hdac inhibitor, is being improved antimalarial curative effect, is being reduced and take in collective's toxicity Obtained significant achievement.
Therefore, the novel HDAC that performance is more excellent and structure is relatively easy and preparation cost is relatively low is developed to inhibit Agent becomes the technical problem to be solved in the invention.
Summary of the invention
The invention discloses a kind of pyrimidine-hydroxamic acid compounds of structure novel, numerous to surviving with plasmodium It grows the HDAC enzyme Inhibition test for having substantial connection and all shows stronger inhibitory activity in the desinsection effect experiment of inside and outside, and this Pyrimidine-hydroxamic acid compound provided by inventing has that structure is relatively simple, preparation process is succinct low with production cost etc. Feature.
In addition, pyrimidine-hydroxamic acid compound provided by the present invention is not only expected to develop into novel single drug The anti-malaria medicaments of mode, but also the anti-malaria medicaments being combined with existing anti-malaria medicaments can be developed into.
Therefore, a purpose of the invention is, discloses a kind of pyrimidine-hydroxamic acid compound of structure novel.
Pyrimidine-hydroxamic acid compound of the present invention is compound shown in Formulas I or it is pharmaceutically acceptable Salt:
In Formulas I, R is that hydrogen (H) or carbon atom number are four to 16 (to be abbreviated as " C4~C16") it is saturated or unsaturated, Substituted or non-substituted carbocylic radical or carbon heterocyclic base；N is 0 or 1；L be it is a kind of in following groups (curve mark be substitution position, Similarly hereinafter):
Wherein, the substituent group of the substituted carbocylic radical or carbon heterocyclic base is selected from: C1~C3Alkyl, C1~C3Alkoxy, halogen (containing two kinds) one or more kinds of in plain (F, Cl, Br or I) or cyano (CN)；The hetero atom of the carbon heterocyclic base is selected from: oxygen (O), a kind of in sulphur (S) or nitrogen (N), hetero atom number is 1 or 2.
It is another object of the present invention to provide a kind of composition.
The composition include above-mentioned pyrimidine-hydroxamic acid compound (compound shown in Formulas I or its pharmaceutically may be used The salt of receiving).
Further object of the present invention is, disclose above-mentioned pyrimidine-hydroxamic acid compound (compound shown in Formulas I or its Pharmaceutically acceptable salt) and combinations thereof a kind of purposes.That is: compound shown in Formulas I or its is pharmaceutically acceptable Salt, and combinations thereof preparing the application in histon deacetylase (HDAC) (HDAC) inhibitor；Or,
Compound shown in Formulas I or its pharmaceutically acceptable salt, and combinations thereof preparation treatment anti-malarial drug in answering With.
In addition, a further object of the invention is, a kind of method of compound shown in preparation formula I is provided.The method Include the following steps:
(1) by the chloro- pyrimidine -5-carboxylic acid's ethyl ester of 2-It is reacted with H-L-Boc, compound shown in Formula II is made Step；
(2) the step of compound as shown in Formula II is reacted with corresponding aldehyde (RCHO), and compound shown in formula III is made；
(3) the step of compound shown in the preparation of compounds of formula IV as shown in formula III；
(4) the step of compound shown in the preparation of compounds of formula V as shown in formula IV；With,
(5) the step of partial target object is made in compound shown in Formula V；
Or,
(2) the step of compound shown in the preparation of compounds of formula iii as shown in Formula II；
(3) the step of compound shown in the preparation of compounds of formula iv as shown in formula iii；
(4) the step of compound shown in the preparation of compounds of formula v as shown in formula iv；
(5) the step of compound shown in the preparation of compounds of formula vi as shown in formula v；
(6) the step of compound shown in formula vi is reacted with corresponding aldehyde (RCHO), and compound shown in Formula V is made；With
(7) the step of remaining object is made in compound shown in the compound as shown in formula vi and Formula V respectively.
Figure of description
Fig. 1 is that part of compounds of the present invention and positive control piperaquine phosphate (PPQ) pharmacodynamic results in Mice Body are illustrated Figure；
Fig. 2 is part of compounds of the present invention and the Western Blot experimental result picture of positive control JL01.
Specific embodiment
In a preferred technical solution of the invention, the pyrimidine-hydroxamic acid compound is Formulas IAShownization Close object or its pharmaceutically acceptable salt:
Formulas IAIn, RAFor hydrogen (H) or C4~C16Saturated or unsaturated, substituted or non-substituted carbocylic radical or carbon heterocyclic Base；N is 0 or 1；
Wherein, the substituent group of the substituted carbocylic radical or carbon heterocyclic base is selected from: C1~C3Alkyl, C1~C3Alkoxy, halogen (containing two kinds) one or more kinds of in element or cyano (CN)；The hetero atom of the carbon heterocyclic base is selected from: oxygen (O), sulphur (S) or nitrogen (N) a kind of in, hetero atom number is 1 or 2.
Further preferred technical solution is: n 1；RAFor 5~6 yuan of aromatic ring yl or aromatic heterocyclic, or the 5~6 of substitution The aromatic ring yl or aromatic heterocyclic of member；
Wherein, the substituent group of the aromatic ring yl or aromatic heterocyclic of substituted 5~6 yuan is C1~C3Alkyl, phenyl(divalent phenyl group is divalent phenyl groupIt is the relationship of " simultaneously " with substituted female ring), substituted divalent phenyl group Or the pyridyl group of divalent (the adjacent carbon atom of any two can be substitution position)；The hetero atom of the aromatic heterocyclic is selected from: oxygen (O), a kind of in sulphur (S) or nitrogen (N), hetero atom number is 1 or 2；
Wherein, the substituent group of the substituted divalent phenyl group is one or more kinds of in following groups (containing two kinds):
C1~C3Alkyl, C1~C3Alkoxy, halogen (F, Cl, Br or I) or cyano (CN).
Further preferred technical solution is: RAFor anthryl, phenanthryl, quinolyl, halogen (F, Cl, Br or I) is for quinoline Group shown in base or Formula IV:
In Formula IV, RA1It is selected from: C1~C3Alkyl, hydrogen (H), C1~C3Alkoxy, halogen (F, Cl, Br or I) or cyano (CN) Middle one or more kinds of (containing two kinds)；X is O, S or NRA2；
Wherein, RA2For hydrogen (H) or C1~C3Alkyl.
Further preferred technical solution is again: RAIt is a kind of in following groups:
In presently preferred technical solution, the pyrimidine-hydroxamic acid compound is Formulas IBShownization Close object or its pharmaceutically acceptable salt:
Formulas IBIn, RBFor 5~6 yuan of aromatic ring yl or aromatic heterocyclic, or 5~6 yuan of the aromatic ring yl or aromatic heterocyclic replaced；
Wherein, the substituent group of the aromatic ring yl or aromatic heterocyclic of substituted 5~6 yuan is C1~C3Alkyl, phenyl(divalent phenyl group is divalent phenyl groupIt is the relationship of " simultaneously " with substituted female ring), substituted divalent phenyl group Or the pyridyl group of divalent (the adjacent carbon atom of any two can be substitution position)；
The substituent group of the substituted divalent phenyl group is one or more kinds of in following groups (containing two kinds):
C1~C3Alkyl, C1~C3Alkoxy, halogen (F, Cl, Br or I) or cyano (CN).
Further preferred technical solution is: RBFor naphthalene, quinolyl, isoquinolyl, C1~C3Alkyl-substituted indazolyl Or group shown in benzimidazolyl or Formula VII:
In Formula VII, RB1It is selected from: C1~C3Alkyl, hydrogen (H), C1~C3Alkoxy, halogen (F, Cl, Br or I) or cyano (CN) (containing two kinds) one or more kinds of in；X is O, S or NRB2；Y is CH or N；
Wherein, RB2For hydrogen (H) or C1~C3Alkyl.
Technical solution still more preferably is: RBIt is a kind of in following groups:
In another optimal technical scheme of the invention, the pyrimidine-hydroxamic acid compound is Formulas ICShownization Close object or its pharmaceutically acceptable salt:
Formulas ICIn, RCFor 5~6 yuan of aromatic ring yl or aromatic heterocyclic, or 5~6 yuan of the aromatic ring yl or aromatic heterocyclic replaced；
Wherein, the substituent group of the aromatic ring yl or aromatic heterocyclic of substituted 5~6 yuan is C1~C3Alkyl, phenyl (divalent phenyl group is divalent phenyl groupAnd itself and female ring are the relationship of " simultaneously ", and similarly hereinafter), substituted two The pyridyl group of valence phenyl or divalent (the adjacent carbon atom of any two can be substitution position)；
The substituent group of the substituted divalent phenyl group is one or more kinds of in following groups (containing two kinds):
C1~C3Alkyl, C1~C3Alkoxy, halogen (F, Cl, Br or I) or cyano (CN).
Further preferred technical solution is: RCSubstituent group for substituted indyl, the substituted indyl is selected from (containing two kinds) one or more kinds of in following groups:
C1~C3Alkyl, C1~C3Alkoxy, halogen (F, Cl, Br or I) or cyano (CN).
Technical solution still more preferably is: RCIt is a kind of in following groups:
It is in terms of 100%, in the combination by the total weight of the composition in another optimal technical scheme of the invention 0.001wt%~99wt% can be contained in object, preferably 0.1wt%~90wt%, the more preferably Formulas I of 1wt%~80wt% institute Show compound or its pharmaceutically acceptable salt.The composition also contains other drug ingedients with anti-malarial activity, It includes but is not limited to: qinghaosu, Artemether, artemisic succinate, lumefantrine, sulfadoxine, pyrimethamine, is coughed up dihydroartemisinine Naphthyridines, Atovaquone, quinine, chloroquine, piperaquine, Mefloquine, amodiaquine, primary amine quinoline or/and tafenoquine etc..
The method of compound shown in preparation formula I provided by the invention, specifically includes the following steps:
(1) by 2- (N4(tertbutyloxycarbonyl)-cis- -1,4- cyclohexanediamineWith the chloro- pyrimidine -5- carboxylic of 2- Acetoacetic ester is dissolved in halogenated hydrocarbons (such as methylene chloride), under the conditions of 0 DEG C~5 DEG C, n,N-diisopropylethylamine is added, finishes, It is warmed to room temperature (25 DEG C, similarly hereinafter), stirs 5~6 hours to temperature.Water is added into reaction solution, vibrates liquid separation, removes under reduced pressure molten Agent, remaining solid silica gel column chromatography separating purification obtain 2- (N4(tertbutyloxycarbonyl)-cis- -1,4- cyclohexanediamine-N1Ammonia Base)-pyrimidine -5-carboxylic acid's ethyl ester (faint yellow solid)；
Above-mentioned faint yellow solid is dissolved in halogenated hydrocarbons (such as methylene chloride), hydrogen chloride-dioxane solution, room is added Warm lower stirring 5-6 hours.Evaporating solvent under reduced pressure obtains grease (2- (cis--Isosorbide-5-Nitrae-cyclohexanediamine-N1Amino)-pyrimidine -5- Carboxylic acid, ethyl ester, Formula IIAShown compound), it is directly used in and reacts in next step；
(2) by Formula IIAShown compound is dissolved in halogenated hydrocarbons (such as methylene chloride), and n,N-diisopropylethylamine is added. Under the conditions of 0 DEG C~5 DEG C, it is added dropwise to benzyl chloro formate, is finished, is warmed to room temperature to reacting liquid temperature, stirred 5~6 hours.Add Enter saturated sodium bicarbonate aqueous solution, vibrate liquid separation, evaporating solvent under reduced pressure, remaining solid silica gel column chromatography separating purification obtains light Yellow solid (2- (N4(benzene methoxycarbonyl group)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5-carboxylic acid's ethyl ester, formula iiiA Shown compound)；
(3) by formula iiiAShown compound is dissolved with the mixed liquor combined by first alcohol and water, potash solid is added, 65 DEG C~70 DEG C of states keep for 5-6 hours.Evaporating solvent under reduced pressure, it is about 1 that residue, which is acidified to pH with hydrochloric acid, is filtered, remaining solid It is about 7 to be washed to pH, drying obtains white solid (2- (N4(benzene methoxycarbonyl group)-cis- -1,4- cyclohexanediamine-N1Amino)- Pyrimidine -5-carboxylic acid, formula ivAShown compound)；
(4) by formula ivAShown compound N,N-dimethylformamide and halogenated hydrocarbons (such as methylene chloride etc.) with being made of Mixed liquor dissolution, sequentially adds I-hydroxybenzotriazole and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, room After the lower stirring of temperature at least 30 minutes, O- (tetrahydro -2H- pyrans -2- base) azanol and triethylamine are sequentially added, then at stirring at room temperature 48 hours.Saturated sodium bicarbonate aqueous solution is added, vibrates liquid separation, evaporating solvent under reduced pressure, remaining solid is separated with silica gel column chromatography Purifying, obtains beige solid (2- (N4(benzene methoxycarbonyl group)-cis- -1,4- cyclohexanediamine-N1Amino)-N- (tetrahydro -2H- pyrrole Mutter -2- base-oxygroup) pyrimidine -5- amide, formula vAShown compound)；
(5) by formula vAThe shown compound mixed liquor being made of methanol and halogenated hydrocarbons (such as methylene chloride) dissolves, according to Secondary addition triethylsilane and palladium carbon, stirring (thin-layer chromatography tracking) to raw material disappears at 35 DEG C, is filtered to remove Pd/C, decompression steaming Except solvent, 2- (2,8- diaza-spiros-[4.5]-decane -8- base)-N- (tetrahydro -2H- pyrans -2- base-oxygroup) pyrimidine -5- is obtained Amide (formula viAShown compound), formula viAShown compound can be directly used for reacting in next step；
(6) by formula viAShown compound is dissolved with methanol, and corresponding aldehyde (R is addedACHO), sodium cyanoborohydride, at room temperature Stirring 24-60 hours.Saturated sodium bicarbonate aqueous solution is added, liquid separation, evaporating solvent under reduced pressure, remaining solid silicagel column are vibrated Chromatography purifying, obtaining 4 N atoms of cyclohexanediamine is RACH2Substituted 2- (cis- -1,4- cyclohexanediamine-N1Amino)-N- (tetrahydro -2H- pyrans -2- base-oxygroup) pyrimidine -5- amide (Formula VAShown compound)；With,
(7) by formula viAShown compound and Formula VAShown compound uses halogenated hydrocarbons (such as methylene chloride) to dissolve respectively, adds Enter hydrogen chloride/dioxane mixed liquor, stirs 30 minutes at room temperature.It filters, gained filter cake is with halogenated hydrocarbons (such as methylene chloride) Solid obtains partial target object (Formulas IAShown compound).
Or,
(1) respectively by 1- oxa- -4,9- diaza spiro [5.5] hendecane -9- carboxylic acid tert-butyl esterWith uncle 2- Half oxalates of butoxy carbonyl -2,6- diaza spiroheptaneIt is molten with the chloro- pyrimidine -5-carboxylic acid's ethyl ester of 2- In halogenated hydrocarbons (such as methylene chloride), under the conditions of 0 DEG C~5 DEG C, n,N-diisopropylethylamine is added, finishes, to temperature liter To being stirred at room temperature 5~6 hours.Water is added into reaction solution, vibrates liquid separation, evaporating solvent under reduced pressure, remaining solid silica gel column layer Analysis isolates and purifies, and obtains 2- (5- (ethoxy carbonyl) pyrimidine -2-base) -1- oxa- -4,9- diaza spiro [5.5] hendecane -9- carboxylic Tert-butyl acrylate (white solid) or 2- (6- tertbutyloxycarbonyl -2,6- diaza spiroheptane -2- base)-pyrimidine -5-carboxylic acid Ethyl ester (white solid)；
Above two white solid is dissolved in halogenated hydrocarbons (such as methylene chloride) respectively, hydrogen chloride-dioxane is added Mixed liquor stirs 5-6 hours at room temperature.Vacuum distillation removes solvent, and remaining mixture is divided by silica gel column chromatography separating purification Oily 2- (1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5-carboxylic acid's ethyl ester (Formula II is not obtainedBShown chemical combination Object) and oily 2- (2,6- diaza spiroheptane -2- base)-pyrimidine -5-carboxylic acid's ethyl ester (Formula IICShown compound)；
(2) respectively by Formula IIBAnd IICShown compound is dissolved in halogenated hydrocarbons (such as 1,2- dichloroethanes etc.), is separately added into phase Aldehyde (the R answeredBCHO and RCCHO), glacial acetic acid, sodium triacetoxy borohydride are stirred overnight at room temperature.Saturated sodium bicarbonate water is added Solution vibrates liquid separation, and organic phase vacuum distillation removes solvent, and remaining mixture silica gel column chromatography separating purification respectively obtains Intermediate: formula IIIBShown compound and formula IIICShown compound；
(3) respectively by formula IIIBAnd IIICShown compound is dissolved with the mixed liquor being made of first alcohol and water, and potassium carbonate is added Solid, 65 DEG C~70 DEG C heating are reacted 5-6 hours, and vacuum distillation removes solvent, and it is about 1 that residue, which is acidified to pH with hydrochloric acid, is subtracted Water is distilled off in pressure, must be mixed with the intermediate of inorganic salts: formula IVBShown compound and formula IVCShown compound, is directly used in down Step reaction；
(4) respectively by formula IVBAnd IVCShown compound n,N-Dimethylformamide solution dissolves, and sequentially adds 1- hydroxyl Benzotriazole and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, after stirring at least 30 minutes at room temperature, successively O- (tetrahydro -2H- pyrans -2- base) azanol and triethylamine is added, stirs 48 hours at room temperature, saturated sodium bicarbonate aqueous solution is added And methylene chloride, liquid separation is vibrated, organic phase water extracts three times, and organic phase vacuum distillation removes solvent, remaining mixture silicon Plastic column chromatography isolates and purifies, and obtains intermediate: Formula VBShown compound and Formula VCShown compound；With,
(5) respectively by Formula VBAnd VCShown compound is dissolved with halogenated hydrocarbons (such as methylene chloride), and hydrogen chloride-dioxy is added Six ring mixed liquors in room temperature or room temperature and under having inert gas (such as nitrogen) existence condition, stir 30 minutes.Filtering, filter cake Through halogenated hydrocarbons (such as methylene chloride) or ether washing to get remaining object (Formulas IBAnd ICShown compound).
The present invention is further elaborated by the following examples, for embodiment be only used for being best understood from invention, but It is not in any way limit the scope of the present invention.In embodiment raw materials used and reagent (including HepG2,293T and its Its biochemical reagents is commercially available, malaria worm strain 3D7, and Dd2 etc. is bought from ATCC cell bank.
Embodiment 1
(1) 2- (cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5-carboxylic acid's ethyl ester (Formula IIAShown compound) system It is standby:
By 21.4 grams of N4(tertbutyloxycarbonyl)-cis- -1,4- cyclohexanediamine and the chloro- pyrimidine -5-carboxylic acid's ethyl ester of 22.4 grams of 2- It is dissolved in 500 milliliters of methylene chloride, ice bath is cooled to 0-5 DEG C, and 25 milliliters of n,N-diisopropylethylamine are added, finishes, removes ice Bath restores to room temperature to reacting liquid temperature, stirs 6 hours.Water is added into reaction solution, vibrates liquid separation, evaporating solvent under reduced pressure remains Remaining solid obtains faint yellow solid with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1 (v/v)).
1H NMR(400MHz,DMSO-d6) δ 8.77 (s, 2H), 4.26 (q, J=7.1Hz, 2H), 3.78 (m, 1H), 3.17 (m, 1H), 2.11-1.80 (m, 6H), 1.55 (m, 2H), 1.40 (s, 9H), 1.29 (t, J=7.1Hz, 3H)
36.4 grams of above-mentioned faint yellow solid are dissolved in 500 milliliters of methylene chloride, hydrogen chloride-dioxy six of 4N is slowly added to 100 milliliters of ring solution, lower at room temperature to stir 6 hours, evaporating solvent under reduced pressure obtains grease (Formula IIAShown compound), directly use It is reacted in next step.
1H NMR(400MHz,DMSO-d6) δ 8.77 (s, 2H), 4.26 (q, J=7.1Hz, 2H), 3.78 (m, 1H), 3.15 (m, 1H), 2.11-1.80 (m, 6H), 1.55 (m, 2H), 1.29 (t, J=7.1Hz, 3H)
(2)2-(N4(benzene methoxycarbonyl group)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5-carboxylic acid's ethyl ester (formula iiiAShown compound) preparation:
By 26.4 grams of Formula IIAShown compound is dissolved in 500 milliliters of methylene chloride, and 41 milliliters of N, N- diisopropyl second is added Amine, ice bath are cooled to 0-5 DEG C, are slowly added dropwise into 17 milliliters of benzyl chloro formates, finish, remove ice bath, extensive to reacting liquid temperature Multiple to room temperature, saturated sodium bicarbonate aqueous solution is added in stirring 6 hours, vibrates liquid separation, evaporating solvent under reduced pressure, remaining solid silicon Plastic column chromatography isolates and purifies (petrol ether/ethyl acetate=5/1 (v/v)), obtains faint yellow solid (formula iiiAShown compound).
1H NMR(400MHz,DMSO-d6)δ8.77(s,2H),7.48–7.27(m,5H),5.07(s,2H),4.26(q,J =7.1Hz, 2H), 3.79 (m, 1H), 3.20 (m, 1H), 2.11-1.80 (m, 6H), 1.55 (m, 2H), 1.29 (t, J=7.1Hz, 3H).
(3)2-(N4(benzene methoxycarbonyl group)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5-carboxylic acid (formula ivAIt is shown Compound) preparation:
By 40 grams of formula iiiAShown compound is dissolved in 500 milliliters of mixed liquor (1:1, v/v) being made of methanol-water, is added 35 grams of potash solids, 65~70 DEG C of heating are reacted 6 hours, and evaporating solvent under reduced pressure, it is about 1 that residue, which is acidified to pH with hydrochloric acid, It filters, remaining solid is about 7 to be washed to pH, and drying obtains white solid (formula ivAShown compound).
1H NMR(400MHz,DMSO-d6)δ8.79(m,2H),7.48–7.27(m,5H),5.07(s,2H),3.79(m, 1H),3.20(m,1H),2.11–1.80(m,6H),1.55(m,2H).
(4)2-(N4(benzene methoxycarbonyl group)-cis- -1,4- cyclohexanediamine-N1Amino)-N- (tetrahydro -2H- pyrans -2- base - Oxygroup) pyrimidine -5- amide (formula vAShown compound) preparation:
By 18.5 grams of formula ivAShown compound is dissolved in the mixed liquor being made of N,N-dimethylformamide and methylene chloride 250 milliliters of (1:1, v/v) sequentially adds 13.5 grams of I-hydroxybenzotriazoles and 19.2 grams of 1- (3- dimethylamino-propyl) -3- second Base carbodiimide hydrochloride sequentially adds 17.8 grams of O- (tetrahydro -2H- pyrans -2- base) azanol after stirring 30 minutes at room temperature It with 21 milliliters of triethylamines, stirs 48 hours at room temperature, addition saturated sodium bicarbonate aqueous solution, oscillation liquid separation, evaporating solvent under reduced pressure, Remaining solid obtains beige solid (formula v with silica gel column chromatography separating purification (methylene chloride/methanol=60/1 (v/v))AIt is shown Compound).
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.67(s,2H),7.46–7.28(m,5H),5.07(s, 2H), 4.95 (d, J=3.4Hz, 1H), 4.09-3.99 (m, 1H), 3.79 (m, 1H), 3.53 (dd, J=10.6,5.4Hz, 1H), 3.20(m,1H),2.11–1.80(m,12H),1.55(m,2H).
(5) 2- (cis- -1,4- cyclohexanediamine-N1Amino)-N- (tetrahydro -2H- pyrans -2- base-oxygroup) pyrimidine -5- acyl Amine (formula viAShown compound) preparation:
By 4.7 grams of formula vA50 milliliters of the mixed liquor (1:1, v/v) being made of methanol and methylene chloride of shown compound Dissolution sequentially adds 2.13 gram of 10% palladium carbon and 8 milliliters of triethylsilanes, and stirring to raw material disappears at 35 DEG C, is filtered to remove Pd/ C, evaporating solvent under reduced pressure obtain white foam solid (formula viAShown compound), it is directly used in and reacts in next step.
1H NMR(400MHz,DMSO-d6) δ 11.51 (s, 1H), 8.67 (s, 2H), 4.95 (d, J=3.4Hz, 1H), 4.09-3.99 (m, 1H), 3.79 (m, 1H), 3.53 (dd, J=10.6,5.4Hz, 1H), 3.20 (m, 1H), 2.11-1.80 (m, 12H),1.55(m,2H).
(6)2-(N4(N- methyl indol -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-N- (tetrahydro -2H- pyrrole Mutter -2- base-oxygroup) pyrimidine -5- amide (Formula VACompound shown in -1) preparation:
By 0.34 gram of 2- (2,8- diaza-spiro-[4.5]-decane -8- base)-N- (tetrahydro -2H- pyrans -2- base-oxygroup) Pyrimidine -5- amide (formula vAShown compound), 0.24 gram of N- methyl indol -3- formaldehyde, 0.31 gram of sodium cyanoborohydride be dissolved in 10 Milliliter anhydrous methanol, is stirred at room temperature to end of reaction.It is included in saturated sodium bicarbonate aqueous solution, liquid separation is vibrated, removes under reduced pressure molten Agent, remaining solid obtain weak yellow foam shape solid with silica gel column chromatography separating purification (methylene chloride/methanol=20/1 (v/v)) (Formula VACompound shown in -1).
1H NMR (400MHz, Chloroform-d) δ 8.66 (s, 2H), 7.68 (d, J=7.9Hz, 1H), 7.32 (s, 1H), 7.23 (d, J=7.9Hz, 1H), 7.13 (t, J=7.3Hz, 2H), 5.06-4.97 (m, 1H), 4.09-3.99 (m, 1H), 3.79 (m, 1H), 3.53 (dd, J=10.6,5.4Hz, 1H), 3.20 (m, 1H), 2.11-1.80 (m, 12H), 1.55 (m, 2H)
(7) 2- (cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (Formulas IAChemical combination shown in -0 Object) and 2- (N4(N- methyl indol -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamate (formula IACompound shown in -1) preparation:
Respectively by 0.17 gram of 2- (cis- -1,4- cyclohexanediamine-N1Amino)-N- (tetrahydro -2H- pyrans -2- base-oxygroup) Pyrimidine -5- amide (formula viAShown compound) it is dissolved in 5 milliliters of methylene chloride and 0.13 gram of 2- (N4(N- methyl indol -3- first Base)-cis- -1,4- cyclohexanediamine-N1Amino)-N- (tetrahydro -2H- pyrans -2- base-oxygroup) pyrimidine -5- amide (Formula VA- 1 institute Show compound) be dissolved in 2.5 milliliters of methylene chloride, then be respectively added slowly to 4N 0.3 milliliter of hydrogen chloride-dioxane solution and It 0.15 milliliter, finishes, stirs 30 minutes at room temperature, filter, gained filter cake is washed with a large amount of methylene chloride, that is, respectively obtains target Object (Formulas IACompound and Formulas I shown in -0ACompound shown in -1).
Formulas IACompound shown in -0:
1H NMR(400MHz,DMSO-d6) δ 8.75 (s, 2H), 8.26 (bs, 3H), 8.18 (d, J=6.2Hz, 1H), 3.90 (m,1H),3.09(m,1H),1.91–1.83(m,2H),1.80–1.71(m,4H),1.70–1.59(m,2H).HRMS(ESI)[M +H]+,C11H18N5O2, theoretical value (cal.): 252.1455, experiment value (found): 252.1459.
Formulas IACompound shown in -1
1H NMR(400MHz,DMSO-d6) δ 11.13 (s, 1H), 9.24 (m, 2H), 8.66 (s, 2H), 7.68 (d, J= 7.9Hz, 1H), 7.32 (s, 1H), 7.23 (d, J=7.9Hz, 1H), 7.13 (t, J=7.3Hz, 2H), 4.35-4.15 (m, 2H), 3.96 (s, 3H), 3.79 (m, 1H), 3.51 (dd, J=10.6,5.4Hz, 1H), 2.11-1.80 (m, 6H), 1.55 (m, 2H)
HRMS(ESI)[M+H]+, C21H27N6O2, theoretical value (cal.): 395.2190, experiment value (found) 395.2195.
Embodiment 2
2-(N4(cyclopentyl-methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -2) preparation:
Divided by cyclopenta formaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -2.
1H NMR(400MHz,DMSO-d6) δ 11.11 (s, 1H), 8.66 (s, 4H), 7.72 (d, J=6.1Hz, 1H), 3.98 (m,1H),3.07(m,1H),2.86(m,2H),2.19(m,1H),1.96(m,2H),1.93–1.72(m,6H),1.68–1.44 (m,6H),1.24(m,2H).HRMS(ESI)[M+H]+, C17H28N5O2, cal.334.2238, found 334.2243.
Embodiment 3
2-(N4(cyclohexyl methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -3) preparation:
Divided by hexahydrobenzaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -3.
1H NMR(400MHz,DMSO-d6) δ 11.11 (s, 1H), 8.65 (m, 4H), 7.74 (d, J=6.1Hz, 1H), 3.98 (m,1H),3.05(m,1H),2.75(m,2H),1.95(m,2H),1.90–1.49(m,12H),1.18(m,3H),0.94(m, 2H).HRMS(ESI)[M+H]+,C18H30N5O2, cal.348.2394, found 348.2399.
Embodiment 4
2-(N4(benzyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (Formulas IA-4 Shown compound) preparation:
Divided by benzaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation side Method obtains Formulas I with embodiment 1ACompound shown in -4.
1H NMR(400MHz,DMSO-d6) δ 11.12 (s, 1H), 9.23 (m, 2H), 8.66 (s, 2H), 7.77 (d, J= 6.0Hz,1H),7.60(m,2H),7.43(m,3H),4.16(m,2H),3.95(m,1H),3.06(m,1H),2.08–1.72(m, 6H),1.71–1.46(m,2H).HRMS(ESI)[M+H]+,C18H24N5O2,cal.342.1925,found 342.1930。
Embodiment 5
2-(N4(2- picolyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -5) preparation:
Divided by 2- pyridine carboxaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -5.
1H NMR(400MHz,DMSO-d6) δ 11.18 (s, 1H), 9.39 (m, 2H), 8.69 (m, 3H), 8.00 (t, J= 7.7Hz, 1H), 7.85 (d, J=6.3Hz, 1H), 7.72 (d, J=7.8Hz, 1H), 7.52 (m, 1H), 4.37 (m, 2H), 3.98 (m,1H),3.17(m,1H),2.06–1.80(m,6H),1.69–1.55(m,2H).HRMS(ESI)[M+H]+,C17H23N6O2, cal.343.1877,found 343.1882。
Embodiment 6
2-(N4(3- picolyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -6) preparation:
Divided by 3- pyridine carboxaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -6.
1H NMR(400MHz,DMSO-d6) δ 9.41 (m, 2H), 8.72 (s, 2H), 8.00 (s, 1H), 7.79 (d, J= 3.0Hz, 1H), 7.61 (m, 1H), 7.42 (d, J=4.9Hz, 1H), 4.17 (t, J=5.7Hz, 2H), 3.97 (m, 1H), 3.02 (m,1H),2.06–1.76(m,6H),1.72–1.54(m,2H).HRMS(ESI)[M+H]+,C17H23N6O2,cal.343.1877, found343.1882。
Embodiment 7
2-(N4(4- picolyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -7) preparation:
Divided by 4- pyridine carboxaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -7.
1H NMR(400MHz,DMSO-d6) δ 11.15 (s, 1H), 10.05 (m, 2H), 8.98 (d, J=5.6Hz, 2H), 8.67 (s, 2H), 8.31 (d, J=6.8Hz, 2H), 7.82 (d, J=6.1Hz, 1H), 4.49 (m, 2H), 3.96 (m, 1H), 3.16 (m,1H),2.08–1.8(m,6H),1.68–1.53(m,2H).HRMS(ESI)[M+H]+,C17H23N6O2,cal.343.1877, found343.1882。
Embodiment 8
2-(N4(3- furfuryl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -8) preparation:
Divided by 3- furtural alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -8.
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.30(m,2H),8.68(s,2H),7.88(m,2H), 7.71(s,1H),6.80(s,1H),4.01(s,2H),3.94(s,1H),3.01(s,1H),2.22–1.70(m,6H),1.70– 1.49(m,2H).HRMS(ESI)[M+H]+,C16H22N5O3,cal.332.1717,found 332.1722。
Embodiment 9
2-(N4(3- thenyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -9) preparation:
Divided by 3- thiophenecarboxaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -9.
1H NMR(400MHz,DMSO-d6) δ 9.45 (m, 2H), 8.70 (s, 2H), 8.28 (s, 1H), 7.96 (d, J= 7.7Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.37 (m, 2H), 4.34 (m, 2H), 3.97 (m, 1H), 3.17 (m, 1H), 2.11–1.84(m,6H),1.70–1.54(m,2H).HRMS(ESI)[M+H]+,C16H22N5O2S,cal.348.1489,found 348.1493。
Embodiment 10
2-(N4(3- benzofuran methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas IACompound shown in -10) preparation:
Outside divided by N- methyl indol -3- formaldehyde in benzofuran -3- formaldehyde alternative embodiment 1, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains Formulas IACompound shown in -10.
1H NMR(400MHz,DMSO-d6) δ 9.91 (m, 2H), 9.21 (s, 1H), 8.94 (d, J=5.4Hz, 1H), 8.87 (d, J=8.0Hz, 1H), 8.70 (s, 2H), 8.18-8.06 (m, 1H), 7.94 (bs, 1H), 4.42 (t, J=5.9Hz, 1H), 3.96(m,1H),3.20(m,1H),2.07–1.80(m,6H),1.75–1.54(m,2H).HRMS(ESI)[M+H]+, C20H24N5O3,cal.382.1874,found 382.1879。
Embodiment 11
2-(N4(3- benzothiophene methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas IACompound shown in -11) preparation:
Outside divided by N- methyl indol -3- formaldehyde in benzothiophene -3- formaldehyde alternative embodiment 1, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains Formulas IACompound shown in -11.
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.38(m,2H),8.69(s,2H),8.13(s,1H), 8.06 (m, 2H), 7.87 (d, J=6.0Hz, 1H), 7.46 (m, 2H), 4.46 (m, 2H), 4.00 (m, 1H), 3.24 (m, 1H), 2.09-1.77 (h, J=10.6,8.7Hz, 6H), 1.75-1.53 (q, J=11.7,8.4Hz, 2H) .HRMS (ESI) [M+H]+, C20H24N5O2S,cal.398.1645,found 398.1649。
Embodiment 12
2-(N4(N- methyl benzo indazole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino) the different hydroxyl oxime of-pyrimidine -5- Acid hydrochloride (Formulas IACompound shown in -12) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl benzo indazole -3- formaldehyde alternative embodiment 1, original needed for remaining Material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -12.
1H NMR(400MHz,DMSO-d6) δ 9.48 (m, 2H), 8.76 (s, 2H), 8.17 (s, 1H), 8.04 (d, J= 8.2Hz, 1H), 7.68 (d, J=8.5Hz, 1H), 7.46 (t, J=7.6Hz, 1H), 7.21 (t, J=7.5Hz, 1H), 4.53 (m, 2H),4.08(s,3H),4.01(m,1H),3.19(m,1H),2.05–1.84(m,6H),1.71–1.57(m,2H).HRMS (ESI)[M+H]+,C20H26N7O2,cal.396.2142,found 396.2146。
Embodiment 13
2-(N4(imidazo [1,2-a] pyridine -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IACompound shown in -13) preparation:
Outside divided by N- methyl indol -3- formaldehyde in imidazo [1,2-a] pyridine -3- formaldehyde alternative embodiment 1, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -13.
1H NMR(400MHz,DMSO-d6) δ 11.10 (s, 1H), 9.87 (m, 2H), 9.20 (d, J=6.9Hz, 1H), 8.65 (s, 2H), 8.44 (s, 1H), 8.03 (d, J=7.0Hz, 2H), 7.71 (d, J=5.9Hz, 1H), 7.60 (t, J=6.4Hz, 1H),4.75(m,2H),3.95(m,1H),3.32(m,1H),2.30–1.83(m,6H),1.73–1.50(m,2H).HRMS (ESI)[M+H]+,C19H24N7O2,cal.382,1986found 382,1990。
Embodiment 14
2-(N4(N- methyl -7- azaindole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IACompound shown in -14) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -7- azaindole -3- formaldehyde alternative embodiment 1, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -14.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.11(m,2H),8.66(s,2H),8.34(m,2H), 7.82 (m, 2H), 7.23 (dd, J=7.7,4.8Hz, 1H), 4.33 (m, 2H), 3.94 (m, 1H), 3.87 (s, 3H), 3.11 (m, 1H),2.02–1.82(m,6H),1.69–1.51(m,2H).HRMS(ESI)[M+H]+,C20H26N7O2,cal.396.2142, found396.2146。
Embodiment 15
2-(N4(N- methyl -6- azaindole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IACompound shown in -15) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -6- azaindole -3- formaldehyde alternative embodiment 1, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -15.
1H NMR(400MHz,DMSO-d6) δ 9.34 (m, 2H), 8.73 (s, 2H), 8.51 (d, J=7.8Hz, 1H), 8.40 (d, J=4.8Hz, 1H), 8.07 (d, J=6.0Hz, 1H), 7.90 (s, 1H), 7.31 (d, J=12.7Hz, 1H), 4.36 (m, 2H),3.98(m,1H),3.92(s,3H),3.11(m,1H),2.05–1.81(m,6H),1.73–1.54(m,2H).HRMS (ESI)[M+H]+,C20H26N7O2,cal.396.2142,found 396.2146。
Embodiment 16
2-(N4(N- methyl -5- azaindole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IACompound shown in -16) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -5- azaindole -3- formaldehyde alternative embodiment 1, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -16.
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.67(s,1H),9.44(m,2H),8.66(s,2H), 8.55 (d, J=6.8Hz, 1H), 8.17 (m, 2H), 7.74 (d, J=5.9Hz, 1H), 4.49 (m, 2H), 4.01 (s, 3H), 3.94 (m,1H),3.15(m,1H),2.10–1.81(m,6H),1.69–1.54(m,2H).HRMS(ESI)[M+H]+,C20H26N7O2, cal.396.2142,found 396.2146。
Embodiment 17
2-(N4(N- methyl -4- azaindole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IACompound shown in -17) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -4- azaindole -3- formaldehyde alternative embodiment 1, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -17.
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.28(m,2H),8.79(m,2H),8.66(m,2H), 8.44(s,1H),7.77(m,2H),4.61(m,2H),4.05(s,3H),3.94(m,1H),3.27(m,1H),2.05–1.82 (m,6H),1.71–1.59(m,2H).HRMS(ESI)[M+H]+,C20H26N7O2,cal.396.2142,found 396.2146。
Embodiment 18
2-(N4-(N4(1- menaphthyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (Formulas IACompound shown in -18) preparation:
Divided by 1- naphthaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 1ACompound shown in -18.
1H NMR(400MHz,DMSO-d6) δ 11.11 (s, 1H), 9.21 (m, 2H), 8.66 (s, 2H), 8.21 (d, J= 8.3Hz, 1H), 8.02 (m, 2H), 7.81 (d, J=7.0Hz, 1H), 7.64 (m, 4H), 4.67 (m, 2H), 4.02 (m, 1H), 3.33(s,1H),2.09–1.86(m,6H),1.78–1.55(m,2H).HRMS(ESI)[M+H]+,C22H26N5O2, cal.392.2081,found392.2086。
Embodiment 19
2-(N4(4- isoquinolin methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (Formulas IACompound shown in -19) preparation
Divided by 4- Isoquindinealdehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and The preparation method is the same as that of Example 1, obtains Formulas IACompound shown in -19.
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.97(s,1H),9.82(m,2H),9.03(s,1H), 8.71 (s, 1H), 8.60 (m, 2H), 8.29 (d, J=8.2Hz, 1H), 8.09 (d, J=8.0Hz, 1H), 7.95 (s, 1H), 4.86 (m,2H),4.03(m,1H),3.43(m,1H),2.17–1.86(m,6H),1.84–1.59(m,2H).HRMS(ESI)[M+H]+, C21H25N6O2,cal.393.2034,found 393.2039。
Embodiment 20
2-(N4(4- quinolylmethyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -20) preparation:
Divided by 4- quinoline aldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -20.
1H NMR(400MHz,DMSO-d6) δ 11.11 (s, 1H), 9.69 (m, 2H), 9.11 (d, J=4.7Hz, 1H), 8.66 (s, 2H), 8.37 (d, J=8.5Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 8.00 (d, J=4.6Hz, 1H), 7.95 (t, J= 7.6Hz, 1H), 7.82 (t, J=7.6Hz, 1H), 7.72 (d, J=5.9Hz, 1H), 4.82 (m, 2H), 4.02 (m, 1H), 3.36 (m,1H),2.10–1.87(m,6H),1.74–1.59(m,2H).HRMS(ESI)[M+H]+,C21H25N6O2,cal.393.2034, found 393.2039。
Embodiment 21
2-(N4(8- isoquinolin methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (Formulas IACompound shown in -21) preparation:
Divided by 8- Isoquindinealdehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and The preparation method is the same as that of Example 1, obtains Formulas IACompound shown in -21.
1H NMR(400MHz,DMSO-d6) δ 10.14 (s, 1H), 9.52 (m, 2H), 8.75 (d, J=6.3Hz, 1H), 8.66 (s, 2H), 8.51 (d, J=6.4Hz, 1H), 8.36 (m, 1H), 8.21 (m, 2H), 7.73 (d, J=6.0Hz, 1H), 4.89 (m, 2H),4.00(m,1H),3.42(m,1H),2.11–1.86(m,6H),1.73–1.60(m,2H).HRMS(ESI)[M+H]+, C21H25N6O2,cal.393.2034,found 393.2039。
Embodiment 22
2-(N4(8- quinolylmethyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -22) preparation:
Divided by 8- quinoline aldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -22.
1H NMR(400MHz,DMSO-d6) δ 11.11 (s, 1H), 9.19 (m, 2H), 9.05 (d, J=3.9Hz, 1H), 8.66 (m, 2H), 8.53 (t, J=7.4Hz, 1H), 8.11 (d, J=8.2Hz, 1H), 7.70 (m, 2H), 4.78 (m, 2H), 3.99 (m, 1H),3.25(m,1H),2.09–1.86(m,6H),1.77–1.55(m,2H).HRMS(ESI)[M+H]+,C21H25N6O2, cal.393.2034,found 393.2039。
Embodiment 23
2-(N4(2- menaphthyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -23) preparation:
Divided by 2- naphthaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 1ACompound shown in -23.
1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),9.49(m,2H),8.71(s,2H),8.13(s,1H), 7.95 (m, 4H), 7.79 (d, J=8.4Hz, 1H), 7.57 (m, 2H), 4.33 (m, 2H), 3.97 (m, 1H), 3.11 (m, 1H), 2.12–1.78(m,6H),1.71–1.45(m,2H).HRMS(ESI)[M+H]+,C22H26N5O2,cal.392.2081,found 392.2086。
Embodiment 24
2-(N4(3- quinolylmethyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -24) preparation:
Divided by 3- quinoline aldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -24.
1H NMR(400MHz,DMSO-d6)δ9.77(m,2H),9.47(s,1H),9.18(s,1H),8.69(s,2H), 8.34 (d, J=8.5Hz, 1H), 8.26 (d, J=8.2Hz, 1H), 8.09 (t, J=7.8Hz, 1H), 7.90 (q, J=6.4, 5.2Hz, 1H), 4.52 (t, J=5.9Hz, 2H), 3.97 (m, 1H), 3.25 (m, 1H), 2.07-1.88 (m, 6H), 1.73-1.60 (m,2H).HRMS(ESI)[M+H]+,C21H25N6O2,cal.393.2034,found 393.2039。
Embodiment 25
2-(N4(2- quinolylmethyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -25) preparation:
Divided by 2- quinoline aldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -25.
1H NMR(400MHz,DMSO-d6) δ 11.09 (s, 1H), 9.34 (m, 2H), 8.65 (s, 2H), 8.51 (dd, J= 10.6,7.3Hz, 1H), 8.08 (m, 2H), 7.85 (t, J=7.6Hz, 1H), 7.69 (m, 2H), 4.59 (m, 2H), 4.00 (m, 1H),3.27(m,1H),2.04–1.86(m,2H),1.74–1.55(m,2H).HRMS(ESI)[M+H]+,C21H25N6O2, cal.393.2034,found 393.2039。
Embodiment 26
2-(N4(6- quinolylmethyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -26) preparation:
Divided by 6- quinoline aldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 1ACompound shown in -26.
1H NMR(400MHz,DMSO-d6) δ 11.11 (s, 1H), 9.55 (m, 2H), 9.22 (d, J=4.6Hz, 1H), 8.91 (d, J=8.4Hz, 1H), 8.66 (s, 2H), 8.44 (s, 1H), 8.35 (d, J=8.8Hz, 1H), 8.27 (d, J=8.9Hz, 1H), 7.95 (dd, J=8.4,4.9Hz, 1H), 7.78 (d, J=5.9Hz, 1H), 4.44 (m, 2H), 3.95 (m, 1H), 3.16 (m, 1H), 2.09-1.80 (m, 6H), 1.79-1.46 (t, J=11.8Hz, 2H) .HRMS (ESI) [M+H]+,C21H25N6O2, cal.393.2034,found 393.2039。
Embodiment 27
2-(N4(9- anthracene methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -27) preparation:
Divided by 9- anthraldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 1ACompound shown in -27.
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.04(m,2H),8.81(s,1H),8.69(s,2H), 8.47 (d, J=8.9Hz, 2H), 8.20 (d, J=8.4Hz, 2H), 7.84 (m, 1H), 7.71 (dd, J=8.7,6.7Hz, 2H), 7.62 (dd, J=8.7,6.7Hz, 2H), 5.25 (m, 1H), 4.08 (m, 1H), 3.58 (m, 2H), 2.19-1.98 (dd, J= 19.5,9.2Hz,6H),1.78–1.65(m,2H).HRMS(ESI)[M+H]+,C26H28N5O2,cal.442.2238, found442.2243。
Embodiment 28
2-(N4(2- anthracene methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -28) preparation:
Divided by 2- anthraldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 1ACompound shown in -28.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.08(m,2H),8.64(m,3H),8.25(s,1H), 8.18 (d, J=8.9Hz, 1H), 8.14 (ddd, J=10.5,6.6,3.4Hz, 2H), 7.73 (d, J=5.8Hz, 1H), 7.68 (d, J=8.7Hz, 1H), 7.56 (dd, J=6.6,3.2Hz, 2H), 4.40 (m, 2H), 3.94 (m, 1H), 3.20 (m, 1H), 2.06-1.82 (m, 6H), 1.71-1.59 (t, J=12.4Hz, 2H) .HRMS (ESI) [M+H]+,C26H28N5O2, cal.442.2238,found 442.2243。
Embodiment 29
2-(N4(9- phenanthrene methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -29) preparation:
Divided by 9- formaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 1ACompound shown in -29.
1H NMR(400MHz,DMSO-d6) δ 11.09 (s, 1H), 9.17 (m, 2H), 8.96 (m, 1H), 8.89 (d, J= 8.1Hz, 1H), 8.66 (s, 2H), 8.25 (m, 1H), 8.11 (s, 1H), 8.02 (d, J=7.3Hz, 1H), 7.76 (m, 5H), 4.73(m,2H),4.02(m,1H),3.40(m,1H),2.21–1.86(m,6H),1.80–1.53(m,2H).HRMS(ESI)[M+ H]+,C26H28N5O2,cal.442.2238,found 442.2243。
Embodiment 30
2-(N4(1- pyrene methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloride (formula IACompound shown in -30) preparation:
Divided by 1- pyrene formaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 1ACompound shown in -30.
1H NMR(400MHz,DMSO-d6) δ 11.08 (s, 1H), 9.20 (m, 2H), 8.66 (s, 2H), 8.51 (d, J= 9.3Hz, 1H), 8.38 (m, 4H), 8.32 (d, J=8.0Hz, 1H), 8.26 (q, J=9.0Hz, 2H), 8.14 (t, J=7.6Hz, 1H), 7.75 (d, J=6.0Hz, 1H), 4.96 (m, 2H), 4.02 (m, 1H), 3.42 (m, 1H), 2.11-1.89 (m, 6H), 1.78–1.59(m,2H).HRMS(ESI)[M+H]+,C28H28N5O2,cal.466.2238,found 466.2243。
Embodiment 31
2-(N4(4- phenyl -1- benzyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas IACompound shown in -31) preparation:
Outside divided by N- methyl indol -3- formaldehyde in 4- phenyl -1- benzaldehyde alternative embodiment 1, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains Formulas IACompound shown in -31.
1H NMR(400MHz,DMSO-d6) δ 11.09 (s, 1H), 9.24 (m, 2H), 8.65 (s, 2H), 7.75 (d, J= 8.2Hz, 2H), 7.70 (td, J=6.3,5.8,2.0Hz, 5H), 7.49 (t, J=7.6Hz, 2H), 7.40 (t, J=7.3Hz, 1H),4.21(m,2H),3.95(m,1H),3.11(m,1H),2.04–1.81(m,6H),1.68–1.55(m,2H).HRMS (ESI)[M+H]+,C24H28N5O2,cal.418.2238,found 418.2243。
Embodiment 32
2-(N4(N- tolimidazole -2- methyl)-cis- -1,4- cyclohexanediamine-N1Amino) the different hydroxyl oxime of-pyrimidine -5- Acid hydrochloride (Formulas IACompound shown in -32) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- tolimidazole -2- formaldehyde alternative embodiment 1, original needed for remaining Material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -32.
1H NMR(400MHz,DMSO-d6) δ 9.85 (m, 2H), 8.68 (s, 2H), 7.83 (d, J=6.0Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.43 (m, 2H), 4.69 (m, 2H), 3.98 (m, 4H), 3.39 (m, 1H), 2.08-1.84 (m, 6H), 1.75–1.58(m,2H).HRMS(ESI)[M+H]+,C20H26N7O2,cal.396.2142,found 396.2146.
Embodiment 33
2-(N4(benzothiophene -2- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas IACompound shown in -33) preparation:
Outside divided by N- methyl indol -3- formaldehyde in benzothiophene -2- formaldehyde alternative embodiment 1, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains Formulas IACompound shown in -33.
1H NMR(400MHz,DMSO-d6) δ 9.71 (m, 2H), 8.74 (s, 2H), 8.11 (s, 1H), 8.00 (d, J= 5.7Hz, 1H), 7.87 (d, J=5.9Hz, 1H), 7.73 (s, 1H), 7.39 (m, 2H), 4.50 (m, 2H), 3.97 (m, 1H), 3.13(m,1H),2.04–1.79(m,6H),1.71–1.53(m,2H).HRMS(ESI)[M+H]+,C20H24N5O2S, cal.398.1645,found 398.1649。
Embodiment 34
2-(N4(N, 6- dimethyl indole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino) the different hydroxyl oxime of-pyrimidine -5- Acid hydrochloride (Formulas IACompound shown in -34) preparation:
It is former needed for remaining in 6- dimethyl indole -3- formaldehyde alternative embodiment 1 outside N- methyl indol -3- formaldehyde divided by N Material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -34.
1H NMR(400MHz,DMSO-d6) δ 9.13 (m, 2H), 8.74 (s, 2H), 8.13 (m, 1H), 7.66 (d, J= 8.1Hz, 1H), 7.52 (s, 1H), 7.26 (s, 1H), 6.95 (d, J=8.0Hz, 1H), 4.26 (m, 2H), 3.97 (m, 1H), 3.76(s,3H),3.07(m,1H),2.43(s,3H),2.01–1.80(m,6H),1.68–1.54(m,2H).HRMS(ESI)[M+ H]+,C22H29N6O2,cal.409.2347,found 409.2352。
Embodiment 35
2-(N4(N- methyl -6- fluoro indole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-different the hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IACompound shown in -35) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -6- fluoro indole -3- formaldehyde alternative embodiment 1, original needed for remaining Material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -35.
1H NMR(400MHz,DMSO-d6) δ 11.13 (s, 1H), 9.00 (m, 2H), 8.67 (s, 2H), 7.80 (dd, J= 8.8,5.1Hz, 2H), 7.60 (s, 1H), 7.37 (dd, J=10.3,2.3Hz, 1H), 7.00 (td, J=9.3,2.3Hz, 1H), 4.30(m,2H),3.95(m,1H),3.78(s,3H),3.13(m,1H),2.15–1.74(m,6H),1.61(m,2H).HRMS (ESI)[M+H]+,C21H26FN6O2,cal.413.2096,found 413.2100。
Embodiment 36
2-(N4(N- methyl -6- chloro-indole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-different the hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IACompound shown in -36) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -6- chloro-indole -3- formaldehyde alternative embodiment 1, original needed for remaining Material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -36.
1H NMR(400MHz,DMSO-d6) δ 9.16 (m, 2H), 8.71 (s, 2H), 7.97 (m, 1H), 7.82 (d, J= 8.5Hz, 1H), 7.67 (s, 1H), 7.63 (d, J=1.8Hz, 1H), 7.14 (dd, J=8.5,1.9Hz, 1H), 4.30 (m, 2H), 3.97(m,1H),3.81(s,3H),3.09(m,1H),2.03–1.79(m,6H),1.70–1.53(m,2H).HRMS(ESI)[M+ H]+,C21H26ClN6O2,cal.429.1800,found429.1805。
Embodiment 37
2-(N4(N- methyl -6- bromo indole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-different the hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IACompound shown in -37) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -6- Bromoindole-3-carboxaldehyde alternative embodiment 1, original needed for remaining Material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -37.
1H NMR(400MHz,DMSO-d6) δ 11.17 (s, 1H), 9.12 (m, 2H), 8.69 (s, 2H), 7.89 (d, J= 6.0Hz, 1H), 7.77 (m, 2H), 7.64 (s, 1H), 7.26 (d, J=8.4Hz, 1H), 4.30 (m, 2H), 3.96 (m, 1H), 3.81(s,3H),3.09(m,1H),2.08–1.84(m,6H),1.74–1.47(m,2H).HRMS(ESI)[M+H]+, C21H26BrN6O2,cal.473.1295,found473.1300。
Embodiment 38
2-(N4(N- methyl -6- methoxy-Indole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- Hydroxamic acid hydrochloride (Formulas IACompound shown in -38) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -6- methoxyindole-3-carboxaldehyde alternative embodiment 1, remaining institute Need raw material, reagent and the preparation method is the same as that of Example 1 obtains Formulas IACompound shown in -38.
1H NMR(400MHz,DMSO-d6) δ 11.15 (s, 1H), 9.00 (m, 2H), 8.68 (s, 2H), 7.84 (d, J= 6.0Hz, 1H), 7.65 (d, J=8.7Hz, 1H), 7.45 (s, 1H), 7.01 (d, J=2.2Hz, 1H), 6.77 (dd, J=8.7, 2.2Hz,1H),4.26(m,2H),3.95(m,1H),3.82(s,3H),3.76(s,3H),3.08(m,1H),2.05–1.79(m, 6H),1.71–1.47(m,2H).HRMS(ESI)[M+H]+,C22H29N6O3,cal.425.2296,found425.2301。
Embodiment 39
2-(N4(N- methyl -6- cyanoindole -3- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IACompound shown in -39) preparation:
Outside divided by N- methyl indol -3- formaldehyde in N- methyl -6- cyanoindole -3- formaldehyde alternative embodiment 1, needed for remaining Raw material, reagent and the preparation method is the same as that of Example 1 obtain Formulas IACompound shown in -39.
1H NMR(400MHz,DMSO-d6) δ 9.28 (m, 2H), 8.73 (s, 2H), 8.15 (s, 1H), 8.01 (d, J= 8.3Hz, 1H), 7.95 (s, 1H), 7.47 (d, J=8.2Hz, 1H), 4.35 (m, 2H), 3.98 (m, 1H), 3.90 (s, 3H), 3.12(m,1H),2.07–1.80(m,6H),1.73–1.53(m,2H).HRMS(ESI)[M+H]+,C22H26N7O2, cal.420.2142,found 420.2147。
Embodiment 40
2-(N4(6- fluorine quinoline -2- methyl)-cis- -1,4- cyclohexanediamine-N1Amino)-pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas IACompound shown in -40) preparation:
Outside divided by N- methyl indol -3- formaldehyde in 6- fluorine quinoline -2- formaldehyde alternative embodiment 1, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains Formulas IACompound shown in -40.
1H NMR(400MHz,DMSO-d6) δ 9.53 (m, 2H), 8.73 (m, 2H), 8.51 (s, 1H), 8.16 (dd, J= 9.3,5.4Hz, 1H), 7.89 (dd, J=9.3,2.9Hz, 1H), 7.77 (m, 2H), 4.58 (m, 2H), 4.03 (m, 1H), 3.28 (m,1H),2.13–1.84(m,6H),1.65(m,2H).HRMS(ESI)[M+H]+,C21H24FN6O2,cal.411.1939, found 411.1943。
Embodiment 41
(1) 2- (1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5-carboxylic acid's ethyl ester (Formula IIBShownization Close object (seing above)) preparation:
By 25.6 grams of 1- oxa- -4,9- diaza spiro [5.5] hendecane -9- carboxylic acid tert-butyl esters and 18.7 grams of chloro- pyrimidines-of 2- 5- carboxylic acid, ethyl ester is dissolved in 500 milliliters of methylene chloride, and ice bath is cooled to 0-5 DEG C, and 18.2 milliliters of n,N-diisopropylethylamine are added, It finishes, removes ice bath, be warmed to room temperature to reacting liquid temperature, stirred 6 hours, water is added into reaction solution, vibrate liquid separation, decompression is steamed Except solvent, remaining solid obtains white solid (2- with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1 (v/v)) (5- (ethoxy carbonyl) pyrimidine -2-base) -1- oxa- -4,9- diaza spiro [5.5] hendecane -9- carboxylic acid tert-butyl ester)；
1H NMR(400MHz,CDCl3) δ 8.82 (s, 2H), 4.34 (q, J=7.1Hz, 2H), 3.97-3.92 (m, 2H), 3.81 (s, 2H), 3.80-3.76 (m, 2H), 3.68 (s, 2H), 3.23 (t, J=10.8Hz, 2H), 1.77 (d, J=13.4Hz, 2H), 1.56-1.47 (m, 2H), 1.45 (s, 9H), 1.36 (t, J=7.1Hz, 3H)
36.6 grams of above-mentioned white solids are dissolved in 500 milliliters of methylene chloride, it is molten that 50 milliliters of 4N hydrogen chloride-dioxane are added Liquid stirs 5-6 hours at room temperature.Vacuum distillation removes solvent, and remaining mixture is obtained transparent by silica gel column chromatography separating purification Oil product (Formula IIBShown compound)；
1H NMR (400MHz, MeOD) δ 8.84 (s, 2H), 4.36 (q, J=7.1Hz, 2H), 3.99-3.93 (m, 2H), 3.88 (d, J=6.9Hz, 2H), 3.84-3.79 (m, 2H), 2.96-2.87 (m, 2H), 2.80 (dt, J=9.5,4.5Hz, 2H), 1.80 (d, J=13.8Hz, 2H), 1.58 (ddd, J=14.0,10.1,4.2Hz, 2H), 1.39 (t, J=7.1Hz, 3H)
(2) 2- (9- ((1- Methyl-1H-indole -3- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- Base) pyrimidine -5-carboxylic acid's ethyl ester (formula IIIBCompound shown in -1) preparation:
By 0.37 gram of 2- (1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5-carboxylic acid's ethyl ester (Formula IIB Shown compound) and 0.19 gram of N- methyl indol -3- formaldehyde, it is dissolved in 15 milliliters of methylene chloride, 0.27 milliliter of glacial acetic acid is added, 0.76 gram of sodium triacetoxy borohydride, is stirred overnight at room temperature.Saturated sodium bicarbonate aqueous solution is added, vibrates liquid separation, organic phase Vacuum distillation removes solvent, and remaining mixture is obtained with silica gel column chromatography separating purification (methylene chloride/methanol=60/1 (v/v)) Faint yellow oil product.
1H NMR(400MHz,CDCl3) δ 8.83 (s, 2H), 7.66 (d, J=7.9Hz, 1H), 7.31 (d, J=8.2Hz, 1H), 7.23 (d, J=7.2Hz, 1H), 7.16-7.12 (m, 1H), 7.09 (s, 1H), 4.33 (q, J=7.1Hz, 2H), 3.93 (s, 2H), 3.78 (s, 3H), 3.72 (s, 2H), 3.64 (t, J=6.9Hz, 2H), 3.46 (d, J=17.7Hz, 2H), 3.37 (d, J=7.3Hz, 2H), 2.27 (t, J=6.9Hz, 2H), 1.36 (t, J=7.1Hz, 3H)
(3) 2- (9- ((1- Methyl-1H-indole -3- base) methyl)) -1- oxa- -4,9- diaza spiro [5.5] hendecane - 4- yl) pyrimidine -5-carboxylic acid's (formula IVBCompound shown in -1) preparation:
0.27 gram of 2- (2- ((1- Methyl-1H-indole -3- base) methyl) -2,6- diaza spiro [3.4] octyl- 6- yl) is phonetic Pyridine -5- carboxylic acid, ethyl ester (compound IB- III-1) it is dissolved in 10 milliliters of the mixed solution (1:1) of methanol-water, 0.25 gram of carbonic acid is added Potassium solid, 65~70 DEG C of heating are reacted 6 hours.Reaction is finished, and evaporating solvent under reduced pressure, it is about 1 that residue, which is acidified to pH with 2N hydrochloric acid, Vacuum distillation removes water, obtains the pale pink solid (formula IV containing inorganic saltsBCompound shown in -1).
1H NMR(400MHz,CDCl3) δ 8.81 (s, 2H), 7.65 (d, J=7.9Hz, 1H), 7.32 (d, J=8.2Hz, 1H), 7.27 (s, 1H), 7.23 (d, J=7.4Hz, 1H), 7.14 (t, J=7.2Hz, 1H), 4.33 (q, J=7.1Hz, 2H), 3.97–3.88(m,4H),3.82(s,2H),3.79(s,3H),3.77–3.73(m,2H),2.84(s,2H),2.66(s,2H), 1.85 (dd, J=24.5,12.6Hz, 4H), 1.40-1.32 (m, 3H)
(4) 2- (11 carbon -4- of 9- ((1- Methyl-1H-indole -3- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] Base)-N- ((tetrahydro -2H- pyrans pyridine -2- base) oxygroup) pyrimidine -5- formamide (Formula VBCompound shown in -1) preparation:
By the above-mentioned pale pink solid (formula IV containing inorganic saltsBCompound shown in -1) to be dissolved in N,N-dimethylformamide molten It 10 milliliters of liquid, sequentially adds 0.16 gram of I-hydroxybenzotriazole and 0.23 gram of 1- (3- dimethylamino-propyl) -3- ethyl carbon two is sub- Amine hydrochlorate sequentially adds 0.35 gram of O- (tetrahydro -2H- pyrans -2- base) azanol and 0.42 milliliter after stirring 30 minutes at room temperature Triethylamine stirs 48 hours at room temperature, and saturated sodium bicarbonate aqueous solution and methylene chloride is added, and vibrates liquid separation, organic phase water Three times, organic phase vacuum distillation removes solvent, remaining mixture silica gel column chromatography separating purification (methylene chloride/methanol for washing =60/1 (v/v)), obtain pale yellowish oil product (Formula VBCompound shown in -1).
1H NMR(400MHz,CDCl3) δ 8.67 (s, 1H), 8.42 (s, 1H), 7.61 (d, J=7.9Hz, 1H), 7.49 (d, J=26.5Hz, 1H), 7.33 (d, J=8.2Hz, 1H), 7.24 (d, J=7.4Hz, 1H), 7.16 (t, J=7.5Hz, 1H), 5.10 (dd, J=16.9,13.5Hz, 1H), 4.09 (d, J=16.7Hz, 2H), 4.01 (d, J=11.6Hz, 1H), 3.86 (dd, J=9.7,4.7Hz, 2H), 3.79 (s, 3H), 3.78 (d, J=1.3Hz, 2H), 3.72 (dd, J=10.7,5.9Hz, 2H), 3.68-3.62 (m, 1H), 3.01 (s, 2H), 2.78 (s, 2H), 1.93 (d, J=15.5Hz, 4H), 1.88-1.78 (m, 3H), 1.67–1.52(m,3H).
(5) 2- (9- ((1- Methyl-1H-indole -3- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- Base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -1) preparation:
By 0.16 gram of Formula VBCompound shown in -1 is dissolved with 10 milliliters of methylene chloride, and 0.5 milliliter of 4N hydrogen chloride-dioxy is added dropwise Six ring solution stir 30 minutes at room temperature.Filter, filter cake washs with a large amount of methylene chloride, drying, obtain object (white solid, Formulas IBCompound shown in -1).
1H NMR(400MHz,DMSO-d6) δ 11.20 (s, 1H), 10.64 (s, 1H), 8.74 (d, J=8.6Hz, 2H), 7.88 (d, J=7.9Hz, 1H), 7.66 (d, J=9.6Hz, 1H), 7.57-7.49 (m, 1H), 7.26 (dd, J=13.9, 6.8Hz, 1H), 7.16 (t, J=7.5Hz, 1H), 4.47 (d, J=3.9Hz, 2H), 3.86 (d, J=4.5Hz, 3H), 3.82 (s, 2H), 3.72 (s, 4H), 3.29 (d, J=11.4Hz, 2H), 3.01 (dd, J=23.0,11.0Hz, 2H), 2.05 (d, J= 14.1Hz, 2H), 1.88 (t, J=12.3Hz, 2H)；HRMS(ESI)m/z calcd for C23H29N6O3[M+H]+ 437.2301,found 437.2302。
Embodiment 42
2- (9- (naphthalene -2- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl oxime of pyrimidine -5- Acid hydrochloride (Formulas IBThe preparation of compound shown in -2:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation side in 2- naphthaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -2.
1H NMR(400MHz,DMSO-d6) δ 11.26-10.99 (m, 2H), 8.71 (d, J=16.9Hz, 2H), 8.16 (d, J=12.5Hz, 1H), 8.03-7.96 (m, 2H), 7.94-7.90 (m, 1H), 7.81 (d, J=8.4Hz, 1H), 7.63-7.55 (m, 2H), 4.47 (d, J=5.0Hz, 2H), 3.87-3.77 (m, 2H), 3.71 (d, J=6.8Hz, 4H), 3.26-3.16 (m, 2H), 3.11-2.98 (m, 2H), 2.03 (d, J=13.9Hz, 2H), 1.91 (t, J=13.6Hz, 2H)；HRMS(ESI)m/z calcd for C24H28N5O3[M+H]+434.2192,found 434.2191。
Embodiment 43
2- (9- (furans -2- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBThe preparation of -3 compounds:
Divided by N- methyl indol -3- formaldehyde in 2 furan carboxyaldehyde alternative embodiment 41, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 41BCompound shown in -3.
1H NMR(400MHz,DMSO-d6) δ 11.17 (s, 2H), 8.70 (s, 2H), 7.82 (d, J=2.5Hz, 1H), 6.73 (s, 1H), 6.56 (d, J=1.7Hz, 1H), 4.39 (s, 2H), 3.85-3.77 (m, 2H), 3.70 (s, 4H), 3.18 (d, J= 12.3Hz, 2H), 2.95 (d, J=11.0Hz, 2H), 2.04 (d, J=14.2Hz, 2H), 1.83 (d, J=14.5Hz, 2H) HRMS (ESI)m/z calcd for C18H24N5O4[M+H]+374.1828,found 374.1830.
Embodiment 44
2- (9- (benzo [b] thiene-3-yl methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine - 5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -4) preparation:
Divided by N- methyl indol -3- formaldehyde in 3- formaldehyde benzothiophene alternative embodiment 41, remaining required raw material, reagent and Preparation method obtains Formulas I with embodiment 41BCompound shown in -4.
1H NMR(400MHz,DMSO-d6) δ 11.33-10.80 (m, 2H), 8.71 (d, J=13.0Hz, 2H), 8.23 (dd, J=16.9,9.0Hz, 2H), 8.08 (t, J=7.1Hz, 1H), 7.55-7.40 (m, 2H), 4.61 (d, J=3.5Hz, 2H), 3.79 (t, J=11.4Hz, 2H), 3.71 (d, J=6.2Hz, 4H), 3.24 (d, J=10.6Hz, 2H), 3.17-3.04 (m, 2H), 2.03 (d, J=14.3Hz, 2H), 1.89 (d, J=9.9Hz, 2H)；HRMS(ESI)m/z calcd forC22H26N5O3S [M+H]+440.1756,found440.1757.
Embodiment 45
2- (9- (naphthalene -1- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl oxime of pyrimidine -5- Acid hydrochloride (Formulas IBCompound shown in -5) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation side in 1- naphthaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -5.
1H NMR(400MHz,DMSO-d6) δ 10.37 (s, 2H), 8.72 (d, J=22.2Hz, 2H), 8.45 (d, J= 8.4Hz, 1H), 8.03 (dd, J=11.8,8.1Hz, 3H), 7.67-7.56 (m, 3H), 4.82 (d, J=4.9Hz, 2H), 3.81 (s, 2H), 3.71 (d, J=19.3Hz, 4H), 3.20 (t, J=13.9Hz, 4H), 1.99 (s, 4H)；HRMS(ESI)m/z calcd for C24H28N5O3[M+H]+434.2192,found 434.2193.
Embodiment 46
2- (9- (quinoline -2- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -6) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system in quinoline -2- formaldehyde alternative embodiment 41 Preparation Method obtains Formulas I with embodiment 41BCompound shown in -6.
1H NMR(400MHz,DMSO-d6) δ 10.97 (s, 2H), 8.71 (s, 2H), 8.53 (d, J=8.5Hz, 1H), 8.08 (t, J=9.1Hz, 2H), 7.86 (t, J=7.5Hz, 2H), 7.70 (t, J=7.4Hz, 1H), 4.73 (s, 2H), 3.88-3.69 (m,6H),3.35(s,2H),3.24(s,2H),2.02(s,4H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+ 435.2145,found 435.2146.
Embodiment 47
2- (9- benzyl -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -7) preparation:
Divided by N- methyl indol -3- formaldehyde in benzaldehyde alternative embodiment 41, remaining required raw material, reagent and preparation method With embodiment 41, Formulas I is obtainedBCompound shown in -7.
1H NMR(400MHz,DMSO-d6) δ 11.15 (s, 2H), 8.71 (d, J=11.6Hz, 2H), 7.63 (s, 2H), 7.47 (d, J=20.9Hz, 3H), 4.34 (t, J=30.1Hz, 2H), 3.81 (d, J=5.0Hz, 2H), 3.74 (d, J= 29.1Hz, 4H), 3.13 (d, J=10.3Hz, 2H), 2.98 (d, J=10.5Hz, 2H), 2.02 (d, J=14.2Hz, 2H), 1.92 (d, J=13.9Hz, 2H)；HRMS(ESI)m/z calcd for C20H26N5O3[M+H]+384.2036,found 384.2037.
Embodiment 48
2- (9- (pyridin-4-yl methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -8) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in 4- pyridine carboxaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -8.
1H NMR(400MHz,DMSO-d6) δ 12.08 (s, 1H), 11.20 (s, 1H), 8.97 (s, 2H), 8.76 (d, J= 19.8Hz, 2H), 8.29 (s, 2H), 4.66 (d, J=51.9Hz, 2H), 3.90-3.83 (m, 2H), 3.78 (d, J=26.1Hz, 4H), 3.21 (d, J=11.2Hz, 2H), 3.06 (d, J=37.6Hz, 2H), 2.02 (d, J=6.1Hz, 4H)；HRMS(ESI)m/ z calcd for C19H25N6O3[M+H]+385.1988,found 385.1989.
Embodiment 49
2- (9- ([1,1'- xenyl] -4- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) is phonetic Pyridine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -9) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system in biphenyl -4- formaldehyde alternative embodiment 41 Preparation Method obtains Formulas I with embodiment 41BCompound shown in -9.
1H NMR(400MHz,DMSO-d6) δ 11.19 (s, 2H), 8.75 (d, J=14.1Hz, 2H), 7.80 (d, J= 3.6Hz, 1H), 7.77 (s, 3H), 7.75-7.71 (m, 2H), 7.51 (t, J=7.5Hz, 2H), 7.42 (t, J=7.3Hz, 1H), 4.37 (d, J=5.1Hz, 2H), 3.84 (dd, J=11.1,6.0Hz, 2H), 3.75 (d, J=7.9Hz, 4H), 3.21 (d, J= 11.5Hz, 2H), 3.04 (dd, J=22.3,10.1Hz, 2H), 2.07 (d, J=13.6Hz, 2H), 1.96 (t, J=11.8Hz, 2H)；HRMS(ESI)m/z calcd for C26H30N5O3[M+H]+460.2349,found460.2348.
Embodiment 50
2- (9- (cyclohexyl methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- hydroxamic acid Hydrochloride (Formulas IBCompound shown in -10) preparation:
Divided by N- methyl indol -3- formaldehyde in hexahydrobenzaldehyde alternative embodiment 41, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 41BCompound shown in -10.
1H NMR(400MHz,DMSO-d6) δ 10.53 (d, J=31.9Hz, 2H), 8.79-8.74 (m, 2H), 3.88-3.82 (m, 2H), 3.76 (d, J=16.5Hz, 4H), 3.30 (d, J=11.2Hz, 2H), 3.07-2.85 (m, 4H), 2.10 (t, J= 12.1Hz, 2H), 2.04-1.95 (m, 2H), 1.86 (d, J=11.4Hz, 2H), 1.82-1.75 (m, 1H), 1.66 (dd, J= 22.6,12.8Hz, 4H), 1.21 (dt, J=17.4,15.6Hz, 4H)；HRMS(ESI)m/z calcd for C20H32N5O3[M+ H]+390.2505,found 390.2506.
Embodiment 51
2- (9- (cyclopentyl-methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- hydroxamic acid Hydrochloride (Formulas IBCompound shown in -11) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in cyclopenta formaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -11.
1H NMR(400MHz,DMSO-d6) δ 11.23 (s, 1H), 10.53 (s, 1H), 8.76 (d, J=2.1Hz, 2H), 3.90-3.84 (m, 2H), 3.76 (s, 4H), 3.34 (d, J=11.3Hz, 2H), 3.05 (dd, J=13.5,7.8Hz, 2H), 2.97 (dd, J=21.8,14.4Hz, 2H), 2.35-2.22 (m, 1H), 2.06-1.83 (m, 6H), 1.68-1.50 (m, 4H), 1.32–1.26(m,2H)；HRMS(ESI)m/z calcd for C19H30N5O3[M+H]+376.2349,found 376.2347.
Embodiment 52
2- (9- ((1H- indoles -4- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- Hydroxamic acid hydrochloride (Formulas IBCompound shown in -12) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in 4- indolecarboxaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -12.
1H NMR(400MHz,DMSO-d6) δ 11.78 (s, 1H), 11.44 (d, J=10.0Hz, 1H), 11.26 (s, 1H), 8.74 (d, J=12.2Hz, 2H), 7.51 (dd, J=14.6,7.2Hz, 2H), 7.27-7.15 (m, 2H), 6.97 (s, 1H), 3.81 (d, J=12.2Hz, 4H), 3.72 (s, 4H), 3.26 (d, J=10.6Hz, 2H), 3.09 (s, 2H), 2.00 (dd, J= 31.7,12.8Hz,4H)；HRMS(ESI)m/z calcd for C22H27N6O3[M+H]+423.2145,found423.2146.
Embodiment 53
2- (9- ((1- methyl-1 H- benzo [d] imidazoles -2- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] 11 Carbon -4- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -13) preparation:
Divided by N- methyl indol -3- formaldehyde in 1- methyl -2- formaldehyde benzimidazole alternative embodiment 41, original needed for remaining Material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -13.
1H NMR(400MHz,DMSO-d6) δ 11.23 (s, 2H), 8.75 (s, 2H), 7.80 (d, J=8.9Hz, 2H), 7.51-7.40 (m, 2H), 4.85 (s, 2H), 4.04 (s, 3H), 3.83 (dd, J=29.6,4.8Hz, 6H), 3.54 (s, 2H), 3.32 (d, J=20.9Hz, 2H), 2.05 (dd, J=28.3,12.5Hz, 4H)；HRMS(ESI)m/z calcd for C22H28N7O3[M+H]+438.2254,found438.2255.
Embodiment 54
2- (9- ((1- methyl-1 H- indazole -3- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) Pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -14) preparation:
Divided by N- methyl indol -3- formaldehyde in 1- methyl-1 H- indazole -3- formaldehyde alternative embodiment 41, original needed for remaining Material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -14.
1H NMR(400MHz,DMSO-d6) δ 11.01 (s, 2H), 8.74 (d, J=4.5Hz, 2H), 8.12 (t, J= 8.1Hz, 1H), 7.78-7.72 (m, 1H), 7.51 (dd, J=14.0,6.8Hz, 1H), 7.30-7.24 (m, 1H), 4.70 (d, J =3.9Hz, 2H), 4.14 (d, J=4.7Hz, 3H), 3.83 (t, J=8.2Hz, 2H), 3.72 (s, 4H), 3.41 (d, J= 10.9Hz, 2H), 3.08 (dd, J=21.8,11.8Hz, 2H), 2.07 (d, J=14.3Hz, 2H), 1.91 (t, J=12.1Hz, 2H)；HRMS(ESI)m/z calcd for C22H28N7O3[M+H]+438.2254,found 438.2255.
Embodiment 55
2- (9- (benzofuran -2- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- Hydroxamic acid hydrochloride (Formulas IBCompound shown in -15) preparation:
Divided by N- methyl indol -3- formaldehyde in benzo [b] furans -2- formaldehyde alternative embodiment 41, remaining required raw material, examination Agent and preparation method obtain Formulas I with embodiment 41BCompound shown in -15.
1H NMR(400MHz,DMSO-d6) δ 11.54 (d, J=71.8Hz, 1H), 10.41 (s, 1H), 8.75 (t, J= 5.3Hz, 2H), 7.80-7.72 (m, 1H), 7.65 (dd, J=8.0,3.0Hz, 1H), 7.46-7.39 (m, 1H), 7.36-7.31 (m, 1H), 7.28 (s, 1H), 4.62 (s, 2H), 3.83 (s, 2H), 3.74 (s, 4H), 3.34 (d, J=11.1Hz, 2H), 3.10 (dd, J=21.7,11.9Hz, 2H), 2.09 (d, J=13.7Hz, 2H), 1.96 (s, 2H)；HRMS(ESI)m/z calcd for C22H26N5O4[M+H]+424.1985,found 424.1986.
Embodiment 56
2- (9- ((1H- indoles -2- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- Carboxylic acid, ethyl ester (Formulas IBCompound shown in -16) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system in indoles -2- formaldehyde alternative embodiment 41 Preparation Method obtains Formulas I with embodiment 41BCompound shown in -16.
1H NMR(400MHz,CDCl3) δ 10.03 (s, 1H), 8.83 (s, 2H), 7.54 (d, J=7.8Hz, 1H), 7.38 (dd, J=8.1,0.7Hz, 1H), 7.18-7.13 (m, 1H), 7.09-7.04 (m, 1H), 6.39 (s, 1H), 4.33 (q, J= 7.1Hz, 2H), 3.95-3.90 (m, 2H), 3.88 (d, J=6.7Hz, 2H), 3.83 (d, J=7.5Hz, 2H), 3.78-3.73 (m, 2H), 2.78 (d, J=11.9Hz, 2H), 2.63 (td, J=11.5,2.8Hz, 2H), 1.88 (d, J=13.8Hz, 2H), 1.82-1.72 (m, 2H), 1.36 (t, J=7.1Hz, 3H)；HRMS(ESI)m/z calcd for C22H27N6O3[M+H]+ 423.2145,found 423.2148.
Embodiment 57
2- (9- (thiophene -2- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -17) preparation:
Divided by N- methyl indol -3- formaldehyde in 2 thiophene carboxaldehyde alternative embodiment 41, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 41BCompound shown in -17.
1H NMR(400MHz,DMSO-d6) δ 11.37 (s, 2H), 8.75 (d, J=8.5Hz, 2H), 7.72 (d, J= 3.2Hz, 1H), 7.46 (s, 1H), 7.23-7.14 (m, 1H), 4.57 (s, 2H), 3.84 (d, J=5.0Hz, 2H), 3.71 (d, J =28.7Hz, 4H), 3.21 (d, J=10.5Hz, 2H), 3.00 (dd, J=22.3,10.7Hz, 2H), 2.08 (d, J= 14.1Hz,2H),1.93(s,2H)；HRMS(ESI)m/z calcd for C18H24N5O3S[M+H]+390.1600,found 390.1601.
Embodiment 58
2- (9- (furans -3- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -18) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in 3- furtural alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -18.
1H NMR(400MHz,DMSO-d6) δ 11.18 (s, 2H), 8.74 (d, J=5.4Hz, 2H), 7.89 (d, J= 10.2Hz, 1H), 7.81 (d, J=17.0Hz, 1H), 6.80 (d, J=16.4Hz, 1H), 4.19 (s, 2H), 3.87-3.83 (m, 2H), 3.75 (s, 4H), 3.20 (s, 2H), 2.96 (d, J=10.5Hz, 2H), 2.07 (d, J=15.1Hz, 2H), 1.90 (s, 2H)；HRMS(ESI)m/z calcd for C18H24N5O4[M+H]+374.1828,found 374.1827.
Embodiment 59
2- (9- ((1- Methyl-1H-indole -2- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) Pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -19) preparation:
Divided by N- methyl indol -3- formaldehyde in 1- methyl indol -2- formaldehyde alternative embodiment 41, remaining required raw material, examination Agent and preparation method obtain Formulas I with embodiment 41BCompound shown in -19.
1H NMR(400MHz,DMSO-d6)δ11.17(s,2H),8.72(s,2H),7.65–7.61(m,1H),7.54(d,J =8.3Hz, 1H), 7.26 (t, J=7.6Hz, 1H), 7.11 (t, J=7.5Hz, 1H), 6.85 (s, 1H), 4.62 (s, 2H), 3.89 (s, 3H), 3.86 (s, 2H), 3.77 (s, 2H), 3.74 (s, 2H), 3.35 (d, J=11.8Hz, 2H), 3.20-3.08 (m, 2H), 2.07 (d, J=14.3Hz, 2H), 1.96 (d, J=10.9Hz, 2H)；HRMS(ESI)m/z calcd for C23H29N6O3 [M+H]+437.2301,found437.2302.
Embodiment 60
2- (9- ((1- methyl-1 H- pyrrolo- [2,3-c] pyridin-3-yl) methyl) -1- oxa- -4,9- diaza spiro [5.5] ten one carbon -4- bases) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -20) preparation:
Divided by N- methyl indol -3- formaldehyde in N- methyl -6- azaindole -3- formaldehyde alternative embodiment 41, needed for remaining Raw material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -20.
1H NMR(400MHz,DMSO-d6) δ 11.07 (s, 2H), 8.74 (d, J=10.0Hz, 2H), 8.52-8.46 (m, 1H), 8.40 (d, J=4.8Hz, 1H), 7.93-7.87 (m, 1H), 7.34-7.27 (m, 1H), 4.49 (d, J=4.3Hz, 2H), 3.92 (d, J=5.5Hz, 3H), 3.85-3.80 (m, 2H), 3.73 (s, 4H), 3.28 (d, J=10.6Hz, 2H), 3.02 (dd, J =22.6,10.9Hz, 2H), 2.05 (d, J=14.0Hz, 2H), 1.92 (t, J=11.2Hz, 2H)；HRMS(ESI)m/z calcd for C22H28N7O3[M+H]+438.2254,found 438.2257.
Embodiment 61
2- (9- ((1- methyl-1 H- pyrrolo- [3,2-b] pyridin-3-yl) methyl) -1- oxa- -4,9- diaza spiro [5.5] ten one carbon -4- bases) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -21) preparation:
Divided by N- methyl indol -3- first in 1- methyl-1 H- pyrrolo- [3,2-b] pyridine -3- formaldehyde alternative embodiment 41 Aldehyde, remaining required raw material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -21.
1H NMR(400MHz,DMSO-d6) δ 11.20 (s, 2H), 8.79 (d, J=4.9Hz, 2H), 8.73 (s, 2H), 8.41 (s, 1H), 7.77 (s, 1H), 4.74 (s, 2H), 4.06 (s, 3H), 3.86 (s, 2H), 3.76 (s, 4H), 3.39 (d, J= 10.4Hz, 2H), 3.18 (d, J=19.3Hz, 2H), 2.07 (d, J=12.7Hz, 2H), 1.87 (s, 2H)；HRMS(ESI)m/z calcd for C22H28N7O3[M+H]+438.2254,found 438.2253.
Embodiment 62
2- (9- (benzo [b] thiophene -2- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine - 5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -22) preparation:
Divided by N- methyl indol -3- formaldehyde in 1- benzothiophene -2- formaldehyde alternative embodiment 41, remaining required raw material, examination Agent and preparation method obtain Formulas I with embodiment 41BCompound shown in -22.
1H NMR(400MHz,DMSO-d6) δ 11.62-11.08 (m, 2H), 8.75 (d, J=12.0Hz, 2H), 8.06 (dd, J=5.6,3.3Hz, 1H), 7.94 (dd, J=5.9,3.0Hz, 1H), 7.77 (s, 1H), 7.46 (dd, J=6.0,3.1Hz, 2H), 4.70 (d, J=3.9Hz, 2H), 3.84 (d, J=5.2Hz, 2H), 3.75 (s, 4H), 3.29 (d, J=10.4Hz, 2H), 3.09 (dd, J=22.1,10.8Hz, 2H), 2.09 (d, J=13.9Hz, 2H), 1.95 (t, J=13.8Hz, 2H)；HRMS (ESI)m/z calcd for C22H26N5O3S[M+H]+440.1756,found 440.1757.
Embodiment 63
2- (9- (pyridine -2- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -23) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in 2- pyridine carboxaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -23.
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.81(s,1H),8.79–8.71(m,3H),8.07– 7.98 (m, 1H), 7.82-7.70 (m, 1H), 7.62-7.50 (m, 1H), 4.56 (s, 2H), 3.85 (d, J=5.2Hz, 2H), 3.79 (t, J=7.9Hz, 2H), 3.76 (d, J=4.7Hz, 2H), 3.21 (t, J=16.8Hz, 4H), 2.01 (t, J= 22.4Hz,4H)；HRMS(ESI)m/z calcd for C19H25N6O3[M+H]+385.1988,found 385.1989.
Embodiment 64
2- (9- (thiene-3-yl methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -24) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in 3- thiophenecarboxaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -24.
1H NMR(400MHz,DMSO-d6) δ 11.32 (s, 2H), 8.77-8.71 (m, 2H), 7.82 (d, J=2.0Hz, 1H), 7.67 (dd, J=4.9,3.0Hz, 1H), 7.45 (d, J=5.0Hz, 1H), 4.32 (d, J=4.8Hz, 2H), 3.89- 3.82 (m, 2H), 3.82-3.71 (m, 4H), 3.15 (d, J=11.6Hz, 2H), 2.96 (dd, J=22.3,10.2Hz, 2H), 2.06 (d, J=13.8Hz, 2H), 2.00-1.87 (m, 2H)；HRMS(ESI)m/z calcd for C18H24N5O3S[M+H]+ 390.1600,found 390.1602.
Embodiment 65
2- (9- (isoquinolin -4- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IBCompound shown in -25) preparation:
Divided by N- methyl indol -3- formaldehyde in isoquinolin -4- formaldehyde alternative embodiment 41, remaining required raw material, reagent and Preparation method obtains Formulas I with embodiment 41BCompound shown in -25.
1H NMR(400MHz,DMSO-d6) δ 11.33 (d, J=60.2Hz, 2H), 9.93 (s, 1H), 9.16 (s, 1H), 8.80 (d, J=8.9Hz, 1H), 8.73 (s, 2H), 8.57 (d, J=8.2Hz, 1H), 8.27 (t, J=7.5Hz, 1H), 8.09- 8.03 (m, 1H), 5.00 (d, J=4.8Hz, 2H), 3.86 (s, 2H), 3.80 (d, J=4.7Hz, 2H), 3.73 (s, 2H), 3.30 (s,4H),2.12–1.92(m,4H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+435.2145, found435.2144.
Embodiment 66
2- (9- (quinoline-8-yl methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -26) preparation:
Divided by N- methyl indol -3- formaldehyde in quinoline-8-formaldehyde alternative embodiment 41, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 41BCompound shown in -26.
1H NMR(400MHz,DMSO-d6) δ 11.03 (s, 2H), 9.11 (d, J=3.1Hz, 1H), 8.79-8.71 (m, 2H), 8.64 (d, J=8.2Hz, 1H), 8.31 (d, J=6.8Hz, 1H), 8.22 (d, J=8.3Hz, 1H), 7.77 (dd, J= 9.6,6.0Hz, 2H), 5.00 (d, J=3.6Hz, 2H), 3.91-3.82 (m, 2H), 3.75 (dd, J=17.0,12.7Hz, 4H), 3.28 (d, J=11.0Hz, 2H), 3.20-3.09 (m, 2H), 2.07-1.90 (m, 4H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+435.2145,found 435.2146.
Embodiment 67
2- (9- (isoquinolin -8- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas IBCompound shown in -27) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system in 8- Isoquindinealdehyde alternative embodiment 41 Preparation Method obtains Formulas I with embodiment 41BCompound shown in -27.
1H NMR(400MHz,DMSO-d6) δ 11.63 (s, 1H), 11.26 (s, 1H), 10.47 (d, J=7.8Hz, 1H), 8.77 (d, J=6.4Hz, 1H), 8.73 (s, 2H), 8.63 (d, J=6.4Hz, 1H), 8.46 (dd, J=13.6,7.7Hz, 2H), 8.28 (t, J=7.7Hz, 1H), 5.07 (d, J=4.7Hz, 2H), 3.87 (s, 2H), 3.81 (s, 2H), 3.72 (s, 2H), 3.30 (s, 4H), 2.02 (d, J=13.9Hz, 4H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+435.2145, found435.2147.
Embodiment 68
2- (9- (pyridin-3-yl methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -28) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in 3- pyridine carboxaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -28.
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),11.22(s,1H),9.15(s,1H),9.00–8.94(m, 1H), 8.80-8.76 (m, 1H), 8.74 (d, J=2.7Hz, 2H), 8.09-8.01 (m, 1H), 4.60 (t, J=27.2Hz, 2H), 3.91-3.85 (m, 2H), 3.84-3.79 (m, 2H), 3.76 (s, 2H), 3.32-3.19 (m, 2H), 3.10 (d, J=10.7Hz, 1H), 2.06 (d, J=14.3Hz, 2H), 2.01-1.89 (m, 2H)；HRMS(ESI)m/z calcd for C19H25N6O3[M+H]+ 385.1988,found 385.1989.
Embodiment 69
2- (9- (imidazo [1,2-a] pyridin-3-yl methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- Base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -29) preparation:
Divided by N- methyl indol -3- formaldehyde in imidazo [1,2-a] pyridine -3- formaldehyde alternative embodiment 41, needed for remaining Raw material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -29.
1H NMR(400MHz,DMSO-d6) δ 11.85 (d, J=32.2Hz, 1H), 11.21 (s, 1H), 9.38 (d, J= 6.8Hz, 1H), 8.84-8.71 (m, 2H), 8.53 (dd, J=19.9,4.5Hz, 1H), 8.06 (d, J=13.7Hz, 2H), 7.70-7.58 (m, 1H), 4.96 (d, J=36.3Hz, 2H), 3.81 (dd, J=32.1,16.5Hz, 6H), 3.47 (dt, J= 13.5,6.8Hz, 2H), 3.21 (d, J=10.9Hz, 2H), 2.07 (d, J=13.3Hz, 2H), 1.97 (d, J=13.6Hz, 2H)；HRMS(ESI)m/z calcd for C21H26N7O3[M+H]+424.2097,found 424.2098.
Embodiment 70
2- (9- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-3-yl) methyl) -1- oxa- -4,9- diaza spiro [5.5] ten one carbon -4- bases) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -30) preparation:
Divided by N- methyl indol -3- first in 1- methyl-1 H- pyrrolo- [2,3-b] pyridine -3- formaldehyde alternative embodiment 41 Aldehyde, remaining required raw material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -30.
1H NMR(400MHz,DMSO-d6) δ 11.26 (s, 2H), 8.74 (d, J=9.1Hz, 2H), 8.40 (d, J= 9.4Hz, 1H), 7.90 (d, J=14.6Hz, 2H), 7.38-7.27 (m, 1H), 4.55 (d, J=44.1Hz, 2H), 3.98-3.80 (m, 6H), 3.73 (s, 3H), 3.28 (d, J=11.1Hz, 2H), 3.02 (dd, J=22.4,10.8Hz, 2H), 2.04 (d, J= 14.1Hz,2H),1.94(s,2H)；HRMS(ESI)m/z calcd for C22H28N7O3[M+H]+438.2254,found 438.2256.
Embodiment 71
2- (9- (quinolyl-4 methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -31) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in 4- quinoline aldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -31.
1H NMR(400MHz,DMSO-d6) δ 11.97 (s, 1H), 9.42 (d, J=4.9Hz, 1H), 8.82 (d, J= 8.5Hz, 1H), 8.76 (d, J=18.4Hz, 3H), 8.54 (d, J=7.1Hz, 1H), 8.19 (t, J=7.6Hz, 1H), 8.08- 7.99 (m, 1H), 5.20 (d, J=37.1Hz, 2H), 3.84 (d, J=16.8Hz, 2H), 3.72 (t, J=26.9Hz, 4H), 3.32(s,4H),2.20–1.96(m,4H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+435.2145, found435.2144.
Embodiment 72
2- (9- (quinoline -5- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -32) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system in quinoline -5- formaldehyde alternative embodiment 41 Preparation Method obtains Formulas I with embodiment 41BCompound shown in -32.
1H NMR(400MHz,DMSO-d6) δ 11.60 (s, 2H), 9.74 (d, J=8.4Hz, 1H), 9.38 (d, J= 5.2Hz, 1H), 8.73 (s, 2H), 8.59 (d, J=8.6Hz, 1H), 8.42 (d, J=7.2Hz, 1H), 8.23 (d, J=7.5Hz, 1H), 8.21-8.14 (m, 1H), 4.99 (d, J=5.0Hz, 2H), 3.86 (s, 2H), 3.79 (d, J=4.6Hz, 2H), 3.73 (d, J=10.1Hz, 2H), 3.27 (s, 4H), 2.03 (s, 4H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+ 435.2145,found 435.2146.
Embodiment 73
2- (9- (quinoline -3- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -33) preparation:
Divided by N- methyl indol -3- formaldehyde in quinoline-3-formaldehyde alternative embodiment 41, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 41BCompound shown in -33.
1H NMR(400MHz,DMSO-d6) δ 11.77 (s, 2H), 9.49 (s, 1H), 9.18 (s, 1H), 8.74 (d, J= 3.2Hz, 2H), 8.35 (d, J=8.6Hz, 1H), 8.25 (d, J=8.3Hz, 1H), 8.17-8.09 (m, 1H), 8.00-7.91 (m, 1H), 4.75 (d, J=48.9Hz, 2H), 3.86 (d, J=4.8Hz, 2H), 3.81-3.72 (m, 4H), 3.34 (d, J= 11.2Hz, 2H), 3.16 (dd, J=21.1,9.4Hz, 2H), 2.07 (d, J=14.1Hz, 2H), 1.95 (t, J=11.8Hz, 2H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+435.2145,found435.2146.
Embodiment 74
2- (9- (quinoline -6- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl of pyrimidine -5- Oxime acid hydrochloride (Formulas IBCompound shown in -34) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and system in quinoline -6- formaldehyde alternative embodiment 41 Preparation Method obtains Formulas I with embodiment 41BCompound shown in -34.
1H NMR(400MHz,DMSO-d6) δ 11.82 (s, 2H), 9.35 (t, J=5.0Hz, 1H), 9.10 (d, J= 8.6Hz, 1H), 8.73 (s, 2H), 8.60 (d, J=7.3Hz, 1H), 8.54-8.47 (m, 2H), 8.10 (dd, J=8.3, 5.0Hz, 1H), 4.71 (dd, J=53.0,5.2Hz, 2H), 3.89-3.72 (m, 6H), 3.34-3.20 (m, 2H), 3.12 (d, J =10.0Hz, 2H), 2.13-1.95 (m, 4H)；HRMS(ESI)m/z calcd for C23H27N6O3[M+H]+435.2145, found435.2147.
Embodiment 75
2- (9- (anthracene -9- ylmethyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) different hydroxyl oxime of pyrimidine -5- Acid hydrochloride (Formulas IBCompound shown in -35) preparation:
Divided by N- methyl indol -3- formaldehyde, remaining required raw material, reagent and preparation in anthracene -9- formaldehyde alternative embodiment 41 Method obtains Formulas I with embodiment 41BCompound shown in -35.
1H NMR(400MHz,DMSO-d6) δ 11.22 (s, 1H), 9.78 (s, 1H), 8.89 (d, J=7.1Hz, 1H), 8.71 (s, 2H), 8.66 (t, J=7.3Hz, 2H), 8.24 (t, J=8.0Hz, 2H), 7.82-7.73 (m, 2H), 7.66 (dd, J= 14.4,6.3Hz, 2H), 5.55 (dd, J=40.9,5.0Hz, 2H), 3.91-3.79 (m, 4H), 3.70 (d, J=18.7Hz, 2H), 3.49 (dd, J=22.2,10.5Hz, 2H), 3.33 (d, J=11.0Hz, 2H), 2.01 (d, J=13.9Hz, 2H), 1.93–1.83(m,2H)；HRMS(ESI)m/z calcd for C28H30N5O3[M+H]+484.249,found484.2350.
Embodiment 76
2- (9- ((1H- indol-3-yl) methyl) -1- oxa- -4,9- diaza spiro [5.5] hendecane -4- base) pyrimidine -5- Hydroxamic acid hydrochloride (Formulas IBCompound shown in -36) preparation:
Divided by N- methyl indol -3- formaldehyde in indole -3-formaldehyde alternative embodiment 41, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 41BCompound shown in -36.
1H NMR(400MHz,DMSO-d6) δ 11.56 (s, 1H), 10.75 (s, 1H), 8.74 (d, J=7.8Hz, 2H), 7.87 (t, J=12.5Hz, 1H), 7.70 (t, J=5.0Hz, 1H), 7.48 (t, J=6.9Hz, 1H), 7.15 (dt, J=14.7, 7.1Hz, 2H), 4.51 (t, J=23.1Hz, 2H), 3.82 (s, 2H), 3.73 (t, J=9.7Hz, 4H), 3.28 (d, J= 11.8Hz, 2H), 3.00 (dd, J=22.1,10.5Hz, 2H), 2.05 (d, J=13.5Hz, 2H), 1.90 (t, J=12.5Hz, 2H)；HRMS(ESI)m/z calcd for C22H27N6O3[M+H]+423.2145,found 423.2146.
Embodiment 77
2- (9- ((6- methoxyl group -1- Methyl-1H-indole -3- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] ten One carbon -4- base) pyrimidine 5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -37) preparation:
Divided by N- methyl indol -3- formaldehyde in 6- methoxyl group -1- Methyl-1H-indole -3- formaldehyde alternative embodiment 41, Raw material needed for remaining, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -37.
1H NMR(400MHz,DMSO-d6) δ 11.19 (s, 1H), 10.54 (s, 1H), 8.74 (d, J=9.7Hz, 2H), 7.76 (t, J=11.2Hz, 1H), 7.50 (d, J=9.9Hz, 1H), 7.05 (d, J=2.0Hz, 1H), 6.85-6.78 (m, 1H), 4.42 (d, J=3.8Hz, 2H), 3.85 (d, J=4.0Hz, 3H), 3.81 (d, J=4.1Hz, 5H), 3.72 (s, 4H), 3.28 (d, J=11.8Hz, 2H), 2.99 (dd, J=22.8,10.6Hz, 2H), 2.05 (d, J=13.9Hz, 2H), 1.87 (t, J= 12.1Hz,2H)；HRMS(ESI)m/z calcd for C24H31N6O4[M+H]+467.2407,found 467.2406.
Embodiment 78
2- (11 carbon-of 9- ((1,6- dimethyl -1H- indol-3-yl) methyl) -1- oxa- -4,9- diaza spiro [5.5] 4- yl) pyrimidine -5- hydroxamic acid hydrochloric acid (Formulas IBCompound shown in -38) preparation:
Divided by N- methyl indol -3- formaldehyde in 1,6- dimethyl -1H- indole -3-formaldehyde alternative embodiment 41, needed for remaining Raw material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -38.
1H NMR(400MHz,DMSO-d6) δ 11.18 (s, 1H), 10.52 (s, 1H), 8.73 (d, J=4.2Hz, 2H), 7.74 (d, J=8.1Hz, 1H), 7.55 (s, 1H), 7.32 (d, J=5.4Hz, 1H), 7.00 (d, J=8.3Hz, 1H), 4.43 (d, J=3.9Hz, 2H), 3.82 (d, J=4.6Hz, 5H), 3.72 (s, 4H), 3.27 (d, J=10.8Hz, 2H), 3.00 (dd, J =22.9,11.0Hz, 2H), 2.48 (d, J=5.7Hz, 3H), 2.05 (d, J=14.4Hz, 2H), 1.86 (t, J=12.3Hz, 2H)；HRMS(ESI)m/z calcd for C24H31N6O3[M+H]+451.2458,found451.2460.
Embodiment 79
2- (9- ((5- methoxyl group -1- Methyl-1H-indole -3- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] ten One carbon -4- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -39) preparation:
Divided by N- methyl indol -3- formaldehyde in 5- methoxyl group -1- Methyl-1H-indole -3- formaldehyde alternative embodiment 41, Raw material needed for remaining, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -39.
1H NMR(400MHz,DMSO-d6) δ 11.17 (s, 1H), 10.35 (s, 1H), 8.73 (d, J=8.0Hz, 2H), 7.58 (d, J=8.9Hz, 1H), 7.48-7.38 (m, 2H), 6.92-6.86 (m, 1H), 4.44 (d, J=3.9Hz, 2H), 3.83 (d, J=3.3Hz, 5H), 3.82 (s, 3H), 3.73 (s, 4H), 3.29 (d, J=11.2Hz, 2H), 3.03 (d, J=12.1Hz, 2H), 2.07 (d, J=14.2Hz, 2H), 1.85 (t, J=12.1Hz, 2H)；HRMS(ESI)m/z calcd for C24H31N6O4 [M+H]+467.2407,found467.2408.
Embodiment 80
2- (9- ((6- cyano -1- Methyl-1H-indole -3- base) methyl) -1- oxa- -4,9- diaza spiro [5.5] 11 Carbon -4- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -40) preparation:
Divided by N- methyl indol -3- formaldehyde in 6- cyano -1- Methyl-1H-indole -3- formaldehyde alternative embodiment 41, remaining Required raw material, reagent and preparation method obtain Formulas I with embodiment 41BCompound shown in -40.
1H NMR(400MHz,DMSO-d6) δ 11.18 (s, 1H), 10.73 (s, 1H), 8.73 (d, J=7.1Hz, 2H), 8.20 (d, J=4.9Hz, 1H), 8.09 (d, J=8.3Hz, 1H), 7.95 (s, 1H), 7.54-7.50 (m, 1H), 4.51 (d, J= 4.3Hz, 2H), 3.93 (s, 3H), 3.83 (s, 2H), 3.73 (s, 4H), 3.27 (d, J=10.5Hz, 3H), 3.07-2.97 (m, 2H), 2.05 (d, J=13.8Hz, 2H), 1.87 (t, J=12.0Hz, 3H)；HRMS(ESI)m/z calcd for C24H28N7O3 [M+H]+462.2254,found462.2253.
Embodiment 81
2- (11 carbon-of 9- ((the bromo- 1- Methyl-1H-indole -3- base of 6-) methyl) -1- oxa- -4,9- diaza spiro [5.5] 4- yl) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IBCompound shown in -41) preparation:
Divided by N- methyl indol -3- formaldehyde in the bromo- 1- Methyl-1H-indole -3- formaldehyde alternative embodiment 41 of 6-, remaining institute It needs raw material, reagent and preparation method with embodiment 41, obtains Formulas IBCompound shown in -40.
1H NMR(400MHz,DMSO-d6) δ 11.21 (s, 1H), 10.74 (s, 1H), 8.72 (s, 2H), 7.87 (d, J= 8.5Hz, 1H), 7.81 (d, J=1.5Hz, 1H), 7.67 (s, 1H), 7.32-7.28 (m, 1H), 4.46 (d, J=4.2Hz, 2H), 3.85 (d, J=4.3Hz, 5H), 3.72 (s, 4H), 3.26 (d, J=10.1Hz, 2H), 3.00 (dd, J=22.5,10.4Hz, 2H), 2.04 (d, J=13.8Hz, 2H), 1.88 (t, J=12.0Hz, 2H)；HRMS(ESI)m/z calcd for C23H28N6O3Br[M+H]+515.1406,found 515.1406.
Embodiment 82
(1) 2- (2,6- diaza spiroheptane -2- base)-pyrimidine -5-carboxylic acid's ethyl ester (Formula IICShown compound) Preparation:
By 24.3 grams of half oxalates of 2- tertbutyloxycarbonyl -2,6- diaza spiroheptane and 18.7 grams of chloro- pyrimidines-of 2- 5- carboxylic acid, ethyl ester is dissolved in 500 milliliters of methylene chloride, and ice bath is cooled to 0-5 DEG C, and 18.2 milliliters of n,N-diisopropylethylamine are added, It finishes, then removes ice bath, restore to reacting liquid temperature to room temperature, stir 6 hours.Water is added into reaction solution, vibrates liquid separation, Evaporating solvent under reduced pressure, remaining solid obtain 2- (6- with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1 (v/v)) Tertbutyloxycarbonyl -2,6- diaza spiroheptane -2- base)-pyrimidine -5-carboxylic acid's ethyl ester (white solid).
1H NMR(400MHz,Chloroform-d)δ8.84(s,2H),4.38–4.29(m,6H),4.13(s,4H), 1.44 (s, 9H), 1.36 (t, J=7.1Hz, 3H)
34.8 grams of white solids are dissolved in 500 milliliters of methylene chloride, 50 milliliters of 4N hydrogen chloride-dioxane mixing is added Liquid stirs 5-6 hours at room temperature.Vacuum distillation removes solvent, obtains product as clear oil (Formula IICShown compound), directly use In in next step.
1H NMR (400MHz, Chloroform-d) δ 8.84 (s, 2H), 4.34 (q, J=7.1Hz, 2H), 4.22 (m, 4H), 4.13 (s, 4H), 1.36 (t, J=7.1Hz, 3H)
(2) 2- (6- ((1- Methyl-1H-indole -3- methyl) methyl) -2,6- diaza spiroheptane -2- base)-is phonetic Pyridine -5- carboxylic acid, ethyl ester (formula IIICCompound shown in -1) preparation:
By 0.25 gram of Formula IICShown compound and 0.19 gram of N- methyl indol -3- formaldehyde, are dissolved in 15 milliliters of methylene chloride In, 0.27 milliliter of glacial acetic acid is added, 0.76 gram of sodium triacetoxy borohydride is stirred overnight at room temperature.Reaction is finished, and saturated carbon is added Sour hydrogen sodium water solution, vibrates liquid separation, and organic phase vacuum distillation removes solvent, remaining mixture silica gel column chromatography separating purification (petrol ether/ethyl acetate=1/3 (v/v)), obtains faint yellow oil product (formula IIICCompound shown in -1).
1H NMR(400MHz,DMSO-d6) δ 8.75 (s, 2H), 7.63 (d, J=7.8Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 7.22 (s, 1H), 7.12 (t, J=7.6Hz, 1H), 6.99 (t, J=7.4Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 4.01-3.82 (m, 8H), 3.73 (s, 3H), 2.86 (d, J=4.3Hz, 2H), 1.28 (t, J=7.1Hz, 3H)
(3) 2- (6- (1- Methyl-1H-indole -3- methyl) -2,6- diaza spiroheptane -2- base)-pyrimidine -5- carboxylic Sour (formula IVCCompound shown in -1) preparation:
By 0.24 gram of formula IIICCompound shown in -1 is dissolved in 10 milliliters of the mixed liquor (1:1, v/v) of methanol-water, is added 0.25 gram of potash solid, 65 DEG C~70 DEG C heating are reacted 6 hours, and evaporating solvent under reduced pressure, residue is acidified to pH with 2N hydrochloric acid About 1, vacuum distillation removes water, obtains pale pink solid (formula IVCCompound shown in -1 (containing inorganic salts)).
1H NMR(400MHz,DMSO-d6) δ 8.75 (s, 2H), 7.63 (d, J=7.8Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 7.22 (s, 1H), 7.12 (t, J=7.6Hz, 1H), 6.99 (t, J=7.4Hz, 1H), 4.01-3.82 (m, 8H), 3.73 (s, 3H), 2.86 (d, J=4.3Hz, 2H)
(4) 2- (6- (1- Methyl-1H-indole -3- methyl) -2,6- diaza spiroheptane -2- base)-N- (tetrahydro - 2H- pyrans -2- base-oxygroup) pyrimidine -5- amide (Formula VCCompound shown in -1) preparation:
Above-mentioned pale pink solid is dissolved in 10 milliliters of n,N-Dimethylformamide solution, 0.16 gram of 1- hydroxyl is sequentially added Benzotriazole and 0.23 gram of 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, after stirring 30 minutes at room temperature, according to 0.35 gram of O- (tetrahydro -2H- pyrans -2- base) azanol of secondary addition and 0.42 milliliter of triethylamine stir 48 hours at room temperature, are added full With sodium bicarbonate aqueous solution and methylene chloride, liquid separation is vibrated, organic phase is extracted with dichloromethane three times, and vacuum distillation removes molten Agent, remaining mixture obtain pale yellowish oil product with silica gel column chromatography separating purification (methylene chloride/methanol=60/1 (v/v)) (Formula VCCompound shown in -1).
1H NMR(400MHz,DMSO-d6) δ 11.53 (s, 1H), 8.64 (s, 2H), 7.57 (d, J=7.8Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 7.20 (s, 1H), 7.13 (t, J=7.5Hz, 1H), 7.01 (t, J=7.4Hz, 1H), 4.94 (d, J= 3.2Hz, 1H), 4.15 (s, 3H), 4.01 (td, J=9.9,7.7,3.7Hz, 1H), 3.74 (s, 4H), 3.64 (s, 2H), 3.55- 3.46 (m, 1H), 3.37 (dt, J=10.5,4.7Hz, 2H), 2.87 (s, 2H), 1.54 (m, 6H)
(5) 2- (6- ((1- Methyl-1H-indole -3- methyl) methyl) -2,6- diaza spiroheptane -2- base) is phonetic Pyridine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -1) preparation:
By 145mg Formula VCCompound shown in -1 is added to flask, is dissolved in 5mL methylene chloride, is slowly added to 0.5mL hydrogen chloride Dioxane mixed liquor, in room temperature and under having nitrogen existence condition, be stirred to react 30 minutes.Evaporating solvent under reduced pressure, residue It is washed, is filtered, gained filter cake is object (Formulas I with appropriate etherCCompound shown in -1).
1H NMR(400MHz,DMSO-d6) δ 8.68 (s, 2H), 7.84 (d, J=7.9Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=8.2Hz, 1H), 7.23 (t, J=7.6Hz, 1H), 7.13 (t, J=7.4Hz, 1H), 4.49 (d, J=5.8Hz, 2H), 4.29 (d, J=4.4Hz, 4H), 4.17 (d, J=8.4Hz, 4H), 3.82 (s, 3H)
Embodiment 83
2- (6- ((anthracene -9- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -2) preparation:
In addition to the N- methyl indol -3- formaldehyde in anthracene -9- formaldehyde alternative embodiment 82, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 82CCompound shown in -2.
1H NMR (400MHz, DMSO) δ 9.29 (s, 1H), 8.82 (s, 1H), 8.73-8.65 (m, 2H), 8.60 (d, J= 8.9Hz, 1H), 8.21 (d, J=8.4Hz, 2H), 7.73 (dd, J=14.4,5.9Hz, 2H), 7.67-7.56 (m, 2H), 5.54 (d, J=5.8Hz, 1H), 5.37 (s, 1H), 4.24 (d, J=15.3Hz, 2H), 4.18 (d, J=9.7Hz, 2H), 4.08 (s, 2H), 3.94 (d, J=9.7Hz, 1H), 3.89 (s, 1H) .HRMS (ESI) m/z calcd C25H24N5O2[M+H]+426.1930, found 426.1931.
Embodiment 84
2- (6- ((isoquinolin -8- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamate Hydrochlorate (Formulas ICCompound shown in -3) preparation:
In addition to the N- methyl indol -3- formaldehyde in isoquinolin -8- formaldehyde alternative embodiment 82, remaining required raw material, reagent And preparation method obtains Formulas I with embodiment 82CCompound shown in -3.
1H NMR (400MHz, DMSO) δ 10.29 (s, 1H), 9.85 (s, 2H), 8.74 (d, J=6.4Hz, 1H), 8.69 (s, 1H), 8.54 (d, J=6.1Hz, 1H), 8.41-8.34 (m, 1H), 8.30-8.21 (m, 1H), 4.98 (s, 2H), 4.24 (d, J=9.6Hz, 2H), 4.16 (s, 2H), 3.96 (d, J=9.8Hz, 2H), 3.63 (s, 2H) .HRMS (ESI) m/z calcdC20H22ClN6O2[M+H]+413.1493,found413.1494.
Embodiment 85
2- (6- ((1- methyl -5- cyano-1 H-indol -3- base) methyl) -2,6- diaza spiroheptane -2- base) is phonetic Pyridine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -4) preparation:
In addition to the N- methyl indol -3- formaldehyde in N- methyl -5- cyanoindole -3- formaldehyde alternative embodiment 82, remaining institute It needs raw material, reagent and preparation method with embodiment 82, obtains Formulas ICCompound shown in -4.
1H NMR (400MHz, DMSO) δ 8.68 (d, J=1.5Hz, 2H), 8.51-8.36 (m, 1H), 7.74-7.49 (m, 3H), 4.54 (d, J=3.6Hz, 2H), 4.39-4.24 (m, 4H), 4.23-4.18 (m, 2H), 4.13 (dd, J=14.7, 9.4Hz, 2H), 3.86 (d, J=14.5Hz, 3H) .HRMS (ESI) m/z calcd C21H22N7O2[M+H]+404.1835, found 404.1836.
Embodiment 86
2- (6- ((1- methyl -5- methoxyl group -1H- indol-3-yl) methyl) -2,6- diaza spiroheptane -2- base) Pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -5) preparation:
In addition to the N- methyl indol -3- formaldehyde in N- methyl -5- methoxyindole-3-carboxaldehyde alternative embodiment 82, remaining Required raw material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -5.
1H NMR (400MHz, DMSO) δ 8.67 (d, J=13.9Hz, 2H), 7.52 (s, 1H), 7.43 (d, J=2.2Hz, 1H), 7.37 (d, J=8.9Hz, 1H), 6.85 (dd, J=8.8,2.3Hz, 1H), 4.44 (d, J=5.6Hz, 2H), 4.27 (d, J =13.6Hz, 4H), 4.20-4.12 (m, 4H), 3.82 (s, 3H), 3.78 (s, 3H) .HRMS (ESI) m/z calcd C21H25N6O3[M+H]+409.1988,found 409.1989.
Embodiment 87
2- (6- ((benzo [d] [1,3] dioxole -5- base) methyl) -2,6- diaza spiroheptane -2- Base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -6) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in piperonal alternative embodiment 82, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 82CCompound shown in -6.
1H NMR (400MHz, DMSO) δ 11.41 (s, 1H), 8.72 (d, J=24.6Hz, 2H), 7.14 (s, 1H), 7.03- 6.93 (m, 2H), 6.06 (s, 2H), 4.29 (d, J=13.0Hz, 2H), 4.23 (d, J=8.3Hz, 4H), 4.14 (dd, J= 11.0,6.2Hz,2H).HRMS(ESI)m/z calcd C18H20N5O4[M+H]+370.1515,found 370.1516.
Embodiment 88
2- (6- ((1H- indol-3-yl) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid Hydrochloride (Formulas ICCompound shown in -7) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in indole -3-formaldehyde alternative embodiment 82, remaining required raw material, reagent And preparation method obtains Formulas I with embodiment 82CCompound shown in -7.
1H NMR (400MHz, DMSO) δ 10.75 (s, 1H), 8.67 (s, 2H), 7.81 (d, J=8.2Hz, 1H), 7.62 (s, 1H), 7.44 (d, J=8.0Hz, 1H), 7.16 (t, J=7.4Hz, 1H), 7.13-7.05 (m, 1H), 4.49 (d, J= 5.2Hz,2H),4.27(s,4H),4.22–4.07(m,4H).HRMS(ESI)m/z calcd C19H21N6O2[M+H]+ 365.1726,found 365.1727.
Embodiment 89
2- (6- ((naphthalene -2- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -8) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in 2- naphthaldehyde alternative embodiment 82, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 82CCompound shown in -8.
1H NMR(400MHz,DMSO)δ11.64(s,1H),8.69(s,2H),8.06(s,1H),8.01–7.92(m, 3H), 7.69-7.65 (m, 1H), 7.61-7.57 (m, 2H), 4.53 (d, J=6.2Hz, 2H), 4.35 (dd, J=15.2, 8.5Hz,4H),4.27–4.16(m,4H).HRMS(ESI)m/z calcd C21H22N5O2[M+H]+376.1773,found 376.1772.
Embodiment 90
2- (6- ((quinoline -2- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas ICCompound shown in -9) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in 2- quinoline aldehyde alternative embodiment 82, remaining required raw material, reagent and Preparation method obtains Formulas I with embodiment 82CCompound shown in -9.
1H NMR (400MHz, DMSO) δ 9.80 (s, 2H), 8.72 (d, J=7.2Hz, 2H), 8.50 (d, J=8.5Hz, 1H), 8.05 (dd, J=23.4,12.2Hz, 2H), 7.90-7.80 (m, 1H), 7.67 (t, J=7.4Hz, 2H), 4.65 (s, 2H),4.33–4.19(m,3H),4.11–3.90(m,3H),3.58(s,2H).HRMS(ESI)m/z calcd C20H22ClN6O2 [M+H]+413.1493,found 413.1494.
Embodiment 91
2- (6- ((quinolyl-4) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas ICCompound shown in -10) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in 4- quinoline aldehyde alternative embodiment 82, remaining required raw material, reagent and Preparation method obtains Formulas I with embodiment 82CCompound shown in -10.
1H NMR (400MHz, DMSO) δ 9.12 (s, 1H), 8.68 (d, J=8.9Hz, 2H), 8.36 (d, J=8.5Hz, 1H), 8.22 (d, J=8.1Hz, 1H), 7.97 (s, 1H), 7.86 (d, J=8.5Hz, 2H), 4.45 (s, 2H), 4.30 (d, J= 31.4Hz, 2H), 4.24-4.15 (m, 1H), 4.10-3.85 (m, 3H), 3.60 (d, J=26.0Hz, 2H) .HRMS (ESI) m/z calcd C20H21N6O2[M+H]+377.1726,found 377.1725.
Embodiment 92
2- (6- ((1- Methyl-1H-indole -2- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas ICCompound shown in -11) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in N- methyl indol -2- formaldehyde alternative embodiment 82, original needed for remaining Material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -11.
1H NMR (400MHz, DMSO) δ 8.70 (d, J=6.9Hz, 2H), 7.58 (d, J=7.7Hz, 1H), 7.50 (d, J =8.3Hz, 1H), 7.23-7.17 (m, 1H), 7.06 (t, J=7.3Hz, 1H), 6.80 (d, J=20.2Hz, 1H), 4.48 (d, J =19.4Hz, 2H), 4.27-4.10 (m, 5H), 3.94 (d, J=9.9Hz, 1H), 3.90-3.74 (m, 6H) .HRMS (ESI) m/z calcd C20H24ClN6O2[M+H]+415.1649,found415.1650.
Embodiment 93
2- (6- ((the chloro- 1H- indol-3-yl of 1- methyl -6-) methyl) -2,6- diaza spiroheptane -2- base) is phonetic Pyridine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -12) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in the chloro- indole -3-formaldehyde alternative embodiment 82 of N- methyl -6-, remaining institute It needs raw material, reagent and preparation method with embodiment 82, obtains Formulas ICCompound shown in -12.
1H NMR (400MHz, DMSO) δ 10.93 (s, 1H), 8.68 (s, 2H), 7.88 (t, J=10.9Hz, 1H), 7.60 (t, J=17.2Hz, 2H), 7.15 (dd, J=8.5,1.6Hz, 1H), 4.48 (d, J=5.5Hz, 2H), 4.34-4.23 (m, 4H),4.22–4.07(m,4H),3.86–3.74(m,3H).HRMS(ESI)m/z calcd C20H22ClN6O2[M+H]+ 413.1493,found 413.1492.
Embodiment 94
2- (6- ((naphthalene -1- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -13) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in 1- naphthaldehyde alternative embodiment 82, remaining required raw material, reagent and system Preparation Method obtains Formulas I with embodiment 82CCompound shown in -13.
1H NMR (400MHz, DMSO) δ 9.68 (s, 2H), 8.76-8.68 (m, 2H), 8.31 (d, J=8.3Hz, 1H), 8.01 (t, J=10.2Hz, 2H), 7.94 (d, J=7.0Hz, 1H), 7.69-7.63 (m, 1H), 7.63-7.56 (m, 2H), 4.86-4.62 (m, 2H), 4.26-4.09 (m, 4H), 3.92 (dd, J=22.2,7.5Hz, 2H), 3.54 (d, J=25.8Hz, 2H).HRMS(ESI)m/z calcd C21H22N5O2[M+H]+376.1773,found 376.1772.
Embodiment 95
2- (6- ((benzofuran -2- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid Hydrochloride (Formulas ICCompound shown in -14) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in benzofuran -2- formaldehyde alternative embodiment 82, remaining required raw material, Reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -14.
1H NMR (400MHz, DMSO) δ 10.05 (s, 2H), 8.72 (d, J=7.6Hz, 2H), 7.71 (d, J=7.5Hz, 1H), 7.61 (d, J=8.2Hz, 1H), 7.40-7.35 (m, 1H), 7.29 (t, J=7.2Hz, 1H), 7.23 (s, 1H), 4.49 (s, 2H), 4.24-4.11 (m, 4H), 3.93 (dd, J=12.8,9.1Hz, 2H), 3.47 (s, 2H) .HRMS (ESI) m/z calcdC19H21ClN5O3[M+H]+402.1333,found402.1335.
Embodiment 96
2- (6- (([1,1'- xenyl] -4- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas ICCompound shown in -15) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in 4- phenyl benzaldehyde alternative embodiment 82, remaining required raw material, reagent And preparation method obtains Formulas I with embodiment 82CCompound shown in -15.
1H NMR (400MHz, DMSO) δ 9.70 (s, 2H), 8.71 (d, J=7.5Hz, 2H), 7.75 (s, 4H), 7.70 (d, J=7.3Hz, 2H), 7.48 (t, J=7.6Hz, 2H), 7.39 (t, J=7.3Hz, 1H), 4.27 (d, J=4.8Hz, 2H), 4.23-4.11 (m, 4H), 3.95 (dd, J=9.8,4.3Hz, 2H), 3.39 (t, J=7.0Hz, 2H) .HRMS (ESI) m/z calcd C23H25ClN5O2[M+H]+438.1697,found438.1698.
Embodiment 97
2- (6- ((1- methyl -6- methoxyl group -1H- indol-3-yl) methyl) -2,6- diaza spiroheptane -2- base) Pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -15) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in N- methyl -6- Methoxv-indole -3- formaldehyde alternative embodiment 82, Raw material needed for remaining, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -16.
1H NMR (400MHz, DMSO) δ 10.86 (s, 1H), 8.72-8.66 (m, 2H), 7.71 (d, J=8.7Hz, 1H), 7.43 (s, 1H), 7.01 (d, J=2.1Hz, 1H), 6.78 (dd, J=8.7,2.2Hz, 1H), 4.43 (d, J=5.7Hz, 2H), 4.31-4.23 (m, 4H), 4.21-4.10 (m, 4H), 3.81 (s, 3H), 3.78 (d, J=9.2Hz, 3H) .HRMS (ESI) m/z calcd C21H25N6O3[M+H]+409.1988,found 409.1989.
Embodiment 98
2- (6- ((1- methyl-1 H- pyrrolo- [2,3-c] pyridin-3-yl) methyl) -2,6- diaza spiroheptane - 2- yl) pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -17) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in N- methyl -6- azaindole -3- formaldehyde alternative embodiment 82, remaining Required raw material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -17.
1H NMR (400MHz, DMSO) δ 11.29 (d, J=5.6Hz, 1H), 8.70 (s, 2H), 8.48 (d, J=7.0Hz, 1H), 8.42-8.37 (m, 1H), 7.83 (d, J=14.4Hz, 1H), 7.30 (dd, J=7.9,4.9Hz, 1H), 4.53 (d, J= 5.8Hz,2H),4.35–4.27(m,4H),4.22(s,2H),4.19–4.13(m,2H),3.90(s,3H).HRMS(ESI)m/z calcd C19H22N7O2[M+H]+380.1835,found 380.1837.
Embodiment 99
2- (6- ((2,3- Dihydrobenzofuranes -5- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- Hydroxamic acid hydrochloride (Formulas ICCompound shown in -18) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in 2,3- Dihydrobenzofuranes -5- formaldehyde alternative embodiment 82, remaining institute It needs raw material, reagent and preparation method with embodiment 82, obtains Formulas ICCompound shown in -18.
1H NMR (400MHz, DMSO) δ 11.23 (s, 1H), 8.68 (s, 2H), 7.39 (s, 1H), 7.24 (d, J= 8.2Hz, 1H), 6.80 (d, J=8.1Hz, 1H), 4.56 (t, J=8.7Hz, 2H), 4.30 (s, 2H), 4.27-4.09 (m, 8H), 3.20 (dd, J=18.6,10.0Hz, 2H) .HRMS (ESI) m/z calcd C19H22N5O3[M+H]+368.1723,found 368.1724.
Embodiment 100
2- (6- ((the fluoro- 1H- indol-3-yl of 1- methyl -6-) methyl) -2,6- diaza spiroheptane -2- base) is phonetic Pyridine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -19) preparation:
Divided by N- methyl -6- it is fluorine-based-indole -3-formaldehyde alternative embodiment 82 in N- methyl indol -3- formaldehyde outside, remaining Required raw material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -19.
1H NMR (400MHz, DMSO) δ 9.49 (s, 2H), 8.70 (d, J=6.6Hz, 2H), 7.92-7.82 (m, 1H), 7.65 (s, 1H), 7.36 (d, J=10.2Hz, 1H), 6.99 (t, J=9.2Hz, 1H), 4.33 (d, J=32.9Hz, 2H), 4.18-4.01 (m, 4H), 3.91 (d, J=9.8Hz, 2H), 3.78 (s, 3H), 3.37 (t, J=7.0Hz, 2H) .HRMS (ESI) m/z calcd C20H23ClFN6O2[M+H]+433.1555,found 433.1549.
Embodiment 101
2- (6- benzyl -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloride (Formulas IC- 20 institute Show compound) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in benzaldehyde alternative embodiment 82, remaining required raw material, reagent and preparation Method obtains Formulas I with embodiment 82CCompound shown in -20.
1H NMR (400MHz, DMSO) δ 9.64 (s, 2H), 8.70 (d, J=7.7Hz, 2H), 7.70-7.60 (m, 2H), 7.50-7.38 (m, 3H), 4.22 (d, J=4.7Hz, 2H), 4.19-4.07 (m, 4H), 3.93 (dd, J=9.8,4.4Hz, 2H), 3.33(s,2H).HRMS(ESI)m/z calcd C17H20N5O2[M+H]+326.1617,found 326.1613.
Embodiment 102
2- (6- ((1- Methyl-1H-indole -4- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas ICCompound shown in -21) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in N- methyl indol -4- formaldehyde alternative embodiment 82, original needed for remaining Material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -21.
1H NMR (400MHz, DMSO) δ 9.48 (s, 1H), 8.72-8.65 (m, 2H), 7.51 (dd, J=8.3,4.3Hz, 1H), 7.45 (dd, J=6.4,4.1Hz, 1H), 7.36 (t, J=5.6Hz, 1H), 7.25-7.20 (m, 1H), 6.76 (d, J= 2.5Hz, 1H), 4.48 (d, J=5.2Hz, 2H), 4.10 (dd, J=18.4,14.6Hz, 6H), 3.90 (d, J=9.8Hz, 2H), 3.80 (d, J=11.4Hz, 3H) .HRMS (ESI) m/z calcd C20H23N6O2[M+H]+379.1882,found 379.1884.
Embodiment 103
2- (6- ((benzofuran -3- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid Hydrochloride (Formulas ICCompound shown in -22) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in benzofuran -3- formaldehyde alternative embodiment 82, remaining required raw material, Reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -22.
1H NMR (400MHz, DMSO) δ 11.44 (d, J=5.7Hz, 1H), 8.73-8.67 (m, 2H), 8.25 (s, 1H), 7.97 (d, J=7.3Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.44-7.31 (m, 2H), 4.55 (d, J=5.9Hz, 2H), 4.40–4.34(m,2H),4.32(s,2H),4.29–4.24(m,2H),4.23(s,2H).HRMS(ESI)m/z calcdC19H20N5O3[M+H]+366.1566,found 366.1565.
Embodiment 104
2- (6- ((thiophene -2- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloric acid Salt (Formulas ICCompound shown in -23) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in thiophene -2-formaldehyde alternative embodiment 82, remaining required raw material, reagent And preparation method obtains Formulas I with embodiment 82CCompound shown in -23.
1H NMR(400MHz,DMSO)δ11.61(s,1H),8.69(s,2H),8.06–7.99(m,1H),7.94–7.87 (m, 1H), 7.65 (s, 1H), 7.42 (dd, J=5.6,3.3Hz, 2H), 4.72 (d, J=5.4Hz, 2H), 4.40-4.31 (m, 4H),4.30–4.22(m,4H).HRMS(ESI)m/z calcd C15H18N5O2S[M+H]+332.1181,found 332.1182.
Embodiment 105
2- (6- ((benzothiophene -2- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid Hydrochloride (Formulas ICCompound shown in -24) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in benzothiophene -2- formaldehyde alternative embodiment 82, remaining required raw material, Reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -24.
1H NMR (400MHz, DMSO) δ 11.35 (d, J=5.2Hz, 1H), 8.69 (d, J=6.2Hz, 2H), 7.67 (dd, J=5.1,1.1Hz, 1H), 7.33 (d, J=2.7Hz, 1H), 7.12 (dd, J=5.1,3.5Hz, 1H), 4.58 (d, J= 5.9Hz, 2H), 4.34-4.27 (m, 4H), 4.19 (d, J=12.4Hz, 4H) .HRMS (ESI) m/z calcd C19H20N5O2S[M +H]+382.1338,found 382.1339.
Embodiment 106
2- (6- ((1- methyl-1 H- indazole -3- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- is different Hydroximic acid hydrochloride (Formulas ICCompound shown in -25) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in N- methylindazole -3- formaldehyde alternative embodiment 82, original needed for remaining Material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -25.
1H NMR (400MHz, DMSO) δ 9.73 (s, 2H), 8.75-8.65 (m, 2H), 8.03 (d, J=7.2Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.47 (t, J=7.6Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 4.61 (s, 2H), 4.16- 4.06 (m, 7H), 3.92 (d, J=9.8Hz, 2H), 3.51 (s, 2H) .HRMS (ESI) m/z calcd C19H22N7O2[M+H]+ 380.1835,found 380.1837.
Embodiment 107
2- (6- ((the bromo- 1H- indol-3-yl of 1- methyl -5-) methyl) -2,6- diaza spiroheptane -2- base) is phonetic Pyridine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -26) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in the bromo- indole -3-formaldehyde alternative embodiment 82 of N- methyl -5-, remaining institute It needs raw material, reagent and preparation method with embodiment 82, obtains Formulas ICCompound shown in -26.
1H NMR (400MHz, DMSO) δ 9.17 (s, 1H), 8.67 (d, J=8.0Hz, 2H), 8.14-8.07 (m, 1H), 7.72-7.63 (m, 1H), 7.52-7.45 (m, 1H), 7.33 (dd, J=8.7,1.8Hz, 1H), 4.39 (s, 2H), 4.13-4.07 (m, 4H), 3.91 (d, J=9.7Hz, 2H), 3.82 (s, 3H), 3.38 (dd, J=13.6,6.6Hz, 2H) .HRMS (ESI) m/z calcd C20H22BrN6O2[M+H]+457.0988,found 457.0988.
Embodiment 108
2- (6- ((benzothiophene -3- base) methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid Hydrochloride (Formulas ICCompound shown in -27) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in benzothiophene -3- formaldehyde alternative embodiment 82, remaining required raw material, Reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -27.
1H NMR (400MHz, DMSO) δ 8.66 (d, J=21.7Hz, 2H), 7.92 (s, 2H), 7.68 (s, 2H), 7.47 (s, 2H), 4.46-4.19 (m, 6H), 3.88 (d, J=16.9Hz, 3H), 3.79 (d, J=9.6Hz, 2H), 3.57-3.46 (m, 2H), 3.38 (dd, J=14.0,7.0Hz, 2H) .HRMS (ESI) m/z calcd C19H20N5O2S[M+H]+382.1338, found382.1333.
Embodiment 109
2- (6- ((1- methyl-1 H- pyrrolo- [2,3-b] pyridin-3-yl) methyl) -2,6- diaza spiroheptane - 2- yl) pyrimidine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -28) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in N- methyl -7- azaindole -3- formaldehyde alternative embodiment 82, remaining Required raw material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -28.
1H NMR (400MHz, DMSO) δ 11.37-11.22 (m, 1H), 8.70 (s, 2H), 8.48 (dd, J=7.9, 1.2Hz, 1H), 8.39 (dd, J=4.9,1.3Hz, 1H), 7.84 (s, 1H), 7.29 (dd, J=7.9,4.9Hz, 1H), 4.53 (d, J=5.8Hz, 2H), 4.32 (d, J=16.0Hz, 4H), 4.22 (s, 2H), 4.15 (dt, J=14.3,7.2Hz, 2H), 3.90(s,3H).HRMS(ESI)m/z calcd C19H22N7O2[M+H]+380.1835,found 380.1837.
Embodiment 110
2- (6- (cyclopentyl-methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloride (formula ICCompound shown in -29) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in cyclopenta formaldehyde alternative embodiment 82, remaining required raw material, reagent and Preparation method obtains Formulas I with embodiment 82CCompound shown in -29.
1H NMR (400MHz, DMSO) δ 8.72-8.67 (m, 2H), 4.14 (d, J=9.9Hz, 4H), 3.95 (d, J= 9.7Hz, 2H), 3.46-3.35 (m, 2H), 2.96 (dd, J=11.9,6.2Hz, 2H), 2.28 (dt, J=14.0,7.0Hz, 1H), 1.78 (dd, J=11.7,7.0Hz, 2H), 1.60 (d, J=6.8Hz, 2H), 1.52 (dd, J=7.3,4.3Hz, 2H), 1.26 (dd, J=12.4,7.4Hz, 2H) .HRMS (ESI) m/z calcd C16H24N5O2[M+H]+318.1930,found 318.1935.
Embodiment 111
2- (6- (cyclohexyl methyl) -2,6- diaza spiroheptane -2- base) pyrimidine -5- hydroxamic acid hydrochloride (formula ICCompound shown in -30) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in hexahydrobenzaldehyde alternative embodiment 82, remaining required raw material, reagent and Preparation method obtains Formulas I with embodiment 82CCompound shown in -30.
1H NMR (400MHz, DMSO) δ 8.66 (d, J=27.1Hz, 2H), 4.01 (d, J=9.3Hz, 3H), 3.95 (d, J =6.3Hz, 3H), 3.69 (s, 2H), 3.40 (d, J=9.2Hz, 1H), 3.09-2.97 (m, 2H), 2.90 (d, J=5.3Hz, 2H), 1.69 (dd, J=30.9,18.8Hz, 8H), 1.45-1.40 (m, 1H), 1.26 (d, J=12.6Hz, 4H), 1.19-1.09 (m, 2H), 0.99 (dt, J=13.6,10.3Hz, 4H) .HRMS (ESI) m/z calcd C17H27ClN5O2[M+H]+ 368.1853,found 368.1852.
Embodiment 112
2- (6- ((1H- pyrrolo- [3,2-c] pyridin-3-yl) methyl) -2,6- diaza spiroheptane -2- base) is phonetic Pyridine -5- hydroxamic acid hydrochloride (Formulas ICCompound shown in -31) preparation:
Outside divided by the N- methyl indol -3- formaldehyde in 5- azaindole -3- formaldehyde alternative embodiment 82, original needed for remaining Material, reagent and preparation method obtain Formulas I with embodiment 82CCompound shown in -31.
1H NMR(400MHz,DMSO)δ10.30(s,1H),10.00–9.84(m,1H),9.73(s,1H),8.69(d,J =3.7Hz, 2H), 8.08-7.98 (m, 1H), 7.28 (dd, J=55.6,46.2Hz, 2H), 4.54 (s, 2H), 4.14 (dd, J= 24.5,11.1Hz, 4H), 3.93 (d, J=9.8Hz, 2H), 3.47-3.32 (m, 2H) .HRMS (ESI) m/z calcd C18H21ClN7O2[M+H]+402.1445,found 402.1438.
Embodiment 113
Growth in vitro half effective inhibition concentration (IC of the compound prepared by the present invention to two plants of plasmodiums 3D7 and Dd250) Measurement
(1) plasmodium is cultivated: plasmodium culture (contains NaHCO using PRMI3、HEPES、Albumax I、 Hypoxanthine, Genaotamicin) complete medium (complete medium), in 37 DEG C of incubator (5%CO2, 5% O2) in culture.
(2) growth in vitro half effective inhibition concentration (IC of the compound to plasmodium50) measurement: 100 μ L are cultivated completely Base is added in 96 orifice plates, and suitable 200 μM of compound is added in the first hole and is settled to 200 μ L with complete medium, makes Final compound concentration is 1000nM, then carries out gradient dilution (11 concentration gradients) in 1/2 ratio, dihydroartemisinine (DHA) it is used as positive drug, any compound is not added as negative group, plasmodium and compound is not added as blank group.It is every later The plasmodium culture (hematocrit 4%, parasite rate 1%) that 100 μ L are added in hole makes final hematocrit 2%, parasite rate 1%, final compound concentration gradient be 500nM, 250nM, 125nM, 62.5nM, 31.25nM, 15.625nM, 7.8125nM, 3.90625nM,1.953125nM,0.9765625nM,0.48828125nM.Sample-adding is completed, and 96 orifice plates are placed in 37 DEG C of incubators (5%CO2, 5%O2) middle culture 72 hours.Culture is completed, 100 μ L supernatants of every hole removing, 100 μ L lysates of addition (10 × SYBR Green I, 0.5%v/v Triton X-100,0.5mg/mL saponin, 0.75%EDTA/Tris-Cl buffering Liquid), it is uniformly mixed, is protected from light incubation 2 hours at room temperature.Every hole numerical value (maximum excitation light/maximum is taken with orifice plate fluorescence reading is machine-readable Receive light: 485nm/535nm).Every hole inhibiting rate is calculated according to fluorescent value:
According to concentration-inhibiting rate, growth inhibition curve is drawn in GraphpadPrism and calculates IC50Value.Test result It is shown in Table 1.1~table 1.3.
1.1 I of tableAIC of the series compound to 3D7 and Dd250Value
Continued 1.1
1.2 I of tableBIC of the series compound to 3D7 and Dd250Value
Continued 1.2
1.3 I of tableCIC of the series compound to 3D7 and Dd250Value
Continued 1.3
3D7 is the strain of wild type worm, to drug without obvious resistance；Dd2 to chloroquine, quinine, sulfadoxine, pyrimethamine, Ah Quinoline is not resistant.Table 1.1-1.3 shows that compound provided by the invention all has stronger external insecticidal activity, and part IC of the compound to 3D7 and Dd250Value is suitable with DHA (positive control).
Embodiment 114
Compound prepared by the present invention is to two plants of normal cell HepG-2 and 293-T half effective inhibition concentration (IC50) Measurement:
(1) measurement of the compound to two plants of normal cell inhibitory activity:
Prepare HepG-2 and 293-T cell, in 37 DEG C in 10cm dish, 5%CO2Culture in cell incubator
First day
Pancreatin digestion is resuspended cell and counts, and by the system in 100 holes μ L/, cell is forwarded to 96 holes by the amount of 7000 cells In plate.37 DEG C, 5%CO2Culture 24 hours in cell incubator；
Second day
1, prepare compound gradient concentration system, 2 times of dilutions, system is 100 holes μ L/.It (need to be according to the toxicity of drug come really Determine maximum concentration, rule is to make EC50Concentration is in the centre of concentration gradient, general to choose higher concentration for the first time It to carry out gradient dilution, and is adjusted according to result).
2, remove the supernatant in first day in 96 orifice plate cell culture systems, and will new configured drug concentration system pair (setting duplicate hole) should be added in the cultivation plate hole of culture cell.37 DEG C, 5%CO272h is cultivated in cell incubator.
5th day
1, after cell culture terminates, remove the supernatant in 96 orifice plate cell culture systems, it is molten that 100 μ L detection is added in every hole Liquid (culture medium containing 10%CCK-8), 37 DEG C, 5%CO2It is incubated for 1h in cell incubator, then takes out and is existed with microplate reader measurement Absorbance at 450nm.
2, data processing is carried out, the inhibiting rate of compounds on cell growth under various concentration is calculated, inhibiting rate is inputted GraphPad Prism calculates the IC of each drug according to non-linear regression method50Readings.Inhibiting rate calculation formula is as follows:
Wherein, A (dosing): the absorbance in the hole with cell, CCK-8 solution and drug solution
A (blank): have culture medium and CCK-8 solution without the absorbance in the hole of cell
A (0): have cell, CCK-8 solution without the absorbance in the hole of drug solution
The calculating of selectivity index SI
(2) test result is shown in Table 2.1~2.3.
2.1 I of tableAIC of the series compound to HepG-2 and 293-T50And SI value
Continued 2.1
2.2 I of tableBIC of the series compound to HepG-2 and 293-T50And SI value
Continued 2.2
2.3 I of tableCIC of the series compound to HepG-2 and 293-T50And SI value
Continued 2.3
By table 2.1-2.3 it is found that compound provided by the invention is weaker to the growth inhibition of normal cell, and part chemical combination Object SI value is higher.
Embodiment 115
Half effective inhibition concentration (IC of the part of compounds to five plants of clinical worm strains50) measurement:
It chooses insecticidal activity and cytotoxicity preferably compound and tests them to five plants according to the method for embodiment 113 The IC of clinical worm strain with different pharmaceutical resistance50Value, the results are shown in Table 3:
IC of 3 part of compounds of table to five plants of clinical worm strains50Value
GB4 is resistant to chloroquine；C2A is resistant to quinine；CP286 has sulfadoxine, pyrimethamine, Mefloquine It is resistant；6218 and 6320 pairs of artemisinin-based drugs have time dependent resistance, only show within 6 hours after the ring phase synchronizes Show.Consolidated statement 1 and table 3,72 hours IC of part of compounds50Value is suitable with DHA, and there is display compound treatment to resist to current The malaria of one line of malaria and Second line Drug tolerance, copes with the potentiality of malaria drug resistance.
Embodiment 116
Part of compounds tests Mouse Liver Microsomes metabolic stability
(1) compound tests Mouse Liver Microsomes metabolic stability
Mouse Liver Microsomes (0.5mg/mL) is selected in experiment, is purchased from Corning company.Positive control selects Ketanserine (ketanserin), untested compound is made into the DMSO solution of 10mM first, with dilution in acetonitrile to 0.5mM；Take above-mentioned 0.5mM molten Liquid is added in the buffer containing hepatomicrosome, makes 1.5 μM of compound concentration；Take above-mentioned 1.5 μM of compounds/hepatomicrosome mixing The NADPH solution of 15 μ L 6mM is added in 30 μ L of liquid, makes 1.5 μM of compound ultimate density, NADPH ultimate density is 2mM.Change It closes object/hepatomicrosome test fluid to be placed on test board, be incubated in 37 DEG C of water-baths, at every point of time (0,5,15,30,45 minute) Each 135 μ L acetonitriles that are added are quenched.It is quenched and finishes to whole samples, with oscillator (IKA, MTS2/4) oscillation sample 10 minutes (600rpm/min) is then centrifuged 15 minutes (Thermo Multifuge × 3R) with 4495g.Supernatant liquor is taken, is added by 1:1 Distilled water dilution, is analyzed with LC-MS.By compound 5,15,30,45 minutes peak area response ratio (PARR) and when Between 0 PARR be compared, to determine the percentage of the test compound retained at every point of time.It is quasi- using Excel software Close one phase exponential decay equation calculation half-life period.
(2) test result is shown in Table 4 (part of compounds is to Mouse Liver Microsomes metabolic stabilities)
Table 4
Embodiment 117
Effect experiment in part of compounds Mice Body
(1) effect experiment method in Mice Body
Internal effect experiment selects balb-c mouse infection P.yoelii model to carry out.Mouse selects the female of 6-8 week old, Each dosage group is arranged 5.Positive drug is piperaquine phosphate (PPQ), and administration mode is intraperitoneal injection, and every group of measurement is average before administration Weight, by the medical fluid of 15 μ L/g injection respective volume.The configuration method of compound injection liquid: the dimethyl for being first dissolved in 5%v/v is sub- Sulfone acutely vibrates, solid portion is partially or completely solubilized, the 20%wt β-hydroxypropyl cyclodextrin for adding 95%v/v is water-soluble Liquid, mixing.P.yoelii restores virulence through two mouse of switching after -78 DEG C of defrostings, takes blood, and PBS dilution is added.Every Mouse inoculation 105Plasmodium, 24 hours after infection start to be administered, and are administered 5 times altogether, every minor tick 24 hours.After infection From starting periodically to take blood film from mouse tail vein for 24 hours, parasite rate is calculated:
(2) experimental result is shown in Fig. 1
Blank group death in 6-8 days after inoculation.Parasite rate curve graph shows that compared to the blank group compound, which has, centainly to kill Worm activity, reduces parasite rate, extends the mouse survival time.
Embodiment 118
Part of compounds is to source of people HDAC half effective inhibition concentration (IC50) measurement
(1) source of people HDAC half effective inhibition concentration (IC50) measuring method
1.hHDAC1-3,6 test method: 250nl DMSO or compound solution are added to by OptiPlate by Echo In TM-384F black assay plate, successively 15 μ l enzyme solutions, 10 μ l GL-8 solution are added in assay plate.60 are incubated at 25 DEG C Minute, use the setting reading value of Ex350-360/Em450-465 (sensitivity 60).Inhibiting rate is calculated, with GraphPad Prism Calculate IC50Value.
2.hHDAC8 test method: 250nl DMSO or compound solution are added to by OptiPlate TM- by Echo In 384F black assay plate, 15 μ l enzyme solutions are sequentially added, 10 μ l substrate solutions react 4 hours at 25 DEG C.Add 10 μ l termination Liquid terminates reaction, uses the setting reading value of Ex350-360/Em450-465.Inhibiting rate is calculated, is calculated with GraphPad Prism IC out50Value.
3.hSirt2 test method: 800nl DMSO or compound solution are added to by OptiPlate TM- by Echo In 384F black assay plate, 10 μ l enzyme solutions, 10 μ l substrate solutions are sequentially added, are reacted 4 hours at 25 DEG C.Add 20 μ l termination Liquid terminates reaction, uses the setting reading value of Ex350-360/Em450-465.Inhibiting rate is calculated, is calculated with GraphPad Prism IC out50Value.
EC of 5 part of compounds of table to source of people HDAC50Value
Continued 5
SAHA and suramin is positive control.
The experimental results showed that part of compounds (i.e. In vitro and in vivo activity preferably compound) of the present invention has centainly hHDACs Inhibit, wherein having hHDAC1-3 compared with high inhibition, to hSirt2 almost unrestraint.
Embodiment 119
Part preferred compound inhibits plasmodium deacetylation enzymatic activity confirmatory experiment
(1) plasmodium is cultivated
Plasmodium culture (contains NaHCO3, HEPES, Albumax I, Hypoxanthine using RPMI Genaotamicin) complete medium (Complete Medium) is cultivated in 37 DEG C of incubators
(2) drug is prepared
The compound (see Table 5 for details) in embodiment 118 is selected to be tested, the IC measured early period according to drug50Value, by medicine Object is dissolved in DMSO, prepares 200 × 20 × IC50Initial concentration.
(3) drug-treated (being carried out in Biohazard Safety Equipment)
Take the plasmodium falciparum of 44h or so with complete medium and red blood cell the preparating mixture (red blood cell in 50ml pipe Content is 2%, parasite rate 8%-10%), 6ml mixture is added in every hole of 6 orifice plates, then 30ul medicine is added in every hole Object (working concentration 20*IC50) adds good mixing plank later, and is put into three gas incubators and is incubated for 4h.
(4) albumen sample is collected
6 orifice plates are taken out, 4mL supernatant is discarded, remaining 2mL worm blood mixture is transferred to 2mLEP pipe, is centrifuged (4000r/ 2min, room temperature), remove supernatant, then by each hole with 1ml PBS be resuspended raffinate and be transferred to former EP pipe with reduce loss, again from The heart removes supernatant, and (note: after 4000rpm centrifugation, to prevent protein degradation, centrifugation later should be carried out at 4 DEG C, and by EP pipe type discharge ice Upper operation)；2mL lysate is added in each EP pipe, vortex instrument oscillation mixes, and cracks 10min on ice, is centrifuged (12000r/ 1min, 4 DEG C), discard supernatant liquid；1mlPBS is added in each EP pipe, and vortex instrument oscillation is mixed, is centrifuged (12000r/1min, 4 DEG C), abandons Supernatant is removed, repeats this step twice；90 1 × PBS of μ L are added and are resuspended and are transferred to 1.5ml ultraphonic pipe, add 10 μ L10%SDS, ultrasound 5min (30s on/30s off) after mixing are centrifuged (12000r/10min, 4 DEG C), take supernatant, are added Loading, oscillation, 100 DEG C of heating 10min, sample can be reserved in -20 DEG C.
(5)Western Blot
Voltage 120V is adjusted to after pre-prepared colloid each hole loading 10ul, voltage 80V race 30min to connect followed by race to loading Nearly separation gel lower edge；The pvdf membrane for cutting corresponding area coverage, using wet robin, quick transferring film buffer, 400mA constant current turns 35min, after take out pvdf membrane；Film is put in confining liquid (5% skimmed milk power is added in TBST), shaking table rocks closing 2h.；It using histone histone H3 antibody and H3K9 acetylation antibody, is diluted with 5% skimmed milk power according to 1:2000, in shaking Bed discards Incubating Solution after being incubated for pvdf membrane 2h, and TBST is added and washes film three times, each 10min.；Secondary antibody is diluted according to 1:5000, in Shaking table discards Incubating Solution after being incubated for pvdf membrane 1h.；Extemporaneous developing solution is simultaneously uniformly layered on pvdf membrane, can be bright according to band Degree adjusts the time for exposure.Experimental result is shown in Fig. 2 by Western Blot.
In Fig. 2, JL01 is positive reference compound.As shown in Figure 2, DMSO or compound (20 × IC is added50) it is incubated for 4h Afterwards, at H3 horizontal consistent (anti-H3), JL01 or compound, which is added, can promote the Acetylation Level (anti-H3- of H3 Acetylation), this shows that the activity of HDAC is inhibited, therefore shows that compound is that the general HDAC of plasmodium inhibits indirectly Agent.
Pyrimidine of the invention-hydroxamic acid compound molecular structure is relatively simple, and preparation process is succinct, production cost It is low, it is shown in the HDAC enzyme Inhibition test and inside and outside desinsection effect experiment for having substantial connection with plasmodium survival and reproduction Therefore stronger inhibitory activity out is not only expected to develop into the anti-malaria medicaments of novel single drug mode, but also can be with Develop into the anti-malaria medicaments that administration mode is combined with existing anti-malaria medicaments.

Claims (14)

1. a kind of pyrimidine-hydroxamic acid compound, which is characterized in that the pyrimidine-hydroxamic acid compound is Formulas I institute Show compound or its pharmaceutically acceptable salt:
In Formulas I, R is hydrogen or C4~C16Saturated or unsaturated, substituted or non-substituted carbocylic radical or carbon heterocyclic base；N is 0 Or 1；L is a kind of in following groups:
Wherein, the substituent group of the substituted carbocylic radical or carbon heterocyclic base is selected from: C1~C3Alkyl, C1~C3Alkoxy, halogen or It is one or more kinds of in cyano；The hetero atom of the carbon heterocyclic base is selected from: it is a kind of in oxygen, sulphur or nitrogen, hetero atom number be 1 or 2。
2. pyrimidine-hydroxamic acid compound as described in claim 1, which is characterized in that the pyrimidine-hydroxamic acid Compound is Formulas IAShown compound or its pharmaceutically acceptable salt:
Formulas IAIn, RAFor hydrogen or C4~C16Saturated or unsaturated, substituted or non-substituted carbocylic radical or carbon heterocyclic base；N is 0 Or 1；
Wherein, the substituent group of the substituted carbocylic radical or carbon heterocyclic base is selected from: C1~C3Alkyl, C1~C3Alkoxy, halogen or It is one or more kinds of in cyano；The hetero atom of the carbon heterocyclic base is selected from: it is a kind of in oxygen, sulphur or nitrogen, hetero atom number be 1 or 2。
3. pyrimidine-hydroxamic acid compound as claimed in claim 2, which is characterized in that wherein, n 1；RAIt is 5~6 yuan Aromatic ring yl or aromatic heterocyclic, or 5~6 yuan of the aromatic ring yl or aromatic heterocyclic replaced；
Wherein, the substituent group of the aromatic ring yl or aromatic heterocyclic of substituted 5~6 yuan is C1~C3Alkyl, phenyl, divalent benzene Base, the pyridyl group of substituted divalent phenyl group or divalent；The hetero atom of the aromatic heterocyclic is selected from: in oxygen (O), sulphur (S) or nitrogen (N) One kind, hetero atom number are 1 or 2；
Wherein, the substituent group of the substituted divalent phenyl group is selected from: C1~C3Alkyl, C1~C3One in alkoxy, halogen or cyano Kind is two or more.
4. pyrimidine-hydroxamic acid compound as claimed in claim 3, which is characterized in that wherein, RAFor anthryl, phenanthryl, quinoline Quinoline base, group shown in halogenated quinoline base or Formula IV:
In Formula IV, RA1It is selected from: C1~C3Alkyl, hydrogen, C1~C3It is one or more kinds of in alkoxy, halogen or cyano；X is O, S Or NRA2；
Wherein, RA2For hydrogen or C1~C3Alkyl.
5. pyrimidine-hydroxamic acid compound as claimed in claim 4, which is characterized in that wherein, RAIt is in following groups one Kind:
6. pyrimidine-hydroxamic acid compound as described in claim 1, which is characterized in that the pyrimidine-hydroxamic acid Compound is Formulas IBShown compound or its pharmaceutically acceptable salt:
Formulas IBIn, RBFor 5~6 yuan of aromatic ring yl or aromatic heterocyclic, or 5~6 yuan of the aromatic ring yl or aromatic heterocyclic replaced；
Wherein, the substituent group of the aromatic ring yl or aromatic heterocyclic of substituted 5~6 yuan is C1~C3Alkyl, phenyl Divalent phenyl group, the pyridyl group of substituted divalent phenyl group or divalent；
The substituent group of the substituted divalent phenyl group is selected from: C1~C3Alkyl, C1~C3One kind or two in alkoxy, halogen or cyano Kind or more.
7. pyrimidine-hydroxamic acid compound as claimed in claim 6, which is characterized in that wherein, RBFor naphthalene, quinolyl, Isoquinolyl, C1~C3Group shown in alkyl-substituted indazolyl or benzimidazolyl or Formula VII:
In Formula VII, RB1It is selected from: C1~C3Alkyl, hydrogen, C1~C3It is one or more kinds of in alkoxy, halogen or cyano；X is O, S or NRB2；Y is CH or N；Wherein, RB2For hydrogen or C1~C3Alkyl.
8. pyrimidine-hydroxamic acid compound as claimed in claim 7, which is characterized in that wherein, RBIt is in following groups one Kind:
9. pyrimidine-hydroxamic acid compound as described in claim 1, which is characterized in that the pyrimidine-hydroxamic acid Compound is Formulas ICShown compound or its pharmaceutically acceptable salt:
Formulas ICIn, RCFor 5~6 yuan of aromatic ring yl or aromatic heterocyclic, or 5~6 yuan of the aromatic ring yl or aromatic heterocyclic replaced；
Wherein, the substituent group of the aromatic ring yl or aromatic heterocyclic of substituted 5~6 yuan is C1~C3Alkyl, phenyl,Two Valence phenyl, the pyridyl group of substituted divalent phenyl group or divalent；
The substituent group of the substituted divalent phenyl group is selected from: C1~C3Alkyl, C1~C3One kind or two in alkoxy, halogen or cyano Kind or more.
10. pyrimidine-hydroxamic acid compound as claimed in claim 9, which is characterized in that wherein, RCFor substituted indoles The substituent group of base, the substituted indyl is selected from: C1~C3Alkyl, C1~C3It is one or two kinds of in alkoxy, halogen or cyano More than.
11. pyrimidine-hydroxamic acid compound as claimed in claim 10, which is characterized in that wherein, RCFor in following groups It is a kind of:
12. a kind of composition comprising pyrimidine-hydroxamic acid compound described in any one of claim 1~11.
13. pyrimidine-hydroxamic acid compound as described in any one of claim 1~11 is preparing histone deacetylase Change the application in enzyme (HDAC) inhibitor.
14. application of the composition as claimed in claim 12 in preparation treatment anti-malarial drug.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101163696A (en) * 2005-05-19 2008-04-16 色品疗法有限公司 Histone deacetylase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101163696A (en) * 2005-05-19 2008-04-16 色品疗法有限公司 Histone deacetylase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GIUSEPPE GIANNINI等: "Hydroxamic acid based histone deacetylase inhibitors with confirmed activity against the malaria parasite", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
K. T. ANDREWS等: ""Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues"", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPHY》 *

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