CN106146479B - A kind of effective compound and the preparation method and application thereof inhibited or kill multiple drug resistant bacteria - Google Patents

A kind of effective compound and the preparation method and application thereof inhibited or kill multiple drug resistant bacteria Download PDF

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CN106146479B
CN106146479B CN201510184027.5A CN201510184027A CN106146479B CN 106146479 B CN106146479 B CN 106146479B CN 201510184027 A CN201510184027 A CN 201510184027A CN 106146479 B CN106146479 B CN 106146479B
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CN106146479A (en
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饶燏
张敬仁
胡建涛
刘雪
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Tsinghua University
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Abstract

The invention discloses the compounds that one kind can effectively inhibit or kill bacterium microbe.Compound provided by the present invention, general structure are shown in formula I.Pharmacodynamics test proves that the compound of the present invention can effectively inhibit or kill the staphylococcus aureus, streptococcus pneumonia and staphylococcus aureus of wide spectrum and multidrug resistant, places hope on and develops a kind of antibacterials that are novel effective and having novel targets.

Description

A kind of compound and preparation method thereof of effective inhibition or killing multiple drug resistant bacteria with Using
Technical field
The invention belongs to field of medicaments, and in particular to a kind of compound for effectively inhibiting or killing multiple drug resistant bacteria and its Preparation method and application.
Background technique
Antibiotic (antibiotics) refers to the secondary metabolite of the microorganisms such as certain bacteriums, actinomyces, fungi, or The same compound or analogue chemically synthesized, at low concentrations to various pathogenic microbes or tumour cell There are strength killing, inhibiting effect or the drug for there are other pharmacological actions.It is currently known not lower ten thousand kinds of natural antibiotics.China is anti- Raw element uses big country and antibiotics production big country.Due to largely using so that China becomes abuse in the world and resists for antibiotic Raw Plain Questions inscribes one of the countries with the most serious ..., and leads to the appearance of many drug resistance venereal bacterias, such as superbacteria.
Synthesising bacteria anti-reflecting medicine refers to the antimicrobial compound in addition to antibiotic, such as Comprecin, sulfa drugs, Oxazolidinones, iloquinoline derivative antimicrobial etc..But since also there is drug-fast bacteria in the long-time service of these compounds.
Based on this, development structure is novel and the unique antibacterials of mechanism of action are for killing or inhibiting wide spectrum drug-fast bacteria Growth have very important significance.
The more serious drug-fast bacteria occurred at present includes: methicillin-resistant staphylococcus aureus MRSA, resistance to mould through the ages Plain staphylococcus aureus VRSA, resistance to quinolone staphylococcus aureus QRSA, penicillin resistance pneumococcus PRSP, it is resistance to through the ages Mycin enterococcus faecalis VRE and the Gram-negative bacteria of multidrug resistant etc..It is quickly found out and is directed to by the methods of high flux screening The small molecule symptom of a trend compound of the above antibody-resistant bacterium, and carry out structure optimization and obtain lead compound, and then obtain drug candidate Object and final patent medicine are the targets that we pursue always.Develop Small-molecule probe simultaneously, finding available novel targets is also us Unremitting pursuit.
Summary of the invention
The object of the present invention is to provide the compounds that one kind can effectively inhibit or kill bacterium microbe.
Compound provided by the present invention, general structure are shown in formula I:
Connected between the carbon atom that the dotted line expression R2 carbon atom connected in Formulas I and R3 are connected by singly-bound or double bond It connects；
In Formulas I, R1、R2、R3、R4It is chosen in particular from substituent group as follows:
In Formulas I, R1、R2、R3、R4The further preferred substituent group shown in following:
In Formulas I, R1、R2、R3、R4Most preferably from substituent group as follows:
Compound pharmaceutically acceptable salt shown in above-mentioned Formulas I also belongs to protection scope of the present invention.
Wherein, the salt is inorganic acid salt or acylate.
The inorganic acid salt is selected from the salt that any one following inorganic acid are formed: hydrochloric acid, sulfuric acid and phosphoric acid.
The acylate is selected from the salt that any one following organic acid are formed: acetic acid, trifluoroacetic acid, malonic acid, lemon Acid and p-methyl benzenesulfonic acid.
The present invention also provides the preparation methods of above-mentioned compound of formula I.
The preparation method of the compound of formula I is divided into following several classes according to the difference of substituent group:
When R1 is nitrogenous aromatic compound (such as pyridine compounds and their, pyrazine compounds), prepare in the following way: Formula II and III compound of formula carry out IV compound of aldol reaction production；Dehydrating condensation occurs for IV compound of formula and substitution hydrazine V compound of production is reacted, V compound of formula occurs intramolecular carbon nitrogen coupling reaction and generates final product.
When R1 is phenyl ring or substituted benzene ring, in the following way:
Formula II and III compound of formula carry out IV compound of aldol reaction production；IV compound of formula and replace hydrazine Dehydration condensation and V compound of intramolecular cyclization production, V compound of formula occur oxidizing aromatic and generate final product.Its In, R1 or R3 are furans or sylvan, can generate cis or trans unsaturation Isosorbide-5-Nitrae-diketone by oxidative cleavage and produce Object.This intermediate can further be converted by reduction, peroxidating etc..
It is described as follows:
In Formulas I, R1、R2、R3、R4Selected from substituent group as follows:
And the R in Formulas I2The carbon atom and R connected3When being connected between the carbon atom connected by double bond,
(the specific preparation method such as D3, D3-1 to D3-18, D3-37) includes the following steps: the compound of formula I
1) Formula II compound represented and III compound represented of formula are subjected to aldol reaction, obtained shown in formula IV Compound；
III formula of Formula II formula, IV formula V
2) IV compound represented of formula and R4NHNH2Dehydration condensation is carried out, V compound represented of formula is obtained；
3) V compound represented of formula carries out coupling reaction, obtains compound of formula I.
In the step 1), the molar ratio of the Formula II compound represented and III compound represented of formula is 1:1.
In the step 1), the aldol reaction carries out under the catalysis of alkali, the alkali concretely sodium hydroxide Or potassium hydroxide, the dosage of the alkali are 1.1 times of the moles total number of Formula II compound represented and III compound represented of formula.
The aldol reaction carries out in ethanol water, and the reaction temperature of the reaction is room temperature, reaction time For 1-6h.
In the step 2), IV compound represented of formula and R4NHNH2Molar ratio be 1:1.2-1.5.Thrown hydrazine Amount is a range, mainly so that unsaturated aldehyde ketone conversion is complete.
In the step 2), the dehydration condensation acetic acid or mass concentration be 98% the concentrated sulfuric acid catalysis under into Row.The dosage of the acetic acid or the concentrated sulfuric acid is 0.3 times of substrate (beta-unsaturated ketone) mole.The dehydration condensation is in ethyl alcohol Middle reflux 2-6h.
In the step 3), the coupling reaction carries out in the presence of ruthenium catalyst and sodium bicarbonate.The ruthenium catalyst Concretely p-cymene ruthenous chloride dimer, molecular formula: [RuCl2(p-cymene)]2.The dosage of the ruthenium catalyst is The 5% of substrate unsaturation hydrazone mole；The dosage of the sodium bicarbonate is 1 times of substrate unsaturation hydrazone mole.
Coupling reaction 100-110 DEG C of reaction 12-24h in dimethyl sulphoxide solution.
In Formulas I, R1、R2、R3、R4Selected from substituent group as follows:
And the R in Formulas I2The carbon atom and R connected3When being connected between the carbon atom connected by singly-bound,
The preparation method of the compound of formula I includes the following steps:
A) Formula II compound represented and III compound represented of formula are subjected to aldol reaction, obtained shown in formula IV Compound；
B) IV compound represented of formula and R4NHNH2Or R4NHNH2HCl carries out dehydrating condensation and intramolecular 1,4- addition Reaction, obtains VI compound represented of formula (i.e. Formulas I compound represented).
In the step a), the molar ratio of the Formula II compound represented and III compound represented of formula is 1:1.
In the step a), the aldol reaction carries out under the catalysis of alkali, the alkali concretely sodium hydroxide Or potassium hydroxide, the dosage of the alkali are 1.1 times of the moles total number of Formula II compound represented and III compound represented of formula.
The aldol reaction carries out in ethanol water, and the reaction temperature of the reaction is room temperature, reaction time For 1-6h.
In the step b), IV compound represented of formula and R4NHNH2Molar ratio be 1:1.2-1.5.Thrown hydrazine Amount is a range, mainly so that unsaturated aldehyde ketone conversion is complete.
Reaction condition in the step b) is to return in methanol solution under the concentrated sulfuric acid (mass concentration 98%) catalysis Flow 4-6h.The additional amount of the concentrated sulfuric acid is that the concentrated sulfuric acid described in 0.2mL is added in every mol substrate (beta-unsaturated ketone).
In Formulas I, R1、R2、R3、R4Selected from substituent group as follows:
And when being connected between the carbon atom that is connected of the carbon atom connected of the R2 in Formulas I and R3 by double bond,
The preparation method of the compound of formula I includes the following steps: in acid condition, VI compound represented of formula into The reaction of row oxidizing aromatic, obtains compound of formula I.
The reaction condition are as follows: under Pd catalysis, the 90-100 DEG C of stirring 8-12h under oxygen atmosphere in acetum.Institute The dosage for stating Pd catalyst is the 30% of substrate pyrazoline quality.The Pd catalyst concretely Pd/C catalyst or Pd (OAc)2.
The concentration of the acetum is 0.2-0.5mol/L.
Work as R3ForThe preparation method of the compound of formula I includes the following steps: R3For 5- methyl The compound of formula I of furans or 5- ethyl furan carries out oxidative cleavage, obtains compound as follows.
The reaction condition of the reaction are as follows: 1h is stirred at room temperature with metachloroperbenzoic acid (m-CPBA) in methylene chloride； The R3It is 1:2.5-3.0 for the compound of formula I of 5- methylfuran or 5- ethyl furan and metachloroperbenzoic acid molar ratio.
Work as R3ForThe preparation method of the compound of formula I includes the following steps: R3For 5- The compound of formula I of methylfuran or 5- ethyl furan carries out oxidative cleavage, obtains compound as follows；
The reaction condition of the reaction are as follows:
1) 1h is stirred at room temperature with the metachloroperbenzoic acid of 2.5-3.0equiv in methylene chloride.
The trans product generated under this condition is secondary product (mainly generating cis-product)；
2) dichloroethanes, acetic acid, the in the mixed solvent of water and potassium peroxydisulfate or ammonium persulfate heating stirring 12h, this condition Lower yield is medium, about 40%-50%；
3) reflux 12h can give birth to the product of the cis- dienone of 5- in diethyl ether solution in the presence of elemental iodine in compound of formula I At the trans- dienone product of the 5- of high yield.
Work as R3ForThe preparation method of the compound of formula I includes the following steps:
By R3Oxidation open loop and peroxidization or mistake are carried out for the compound of formula I of 5- methylfuran or the cis- dienone of 5- Oxidation reaction (controls the amount of oxidant according to different substrates), obtains compound as follows.
The reaction condition of the reaction be compound of formula I that R3 is 5- methylfuran in methylene chloride be greater than The reaction of 4.0equiv metachloroperbenzoic acid generates high yield Peroxidation Product；Or R3 is the compound of formula I of the cis- dienone of 5- It is reacted in methylene chloride with 1.5equiv metachloroperbenzoic acid and generates high yield Peroxidation Product.
When R2 is bromine, iodine, the preparation method of the Formulas I the following steps are included:
1) by -1 compound represented of Formulas I (compound of formula I that R2 is hydrogen) and NBS (N- bromo-succinimide) or NIS (N- N-iodosuccinimide) back flow reaction in dichloromethane solution, obtains compound shown in Formulas I -2；(wherein R1 is list In any aryl group containing phenyl ring)
2) compound shown in formula I -3 can be obtained in the open loop under metachloroperbenzoic acid effect of compound shown in Formulas I -2.
Wherein, step 1) Chinese style I-1 compound represented and NBS (N- bromo-succinimide) or NIS (N- iodo fourth two Acid imide) molar ratio be 1:1.2.
Step 2) Chinese style I-2 compound represented and the molar ratio of metachloroperbenzoic acid are 1:2.5.
When R2 isWhen, the preparation method of the Formulas I the following steps are included:
1) by -1 compound represented of Formulas I and NBS (N- bromo-succinimide) back flow reaction in dichloromethane solution, Obtain R shown in Formulas I -22For the product of bromine；(wherein R1 is any aryl group containing phenyl ring in list)
2) by -2 compound represented of Formulas I and 3- butyne-1-ol at Pd (dba)2Catalytic action under, made using cesium carbonate It is reacted in toluene for additive, obtains -3 compound represented of Formulas I；
3) by -3 compound represented of Formulas I, open loop be can be obtained shown in Formulas I -4 under the action of metachloroperbenzoic acid Compound.
Wherein, step 1) Chinese style I-1 compound represented and the molar ratio of NBS are 1:1.2.
Step 2) Chinese style I-2 compound represented and Pd (dba)2Molar ratio be 1:0.1；- 2 compound represented of Formulas I Molar ratio with cesium carbonate is 1:2；The reaction temperature of the reaction is 110 DEG C, and the reaction time is 24 hours.
Step 3) Chinese style I-2 compound represented and the molar ratio of metachloroperbenzoic acid are 1:2.5.
Work as R4For hydrogen, ethyl orWhen, the preparation method of the compound of formula I includes the following steps:
1) IV compound represented of formula and unifor are under hydrochloric acid (0.1equiv) catalysis in ethyl alcohol (1mmol/ 1-2h 5mL) is reacted at room temperature in solution, obtains Formula V compound；
2) Formula V compound under the conditions of equivalent sodium bicarbonate in dimethyl sulfoxide (1mmol/5mL) solution 100 DEG C plus Intramolecular cyclization elimination reaction 4h production VII compound (i.e. the compound of formula I that R4 is hydrogen) occurs for heat；
3) Formula VII compound 2 times of moles sodium hydride in anhydrous tetrahydrofuran solution with iodoethane or propargyl bromide Nucleophilic substitution occurs, obtains R4For the compound of formula I of ethyl or propargyl；
4) compound of formula I (R4For hydrogen or the compound of ethyl or propargyl) it can carry out further aoxidizing as described above and open Ring conversion, obtaining R1 is that cited each aryl substituent, R2 are hydrogen, R3 is cis and trans Isosorbide-5-Nitrae-diketone, R4 is hydrogen, second in table The compound of formula I of base or propargyl.
When R4 isWhen, the preparation method of the Formulas I the following steps are included:
By -3 compound represented of Formulas I and morpholine under 4-dimethylaminopyridine, EDCI condensing agent, triethylamine effect in It is reacted in anhydrous methylene chloride solution, obtains -4 compound represented of Formulas I.(wherein R1 is arbitrarily to contain phenyl ring in list Aryl group)
In the above method, -3 compound represented of Formulas I, morpholine, 4-dimethylaminopyridine, EDCI condensing agent, three second The molar ratio of amine is 1:1.2:0.1:1.0:1.0.
The reaction of the reaction is room temperature, and the reaction time is 12 hours.
Above-mentioned IV compound represented of formula for preparing formula Compound I and Formula V compound represented and they Preparation method also belongs to protection scope of the present invention.
It is also another object of the present invention to provide the purposes of compound shown in Formulas I and its pharmaceutically acceptable salt.
Compound shown in Formulas I provided by the present invention and its pharmaceutically acceptable salt purposes are them in preparation antibacterials In application.
The antibacterials are anti-bacterial drug.The bacterium is the streptococcus pneumonia of streptococcus pneumonia, multidrug resistant (MRSP), staphylococcus aureus, methicillin-resistant staphylococcus aureus (MRSA), enterococcus faecalis, multidrug resistant excrement intestines Coccus (MDEF)；The enterococcus faecalis (VRE) of vancomycin resistance.
Heretofore described multi-drug resistant bacteria (multiple resistant bacteria) refers to there is multi-drug resistant Pathogen.It is defined as a kind of microorganism to three classes (such as aminoglycoside, erythromycin, beta-lactam class) or three classes with Upper antibiotic while drug resistance.
This is also belonged to using Formulas I compound represented and its pharmaceutically acceptable salt as antibacterials prepared by active constituent The protection scope of invention.
The antibacterials can pass through injection, injection, collunarium, eye drip, infiltration, absorption, the physically or chemically method that mediates Import body such as muscle, intradermal, subcutaneous, vein, mucosal tissue；Or body is imported after other material mixings or package.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.The load Body includes diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, the sorbefacient, surface of pharmaceutical field routine Activating agent, absorption carrier, lubricant etc..
Note can be made using the antibacterials that compound shown in Formulas I and its pharmaceutically acceptable salt are prepared as active constituent Penetrate the diversified forms such as liquid, tablet, pulvis, granule, capsule, oral solution.The drug of above-mentioned various dosage forms can be according to pharmacy It is prepared by the conventional method in field.
Pharmacodynamics test proves that the compound of the present invention can effectively inhibit or kill the golden yellow of wide spectrum and multidrug resistant Staphylococcus, streptococcus pneumonia and staphylococcus aureus are placed hope on and develop a kind of novel effective and have the anti-of novel targets Bacterium drug.
Detailed description of the invention
Fig. 1 is the synthetic route flow chart of compound D3.
Fig. 2 is the synthetic route flow chart of compound D3-1.
Fig. 3 is the synthetic route flow chart of compound D3-2.
Fig. 4 is the synthetic route flow chart of compound D3-3.
Fig. 5 is the synthetic route flow chart of compound D3-4.
Fig. 6 is the synthetic route flow chart of compound D3-8.
Fig. 7 is the synthetic route flow chart of compound D3-9.
Fig. 8 is the synthetic route flow chart of compound D3-10.
Fig. 9 is the synthetic route flow chart of compound D3-13.
Figure 10 is the synthetic route flow chart of compound D3-14.
Figure 11 is the synthetic route flow chart of compound D3-15.
Figure 12 is the synthetic route flow chart of compound D3-16.
Figure 13 is the synthetic route flow chart of compound D3-17.
Figure 14 is the synthetic route flow chart of compound D3-18.
Figure 15 is the synthetic route flow chart of compound D3-37.
Figure 16 is the synthetic route flow chart of compound D3-5.
Figure 17 is the synthetic route flow chart of compound D3-6.
Figure 18 is the synthetic route flow chart of compound D3-7.
Figure 19 is the synthetic route flow chart of compound D3-11.
Figure 20 is the synthetic route flow chart of compound D3-12.
Figure 21 is the synthetic route flow chart of compound D3-19.
Figure 22 is the synthetic route flow chart of compound D3-20.
Figure 23 is the synthetic route flow chart of compound D3-21.
Figure 24 is the synthetic route flow chart of compound D3-22.
Figure 25 is the synthetic route flow chart of compound D3-23.
Figure 26 is the synthetic route flow chart of compound D3-25.
Figure 27 is the synthetic route flow chart of compound D3-30.
Figure 28 is the synthetic route flow chart of compound D3-24.
Figure 29 is the synthetic route flow chart of compound D3-31.
Figure 30 is the synthetic route flow chart of compound D3-26.
Figure 31 is the synthetic route flow chart of compound D3-32 and compound D3-33.
Figure 32 is the synthetic route flow chart of compound D3-34.
Figure 33 is the synthetic route flow chart of compound D3-35.
Figure 34 is the synthetic route flow chart of compound D3-36.
Figure 35 is the synthetic route flow chart of compound D3-38 and D3-38 '.
Figure 36 is the synthetic route flow chart of compound D3-39.
Figure 37 is the synthetic route flow chart of compound D3-40, D3-41, D3-42.
Figure 38 is the synthetic route flow chart of compound D3-43 and D3-43 '.
Figure 39 is the synthetic route flow chart of compound D3-44, D3-45, D3-46.
Figure 40 is the synthetic route flow chart of compound D3-48.
Figure 41 is the synthetic route flow chart of compound D3-49.
Figure 42 is the synthetic route flow chart of compound D3-50.
Figure 43 is the synthetic route flow chart of compound D3-51.
Figure 44 is the synthetic route flow chart of compound D3-52.
Figure 45 is the synthetic route flow chart of compound D3-53 and D3-54.
Figure 46 is the synthetic route flow chart of compound D3-55.
Figure 47 is the synthetic route flow chart of compound D3-56.
Figure 48 is the synthetic route flow chart of compound D3-57.
Figure 49 is the synthetic route flow chart of compound D3-58.
Figure 49 is the synthetic route flow chart of compound D3-58.
Figure 50 is the synthetic route flow chart of compound D3-59.
Figure 51 is the synthetic route flow chart of compound D3-60.
Figure 52 is the synthetic route flow chart of compound D3-61.
Figure 53 is the synthetic route flow chart of compound D3-62.
Figure 54 is the synthetic route flow chart of compound D3-63.
Figure 55 is the synthetic route flow chart of compound D3-64, D3-65.
Figure 56 is the synthetic route flow chart of compound D3-67.
Figure 57 is the synthetic route flow chart of compound D3-69, D3-70.
Figure 58 is the synthetic route flow chart of compound D3-71.
Figure 59 is the synthetic route flow chart of compound D3-73, D3-74.
Figure 60 is the synthetic route flow chart of compound D3-76.
Figure 61 be compound D3-77, D3-77 ' synthetic route flow chart.
Figure 62 is the synthetic route flow chart of compound D3-78.
Figure 63 is the synthetic route flow chart of compound D3-79.
Figure 64 is the synthetic route flow chart of compound D3-80.
Figure 65 is the synthetic route flow chart of compound D3-81.
Figure 66 is the synthetic route flow chart of compound D3-82.
Figure 67 is the synthetic route flow chart of compound D3-83a and compound D3-83b.
Figure 68 is the synthetic route flow chart of compound D3-84.
Figure 69 is the synthetic route flow chart of compound D3-85b.
Figure 70 is the synthetic route flow chart of compound D3-86.
Figure 71 is the synthetic route flow chart of compound D3-87.
Figure 72 is the synthetic route flow chart of compound D3-88b.
Figure 73 is the synthetic route flow chart of compound D3-89.
Figure 74 is the synthetic route flow chart of compound D3-90.
Figure 75 is the synthetic route flow chart of compound D3-91, compound D3-92, compound D3-93.
Figure 76 is the synthetic route flow chart of compound D3-94.
Figure 77 is the synthetic route flow chart of compound D3-95.
Figure 78 is the synthetic route flow chart of compound D3-96.
Figure 79 is the synthetic route flow chart of compound D3-97.
Figure 80 is the synthetic route flow chart of compound D3-101.
Figure 81 is the synthetic route flow chart of compound D3-102.
Figure 82 is the synthetic route flow chart of compound D3-106.
Figure 83 is the synthetic route flow chart of compound D3-107.
Figure 84 is the synthetic route flow chart of compound D3-108.
Figure 85 is the synthetic route flow chart of compound D3-109.
Specific embodiment
Method of the invention is illustrated below by specific embodiment, but the present invention is not limited thereto.
Experimental method described in following embodiments is unless otherwise specified conventional method；The reagent and biological material Material, unless otherwise specified, commercially obtains.
Streptococcus pneumonia as used in the following examples, staphylococcus aureus, the bacterial strain of enterococcus faecalis are specific as follows:
Staphylococcus aureus (Staphylococcus aureus): ATCC number is 29213；
Streptococcus pneumonia (Streptococcus pneumoniae): NCTC number is 7466；
Enterococcus faecalis (Enterococcus faecalis): ATCC number is 29212
MRSP used in embodiment: the streptococcus pneumonia of multidrug resistant；MDEF: the enterococcus faecalis of multidrug resistant； VRE: the enterococcus faecalis of vancomycin resistance；MRSA: methicillin-resistant staphylococcus aureus；It is that hospital is clinically separated bacterium Strain.Its drug resistance have passed through stringent drug sensitive test verifying.The public can obtain the biomaterial from applicant, and the biomaterial is only Used in the related experiment of duplicate of attaching most importance to invention, it not can be used as other purposes and use.
The preparation of first part, compound
Embodiment 1, prepare compound D3
1, intermediate α, the preparation of alpha, beta-unsaturated ketone a
Specific steps are as follows: 20.0mL dehydrated alcohol is added in round-bottomed flask, it is cooled to 0 DEG C with ice-water bath, is added Enter 1.10mL (10mmol) 3- acetylpyridine and 1.00mL (10mmol) 5 methyl furfural, 480mg sodium hydrate solid is molten The solution of sodium hydroxide is added dropwise in the solution of substrate, instead by solution in the mixed liquor of 10.0mL ethyl alcohol and 10.0mL water Answer 2h.Saturated ammonium chloride solution is added and adjusts reaction solution to neutrality, 100ml water is added to be diluted, then uses methylene chloride Extraction 3 times (25ml methylene chloride is added every time), merges the organic phase extracted three times, use anhydrous sodium sulfate after being washed twice with water Dry, then decompression is spin-dried for solvent, residue petroleum ether: ethyl acetate=6:1-3:1 (volume ratio) crosses silicagel column, obtains 1.6g intermediate a (intermediate a is light yellow solid), yield 75%.
Characterization of compound data are as follows:
1H NMR(400MHz,CDCl3) δ (ppm) 9.23 (s, 1H), 8.77 (dd, J=1.8Hz, J=5.0Hz, 1H), 8.28 (m, J=1.8Hz, J=8.0Hz, 1H), 7.56 (d, J=14.8Hz, 1H), 7.42 (dd, J=5.0Hz, J=8.0Hz, 1H), 7.32 (d, J=14.8Hz, 1H), 7.68 (d, J=2.8Hz, 1H), 6.15 (d, J=2.8Hz, 1H), 2.39 (s, 3H)；
13C NMR(100MHz,CDCl3) δ (ppm) 188.22,156.49,152.83,150.00,149.62,135.60, 133.57,131.47,123.47,119.20,116.65,109.62,13.94.
2, the preparation of intermediate hydrazone b
Specific steps are as follows: α is added in round-bottomed flask, 6.0mL dehydrated alcohol is added in alpha, beta-unsaturated ketone 426mg 57 μ L of acetic acid is added in dissolution, after stirring 10min, 256 μ L of phenylhydrazine is added, reaction solution is heated to reflux 8h, and reaction solution is cooled to room Saturated sodium bicarbonate solution and methylene chloride extraction is added three times in temperature, and combined organic phase is washed with saturated common salt.Organic phase is used Anhydrous sodium sulfate is dry, and then decompression is spin-dried for solvent, residue petroleum ether: ethyl acetate=4:1-3:1 (volume ratio) crosses silicon Rubber column gel column obtains 546mg intermediate hydrazone b (intermediate b is yellow solid), yield 90%.
It is hydrazone along anti-mixture, the confirmation of LC-MS molecular weight that hydrogen, which composes true structure,.
3, the preparation of product pyrazoles c
Specific steps are as follows: 546mg hydrazone b is added in round-bottomed flask, the anhydrous DMSO dissolution of 3.0mL is added, is added P-cymene ruthenous chloride dimer 6.1mg, NaHCO3168mg, reaction system are protected with replacement of oxygen, are heated to 110 DEG C and are stirred Mix 4h.Reaction solution is cooled to room temperature, and water and methylene chloride extraction is added three times, combined organic phase is washed with saturated common salt.Have Machine is mutually dry with anhydrous sodium sulfate, and then decompression is spin-dried for solvent, residue methylene chloride: ethyl acetate=20:1-15:1 (body Product ratio) silicagel column is crossed, obtain 188mg pyrazole compound c (white solid), yield 35%.
Compound data is characterized as below:
1H NMR(400MHz,CDCl3): δ (ppm) 9.116 (d, J=1.6Hz, 1H), 8.576 (dd,3J=4.8Hz,4J =1.6Hz, 1H), 8.208 (dt,3J=8.0Hz,4J=1.6Hz, 1H), 7.507-7.475 (m, 5H), 7.344 (dd,3J= 8.0Hz,3J=4.8Hz, 1H), 6.987 (s, 1H), 5.924 (d,3J=3.2Hz, 1H), 5.798 (d,3J=3.2Hz, 1H), 2.310(s,3H)；13CNMR(100MHz,CDCl3):δ(ppm)152.83,149.04,148.99,147.32,142.40, 140.15,136.59,132.96,129.17,128.88,128.84,126.21,123.56,110.03,107.44,102.37, 13.56；LC-MS(ESI+):m/z calculated for C19H16N3O(M+H)+:302.13,found:301.22.
Embodiment 2-15
According to method substantially the same manner as Example 1, it is only necessary to by 3- acetylpyridine or 5- methyl in 1 step 1 of embodiment Phenylhydrazine in furfural and step 2 replace accordingly, other operations obtain following compounds with embodiment 1.
4-(5-(5-methylfuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)pyridine
1H-NMR(400MHz,CDCl3) δ (ppm) 8.628 (d, J=5.12Hz, 2H), 7.756 (d, J=5.12Hz, 2H), 7.428-7.464 (m, 5H), 7.006 (s, 1H), 5.906 (d, J=2.52Hz, 1H), 5.782 (d, J=3.16Hz, 1H), 2.284(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)152.94,150.27,149.34,142.25,140.34,140.11, 136.84,129.21,129.00,126.20,120.14,110.22,107.52,102.96,13.55；
LC-MS(ESI+):m/z calculated forC19H16N3O(M+H)+:302.13,found 302.22.
2-(5-(5-methylfuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)pyridine
1H-NMR(400MHz,CDCl3) δ (ppm) 8.659 (d, J=4.74Hz, 1H), 8.046 (d, J=7.92Hz, 1H), 7.156 (t, J=7.70Hz, 1H), 7.517-7.435 (m, 5H), 7.284 (s, 1H), 7.231-7.201 (m, 1H), 5.912 (d, J=7.08Hz, 1H), 5.852 (d, J=7.08Hz, 1H), 2.264 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)152.68,152.21,151.90,149.48,142.63,140.37, 136.50,136.45,128.99,128.63,126.22,122.67,120.23,109.87,107.29,103.98,13.48；
LC-MS(ESI+):m/z calculated forC19H16N3O(M+H)+:302.13,found 302.21.
3-(1-phenyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 9.110 (s, 1H), 8.579 (d, J=4.44 Hz, 1H), 8.203 (d, J=7.84Hz, 1H), 7.460-7.432 (m, 5H), 7.345 (dd, J=7.80 Hz, J=4.88 Hz, 1H), 7.305 (d, J =5.08 Hz, 1H), 6.964 (t, J=4.24 Hz, 1H), 6.907 (s, 1H), 6.864 (d, J=3.60 Hz, 1H)；
13C-NMR(100 MHz,CDCl3)δ(ppm)149.25,149.11,147.44,139.76,138.75,133.08, 130.99,129.26,128.91,128.74,127.63,127.57,126.93,126.33,123.69,105.00；
LC-MS(ESI+):m/z calculated forC18H14N3S(M+H)+:304.09,found 304.19.
3-(1-(4-methoxyphenyl)-5-(5-methylfuran-2-yl)-1H-pyrazol-3-yl) pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 9.107 (s, 1H), 8.563 (d, J=4.60 Hz, 1H), 8.192 (d, J=7.72Hz, 1H), 7.404 (d, J=8.44 Hz, 2H), 7.331 (dd, J=7.80 Hz, J=4.84 Hz, 1H), 6.997 (d, J=8.48 Hz, 2H), 6.966 (s, 1H), 5.911 (d, J=2.84 Hz, 1H), 5.733 (d, J=3.12 Hz, 1H), 3.877(s,3H),2.317(s,3H)；
13C-NMR(100 MHz,CDCl3)δ(ppm)159.93,152.69,148.97,148.70,147.33,142.63, 136.88,133.18,132.89,128.97,127.73,123.51,114.32,109.74,107.42,101.71,55.60, 13.54；
LC-MS(ESI+):m/z calculated forC20H18N3O2(M+H)+:332.14,found 332.22.
3-(5-(furan-2-yl)-1-phenyl-1H-pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 9.122 (s, 1H), 8.575 (s, 1H), 8.199 (d, J=7.88 Hz, 1H), 7.487-7.451 (m, 5H), 7.422 (d, J=1.12 Hz, 1H), 7.338 (dd, J=7.76 Hz, J=4.84 Hz, 1H), 7.015 (s, 1H), 6.345 (dd, J=3.16 Hz, J=1.72 Hz, 1H), 5.986 (d, J=3.40 Hz, 1H)；
13C-NMR(100 MHz,CDCl3)δ(ppm)149.10,149.08,147.32,144.08,142.77,140.07, 136.14,132.97,129.20,128.82,125.98,123.57,111.32,109.19,103.26；
LC-MS(ESI+):m/z calculated forC18H14N3O(M+H)+:288.11,found 288.20.
3-(1-(3-chlorophenyl)-5-(furan-2-yl)-1H-pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 9.101 (d, J=1.48 Hz, 1H), 8.585 (dd, J=4.72 Hz, J=1.28Hz, 1H), 8.187 (dt, J=7.92 Hz, J=1.84 Hz, 1H), 7.539 (t.J=1.64 Hz, 1H), 7.444-7.330 (m, 5H), 6.995 (s, 1H), 6.402 (dd, J=3.36 Hz, J=1.80 Hz, 1H), 6.162 (d, J= 3.20 Hz, 1H)；
13C-NMR(100 MHz,CDCl3)δ(ppm)149.51,149.30,147.32,143.56,143.09,141.02, 135.98,134.76,132.99,130.03,128.72,128.49,125.98,123.72,123.59,111.45,109.76, 104.06；
LC-MS(ESI+):m/z calculated forC18H12ClN3O(M+H)+:321.07,found 321.52.
4-(1-(tert-butyl)-5-(5-methylfuran-2-yl)-1H-pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 8.597 (d, J=4.48Hz, 2H), 7.697 (d, J=5.12 Hz, 2H), 6.722 (s, 1H), 6.367 (d, J=3.00 Hz, 1H), 6.090 (d, J=2.40 Hz, 1H), 2.378 (s, 3H), 1.589(s,12H).
LC-MS(ESI+):m/z calculated forC17H20N3O(M+H)+:282.16,found 282.25.
4-(4-methyl-5-(5-methylfuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 8.672 (d, J=5.36 Hz, 2H), 7.716 (d, J=5.48 Hz, 2H), 7.401-7.335 (m, 5H), 6.137 (d, J=3.04 Hz, 1H), 6.028 (d, J=3.04 Hz, 1H), 2.382 (s, 3H),2.249(s,3H)；
13C-NMR(100 MHz,CDCl3)δ(ppm)153.29,150.15,148.40,141.63,141.41,140.44, 133.80,128.93,127.92,124.84,122.15,115.91,112.49,107.31,13.65,10.38；
LC-MS(ESI+):m/z calculated forC20H18N3O(M+H)+:316.14,found 316.16.
4-(1-phenyl-5-(1H-pyrrol-2-yl)-1H-pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 8.628 (d, J=5.40 Hz, 2H), 8.344 (bs, 1H), 7.759 (d, J=5.56 Hz, 2H), 7.466-7.436 (m, 5H), 6.847 (s, 1H), 6.780 (s, 1H), 6.200 (dd, J=5.56 Hz, J=2.72Hz, 1H), 6.139 (s, 1H)；
13C-NMR(100 MHz,CDCl3)δ(ppm)150.20,149.48,140.68,140.08,138.28,129.46, 128.82,125.78,120.71,120.27,119.76,110.21,109.83,103.30；
LC-MS(ESI+):m/z calculated forC18H15N4(M+H)+:287.13,found 287.22.
4-(1-(4-fluorophenyl)-5-(5-methylfuran-2-yl)-1H-pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 8.651 (d, J=5.24 Hz, 2H), 7.757 (d, J=5.40 Hz, 2H), 7.477 (dd, J=8.64 Hz, J=4.84 Hz, 2H), 7.183 (t, J=8.44 Hz, 2H), 7.007 (s, 1H), 5.948 (d, J=3.12 Hz, 1H), 5.841 (d, J=3.12 Hz, 1H), 2.305 (s, 3H)；
13C-NMR(100 MHz,CDCl3) δ (ppm) 162.74 (d, J=242.0 Hz, C), 153.24,150.42, 149.62,142.18,140.29,137.05,136.33 (d, J=3.6 Hz, C), 128.21 (d, J=8.8 Hz, CH), 120.22,116.26 (d, J=22.9Hz, CH), 110.40,107.64,103.15,13.66；
LC-MS(ESI+):m/z calculated forC19H15FN3O(M+H)+:320.12,found 320.11.
4-(5-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3- yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 8.668 (d, J=4.96 Hz, 2H), 7.769-7.731 (m, 4H), 7.640 (d, J=8.28 Hz, 2H), 7.019 (s, 1H), 6.054 (d, J=3.20 Hz, 1H), 6.008 (d, J=3.20 Hz, 1H),2.300(s,3H)；13C-NMR(100 MHz,CDCl3)δ(ppm)153.62,150.49,150.25,143.00, (141.66,140.00,136.64,130.60 q, J=33.9 Hz, C), 126.36 (q, J=3.7 Hz, CH), 125.84, 123.89 (q, J=269.6 Hz, C), 120.23,111.18,107.76,104.60,13.66；
LC-MS(ESI+):m/z calculated forC20H15F3N3O(M+H)+:370.12,found 370.15.
2-(5-(5-methylfuran-2-yl)-1-phenyl-1H-pyrazol-3-yl)pyrazine
1H-NMR(400 MHz,CDCl3) δ (ppm) 9.305 (s, 1H), 8.594 (s, 1H), 8.498 (d, J=2.40 Hz, 1H), 7.516-7.481 (m, 5H), 7.286 (s, 1H), 5.926 (d, J=3.20 Hz, 1H), 5.848 (d, J=3.20 Hz, 1H),2.284(s,3H)；
13C-NMR(100 MHz,CDCl3)δ(ppm)153.07,149.82,147.73,144.13,143.42,142.42, 142.38,140.24,136.87,129.24,129.07,126.32,110.33,107.52,104.38,13.61；
LC-MS(ESI+):m/z calculated forC18H15N4O(M+H)+:303.12,found 303.44.
4-(4-methyl-5-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)pyridine
1H-NMR(400 MHz,CDCl3) δ (ppm) 8.689 (s, 2H), 7.713 (d, J=5.56 Hz, 2H), 7.643 (d, J=8.40Hz, 2H), 7.512 (d, J=8.40 Hz, 2H), 6.306 (d, J=3.08 Hz, 1H), 6.100 (d, J=2.24 Hz,1H),2.351(s,3H),2.253(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)153.87,150.24,149.22,143.09,141.00,140.77, 133.68,129.41 (q, J=33.0Hz, C), 126.08 (q, J=4.0Hz, CH), 124.11,124.00 (q, J= 272.0Hz,C),122.09,117.20,113.23,107.58,13.66,10.32；
LC-MS(ESI+):m/z calculated forC21H17F3N3O(M+H)+:384.13,found 384.48.
4-(5-(thiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl) pyridine
1H-NMR(400MHz,CDCl3) δ (ppm) 8.676 (dd, J=4.68Hz, J=1.44Hz, 2H), 7.766 (dd, J =4.56Hz, J=1.52Hz, 2H), 7.692 (d, J=8.48Hz, 2H), 7.585 (d, J=8.40Hz, 2H), 7.393 (dd, J =5.08Hz, J=0.84Hz, 1H), 7.029 (dd, J=5.04Hz, J=3.64Hz, 1H), 6.911 (dd, J=3.52Hz, J =0.80Hz, 1H)；
LC-MS(ESI+):m/z calculated forC19H13F3N3S(M+H)+:372.08,found 372.59.
Embodiment 16, prepare compound D3-5
Embodiment 16 is similar with 1-15, and only the preparation method of intermediate hydrazone is different.
In embodiment 16, beta-unsaturated ketone is prepared by aldol condensation, is generated by sulphuric acid catalysis dehydrating condensation unsaturated Hydrazone generates pyrazole product by transition metal-catalyzed intramolecular carbonnitrogen bond coupling.
Compound data is characterized as below:
1H-NMR(400MHz,CDCl3) δ (ppm) 9.108 (s, 1H), 8.617 (d, J=4.44Hz, 1H), 8.318 (d, J =8.80Hz, 2H), 8.203 (d, J=7.92Hz, 1H), 7.689 (d, J=8.84Hz, 2H), 7.379 (dd, J=7.88Hz, J =4.84Hz, 1H), 6.983 (s, 1H), 6.256 (d, J=3.16Hz, 1H), 6.064 (d, J=3.12Hz, 1H), 2.300 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)153.84,150.40,149.61,147.39,146.60,145.03, 141.16,136.21,133.05,128.19,125.04,124.45,123.66,111.72,107.74,105.45,13.58；
LC-MS(ESI+):m/z calculated forC19H15N4O3(M+H)+:347.11,found 347.20.
Embodiment 17-18
According to method substantially the same manner as Example 16, it is only necessary to carry out paranitrophenylhydrazine in 16 step 2 of embodiment corresponding Replacement (such as 2, the hydrazine of 4,6- trichlorobenzene hydrazines, hydrochloride), other operation with embodiment 15, obtain following compounds.
3-(5-(5-methylfuran-2-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl) pyridine
1H-NMR(400MHz,CDCl3) δ (ppm) 9.115 (s, 1H), 8.589 (d, J=4.56Hz, 1H), 8.194 (d, J =7.92Hz, 1H), 7.533 (s, 2H), 7.346 (dd, J=7.80Hz, J=4.84Hz, 1H), 7.041 (s, 1H), 5.946 (d, J=2.84Hz, 1H), 5.727 (d, J=3.20Hz, 1H), 2.290 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)153.27,150.58,149.34,147.46,141.76,137.93, 136.57,136.20,134.97,133.18,128.82,128.53,123.55,108.80,107.74,101.09,13.52；
LC-MS(ESI+):m/z calculated forC19H13Cl3N3O(M+H)+:404.01,found 404.08.
4-(5-(5-methylfuran-2-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl) benzenesulfonamide
1H-NMR(400MHz,DMSO-d6) δ (ppm) 8.651 (s, J=5.28Hz, 2H), 7.980 (d, J=8.36Hz, 2H), 7.886 (d, J=5.56Hz, 2H), 7.714 (d, J=8.40Hz, 2H), 7.534 (s, 2H), 7.436 (s, 1H), 6.199-6.181(m,2H),2.265(s,3H)；
LC-MS(ESI+):m/z calculated forC19H17N4O3O(M+H)+:381.10,found 381.21.
Embodiment 19, prepare compound D3-11
1, intermediate α, the preparation of alpha, beta-unsaturated ketone a
With embodiment 1.
2, the preparation of intermediate hydrazone b
According to the method essentially identical with 1 step 2 of embodiment, it is only necessary to which phenylhydrazine therein replaces with unifor i.e. It can.
3, the preparation of product pyrazoles c
According to the method essentially identical with 1 step 3 of embodiment, it is only necessary to which removing ruthenium catalyst therein can compound data It is characterized as below:
1H-NMR(400MHz,CDCl3) δ (ppm) 8.591 (d, J=5.68Hz, 2H), 7.659 (d, J=5.44Hz, 2H), 6.782 (s, 1H), 6.505 (d, J=3.16Hz, 1H), 6.013 (d, J=2.88Hz, 1H), 2.293 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)152.58,150.05,120.12,108.06,107.77,99.35, 13.64；
LC-MS(ESI+):m/z calculated forC13H12N3O(M+H)+:226.10,found 226.22.
Embodiment 20, prepare compound D3-12
The preparation method is as follows: compound D3-11 is dissolved in anhydrous tetrahydrofuran solution in round-bottomed flask, ice bath is cold But, sodium hydride 2.0equiv and iodoethane 2.0equiv is added, is stirred 1 hour under ice bath.Water quenching reaction is added, after post-processing It crosses column purification and obtains two kinds of isomers.Through repeatedly this available main isomer after purification, yield 50%.
Compound data is characterized as below:
4-(1-ethyl-5-(5-methylfuran-2-yl)-1H-pyrazol-3-yl)pyridine
1H-NMR(400MHz,CDCl3) δ (ppm) 8.612 (d, J=4.24Hz, 2H), 7.688 (d, J=5.88Hz, 2H), 6.791 (s, 1H), 6.474 (d, J=3.20Hz, 1H), 6.112 (d, J=3.20Hz, 1H), 4.406 (q, J=7.24Hz, 2H), 2.384 (s, 3H), 1.507 (t, J=7.24Hz, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)153.09,150.32,147.87,142.59,140.82,135.47, 120.00,109.96,107.71,102.52,46.49,15.56,13.76；
LC-MS(ESI+):m/z calculated forC15H16N3O(M+H)+:254.13,found 254.18.
Embodiment 21, prepare compound D3-19
The preparation method is as follows: compound D3-16 (37mg, 0.1mmol, 1.0equiv) is dissolved in 2mL in round-bottomed flask In methylene chloride, it is added N-bromo-succinimide (NBS) (21mg, 0.12mmol, 1.2equiv), reaction solution was heated to reflux Night.After reaction solution is cooled to room temperature, with methylene chloride and saturated salt solution extraction post-processing.Organic phase after merging through drying, After filtering, being spin-dried for, crude product obtains white solid D3-19 (29mg, 66% yield) by column purification.
Compound data is characterized as below:
4-(4-bromo-5-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)pyridine
1H-NMR(400MHz,CDCl3) δ (ppm) 8.713 (d, J=4.72Hz, 2H), 7.953 (d, J=4.88Hz, 2H), 7.680 (d, J=8.20Hz, 2H), 7.516 (d, J=8.20Hz, 2H), 6.706 (d, J=1.76Hz, 1H), 6.141 (d, J= 1.76Hz,1H),2.201(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)154.42,150.26,147.79,142.94,139.15,139.03, 134.75,130.26 (q, J=32.0Hz, C), 126.16 (q, J=4.0Hz, CH), 124.50,123.87 (q, J= 270.0Hz,C),121.99,114.69,107.87,95.89,13.59；
LC-MS(ESI+):m/z calculated forC20H14BrF3N3O(M+H)+:448.03,found 448.20.
Embodiment 22, prepare compound D3-20
The preparation method is as follows: by compound D3-19 (26mg, 0.058mmol, 1.0equiv) and to trifluoro in round-bottomed flask Methoxyphenylboronic acid (18mg, 0.087mmol, 1.5equiv) is dissolved in 4mL in the mixed solvent (toluene: ethyl alcohol: water/20:5:1), Addition four triphenyl phosphorus palladium (6.7mg, 0.1equiv) of catalyst, triphenyl phosphorus (3.0mg, 0.2equiv), potassium carbonate (20mg, 2.5equiv), reaction mixture heating stirring in 80 DEG C of oil baths is stayed overnight.After being cooled to room temperature, eaten with methylene chloride and saturation Salt water does extraction post-processing.Product D3-20 and raw material are obtained by column purification (petroleum ether: ethyl acetate/5:1-3:1-1:1) The mixture 17mg of D3-19, ratio 3:1.
Compound data is characterized as below:
4-(5-(5-methylfuran-2-yl)-4-(4-(trifluoromethoxy)phenyl)-1-(4- (trifluoromethyl)phenyl)-1H-p yrazol-3-yl)pyridine(D3-20)
1H-NMR(400MHz,CDCl3) δ (ppm) 8.540 (d, J=4.56Hz, 2H), 7.694 (d, J=8.40Hz, 2H), 7.578 (d, J=8.32Hz, 2H), 7.402 (d, J=5.56Hz, 2H), 7.301 (d, J=8.56Hz, 2H), 7.221 (d, J= 8.28Hz, 2H), 6.037 (d, J=3.04Hz, 1H), 5.954 (d, J=3.04Hz, 1H), 2.155 (s, 3H), 1.255 (s, 3H)；LC-MS(ESI+):m/z calculated forC27H18F6N3O2(M+H)+:530.13,found 530.30.
Embodiment 23, prepare compound D3-21
1, intermediate α, the preparation of alpha, beta-unsaturated ketone a
It is carried out referring to the method for 1 step 1 of embodiment
2, it the preparation of intermediate hydrazone b: is carried out referring to the method for 1 step 2 of embodiment.
3, it the preparation of product pyrazoles c: is carried out referring to the method for 1 step 3 of embodiment.
Compound data is characterized as below:
4-(5-(furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl) pyridine
1H-NMR(400MHz,CDCl3) δ (ppm) 8.668 (d, J=5.36Hz, 2H), 7.761 (d, J=6.00Hz, 2H), 7.732 (d, J=8.48Hz, 2H), 7.605 (d, J=8.32Hz, 2H), 7.451 (d, J=1.12Hz, 1H), 7.049 (s, 1H), 6.432 (dd, J=3.36Hz, J=1.80Hz, 1H), 6.245 (d, J=3.28Hz, 1H)；
13C-NMR(100MHz,CDCl3)δ(ppm)150.42,150.26,143.46,143.33,142.85,139.89, 136.13,130.55 (q, J=33.0Hz, C), 126.40 (q, J=4.0Hz, CH), 125.55,123.84 (q, J= 271.0Hz,C),120.20,111.63,110.33,105.41；
LC-MS(ESI+):m/z calculated forC19H13F3N3O(M+H)+:356.10,found 356.30.
Embodiment 24, prepare compound D3-22
1, the preparation of alpha, beta-unsaturated ketone a: intermediate α is carried out referring to the method for 1 step 1 of embodiment.
2, in a round bottom flask by substrate beta-unsaturated ketone (426mg, 2.0mmol, 1.0equiv) and to trifluoromethyl phenyl hydrazine (423mg, 1.2equiv) is dissolved in 8.0mL methanol, and a few drop concentrated sulfuric acids are added, and is heated to reflux 6h, after reaction is cooled to room temperature, rotation Extraction post-processing is done with methylene chloride and saturated sodium bicarbonate solution after dry solvent.Organic phase after merging by dry, filtering, Column purification (methylene chloride: ethyl acetate/15:1-5:1-3:1) is crossed after being spin-dried for obtains yellow solid D3-22, yield 60%.
Embodiment 25, prepare compound D3-23
1, the preparation of alpha, beta-unsaturated ketone a: intermediate α is carried out referring to the method for 1 step 1 of embodiment.
2, method is the same as embodiment 24.
Embodiment 26, prepare compound D3-25
The preparation method is as follows: it is molten that compound D3-16 (185mg, 0.5mmol, 1.0equiv) is dissolved in 5.0mL methylene chloride It in liquid, is added metachloroperbenzoic acid m-CPBA (91mg, 0.525mmol, 1.05equiv), stirring 1 is small at room temperature for reaction When.With methylene chloride and saturated sodium bicarbonate solution extraction post-processing, combined organic phase by drying, filter, be spin-dried for after Purified on silica column (methylene chloride: methanol/40:1-20:1-15:1) obtains white solid D3-25, yield 90%.
The two condition is identical, but the equivalent of metachloroperbenzoic acid used is different, so product is different, D3-25 is The raw material of D3-26
Compound data is characterized as below:
4-(5-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3- yl)pyridine 1-oxide
1H-NMR(400MHz,CDCl3) δ (ppm) 8.238 (d, J=7.00Hz, 2H), 7.765-7.722 (m, 4H), 7.608 (d, J=8.32Hz, 2H), 6.930 (s, 1H), 6.041 (d, J=3.20Hz, 1H), 5.997 (d, J=2.80Hz, 1H),2.285(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)153.77,148.57,142.81,141.36,139.51,136.98, 130.91 (q, J=6.10Hz, CH), 126.37 (q, J=3.80Hz, CH), 125.77,122.59,111.38,107.80, 104.10,13.63；
LC-MS(ESI+):m/z calculated forC20H15F3N3O2(M+H)+:386.11,found 386.24.
Embodiment 27, prepare compound D3-30
The preparation method is as follows: compound D3-21 (43mg, 0.12mmol, 1.0equiv) is dissolved in the anhydrous N of 2.0mL, N- bis- In methylformamide, ice bath is cooling, is added phosphorus oxychloride (112 μ l, 10.0equiv), and 1h is stirred at room temperature in reaction.Reaction solution Extracted with water and methylene chloride, the organic phase after merging by drying, filter, be spin-dried for after obtained crude product by column purification White solid D3-30 (4mg, yield 9%) is obtained after (petroleum ether: ethyl acetate/1:1-1:2).
Compound data is characterized as below:
5-(3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl) furan-2-carbaldehyde
1H-NMR(400MHz,CDCl3) δ (ppm) 9.650 (s, 1H), 8.701 (d, J=4.32Hz, 2H), 7.817- 7.766 (m, 4H), 7.660 (d, J=8.20Hz, 2H), 7.324 (s, 1H), 7.210 (d, J=3.60Hz, 1H), 6.228 (d, J =3.56Hz, 1H)；
LC-MS(ESI+):m/z calculated forC20H13F3N3O2(M+H)+:384.10,found 384.34.
Embodiment 28, prepare compound D3-24
The preparation method is as follows: substrate D3-16 (181mg, 0.49mmol, 1.0equiv) is added in round-bottomed flask, oxidant Ammonium Persulfate 98.5 (168mg, 0.735mmol, 1.5equiv), AcOH (0.3mL), DCE (2.5mL), water (2.5mL), reaction mixing Liquid heating stirring in 50 DEG C of oil baths is stayed overnight.After reaction solution is cooled to room temperature, methylene chloride dilution is added, unsaturated carbonate hydrogen is added Water phase is extracted with dichloromethane until product all extracts out in sodium.Merge organic phase, the crude product after drying, filter, being spin-dried for passes through silicon Rubber column gel column purifying (methylene chloride: ethyl acetate/2:1-1:1, then methylene chloride: acetone/2:1) obtains light yellow solid D3-24 (95mg, 50% yield).
Compound data is characterized as below:
(E)-1-(3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5- yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 8.714 (d, J=5.92Hz, 2H), 7.785-7.759 (m, 4H), 7.597 (d, J=8.28Hz, 2H), 7.511 (s, 1H), 7.494 (d, J=15.6Hz, 1H), 7.138 (d, J=15.6Hz, 1H),2.428(s,3H)；
LC-MS(ESI+):m/z calculated forC20H15F3N3O2(M+H)+:386.11,found 386.29.
Embodiment 29, prepare compound D3-31
Substrate with compound D3-24, only need to be replaced with compound D3-21 by compound D3-16 substantially by preparation method.
Compound data is characterized as below:
(E)-4-oxo-4-(3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)but-2-enal
1H-NMR(400MHz,CDCl3) δ (ppm) 9.908 (d, J=7.00Hz, 1H), 8.719 (d, J=5.68Hz, 2H), 7.797-7.764 (m, 4H), 7.609 (d, J=8.28Hz, 2H), 7.528 (d, J=14.84Hz, 1H), 7.509 (s, 1H), 7.056 (dd, J=15.72Hz, J=7.04Hz, 1H),
LC-MS(ESI+):m/z calculated forC19H35F3N3O2(M+H)+:372.10,found 372.29.
Embodiment 30, prepare compound D3-26
The preparation method is as follows: substrate D3-16 (42mg, 0.114mmol, 1.0equiv) is dissolved in 1mL in round-bottomed flask In methylene chloride (DCM), it is added metachloroperbenzoic acid (m-CPBA) (78.5mg, 0.455mmol, 4.0equiv), at room temperature 5h is stirred, methylene chloride is added and saturated sodium bicarbonate solution extracts, organic phase extracted is by drying, filtering, being spin-dried for Obtaining faint yellow solid product D3-26 by silica gel column purification (methylene chloride: methanol/30:1-15:1) afterwards, (15mg, 34% produces Rate).Compound data is characterized as below:
(Z)-4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)pyridine 1-oxide1H-NMR(400MHz,CDCl3) δ (ppm) 8.233 (d, J=7.12Hz, 2H), 7.826 (d, J=8.44Hz, 2H), 7.764 (d, J=8.52Hz, 2H), 7.724 (d, J=7.16Hz, 2H), 7.130 (s, 1H), 6.690 (d, J=11.68Hz, 1H), 6.646 (d, J=11.68Hz, 1H), 2.315 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.28,182.99,148.00,142.73,140.96,139.66, 136.31,135.86,129.89,126.19 (q, J=3.6Hz, CH), 125.81,122.65,30.21；
LC-MS(ESI+):m/z calculated forC20H15F3N3O3(M+H)+:402.11,found 402.28.
Embodiment 31, prepare compound D3-32 and compound D3-33
The preparation method is as follows: compound D3-16 (36.9mg, 0.1mmol, 1.0equiv) is dissolved in the 1.2mL tert-butyl alcohol With (5:1) in the mixed liquor of water, it is added sodium chlorite (54mg, 0.6mmol, 6.0equiv), hypophosphite monohydrate sodium dihydrogen (42mg, 0.3mmol, 3.0equiv) reaction mixture stirs 4h at room temperature.It is post-processed with ethyl acetate and saturated sodium bicarbonate solution (general extraction), through drying, filter, be spin-dried for after crude product silica gel column purification (methylene chloride: acetone/3:1-2:1) separated Two kinds of compound D3-32 (principal product, 10mg) and D3-33 (a small amount of product, 3mg) afterwards
Compound data is characterized as below:
1-(3-(3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5- carbonyl)oxiran-2-yl)ethanone
1H-NMR(400MHz,CDCl3) δ (ppm) 8.704 (d, J=5.80Hz, 2H), 7.775-7.743 (m, 4H), 7.649 (s, 1H), 7.565 (d, J=8.36Hz, 2H), 4.095 (d, J=1.64Hz, 1H), 3.732 (d, J=1.64Hz, 1H),2.208(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)201.90,182.38,150.75,150.35,142.66,138.57, 138.07,126.34,126.29,120.15,58.86,56.59,25.09；
LC-MS(ESI+):m/z calculated forC20H15F3N3O3(M+H)+:402.11,found 402.28.
1-(3-(3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5- carbonyl)oxiran-2-yl)ethanone
1H-NMR(400MHz,CDCl3) δ (ppm) 8.710 (d, J=5.08Hz, 2H), 7.778-7.746 (m, 4H), 7.666 (s, 1H), 7.596 (d, J=8.40Hz, 2H), 4.192 (d, J=4.80Hz, 1H), 3.882 (d, J=4.80Hz, 1H),2.331(s,3H)；
LC-MS(ESI+):m/z calculated forC20H15F3N3O3(M+H)+:402.11,found 402.33.
Embodiment 32, prepare compound D3-34
The preparation method is as follows: compound D3-24 (19mg, 0.05mmol, 1.0equiv) is dissolved in 1mL methanol, add Enter sodium borohydride (2-3mg, 1.2equiv), reaction solution stirs 20min under condition of ice bath.Water quenching reaction is added, uses acetic acid After ethyl ester and weak acid solution post-processing, the crude product after drying, filter, being spin-dried for passes through silica gel column purification (methylene chloride: methanol
/ 20:1-10:1) obtain the above mixture D 3-34 (nuclear magnetic data: ratio is about 0.55:0.45).
LC-MS(ESI+):m/z calculated forC20H21F3N3O2(M+H)+:392.16,found 392.33.
LC-MS(ESI+):m/z calculated forC20H19F3N3O2(M+H)+:390.14,found 390.33.
Embodiment 33, prepare compound D3-35
The preparation method is as follows: compound D3-24 (19mg, 0.05mmol, 1.0equiv) is dissolved in 2mL methanol solution In, it is added 10%Pd/C (10mg), after reaction flask sealing three times with hydrogen balloon exchange.Reaction solution is vigorously stirred 5h at room temperature. Diatomite filters out palladium carbon, is spin-dried for solvent methanol, and residue obtains white by silica gel column purification (petroleum ether: acetone/3:1-1:1) Color solid D3-35 (16mg, 80% yield).
1-(3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl) pentane-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 8.689 (d, J=5.20Hz, 2H), 7.753-7.722 (m, 4H), 7.575 (d, J=8.28Hz, 2H), 7.460 (s, 1H), 3.208 (t, J=6.00Hz, 2H), 2.881 (t, J=6.00Hz, 2H),2.208(s,3H)；
13C-NMR(100MHz,CDCl3) δ (ppm) 206.60,188.86,150.65,149.72,140.14 (q, J= 204Hz, C), 130.90 (q, J=33Hz, C), 136.31,126.08 (q, J=3.0Hz, CH), 120.16,110.36, 37.00,34.42,29.85；
LC-MS(ESI+):m/z calculated forC20H17F3N3O2(M+H)+:388.13,found 388.33.
Embodiment 34, prepare compound D3-36
The preparation method is as follows: compound D3-31 (17mg, 0.046mmol, 1.0equiv) is dissolved in 0.6mL tetrahydro furan Mutter in the 0.6mL tert-butyl alcohol.By sulfamic acid (36mg, 0.37mmol, 8.0equiv), sodium chlorite (13mg, 0.137mmol, 3.0equiv), a hypophosphite monohydrate sodium dihydrogen (45mg, 0.322mmol, 7.0equiv) is dissolved in 0.6mL water.By above-mentioned solution It is added drop-wise in the solution of substrate.Reaction solution is stirred at room temperature overnight.Post-processing ethyl acetate and water, dry, filter, are spin-dried for Crude product afterwards obtains the white solid D3-36 of 5mg by silica gel column purification (methylene chloride: methanol/20:1-7:1-5:1).
(E)-4-oxo-4-(3-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)but-2-enoic acid
1H-NMR(400MHz,CDCl3) δ (ppm) 8.672 (d, J=5.44Hz, 2H), 7.733-7.718 (m, 4H), 7.578 (d, J=8.24Hz, 2H), 7.469 (s, 1H), 7.406 (d, J=15.56Hz, 1H), 7.050 (d, J=15.56Hz, 1H)。
Embodiment 35, prepare compound D3-38 and D3-38 '
Preparation method is referring to Figure 35.Crude product after post-processing passes through silica gel column purification (methylene chloride: acetone/2:1-1:1) The mixture of both the above is obtained, the ratio of the two confirms by nuclear-magnetism.
(Z)-4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)-2-(4-(trifluorome thoxy)phenyl)pyridine 1-oxide
1H-NMR(400MHz,CDCl3)δ(ppm)8.417-8.383(m,1.65H),7.627(s,1H),7.159(s, 0.66H), 6.688 (d, J=11.60Hz, 0.65H), 6.645 (d, J=11.60Hz, 0.65H), 4.146 (d, J=4.40Hz, 1H), 3.889 (d, J=4.40Hz, 1H), 2.332 (s, 3H), 2.315 (s, 1.98H)；
LC-MS(ESI+):m/z calculated forC27H18F6N3O4(M+H)+:562.12,found 562.33.
LC-MS(ESI+):m/z calculated forC27H18F6N3O5(M+H)+:578.12,found 578.32.
Embodiment 36, prepare compound D3-39
The preparation method is as follows: compound D3-24 (32mg, 0.083mmol, 1.0equiv) is dissolved in 2.0mL dichloromethane In alkane, it is added metachloroperbenzoic acid (36mg, 0.208mmol, 2.5equiv), reaction solution stirs 3h at room temperature.Use dichloro Methane and saturated sodium bicarbonate solution normally post-process, and the crude product after drying, filter, being spin-dried for (is eluted by the purifying of silicagel column System is methylene chloride: methanol/30:1-25:1) obtain 24mg product as light yellow solid D3-39, yield 73%.
(E)-4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)pyridine 1-oxide
1H-NMR(400MHz,CDCl3) δ (ppm) 8.314 (d, J=6.56Hz, 2H), 7.802-7.769 (m, 4H), 7.577 (d, J=8.24Hz, 2H), 7.465 (d, J=15.56Hz, 1H), 7.430 (s, 1H), 7.137 (d, J=15.60Hz, 1H),2.424(s,3H)；
LC-MS(ESI+):m/z calculated forC20H15F3N3O3(M+H)+:402.11,found 402.03.
Embodiment 37, prepare compound D3-40, D3-41, D3-42
Preparation method is referring to Figure 37.Wherein D3-40 and D3-41 is two kinds of products that same reaction generates.D3-42 is identical The product that substrate different condition generates.
For D3-40 and D3-41, crude product is by silica gel column purification (first time: petroleum ether: ethyl acetate/3:1- after reaction 2:1；Second: petroleum ether: methylene chloride/2:1-1:1-1:2)
For D3-42, the same D3-43 of method.Silicagel column purification system ketone D3-40.
(Z)-1-(3-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pent-2- Ene-1,4-dione (compound D3-40)
1H-NMR(400MHz,CDCl3) δ (ppm) 7.862-7.830 (m, 4H), 7.751 (d, J=8.28Hz, 2H), 7.441 (t, J=7.28Hz, 2H), 7.378 (t, J=7.04Hz, 1H), 7.167 (s, 1H), 6.715 (d, J=11.76Hz, 1H), 6.609 (d, J=11.76Hz, 1H), 2.302 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.76,182.78,152.33,143.22,140.35,136.56, (135.65,131.68,130.36 q, J=33.0Hz, C), 128.96,128.93,126.04 (q, J=4.0Hz, CH), 125.95,125.86,110.48,30.08；
(E)-1-(3-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pent-2- Ene-1,4-dione (compound D3-41)
1H-NMR(400MHz,CDCl3) δ (ppm) 7.892 (d, J=7.64Hz, 2H), 7.758 (d, J=8.24Hz, 2H), 7.608 (d, J=8.20Hz, 2H), 7.505 (d, J=15.44Hz, 1H), 7.468-7.387 (m, 4H), 7.129 (d, J= 15.44Hz,1H),2.425(s,3H)；
LC-MS(ESI+):m/z calculated forC21H16F3N2O2(M+H)+:385.12,found 385.31.
1-(3-(3-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carbonyl) Oxiran-2-yl) ethanone (compound D3-42)
1H-NMR(400MHz,CDCl3) δ (ppm) 7.886 (d, J=7.60Hz, 2H), 7.734 (d, J=8.28Hz, 2H), 7.590 (d, J=8.28Hz, 2H), 7.552 (s, 1H), 7.458 (t.J=7.40Hz, 2H), 7.397 (t, J=7.24Hz, 1H), 4.221 (d, J=4.84Hz, 1H), 3.834 (d, J=4.84Hz, 1H), 2.302 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)202.59,182.25,152.85,142.86,138.88,131.38, 130.76 (q, J=33.0Hz, C), 129.13,129.03,126.16,126.13,126.06,123.91 (q, J=271.0Hz, C),111.61,59.18,57.81,28.64；
LC-MS(ESI+):m/z calculated forC21H16F3N2O3(M+H)+:401.11,found 401.01.
Embodiment 38, prepare compound D3-43 and D3-43 '
Preparation method is referring to Figure 38.
Pyrazoles (156mg, 0.45mmol, 1.0equiv) is added in round-bottomed flask, sodium chlorite (123mg, 1.35mmol, 3.0equiv), hypophosphite monohydrate sodium dihydrogen (311mg, 2.25mmol, 5.0equiv), 2-methyl butadiene (756 μ L, 9.0mmol, 20.0equiv), tetrahydrofuran 2mL, tert-butyl alcohol 3mL and water 1mL, reaction solution and stir 12h at room temperature.With methylene chloride and water Post-processing, dry, filters, be spin-dried for rear crude product pass through silica gel column purification (gradient elution system is methylene chloride: ethyl acetate/2: 1-1:1-1:2-1:3) obtain mixture D 3-43 and D3-43 ' (ratio is confirmed by nuclear-magnetism).Product is white solid, conversion ratio It is lower, most of starting material left.
1H-NMR(400MHz,CDCl3) δ (ppm) 8.725 (s, 2H), 8.363 (d, J=8.24Hz, 2H), 7.781- 7.753 (m, 2H), 7.700-7.622 (m, 3H), 4.189 (d, J=4.68Hz, 0.60H), 4.113 (d, J=1.64Hz, 0.40H), 3.914 (d, J=4.68Hz, 0.60H), 3.749 (d, J=1.64Hz, 0.40H)
LC-MS(ESI+):m/z calculated forC19H15N4O5(M+H)+:379.10,found 379.36.
Embodiment 39, prepare compound D3-44, D3-45, D3-46
Preparation method is referring to Figure 39.Crude product after reaction (purifies: petroleum ether: acetic acid second for the first time by silica gel column purification Ester/10:1-5:1-3:1), for relatively pure D3-45 and D3-46, again silica gel column purification (petroleum ether: methylene chloride/1: 1- methylene chloride: acetone/20:1-10:1) obtain the D3-45 (light yellow solid) and D3-46 (light yellow solid) of sterling.
Methyl 4- (3-phenyl-1H-pyrazol-1-yl) benzoate (compound D3-44)
1H-NMR(400MHz,CDCl3) δ (ppm) 8.126 (d, J=8.56Hz, 2H), 7.982 (d, J=2.24Hz, 1H), 7.927 (d, J=7.48Hz, 2H), 7.834 (d, J=8.56Hz, 2H), 7.446 (t, J=7.44Hz, 2H), 7.363 (t, J= 7.24Hz, 1H), 6.786 (d, J=2.20Hz, 1H), 3.928 (s, 3H)；
(E)-methyl 4-(5-(4-oxopent-2-enoyl)-3-phenyl-1H-pyrazol-1-yl)benzoate (compound D3-45)
1H-NMR(400MHz,CDCl3) δ (ppm) 8.162 (d, J=8.28Hz, 2H), 7.890 (d, J=7.52Hz, 2H), 7.546 (d, J=8.40Hz, 2H), 7.509-7.377 (m, 5H), 7.105 (d, J=15.68Hz, 1H), 3.956 (s, 3H), 2.406(s,3H)；
LC-MS(ESI+):m/z calculated forC22H19N2O4(M+H)+:375.13,found 375.03.
(Z)-methyl 4-(5-(4-oxopent-2-enoyl)-3-phenyl-1H-pyrazol-1-yl)benzoate (compound D3-46)
1H-NMR(400MHz,CDCl3) δ (ppm) 8.157 (d, J=8.36Hz, 2H), 7.847 (d, J=7.60Hz, 2H), 7.752 (d, J=8.36Hz, 2H), 7.428 (t, J=7.04Hz, 2H), 7.365 (t, J=7.04Hz, 1H), 7.169 (s, 1H), 6.700 (d, J=11.80Hz, 1H), 6.583 (d, J=11.80Hz, 1H), 3.944 (s, 3H), 2.293 (s, 3H).
Embodiment 40, prepare compound D3-48
Preparation method referring to fig. 40.
The specific method is as follows: by beta-unsaturated ketone (545mg, 2.0mmol, 1.0equiv) in 25mL round-bottomed flask, to three Methyl fluoride phenylhydrazine (388mg, 2.2mmol, 1.1equiv) mixing is dissolved in 5.0mL ethyl alcohol, is added dropwise to the 0.2mL concentrated sulfuric acid, is heated Reaction reflux for 24 hours, reaction solution is cooled to room temperature, solvent is spin-dried for, with methylene chloride and saturated sodium bicarbonate extraction post-processing. After drying, filter, being spin-dried for, crude product obtains purer elimination by silica gel column purification (petroleum ether: ethyl acetate/20:1-10:1) and produces Object D3-48, the pyrazoline intermediate that do not eliminate on a small quantity contained generate the pyrazoles that 5- replaces by oxidation reaction, can pass through silicon Glue goes out simple purification and obtains sterling D3-48 (white solid, 80% yield).
3-(3,4-dimethoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole
1H-NMR(400MHz,CDCl3) δ (ppm) 7.816 (s, 1H), 7.764 (d, J=8.32Hz, 2H), 7.599 (d, J =8.32Hz, 2H), 7.491 (s, 1H), 7.342 (d, J=8.24Hz, 1H), 6.848 (d, J=8.28Hz, 1H), 6.618 (s, 1H),3.928(s,3H),3.844(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)153.38,149.41,149.18,142.32,127.80,127.48 (q, J=33.0Hz, C), 126.41 (q, J=4.0Hz, CH), 125.88,123.98 (q, J=270.0Hz, CF3),118.60, 118.13,111.15,108.85,105.43,55.77,55.69；
LC-MS(ESI+):m/z calculated forC18H16F3N2O2(M+H)+:349.12,found 349.33.
Embodiment 41, prepare compound D3-49
Preparation method referring to fig. 41.
(Z)-1-(3-(3,4-dimethoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.814 (d, J=8.20Hz, 2H), 7.720 (d, J=8.24Hz, 2H), 7.423 (s, 1H), 7.323 (d, J=8.24Hz, 1H), 7.094 (s, 1H), 6.894 (d, J=8.20Hz, 1H), 6.681 (d, J =11.76Hz, 1H), 6.564 (d, J=11.76Hz, 1H), 3.926 (s, 3H), 3.885 (s, 3H), 2.267 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.82,182.66,152.13,149.80,149.39,143.14, 140.21,136.56,135.42,130.09 (q, J=33.0Hz, C), 125.89 (q, J=4.0Hz, CH), 125.79, 124.56,123.96 (q, J=270.0Hz, CF3),118.64,111.33,110.10,108.93,56.03,55.95, 29.94；
LC-MS(ESI+):m/z calculated forC23H20F3N2O4(M+H)+:445.14,found 445.37.
Embodiment 42, prepare compound D3-50
Preparation method referring to fig. 42.
3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole
1H-NMR(400MHz,CDCl3) δ (ppm) 7.941 (d, J=2.52Hz, 1H), 7.831 (d, J=8.44Hz, 2H), 7.755-7.687 (m, 1H), 7.698 (d, J=8.44Hz, 2H), 7.597-7.566 (m, 1H), 7.229-7.162 (m, 1H), 6.701 (d, J=2.52Hz, 1H)；
LC-MS(ESI+):m/z calculated forC16H10F5N2(M+H)+:325.08,found 325.30.
Embodiment 43, prepare compound D3-51
Preparation method referring to fig. 43.
(Z)-1-(3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-di one
1H-NMR(400MHz,CDCl3) δ (ppm) 7.823 (d, J=8.36Hz, 2H), 7.746 (d, J=8.44Hz, 2H), 7.687-7.640 (m, 1H), 7.564-7.538 (m, 1H), 7.237-7.170 (m, 1H), 7.092 (s, 1H), 6.696 (d, J= 11.72Hz, 1H), 6.624 (d, J=11.72Hz, 1H), 2.304 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.67,182.88,152.08,151.97,151.92,150.34, 149.58,149.41,142.98,140.56,136.30,135.84,130.68,130.35,128.94,128.90,128.88, 128.84,126.13,126.09,126.05,126.02,125.82,125.32,122.61,122.11,122.07,122.05, 122.01,117.91,117.74,115.80,114.90,110.09,30.08；
LC-MS(ESI+):m/z calculated forC21H14F5N2O2(M+H)+:421.10,found 420.99.
Embodiment 44, prepare compound D3-52
Preparation method referring to fig. 44.
methyl 4-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzoate
1H-NMR(400MHz,CDCl3) δ (ppm) 8.103 (d, J=8.16Hz, 2H), 8.002 (d, J=2.08Hz, 1H), 7.972 (d, J=8.16Hz, 2H), 7.881 (d, J=8.40Hz, 2H), 7.716 (d, J=8.40Hz, 2H), 6.846 (d, J= 2.08Hz,1H),3.934(s,3H)；
LC-MS(ESI+):m/z calculated forC18H14F3N2O2(M+H)+:347.10,found 347.33.
Embodiment 45, prepare compound D3-53 and D3-54
Preparation method referring to fig. 45.Crude product passes through silica gel column purification (eluent system petroleum ether: ethyl acetate/15:1-7:1- 5:1-3:1-1:1, then petroleum ether: methylene chloride/1:2-1:9) obtain the D3-53 of 30% yield and the D3-54 of 30% yield.
The structural identification data of compound D3-53:
(E)-methyl 4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)benzoate
1H-NMR(400MHz,CDCl3) δ (ppm) 8.119 (d, J=8.24Hz, 2H), 7.955 (d, J=8.20Hz, 2H), 7.756 (d, J=8.32Hz, 2H), 7.598 (d, J=8.24Hz, 2H), 7.490 (d, J=15.60Hz, 1H), 7.477 (s, 1H), 7.123 (d, J=15.60Hz, 1H), 3.935 (s, 3H), 2.418 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)197.24,179.19,166.78,151.54,142.97,141.01, (139.12,135.62,134.24,130.37 q, J=33.0Hz, C), 130.38,126.25,126.18 (q, J=4.0Hz, CH),125.82,111.36,52.34,29.44；
LC-MS(ESI+):m/z calculated forC23H18F3N2O4(M+H)+:443.12,found 443.37.
The structural identification data of compound D3-54:
(Z)-methyl 4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)benzoate
1H-NMR(400MHz,CDCl3) δ (ppm) 8.075 (d, J=8.20Hz, 2H), 7.896 (d, J=8.16Hz, 2H), 7.830 (d, J=8.32Hz, 2H), 7.735 (d, J=8.32Hz, 2H), 6.686 (d, J=11.76Hz, 1H), 6.598 (d, J =11.76Hz, 1H), 3.901 (s, 3H), 2.276 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.63,182.81,166.70,151.04,143.01,140.49, (136.33,135.84,135.71,130.39 q, J=33.0Hz, C), 130.21,130.17,125.99 (q, J=2.0Hz, ), CH 125.79,125.66,123.92 (q, J=270.0Hz, CF3)110.69,52.18,29.99；
LC-MS(ESI+):m/z calculated forC23H18F3N2O4(M+H)+:443.12,found 443.32.
Embodiment 46, prepare compound D3-55
Preparation method referring to fig. 46.
(Z)-N-cyclopropyl-4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl) phenyl)-1H-pyrazol-3-yl)be nzamide
1H-NMR(400MHz,CDCl3) δ (ppm) 7.856-7.716 (m, 8H), 7.166 (s, 1H), 6.694 (d, J= 11.76Hz, 1H), 6.608 (d, J=11.76Hz, 1H), 6.546 (s, 1H), 2.878 (s, 1H), 2.287 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.71,182.90,168.46,151.15,143.00,140.46, (136.33,135.84,134.55,134.46,130.50 q, J=33.0Hz, C), 127.59,126.07 (q, J=4.0Hz, ), CH 125.86,125.82,123.93 (q, J=271.0Hz, CF3),110.61,30.13,23.31,6.80.
LC-MS(ESI+):m/z calculated forC25H21F3N3O3(M+H)+:468.15,found 468.38.
Embodiment 47, prepare compound D3-56
Preparation method referring to fig. 47.
(Z)-N-(4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)phenyl)acetam ide
1H-NMR(400MHz,CDCl3) δ (ppm) 7.823-7.767 (m, 4H), 7.734 (d, J=8.52Hz, 2H), 7.574 (d, J=8.52Hz, 2H), 7.436 (s, 1H), 7.110 (s, 1H), 6.717 (d, J=11.76Hz, 1H), 6.619 (d, J=11.76Hz, 1H), 2.308 (s, 3H), 2.183 (s, 3H)
Embodiment 48, prepare compound D3-57
Preparation method referring to fig. 48.
(Z)-4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)benzoic acid
1H-NMR(400MHz,CDCl3) δ (ppm) 8.168 (d, J=8.40Hz, 2H), 7.958 (d, J=8.48Hz, 2H), 7.854 (d, J=8.44Hz, 2H), 7.769 (d, J=8.40Hz, 2H), 7.229 (s, 1H), 6.732 (d, J=11.76Hz, 1H), 6.651 (d, J=11.76Hz, 1H), 2.234 (s, 3H)；
LC-MS(ESI+):m/z calculated forC22H16F3N2O4(M+H)+:429.11,found 429.38.
Embodiment 49, prepare compound D3-58
Preparation method referring to fig. 49.
(Z)-1-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pent-2- ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.987 (d, J=7.72Hz, 2H), 7.583 (d, J=7.84Hz, 2H), 6.682 (s, 1H), 6.654 (d, J=11.80Hz, 1H), 6.566 (d, J=11.80Hz, 1H), 2.358 (s, 3H), 2.299 (s,3H)；
LC-MS(ESI+):m/z calculated forC16H14F3N2O2(M+H)+:323.10,found 323.35.
Embodiment 50, prepare compound D3-59
Preparation method is referring to Figure 50.
(Z)-4-(5-(4-oxopent-2-enoyl)-3-phenyl-1H-pyrazol-1-yl)benzoic acid
1H-NMR(400MHz,CDCl3) δ (ppm) 8.252 (d, J=8.24Hz, 2H), 7.865 (d, J=8.40Hz, 2H), 7.821 (d, J=8.60Hz, 2H), 7.443 (t, J=7.28Hz, 2H), 7.379 (t, J=7.28Hz, 1H), 7.186 (s, 1H), 6.730 (d, J=11.76Hz, 1H), 6.619 (d, J=11.76Hz, 1H), 2.323 (s, 3H)；
LC-MS(ESI+):m/z calculated forC21H17N2O4(M+H)+:361.12,found 361.37.
Embodiment 51, prepare compound D3-60
Preparation method is referring to Figure 51.
(Z)-1-(3-(4-hydroxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol- 5-yl)pent-2-ene-1,4-dion e
1H-NMR(400MHz,CDCl3) δ (ppm) 7.764 (d, J=8.44Hz, 2H), 7.686 (d, J=8.56Hz, 2H), 7.604 (d, J=8.64Hz, 2H), 7.021 (s, 1H), 6.754 (d, J=8.64Hz, 2H), 6.685 (d, J=11.76Hz, 1H), 6.582 (d, J=11.76Hz, 1H), 2.298 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)200.36,182.78,156.84,152.33,143.02,140.00, 136.99,135.15,130.23 (q, J=33.0Hz, C), 127.39,125.99 (q, J=4.0Hz, CH), 125.90, 123.95 (q, J=270.0Hz, CF3),115.89,110.27,30.02；
LC-MS(ESI+):m/z calculated forC21H16F3N2O3(M+H)+:401.11,found 401.35.
Embodiment 52, prepare compound D3-61
Preparation method is referring to Figure 52.
(Z)-1-(1-(4-nitrophenyl)-3-phenyl-1H-pyrazol-5-yl)pent-2-ene-1,4- dione
1H-NMR(400MHz,CDCl3) δ (ppm) 8.324 (d, J=8.84Hz, 2H), 7.930 (d, J=8.88Hz, 2H), 7.843 (d, J=7.32Hz, 2H), 7.459-7.366 (m, 3H), 7.180 (s, 1H), 6.735 (d, J=11.68Hz, 1H), 6.663 (d, J=11.68Hz, 1H), 2.313 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.57,183.24,152.76,146.99,145.18,140.51, 136.26,136.04,131.32,129.12,129.03,128.98,125.94,125.93,124.27,111.05,30.14；
LC-MS(ESI+):m/z calculated forC20H16N3O4(M+H)+:362.11,found 362.02.
Embodiment 53, prepare compound D3-62
Preparation method is referring to Figure 53.
(Z)-1-(3-(3,4-difluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl) pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3)δ(ppm)7.695-7.642(m,1H),7.576-7.526(m,1H),7.504(d, J=8.80Hz, 2H), 7.224-7.158 (m, 1H), 6.982 (d, J=8.80Hz, 2H), 6.626 (d, J=11.84Hz, 1H), 6.507 (d, J=11.84Hz, 1H), 3.857 (s, 3H), 2.283 (s, 3H)；
LC-MS(ESI+):m/z calculated forC21H17F2N2O3(M+H)+:383.12,found 383.02.
Embodiment 54, prepare compound D3-63
Preparation method is referring to Figure 54.
(Z)-1-(3-(3,4-difluorophenyl)-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl) pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3)δ(ppm)7.668-7.648(m,1H),7.588-7.527(m,1H),7.390- 7.368 (m, 1H), 7.234 (d, J=8.68Hz, 2H), 7.091 (s, 1H), 6.823 (d, J=8.84Hz, 2H), 6.650 (d, J =11.76Hz, 1H), 6.540 (d, J=11.76Hz, 1H), 2.182 (s, 3H)；
LC-MS(ESI+):m/z calculated forC20H15F2N2O3(M+H)+:369.11,found 369.32.
Embodiment 55, prepare compound D3-64 and compound D3-65
Preparation method is referring to Figure 55.Crude product passes through silica gel column purification (eluent system petroleum ether: ethyl acetate/4:1-2:1) Obtain a small amount of D3-64 and principal product D3-65 (D3-64 (nuclear magnetic data) for still containing < 10% amount)
The structural identification data of compound D3-64:
(E)-1-(3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)hex-2-ene-1,4-dio ne
1H-NMR(400MHz,CDCl3) δ (ppm) 7.758 (d, J=8.36Hz, 2H), 7.730-7.710 (m, 1H), 7.594-7.574 (m, 3H), 7.534 (d, J=15.52Hz, 1H), 7.376 (s, 1H), 7.280-7.234 (m, 1H), 7.167 (d, J=15.52Hz, 1H), 2.712 (q, J=7.20Hz, 2H), 1.171 (t, J=7.20Hz, 3H)；
LC-MS(ESI+):m/z calculated forC22H16F5N2O2(M+H)+:435.11,found 435.03.
The structural identification data of compound D3-65:
(Z)-1-(3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)hex-2-ene-1,4-dio ne
1H-NMR(400MHz,CDCl3) δ (ppm) 7.844 (d, J=8.40Hz, 2H), 7.743 (d, J=8.60Hz, 2H), 7.685-7.633 (m, 1H), 7.596-7.528 (m, 1H), 7.224-7.157 (m, 1H), 7.088 (s, 1H), 6.682 (d, J= 11.76Hz, 1H), 6.626 (d, J=11.76Hz, 1H), 2.590 (q, J=7.24Hz, 2H), 1.081 (t, J=7.24Hz, 3H)
Embodiment 56, prepare compound D3-67
Preparation method is referring to Figure 56.
(Z)-methoxymethyl4-(3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl) phenyl)-1H-pyrazol-5-yl)-4-oxobut-2-enoate
1H-NMR(400MHz,CDCl3) δ (ppm) 7.800 (d, J=8.48Hz, 2H), 7.740 (d, J=8.60Hz, 2H), 7.704-7.652 (m, 1H), 7.571-7.359 (m, 1H), 7.238-7.171 (m, 1H), 6.876 (d, J=11.90Hz, 1H), 6.369 (d, J=11.90Hz, 1H), 5.263 (s, 2H), 3.395 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)182.50,164.42,152.12,152.04,151.91,151.888, 150.35,149.55,149.38,149.34,142.90,140.42,140.39,130.49 (q, J=33.0Hz, C), 128.81 (q, J=4.0Hz, C), 127.25,126.00 (q, J=4.0Hz, CH), 125.83,123.93 (q, J=271.0Hz, C), 122.04 (q, J=3.0Hz, C), 117.80 (d, J=18.0Hz, CH), 114.93 (d, J=18.0Hz, CH), 110.77, 91.61,57.96.
LC-MS(ESI+):m/z calculated forC22H16F5N2O4(M+H)+:467.10,found 467.46
Embodiment 57, prepare compound D3-69 and compound D3-70
Preparation method is referring to Figure 57.Crude product passes through silica gel column purification (eluent system petroleum ether: ethyl acetate/4:1-2:1) Obtain the D3-69 of 3% yield and the D3-70 of 67% yield.
The structural identification data of compound D3-69:
(E)-1-(3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)-3-methylpent-2-e ne-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.744 (d, J=8.44Hz, 2H), 7.719-7.686 (m, 1H), 7.620-7.572 (m, 1H), 7.562 (d, J=8.52Hz, 2H), 7.403 (s, 1H), 7.277-7.210 (m, 1H), 4.029 (s,1H),2.287(s,3H),1.253(s,3H)；
LC-MS(ESI+):m/z calculated forC22H16F5N2O2(M+H)+:435.11,found 435.38；
The structural identification data of compound D3-70:
1H-NMR(400MHz,CDCl3) δ (ppm) 7.720 (d, J=8.32Hz, 2H), 7.695-7.667 (m, 1H), 7.589 (d, J=8.32Hz, 2H), 7.579-7.564 (m, 1H), 7.237 (s, 1H), 7.237-7.194 (m, 1H), 6.574 (d, J=1.48Hz, 1H), 2.295 (s, 3H), 2.116 (d, J=1.48Hz, 3H)；
13C-NMR(100MHz,CDCl3) δ (ppm) 205.64,179.03,158.25,152.02 (d, J=3.0Hz, C), 150.45,149.66,142.96,141.28,133.83,130.83-128.85 (m), 126.08 (q, J=4.0Hz, CH), (125.25,123.15,122.55,122.09 q, J=4.0Hz, C), 117.91 (d, J=18.0Hz, CH), 115.06 (d, J= 19.0Hz,CH),109.90,28.18,20.83；
LC-MS(ESI+):m/z calculated forC22H16F5N2O2(M+H)+:435.11,found 435.38
Embodiment 58, prepare compound D3-71
Preparation method is referring to Figure 58.
(Z)-1-(3-(3,4-difluorophenyl)-1-phenyl-1H-pyrazol-5-yl)pent-2-ene-1, 4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.698-7.646 (m, 1H), 7.610 (d, J=7.24Hz, 2H), 7.559-7.528 (m, 1H), 7.492-7.412 (m, 3H), 7.214-7.147 (m, 1H), 7.100 (s, 1H), 6.621 (d, J= 11.84Hz, 1H), 60506 (d, J=11.84Hz, 1H), 2.263 (s, 3H)；
13C-NMR(100MHz,CDCl3) δ (ppm) 199.17,182.31,151.75 (t, J=12.0Hz, C), 149.62, 149.27 (t, J=12.0Hz, C), 140.49,140.22,136.87,134.80,129.25-128.79 (m), 125.62, 125.56,121.94 (q, J=3.0Hz, CH), 117.64 (d, J=17.0Hz, CH), 114.81 (d, J=20.0Hz, CH), 110.49,109.51,29.90；
LC-MS(ESI+):m/z calculated forC20H15F2N2O2(M+H)+:353.11,found 353.05.
Embodiment 59, prepare compound D3-73, compound D3-74
Preparation method is referring to Figure 59.
Crude product by silica gel column purification (eluant, eluent is petroleum ether: ethyl acetate/3:1-1:1- methylene chloride: methanol/20: 1) sterling D3-73 and D3-74 are obtained.
The structural identification data of compound D3-73:
(Z)-1-(3-(6-bromopyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 8.778 (d, J=2.28Hz, 1H), 8.052 (dd, J=8.32Hz, J= 2.48Hz, 1H), 7.832 (d, J=8.48Hz, 2H), 7.761 (d, J=8.48Hz, 2H), 7.556 (d, J=8.28Hz, 1H), 7.162 (s, 1H), 6.710 (d, J=11.68Hz, 1H), 6.651 (d, J=11.68Hz, 1H), 2.318 (s, 3H)；
LC-MS(ESI+):m/z calculated forC20H14BrF3N3O2(M+H)+:464.02,found 464.29
The structural identification data of compound D3-74:
(Z)-2-bromo-5-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)- 1H-pyrazol-3-yl)pyridine 1-oxide
1H-NMR(400MHz,CDCl3) δ (ppm) 8.954 (s, 1H), 7.819 (d, J=8.48Hz, 2H), 7.758 (d, J =8.48Hz, 2H), 7.724-7.648 (m, 1H), 7.568 (d, J=8.36Hz, 1H), 7.175 (s, 1H), 6.704 (d, J= 11.68Hz, 1H), 6.666 (d, J=11.68Hz, 1H), 2.311 (s, 3H)；
LC-MS(ESI+):m/z calculated forC20H14BrF3N3O3(M+H)+:480.02,found 480.23.
Embodiment 60, prepare compound D3-76
Preparation method is referring to Figure 60.Crude product by silica gel column separating purification (eluant, eluent system be petroleum ether: ethyl acetate/ 3:1-2:1) obtain sterling.
(Z)-1-(3-(3,4-difluorophenyl)-1H-pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3)δ(ppm)7.722-7.670(m,1H),7.560-7.529(m,1H),7.251- 7.184 (m, 1H), 7.116 (s, 1H), 7.025 (d, J=10.52Hz, 1H), 6.421 (d, J=10.52Hz, 1H), 2.005 (s,3H)；
LC-MS(ESI+):m/z calculated forC14H11F2N2O2(M+H)+:277.18,found 277.33.
Embodiment 61, prepare compound D3-77 and compound D3-77 '
Preparation method is referring to Figure 61.
Crude product after reaction obtains two by silica gel column purification (eluent petroleum ether: ethyl acetate/1:1-1:3-1:20) The mixture of person.Products therefrom without be further purified be directly used in survey live.The ratio of the two passes through nuclear magnetic resonance measuring institute ?.
1H-NMR(400MHz,CDCl3) δ (ppm) 7.937 (d, J=8.08Hz, 0.86H), 7.889 (d, J=8.12Hz, 2H), 7.828 (d, J=8.40Hz, 2H), 7.758-7.737 (m, 2.95H), 7.594 (d, J=8.44Hz, 0.92H), 7.519-7.451 (m, 3.71H), 7.171 (s, 1H), 7.124 (d, J=15.60Hz, 0.37H), 6.716 (d, J= 11.72Hz, 1H), 6.629 (d, J=11.72Hz, 1H), 3.751-3.722 (m, 11H), 2.418 (s, 1.09H), 2.306 (s, 3H)；
LC-MS(ESI+):m/z calculated forC26H23F3N3O4(M+H)+:498.16,found 498.46.
Embodiment 62, prepare compound D3-78
Preparation method is referring to Figure 62.
(E)-1-(1-(4-(morpholine-4-carbonyl)phenyl)-3-phenyl-1H-pyrazol-5-yl) pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.875 (d, J=7.16Hz, 2H), 7.524 (s, 4H), 7.465- 7.383 (m, 4H), 7.452 (d, J=15.68Hz, 1H), 7.095 (d, J=15.68Hz, 1H), 3.716-3.640 (m, 8H), 2.399(s,3H)；LC-MS(ESI+):m/z calculated forC25H24N3O4(M+H)+:430.18,found 430.11.
Embodiment 63, prepare compound D3-79
Preparation method is referring to Figure 63.
(Z)-di-tert-butyl
(4-(5-(4-oxopent-2-enoyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3- yl)phenyl)phosphate
1H-NMR(400MHz,CDCl3) δ (ppm) 7.830-7.782 (m, 4H), 7.738 (d, J=8.32Hz, 2H), 7.283 (d, J=8.48Hz, 2H), 7.112 (s, 1H), 6.714 (d, J=11.72Hz, 1H), 6.615 (d, J=11.72Hz, 1H),2.302(s,3H),1.515(s,18H)；
LC-MS(ESI+):m/z calculated forC29H33F3N2O6P(M+H)+:593.20,found 593.48.
Embodiment 64, prepare compound D3-80
Preparation method is referring to Figure 64.
(Z)-1-(3-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol- 5-yl)pent-2-ene-1,4-dio ne
1H-NMR(400MHz,CDCl3) δ (ppm) 7.821 (d, J=8.40Hz, 2H), 7.772 (d, J=8.72Hz, 2H), 7.736 (d, J=8.48Hz, 2H), 7.091 (s, 1H), 6.958 (d, J=8.72Hz, 2H), 6.704 (d, J=11.76Hz, 1H), 6.592 (d, J=11.76Hz, 1H), 3.838 (s, 3H), 2.294 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.87,182.74,160.29,152.18,143.22,140.22, (136.59,135.56,130.19 q, J=33.0Hz, C), 127.26,127.26,126.19,125.96 (q, J=4.0Hz, ), CH 124.33,124.05 (q, J=270.0Hz, CF3),114.44,114.35,110.10,55.43,30.06；
LC-MS(ESI+):m/z calculated forC22H18F3N2O3(M+H)+:415.13,found 415.04.
Embodiment 65, prepare compound D3-81
Preparation method is referring to Figure 65.
(Z)-1-(3-(3,4-difluorophenyl)isoxazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3)δ(ppm)7.713-7.663(m,1H),7.589-7.541(m,1H),7.315- 7.249 (m, 1H), 7.221 (s, 1H), 6.817 (d, J=11.84Hz, 1H), 6.726 (d, J=11.84Hz, 1H), 2.367 (s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)200.01,180.30,166.96,161.67,141.00,130.40, 123.61 (q, J=4.0Hz, C), 118.36 (d, J=18.0Hz, CH), 116.30 (d, J=19.0Hz, CH), 105.77, 29.65；
LC-MS(ESI+):m/z calculated forC14H10F2NO3(M+H)+:278.06,found 278.35.
Embodiment 66, prepare compound D3-82
Preparation method is referring to Figure 66.Identical as preparation method used in Figure 43, the equivalent of m-CPBA used is different.
1-(3-(3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazole-5-carbonyl)oxiran-2-y l)ethanone
1H-NMR(400MHz,CDCl3) δ (ppm) 7.757 (d, J=8.40Hz, 2H), 7.737-7.685 (m, 1H), 7.606-7.584 (m, 1H), 7.558 (d, J=8.56Hz, 2H), 7.495 (s, 1H), 7.278-7.212 (m, 1H), 4.084 (d, J=1.56Hz, 1H), 3.724 (d, J=1.56Hz, 1H), 2.207 (s, 3H)；
LC-MS(ESI+):m/z calculated forC21H14F5N2O3(M+H)+:437.09,found 437.38.
Embodiment 67, prepare compound D3-83a and compound D3-83b
Preparation method is referring to Figure 67.Also D3-82b has been obtained in reaction, the crude product after being spin-dried for is by silicagel column gradient three times Purifying is (for the first time: methylene chloride: ethyl acetate/50:1-30:1；Second: petroleum ether: acetone/3:1-2:1；For the third time: stone Oily ether: acetone/2:1) obtain the sterling of two compounds.
The structural identification data of compound D3-83a:
(E)-1-(3-(3,4-dihydroxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.695 (d, J=8.00Hz, 2H), 7.529 (d, J=8.04Hz, 2H), 7.449 (d, J=15.76Hz, 1H), 7.345 (s, 1H), 7.260 (s, 1H), 7.231 (d, J=7.76Hz, 1H), 7.101 (d, J=15.60Hz, 1H), 6.878 (d, J=8.20Hz, 1H), 2.415 (s, 3H)；
LC-MS(ESI+):m/z calculated forC21H16F3N2O4(M+H)+:417.11,found 417.44.
The structural identification data of compound D3-83b:
(Z)-1-(3-(3,4-dihydroxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.722 (d, J=7.96Hz, 2H), 7.658 (d, J=7.88Hz, 2H), 7.271 (d, J=2.28Hz, 1H), 7.186-7.146 (m, 1H), 6.971 (s, 1H), 6.808-6.774 (m, 1H), 6.659 (d, J=11.76Hz, 1H), 6.574 (d, J=11.76Hz, 1H), 2.289 (s, 3H)；
Embodiment 68, prepare compound D3-84
Preparation method is referring to Figure 68.
(Z)-1-(1,3-bis(4-hydroxyphenyl)-1H-pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.669 (d, J=8.40Hz, 2H), 7.340 (d, J=8.56Hz, 2H), 7.262 (s, 1H), 6.866 (d, J=8.40Hz, 2H), 6.835 (d, J=8.40Hz, 2H), 6.744 (d, J=11.84Hz, 1H), 6.590 (d, J=11.84Hz, 1H)
Embodiment 69, prepare compound D3-85b
Preparation method is referring to Figure 69.
1H-NMR(400MHz,CDCl3) δ (ppm) 7.846-7.818 (m, 4H), 7.746 (d, J=8.40Hz, 2H), 7.429 (d, J=7.60Hz, 2H), 7.159 (s, 1H), 6.721 (d, J=12.0Hz, 1H), 6.618 (d, J=12.0Hz, 1H),4.730(s,2H),2.310(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)198.82,182.78,152.07,143.19,141.69,140.37, (136.58,135.68,131.03,127.49,126.27,126.09 q, J=4.0Hz, CH), 125.89,110.46,65.10, 30.12.
Embodiment 70, prepare compound D3-86
Preparation method is referring to Figure 70.
(E)-1-(3-(3-fluoro-4-morpholinophenyl)-1-(4-(trifluoromethyl)phenyl)- 1H-pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.745 (d, J=8.44Hz, 2H), 7.600-7.556 (m, 4H), 7.480 (d, J=15.60Hz, 1H), 7.341 (s, 1H), 7.116 (d, J=15.60Hz, 1H), 6.986 (t, J=8.68Hz, 1H), 3.887 (t, J=4.40Hz, 4H), 3.151 (t, J=4.40Hz, 4H), 2.417 (s, 3H)；
13C-NMR(100MHz,CDCl3) δ (ppm) 197.30,179.24,155.79 (d, J=245.0Hz, C), (151.59,143.07,140.87,140.67 d, J=8.0Hz, C), 139.00,134.40,126.22,126.16 (d, J= 3.0Hz, CH), 125.94 (d, J=8.0Hz, C), 123.83,122.13 (d, J=4.0Hz, CH), 118.89 (d, J= 3.0Hz, CH), 113.96 (d, J=23.0Hz, CH), 110.67,67.08,50.86,29.50；
LC-MS(ESI+):m/z calculated forC25H22F4N3O3(M+H)+:488.16,found 488.47.
Embodiment 71, prepare compound D3-87
Preparation method is referring to Figure 71.
(E)-1-(3-(6-morpholinopyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 8.657 (d, J=2.04Hz, 1H), 8.010 (dd, J=8.80Hz, J= 2.28Hz, 1H), 7.740 (d, J=8.40Hz, 2H), 7.580 (d, J=8.28Hz, 2H), 7.478 (d, J=15.64Hz, 1H), 7.325 (s, 1H), 7.113 (d, J=15.64Hz, 1H), 6.698 (d, J=8.88Hz, 1H), 3.836 (t, J= 4.72Hz, 4H), 3.583 (t, J=4.72Hz, 4H), 2.413 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)197.37,179.26,159.61,150.63,145.88,143.08, (140.74,138.96,135.13,134.42,126.16 q, J=4.0Hz, CH), 123.71,117.51,110.10, 106.68,66.83,45.55,29.51；
LC-MS(ESI+):m/z calculated forC24H22F3N4O3(M+H)+:471.16,found 471.45.
Embodiment 72, prepare compound D3-88b
Preparation method is referring to Figure 72.
(Z)-methyl 3-(3-(3,4-difluorophenyl)-5-(4-oxopent-2-enoyl)-1H- pyrazol-1-yl)benzoate
1H-NMR(400MHz,CDCl3) δ (ppm) 8.28 (s, 1H), 8.13 (d, J=8.0Hz, 1H), 7.86-7.84 (m, 1H), 7.71-7.66 (m, 1H), 7.55-7.60 (m, 2H), 7.25-7.18 (m, 1H), 7.10 (s, 1H), 6.685 (d, J= 12.0Hz, 1H), 6.585 (d, J=12.0Hz, 1H), 3.94 (s, 2H), 2.30 (s, 3H)
Embodiment 73, prepare compound D3-89
Preparation method is referring to Figure 73.
(Z)-1-(3-(3,4-difluorophenyl)-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol- 5-yl)pent-2-ene-1,4-di one
1H-NMR(400MHz,CDCl3)δ(ppm)7.693-7.646(m,1H),7.587(s,1H),7.544-7.526(m, 2H), 7.484-7.417 (m, 2H), 7.233-7.167 (m, 1H), 7.090 (s, 1H), 6.632 (d, J=11.80Hz, 1H), (6.526 d, J=11.80Hz, 1H), 4.755 (s, 2H), 2.290 (s, 3H)
Embodiment 74, prepare compound D3-90
Preparation method is referring to Figure 74.
(Z)-1-(5-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol- 3-yl)pent-2-ene-1,4-dio ne
1H-NMR(400MHz,CDCl3) δ (ppm) 7.606 (d, J=8.36Hz, 2H), 7.444 (d, J=8.12Hz, 2H), 7.222 (d, J=12.08Hz, 1H), 7.104 (d, J=8.64Hz, 2H), 6.973 (s, 1H), 6.840 (d, J=8.64Hz, 2H), 6.517 (d, J=12.08Hz, 1H), 3.778 (s, 3H), 2.343 (s, 3H)
Embodiment 75, prepare compound D3-91, compound D3-92, compound D3-93
Preparation method is referring to Figure 75.Obtained intermediate is the mixture 372mg of pyrazoline and elimination product in Figure 75, Ratio is 1:0.17, and reaction is direct plungeed into and reacted in next step without further separating, and metachloroperbenzoic acid used is 503mg, Reaction by methylene chloride and saturated sodium bicarbonate solution post-processing after, silicagel column it is gradient-purified (petroleum ether: ethyl acetate/7: 1-3:1-2:1-1:1) successively obtain the sterling of three kinds of compounds D3-91, D3-92 and D3-93.
The structural identification data of compound D3-92:
(Z)-1-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)pent-2-ene-1,4- dione
1H-NMR(400MHz,CDCl3) δ (ppm) 8.031 (d, J=2.56Hz, 1H), 7.871 (d, J=8.48Hz, 2H), 7.742 (d, J=8.56Hz, 2H), 7.261 (d, J=12.08Hz, 1H), 7.057 (d, J=2.56Hz, 1H), 6.570 (d, J =12.08Hz, 1H), 2.370 (s, 3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)202.68,185.06,152.48,142.04,141.48,130.33, 129.74 (q, J=33.0Hz, C), 129.46,129.34,129.15,127.06 (q, J=4.0Hz, CH), 123.82 (q, J= 270.0Hz,CF3),119.73,109.62,29.73；
LC-MS(ESI+):m/z calculated forC15H12F3N2O2(M+H)+:309.09,found 309.36.
The structural identification data of compound D3-91:
(Z)-1-(5-(5-methylfuran-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-3-yl)pent-2-ene-1,4-di one
1H-NMR(400MHz,CDCl3) δ (ppm) 7.745 (d, J=8.48Hz, 2H), 7.591 (d, J=8.16Hz, 2H), 7.195 (d, J=12.12Hz, 1H), 7.144 (s, 1H), 6.529 (d, J=12.12Hz, 1H), 6.042 (d, J=3.20Hz, 1H), 5.982 (d, J=2.44Hz, 1H), 2.376 (s, 3H), 2.252 (s, 3H)
The structural identification data of compound D3-93:
(2Z,2'Z)-1,1'-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3,5-diyl)bis (pent-2-ene-1,4-dione)
1H-NMR(400MHz,CDCl3) δ (ppm) 7.765 (d, J=8.52Hz, 2H), 7.690 (d, J=8.48Hz, 2H), 7.305 (s, 1H), 7.058 (d, J=12.04Hz, 1H), 6.588 (s, 2H), 6.510 (d, J=12.04Hz, 1H), 2.257 (s,3H),2.187(s,3H)；
13C-NMR(100MHz,CDCl3)δ(ppm)201.93,198.42,184.65,183.16,150.52,142.50, (141.38,140.74,135.91,130.74 q, J=33.0Hz, C), 129.01,125.93 (q, J=4.0Hz, CH), 125.79,123.63 (q, J=270.0Hz, CF3),113.10,29.78,29.36；
LC-MS(ESI+):m/z calculated forC20H16F3N2O4(M+H)+:405.11,found 405.40.
Embodiment 76, prepare compound D3-94
Preparation method is referring to Figure 76.
(Z)-1-(3-(4-(prop-2-yn-1-yloxy)phenyl)-1-(4-(trifluoromethyl)phenyl)- 1H-pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.830-7.708 (m, 6H), 7.091 (s, 1H), 7.029 (d, J= 8.64Hz, 2H), 6.702 (d, J=11.72Hz, 1H), 6.598 (d, J=11.72Hz, 1H), 4.721 (d, J=2.32Hz, 2H), 2.544 (t, J=2.32Hz, 1H), 2.293 (s, 3H).
Embodiment 77, prepare compound D3-95
Preparation method is referring to Figure 77.
(Z)-1-(3-(3,4-difluorophenyl)-1-(4-(prop-2-yn-1-yloxy)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3)δ(ppm)7.769-7.627(m,1H),7.536-7.514(m,3H),7.211- 7.144 (m, 1H), 7.070-7.030 (m, 3H), 6.622 (d, J=11.80Hz, 1H), 6.508 (d, J=11.80Hz, 1H), 4.725 (d, J=2.24Hz, 2H), 2.549 (t, J=2.24Hz, 1H), 2.265 (s, 3H)；
13C-NMR(100MHz,CDCl3) δ (ppm) 199.11,182.42,157.79,151.81 (t, J=13.0Hz, C), 149.49,149.38,149.34,149.21,140.48,136.71,135.06,134.14 129.27 (q, J=4.0Hz, C), (127.01,126.94,121.93 q, J=4.0Hz, CH), 117.78,117.60,115.02 (q, J=10.0Hz, CH), 110.27,109.28,78.25,76.04,69.60,56.15,29.34
Embodiment 78, prepare compound D3-96
Preparation method is referring to Figure 78.
(Z)-1-(4-bromo-3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)- 1H-pyrazol-5-yl)pent-2-ene-1,4-dione1H-NMR(400MHz,CDCl3) δ (ppm) 7.840 (d, J= 8.44Hz, 2H), 7.785-7.745 (m, 1H), 7.756 (d, J=8.52Hz, 2H), 7.677-7.641 (m, 1H), 7.297- 7.220 (m, 2H), 6.706 (d, J=11.76Hz, 1H), 6.616 (d, J=11.76Hz, 1H), 2.324 (s, 3H)；
LC-MS(ESI+):m/z calculated forC21H13BrF5N2O2(M+H)+:499.01,found 498.94.
Embodiment 79, prepare compound D3-97
Preparation method is referring to Figure 79.
(Z)-1-(3-(3,4-difluorophenyl)-4-iodo-1-(4-(trifluoromethyl)phenyl)- 1H-pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.813 (d, J=8.52Hz, 2H), 7.750 (d, J=8.64Hz, 2H), 7.695-7.643 (m, 1H), 7.596-7.574 (m, 1H), 7.291-7.224 (m, 1H), 6.707 (d, J=11.80Hz, 1H), 6.581 (d, J=11.80Hz, 1H), 2.321 (s, 3H)
Embodiment 80, prepare compound D3-101
Preparation method is referring to Figure 80.
(Z)-1-(4-(but-3-yn-1-yloxy)-3-(3,4-difluorophenyl)-1-(4- (trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3)δ(ppm)8.021-7.968(m,1H),7.878-7.847(m,1H),7.770(d, J=8.48Hz, 2H), 7.744 (d, J=8.48Hz, 2H), 7.221 (q, J=4.64Hz, 1H), 6.851 (d, J=11.80Hz, 1H), 6.581 (d, J=11.80Hz, 1H), 3.886 (t, J=6.12Hz, 2H), 2.785 (t, J=6.12Hz, 2H), 2.314 (s,3H)；
LC-MS(ESI+):m/z calculated for C25H18F5N2O3(M+H)+:489.12,found 489.09.
Embodiment 81, prepare compound D3-102
Preparation method is referring to Figure 81.
(Z)-1-(3-(3,4-difluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)-4-(4-nitrophenyl)but-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 8.312 (d, J=9.68Hz, 2H), 8.074 (d, J=8.68Hz, 2H), 7.719-7.632 (m, 5H), 7.555-7.534 (m, 1H), 7.250 (t, J=8.44Hz, 1H), 7.209 (s, 1H), 7.172 (d, J=11.68Hz, 1H), 7.118 (d, J=11.68Hz, 1H)；
LC-MS(ESI+):m/z calculated for C26H15F5N3O4(M+H)+:528.10,found 528.15.
Embodiment 82, prepare compound D3-106
Preparation method is referring to Figure 82.
(Z)-1-(3-(3,4-difluorophenyl)-1-(prop-2-yn-1-yl)-1H-pyrazol-5-yl) pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3)δ(ppm)7.642-7.590(m,1H),7.540-7.479(m,1H),7.212- 7.145 (m, 1H), 6.990 (s, 1H), 6.766 (d, J=11.92Hz, 1H), 6.582 (d, J=11.92Hz, 1H), 5.406 (d, J=2.44Hz, 2H), 2.390 (t, J=2.44Hz, 1H), 2.343 (s, 3H)
Embodiment 83, prepare compound D3-107
Preparation method is referring to Figure 83.
(Z)-4-(3-(3,4-difluorophenyl)-5-(4-oxopent-2-enoyl)-1H-pyrazol-1-yl) benzenesulfonamide
1H-NMR(400MHz,CDCl3) δ (ppm) 8.052 (d, J=4.68Hz, 2H), 7.877 (d, J=4.68Hz, 2H), 7.689-7.646 (m, 1H), 7.568-7.519 (m, 1H), 7.260-7.189 (m, 1H), 7.087 (s, 1H), 6.714 (d, J= 11.60Hz, 1H), 6.656 (d, J=11.60Hz, 1H), 4.837 (s, 2H), 2.323 (s, 3H)；
LC-MS(ESI+):m/z calculated for C20H16F2N3O4S(M+H)+:432.08,found 432.01.
Embodiment 84, prepare compound D3-108
Preparation method is referring to Figure 84.
(Z)-1-(3-(3-hydroxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol- 5-yl)pent-2-ene-1,4-dion e
1H-NMR(400MHz,CDCl3) δ (ppm) 7.782 (d, J=8.40Hz, 2H), 7.706. (d, J=8.44Hz, 2H), 7.339 (d, J=7.68Hz, 1H), 7.301 (s, 1H), 7.262 (d, J=7.84Hz, 1H), 7.100 (s, 1H), 6.807 (d, J=8.04Hz, 1H), 6.697 (d, J=11.76Hz, 1H), 6.604 (d, J=11.74Hz, 1H), 2.304 (s, 3H)
Embodiment 85, prepare compound D3-109
Preparation method is referring to Figure 85.
(Z)-1-(3-(4-chlorophenyl)-4-methyl-1-(4-(trifluoromethyl)phenyl)-1H- pyrazol-5-yl)pent-2-ene-1,4-dione
1H-NMR(400MHz,CDCl3) δ (ppm) 7.732 (d, J=8.36Hz, 2H), 7.645 (d, J=8.48Hz, 2H), 7.558 (d, J=8.48Hz, 2H), 7.455 (d, J=8.52Hz, 2H), 6.955 (d, J=15.92Hz, 1H), 6.879 (d, J =15.92Hz, 1H), 2.399 (s, 3H), 2.225 (s, 3H)；
LC-MS(ESI+):m/z calculated forC22H17ClF3N2O2(M+H)+:433.09,found 433.03.
The effect experiment of second part, compound
The Determination of Antibacterial Activity of embodiment 86, compound
1, compound is to streptococcus pneumonia, staphylococcus aureus, and all compounds of the determination of activity of enterococcus faecalis are most Small Mlc (MIC) measurement is referring to CLSI (Clinical And Laboratory Standards Insititute) The standard method of offer carries out, this experiment measures minimal inhibitory concentration using trace liquid diluting method.
1) all untested compounds are dissolved to 20mg/ml with DMSO, are stored in -20 DEG C of refrigerators as storing liquid, use Mueller-Hinton Broth (MHB) culture medium is by drug dilution at the concentration of 128 μ g/ml.
2) selection of culture medium: staphylococcus aureus and enterococcus faecalis use MHB culture medium, and streptococcus pneumonia use contains There is the MHB culture medium of the horse blood of 2.5% cracking.
3) preparation of inoculum: above-mentioned three kinds of bacteriums are cultivated in MHB culture medium respectively to logarithmic growth phase, then dilute It releases to 106CFU/ml。
4) prepared by MIC plate: selecting sterile 96 orifice plate, adds medical fluid in the 1st to the 11st hole of plank A row, 200 μ l of every hole is dense Degree is 128 μ g/ml, and the 12nd hole not dosing is used as growth control.Every time test in be arranged vancomycin control, A row in through the ages The concentration of mycin is 8 μ g/ml.
5) it is arranged using the volley of rifle fire in B to H.Add the not antibiotic MHB culture medium of 100 μ l in advance, is drawn from first row 100 μ l medical fluids, are added in the 2nd row, and inhale and play mixing, and every hole is sucked out 100 μ l and moves to the 3rd row, and mixing is played in suction, and so on, It is diluted to 2 μ g/ml of minimum concentration (the 7th row), there is 200 μ l of culture medium in the 8th row at this time, 100 μ l should be sucked out, keep in all holes Volume is 100 μ l.
1 2 3 4 5 6 7 8 9 10 11 12
A
B
C
D
E
F
G
H
6) inoculum for adding 100 μ l to prepare in containing 96 orifice plates for having diluted medical fluid with the volley of rifle fire is set common at 37 DEG C In air incubator, the incubation time of streptococcus pneumonia is 20~for 24 hours, staphylococcus and enterococcus are tested to the susceptibility of vancomycin Test need to incubate for 24 hours.At this point, the drug final concentration in the 1st hole to the 11st hole is respectively 64,32,16,8,4,2,1 μ g/ml.
7) result judges: being MIC (μ g/ml) to completely inhibit the lowest concentration of drug of bacterial growth in aperture.Work as sun Property the obvious growth test of control wells (be free of antibiotic) interior bacterium it is just significant.
8) concrete outcome see the table below:
Test institute according to principle be:
The dilution of compound concentration equimultiple, according to bacterial growth under low concentration, the non-growing principle of bacterium is obtained under high concentration To value range.The measurement of specific MIC numerical value needs the design of more exact gradient, it is contemplated that cost factor temporarily now provides range Value.
Note:
Streptococcus pneumoniae indicates streptococcus pneumonia；
Staphylcoccusaureus indicates staphylococcus aureus；
Enterococcus faecalis is expressed as enterococcus faecalis.
2, part of compounds is to multidrug resistant streptococcus pneumonia (MRSP), methicillin-resistant staphylococcus aureus (MRSA), the determination of activity of vancomycin resistance enterococcus faecalis (VRE)
1) multidrug resistant streptococcus pneumonia, methicillin-resistant staphylococcus aureus, vancomycin resistance enterococcus faecalis are Clinical isolation.
2) compound sets ammonia benzyl simultaneously for these drug-fast bacterias to the MIC method for measuring of these drug-fast bacterias with 2.1 The control in XiLin and vancomycin.
3) concrete outcome see the table below:
Table 2
Note:
TH2784, TH2882, TH2889, TH2863: the Antimicrobial Streptococcus Pneumoniae strain clinically separated；
MRSA: methicillin-resistant staphylococcus aureus；
Table 3
Note:
MRSP: the streptococcus pneumonia of multidrug resistant；
MDEF: the enterococcus faecalis of multidrug resistant；
VRE: the enterococcus faecalis of vancomycin resistance；
MRSA: methicillin-resistant staphylococcus aureus；
Vancomycin: vancomycin；
Ampicillin: ampicillin.

Claims (8)

1. Formulas I compound represented or its pharmaceutically acceptable salt:
It is connected between the carbon atom that the dotted line expression R2 carbon atom connected in Formulas I and R3 are connected by double bond；
In Formulas I, R1、R2、R3、R4Substituent group be divided into following several situations:
R2 be selected from it is following it is any shown in substituent group: hydrogen, the alkyl of C1-C6,
And R3 be selected from it is following it is any shown in substituent group:
And R1 be selected from it is following it is any shown in substituent group:
Or the alkyl of C1-C6；
And R4 be selected from it is following it is any shown in substituent group: hydrogen, ethyl, tert-butyl, phenyl, p-nitrophenyl, to trifluoromethylbenzene Base, p-fluorophenyl, p-methoxyphenyl, chlorphenyl, 2,4,6- trichlorophenyl, to sulfoamido phenyl, p-hydroxybenzene, right Hydroxymethyl phenyl, to carboxyl phenyl, between hydroxy phenyl methyl formate phenyl, hydroxy phenyl, methyl formate phenyl,
(2) R2 be selected from it is following it is any shown in substituent group: hydrogen, the alkyl of C1-C6,
And R1 is selected from substituent group as follows:
And R3 be selected from it is following it is any shown in substituent group:
And R4 be selected from it is following it is any shown in substituent group: hydrogen, ethyl, tert-butyl, phenyl, p-nitrophenyl, to trifluoromethylbenzene Base, p-fluorophenyl, p-methoxyphenyl, chlorphenyl, 2,4,6- trichlorophenyl, to sulfoamido phenyl, p-hydroxybenzene, right Hydroxymethyl phenyl, to carboxyl phenyl, between hydroxy phenyl methyl formate phenyl, hydroxy phenyl, methyl formate phenyl,
(3) following compounds are selected from:
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that: described pharmaceutically to connect The salt received is inorganic acid salt or acylate；
The inorganic acid salt is selected from the salt that any one following inorganic acid are formed: hydrochloric acid, sulfuric acid and phosphoric acid；
The acylate be selected from any one following organic acid formed salt: acetic acid, trifluoroacetic acid, malonic acid, citric acid and P-methyl benzenesulfonic acid.
3. preparing R in Formulas I described in claim 11、R2、R3、R4R in substituent group and Formulas I as follows2It is connected Carbon atom and R3By the method for doubly linked compound between the carbon atom connected,
R1
R2Hydrogen, the alkyl of C1-C6
R3
R4Tert-butyl, phenyl, p-nitrophenyl, p-trifluoromethyl phenyl, p-fluorophenyl, p-methoxyphenyl, chlorphenyl, 2, 4,6- trichlorophenyl or to sulfoamido phenyl；
Include the following steps:
1) Formula II compound represented and III compound represented of formula are subjected to aldol reaction, obtain chemical combination shown in formula IV Object；
2) IV compound represented of formula and R4NHNH2Dehydration condensation is carried out, V compound represented of formula is obtained；
3) V compound represented of formula carries out coupling reaction, obtains the compound of formula I；
Wherein, R in the Formula II compound represented1、R2The same Formulas I of definition；
R in III compound represented of formula3The same Formulas I of definition；
R in IV compound represented of formula1、R2、R3The same Formulas I of definition；
R in V compound represented of formula1、R2、R3、R4The same Formulas I of definition.
4. according to the method described in claim 3, it is characterized by: in the step 1), the Formula II compound represented with The molar ratio of III compound represented of formula is 1:1；
In the step 1), the aldol reaction carries out under the catalysis of alkali, and the alkali is specially sodium hydroxide or hydrogen-oxygen Change potassium, the dosage of the alkali is 1.1 times of the moles total number of Formula II compound represented and III compound represented of formula；
The aldol reaction carries out in ethanol water, and the reaction temperature of the reaction is room temperature, reaction time 1- 6h；
In the step 2), IV compound represented of formula and R4NHNH2Molar ratio be 1:1.2-1.5；
In the step 2), the dehydration condensation acetic acid or mass concentration be 98% the concentrated sulfuric acid catalysis under carry out； The dosage of the acetic acid or the concentrated sulfuric acid is 0.3 times of IV compound represented mole of formula；The dehydration condensation is in ethyl alcohol Middle reflux 2-6h；
In the step 3), the coupling reaction carries out in the presence of ruthenium catalyst and sodium bicarbonate；The ruthenium catalyst is specific For p-cymene ruthenous chloride dimer, molecular formula: [RuCl2(p-cymene)]2；The dosage of the ruthenium catalyst be substrate not It is saturated the 5% of hydrazone mole；The dosage of the sodium bicarbonate is 1 times of substrate unsaturation hydrazone mole；
Coupling reaction 100-110 DEG C of reaction 12-24h in dimethyl sulphoxide solution.
5. application of the compound described in claim 1 in preparation antibacterials.
6. application according to claim 5, it is characterised in that: the antibacterials are anti-bacterial drug；
The bacterium is streptococcus pneumonia, the streptococcus pneumonia of multidrug resistant, staphylococcus aureus, methicillin-resistant staphylococcus Staphylococcus, enterococcus faecalis, multidrug resistant enterococcus faecalis；The enterococcus faecalis of vancomycin resistance.
7. a kind of antibacterials, active ingredient is compound described in claim 1.
8. drug as claimed in claim 7, it is characterised in that: the antibacterials are anti-bacterial drug.
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