CN111662280B - Piperidinyl tetrahydrobenzothiazole oxime ether derivative and application thereof - Google Patents

Piperidinyl tetrahydrobenzothiazole oxime ether derivative and application thereof Download PDF

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CN111662280B
CN111662280B CN202010689526.0A CN202010689526A CN111662280B CN 111662280 B CN111662280 B CN 111662280B CN 202010689526 A CN202010689526 A CN 202010689526A CN 111662280 B CN111662280 B CN 111662280B
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trifluoromethyl
methyl
piperidin
pyrazol
tetrahydrobenzo
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CN111662280A (en
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赵卫光
边强
赵瑞琪
彭星洁
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Abstract

The invention relates to a piperidyl tetrahydrobenzothiazole oxime ether derivative shown as a general formula (I) and application thereof as a bactericide. The compound represents a novel bactericide structure type, has excellent bactericidal activity, and can be used for preventing and treating diseases caused by oomycete pathogenic bacteria, such as downy mildew, late blight, downy blight and the like, and specifically comprises cucumber downy mildew, grape downy mildew, chinese cabbage downy mildew, tomato late blight, potato late blight, pepper late blight, peronophythora litchi, phytophthora sojae and the like. The compounds of the present invention are also suitable for sclerotinia rot, ring spot, gray mold, sheath blight, etc. The compound of the invention can be directly used, can be added with an agriculturally acceptable carrier for use, and can also be compounded with other bactericides for use.

Description

Piperidyl tetrahydrobenzothiazole oxime ether derivative and application thereof
Technical Field
The invention belongs to the field of pesticides, and particularly relates to piperidyl tetrahydrobenzothiazole oxime ether derivatives and application thereof as a bactericide.
Background
In agricultural production, the crop is often damaged by pests such as insects, grass, bacteria and the like to cause the yield reduction and even the failure of the production. The oomycete pathogenic bacteria are important pathogenic bacteria in agriculture, have wide host range and comprise various crops such as vegetables, fruits, flowers, woods, cotton, hemp, oil and the like. The pathogenic bacteria of oomycete plants have strong destructiveness and harmfulness to host plants, short incubation period and frequent re-infection, so that the pathogenic bacteria can be spread and infected everywhere in a growing season of the plants and are difficult to control, thereby causing serious loss in agriculture and forestry.
The piperidyl thiazole bactericide is a bactericide with a novel structure for preventing and treating plant oomycetes diseases, and the action mechanism of the bactericide is different from that of the original carboxamide bactericide for treating oomycetes. The DuPont company conducts high-throughput activity screening on thiazolyl piperidine derivatives used for inhibiting MTP (microsomal triglyceride transfer protein) in a database of Tripos of Germany, and finds that the compound 1-1 has weak prevention effect on tomato late blight and cucumber downy mildew, so that piperidine-thiazole-carbonyl is used as an active fragment, the structure is optimized from the left and right aspects, and the first piperidyl thiazole isoxazoline bactericide oxathiapirolin (fluorothiazole pyriethanone) is developed in 2007.
Figure BDA0002588790490000021
Oxathiapiprolin, a novel fungicide developed by dupont, belongs to the family of the oxysterol binding protein homolog inhibitors (OSPPI), trade name: zorvec, orobdis et al, published 2012, marketed 2016, and over 14 years from discovery to marketing. It exhibits excellent activity against pathogenic oomycetes, including Phytophthora capsici (Phytophthora capsaici), phytophthora infestans (Phytophthora infestans), phytophthora sojae (Phytophthora sojae), phytophthora melonis (Phytophthora melonis), peronospora viticola (Phytophthora viticola), peronospora cucumerinum (Phytophthora cubensis) and the like. At 10mg L -1 Can effectively inhibit the release and movement of phytophthora capsici zoospores. Oxathiapiprolin is effective in treatment and defense of leaf surfaces and root systems of plants, and has the characteristic of conduction from suction to top. Therefore, the piperidyl thiazole derivatives have attracted high attention of various agricultural chemical companies in the world in recent years, and have been invested with huge resources in the research and development of the bactericide.
Compound 1-2 (WO 2010065579A 2) reported by DuPont in Oxathiapirolin introduction of oxime at 10mg L -1 The treatment control rate of the compound reaches 100 percent under the concentration of the compound. Compound 1-3 (WO 2009094407 A2) at 40mg L -1 The control rate of the treatment on the grape downy mildew and the tomato late blight reaches more than 99 percent.
Figure BDA0002588790490000022
Bayer and Zhanghengda take the lead compounds of Bayer as a lead compound to carry out derivation, and some patents are filed. Bayer introduces oxime ether structure into thiazole ring to obtain compound 1-4 (WO 2010037479A 1) in 100mg L -1 The effect on the downy mildew of grapes, the late blight of grapes and the treatment control rate of the grape can reach more than 80 percent; introducing ketene structure on thiazole ring to obtain compound 1-5 ( US 20110312999 Al)，500mg L -1 The control effect on the tomato epidemic disease reaches 100 percent under the concentration of (3). In 2011, bayer developed another piperidyl thiazole isoxazoline bactericide-fluoxaprirolin (CN 103180317A), which is the second bactericide to obtain the common name of ISO (international organization for standardization) and is going to be on the market.
Figure BDA0002588790490000031
Cyclopropyl was introduced into an isoxazole ring in a mother nucleus of the fluorothiazole pyrithylone by the company of Jungda in 2014 to obtain the compounds 1-6 (WO 2014118142 A1) with 200mg L -1 The prevention and treatment effects on tomato late blight, potato late blight and grape downy mildew can reach more than 80%. Compounds 1-7 (WO 2014154530 A1), 200mg L, were also reported in the same year -1 The prevention and treatment effects on tomato late blight, potato late blight and downy glucose mildew can reach more than 80%.
Figure BDA0002588790490000032
The invention optimizes the compound of the fluorothiazole pyrithylone, designs and synthesizes a brand-new compound of piperidyl tetrahydrobenzothiazole oxime ether, and the result of the bactericidal activity test of phytophthora capsici pathogenic bacteria shows that the compound of the invention has excellent bactericidal activity.
Disclosure of Invention
The invention aims to provide a piperidyl tetrahydrobenzothiazole oxime ether derivative. The compound has excellent bactericidal activity and wide medicine preparing foreground.
The piperidyl tetrahydrobenzothiazole oxime ether derivative provided by the invention is a compound with the following general formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0002588790490000041
wherein X and Y are respectively N, S or S, N or N, O or O, N;
z is CH 2 ，CO，CHCH 3 ；
R is optionally 1-5 substituents selected from hydrogen, hydroxy, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, halo C 2-6 Alkenyl, halo C 2-6 Alkynyl, benzyloxy, phenyl, the hydrogen on the benzyloxy and phenyl rings is optionally substituted by 1-5 selected from halogen, hydroxyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, halo C 2-6 Alkenyl, halo C 2-6 Substituent substitution of alkynyl;
x and Y are preferably N and S;
z is preferably CH 2 ；
R is preferably hydrogen, methyl, halogen, methoxy or trifluoromethyl.
In addition, the invention relates to the use of a compound as defined in formula (I) as a plant fungicide.
In the present invention, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon. Examples of such substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl.
Likewise, the term "alkoxy" refers to a straight or branched chain saturated alkoxy group. Examples of such substituents include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy.
The term "alkenyl" refers to straight or branched chain alkenyl groups, and examples of such substituents include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl.
The term "alkynyl" refers to straight or branched chain alkynyl groups, and examples of such substituents include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 1-hexynyl.
The term "haloalkyl" is a straight-chain or branched alkyl group, on which the hydrogen atoms may be partially or totally substituted by halogen atoms; the terms "haloalkoxy", "haloalkenyl", "haloalkynyl" are defined analogously to the term "haloalkyl".
The term "halogen" refers to fluorine, chlorine, bromine, iodine.
The invention further provides a pesticidal composition comprising an effective amount of a compound of formula (I) and a carrier. The invention also provides a pesticidal composition comprising an effective amount of one of the specific compounds disclosed in the examples section and a carrier.
The compound (I) of the present invention is prepared by the following route, and all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry.
The compounds of general formula (I) according to the invention, X and Y, Z, R are as defined in the description.
When X and Y are N and S, respectively, Z is CH 2 The synthetic route of compound 11 of the general formula is:
Figure BDA0002588790490000051
synthetic route to compound 11 of formula
In the synthetic route, compound 1 is protected by morpholine nitrogen atom to obtain compound 2; carrying out a thionation reaction on the compound 2 to obtain a compound 3; carrying out cyclization condensation reaction on the compound 3 and 2-bromo-1, 3-diketocyclohexane to obtain a compound 5; hydrolyzing the compound 5 to obtain a compound 6; reacting the compound 6 with the compound 7 to obtain a compound 8; the compound 8 reacts with hydroxylamine hydrochloride to obtain a compound 9, and then reacts with benzyl bromide to obtain a compound shown in a general formula 11.
The present invention also provides a method for preparing the compound of formula 11, comprising the steps of:
1) Dissolving 4-piperidinecarboxamide in an organic solvent, adding dicarbonyl di-tert-butyl ester and an acid-binding agent, stirring at room temperature until the reaction is completed, desolventizing, adding the organic solvent for redissolving, washing an organic layer with saturated sodium bicarbonate and water, drying the organic layer with anhydrous magnesium sulfate, and desolventizing to obtain a white solid compound 2, wherein the organic solvent refers to diethyl ether, isopropyl ether, ethyl acetate, dichloroethane, chloroform or toluene.
2) Dissolving N-Boc-4-piperidinecarboxamide 2 in an organic solvent, adding a Lawson reagent, stirring at room temperature until the reaction is completed, desolventizing, adding the organic solvent for redissolving, washing an organic layer by using a citric acid solution, saturated sodium carbonate and water in sequence, drying the organic layer by using anhydrous magnesium sulfate, desolventizing, and obtaining a compound 3.
3) Dissolving Boc-4-piperidine thiocarboxamide 3 in an organic solvent, adding 2-bromo-1, 3-diketocyclohexane 4 at room temperature, heating and stirring until the reaction is finished, filtering, desolventizing, adding an organic solvent for redissolving, adding saturated sodium bicarbonate and water for washing an organic layer, drying the organic layer by anhydrous magnesium sulfate, and desolventizing to obtain a compound 5.
4) Adding hydrochloric acid and an organic solvent with proper concentration into the compound 5, heating and refluxing until the reaction is finished, cooling the reaction solution, adding alkali to adjust the water layer to be alkalescent, separating an organic layer, extracting the water layer, combining the organic layers, drying and desolventizing to obtain a compound 6.
5) Dissolving the compound 6 in an organic solvent, adding alkali, stirring at room temperature, adding the compound 7, reacting at room temperature until the reaction is finished, desolventizing, adding the organic solvent for redissolving, washing the organic layer with water respectively, drying, and desolventizing to obtain a white solid 8. The alkali refers to sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, N-methylmorpholine or pyridine.
6) Dissolving the compound 8 in an organic solvent, adding hydroxylamine hydrochloride and alkali, heating and refluxing until the reaction is finished, cooling the reaction solution, filtering, desolventizing, adding the organic solvent for redissolving, washing with water, drying, and desolventizing to obtain the compound 9.
7) Adding alkali and a compound 9 into an organic solvent, stirring for a while, dropwise adding benzyl bromide, stirring until the reaction is finished, adding water, extracting with the organic solvent, drying, filtering, and desolventizing to obtain a compound 11.
Intermediates 5,6, 8 and 9
Figure BDA0002588790490000071
Intermediates 5,6, 8 and 9 are specific intermediates used to prepare compounds of formula (I).
When X and Y are N and S, respectively, and Z is CO, compound 9 is reacted with benzoyl chloride 12 to give compound 13, which is synthesized by the following synthetic route:
Figure BDA0002588790490000072
the specific experimental steps of the route are as follows:
adding alkali and the compound 9 into an organic solvent, stirring for a while, dropwise adding benzoyl chloride 12, stirring until the reaction is completed, adding water, extracting with the organic solvent, drying, and filtering to obtain a compound 13.
When X and Y are S and N, respectively, Z is CH 2 The synthetic route for compound 20 of formula (la) is:
Figure BDA0002588790490000081
in the synthetic route, a compound 15 is obtained by a cyclized condensation reaction of a compound 3 and 3-bromo-1, 2-diketocyclohexane 14; hydrolyzing the compound 15 to obtain a compound 16; reacting compound 16 with compound 17 to give compound 18; reacting the compound 18 with hydroxylamine hydrochloride to obtain a compound 19; the compound 19 is reacted with benzyl bromide 20 to give the compound of formula 21.
The invention also provides a preparation method of the compound with the general formula 21.
When X and Y are S and N, respectively, and Z is CO, compound 19 is reacted with benzoyl chloride 22 to give compound 23, which is synthesized by the following scheme:
Figure BDA0002588790490000082
intermediates 15, 16, 18 and 19
Figure BDA0002588790490000091
Intermediates 15, 16, 18 and 19 are specifically used to prepare compounds of formula (I).
The compound with the structural formula (I) provided by the invention has excellent bactericidal activity, and can be used for preventing and treating diseases caused by oomycete pathogenic bacteria, such as downy mildew, late blight, downy blight and the like, specifically cucumber downy mildew, grape downy mildew, cabbage downy mildew, tomato late blight, potato late blight, pepper late blight, peronophythora litchi, phytophthora root rot of soybean and the like. The compounds of the present invention are also suitable for sclerotinia rot, ring spot, gray mold, sheath blight, etc. The compound of the invention can be directly used, can be added with an agriculturally acceptable carrier for use, and can also be compounded with other bactericides for use.
Detailed Description
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
Example 1: synthesis of N-Boc-4-piperidinecarboxamide 2
4-Piperidinecarboxamide 1 (12.00g, 93.63mmol) was dissolved in 220mL of acetonitrile, mechanically stirred, and di-carbonyl di-tert-butyl ester (22.48g, 102.99mmol) and 4-Dimethylaminopyridine (DMAP) (1.20g, 9.82mmol) were added, respectively, then stirred at room temperature for 10h, TLC was monitored until the reaction was completed, desolventized, redissolved by adding 150mL of dichloromethane, washed with 80mL of saturated sodium bicarbonate, washed with 80mL of saturated ammonium chloride, washed with 80mL of water, washed with 80mL of saturated sodium chloride, dried with anhydrous magnesium sulfate, filteredDesolventizing to obtain 17.54g of white solid, yield 82.1%, melting point: 153-155 ℃. 1 H NMR(400MHz,CDCl 3 )δ5.54(s,2H,CNH 2 ),4.13(s,2H,CH 2 ),2.75(s,2H,CH 2 ),2.25-2.33(m,1H,CH),1.84(d,J＝15.8Hz,2H,CH 2 ),1.60-1.67(m,2H,CH 2 ),1.44(s,9H,t-Bu-H).
Example 2: synthesis of N-Boc-4-piperidinethioamide 3
N-Boc-4-piperidinecarboxamide 2 (1.00g, 4.38mmol) was dissolved in 20mL of tetrahydrofuran solution, followed by addition of Lawson's Reagent (LR) (1.06g, 2.63mmol), mechanical stirring at room temperature for 12h, tlc monitoring until the reaction was complete, desolvation, redissolving by addition of 20mL of ethyl acetate, washing of the organic layer with 15ml of 10% citric acid x 2, washing of the organic layer with 15ml of saturated sodium carbonate x 2, washing of the organic layer with 15mL of water, drying of the organic layer with anhydrous magnesium sulfate, filtration, desolvation to give 0.88g of a white solid, yield 82.2%, melting point: 126-129 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H,NH 2 ),6.90(s,1H,NH 2 ),4.22(s,2H,CH 2 ),2.65-2.82(m,3H,CH+CH 2 ),1.85-1.91(m,2H,CH 2 ),1.66-1.77(m,2H,CH 2 ),1.46(s,9H,t-Bu-H).
Example 3: synthesis of tert-butyl 4- (7-oxo-4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidine-1-carboxylate 5
Adding Boc-4-piperidine thiocarboxamide 3 (1.00g, 4.09mmol) into 20mL of ethanol solvent, stirring at room temperature, adding 2-bromo-1, 3-diketocyclohexane 4 (0.78g, 4.09mmol) in six batches, adding 0.26g each time, and separating for 15min, stirring at room temperature for 15min, heating to 85 ℃, heating and refluxing for 3h, monitoring by TLC until the reaction is completed, cooling the reaction solution, filtering, desolventizing to obtain oily substance 1.02g, redissolving with 20mL of dichloromethane, adding 15mL of water to wash the organic layer, drying the organic layer with anhydrous magnesium sulfate, filtering, desolventizing to obtain yellow oily substance 0.72g, performing normal pressure column chromatography to obtain yellow solid 0.35g, wherein the waxy yield is 25.4%, and the melting point: 77-79 ℃. 1 H NMR(400MHz,CDCl 3 )δ4.21(s,2H,CH 2 ),3.09-3.16(m,1H,CH),3.02(d,J＝5.8Hz,2H,CH 2 ),2.85(s,2H,CH 2 ),2.61(d,J＝5.6Hz,2H,CH 2 ),2.18-2.24(m,2H,CH 2 ),2.04-2.09(m,2H,CH 2 ),1.67-1.77(m,2H,CH 2 ),1.46(s,9H,t-Bu-H).
Example 4: synthesis of 2- (piperidin-4-yl) -5, 6-dihydrobenzo [ d ] thiazol-7 (4H) -one 6
Taking 4- (7-oxo-4, 5,6, 7-tetrahydrobenzo [ d ]]Thiazole-2-yl) piperidine-1-carboxylic acid tert-butyl ester 5 (3.00g, 8.92mmol), 30mL of 10% hydrochloric acid and 30mL of dichloromethane solvent are respectively added, the temperature is raised to 40 ℃, heating reflux is carried out for 10h, TLC monitoring is carried out until the reaction is completed, the temperature of reaction liquid is reduced, sodium carbonate solution is added to adjust the pH of a water layer to be 9-10, an organic layer is separated, 30mL of 5 dichloromethane is added to extract the water layer, extraction solutions are combined, anhydrous magnesium sulfate is used for drying the extraction solutions, filtration and desolventization are carried out to obtain 2.01g of yellow oily matter, and the yield is 95.4%. 1 H NMR(400MHz,CDCl 3 )δ3.57(d,J＝11.8Hz,2H,CH 2 ),3.29-3.33(m,1H,CH),3.13(t,J＝9.8Hz,2H,CH 2 ),3.02(t,J＝5.6Hz,2H,CH 2 ),2.63(t,J＝5.6Hz,2H,CH 2 ),2.41(d,J＝15.6Hz,2H,CH 2 ),2.19-2.33(m,4H,CH 2 +CH 2 ).
Example 5: synthesis of 2- (1- (2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) acetyl) piperidin-4-yl) -5, 6-dihydrobenzo [ d ] thiazole-7 (4H) -1 8
Reacting 2- (piperidin-4-yl) -5, 6-dihydrobenzo [ d]Thiazole-7 (4H) -one 6 (1g, 2.975 mmol) was dissolved in 15mL of dichloromethane, triethylamine (0.90g, 8.925 mmol) was added, 2- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) acetyl chloride 7 (0.67g, 2.975 mmol) was dissolved in 5mL of dichloromethane, the reaction solution was slowly dropped, reacted at room temperature for 10h, TLC was monitored until the reaction was completed, the reaction solution was washed with 10mL of dilute hydrochloric acid, 10mL of saturated sodium carbonate, 10mL of water, anhydrous magnesium sulfate was dried, filtered, desolventized, and recrystallized from ethyl acetate to give 0.89g of a white solid, a yield of 70.2%, a melting point: 150-152 ℃. 1 H NMR(400MHz,CDCl 3 )δ6.35(s,1H,Pyrazolyl-H),5.02(d,J＝3.4Hz,2H,CH 2 ),4.62(d,J＝15.8Hz,1H,CH 2 ),3.25-3.33(m,2H,CH 2 ),3.04(t,J＝5.6Hz,2H,CH 2 ),2.87(t,J＝13.2Hz,1H,CH),2.64(t,J＝7.2Hz,2H,CH 2 ),2.33(s,3H,Pyrazolyl-CH 3 ),2.16-2.27(m,4H,CH 2 +CH 2 ),1.73-1.85(m,2H,CH 2 ).
Example 6: synthesis of 1- (4- (7- (hydroxyimino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 9
Reacting 2- (1- (2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) acetyl) piperidin-4-yl) -5, 6-dihydrobenzo [ d]Thiazole-7 (4H) -1 (4.00g, 9.38mmol) was added to 80mL of anhydrous methanol, then hydroxylamine hydrochloride (0.98g, 14.08mmol) and potassium carbonate (1.95g, 14.08mmol) were added respectively, the temperature was raised to 65 ℃, reflux stirring was carried out for 1 hour, tlc monitoring was carried out until the reaction was completed, the temperature was reduced, filtration and desolventization were carried out to obtain 5.43g of yellow solid, 70mL of dichloromethane was added to redissolve, 40ml × 3 of water was used to wash the organic layer, the organic layer was dried over anhydrous magnesium sulfate, filtration and desolventization were carried out, normal pressure column chromatography was carried out to obtain 3.33g of white solid, yield was 80.8%, melting point: 120-122 ℃. 1 H NMR(400MHz,CDCl 3 )δ9.45(s,1H,NOH),6.33(s,1H,Pyrazolyl-H),4.95-5.05(m,2H,CH 2 ),4.61(d,J＝13.6Hz,1H,CH 2 ),3.23-3.31(m,2H,CH 2 ),2.99(t,J＝5.8Hz,2H,CH 2 ),2.80-2.89(m,1H,CH),2.65(t,J＝5.4Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.19(t,J＝13.6Hz,2H,CH 2 ),2.04-2.10(m,2H,CH 2 ),1.74-1.82(m,2H,CH 2 ).
Example 7: synthesis of 1- (4- (7- ((benzoyloxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11a
Sodium hydride (0.06g, 1.50mmol) was added to 15mL of anhydrous N, N-Dimethylformamide (DMF) reaction solvent, and after stirring, 1- (4- (7- (hydroxyidene) -4,5,6, 7-tetrahydrobenzo [ d ] was added]Thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 9 (0.60g, 1.36mmol), stirring for 1H, then slowly adding benzyl bromide 10a (0.24g, 1.50mmol) dropwise, after completion of dropping, raising the temperature to room temperature and stirring for 2H, monitoring by TLC until completion of the reaction, adding a small amount of saturated aqueous ammonium chloride solution dropwise to quench the reaction until the reaction solution is free from bubbles, adding 50mL of water, extracting with 30mL of 3 ethyl acetate, combining the extracts, backwashing with 30mL of 3 water, and drying with anhydrous magnesium sulfateFiltering an organic layer, desolventizing, and carrying out normal pressure column chromatography to obtain 0.6g of white solid, wherein the yield is as follows: 71.9%, melting point: 110-112 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.32-7.42(m,5H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.24(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.02(d,J＝14.0Hz,1H,CH 2 ),3.22-3.30(m,2H,CH 2 ),2.96(t,J＝6.2Hz,2H,CH 2 ),2.81-2.87(m,1H,CH),2.62(t,J＝6.2Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.11-2.19(m,2H,CH 2 ),2.03-2.06(m,2H,CH 2 ),1.75-1.81(m,2H,CH 2 ).
By following the procedure of example 7, compounds 11b to 11s were prepared, respectively, by selecting appropriate starting materials and reagents. It is understood that one skilled in the art can select appropriate starting materials and reagents according to the needs of the examples.
Example 8: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((2-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 11b
White solid, melting point: 103-105 ℃, yield: 12.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.31-7.39(m,1H,Ar-H),7.18-7.24(m,3H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.25(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.02(d,J＝14.0Hz,1H,CH 2 ),3.17-3.28(m,2H,CH 2 ),2.95(t,J＝6.2Hz,2H,CH 2 ),2.83-2.86(m,1H,CH),2.63(t,J＝6.2Hz,2H,CH 2 ),2.41(s,3H,Ar-CH 3 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.02-2.17(m,4H,CH 2 +CH 2 ),1.71-1.80(m,2H,CH 2 ).
Example 9: synthesis of 1- (4- (7- ((((2-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11c
White solid, melting point: 101-103 ℃, yield: 31.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.35-7.45(m,2H,Ar-H),7.24-7.27(m,2H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.35(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.6Hz,1H,CH 2 ),4.02(d,J＝13.6Hz,1H,CH 2 ),3.17-3.30(m,2H,CH 2 ),2.96(t,J＝6.2Hz,2H,CH 2 ),2.84-2.89(m,1H,CH),2.63(t,J＝6.2Hz,2H,CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.11-2.23(m,2H,CH 2 ),2.05-2.08(m,2H,CH 2 ),1.75-1.81(m,2H,CH 2 ).
Example 10: synthesis of 1- (4- (7- (((2-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11d
White solid, melting point: 109-111 ℃, yield: 28.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.42-7.46(m,1H,Ar-H),7.29-7.34(m,1H,Ar-H),7.13-7.17(m,1H,Ar-H),7.06-7.10(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.31(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.02(d,J＝13.6Hz,1H,CH 2 ),3.18-3.30(m,2H,CH 2 ),2.95(t,J＝6.2Hz,2H,CH 2 ),2.81-2.88(m,1H,CH),2.62(t,J＝6.4Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.11-2.19(m,2H,CH 2 ),2.02-2.08(m,2H,CH 2 ),1.72-1.84(m,2H,CH 2 ).
Example 11: synthesis of 1- (4- (7- ((((2-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11e
White solid, melting point: 99-101 ℃, yield: 18.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.57-7.59(m,1H,Ar-H),7.42-7.44(m,1H,Ar-H),7.30-7.34(m,1H,Ar-H),7.16-7.21(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.33(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.21-3.31(m,2H,CH 2 ),2.97(t,J＝6.2Hz,2H,CH 2 ),2.82-2.88(m,1H,CH),2.64(t,J＝6.2Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.13-2.21(m,2H,CH 2 ),2.03-2.09(m,2H,CH 2 ),1.76-1.82(m,2H,CH 2 ).
Example 12: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((3-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 11f
White solid, melting point: 101-103 ℃, yield: 79.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.25-7.29(m,1H,Ar-H),7.20-7.22(m,2H,Ar-H),7.12-7.14(m,1H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.20(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.58(d,J＝13.2Hz,1H,CH 2 ),4.02(d,J＝14.0Hz,1H,CH 2 ),3.18-3.30(m,2H,CH 2 ),2.95(t,J＝6.2Hz,2H,CH 2 ),2.81-2.87(m,1H,CH),2.62(t,J＝6.4Hz,2H,CH 2 ),2.36(s,3H,Ar-CH 3 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.11-2.19(m,2H,CH 2 ),2.01-2.08(m,2H,CH 2 ),1.75-1.81(m,2H,CH 2 ).
Example 13: synthesis of 1- (4- (7- ((((3-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11g
White solid, melting point: 95-97 ℃, yield: 22.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.40(s,1H,Ar-H),7.27-7.30(m,3H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.20(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.6Hz,1H,CH 2 ),4.03(d,J＝14.0Hz,1H,CH 2 ),3.19-3.31(m,2H,CH 2 ),2.96(t,J＝6.0Hz,2H,CH 2 ),2.82-2.88(m,1H,CH),2.61(t,J＝6.2Hz,2H,CH 2 ),2.30(s,3H,PyraZolyl-CH 3 ),2.12-2.21(m,2H,CH 2 ),2.02-2.08(m,2H,CH 2 ),1.72-1.85(m,2H,CH 2 ).
Example 14: synthesis of 1- (4- (7- ((((3-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11H
White solid, melting point: 89-91 ℃, yield: 35.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.29-7.36(m,1H,Ar-H),7.10-7.17(m,2H,Ar-H),6.98-7.03(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.23(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.58(d,J＝13.6Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.21-3.31(m,2H,CH 2 ),2.96(t,J＝5.4Hz,2H,CH 2 ),2.82-2.88(m,1H,CH),2.62(t,J＝5.2Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.12-2.20(m,2H,CH 2 ),2.03-2.07(m,2H,CH 2 ),1.73-1.85(m,2H,CH 2 ).
Example 15: synthesis of 1- (4- (7- ((((3-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11i
White solid, melting point: 88-90 ℃, yield: 48.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.57-7.58(m,1H,Ar-H),7.43-7.46(m,1H,Ar-H),7.31-7.34(m,1H,Ar-H),7.20-7.24(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.20(s,2H,CH 2 ),4.99(s,2H,CH 2 ),4.59(d,J＝13.4Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.20-3.32(m,2H,CH 2 ),2.96(t,J＝6.0Hz,2H,CH 2 ),2.83-2.90(m,1H,CH),2.60-2.64(m,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.17(t,J＝16.0Hz,2H,CH 2 ),2.02-2.08(m,2H,CH 2 ),1.73-1.86(m,2H,CH 2 ).
Example 16: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((4-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 11j
White solid, melting point: 150-152 ℃, yield: 66.5 percent. 1 H NMR(400MHz,CDCl 3 )δ7.25-7.32(m,2H,Ar-H),7.14-7.19(m,2H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.20(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.01(d,J＝13.6Hz,1H,CH 2 ),3.18-3.29(m,2H,CH 2 ),2.95(t,J＝6.2Hz,2H,CH 2 ),2.80-2.88(m,1H,CH),2.62(t,J＝6.2Hz,2H,CH 2 ),2.36(s,3H,PH-H),2.32(s,3H,Pyrazolyl-CH 3 ),2.10-2.18(m,2H,CH 2 ),2.01-2.07(m,2H,CH 2 ),1.74-1.83(m,2H,CH 2 ).
Example 17: synthesis of 1- (4- (7- ((((4-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11k
White solid, melting point: 106-108 ℃ and yield: 68.6 percent. 1 H NMR(400MHz,CDCl 3 )δ7.28-7.33(m,4H,Ar-H)6.32(s,1H,Pyrazolyl-H),5.18(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.58(d,J＝13.6Hz,1H,CH 2 ),4.01(d,J＝13.6Hz,1H,CH 2 ),3.19-3.29(m,2H,CH 2 ),2.94(t,J＝6.0Hz,2H,CH 2 ),2.79-2.86(m,1H,CH),2.60(t,J＝6.2Hz,2H,CH 2 ),2.29(s,3H,Pyrazolyl-CH 3 ),2.10-2.18(m,2H,CH 2 ),2.00-2.06(m,2H,CH 2 ),1.71-1.84(m,2H,CH 2 ).
Example 18: synthesis of 1- (4- (7- ((((4-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11l
White solid, melting point: 109-111 ℃, yield: 61.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.36-7.40(m,2H,Ar-H),7.03-7.08(m,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.19(s,2H,CH 2 ),4.98(d,J＝3.2Hz,2H),4.60(d,J＝13.2Hz,1H,CH 2 ),4.04(d,J＝13.6Hz,1H,CH 2 ),3.18-3.30(m,2H,CH 2 ),2.95(t,J＝6.0Hz,2H,CH 2 ),2.80-2.87(m,1H,CH),2.60-2.63(m,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.11-2.19(m,2H,CH 2 ),2.01-2.08(m,2H,CH 2 ),1.71-1.84(m,2H,CH 2 ).
Example 19: synthesis of 1- (4- (7- ((((4-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11m
White solid, melting point: 113-115 ℃, yield: 46.8 percent. 1 H NMR(400MHz,CDCl 3 )δ7.45-7.51(m,2H,Ar-H),7.24-7.32(m,2H,Ar-H),6.35(s,1H,Pyrazolyl-H),5.20(s,2H,CH 2 ),5.01(s,2H,CH 2 ),4.62(d,J＝14.0Hz,1H,CH 2 ),4.05(d,J＝13.6Hz,1H,CH 2 ),3.18-3.33(m,2H,CH 2 ),2.98(t,J＝6.0Hz,2H,CH 2 ),2.83-2.90(m,1H,CH),2.63(t,J＝6.2Hz,2H,CH 2 ),2.33(s,3H,Pyrazolyl-CH 3 ),2.14-2.22(m,2H,CH 2 ),2.03-2.10(m,2H,CH 2 ),1.74-1.87(m,2H,CH 2 ).
Example 20: synthesis of 1- (4- (7- ((3-bromo-2-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11n
Pale yellow solid, melting point: 120-122 ℃, yield: 32.8 percent. 1 H NMR(400MHz,CDCl 3 )δ7.47-7.53(m,1H,Ar-H),7.34-7.39(m,1H,Ar-H),7.00-7.05(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.30(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.59(d,J＝13.6Hz,1H,CH 2 ),4.02(d,J＝13.6Hz,1H,CH 2 ),3.18-3.31(m,2H,CH 2 ),2.95(t,J＝6.2Hz,2H,CH 2 ),2.81-2.89(m,1H,CH),2.61(t,J＝6.2Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.12-2.20(m,2H,CH 2 ),2.00-2.07(m,2H,CH 2 ),1.72-1.85(m,2H,CH 2 ).
Example 21: synthesis of 1- (4- (7- ((2-chloro-6-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11o
White solid, melting point: 128-130 ℃, yield: 62.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.20-7.33(m,2H,Ar-H),7.01-7.08(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.38(d,J＝2.0Hz,2H,CH 2 ),4.98(s,2H,CH 2 ),4.58(d,J＝13.6Hz,1H,CH 2 ),3.99(d,J＝13.6Hz,1H,CH 2 ),3.16-3.28(m,2H,CH 2 ),2.88-2.95(m,2H,CH 2 ),2.79-2.86(m,1H,CH),2.61(t,J＝6.4Hz,2H,CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),1.99-2.16(m,4H,CH 2 +CH 2 ),1.68-1.80(m,2H,CH 2 ).
Example 22: synthesis of 1- (4- (7- ((2-bromo-5-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11p
White solid, melting point:99-101 ℃, yield: 43.8 percent. 1 H NMR(400MHz,CDCl 3 )δ7.48-7.53(m,1H,Ar-H),7.11-7.15(m,1H,Ar-H),6.86-6.93(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.28(s,2H,CH 2 ),4.99(s,2H,CH 2 ),4.60(d,J＝14.0Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.19-3.32(m,2H,CH 2 ),2.98(t,J＝6.2Hz,2H,CH 2 ),2.86-2.90(m,1H,CH),2.64(t,J＝6.4Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.15-2.22(m,2H,CH 2 ),2.02-2.10(m,2H,CH 2 ),1.74-1.87(m,2H,CH 2 ).
Example 23: synthesis of 1- (4- (7- ((2, 6-dichlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11q
White solid, melting point: 126-128 ℃, yield: 41.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.33-7.38(m,2H,Ar-H),7.20-7.25(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.50(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.58(d,J＝13.6Hz,1H,CH 2 ),4.00(d,J＝13.6Hz,1H,CH 2 ),3.15-3.28(m,2H,CH 2 ),2.93(t,J＝6.0Hz,2H,CH 2 ),2.80-2.86(m,1H,CH),2.63(t,J＝6.2Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.01-2.16(m,4H,CH 2 +CH 2 ),1.69-1.79(m,2H,CH 2 ).
Example 24: synthesis of 1- (4- (7- ((((2, 6-dimethylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11r
White solid, melting point: 98-100 ℃, yield: 56.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.03-7.18(m,3H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.28(s,2H,CH 2 ),4.97(s,2H,CH 2 ),4.57(d,J＝13.6Hz,1H,CH 2 ),4.00(d,J＝13.6Hz,1H,CH 2 ),3.17-3.27(m,2H,CH 2 ),2.93(t,J＝6.0Hz,2H,CH 2 ),2.81-2.84(m,1H,CH),2.63(t,J＝6.2Hz,2H,CH 2 ),2.43-2.47(m,6H,CH 3 +CH 3 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.01-2.16(m,4H,CH 2 +CH 2 ),1.67-1.77(m,2H,CH 2 ).
Example 25: synthesis of 1- (4- (7- ((((2, 6-difluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 11s
White solid, melting point: 139-141 ℃ and yield: 18.1 percent. 1 H NMR(400MHz,CDCl 3 )δ7.27-7.35(m,1H,Ar-H),6.88-6.96(m,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.30(s,2H,CH 2 ),4.98(s,2H,CH 2 ),4.58(d,J＝13.2Hz,1H,CH 2 ),4.00(d,J＝13.6Hz,1H,CH 2 ),3.16-3.30(m,2H,CH 2 ),2.92(t,J＝6.2Hz,2H,CH 2 ),2.85-2.88(m,1H,CH),2.60(t,J＝6.2Hz,2H,CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.08-2.16(m,2H,CH 2 ),1.99-2.05(m,2H,CH 2 ),1.72-1.81(m,2H,CH 2 ).
Example 26: synthesis of 1- (4- (7- ((benzyloxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13a
Sodium hydride (0.07g, 1.75mmol) was added to 20mL of anhydrous N, N-Dimethylformamide (DMF) reaction solvent at low temperature, and after stirring, 1- (4- (7- (hydroxyimino) -4,5,6, 7-tetrahydrobenzo [ d ] was added]Thiazole-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethane-1-one 9 (1.59g, 0.70mmol), stirring for 1H, then slowly adding benzoyl chloride 12a (0.23g, 1.67mmol) dropwise for 5min, stirring at room temperature for 1h after finishing dropping, monitoring by tlc (thin layer chromatography) until the reaction is finished, adding a small amount of saturated aqueous ammonium chloride solution dropwise to quench the reaction until the reaction solution has no air bubbles, then adding 75mL of water to the reaction solution, extracting with 50ml of ethyl acetate of 50ml of 3, combining the extracts, backwashing with 70ml of 3 of water, drying the organic layer with anhydrous magnesium sulfate, filtering, desolventizing, and performing normal-pressure column chromatography to obtain 0.73g of a white solid, yield: 84.7%, melting point: 220-222 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.19-8.21(m,2H,Ar-H),7.65-7.69(m,1H,Ar-H),7.54-7.58(m,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),4.99(d,J＝4.4Hz,2H,CH 2 ),4.62(d,J＝13.6Hz,1H,CH 2 ),4.06(d,J＝13.6Hz,1H,CH 2 ),3.24-3.32(m,2H,CH 2 ),3.04(t,J＝6.2Hz,2H,CH 2 ),2.83-2.91(m,3H,CH 2 +CH),2.31(s,3H,Pyrazolyl-CH 3 ),2.14-2.18(m,4H,CH 2 +CH 2 ),1.77-1.81(m,2H,CH 2 ).
By following the procedure of example 26, selecting appropriate starting materials and reagents, compounds 13b to 13m were prepared, respectively. It is understood that one skilled in the art can select appropriate starting materials and reagents according to the needs of the examples.
Example 27: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((2-methylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 13b
Pale yellow solid, melting point: 93-95 ℃, yield: 72.5 percent. 1 H NMR(400MHz,CDCl 3 )δ7.90-7.98(m,1H,Ar-H),7.43-7.52(m,1H,Ar-H),7.28-7.36(m,2H,Ar-H),6.33(d,J＝9.2Hz,1H,Pyrazolyl-H),4.97-5.00(m,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.18-3.29(m,2H,CH 2 ),3.03(t,J＝6.2Hz,2H,CH 2 ),2.93-2.98(m,1H,CH),2.86-2.90(m,2H,CH 2 ),2.64(s,3H,Ar-CH 3 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.07-2.23(m,4H,CH 2 +CH 2 ),1.72-1.80(m,2H,CH 2 ).
Example 28: synthesis of 1- (4- (7- ((((2-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13c
White solid, melting point: 188-190 ℃, yield: 80.8 percent. 1 H NMR(400MHz,CDCl 3 )δ7.99-8.03(m,1H,Ar-H),7.59-7.65(m,1H,Ar-H),7.22-7.33(m,2H,Ar-H),6.32(s,1H,Pyrazolyl-H),4.92-5.02(m,2H,CH 2 ),4.59(d,J＝13.6Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.20-3.30(m,2H,CH 2 ),3.02(t,J＝6.2Hz,2H,CH 2 ),2.84-2.89(m,3H,CH+CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.10-2.19(m,4H,CH 2 +CH 2 ),1.70-1.80(m,2H,CH 2 ).
Example 29: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((3-methylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 13d
White solid, melting point: 143-145 ℃, yield: 48.6 percent. 1 H NMR(400MHz,CDCl 3 )δ7.87-8.02(m,2H,Ar-H),7.35-7.48(m,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),4.93-5.02(m,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.02(d,J＝14.0Hz,1H,CH 2 ),3.23-3.32(m,2H,CH 2 ),3.03(t,J＝6.2Hz,2H,CH 2 ),2.94-3.00(m,1H,CH),2.87-2.90((m,2H,CH 2 ),2.44(d,J＝7.2Hz,3H,Ar-CH 3 ),2.32(d,J＝4.8Hz,3H,Pyrazolyl-CH 3 ),2.07-2.22(m,4H,CH 2 +CH 2 ),1.75-1.85(m,2H,CH 2 ).
Example 30: synthesis of 1- (4- (7- ((((3-chlorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13e
White solid, melting point: 160-162 ℃, yield: 62.2 percent. 1 H NMR(400MHz,CDCl 3 )δ8.20(t,J＝1.8Hz,1H,Ar-H),8.05-8.08(m,1H,Ar-H),7.60-7.63(m,1H,Ar-H),7.49(t,J＝8.0Hz,1H,Ar-H),6.31(s,1H,Pyrazolyl-H),4.98(s,2H,CH 2 ),4.59(d,J＝13.6Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.24-3.33(m,2H,CH 2 ),3.03(t,J＝6.0Hz,2H,CH 2 ),2.90-2.99(m,1H,CH),2.84-2.88(m,2H,CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.08-2.23(m,4H,CH 2 +CH 2 ),1.74-1.87(m,2H,CH 2 ).
Example 31: synthesis of 1- (4- (7- ((((3-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13f
White solid, melting point: 155-157 ℃, yield: 48.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.98(d,J＝8.0Hz,1H,Ar-H),7.86-7.90(m,1H,Ar-H),7.50-7.56(m,1H,Ar-H),7.33-7.38(m,1H,Ar-H),6.32(s,1H,Pyrazolyl-H),4.98(s,2H,CH 2 ),4.61(d,J＝13.6Hz,1H,CH 2 ),4.06(d,J＝14.0Hz,1H,CH 2 ),3.21-3.33(m,2H,CH 2 ),3.03(t,J＝6.2Hz,2H,CH 2 ),2.82-2.89(m,3H,CH+CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.09-2.22(m,4H,CH 2 +CH 2 ),1.73-1.86(m,2H,CH 2 ).
Example 32: synthesis of 1- (4- (7- ((((3-bromobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13g
White solid, melting point: 159-161 ℃, yield: 52.4 percent. 1 H NMR(400MHz,CDCl3)δ8.38(t,J＝1.8Hz,1H,Ar-H),8.10-8.13(m,1H,Ar-H),7.76-7.79(m,1H,Ar-H),7.43(t,J＝8.0Hz,1H,Ar-H),6.32(s,1H,Pyrazolyl-H),4.98(s,2H,CH 2 ),4.59(d,J＝13.2Hz,1H,CH 2 ),4.04(d,J＝13.6Hz,1H,CH 2 ),3.24-3.3 4(m,2H,CH 2 ),3.04(t,J＝6.2Hz,2H,CH 2 ),2.86-2.99(m,3H,CH+CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.09-2.25(m,4H,CH 2 +CH 2 ),1.77-1.88(m,2H,CH 2 ).
Example 33: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((4-methylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 13H
White solid, melting point: 207-209 ℃, yield: 53.0 percent. 1 H NMR(400MHz,CDCl 3 )δ8.06-8.08(m,2H,Ar-H),7.34(d,J＝10.4Hz,2H,Ar-H),6.32(s,1H,Pyrazolyl-H),4.94-5.03(m,2H,CH 2 ),4.61(d,J＝14.0Hz,1H,CH 2 ),4.04(d,J＝14.0Hz,1H,CH 2 ),3.22-3.31(m,2H,CH 2 ),3.02(t,J＝6.0Hz,2H,CH 2 ),2.81-2.97(m,3H,CH+CH 2 ),2.46(s,3H,Ar-CH 3 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.08-2.21(m,4H,CH 2 +CH 2 ),1.73-1.83(m,2H,CH 2 ).
Example 34: synthesis of 1- (4- (7- ((((4-chlorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13i
White solid, melting point: 210-212 ℃, yield: 79.6 percent. 1 H NMR(400MHz,CDCl 3 )δ8.11-8.14(m,2H,Ar-H),7.51-7.54(m,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),4.98(d,J＝6.0Hz,2H,CH 2 ),4.62(d,J＝14.0Hz,1H,CH 2 ),4.07(d,J＝13.6Hz,1H,CH 2 ),3.23-3.32(m,2H,CH 2 ),3.03(t,J＝6.2Hz,2H,CH 2 ),2.85-2.89(m,3H,CH+CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.10-2.21(m,4H,CH 2 +CH 2 ),1.73-1.86(m,2H,CH 2 ).
Example 35: synthesis of 1- (4- (7- ((((4-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13j
White solid, melting point: 195-197 ℃, yield: 58.4 percent. 1 H NMR(400MHz,CDCl 3 )δ8.20-8.23(m,2H,Ar-H),7.21-7.25(m,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),4.98(d,J＝7.6Hz,2H,CH 2 ),4.62(d,J＝14.0Hz,1H,CH 2 ),4.08(d,J＝14.0Hz,1H,CH 2 ),3.23-3.32(m,2H,CH 2 ),3.04(t,J＝6.2Hz,2H,CH 2 ),2.94-3.00(m,1H,CH),2.87-2.90(m,2H,CH 2 ),2.32(s,3H,Pyrazolyl-CH 3 ),2.07-2.20(m,4H,CH 2 +CH 2 ),175-1.85(m,2H,CH 2 ).
Example 36: synthesis of 1- (4- (7- ((((4-bromobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13k
White solid, melting point: 205-207 ℃, yield: 73.0 percent. 1 H NMR(400MHz,CDCl 3 )δ8.02-8.05(m,2H,CH 2 ),7.67-7.70(m,2H,CH 2 ),6.31(s,1H,Pyrazolyl-H),4.98(d,J＝4.8Hz,2H,CH 2 ),4.61(d,J＝13.2Hz,1H,CH 2 ),4.05(d,J＝16.0Hz,1H,CH 2 ),3.22-3.31(m,2H,CH 2 ),3.02(t,J＝6.2Hz,2H,CH 2 ),2.84-2.87(m,3H,CH+CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.09-2.20(m,4H,CH 2 +CH 2 ),1.72-1.85(m,2H,CH 2 ).
Example 37: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((4-trifluoromethylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 13l
White solid, melting point 195-197 ℃, yield: 32.0 percent. 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝8.4Hz,2H,CH 2 ),7.82(d,J＝8.4Hz,2H,CH 2 ),6.32(s,1H,Pyrazolyl-H),4.93-5.03(m,2H,CH 2 ),4.63(d,J＝14.0Hz,1H,CH 2 ),4.09(d,J＝13.2Hz,1H,CH 2 ),3.25-3.32(m,2H,CH 2 ),3.05(t,J＝6.0Hz,2H,CH 2 ),2.82-2.91(m,3H,CH+CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.14-2.21(m,4H,CH 2 +CH 2 ),1.75-1.86(m,2H,CH 2 ).
Example 38: synthesis of 1- (4- (7- ((((2-methoxybenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 13m
White solid, melting point: 133-135 ℃, yield: 35.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.80-7.84(m,1H,Ar-H),7.49-7.57(m,1H,Ar-H),6.99-7.07(m,2H,Ar-H),6.31(s,1H,Pyrazolyl-H),4.91-5.01(m,2H,CH 2 ),4.58(d,J＝13.6Hz,1H,CH 2 ),4.01(d,J＝13.6Hz,1H,CH 2 ),3.89(s,3H,OCH 3 ),3.16-3.31(m,2H,CH 2 ),3.00(t,J＝6.0Hz,2H,CH 2 ),2.78-2.87(m,3H,CH+CH 2 ),2.29(s,3H,Pyrazolyl-CH 3 ),2.06-2.17(m,4H,CH 2 +CH 2 ),1.69-1.75(m,2H,CH 2 ).
Example 39: synthesis of tert-butyl 4- (4-oxo-4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidine-1-carboxylate 15
Adding Boc-4-piperidine thiocarboxamide 3 (1.00g, 4.09mmol) into 20mL of tert-butanol solvent, stirring at room temperature, adding 3-bromo-1, 2-diketocyclohexane 14 (0.86g, 4.50mmol), stirring at room temperature for 15min, heating to 85 ℃, heating and refluxing for 5h, monitoring by TLC until the reaction is completed, cooling the reaction solution, filtering, desolventizing, adding 20mL of di-tert-butyl alcoholThe chloromethane was redissolved, 15mL of water was added to wash the organic layer, 15ml of saturated sodium bicarbonate was added to wash the organic layer, 15mL of water was added to wash the organic layer, the organic layer was dried over anhydrous magnesium sulfate, filtered, desolventized, and column chromatographed at normal pressure to give a yellow oily solid 0.64g, with a yield of 46.5%. 1 H NMR(400MHz,CDCl 3 )δ4.20(s,2H,CH 2 ),3.14-3.21(m,1H,CH),3.08(t,J＝6.2Hz,2H,CH 2 ),2.84(t,J＝13.6Hz,2H,CH 2 ),2.66(t,J＝6.6Hz,2H,CH 2 ),2.22-2.28(m,2H,CH 2 ),2.06-2.10(m,2H,CH 2 ),1.67-1.77(m,2H,CH 2 ),1.47(s,9H,t-Bu-H).
Example 40: synthesis of 2- (piperidin-4-yl) -6, 7-dihydrobenzo [ d ] thiazol-4 (5H) -one 16
Taking 4- (4-oxo-4, 5,6, 7-tetrahydrobenzo [ d ]]T-butyl thiazol-2-yl) piperidine-1-carboxylate 15 (7.62g, 22.67mmol), 75mL of 10% hydrochloric acid solution and 75mL of dichloromethane were added, the reaction solution was heated to 40 ℃, heated under reflux for 10h, tlc monitoring was performed until the reaction was completed, the reaction solution was cooled, sodium carbonate was added, pH = 9-10 was adjusted, the organic layer was separated, 60ml of 4 dichloromethane was added to the aqueous layer for extraction, the extracts were combined, dried over anhydrous magnesium sulfate, filtered, and desolventized to give 1.46g of yellow oil, with a yield of 53.3%. 1 H NMR(400MHz,CDCl 3 )δ3.17-3.19(m,1H,CH),3.12-3.16(m,2H,CH 2 ),3.06(t,J＝6.2Hz,2H,CH 2 ),2.68-2.75(m,2H,CH 2 ),2.63(t,J＝6.6Hz,2H,CH 2 ),2.19-2.26(m,2H,CH 2 ),2.08-2.11(m,2H,CH 2 ),2.05-2.07(m,1H,NH),1.64-1.74(m,2H,CH 2 ).
Example 41: synthesis of 2- (1- (2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) acetyl) piperidin-4-yl) -6, 7-dihydrobenzo [ d ] thiazole-4 (5H) -118
In an ice-water bath, 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) acetic acid 17 (2.56g, 12.32mmol) was dissolved in 25mL of tetrahydrofuran, N' -Carbonyldiimidazole (CDI) (2.20g, 13.55mmol) was added thereto, the mixture was stirred at room temperature for 1 hour, triethylamine (1.87g, 18.48mmol) and 4-Dimethylaminopyridine (DMAP) (0.32g, 2.62mmol) were further added thereto, and then 2- (piperidin-4-yl) -6, 7-dihydrobenzo [ d ] was added thereto]Thiazol-4 (5H) -one 16 (3.20g, 13.55mmol) was dissolved in 25mL of THF, and slowly droppedAdding the reaction solution, reacting at room temperature for 10h, monitoring by TLC until the reaction is completed, adjusting the pH of the reaction solution to be =1 by dropwise adding dilute hydrochloric acid, adding 40mL of 3 ethyl acetate to extract an organic layer, combining, drying extract by anhydrous magnesium sulfate, filtering and desolventizing to obtain 3.89g of light yellow solid, wherein the yield is 74.1%, and the melting point is: 145-147 ℃. 1 H NMR(400MHz,CDCl 3 )δ6.33(s,1H,Pyrazolyl-H),4.98(d,J＝6.4Hz,2H,CH 2 ),4.58(d,J＝13.6Hz,1H,CH 2 ),3.22-3.33(m,2H,CH 2 ),3.09(t,J＝6.2Hz,2H,CH 2 ),2.79-2.86(m,1H,CH),2.65(t,J＝6.4Hz,2H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.22-2.28(m,2H,CH 2 ),2.12-2.19(m,2H,CH 2 ),1.68-1.84(m,2H,CH 2 ).
Example 42: synthesis of 1- (4- (4- (hydroxyimino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 19
Reacting 2- (1- (2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) acetyl) piperidin-4-yl) -6, 7-dihydrobenzo [ d ]]Thiazole-4 (5H) -118 (0.6 g, 1.41mmol) was added to 15mL of anhydrous methanol, then hydroxylamine hydrochloride (0.15g, 2.11mmol) and potassium carbonate (0.29g, 2.11mmol) were added, respectively, the temperature was raised to 65 ℃, reflux stirring was carried out for 10h, TLC was monitored until the reaction was completed, the temperature was reduced, filtration and desolventization were carried out to obtain a yellow solid, 15mL of dichloromethane was redissolved, 10mL of x 3 water was added to wash the organic layer, the organic layer was dried over anhydrous magnesium sulfate, filtration, desolventization and normal pressure column chromatography were carried out to obtain 0.42g of a white solid, the yield was 67.7%, the melting point: 116-118 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.71(s,1H,NOH),6.31(s,1H,Pyrazolyl-H),4.99(s,2H,CH 2 ),4.54(d,J＝13.8Hz,1H,CH 2 ),3.21-3.29(m,2H,CH 2 ),2.79-2.88(m,5H,CH 2 +CH+CH 2 ),2.29(s,3H,Pyrazolyl-CH 3 ),2.11-1.20(m,2H,CH 2 ),1.96-2.02(m,2H,CH 2 ),1.68-1.81(m,2H,CH 2 ).
Example 43: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (4- ((((2-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 21a
At low temperature, sodium hydride (0.0)6g, 1.50mmol) was added to 15mL of anhydrous N, N-Dimethylformamide (DMF) reaction solvent, and after stirring, 1- (4- (4- (hydroxyimino) -4,5,6, 7-tetrahydrobenzo [ d ] was added]Thiazole-2-yl) piperidine-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazole-1-yl) ethane-1-ketone 19 (0.60g, 1.36mmol), stirring for 1H, then slowly dropwise adding 2-methylbenzyl bromide 20a (0.26g, 1.43mmol), dripping for 5min, stirring for 2H at room temperature after finishing dripping, monitoring by TLC until the reaction is finished, dropwise adding a small amount of saturated aqueous ammonium chloride solution to quench the reaction until the reaction solution has no bubbles, then adding 50mL of water into the reaction solution, extracting with 30mL of ethyl acetate of 3, combining the extracts, backwashing with 30mL of 3 of water, drying the organic layer by anhydrous magnesium sulfate, filtering, desolventizing, and performing normal-pressure column chromatography to obtain a white solid with the yield of 0.6 g: 80.9%, melting point: 150-152 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.36-7.38(m,1H,Ar-H),7.16-7.24(q,J＝21.2,3H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.32(s,2H,CH 2 ),4.98(m,2H,CH 2 ),4.64(d,J＝13.6Hz,1H,CH 2 ),4.02(d,J＝14.0Hz,1H,CH 2 ),3.34-3.42(m,1H,CH),3.19-3.26(m,1H,CH 2 ),2.86(t,J＝6.0Hz,2H,CH 2 ),2.81(t,J＝6.4Hz,2H,CH 2 ),2.72-2.76(m,1H,CH 2 ),2.37(s,3H,Ar-CH 3 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.14-2.24(m,2H,CH 2 ),1.93-1.20(m,2H,CH 2 ),1.63-1.77(m,2H,CH 2 ).
By following the procedure of example 43, compounds 21b to 21j were each prepared by selecting appropriate starting materials and reagents. It is understood that one skilled in the art can select appropriate starting materials and reagents according to the needs of the examples.
Example 44: synthesis of 1- (4- (4- ((((2-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 21b
White solid, melting point: 159-161 ℃, yield: 77.6 percent. 1 H NMR(400MHz,CDCl 3 )δ7.42-7.46(m,1H,Ar-H),7.25-7.30(m,1H,Ar-H),7.10-7.14(m,1H,Ar-H),7.01-7.06(m,1H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.36(s,1H,CH),4.98(q,J＝20.4Hz,2H,CH 2 ),4.64(d,J＝13.6Hz,1H,CH 2 ),4.02(d,J＝13.6Hz,1H,CH 2 ),3.34-3.40(m,1H,CH),3.23(t,J＝11.8Hz,1H,CH 2 ),2.81-2.88(m,4H,CH 2 +CH 2 ),2.74-2.76(m,1H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.14-2.24(m,2H,CH 2 ),1.94-2.01(m,2H,CH 2 ),1.63-1.76(m,2H,CH 2 ).
Example 45: synthesis of 1- (4- (4- ((((2-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 21c
White solid, melting point: 168-170 ℃ and yield: 70.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.44-7.47(m,1H,Ar-H),7.34-7.36(m,1H,Ar-H),7.21-7.25(m,2H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.41(s,1H,CH),4.97(q,J＝22.0Hz,2H,CH 2 ),4.63(d,J＝13.6Hz,1H,CH 2 ),4.00(d,J＝13.6Hz,1H,CH 2 ),3.32-3.40(m,1H,CH),3.21(t,J＝11.6Hz,1H,CH 2 ),2.85-2.88(m,4H,CH 2 +CH 2 ),2.72-2.78(m,1H,CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.12-2.22(m,2H,CH 2 ),1.96-2.02(m,2H,CH 2 ),1.61-1.74(m,2H,CH 2 ).
Example 46: synthesis of 1- (4- (4- ((((2-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 21d
White solid, melting point: 156-158 ℃, yield: 74.5 percent. 1 H NMR(400MHz,CDCl 3 )δ7.54-7.56(m,1H,Ar-H),7.44-7.46(m,1H,Ar-H),7.28-7.32(m,1H,Ar-H),7.13-7.17(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.38(s,2H,CH 2 ),4.91-5.05(m,2H,CH 2 ),4.64(d,J＝13.8Hz,1H,CH 2 ),4.03(d,J＝14.0Hz,1H,CH 2 ),3.34-3.41(m,1H,CH),3.22(t,J＝13.0Hz,1H,CH 2 ),2.88(t,J＝6.4Hz,4H,CH 2 +CH 2 ),2.76(t,J＝12.8Hz,1H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.13-2.23(m,2H,CH 2 ),1.97-2.03(m,2H,CH 2 ),1.66-1.75(m,2H,CH 2 ).
Example 47: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (4- ((((3-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one 21e
Yellow oil, yield: 73.6 percent. 1 H NMR(400MHz,CDCl 3 )δ7.20-7.25(m,3H,Ar-H),7.11-7.14(m,1H,Ar-H),6.34(s,1H,Pyrazolyl-H),5.27(s,2H,CH 2 ),4.92-5.05(m,2H,CH 2 ),4.64(d,J＝13.4Hz,1H,CH 2 ),3.34-3.42(m,1H,CH),3.20-3.27(m,1H,CH 2 ),2.81-2.88(m,4H,CH 2 +CH 2 ),2.73-2.80(m,1H,CH 2 ),2.36(s,3H,Ar-CH 3 ),2.32(s,3H,Pyrazolyl-CH 3 ),2.14-2.24(m,2H,CH 2 ),1.94-2.01(m,2H,CH 2 ),1.67-1.73(m,2H,CH 2 ).
Example 48: synthesis of 1- (4- (4- ((((3-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 21f
Yellow oil, yield: 65.5 percent. 1 H NMR(400MHz,CDCl 3 )δ7.39-7.40(m,1H,Ar-H),7.27-7.28(m,3H,Ar-H),6.34(s,1H,Pyrazolyl-H),5.28(s,2H,CH 2 ),4.92-5.05(m,2H,CH 2 ),4.64(d,J＝13.2Hz,1H,CH 2 ),4.04(d,J＝13.6Hz,1H,CH 2 ),3.33-3.41(m,1H,CH),3.20-3.27(m,1H,CH 2 ),2.82-2.90(m,4H,CH 2 +CH 2 ),2.73-2.81(m,1H,CH 2 ),2.32(s,3H,Pyrazolyl-CH 3 ),2.14-2.24(m,2H,CH 2 ),1.96-2.03(m,2H,CH 2 ),1.63-1.76(m,2H,CH 2 ).
Example 49: synthesis of 1- (4- (4- ((((3-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 21g
Yellow oil, yield: 68.7 percent. 1 H NMR(400MHz,CDCl 3 )δ7.53(s,1H,Ar-H),7.41(d,J＝8.0Hz,1H,Ar-H),7.30(d,J＝7.6Hz,1H,Ar-H),7.21(t,J＝7.8,1H,Ar-H),6.32(s,1H,Pyrazolyl-H),5.25(s,2H,CH 2 ),4.90-5.03(m,2H,CH 2 ),4.62(d,J＝13.2Hz,1H,CH 2 ),4.01(d,J＝14.4Hz,1H,CH 2 ),3.31-3.39(m,1H,CH),3.22(t,J＝12.8Hz,1H,CH 2 ),2.80-2.88(m,4H,CH 2 +CH 2 ),2.75(t,J＝11.6Hz,1H,CH 2 ),2.30(s,3H,Pyrazolyl-CH 3 ),2.12-2.22(m,2H,CH 2 ),1.94-2.01(m,2H,CH 2 ),1.63-1.74(m,2H,CH 2 ).
Example 50: synthesis of 2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (4- ((((4-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one for 21H
Brown solid, melting point: 117-119 ℃, yield: 97.1 percent. 1 H NMR(400MHz,CDCl 3 )δ7.30(d,J＝7.6Hz,2H,Ar-H),7.16(d,J＝7.6Hz,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.25(s,2H,CH 2 ),4.91-5.04(m,2H,CH 2 ),4.63(d,J＝13.6Hz,1H,CH 2 ),4.01(d,J＝13.6Hz,1H,CH 2 ),3.33-3.40(m,1H,CH),3.19-3.26(m,1H,CH 2 ),2.85(t,J＝6.2Hz,2H,CH 2 ),2.80(t,J＝6.6Hz,2H,CH 2 ),2.73-2.76(m,1H,CH 2 ),2.34(s,3H,CH 3 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.13-2.23(m,2H,CH 2 ),1.92-1.98(m,2H,CH 2 ),1.62-1.75(m,2H,CH 2 ).
Example 51: synthesis of 1- (4- (4- ((((4-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 21i
White solid, melting point: 143-145 ℃, yield: 65.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.47(d,J＝8.4Hz,2H,Ar-H),7.27(d,J＝6.4Hz,2H,Ar-H),6.33(s,1H,Pyrazolyl-H),5.24(s,2H,CH 2 ),4.91-5.05(m,2H,CH 2 ),4.63(d,J＝13.6Hz,1H,CH 2 ),4.02(d,J＝13.6Hz,1H,CH 2 ),3.32-3.40(m,1H,CH),3.19-3.26(m,1H,CH 2 ),2.86(t,J＝6.2Hz,2H,CH 2 ),2.80(t,J＝6.4Hz,2H,CH 2 ),2.72-2.75(m,1H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.13-2.22(m,2H,CH 2 ),1.94-2.00(m,2H,CH 2 ),1.62-1.75(m,2H,CH 2 ).
Example 52: synthesis of 1- (4- (4- ((((2, 6-dimethylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 21j
White solid, melting point: 89-91 ℃, yield: 33.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.12-7.16(m,1H,Ar-H),7.04-7.06(m,2H,Ar-H),6.34(s,1H,Pyrazolyl-H),5.36(s,2H,CH 2 ),4.92-5.06(m,2H,CH 2 ),4.64(d,J＝13.2Hz,1H,CH 2 ),4.03(d,J＝13.6Hz,1H,CH 2 ),3.35-3.43(m,1H,CH),3.21-3.27(m,1H,CH 2 ),2.85(t,J＝6.0Hz,2H,CH 2 ),2.78-2.81(m,1H,CH 2 ),2.74(t,J＝6.4Hz,2H,CH 2 ),2.43(s,6H,CH 3 +CH 3 ),2.32(s,3H,Pyrazolyl-CH 3 ),2.16-2.25(m,2H,CH 2 ),1.90-1.97(m,2H,CH 2 ),1.64-1.77(m,2H,CH 2 ).
Example 53: synthesis of 1- (4- (4- ((((2-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one 23a
Sodium hydride (0.10 g, 2.49mmol) was added to 20mL of anhydrous N, N-Dimethylformamide (DMF) reaction solvent at low temperature, and after stirring, 1- (4- (4- (hydroxyimino) -4,5,6, 7-tetrahydrobenzo [ d ] was added]Thiazole-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethane-1-one 19 (1.00g, 2.27mmol), stirring for 1H, then slowly adding o-fluorobenzoyl chloride 22a (0.38g, 2.38mmol) dropwise, stirring for 5min, raising the temperature to room temperature after finishing dropping, monitoring by tlc (thin layer chromatography) until the reaction is finished, adding a small amount of saturated aqueous ammonium chloride solution dropwise to quench the reaction until the reaction solution has no bubbles, then adding 75mL of water to the reaction solution, extracting with 50ml of ethyl acetate of 3, combining the extracts, backwashing with 70ml of 3 water, drying the organic layer of anhydrous magnesium sulfate, filtering, desolventizing, and performing normal-pressure column chromatography to obtain 0.81g of a white solid, a melting point: 109-111 ℃, yield: and (4) 63.4%. 1 H NMR(400MHz,CDCl 3 )δ8.02-8.06(m,1H,Ar-H),7.54-7.59(m,1H,Ar-H),7.24-7.28(m,1H,Ar-H),7.15-7.19(m,1H,Ar-H),6.33(s,1H,Pyrazolyl-H),4.96-5.05(m,2H,CH 2 ),4.60(d,J＝13.6Hz,1H,CH 2 ),4.03(d,J＝14.0Hz,1H,CH 2 ),3.32-3.36(m,1H,CH),3.24-3.30(m,1H,CH 2 ),3.02(t,J＝6.4Hz,2H,CH 2 ),2.96(t,J＝6.2Hz,2H,CH 2 ),2.80-2.87(m,1H,CH 2 ),2.31(s,3H,Pyrazolyl-CH 3 ),2.15-2.27(m,2H,CH 2 ),2.05-2.11(m,2H,CH 2 ),1.68-1.86(m,2H,CH 2 ).
Example 54: activity test Experimental example
In vitro plate method for determining bactericidal activity
The tested germs are inoculated into a bacterium-forming tablet containing 50 mu g mL -1 Placing the liquid medicine into a culture dish of the liquid medicine, placing the liquid medicine into a biochemical incubator at 25 ℃ for dark culture, and investigating the antibacterial effect after 3 days. Each treatment was repeated 5 times. The control was sterile water alone without drug.
Figure BDA0002588790490000261
TABLE 1 in vitro fungicidal Activity of Phytophthora capsici of the general formula Compound (I) (inhibition ratio 100%)
Figure BDA0002588790490000262
Figure BDA0002588790490000271
"-": activity not tested
The screening concentration of the compound with better activity in the general formula compound (I) is reduced, and the in vitro bactericidal activity screening of phytophthora capsici is further carried out.
Table 2 partial compounds show in vitro bactericidal activity against Phytophthora capsici at lower concentrations (inhibition rate 100%)
Figure BDA0002588790490000281
"-": activity not tested

Claims (5)

1. A compound having the following general formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003928369170000011
wherein X and Y are N and S respectively;
z is CH 2 ，CO，CHCH 3 ；
R is optionally 1-5 substituents selected from hydrogen, hydroxy, cyano, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, halo C 2-6 Alkenyl, halo C 2-6 Alkynyl, benzyloxy, phenyl, said benzyloxy and phenyl ring optionally substituted with 1-5 hydrogens selected from halogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, halo C 2-6 Alkenyl, halo C 2-6 And substituent of alkynyl.
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein:
z is preferably CH 2 ；
R is preferably hydrogen, methyl, halogen, methoxy or trifluoromethyl.
3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, selected from:
1- (4- (7- ((benzoyloxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((2-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (7- ((((2-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- (((2-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((2-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((3-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (7- ((((3-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((3-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((3-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((4-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (7- ((((4-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((4-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((4-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((3-bromo-2-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((2-chloro-6-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((2-bromo-5-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((2, 6-dichlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((2, 6-dimethylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((2, 6-difluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((benzyloxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((2-methylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (7- ((((2-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((3-methylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (7- ((((3-chlorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((3-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((3-bromobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((4-methylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (7- ((((4-chlorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((4-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (7- ((((4-bromobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (7- ((((4-trifluoromethylbenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (7- ((((2-methoxybenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (4- ((((2-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (4- ((((2-fluorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (4- ((((2-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (4- ((((2-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (4- ((((3-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (4- ((((3-chlorobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (4- ((((3-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) -1- (4- (4- ((((4-methylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) ethan-1-one
1- (4- (4- ((((4-bromobenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (4- ((((2, 6-dimethylbenzyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one
1- (4- (4- ((((2-fluorobenzoyl) oxy) imino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) piperidin-1-yl) -2- (5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl) ethan-1-one.
4. A pesticidal composition comprising a compound of any one of claims 1-3 and pharmaceutically acceptable salts thereof and a carrier.
5. The use of a compound according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof as fungicides for the control of oomycetes diseases in plants.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101970432A (en) * 2008-01-25 2011-02-09 杜邦公司 Fungicidal hetercyclic compounds
CN102227423A (en) * 2008-12-02 2011-10-26 纳幕尔杜邦公司 Fungicidal heterocyclic compounds
WO2013191866A1 (en) * 2012-06-22 2013-12-27 E. I. Du Pont De Nemours And Company Fungicidal heterocyclic compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101970432A (en) * 2008-01-25 2011-02-09 杜邦公司 Fungicidal hetercyclic compounds
CN102227423A (en) * 2008-12-02 2011-10-26 纳幕尔杜邦公司 Fungicidal heterocyclic compounds
WO2013191866A1 (en) * 2012-06-22 2013-12-27 E. I. Du Pont De Nemours And Company Fungicidal heterocyclic compounds

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