CN114075187A - Carbonyl pyrazole anti-tumor compound and preparation method and application thereof - Google Patents

Carbonyl pyrazole anti-tumor compound and preparation method and application thereof Download PDF

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CN114075187A
CN114075187A CN202011039501.2A CN202011039501A CN114075187A CN 114075187 A CN114075187 A CN 114075187A CN 202011039501 A CN202011039501 A CN 202011039501A CN 114075187 A CN114075187 A CN 114075187A
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thiazol
phenyl
dihydro
conoh
oxo
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CN114075187B (en
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方浩
梁涛
杨新颖
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Shandong University
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract

The invention relates to carbonyl pyrazole antitumor compounds, a preparation method and application thereof, wherein the compounds have a structure shown in a general formula I, have better activity of resisting tumor cell proliferation, can be used for preparing medicaments for preventing or treating cancers, and also relates to pharmaceutical application of a composition of the compounds with the structure shown in the general formula I.

Description

Carbonyl pyrazole anti-tumor compound and preparation method and application thereof
Technical Field
The invention relates to a carbonyl pyrazole antitumor compound, a preparation method thereof, a pharmaceutical composition and medical application, and belongs to the technical field of medicines.
Background
The carbonyl pyrazole compound has various biological activities, is widely applied to various fields of antibiosis, antivirus, malaria resistance and the like, and achieves good effects.
In 2012, Evripidis et al discovered a carbonyl pyrazole compound BAM7 through virtual screening and other means, wherein the compound can induce the Bax allosteric activation of a pro-apoptotic protein of a Bcl-2 family, and initiate a mitochondria-mediated endogenous apoptosis pathway, thereby inducing apoptosis. Considering the poor affinity of BAM7 for Bax protein (IC)503.3 mu M), and the compound takes BAM7 as a lead compound, and the structure of the compound is modified and reformed to obtain carbonyl pyrazole derivative BTSA1 with higher activity. BTSA1 has 13-fold higher affinity for Bax protein than BAM7, and is the most active Bax agonist so far. In subsequent biological activity evaluation, the BTSA1 can effectively kill blood tumor cells without damaging normal cells, but the inhibitory activity of BTSA1 on solid tumor cells still has a larger promotion space. According to the invention, BTSA1 is used as a lead compound, carbonyl pyrazole is used as a mother nucleus, and a series of carbonyl pyrazole antitumor compounds with novel structures are discovered through multiple rounds of structural modification and reformation. In subsequent biological activity evaluation, the carbonyl pyrazole compounds show high solid tumor inhibition activity, and are expected to be developed into novel high-efficiency low-toxicity antitumor drugs.
Disclosure of Invention
The invention provides a carbonyl pyrazole antitumor compound, and a preparation method and application thereof.
The invention further provides a pharmaceutical composition and medical application of the compound.
The technical scheme of the invention is as follows:
carbonyl pyrazole anti-tumor compound
A carbonyl pyrazole antitumor compound is a compound with a structure shown as a general formula I, and a stereoisomer and pharmaceutically acceptable salt thereof;
Figure BDA0002706199010000011
in the general formula I, R1Represents alkyl, alkoxy, cycloalkyl, C, substituted or unsubstituted by 1 to 3 substituents5-C15Aryl radical, C6-C15Aryl radical C1-C6Alkyl radical, C3-C14Heteroaryl group, C3-C14Heteroaryl C1-C6Alkyl, the substituent is selected from hydroxyl, cyano, nitro, halogen and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C8Cycloalkyl, said heteroatoms being independently selected from O, S, N or oxidized S or N;
in the general formula I, R2Represents hydrogen or C which is substituted or unsubstituted by 1 to 3 substituents1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C14Cycloalkyl radical, C6-C15Aryl radical, C6-C15Aryl radical C1-C6Alkyl radical, C3-C14Heteroaryl group, C3-C14Heteroaryl C1-C6Alkyl, said substituents selected from hydroxy, halogen, alkyl, haloalkyl, cyano, nitro, guanidino, amino, carboxy, said heteroatoms independently selected from O, S, N or oxidized S or N;
z represents hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nl,n2And n3 represents an integer of 0 to 10;
x represents a nitrogen atom, an oxygen atom, an amide;
ar represents C substituted or unsubstituted with 1 to 3 substituents5-C7Aryl radical, C5-C7Aryl radical C1-C5Alkyl radical, C5-C7Aryl radical C2-C5Alkenyl radical, C3-C6Heteroaryl group, C3-C6Heteroaryl C1-C5Alkyl radical, C3-C6Heteroaryl C2-C5Alkenyl, said substituent being selected from C1-C6Haloalkyl, C1-C6Alkoxy, haloalkyl, halogen, hydroxy, nitro, cyano, C3-C8Cycloalkyl, aryl, heteroaryl.
Preferred according to the invention are those of the formula I:
R1is C substituted or unsubstituted by 1 to 3 substituents3-C8Cycloalkyl, monocyclic aryl having 5 or 6 ring atoms or bicyclic aryl having 8 to 15 ring atoms, monocyclic 5 or 6 ring atoms containing 1 to 2 heteroatoms, or bicyclic 8 to 15 ring atoms containing 1 to 4 heteroatoms, said substituents being selected from hydroxy, cyano, nitro, halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy, said heteroatoms being independently selected from O, S, N or oxidized S or N;
R2is hydrogen, C substituted or unsubstituted by 1 to 3 substituents1-C12Alkyl radical, C3-C14Cycloalkyl radical, C6-C10Aryl radical, C6-C10Aryl radical C1-C6Alkyl radical, C3-C9Heteroaryl group, C3-C9Heteroaryl C1-C6Alkyl, said substituent being selected from cyano, halogen, nitro, carboxy, methyl, trifluoromethyl, guanidino or amino;
z represents hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nl,n2And n3 represents an integer of 0 to 8;
x represents a nitrogen atom or an oxygen atom;
ar represents C substituted or unsubstituted with 1 to 3 substituents6-C7Aryl radical, C6-C7Aryl radical C1-C3Alkyl radical, C6-C7Aryl radical C2-C3Alkenyl radical, C3-C6Heteroaryl group, C3-C6Heteroaryl C1-C3Alkyl radical, C3-C6Heteroaryl C2-C3Alkenyl, said substituent being selected from C1-C6Alkyl, trifluoromethyl, halogen, hydroxy, nitro, cyano.
According to a further preferred embodiment of the invention, in formula I:
R1represents C5-C6Cycloalkyl, thiazolyl or substituted phenyl;
R2represents C1-C6Alkyl radical, C3-C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, said substituents being selected from cyano, halogen, nitro, carboxy, methyl, trifluoromethyl, guanidino or amino;
z represents hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nlRepresents an integer of 3 to 8, n2Represents an integer of 0 to 2, and n3 represents an integer of 0 to 3;
x represents a nitrogen atom or an oxygen atom;
ar represents phenyl, pyridazinyl, pyrazinyl, pyridyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, thienyl, oxazolyl, substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxy, nitro, cyano.
According to the invention, it is still further preferred, in formula I:
R1represents thiazole;
R2a phenyl group;
z hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nlRepresents an integer of 3 to 8;
n2is 1;
n3is 0 or 2;
x represents a nitrogen atom;
ar represents a benzene ring.
The compound of the above formula I, most preferably one of the following:
(Z) -N-hydroxy-4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (4)
(Z) -N- (5- (hydroxyamino) -5-oxopentyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (20)
(Z) -N- (6- (hydroxyamino) -6-oxohexyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (21)
(Z) -N- (7- (hydroxyamino) -7-oxoheptyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (22)
(Z) -N-hydroxy-4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamido) methylbenzamide (23)
N- (4- ((E) -3- (hydroxyamino) -3-oxoprop-1-en-1-yl) benzyl) -4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazinoylidene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (24)
(Z) -N-hydroxy-4- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) alkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) butanamide (46)
(Z) -N-hydroxy-5- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) alkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) pentanamide (47)
(Z) -N-hydroxy-6- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) hexanamide (48)
(Z) -N-hydroxy-7- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) heptanamide (49)
(Z) -N-hydroxy-8- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) octanamide (50)
(Z) -N-hydroxy-4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) methyl) benzamide (51)
(E) -N-hydroxy-3- (4- ((4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4], 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) methyl) phenyl) acrylamide (52)
The above compounds are preferred, and the following numbers in parentheses are numbers corresponding to the structures of the compounds in the following schemes and table 1.
Detailed Description
The terms and definitions used herein have the following meanings:
the halogen atom in the invention comprises fluorine atom, chlorine atom, bromine atom and iodine atom;
said "C" of the present invention1-10The alkyl group "means a straight-chain or branched alkyl group derived by removing one hydrogen atom from an alkane moiety having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, nonyl and decyl. Preferably C1-6Alkyl, more preferably C1-4Alkyl radical, the term "C1-6Alkyl group "," C1-4 alkyl group "means a specific example of the above examples containing 1 to 6, 1 to 4 carbon atoms;
"C" according to the invention3-8The cycloalkyl group refers to a cyclic alkyl group derived from an alkane moiety of 3 to 8 carbon atoms by removing one hydrogen atom, such as cyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably C4-7Cycloalkyl radical, C4-6Cycloalkyl and C5-6A cycloalkyl group;
examples of such "mono-heterocyclic" are: oxiranyl, dioxiranepropyl, thietanyl, aziridinyl, 2H-aziridinyl, diazacyclopropyl, 3H-diazacyclopropenyl, oxazetank, oxetanyl, 1, 2-dioxetane, thietanyl, 1, 2-dithiocyclobutenyl, azetidinyl, 1, 2-diazacyclobutyl, azetidinyl, 1, 2-diazacyclobutenyl, furyl, tetrahydrofuryl, thienyl, 2, 5-dihydrothienyl, tetrahydrothienyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, 1, 3-dioxolanyl, 1, 3-dioxol-2-onyl, 1, 2-dithiolyl, 1, 3-dithiolanyl, Imidazolyl, 4, 5-dihydroimidazolyl, imidazolidinyl, pyrazolyl, 4, 5-dihydropyrazolyl, pyrazolidinyl, oxazolyl, 4, 5-dihydrooxazolyl, isoxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, thiazolyl, 4, 5-dihydrothiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, tetrazolyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl, 4H-pyranyl, Tetrahydropyranyl, 4H-pyran-4-keto, pyridinyl, 2-pyridonyl, 4-pyridonyl, piperidinyl, 1, 4-dioxadienyl, 1, 4-dithiadienyl, 1, 4-oxacyclohexadienyl, 1, 4-dioxanyl, 1, 3-oxathianyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 2H-1, 4-oxazinyl, 4H-1, 4-oxazinyl, 5, 6-dihydro-4H-1, 3-oxazinyl, morpholinyl, 2H-1, 3-thiazinyl, 4H-1, 3-thiazinyl, 5, 6-dihydro-4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-1, 4-thiazinyl, 4H-1, 4-thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, oxepitrienyl, thiepintrienyl, 1, 4-dioxacyclooctatrienyl, azepintrienyl, 1, 2-diazacycloheptatrienyl, 1, 3-diazacyclotrienyl-trienyl, 1, 3-diazacyclo-trienyl, 1, 4-diazepanyl, azocyclotetraenyl, 1, 4-dihydro-1, 4-diazacyclooctenyl, and the like;
"aryl" means an aromatic ring-containing substituent, such as phenyl or benzyl, optionally fused with a cycloalkyl group, preferably having 4 to 7 ring atoms, more preferably having 5 to 6 ring atoms. Preferred aryl groups contain 5 to 15 carbon atoms;
"heteroaryl" is an aromatic heterocycle, which may be a monocyclic or bicyclic group. They contain an aromatic hetero group containing one or more heteroatoms, preferably 1 to 3 heteroatoms, even more preferably 1 to 2 heteroatoms, independently selected from O, S and N. "arylalkyl" means C1-C4An alkylene-linked aryl group;
"arylalkyl" means C1-C4An alkylene-linked aryl group;
"arylalkyl" means C1-C4An alkylene-linked heteroaryl;
"alkenyl", alone or in combination, is herein defined as a straight or branched chain hydrocarbon containing from 2 to 6, preferably from 2 to 4, carbon atoms; and contains 1-2 carbon-carbon double bonds, preferably 1 carbon-carbon double bond;
"alkoxy" represents the group-O-alkyl;
the integer of 0-8 in the invention refers to 0, 1,2,3, 4,5, 6, 7 and 8;
the compound shown in the general formula I can be prepared into pharmaceutically acceptable salts by a known method, wherein the salts are prepared by mixing the compound shown in the general formula I with acid or alkali;
suitable acid addition salts are formed from acids which form non-toxic salts. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, bicarbonate, butyrate, camphorate, camphorsulfonate, carbonate, citrate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malate, malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, pectate (pectate), persulfate, 3-phenylpropionate, propionate, and mixtures thereof, Picrate (picrate), pivalate), propionate, sucrose, stearate, succinate, sulfate, tartrate, thiocyanate, phosphate, hydrogen phosphate, dihydrogen phosphate, p-toluenesulfonate, trifluoroacetate and undecanoate;
base addition salts can be prepared in situ during the final isolation and purification of the compounds by reacting the carboxylic acid containing moiety with an appropriate base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali or alkaline earth metals, such as, but not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like, as well as non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like;
"stereoisomers" as used herein refers to all possible stereoisomeric forms of the compounds of the present invention or of the physiologically antitumor compounds thereof. Unless otherwise indicated, the chemical designation of compounds referred to in this invention includes mixtures of all possible stereochemical forms, including all enantiomers and diastereomers of the basic structural molecule, as well as the substantially pure individual isomeric forms of the compounds, i.e., containing less than 10%, preferably less than 5%, particularly less than 2%, and most preferably less than 1% of the other isomers. Various stereoisomeric forms of the peptoid compounds of the present invention are expressly included within the scope of the present invention;
the compounds of formula I can also exist in other protected forms or in the form of antitumor compounds, which forms are obvious to the person skilled in the art and are intended to be included within the scope of the present invention;
the substituents described above may themselves be substituted by one or more substituents. Such substituents include those listed in c.hansch and a.leo, scientific Constants for Correlation Analysis in Chemistry and Biology (1979); preferred substituents include alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, aminoalkyl, cyano, halogen, carboxy, thio, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof;
the compounds of the present invention can be prepared into any pharmaceutical preparation by methods known in the art, and administered to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration, and when used for oral administration, the compounds can be prepared into conventional solid preparations such as tablets, capsules, pills, granules, etc., and also can be prepared into oral liquid preparations such as oral solutions, oral suspensions, syrups, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray;
the amount and frequency of administration of the compounds of the invention may be adjusted at the discretion of the clinician or pharmacist taking into account factors such as: the age, health and size of the patient, and the severity of the condition being treated. Generally, the total daily dose of the compounds of the present invention will range from about 0.1 to about 2000mg per day, although variations will occur if necessary depending on the purpose of the treatment, the patient and the route of administration. In one embodiment, the dose is from about 1 to about 200 mg/day, administered as a single dose or as 2-4 separate doses. In another embodiment, the dose is from about 10 to about 2000 mg/day, administered as a single dose or as 2-4 separate doses. In another embodiment, the dose is from about 100 to about 2000 mg/day, administered as a single dose or as 2-4 separate doses. In yet another embodiment, the dose is from about 500 to about 2000 mg/day, administered as a single dose or as 2-4 separate doses. When the compound of the present invention, its pharmaceutically acceptable salt, ester or solvate, or prodrug or isomer thereof is used in combination with other therapeutically active substances, they are administered simultaneously, separately or sequentially, and a pharmaceutical composition of single administration form can be prepared. The amount of the other therapeutically active substance used in combination may be based on the amount used clinically and may be appropriately selected depending on the administration subject, the administration route, the disease, the combination, and the like. There is no particular limitation on the administration form of the other therapeutically active substance as long as the compound of the present invention and the other therapeutically active substance are combined at the time of administration.
"pharmaceutical composition (melting point) refers to a preparation containing a therapeutically significant amount of an active agent, which is prepared in a form suitable for administration to a patient. Thus, the preparation does not contain any component or components in such amounts that a properly cautious medical practitioner finds the preparation unsuitable for administration to an ordinary subject. In many cases, such pharmaceutical compositions are sterile preparations.
The specific temperature range of "room temperature" referred to in the present invention is 25-30 ℃.
Preparation method of di-or carbonyl pyrazole antitumor compound
The preparation method of the carbonyl pyrazole antitumor compound comprises the following steps:
scheme 1: 2-aminothiazole reacts with sodium nitrite under the condition of strong acid to generate diazonium salt firstly, then reacts with ethyl benzoylacetate to generate an intermediate 2, the intermediate 2 reacts with 4- (2-bromoacetyl) benzoic acid to prepare an intermediate 3 under the condition of existence of thiosemicarbazide, and then hydroxamic acid group is introduced to obtain a final compound 4;
scheme 2: performing amide condensation on p-acetylbenzoic acid and various amino acid methyl ester hydrochlorides to obtain an intermediate 5-9, performing bromination reaction to obtain an intermediate 10-14, performing multi-step cyclization reaction to obtain a key intermediate 15-19, and finally introducing hydroxamic acid groups to obtain a final product 20-24;
scheme 3: p-hydroxyacetophenone reacts with methyl bromoformate with different structures to obtain an intermediate 25-31, reacts with copper bromide to obtain a bromo-product 32-38, and is subjected to multi-step cyclization reaction to obtain a key intermediate 39-45, and finally, a hydroxamic acid group is introduced to obtain a final product 46-52;
the synthetic route is as follows:
synthesis scheme 1
Figure BDA0002706199010000081
Reaction reagents and reaction conditions: (a) (i) sodium nitrite, concentrated hydrochloric acid, water, 0 ℃,30 min; (ii) sodium acetate, ethyl benzoylacetate and ethanol at 0 ℃ for 1 h; (b) 2-bromoacetophenone or 4- (2-bromoacetyl) benzoic acid, thiosemicarbazide, ethanol, 80 ℃; (c) isobutyl chloroformate, N-methylmorpholine, tetrahydrofuran, hydroxylamine hydrochloride, potassium hydroxide, methanol, rt,6 h;
synthesis scheme 2
Figure BDA0002706199010000082
Reaction reagents and reaction conditions: (a) HATU, DIPEA, dichloromethane, room temperature; (b) copper bromide in a volume ratio of 1:1, ethyl acetate/chloroform, 80 ℃,3 hours; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
synthesis scheme 3
Figure BDA0002706199010000091
Reaction reagents and reaction conditions: (a) potassium carbonate, room temperature; (b) copper bromide, ethyl acetate/chloroform with the volume ratio of 1:1, at 80 ℃ for 3 h; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
the amino acid methyl ester hydrochloride is 5-amino pentanoic acid methyl ester hydrochloride, 6-amino hexanoic acid methyl ester hydrochloride, 7-amino heptanoic acid methyl ester hydrochloride, 8-amino octanoic acid methyl ester hydrochloride, 4-aminomethyl benzoic acid methyl ester hydrochloride, 4-aminomethyl cinnamic acid methyl ester hydrochloride; the methyl bromoformate is 4-methyl bromobutyrate, 5-methyl bromovalerate, 6-methyl bromohexanoate, 7-methyl bromoheptanoate, 8-methyl bromooctanoate, 4-methyl bromomethylbenzoate and 4-methyl bromocinnamate;
the structures of the target compounds in the synthetic routes are shown in table 1 below:
TABLE 1 Structure of target Compounds
Figure BDA0002706199010000092
Figure BDA0002706199010000101
The specific procedures for the compounds are detailed in the examples.
The skilled in the art can modify the above steps to increase the yield, and they can design the synthetic route according to the basic knowledge in the art, such as selecting reactants, reaction solvent, reaction temperature, and can also improve the yield by using various Protecting Groups to avoid side reactions, and these conventional Protecting methods can be found in, for example, T.Green Protecting Groups in Organic Synthesis.
Application of tri-carbonyl pyrazole antitumor compounds
The invention also provides application of the series of compounds in preparation of medicines for preventing or treating cancers.
In addition, the present invention also includes a pharmaceutical composition suitable for oral administration to a mammal comprising a compound of any of the above general formula I, a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.
In addition, the present invention also includes a pharmaceutical composition suitable for parenteral administration to a mammal comprising a compound of any of the above general formula I, a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.
In vitro antitumor cell proliferation activity was tested.
The cellular activity of the compounds was tested using the MTT assay. Inoculating tumor cell suspension (human cervical cancer cell HeLa) to 96-well plate, adding compounds with different concentrations diluted with culture medium into each well, incubating for 48 hr, staining with MTT, incubating for 4 hr, measuring absorbance OD at 490/570nm with enzyme labeling instrument, and calculating inhibition rate and IC50And thereby determining the antiproliferative activity of the compound of interest.
The in vitro Bax protein affinity experiment result shows that all target compounds show better Bax protein affinity, wherein the affinity of the compound 23 to Bax protein is equivalent to that of a positive control drug BTSA 1.
In vitro anti-tumor cell proliferation experiments show that part of target compounds, especially compound 23, show good anti-proliferation activity on HeLa cells, and growth inhibition activity IC of the compound on the HeLa cells50The values were 0.86. mu.M, respectively. Therefore, part of the compounds in the invention have good antitumor cell proliferation activity, have great development prospect and can be used for guiding the discovery of novel antitumor active molecules.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
EXAMPLE 1 (Z) -3-oxo-3-phenyl-2- (2- (thiazol-2-yl) hydrazino) propionic acid ethyl ester (2)
2-aminothiazole solution (8g,80mmol) is dripped into concentrated hydrochloric acid in ice bath with aqueous solution of sodium nicotinate (6.62g,96mmol), and after dripping is finished, reaction is carried out for 20min in ice bath to obtain diazonium salt solution. With ethanol (240)mL) was dissolved in ethyl benzoylacetate (12.30g,64mmol), and an aqueous solution of sodium acetate (38g,460.8mmol) was added and stirred at room temperature for 30 min. And (3) dripping the diazonium salt solution into ethyl benzoylacetate, reacting for 1h in an ice bath, reacting for 1h at room temperature, evaporating to remove ethanol, extracting the water phase for three times by using ethyl acetate, combining organic phases, drying by using anhydrous magnesium sulfate, evaporating to remove a solvent to obtain a crude product, and performing column chromatography to obtain an orange oily liquid, wherein the yield is 54%.1H NMR(400MHz,CDCl3)δ12.80(s,1H),7.96(d,J＝7.7Hz,2H),7.61(t,J＝7.4Hz,2H),7.48(t,J＝7.7Hz,2H),7.39(d,J＝3.6Hz,1H),6.84(d,J＝3.5Hz,1H),4.37(q,J＝7.2Hz,2H),1.32(t,J＝7.1Hz,3H).
(Z) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzoic acid (3)
4- (2-Bromoacetyl) benzoic acid (0.41g,1.66mmol) was dissolved in ethanol (20mL), thiosemicarbazide (0.15g,1.66mmol) was added and the reaction was allowed to react at room temperature for 1h, then intermediate 1(0.5g,1.66mmol) was added and the mixture was refluxed at 80 ℃ for 3h, whereupon a solid precipitated. Cooling to room temperature, washing the solid with glacial ethanol and diethyl ether, and filtering to obtain red solid with yield of 48% and melting point 268-269 ℃.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝7.4Hz,2H),8.14–8.11(m,2H),8.06–8.01(m,3H),7.73(d,J＝4.1Hz,1H),7.60–7.51(m,3H),7.38(d,J＝4.0Hz,1H).13C NMR(101MHz,DMSO-d6)δ179.37,167.55,155.33,153.46,149.60,149.30,138.42,132.15,130.88,130.47,130.41,130.36,130.33,128.99,128.50,126.37,114.52,111.81.HRMS(AP-ESI)m/z,Calcd for C22H14N6O3S2,([M+H]+):475.0642,found:475.0634.
(Z) -N-hydroxy-4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (4)
Compound 3(1.59g,4mmol) was dissolved in DMF and isobutyl chloroformate (0.61mL,4.8mmol) and N-methylmorpholine (0.58mL,5.2mmol) were added dropwise over ice and reacted for 30min to give a mixed anhydride. A freshly prepared hydroxylamine solution (0.53g,16mmol) was added dropwise to the mixed anhydride and reacted at room temperature for 6h. Pouring the reaction solution into water, and performing suction filtration to obtain a crude product. The red solid is obtained by column chromatography, the yield is 45 percent, and the melting point is 194 ℃ and 195 ℃.1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),9.05(s,1H),8.23–7.93(m,5H),7.86(d,J＝8.1Hz,2H),7.72(d,J＝3.9Hz,1H),7.55(q,J＝7.2Hz,3H),7.35(d,J＝3.9Hz,1H).13C NMR(101MHz,DMSO-d6)δ179.76,164.39,155.40,149.41,137.04,133.69,132.33,131.20,130.35,130.26,129.25,128.91,128.51,127.90,126.23,114.76,110.95.HRMS(AP-ESI)m/z,Calcd for C22H15N7O3S2,([M+H]+):490.0751,found:490.0746.
Example 2.5- (4-Acetylbenzamido) pentanoic acid methyl ester (5)
4-Acetylbenzoic acid (1.64g,10mmol) was dissolved in dichloromethane, DIPEA (1.65mL,10mmol) and HATU (4.56g,12mmol) were added, and the mixture was stirred at room temperature for 30 min. Methyl 5-aminopentanoate hydrochloride (2.01g,11mmol) was added and reacted at room temperature for 8h. Washing the reaction solution with 1M HCl, saturated sodium bicarbonate solution and saturated sodium chloride solution, drying with anhydrous sodium sulfate, and performing column chromatography to obtain white solid with yield of 85% and melting point of 89-90 deg.C.1H NMR(400MHz,CDCl3)δ8.01(d,J＝8.1Hz,2H),7.87(d,J＝8.0Hz,2H),6.48(s,1H),3.69(s,3H),3.49(q,J＝6.2Hz,2H),2.64(s,3H),2.40(t,J＝6.7Hz,2H),1.72(qd,J＝14.1,7.0Hz,4H).
6- (4-Acetylbenzamido) hexanoic acid methyl ester (6)
The specific procedure was carried out with reference to the synthesis of Compound 5, yield 67%, melting point 96-98 ℃.1H NMR(400MHz,CDCl3)δ8.00(d,J＝7.9Hz,2H),7.86(d,J＝7.9Hz,2H),6.38(s,1H),3.67(s,3H),3.49(q,J＝6.6Hz,2H),2.64(s,3H),2.34(t,J＝7.3Hz,2H),1.76–1.60(m,4H),1.50–1.34(m,2H).
7- (4-Acetylbenzamido) heptanoic acid methyl ester (7)
The specific operation was carried out with reference to the synthesis of compound 5, yield 96%, melting point 101-.1H NMR(400MHz,DMSO-d6)δ8.62(t,J＝5.1Hz,1H),8.02(d,J＝7.6Hz,2H),7.94(d,J＝8.0Hz,2H),3.57(s,3H),3.26(dd,J＝12.9,6.5Hz,2H),2.62(s,3H),2.30(t,J＝7.3Hz,2H),1.53(s,4H),1.30(s,4H).
4- ((4-Acetylbenzamido) methyl) benzoic acid methyl ester (8)
Gym for doing thingsAs a synthesis of reference compound 5, the yield was 99%, the melting point was 132-.1H NMR(600MHz,CDCl3)δ8.03–7.99(m,4H),7.90(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),6.78(t,J＝6.0Hz,1H),4.72(d,J＝5.9Hz,2H),3.91(s,3H),2.63(s,3H).
(E) -methyl 3- (4- (((4-acetylbenzamido) methyl) phenyl) acrylate (9)
The specific operation was carried out with reference to the synthesis of compound 5, yield 71%, melting point 175-.1H NMR(400MHz,DMSO-d6)δ9.28(t,J＝5.7Hz,1H),8.04(q,J＝8.1Hz,4H),7.70(d,J＝7.8Hz,2H),7.66(d,J＝16.0Hz,1H),7.38(d,J＝7.8Hz,2H),6.63(d,J＝16.0Hz,1H),4.53(d,J＝5.8Hz,2H),3.73(s,3H),2.63(s,3H).
5- (4- (2-Bromoacetyl) benzamido) pentanoic acid methyl ester (10)
Dissolving the intermediate 5(2.3g,8.3mmol) in ethyl acetate/chloroform (1:1,80mL), adding copper bromide (3.71g,16.6mmol), refluxing at 80 deg.C for 3h, vacuum filtering, and performing column chromatography to obtain white solid with yield of 72% and melting point of 82-84 deg.C.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.1Hz,2H),7.90(d,J＝8.1Hz,2H),6.48(s,1H),4.46(s,2H),3.69(s,3H),3.49(q,J＝6.2Hz,2H),2.40(t,J＝6.7Hz,2H),1.80–1.65(m,4H).
Methyl 6- (4- (2-bromoacetyl) benzamido) hexanoate (11)
The specific operation refers to the synthesis of an intermediate 10, the yield is 70 percent, and the melting point is 97-99 ℃.1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.07(d,J＝8.0Hz,2H),7.96(d,J＝7.7Hz,2H),4.98(s,2H),3.57(s,3H),3.26(dd,J＝12.4,6.2Hz,2H),2.31(t,J＝7.3Hz,2H),1.64–1.43(m,4H),1.38–1.26(m,2H).
7- (4- (2-Bromoacetyl) benzamido) heptanoic acid methyl ester (12)
The specific operation refers to the synthesis of an intermediate 10, the yield is 80 percent, and the melting point is 99-101 ℃.1H NMR(400MHz,CDCl3)δ8.04(d,J＝7.9Hz,2H),7.87(d,J＝7.9Hz,2H),6.23(s,1H),4.46(s,2H),3.67(s,3H),3.47(dd,J＝13.3,6.6Hz,2H),2.32(t,J＝7.4Hz,2H),1.64(dd,J＝14.1,7.1Hz,4H),1.50–1.33(m,4H).
4- ((4- (2-Bromoacetyl) benzamido) methyl) benzoic acid methyl ester (13)
The specific operation was carried out with reference to the synthesis of intermediate 10, yield 76%, melting point 126-.1H NMR(400MHz,DMSO-d6)δ9.36(dd,J＝13.5,6.7Hz,1H),8.14–8.01(m,4H),7.94(d,J＝7.7Hz,2H),7.47(d,J＝7.9Hz,2H),5.00(s,2H),4.58(d,J＝5.7Hz,2H),3.84(s,3H).
(E) -methyl 3- (4- ((4- (2-bromoacetyl) benzamido) methyl) phenyl) acrylate (14)
The specific operation was carried out with reference to the synthesis of intermediate 10, yield 63%, melting point 149-.1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.1Hz,2H),7.91(d,J＝8.0Hz,2H),7.68(d,J＝16.0Hz,1H),7.52(d,J＝7.8Hz,2H),7.38(d,J＝7.9Hz,2H),6.54(s,1H),6.43(d,J＝16.0Hz,1H),4.69(d,J＝5.7Hz,2H),4.45(s,2H),3.81(s,3H).
(Z) -5- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamido) pentanoate (15)
The intermediate 10(0.42g,1mmol) was dissolved in methanol (20mL), thiosemicarbazide (0.09g,1mmol) was added and reacted at room temperature for 1h, and after the intermediate 1(0.36g,1mmol) was added, the mixture was refluxed at 80 ℃ for 3h to obtain a red solid at a yield of 64% and a melting point of 196-.1H NMR(400MHz,DMSO-d6)δ8.53(t,J＝5.4Hz,1H),8.16(d,J＝6.7Hz,2H),8.08(d,J＝7.9Hz,2H),7.98(s,1H),7.93(d,J＝8.1Hz,2H),7.73(d,J＝4.0Hz,1H),7.60–7.51(m,3H),7.37(d,J＝3.9Hz,1H),3.59(s,3H),3.28(d,J＝5.6Hz,2H),2.36(t,J＝6.7Hz,2H),1.66–1.48(m,4H).
(Z) -6- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-ylthiazol-4-yl) benzamidohexanoic acid (16)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 59%, and the melting point is 199-.1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.16(s,2H),8.07(s,2H),8.01–7.84(m,3H),7.73(s,1H),7.55(s,3H),7.37(s,1H),3.58(s,3H),3.26(s,2H),2.37–2.24(m,2H),1.61–1.45(m,4H),1.39–1.29(m,2H).
(Z) -7- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamido) heptanoate (17)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 60%, and the melting point is 219-.1H NMR(400MHz,DMSO-d6)δ8.50(t,J＝5.2Hz,1H),8.17(d,J＝6.8Hz,2H),8.07(d,J＝7.8Hz,2H),7.98(s,1H),7.93(d,J＝7.8Hz,2H),7.73(d,J＝3.7Hz,1H),7.63–7.49(m,3H),7.37(d,J＝3.9Hz,1H),3.58(s,3H),3.27(q,J＝6.1Hz,2H),2.31(t,J＝7.3Hz,2H),1.54(m,4H),1.32(m,4H).
(Z) -methyl 4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-) thiazol-4-yl) benzamido) benzoate (18)
The specific synthesis method refers to the synthesis of intermediate 15, yield 33%, melting point 182-.1H NMR(600MHz,DMSO-d6)δ9.20(t,J＝6.0Hz,1H),8.17(d,J＝7.4Hz,2H),8.12(dd,J＝9.5,7.6Hz,2H),8.04(d,J＝6.5Hz,1H),8.01(d,J＝9.1Hz,2H),7.97–7.93(m,2H),7.73(d,J＝4.1Hz,1H),7.60–7.53(m,4H),7.51–7.47(m,2H),7.37(d,J＝4.0Hz,1H),4.59(d,J＝5.9Hz,2H),3.85(s,3H).
(E) -3- (4- ((4- (2- ((Z) -5-oxo-3-phenyl-4-2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamido) methyl) phenyl) acrylate (19)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 68%, and the melting point is 250-.1H NMR(400MHz,DMSO-d6)δ9.16(t,J＝5.6Hz,1H),8.16(d,J＝6.7Hz,2H),8.11(d,J＝7.8Hz,2H),8.00(d,J＝7.0Hz,3H),7.74(d,J＝3.8Hz,1H),7.70(d,J＝7.6Hz,2H),7.66(d,J＝16.3Hz,1H),7.56(d,J＝6.5Hz,2H),7.38(t,J＝6.0Hz,3H),6.62(d,J＝16.0Hz,1H),4.53(d,J＝5.4Hz,2H),3.72(s,3H).
(Z) -N- (5- (hydroxyamino) -5-oxopentyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (20)
Dissolving hydroxylamine hydrochloride (2.92g,42mmol) and potassium hydroxide (3.53g,63mmol) with methanol respectively, dripping methanol solution of potassium hydroxide into hydroxylamine hydrochloride under ice bath, reacting for 10min under ice bath, and vacuum filtering to obtain methanol solution of hydroxylamine and potassium hydroxide. Intermediate 15(1.76g,3mmol) was dissolved in DMF (8mL) and addedThe solution of hydroxylamine and potassium hydroxide in methanol was reacted at room temperature for 6 hours, 20mL of water was added, the pH was adjusted to 4 with 6M hydrochloric acid, and the crude product was obtained by suction filtration. The red solid is obtained by column chromatography, the yield is 55 percent, and the melting point is 219 and 220 ℃.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.54(t,J＝5.2Hz,1H),8.17(d,J＝6.9Hz,2H),8.08(d,J＝7.9Hz,2H),7.98(s,1H),7.94(d,J＝7.8Hz,2H),7.73(d,J＝3.7Hz,1H),7.61–7.50(m,3H),7.37(d,J＝3.6Hz,1H),3.27(t,J＝5.1Hz,2H),1.99(t,J＝6.2Hz,2H),1.62–1.45(m,4H).13C NMR(101MHz,DMSO-d6)δ179.49,174.94,169.56,166.22,155.34,153.47,149.51,136.87,134.23,133.06,131.03,130.34,129.76,128.93,128.51,128.15,126.10,114.64,110.95,39.48,32.54,29.31,23.29.HRMS(AP-ESI)m/z,Calcd for C27H24N8O4S2,([M+H]+):589.1435,found:589.1422.
EXAMPLE 3 (Z) -N- (6- (hydroxyamino) -6-oxohexyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (21)
Specific Synthesis method of the Compound please refer to the Synthesis of Compound 20, yield 46%, melting Point>280℃.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.67(s,1H),8.54(s,1H),8.19(d,J＝6.3Hz,2H),8.07(d,J＝8.0Hz,2H),7.93(d,J＝7.9Hz,2H),7.89(s,1H),7.68(d,J＝2.7Hz,1H),7.50(dd,J＝14.1,7.2Hz,3H),7.30(d,J＝3.5Hz,1H),3.26(d,J＝6.4Hz,2H),1.96(t,J＝7.1Hz,2H),1.53(s,4H),1.30(d,J＝6.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ182.94,169.59,166.24,155.91,153.45,150.30,149.03,141.82,137.26,134.00,133.22,129.14,128.59,128.14,126.03,122.52,116.12,110.20,49.07,32.72,29.42,26.63,25.43.HRMS(AP-ESI)m/z,Calcd for C28H26N8O4S2,([M+H]+):603.1591,found:603.1589.
EXAMPLE 4 (Z) -N- (7- (hydroxyamino) -7-oxoheptyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (22)
Specific Synthesis method of the Compound please refer to the Synthesis of Compound 20, yield 77%, melting Point187-188℃.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.51(t,J＝5.2Hz,1H),8.17(d,J＝6.8Hz,2H),8.07(d,J＝7.8Hz,2H),7.98(s,1H),7.93(d,J＝7.9Hz,2H),7.73(d,J＝3.7Hz,1H),7.62–7.50(m,3H),7.37(d,J＝3.7Hz,1H),3.27(d,J＝6.2Hz,2H),1.95(t,J＝7.2Hz,2H),1.63–1.44(m,4H),1.38–1.22(m,4H).13C NMR(101MHz,DMSO-d6)δ179.77,169.61,166.18,155.35,153.40,149.65,149.53,136.83,134.31,132.81,131.07,130.37,129.92,128.96,128.52,128.17,126.09,114.61,110.96,39.70,32.73,29.55,28.85,26.75,25.59.HRMS(AP-ESI)m/z,Calcd for C29H28N8O4S2,([M+H]+):617.1748,found:617.1735.
EXAMPLE 5 (Z) -N-hydroxy-4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamido) methylbenzamide (23)
The specific synthesis method of the compound refers to the synthesis of the compound 20, with a yield of 29%, a melting point of 217-219 ℃.1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),11.18(s,1H),9.15(s,1H),8.99(s,1H),8.19(d,J＝6.3Hz,1H),8.11(d,J＝7.9Hz,1H),8.05–7.84(m,6H),7.72(d,J＝7.7Hz,2H),7.66(d,J＝2.9Hz,1H),7.56–7.37(m,4H),7.26(d,J＝3.1Hz,1H),4.54(s,2H).13C NMR(101MHz,DMSO-d6)δ179.58,166.45,164.64,155.43,153.53,149.67,149.44,143.48,137.21,133.89,133.73,131.79,131.20,130.25,129.15,128.90,128.53,128.31,127.63,127.46,126.21,114.79,111.07,42.99.HRMS(AP-ESI)m/z,Calcd for C30H22N8O4S2,([M+H]+):623.1278,found:623.1270.
Example 6N- (4- ((E) -3- (hydroxyamino) -3-oxoprop-1-en-1-yl) benzyl) -4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazinoalkylidene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (24)
The specific synthesis method of the compound refers to the synthesis of the compound 20, the yield is 36%, and the melting point is 251-.1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),10.09(s,1H),9.15(t,J＝5.9Hz,1H),8.18(d,J＝6.7Hz,2H),8.10(d,J＝7.8Hz,2H),8.00(d,J＝7.9Hz,2H),7.94(s,1H),7.77–7.64(m,3H),7.60(d,J＝15.9Hz,,1H),7.53(m,3H),7.38(d,J＝7.7Hz,2H),7.32(d,J＝3.3Hz,1H),6.50(d,J＝15.9Hz,1H),4.53(d,J＝5.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ181.07,168.08,166.42,155.60,153.45,149.26,144.21,142.59,137.31,133.70,133.29,131.97,129.87,128.90,128.81,128.73,128.58,128.29,128.21,127.94,127.20,126.17,119.20,115.14,110.80,42.99.HRMS(AP-ESI)m/z,Calcd for C32H24N8O4S2,([M+H]+):649.1435,found:649.1445.
Example 7.4- (4-Acetylphenoxy) butanoic acid methyl ester (25)
P-hydroxyacetophenone (2.7g,20mmol) was dissolved in DMF and K was added2CO3(8.3g,60mmol), KI (0.1g) and methyl 4-bromobutyrate (3.77mL,30mmol) were stirred at room temperature for 8h, the reaction was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered with suction, and column chromatographed to give 3.94g of a white solid, yield 83%, melting point 64-66 ℃.1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.2Hz,2H),6.91(d,J＝8.3Hz,2H),4.08(t,J＝6.0Hz,2H),3.70(s,3H),2.55(s,3H),2.53(d,J＝7.4Hz,2H),2.14(p,J＝6.6Hz,2H).
5- (4-Acetylphenoxy) pentanoic acid methyl ester (26)
The specific synthesis method refers to the synthesis of an intermediate 25, the yield is 90 percent, and the melting point is 56-57 ℃.1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.2Hz,2H),6.91(d,J＝8.2Hz,2H),4.03(d,J＝5.2Hz,2H),3.68(s,3H),2.55(s,3H),2.41(t,J＝6.2Hz,2H),1.92–1.76(m,4H).
6- (4-Acetylphenoxy) hexanoic acid methyl ester (27)
The specific synthesis method refers to the synthesis of an intermediate 25, the yield is 94%, and the melting point is 46-48 ℃.1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.4Hz,2H),6.91(d,J＝8.4Hz,2H),4.02(t,J＝6.3Hz,2H),3.68(s,3H),2.55(s,3H),2.44–2.31(m,2H),1.94–1.79(m,2H),1.72(dt,J＝15.2,7.4Hz,2H),1.52(dt,J＝15.1,7.7Hz,2H).
7- (4-Acetylphenoxy) heptanoic acid methyl ester (28)
The specific synthesis method refers to the synthesis of an intermediate 25, the yield is 90 percent, and the melting point is 63-65 ℃.1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.1Hz,2H),6.91(d,J＝8.2Hz,2H),4.02(t,J＝6.4Hz,2H),3.67(s,3H),2.55(s,3H),2.33(t,J＝7.4Hz,2H),1.89–1.76(m,2H),1.74–1.62(m,2H),1.50(dt,J＝14.8,7.3Hz,2H),1.40(dt,J＝14.7,7.4Hz,2H).
8- (4-Acetylphenoxy) octanoic acid methyl ester (29)
The specific synthesis method refers to the synthesis of an intermediate 25, the yield is 92 percent, and the melting point is 52-54 ℃.1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.4Hz,2H),6.91(d,J＝8.4Hz,2H),4.01(t,J＝6.4Hz,2H),3.67(s,3H),2.55(s,3H),2.32(t,J＝7.4Hz,2H),1.79(dq,J＝13.4,6.6Hz,2H),1.64(dt,J＝12.1,6.2Hz,2H),1.56–1.44(m,2H),1.43–1.26(m,4H).
4- ((4-Acetylphenoxy) methyl) benzoic acid methyl ester (30)
The specific synthesis method refers to the synthesis of intermediate 25, the yield is 88%, and the melting point is 119-.1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.8Hz,2H),7.94(d,J＝8.3Hz,2H),7.50(d,J＝7.9Hz,2H),7.00(d,J＝8.3Hz,2H),5.19(s,2H),3.93(s,3H),2.56(s,3H).
(E) -methyl 3- (4- (((4-acetylphenoxy) methyl) phenyl) acrylate (31)
The specific synthesis method refers to the synthesis of an intermediate 25, the yield is 84%, and the melting point is 150-.1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.3Hz,2H),7.68(t,J＝15.4Hz,1H),7.55(d,J＝7.9Hz,2H),7.45(d,J＝7.9Hz,2H),7.00(d,J＝8.4Hz,2H),6.45(d,J＝16.0Hz,1H),5.15(s,2H),3.81(s,3H),2.55(s,3H).
4- (4- (2-Bromoacetyl) phenoxy) butanoic acid methyl ester (32)
The specific synthesis method refers to the synthesis of an intermediate 10, the yield is 70 percent, and the melting point is 90-92 ℃.1H NMR(400MHz,CDCl3)δ7.96(d,J＝7.9Hz,2H),6.94(d,J＝8.2Hz,2H),4.40(s,2H),4.10(dd,J＝12.4,6.3Hz,2H),3.70(s,3H),2.54(t,J＝7.1Hz,2H),2.22–2.09(m,2H).
5- (4- (2-Bromoacetyl) phenoxy) pentanoic acid methyl ester (33)
Specific synthesis methodThe method was carried out in accordance with the synthesis of intermediate 10, yield 83%, melting point 61-62 ℃.1H NMR(400MHz,CDCl3)δ7.95(d,J＝8.6Hz,2H),6.94(d,J＝8.6Hz,2H),4.40(s,2H),4.05(d,J＝5.4Hz,2H),3.68(s,3H),2.41(t,J＝6.3Hz,2H),1.92–1.77(m,4H).
Methyl 6- (4- (2-bromoacetyl) phenoxy) hexanoate (34)
The specific synthesis method refers to the synthesis of an intermediate 10, the yield is 65 percent, and the melting point is 61-63 ℃.1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.3Hz,2H),6.94(d,J＝8.3Hz,2H),4.40(s,2H),4.04(t,J＝6.1Hz,2H),3.68(s,3H),2.36(t,J＝7.4Hz,2H),1.90–1.79(m,2H),1.78–1.67(m,2H),1.57–1.47(m,2H).
7- (4- (2-Bromoacetyl) phenoxy) heptanoic acid methyl ester (35)
The specific synthesis method refers to the synthesis of an intermediate 10, the yield is 57 percent, and the melting point is 60-61 ℃.1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.3Hz,2H),6.94(d,J＝8.3Hz,2H),4.40(s,2H),4.08–4.00(m,2H),3.67(s,3H),2.33(t,J＝7.3Hz,2H),1.89–1.77(m,2H),1.68(dd,J＝14.9,7.4Hz,2H),1.50(dt,J＝14.2,6.9Hz,2H),1.40(dt,J＝14.6,7.4Hz,2H).
8- (4- (2-Bromoacetyl) phenoxy) octanoic acid methyl ester (36)
The specific synthesis method refers to the synthesis of an intermediate 10, the yield is 53 percent, and the melting point is 62-64 ℃.1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.6Hz,2H),6.94(d,J＝8.6Hz,2H),4.40(s,2H),4.03(t,J＝6.3Hz,2H),3.67(s,3H),2.32(t,J＝7.4Hz,2H),1.89–1.75(m,2H),1.64(dt,J＝14.5,7.4Hz,2H),1.55–1.44(m,2H),1.44–1.31(m,4H).
4- ((4- (2-Bromoacetyl) phenoxy) methyl) benzoic acid methyl ester (37)
The specific synthesis method refers to the synthesis of an intermediate 10, the yield is 84%, and the melting point is 121-.1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.7Hz,2H),7.98(d,J＝8.2Hz,2H),7.50(d,J＝7.9Hz,2H),7.03(d,J＝8.2Hz,2H),5.21(s,2H),4.39(s,2H),3.93(s,3H).
(E) -methyl 3- (4- (((4- (2-bromoacetyl) phenoxy) methyl) phenyl) acrylate (38)
The specific synthetic method refers to the synthesis of an intermediate 10, and the yield is 75% and a melting point of 140 ℃ and 141 ℃.1H NMR(400MHz,CDCl3)δ7.97(d,J＝8.4Hz,2H),7.70(d,J＝16.0Hz,1H),7.56(d,J＝7.8Hz,2H),7.45(d,J＝7.8Hz,2H),7.03(d,J＝8.4Hz,2H),6.46(d,J＝16.0Hz,1H),5.16(s,2H),4.39(s,2H),3.81(s,3H).
(Z) -4- (4- (2- (5- (oxo-3-phenyl) -4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) butanoate (39)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 52%, and the melting point is 196-.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝7.0Hz,2H),7.91(d,J＝8.0Hz,2H),7.72(d,J＝3.7Hz,1H),7.66(s,1H),7.61–7.51(m,3H),7.36(d,J＝3.7Hz,1H),7.01(d,J＝8.1Hz,2H),4.04(t,J＝6.1Hz,2H),3.62(s,3H),2.50–2.46(m,2H),2.10–1.94(m,2H).
(Z) -5- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) pentanoate (40)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 54%, and the melting point is 173-174 ℃.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.9Hz,2H),7.91(d,J＝8.1Hz,2H),7.72(d,J＝3.8Hz,1H),7.66(s,1H),7.63–7.48(m,3H),7.37(d,J＝3.8Hz,1H),7.01(d,J＝8.1Hz,2H),4.13–3.94(m,2H),3.60(s,3H),2.40(t,J＝6.8Hz,2H),1.73(dd,J＝12.3,6.5Hz,4H).
(Z) -6- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) hexanoate (41)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 71%, and the melting point is 198-200 ℃.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.9Hz,2H),7.91(d,J＝8.1Hz,2H),7.72(d,J＝3.7Hz,1H),7.66(s,1H),7.63–7.50(m,3H),7.36(d,J＝3.7Hz,1H),7.00(d,J＝8.1Hz,2H),4.00(t,J＝6.2Hz,2H),3.59(s,3H),2.34(t,J＝7.3Hz,2H),1.73(dd,J＝13.7,6.6Hz,2H),1.61(dt,J＝14.7,7.2Hz,2H),1.54–1.38(m,2H).
(Z) -7- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) heptanoate (42)
The specific synthesis method refers to the synthesis of the intermediate 15, the yield is 68%, and the melting point is 146-.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝7.0Hz,2H),7.90(d,J＝8.0Hz,2H),7.72(d,J＝3.7Hz,1H),7.66(s,1H),7.54(t,J＝9.9Hz,3H),7.36(d,J＝3.8Hz,1H),7.00(d,J＝8.2Hz,2H),4.00(t,J＝6.2Hz,2H),3.59(s,3H),2.32(t,J＝7.3Hz,2H),1.72(dd,J＝13.6,6.7Hz,2H),1.63–1.51(m,2H),1.48–1.39(m,2H),1.39–1.30(m,2H).
(Z) -8- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) octanoate (43)
The specific synthesis method refers to the synthesis of the intermediate 15, the yield is 76%, and the melting point is 166-167 ℃.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.8Hz,2H),7.90(d,J＝8.1Hz,2H),7.72(d,J＝3.4Hz,1H),7.66(s,1H),7.63–7.49(m,3H),7.37(d,J＝3.7Hz,1H),7.00(d,J＝8.0Hz,2H),4.01(t,J＝6.2Hz,2H),3.58(s,3H),2.30(t,J＝7.6Hz,2H),1.72(dd,J＝13.4,6.6Hz,2H),1.60–1.50(m,2H),1.42(d,J＝6.7Hz,2H),1.32(m,4H).
(Z) -4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-) thiazol-4-yl) phenoxy) methyl) benzoate (44)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 61%, and the melting point is 215-.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.9Hz,2H),8.00(d,J＝7.5Hz,2H),7.94(d,J＝8.1Hz,2H),7.72(d,J＝3.7Hz,1H),7.69(s,1H),7.63(d,J＝8.1Hz,2H),7.60–7.50(m,3H),7.37(d,J＝3.7Hz,1H),7.12(d,J＝8.2Hz,2H),5.27(s,2H),3.86(s,3H).
(E) -3- (4- ((4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) methyl) phenyl) acrylate (45)
The specific synthesis method refers to the synthesis of intermediate 15, the yield is 78%, and the melting point is 222-.1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.8Hz,2H),7.93(d,J＝8.2Hz,2H),7.76(d,J＝7.8Hz,2H),7.72(d,J＝4.0Hz,1H),7.71–7.64(m,2H),7.53(m,5H),7.37(d,J＝3.7Hz,1H),7.11(d,J＝8.3Hz,2H),6.66(d,J＝16.0Hz,1H),5.21(s,2H),3.73(s,3H).
(Z) -N-hydroxy-4- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) alkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) butanamide (46)
The specific synthesis method refers to the synthesis of the target compound 20, the yield is 67%, and the melting point is 242-244 ℃.1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.72(s,1H),8.21(d,J＝6.5Hz,2H),7.91(d,J＝8.1Hz,2H),7.64(s,1H),7.57–7.38(m,4H),7.25(d,J＝2.7Hz,1H),7.00(d,J＝8.2Hz,2H),4.01(t,J＝6.1Hz,2H),2.16(t,J＝7.2Hz,2H),2.02–1.90(m,2H).13C NMR(101MHz,DMSO)δ182.87,169.13,158.71,155.61,153.40,149.95,149.71,141.20,133.19,129.11,128.85,128.58,127.88,127.70,123.08,115.82,115.00,106.49,67.32,29.24,25.34.HRMS(AP-ESI)m/z,Calcd for C25H21N7O4S2,([M+H]+):548.1169,found:548.1170.
EXAMPLE 8 (Z) -N-hydroxy-5- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) alkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) pentanamide (47)
The specific synthesis method refers to the synthesis of the target compound 20, the yield is 83 percent, and the melting point is 153-155 ℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.69(s,1H),8.19(d,J＝6.6Hz,2H),7.91(d,J＝8.3Hz,2H),7.67(d,J＝3.2Hz,1H),7.57(s,1H),7.49(dt,J＝21.4,7.3Hz,3H),7.29(d,J＝3.2Hz,1H),7.01(d,J＝8.3Hz,2H),4.01(d,J＝5.8Hz,2H),2.04(t,J＝6.6Hz,2H),1.80–1.61(m,4H).13C NMR(101MHz,DMSO-d6)δ181.73,169.44,158.86,155.43,153.42,149.97,149.74,138.27,132.38,129.60,128.75,128.51,127.72,127.61,125.59,115.48,115.00,106.82,67.56,32.40,28.68,22.28.HRMS(AP-ESI)m/z,Calcd for C26H23N7O4S2,([M+H]+):562.1326,found:562.1320.
EXAMPLE 9 (Z) -N-hydroxy-6- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) hexanamide (48)
Specific synthetic methods reference to target Compound 20The synthesis was carried out in 55% yield and melting point 132-.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.16(d,J＝6.9Hz,1H),7.91(d,J＝8.2Hz,1H),7.72(d,J＝3.5Hz,1H),7.66(s,1H),7.60–7.49(m,1H),7.36(d,J＝3.7Hz,1H),7.01(d,J＝8.2Hz,1H),4.00(t,J＝6.0Hz,1H),1.99(t,J＝7.1Hz,1H),1.78–1.69(m,1H),1.56(dd,J＝14.4,7.1Hz,1H),1.48–1.37(m,1H).13C NMR(101MHz,DMSO-d6)δ179.00,172.51,169.52,159.01,154.98,153.43,150.29,149.32,132.75,130.92,130.42,130.31,128.99,128.44,127.75,127.29,114.99,114.52,107.31,67.86,32.72,28.94,25.67,21.53.HRMS(AP-ESI)m/z,Calcd for C27H25N7O4S2,([M+H]+):576.1482,found:576.1481.
EXAMPLE 10 (Z) -N-hydroxy-7- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) alkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) heptanamide (49)
The specific synthesis method refers to the synthesis of the target compound 20, the yield is 64 percent, and the melting point is 127-.1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.16(d,J＝6.9Hz,2H),7.91(d,J＝8.0Hz,2H),7.72(d,J＝3.5Hz,1H),7.65(s,1H),7.61–7.49(m,3H),7.36(d,J＝3.5Hz,1H),7.01(d,J＝8.1Hz,2H),4.01(t,J＝6.2Hz,2H),1.96(t,J＝7.2Hz,2H),1.78–1.68(m,2H),1.52(dd,J＝14.6,7.2Hz,2H),1.47–1.39(m,2H),1.36–1.28(m,2H).13C NMR(101MHz,DMSO-d6)δ179.45,169.57,159.03,155.01,153.40,150.28,149.37,132.71,131.00,130.40,130.21,129.00,128.46,127.76,127.30,115.02,114.53,107.30,67.91,32.69,29.09,28.84,25.75,25.56.HRMS(AP-ESI)m/z,Calcd for C28H27N7O4S2,([M+H]+):590.1639,found:590.1628.
EXAMPLE 11 (Z) -N-hydroxy-8- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) octanamide (50)
The specific synthesis method refers to the synthesis of the target compound 20, the yield is 60%, and the melting point is 144-.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.16(d,J＝7.1Hz,2H),7.91(d,J＝8.2Hz,2H),7.72(d,J＝3.6Hz,1H),7.65(s,1H),7.61–7.49(m,3H),7.36(d,J＝3.7Hz,1H),7.01(d,J＝8.1Hz,2H),4.01(t,J＝6.2Hz,2H),1.95(t,J＝7.2Hz,2H),1.80–1.67(m,2H),1.57–1.47(m,2H),1.45–1.38(m,2H),1.37–1.21(m,4H).13C NMR(101MHz,DMSO-d6)δ179.08,169.62,159.02,154.98,153.42,150.29,149.32,132.76,130.94,130.40,130.27,128.98,128.44,127.75,127.26,114.98,114.53,107.28,67.93,32.73,29.16,29.01,29.00,25.92,25.56.HRMS(AP-ESI)m/z,Calcd for C29H29N7O4S2,([M+H]+):604.1795,found:604.1787.HPLC tR＝5.994min(99.01％purity).
EXAMPLE 12 (Z) -N-hydroxy-4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) methyl) benzamide (51)
The specific synthesis method refers to the synthesis of the target compound 20, the yield is 60 percent, and the melting point is 216-217 ℃.1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),9.03(s,1H),8.18(d,J＝7.0Hz,2H),7.93(d,J＝8.1Hz,2H),7.78(d,J＝7.6Hz,2H),7.69(d,J＝3.3Hz,1H),7.62(s,1H),7.59–7.46(m,5H),7.31(d,J＝3.2Hz,1H),7.11(d,J＝8.1Hz,2H),5.22(s,2H).13C NMR(101MHz,DMSO-d6)δ180.80,172.51,164.43,158.43,155.27,153.40,149.94,140.67,135.92,132.73,131.87,129.99,129.96,129.90,128.83,128.51,127.93,127.77,127.52,115.44,115.00,107.22,69.18.HRMS(AP-ESI)m/z,Calcd for C29H21N7O4S2,([M+H]+):596.1169,found:596.1156.
EXAMPLE 13 (E) -N-hydroxy-3- (4- ((4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4], 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) methyl) phenyl) acrylamide (52)
The specific synthesis method refers to the synthesis of the target compound 20, the yield is 70%, and the melting point is 186-.1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.13(s,1H),8.16(d,J＝6.9Hz,2H),7.93(d,J＝8.2Hz,2H),7.71(d,J＝3.6Hz,1H),7.66(s,1H),7.53(ddd,J＝31.3,21.8,11.8Hz,8H),7.35(d,J＝3.6Hz,1H),7.11(d,J＝8.2Hz,2H),6.48(d,J＝15.8Hz,1H),5.19(s,2H).13C NMR(101MHz,DMSO-d6)δ179.19,163.15,158.56,155.07,153.46,150.17,149.38,138.83,138.42,134.86,133.34,131.07,130.32,129.79,128.95,128.64,128.46,128.07,127.79,127.75,119.66,115.42,114.63,107.48,69.35.HRMS(AP-ESI)m/z,Calcd for C31H23N7O4S2,([M+H]+):622.1326,found:622.1320.
Evaluation of Activity of target Compound
Experimental example 1 inhibition of proliferation of human cervical cancer cell (HeLa cell) by target Compound
1.[ Material ]
K562, KG1, HL-60, A549, HeLa, MTT, 10% fetal bovine serum (Hyclone, USA), 2.5 g.L-1 trypsin (Gibco, USA), modified RPMI1640 medium (Hyclone, USA), 96-well plate;
[ method ]
Culturing cells in a conventional mode, and collecting cells with logarithmic growth for experiment; cells in logarithmic growth phase were diluted to 4X 10 with RPMI1640 medium containing 10% fetal bovine serum4each.mL-1Then inoculating the cells into a 96-well plate (adding 100 mu L of the cells into each well), taking the cells without the cells as blank wells, and then culturing the cells in a constant-temperature incubator (37 ℃, 5% carbon dioxide) for 8 hours; adding the target compound solution prepared with culture medium, using non-medicated as 100% well, culturing in constant temperature incubator (37 deg.C, 5% carbon dioxide) for 48 hr, adding 30 μ L MTT, removing the liquid in the well after four hr (suspension cells need centrifugation), adding 150 μ L DMSO, shaking in constant temperature shaking table for 10min, measuring absorbance value of each well at 570nm wavelength with microplate reader, and calculating inhibition rate and IC50A value;
Figure BDA0002706199010000221
TABLE 2 results of in vitro tumor cell proliferation inhibition experiments with target compounds
Figure BDA0002706199010000222
The data in table a is the average value of three experiments, and the value after +/-represents the standard error
Description of terms: k562, human chronic myelogenous leukemia cells; HL-60, human promyelocytic leukemia cells;
and (4) conclusion: the anti-tumor proliferation activity of all target compounds is better than that of a positive control drug, wherein the activity of the target compound 23 for inhibiting K562 cell proliferation is 9 times that of the positive control drug BTSA1, and the activity for inhibiting HL-60 cell proliferation is 11 times that of the positive control drug.
The compounds can be deeply researched for activity, and more active compounds are developed for preparing medicaments for preventing and treating cancers.

Claims (10)

1. The carbonyl pyrazole antitumor compound is characterized by being a compound with a structure shown in a general formula I, a stereoisomer and pharmaceutically acceptable salt thereof;
Figure FDA0002706197000000011
in the general formula I, R1Represents alkyl, alkoxy, cycloalkyl, C, substituted or unsubstituted by 1 to 3 substituents5-C15Aryl radical, C6-C15Aryl radical C1-C6Alkyl radical, C3-C14Heteroaryl group, C3-C14Heteroaryl C1-C6Alkyl, the substituent is selected from hydroxyl, cyano, nitro, halogen and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C8Cycloalkyl, said heteroatoms being independently selected from O, S, N or oxidized S or N;
in the general formula I, R2Represents hydrogen or C which is substituted or unsubstituted by 1 to 3 substituents1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C14A cycloalkyl group, a,C6-C15Aryl radical, C6-C15Aryl radical C1-C6Alkyl radical, C3-C14Heteroaryl group, C3-C14Heteroaryl C1-C6Alkyl, said substituents selected from hydroxy, halogen, alkyl, haloalkyl, cyano, nitro, guanidino, amino, carboxy, said heteroatoms independently selected from O, S, N or oxidized S or N;
z represents hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nl,n2And n3 represents an integer of 0 to 10;
x represents a nitrogen atom, an oxygen atom, an amide;
ar represents C substituted or unsubstituted with 1 to 3 substituents5-C7Aryl radical, C5-C7Aryl radical C1-C5Alkyl radical, C5-C7Aryl radical C2-C5Alkenyl radical, C3-C6Heteroaryl group, C3-C6Heteroaryl C1-C5Alkyl radical, C3-C6Heteroaryl C2-C5Alkenyl, said substituent being selected from C1-C6Haloalkyl, C1-C6Alkoxy, haloalkyl, halogen, hydroxy, nitro, cyano, C3-C8Cycloalkyl, aryl, heteroaryl.
2. The carbonylpyrazole antitumor compound according to claim 1, wherein in formula I:
R1is C substituted or unsubstituted by 1 to 3 substituents3-C8Cycloalkyl, monocyclic aryl having 5 or 6 ring atoms or bicyclic aryl having 8 to 15 ring atoms, monocyclic 5 or 6 ring atoms containing 1 to 2 heteroatoms, or bicyclic 8 to 15 ring atoms containing 1 to 4 heteroatoms, said substituents being selected from hydroxy, cyano, nitro, halogen、C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy, said heteroatoms being independently selected from O, S, N or oxidized S or N;
R2is hydrogen, C substituted or unsubstituted by 1 to 3 substituents1-C12Alkyl radical, C3-C14Cycloalkyl radical, C6-C10Aryl radical, C6-C10Aryl radical C1-C6Alkyl radical, C3-C9Heteroaryl group, C3-C9Heteroaryl C1-C6Alkyl, said substituent being selected from cyano, halogen, nitro, carboxy, methyl, trifluoromethyl, guanidino or amino;
z represents hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nl,n2And n3 represents an integer of 0 to 8;
x represents a nitrogen atom or an oxygen atom;
ar represents C substituted or unsubstituted with 1 to 3 substituents6-C7Aryl radical, C6-C7Aryl radical C1-C3Alkyl radical, C6-C7Aryl radical C2-C3Alkenyl radical, C3-C6Heteroaryl group, C3-C6Heteroaryl C1-C3Alkyl radical, C3-C6Heteroaryl C2-C3Alkenyl, said substituent being selected from C1-C6Alkyl, trifluoromethyl, halogen, hydroxy, nitro, cyano.
3. The carbonylpyrazole antitumor compound according to claim 2, wherein in formula I:
R1represents C5-C6Cycloalkyl, thiazolyl or substituted phenyl;
R2represents C1-C6Alkyl radical, C3-C6Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, said substituents being selected from cyano, halogen, nitro, carboxy, methyl, trifluoromethyl, guanidino or amino;
z represents hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nlRepresents an integer of 3 to 8, n2Represents an integer of 0 to 2, and n3 represents an integer of 0 to 3;
x represents a nitrogen atom or an oxygen atom;
ar represents phenyl, pyridazinyl, pyrazinyl, pyridyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, thienyl, oxazolyl, substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxy, nitro, cyano.
4. The carbonylpyrazole antitumor compound according to claim 3, wherein in formula I:
R1represents thiazole;
R2a phenyl group;
z hydrogen, -COOH, -O- (CH)2)n1-CONOH，-CO-X-(CH2)n1-CONOH，-O-(CH2)n2-Ar-(CH)n3-CONOH or-CO-X- (CH)2)n2-Ar-(CH)n3-CONOH；
nlRepresents an integer of 3 to 8;
n2is 1;
n3is 0 or 2;
x represents a nitrogen atom;
ar represents a benzene ring.
5. The carbonylpyrazole antitumor compound according to claim 4, which is one of the following compounds:
(Z) -N-hydroxy-4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (4)
(Z) -N- (5- (hydroxyamino) -5-oxopentyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (20)
(Z) -N- (6- (hydroxyamino) -6-oxohexyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (21)
(Z) -N- (7- (hydroxyamino) -7-oxoheptyl) -4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (22)
(Z) -N-hydroxy-4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamido) methylbenzamide (23)
N- (4- ((E) -3- (hydroxyamino) -3-oxoprop-1-en-1-yl) benzyl) -4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazinoylidene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (24)
(Z) -N-hydroxy-4- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) alkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) butanamide (46)
(Z) -N-hydroxy-5- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) alkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) pentanamide (47)
(Z) -N-hydroxy-6- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) hexanamide (48)
(Z) -N-hydroxy-7- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) heptanamide (49)
(Z) -N-hydroxy-8- (4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) octanamide (50)
(Z) -N-hydroxy-4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino)) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) methyl) benzamide (51)
(E) -N-hydroxy-3- (4- ((4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) -4], 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) phenoxy) methyl) phenyl) acrylamide (52).
6. A preparation method of carbonyl pyrazole antitumor compounds comprises the following steps:
scheme 1: 2-aminothiazole reacts with sodium nitrite under the condition of strong acid to generate diazonium salt firstly, then reacts with ethyl benzoylacetate to generate an intermediate 2, the intermediate 2 reacts with 4- (2-bromoacetyl) benzoic acid to prepare an intermediate 3 under the condition of existence of thiosemicarbazide, and then hydroxamic acid group is introduced to obtain a final compound 4;
scheme 2: performing amide condensation on p-acetylbenzoic acid and various amino acid methyl ester hydrochlorides to obtain an intermediate 5-9, performing bromination reaction to obtain an intermediate 10-14, performing multi-step cyclization reaction to obtain a key intermediate 15-19, and finally introducing hydroxamic acid groups to obtain a final product 20-24;
scheme 3: p-hydroxyacetophenone reacts with methyl bromoformate with different structures to obtain an intermediate 25-31, reacts with copper bromide to obtain a bromo-product 32-38, and is subjected to multi-step cyclization reaction to obtain a key intermediate 39-45, and finally, a hydroxamic acid group is introduced to obtain a final product 46-52;
the synthetic route is as follows:
synthesis scheme 1
Figure FDA0002706197000000041
Reaction reagents and reaction conditions: (a) (i) sodium nitrite, concentrated hydrochloric acid, water, 0 ℃,30 min; (ii) sodium acetate, ethyl benzoylacetate and ethanol at 0 ℃ for 1 h; (b) 2-bromoacetophenone or 4- (2-bromoacetyl) benzoic acid, thiosemicarbazide, ethanol, 80 ℃; (c) isobutyl chloroformate, N-methylmorpholine, tetrahydrofuran, hydroxylamine hydrochloride, potassium hydroxide, methanol, rt,6 h;
synthesis scheme 2
Figure FDA0002706197000000042
Reaction reagents and reaction conditions: (a) HATU, DIPEA, dichloromethane, room temperature; (b) copper bromide in a volume ratio of 1:1, ethyl acetate/chloroform, 80 ℃,3 hours; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
synthesis scheme 3
Figure FDA0002706197000000051
Reaction reagents and reaction conditions: (a) potassium carbonate, room temperature; (b) copper bromide, ethyl acetate/chloroform with the volume ratio of 1:1, at 80 ℃ for 3 h; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
the amino acid methyl ester hydrochloride is 5-amino pentanoic acid methyl ester hydrochloride, 6-amino hexanoic acid methyl ester hydrochloride, 7-amino heptanoic acid methyl ester hydrochloride, 8-amino octanoic acid methyl ester hydrochloride, 4-aminomethyl benzoic acid methyl ester hydrochloride, 4-aminomethyl cinnamic acid methyl ester hydrochloride; the methyl bromoformate is 4-methyl bromobutyrate, 5-methyl bromovalerate, 6-methyl bromohexanoate, 7-methyl bromoheptanoate, 8-methyl bromooctanoate, 4-methyl bromomethylbenzoate and 4-methyl bromocinnamate.
7. The carbonyl pyrazole antitumor compound according to any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for preventing or treating cancer.
8. A pharmaceutical composition suitable for oral administration to a mammal comprising a carbonylpyrazole antitumor compound according to any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers or excipients.
9. A pharmaceutical composition suitable for parenteral administration to a mammal comprising a carbonylpyrazole antitumor compound according to any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers or excipients.
10. A pharmaceutical composition comprising the carbonylpyrazole antitumor compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and one or more therapeutically active substances selected from the group consisting of an antitumor agent, an anticancer agent and a chemotherapeutic agent.
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