CN114075187B - Carbonyl pyrazole antitumor compound as well as preparation method and application thereof - Google Patents

Carbonyl pyrazole antitumor compound as well as preparation method and application thereof Download PDF

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CN114075187B
CN114075187B CN202011039501.2A CN202011039501A CN114075187B CN 114075187 B CN114075187 B CN 114075187B CN 202011039501 A CN202011039501 A CN 202011039501A CN 114075187 B CN114075187 B CN 114075187B
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thiazol
phenyl
dihydro
oxo
hydrazino
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CN114075187A (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 compoundsThe compound has a structure shown in a general formula I, has good activity of resisting tumor cell proliferation, can be used for preparing a medicament for preventing or treating cancers, and also relates to pharmaceutical application of a composition of the compound with the general formula I.

Description

Carbonyl pyrazole antitumor compound as well as 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 thereof, and belongs to the technical field of medicines.
Background
Carbonyl pyrazole compounds have various biological activities, are widely applied to various fields of antibiosis, antivirus, antimalarial and the like, and achieve good effects.
In 2012, evripidis et al found carbonyl pyrazole compound BAM7 through means such as virtual screening, which can induce the activation of pro-apoptotic protein Bax allosteric of Bcl-2 family, and start the endogenous apoptosis pathway mediated by mitochondria, thereby inducing apoptosis. Considering that BAM7 has poor affinity for Bax protein (IC 50 =3.3 μm), they used BAM7 as a lead compound, and modified and transformed the structure to obtain carbonyl pyrazole derivative BTSA1 with higher activity. BTSA1 has 13 times higher affinity for Bax protein than BAM7 and is the most active Bax agonist to date. In subsequent biological activity evaluations, they found that BTSA1 can kill hematological tumor cells effectively without damaging normal cells, but that BTSA1 has a large room for improvement in the inhibitory activity against solid tumor cells. 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 reconstruction. In subsequent biological activity evaluation, the carbonyl pyrazole compound shows high performanceIs hopeful to be developed into a novel high-efficiency low-toxicity anti-tumor drug.
Disclosure of Invention
The invention provides a carbonyl pyrazole antitumor compound, 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:
1. carbonyl pyrazole antitumor compound
Carbonyl pyrazole antitumor compound is a compound with a structure shown in a general formula I, and stereoisomers and pharmaceutically acceptable salts thereof;
Figure BDA0002706199010000011
in the general formula I, R 1 Represents alkyl, alkoxy, cycloalkyl, C which are substituted or unsubstituted by 1 to 3 substituents 5 -C 15 Aryl, C 6 -C 15 Aryl C 1 -C 6 Alkyl, C 3 -C 14 Heteroaryl, C 3 -C 14 Heteroaryl C 1 -C 6 Alkyl, said substituents being selected from hydroxy, cyano, nitro, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyl, the heteroatoms are independently selected from O, S, N or oxidized S or N;
in the general formula I, R 2 Represents hydrogen or C substituted or unsubstituted by 1 to 3 substituents 1 -C 12 Alkyl, C 1 -C 12 Alkoxy, C 3 -C 14 Cycloalkyl, C 6 -C 15 Aryl, C 6 -C 15 Aryl C 1 -C 6 Alkyl, C 3 -C 14 Heteroaryl, C 3 -C 14 Heteroaryl C 1 -C 6 Alkyl, said substituents being selected from hydroxy, halogen, alkyl, haloalkyl, cyano, nitro, guanidino, ammoniaA group, a carboxyl group, the heteroatoms independently selected from O, S, N or oxidized S or N;
z represents hydrogen, -COOH, -O- (CH) 2 ) n1 -CONOH，-CO-X-(CH 2 ) n1 -CONOH，-O-(CH 2 ) n2 -Ar-(CH) n3 -CONOH or-CO-X- (CH) 2 ) n2 -Ar-(CH) n3 -CONOH；
n l ,n 2 And n3 represents an integer of 0 to 10;
x represents a nitrogen atom, an oxygen atom, or an amide;
ar represents C substituted or unsubstituted with 1 to 3 substituents 5 -C 7 Aryl, C 5 -C 7 Aryl C 1 -C 5 Alkyl, C 5 -C 7 Aryl C 2 -C 5 Alkenyl, C 3 -C 6 Heteroaryl, C 3 -C 6 Heteroaryl C 1 -C 5 Alkyl, C 3 -C 6 Heteroaryl C 2 -C 5 Alkenyl, said substituents being selected from C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, haloalkyl, halogen, hydroxy, nitro, cyano, C 3 -C 8 Cycloalkyl, aryl, heteroaryl.
According to a preferred embodiment of the invention, in the general formula I:
R 1 is C substituted or unsubstituted by 1 to 3 substituents 3 -C 8 Cycloalkyl, monocyclic aryl having 5 or 6 ring atoms or bicyclic aryl having 8 to 15 ring atoms, monocyclic aryl having 5 or 6 ring atoms having 1 to 2 hetero atoms or bicyclic aryl having 8 to 15 ring atoms having 1 to 4 hetero atoms, said substituents being selected from hydroxy, cyano, nitro, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, the heteroatoms are independently selected from O, S, N or oxidized S or N;
R 2 is hydrogen, C substituted or unsubstituted by 1-3 substituents 1 -C 12 Alkyl, C 3 -C 14 Cycloalkyl, C 6 -C 10 Aryl, C 6 -C 10 Aryl C 1 -C 6 Alkyl, C 3 -C 9 Heteroaryl, C 3 -C 9 Heteroaryl C 1 -C 6 Alkyl, said substituent being selected from cyano, halogen, nitro, carboxyl, methyl, trifluoromethyl, guanidino or amino;
z represents hydrogen, -COOH, -O- (CH) 2 ) n1 -CONOH，-CO-X-(CH 2 ) n1 -CONOH，-O-(CH 2 ) n2 -Ar-(CH) n3 -CONOH or-CO-X- (CH) 2 ) n2 -Ar-(CH) n3 -CONOH；
n l ,n 2 And 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 substituents 6 -C 7 Aryl, C 6 -C 7 Aryl C 1 -C 3 Alkyl, C 6 -C 7 Aryl C 2 -C 3 Alkenyl, C 3 -C 6 Heteroaryl, C 3 -C 6 Heteroaryl C 1 -C 3 Alkyl, C 3 -C 6 Heteroaryl C 2 -C 3 Alkenyl, said substituents being selected from C 1 -C 6 Alkyl, trifluoromethyl, halogen, hydroxy, nitro, cyano.
According to a further preferred embodiment of the invention, in the general formula I:
R 1 represents C 5 -C 6 Cycloalkyl, thiazolyl or substituted phenyl;
R 2 represents C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, said substituents being selected from cyano, halogen, nitro, carboxyl, methyl, trifluoromethyl, guanidino or amino;
z represents hydrogen, -COOH, -O- (CH) 2 ) n1 -CONOH，-CO-X-(CH 2 ) n1 -CONOH，-O-(CH 2 ) n2 -Ar-(CH) n3 -CONOH or-CO-X- (CH) 2 ) n2 -Ar-(CH) n3 -CONOH；
n l Represents an integer of 3 to 8, n 2 Represents 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 which are substituted or unsubstituted by 1-3 substituents selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxy, nitro, cyano.
According to the invention, it is still further preferred that in formula I:
R 1 represents thiazole;
R 2 a phenyl group;
z hydrogen, -COOH, -O- (CH) 2 ) n1 -CONOH，-CO-X-(CH 2 ) n1 -CONOH，-O-(CH 2 ) n2 -Ar-(CH) n3 -CONOH or-CO-X- (CH) 2 ) n2 -Ar-(CH) n3 -CONOH；
n l Represents an integer of 3 to 8;
n 2 1 is shown in the specification;
n 3 0 or 2;
x represents a nitrogen atom;
ar represents a benzene ring.
The compounds of formula I are 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) benzamide (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) hydrazino) subunit) -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) pentanoic acid amide (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 preferred compounds are numbered in parentheses below, corresponding to the following schemes and to the structures of the compounds in Table 1.
Detailed Description
The terms and definitions used herein have the following meanings:
the "halogen atom" in the present invention includes fluorine atom, chlorine atom, bromine atom and iodine atom;
the invention is described as "C 1-10 Alkyl "refers to a straight or branched chain alkyl derived from the removal of one hydrogen atom from an alkane moiety containing 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, 2-trimethylpropyl, 1, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, nonyl and decyl. Preferably C 1-6 Alkyl, more preferably C 1-4 Alkyl, term "C 1-6 Alkyl "," C1-4 alkyl "refers to specific examples of the above examples containing 1 to 6, 1 to 4 carbon atoms;
"C" as described in the present invention 3-8 Cycloalkyl "refers to a cyclic alkyl group derived from an alkane moiety of 3 to 8 carbon atoms with one hydrogen atom removed, such as cyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably C 4-7 Cycloalkyl, C 4-6 Cycloalkyl and C 5-6 Cycloalkyl;
examples of such "mono-heterocyclyl" groups are: ethylene oxide, dioxane, thietanyl, aziridine, 2H-aziridine, diazabicycloalkyl, 3H-diazapropenyl, oxazalane, oxetanyl, 1, 2-dioxatidinyl, thietanyl, 1, 2-dithiabutenyl, azetidinyl, 1, 2-diazabutadienyl, azetidinyl, 1, 2-diazabutenyl, furyl, tetrahydrofuranyl, thienyl, 2, 5-dihydrothienyl, tetrahydrothienyl, pyrrolyl, dihydropyrrole, pyrrolidinyl, 1, 3-dioxolanyl, 1, 3-dioxol-2-onyl, 1, 2-dithiapentenyl, 1, 3-dithiapentanyl, 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-onyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, piperidinyl, 1, 4-dioxanyl, 2-triazolyl, 2, 3-triazolyl, 4-pyranyl, 4H-2-oxo-3-yl, 3H-dihydro-pyranyl, 4-oxo-pyridyl, 1, 4-dithiahexdienyl, 1, 4-oxahexdienyl, 1, 4-dioxanyl, 1, 3-oxahexanyl, 1, 3-oxathiahexanyl, 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, oxacycloheptatrienyl, thiepinyl, 1, 4-dioxacyclooctatrienyl, azepinyl, 1, 2-diazacycloheptatrienyl, 1, 3-diazacycloheptatrienyl, 1, 4-diazacycloheptatrienyl, azacyclooctatetraenyl, 1, 4-dihydro-1, 4-diaza Xin San alkenyl and the like;
"aryl" means a substituent containing an aromatic ring, such as phenyl or benzyl, optionally fused to 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 heteroatom containing one or more heteroatoms, preferably 1-3 heteroatoms, even more preferably 1-2 heteroatoms, independently selected from O, S and N. "arylalkyl" means C 1 -C 4 An alkylene-linked aryl group;
"arylalkyl" means C 1 -C 4 An alkylene-linked aryl group;
"arylalkyl" means C 1 -C 4 An alkylene-linked heteroaryl group;
"alkenyl", singly or in combination, refers to straight or branched chain hydrocarbons containing from 2 to 6, preferably from 2 to 4, carbon atoms; and contains 1 to 2 carbon-carbon double bonds, preferably 1 carbon-carbon double bond;
"alkoxy" means the group-O-alkyl;
the integer of 0-8 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 refer to salts prepared by mixing the compound shown in the general formula I with acid or alkali;
suitable acid addition salts are formed from acids that 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 (digluconate), glycerophosphate, hemisulfate (hemisulfate), heptanoate, caproate, formate, fumarate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malate, malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, nicotinic acid salt (nicotinate), nitrate, orotate, oxalate, palmitate, pamoate, pectate (pecinate), persulfate, 3-phenylpropionate, picrate (pivalate), trimethacetate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, phosphate, hydrogen phosphate, dihydrogenphosphate, p-toluenesulfonate, triflate, 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, a 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, alkali or alkaline earth metal based cations 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, tetramethyl ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful in forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like;
"stereoisomers" herein refers to all possible stereoisomeric forms of the compounds of the invention or of their physiologically antitumor compounds. Unless otherwise indicated, the chemical designation of compounds referred to in the present invention includes mixtures of all possible stereochemical forms, including all enantiomers and diastereomers of the basic structural molecule, as well as individual isomeric forms of the substantially pure compounds, i.e., other isomers having less than 10%, preferably less than 5%, particularly less than 2%, most preferably less than 1%, therein. The various stereoisomeric forms of the peptoid compounds of the invention are expressly included within the scope of the invention;
the compounds of the general formula I can also be present 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 also be substituted with one or more substituents. Such substituents include those listed in c.hansch and a.leo, substituent Constants for Correlation Analysis in Chemistry and Biology (1979); preferred substituents include alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, aminoalkyl, cyano, halogen, carboxyl, thio, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof;
the compounds of the present invention may be formulated into any pharmaceutical formulation by methods known in the art, and administered orally, parenterally, rectally, or pulmonary to a patient in need of such treatment, and, when administered orally, may be formulated into conventional solid formulations, such as tablets, capsules, pills, granules, and the like, and also may be formulated into oral liquid formulations, such as oral solutions, oral suspensions, syrups, and the like. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, it can be formulated into injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, it can be made into suppository. 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 to be treated. Generally, the total daily dosage of the compounds of the present invention will range from about 0.1 to about 2000mg per day, although there will be variations if necessary, depending on the purpose of the treatment, the patient and the route of administration. In one embodiment, the dose is about 1 to about 200 mg/day, administered as a single dose or as 2-4 separate doses. In another embodiment, the dose is about 10 to about 2000 mg/day, administered as a single dose or in 2-4 separate doses. In another embodiment, the dose is 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 about 500 to about 2000 mg/day, administered as a single dose or as 2-4 separate doses. When the compounds of the present invention, their pharmaceutically acceptable salts, esters or solvates or their prodrugs or isomers are used in combination with other therapeutically active substances, they may be administered simultaneously, separately or sequentially, and may be formulated into pharmaceutical compositions for single administration. The amount of the other therapeutically active substances to be used in combination may be based on the clinically used amount and may be appropriately selected according to the administration subject, administration route, disease, combination, etc. There are no particular restrictions on the form of administration of the other therapeutically active substances, provided that the compounds of the invention and the other therapeutically active substances are combined at the time of administration.
"pharmaceutical composition (pharmaceutical co 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 such an amount of any component or components that the appropriately careful medical practitioner finds the preparation unsuitable for administration to a normal 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 ℃.
2. Preparation method of carbonyl pyrazole antitumor compound
The preparation method of carbonyl pyrazole antitumor compound comprises the following steps:
synthetic route 1: reacting 2-aminothiazole with sodium nitrite under strong acid condition to generate diazonium salt firstly, then reacting with ethyl benzoylacetate to generate intermediate 2, reacting intermediate 2 with 4- (2-bromoacetyl) benzoic acid under the condition of thiosemicarbazide to generate intermediate 3, and introducing hydroxamic acid group to obtain final compound 4;
synthetic route 2: the method comprises the steps of (1) condensing p-acetyl benzoic acid and various amino acid methyl ester hydrochloride through amide to obtain an intermediate 5-9, brominating to obtain an intermediate 10-14, performing multi-step cyclization to obtain a key intermediate 15-19, and finally introducing hydroxamic acid groups to obtain a final product 20-24;
synthetic route 3: reacting p-hydroxyacetophenone with methyl bromoformate with different structures to obtain an intermediate 25-31, reacting with copper bromide to obtain a brominated product 32-38, performing multi-step cyclization to obtain a key intermediate 39-45, and finally introducing hydroxamic acid groups to obtain a final product 46-52;
the synthetic route is as follows:
scheme 1
Figure BDA0002706199010000081
Reagents and reaction conditions: (a) (i) sodium nitrite, concentrated hydrochloric acid, water, at 0 ℃ for 30min; (ii) sodium acetate, ethyl benzoylacetate, ethanol, 0deg.C, 1h; (b) 2-bromoacetophenone or 4- (2-bromoacetyl) benzoic acid, thiosemicarbazide, ethanol, 80 ℃; (c) Isobutyl chloroformate, N-methylmorpholine, tetrahydrofuran, hydroxylamine hydrochloride, potassium hydroxide, methanol, rt,6h;
scheme 2
Figure BDA0002706199010000082
Reagents and reaction conditions: (a) HATU, DIPEA, dichloromethane, room temperature; (b) copper bromide, volume ratio 1: ethyl acetate/chloroform at 80 ℃ for 3h; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
scheme 3
Figure BDA0002706199010000091
Reagents and reaction conditions: (a) potassium carbonate, room temperature; (b) Copper bromide, ethyl acetate/chloroform with volume ratio of 1:1, at 80 ℃ for 3h; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
the amino acid methyl ester hydrochloride is 5-aminopentanoic acid methyl ester hydrochloride, 6-aminocaproic acid methyl ester hydrochloride, 7-aminoheptanoic acid methyl ester hydrochloride, 8-aminocaprylic acid methyl ester hydrochloride, 4-aminomethylbenzoic acid methyl ester hydrochloride and 4-aminomethylcinnamic acid methyl ester hydrochloride; the methyl bromoformate is 4-bromobutyrate, 5-bromovalerate, 6-bromohexanoate, 7-bromoheptanoate, 8-bromooctanoate, 4-bromomethylbenzoate and 4-bromomethyl cinnamate;
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 procedure for the compounds will be described in detail in the examples.
Those skilled in the art can vary the above steps to increase the yield, they can design synthetic routes according to basic knowledge in the art, such as selecting reactants, reaction solvents, reaction temperatures, and can also increase the yield by using various protecting groups to avoid side reactions, and these conventional protecting methods can be seen in, for example, t.green Protecting Groups in Organic Synthesis.
3. Application of carbonyl pyrazole antitumor compound
The invention also provides application of the series of compounds in preparing medicines for preventing or treating cancers.
In addition, the invention also includes a pharmaceutical composition suitable for oral administration to a mammal comprising any of the compounds of formula I above, 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 any of the compounds of formula I above, a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.
In vitro anti-tumor cell proliferation activity was tested.
The compounds were tested for their cellular activity using the MTT assay. Inoculating tumor cell suspension (human cervical cancer cell HeLa) into 96-well plate, adding compound diluted with culture medium at different concentrations into each well, incubating for 48 hr, staining with MTT, incubating for 4 hr, measuring absorbance OD value of each well at 490/570nm with enzyme-labeled instrument, and calculating inhibition rate and IC 50 Values, thereby determining the antiproliferative activity of the compound of interest.
In vitro Bax protein affinity experiment results show 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 BTSA1.
In vitro anti-tumor cell proliferation experiments show that part of target compounds, especially compound 23, show better anti-proliferation activity on HeLa cells, and have growth inhibition activity IC on HeLa cells 50 The values were 0.86. Mu.M respectively. Therefore, part of the compounds in the invention have better anti-tumor cell proliferation activity, have great development prospect, and can be used for guiding the discovery of novel anti-tumor active molecules.
Detailed Description
The invention is further illustrated, but not limited, by the following examples.
EXAMPLE 1 Ethyl (Z) -3-oxo-3-phenyl-2- (2- (thiazol-2-yl) hydrazino) propionate (2)
2-aminothiazole solution (8 g,80 mmol) was added dropwise with an aqueous solution of sodium nicotinate (6.62 g,96 mmol) in concentrated hydrochloric acid in ice bath, and after the addition was completed, the reaction was carried out in ice bath for 20min to obtain diazonium salt solution. Ethyl benzoylacetate (12.30 g,64 mmol) was dissolved in ethanol (240 mL), and an aqueous solution of sodium acetate (38 g,460.8 mmol) was added thereto and stirred at room temperature for 30min. Dropwise adding the diazonium salt solution into ethyl benzoylacetate, reacting for 1h in ice bath, reacting for 1h at room temperature, evaporating ethanol, extracting aqueous phase with ethyl acetate for three times, mixing organic phases, drying anhydrous magnesium sulfate, evaporating solvent to obtain crude product, and performing column chromatography to obtain orange oily liquid with the yield of 54%. 1 H NMR(400MHz,CDCl 3 )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 (0.41 g,1.66 mmol) was dissolved in ethanol (20 mL), thiosemicarbazide (0.15 g,1.66 mmol) was added and reacted at room temperature for 1h, then intermediate 1 (0.5 g,1.66 mmol) was added, and the mixture was refluxed at 80℃for 3h, and a solid was precipitated. Cooling to room temperature, washing the solid with glacial ethanol and diethyl ether, and suction filtering to obtain red solid with a yield of 48%, and a melting point of 268-269 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 22 H 14 N 6 O 3 S 2 ,([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 (1.59 g,4 mmol) was dissolved in DMF and isobutyl chloroformate (0.61 mL,4.8 mmol) and N-methylmorpholine (0.58 mL,5.2 mmol) were added dropwise under ice-bath and reacted for 30min to give mixed anhydride. A fresh hydroxylamine solution (0.53 g,16 mmol) was added dropwise to the mixed anhydride and reacted at room temperature for 6 hours. Pouring the reaction solution into water, and suction-filtering to obtain a crude product. Column chromatography gives a red solid with a yield of 45% and a melting point of 194-195 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 22 H 15 N 7 O 3 S 2 ,([M+H] + ):490.0751,found:490.0746.
Example 2.5- (4-Acetylbenzamide) methyl valerate (5)
4-Acetylbenzoic acid (1.64 g,10 mmol) was dissolved in dichloromethane, and after DIPEA (1.65 mL,10 mmol) and HATU (4.56 g,12 mmol) were added, stirring was performed at room temperature for 30min. Methyl 5-aminopentanoate hydrochloride (2.01 g,11 mmol) was added and reacted at room temperature for 8h. The reaction mixture was washed with 1M HCl, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and column chromatographed to give a white solid in 85% yield, melting point 89-90 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 6- (4-acetylbenzamide) hexanoate (6)
Specific procedures refer to the synthesis of compound 5 in 67% yield and 96-98 ℃ melting point. 1 H NMR(400MHz,CDCl 3 )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-Acetylbenzoylamino) heptanoic acid methyl ester (7)
Specific procedures refer to the synthesis of compound 5 in 96% yield, melting point 101-103 ℃. 1 H NMR(400MHz,DMSO-d 6 )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).
Methyl 4- ((4-acetylbenzamide) methyl) benzoate (8)
Specific procedures refer to the synthesis of compound 5 in 99% yield with a melting point of 132-134 ℃. 1 H NMR(600MHz,CDCl 3 )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)
Specific procedures refer to the synthesis of compound 5 in 71% yield with a melting point of 175-176 ℃. 1 H NMR(400MHz,DMSO-d 6 )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).
Methyl 5- (4- (2-bromoacetyl) benzamide) pentanoate (10)
Intermediate 5 (2.3 g,8.3 mmol) was dissolved in ethyl acetate/chloroform (1:1, 80 mL), copper bromide (3.71 g,16.6 mmol) was added, reflux was performed at 80℃for 3h, suction filtration was performed, and the filtrate column chromatography gave a white solid with a yield of 72%, melting point 82-84 ℃. 1 H NMR(400MHz,CDCl 3 )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) benzamide) (11)
For specific procedures reference is made to the synthesis of intermediate 10 in 70% yield, melting point 97-99 ℃. 1 H NMR(400MHz,DMSO-d 6 )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) benzamide) heptanoic acid methyl ester (12)
For specific procedures reference is made to the synthesis of intermediate 10 in 80% yield, melting point 99-101 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 4- ((4- (2-bromoacetyl) benzamide) methyl) benzoate (13)
For specific procedures reference is made to the synthesis of intermediate 10 in 76% yield, melting point 126-129 ℃. 1 H NMR(400MHz,DMSO-d 6 )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)
For specific procedures reference is made to the synthesis of intermediate 10 in 63% yield, melting point 149-151 ℃. 1 H NMR(400MHz,CDCl 3 )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) benzamide) pentanoate (15)
Intermediate 10 (0.42 g,1 mmol) was dissolved in methanol (20 mL), thiosemicarbazide (0.09 g,1 mmol) was added and reacted at room temperature for 1h, addedAfter intermediate 1 (0.36 g,1 mmol), reflux was carried out at 80℃for 3h to give a red solid in 64% yield, melting point 196-197 ℃. 1 H NMR(400MHz,DMSO-d 6 )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-yl thiazol-4-yl) benzamide hexanoic acid (16)
Specific synthetic methods refer to the synthesis of intermediate 15 in 59% yield, melting point 199-200 ℃. 1 H NMR(400MHz,DMSO-d 6 )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) benzamide) heptanoate (17)
Specific synthetic methods refer to the synthesis of intermediate 15 in 60% yield, melting point 219-220 ℃. 1 H NMR(400MHz,DMSO-d 6 )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) -4- ((4- (2- (5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) methylene) -4, 5-dihydro-1H-pyrazol-1-) thiazol-4-yl) benzamide) benzoic acid methyl ester (18)
Specific synthetic methods refer to the synthesis of intermediate 15 in 33% yield with melting point 182-183 ℃. 1 H NMR(600MHz,DMSO-d 6 )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) benzamide) methyl) phenyl) acrylate (19
Specific synthetic methods refer to the synthesis of intermediate 15 in 68% yield with a melting point of 250-251 ℃. 1 H NMR(400MHz,DMSO-d 6 )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)
Hydroxylamine hydrochloride (2.92 g,42 mmol) and potassium hydroxide (3.53 g,63 mmol) were dissolved in methanol, respectively, and a methanol solution of potassium hydroxide was added dropwise to hydroxylamine hydrochloride in an ice bath, followed by reaction in an ice bath for 10min, followed by suction filtration to obtain a methanol solution of hydroxylamine and potassium hydroxide. Intermediate 15 (1.76 g,3 mmol) was dissolved in DMF (8 mL), fresh hydroxylamine, potassium hydroxide in methanol was added and reacted at room temperature for 6h 20mL water was added and ph=4 was adjusted with 6M hydrochloric acid and suction filtration was performed to give crude product. Column chromatography gave a red solid in 55% yield, melting point 219-220 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 27 H 24 N 8 O 4 S 2 ,([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 synthetic method of compoundPlease refer to the synthesis of compound 20, yield 46%, melting point>280℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 28 H 26 N 8 O 4 S 2 ,([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)
For a specific synthesis method of the compound, please refer to the synthesis of the compound 20, the yield is 77%, and the melting point is 187-188 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 29 H 28 N 8 O 4 S 2 ,([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) benzamide (23)
For a specific synthesis method of the compound, please refer to the synthesis of the compound 20, the yield is 29%, and the melting point is 217-219 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 30 H 22 N 8 O 4 S 2 ,([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) hydrazinoalkylene) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide (24)
For a specific synthesis method of the compound, please refer to the synthesis of the compound 20, the yield is 36%, and the melting point is 251-253 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 32 H 24 N 8 O 4 S 2 ,([M+H] + ):649.1435,found:649.1445.
EXAMPLE 7 methyl 4- (4-Acetylphenoxy) butanoate (25)
P-hydroxyacetophenone (2.7 g,20 mmol) was dissolved in DMF and K was added 2 CO 3 (8.3 g,60 mmol), KI (0.1 g) and methyl 4-bromobutyrate (3.77 mL,30 mmol) were stirred at room temperature for 8h the reaction solution 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, suction filtered, and column chromatographed to give 3.94g of a white solid with a yield of 83%, melting point 64-66 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 5- (4-Acetylphenoxy) pentanoate (26)
Specific synthetic methods refer to the synthesis of intermediate 25 in 90% yield, melting point 56-57 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 6- (4-Acetylphenoxy) hexanoate (27)
Specific synthetic methods refer to the synthesis of intermediate 25 in 94% yield, melting point 46-48 ℃. 1 H NMR(400MHz,CDCl 3 )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)
Specific synthetic methods refer to the synthesis of intermediate 25 in 90% yield with melting point 63-65 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 8- (4-Acetylphenoxy) octanoate (29)
Specific synthetic methods refer to the synthesis of intermediate 25 in 92% yield, melting point 52-54 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 4- ((4-Acetylphenoxy) methyl) benzoate (30)
Specific synthetic methods refer to the synthesis of intermediate 25 in 88% yield, melting point 119-121 ℃. 1 H NMR(400MHz,CDCl 3 )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)
Specific synthetic methods refer to the synthesis of intermediate 25 in 84% yield with a melting point of 150-151 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 4- (4- (2-bromoacetyl) phenoxy) butyrate (32)
Specific synthetic methods refer to the synthesis of intermediate 10 in 70% yield with melting points of 90-92 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 5- (4- (2-bromoacetyl) phenoxy) pentanoate (33)
Specific synthetic methods refer to the synthesis of intermediate 10 in 83% yield, melting point 61-62 ℃. 1 H NMR(400MHz,CDCl 3 )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)
Specific synthetic methods refer to the synthesis of intermediate 10 in 65% yield, melting point 61-63 ℃. 1 H NMR(400MHz,CDCl 3 )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)
Specific synthetic methods refer to the synthesis of intermediate 10 in 57% yield with melting point 60-61 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 8- (4- (2-bromoacetyl) phenoxy) octanoate (36)
Specific synthetic methods refer to the synthesis of intermediate 10 in 53% yield, melting point 62-64 ℃. 1 H NMR(400MHz,CDCl 3 )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).
Methyl 4- ((4- (2-bromoacetyl) phenoxy) methyl) benzoate (37)
Specific synthetic methods refer to the synthesis of intermediate 10 in 84% yield, melting point 121-123 ℃. 1 H NMR(400MHz,CDCl 3 )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)
Specific synthetic methods refer to the synthesis of intermediate 10 in 75% yield, melting point 140-141 ℃. 1 H NMR(400MHz,CDCl 3 )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) butanoic acid ester (39)
Specific synthetic methods refer to the synthesis of intermediate 15 in 52% yield with melting points of 196-198 ℃. 1 H NMR(400MHz,DMSO-d 6 )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)
Specific synthetic methods refer to the synthesis of intermediate 15 in 54% yield, melting point 173-174 ℃. 1 H NMR(400MHz,DMSO-d 6 )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) hexanoic acid ester (41)
Specific synthetic methods refer to the synthesis of intermediate 15 in 71% yield with melting points of 198-200 ℃. 1 H NMR(400MHz,DMSO-d 6 )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)
Specific synthetic methods refer to the synthesis of intermediate 15 in 68% yield, melting point 146-147 ℃. 1 H NMR(400MHz,DMSO-d 6 )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) octanoic acid ester (43)
Specific synthetic methods refer to the synthesis of intermediate 15 in 76% yield, melting point 166-167 ℃. 1 H NMR(400MHz,DMSO-d 6 )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)
Specific synthetic methods refer to the synthesis of intermediate 15 in 61% yield, melting point 215-216 ℃. 1 H NMR(400MHz,DMSO-d 6 )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)
Specific synthetic methods refer to the synthesis of intermediate 15 in 78% yield, melting point 222-223 ℃. 1 H NMR(400MHz,DMSO-d 6 )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)
Specific synthetic methods refer to the synthesis of the target compound 20 in 67% yield, melting point 242-244 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C 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 C 25 H 21 N 7 O 4 S 2 ,([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)
Specific synthetic methods refer to the synthesis of target compound 20 in 83% yield, melting point 153-155 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 26 H 23 N 7 O 4 S 2 ,([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 refer to the synthesis of the target compound 20 in 55% yield with a melting point of 132-134 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 27 H 25 N 7 O 4 S 2 ,([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)
Specific synthetic methods refer to the synthesis of the target compound 20 in 64% yield with a melting point of 127-128 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 28 H 27 N 7 O 4 S 2 ,([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)
Specific synthetic methods refer to the synthesis of the target compound 20 in 60% yield with a melting point of 144-145 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 29 H 29 N 7 O 4 S 2 ,([M+H] + ):604.1795,found:604.1787.HPLC t R ＝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)
Specific synthetic methods refer to the synthesis of the target compound 20 in a yield of 60% and a melting point of 216-217 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 29 H 21 N 7 O 4 S 2 ,([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)
Specific synthetic methods refer to the synthesis of the target compound 20 in a yield of 70% and a melting point of 186-188 ℃. 1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(101MHz,DMSO-d 6 )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 C 31 H 23 N 7 O 4 S 2 ,([M+H] + ):622.1326,found:622.1320.
Evaluation of Activity of target Compounds
Experimental example 1 proliferation test of target Compounds for inhibiting human cervical cancer cells (HeLa cells)
[ Material ]
K562, KG1, HL-60, A549, heLa, tetramethylazo salt MTT,10% fetal bovine serum (Hyclone Co., USA), 2.5g.L-1 trypsin (Gibco Co., USA), modified RPMI1640 medium (Hyclone Co., USA), 96 well plates;
[ method ]
Conventionally culturing cells, and collecting the cells growing logarithmically for experiments; logarithmic growth was performed on 10% RPMI1640 medium containing fetal bovine serumLong term cell dilution to 4X 10 4 Individual mL -1 Inoculating into 96-well plate (100 μl of each well) without adding cells as blank hole, and culturing in constant temperature incubator (37deg.C, 5% carbon dioxide) for 8 hr; adding a target compound solution prepared by a culture medium, taking the solution as 100% of a non-medicated well, culturing in a constant temperature incubator (37 ℃ C., 5% carbon dioxide) for 48 hours, adding 30 mu L of MTT, removing liquid in the well after four hours (suspended cells need to be centrifuged), adding 150 mu L of DMSO, finally shaking for 10 minutes in a constant temperature shaking table, measuring the absorbance value of each well at 570nm wavelength by using an enzyme-labeled instrument, and calculating the inhibition rate and IC (integrated circuit) 50 A value;
Figure BDA0002706199010000221
TABLE 2 experimental results of in vitro inhibition of tumor cell proliferation by target compounds
Figure BDA0002706199010000222
The data in table a are the average of three experiments, and the values after ". + -." represent standard errors
Description of the terminology: k562, human chronic myelogenous leukemia cells; HL-60, human promyelocytic leukemia cells;
conclusion: the anti-tumor proliferation activity of all the target compounds is superior to that of the positive control medicine, wherein the activity of the target compound 23 for inhibiting the proliferation of K562 cells is 9 times that of the positive control medicine BTSA1, and the activity for inhibiting the proliferation of HL-60 cells is 11 times that of the positive control medicine.
The compound can be subjected to activity research in depth, and more active compounds are developed to be used for preparing medicines for preventing and treating cancers.

Claims (10)

1. A carbonyl pyrazole derivative which is a compound with a structure shown in a general formula I and pharmaceutically acceptable salt;
Figure FDA0004072558120000011
in the general formula I, R 1 Is thiazole;
in the general formula I, R 2 Is phenyl;
z represents-O- (CH) 2 ) n1 -CONHOH,-CO-X-(CH 2 ) n1 -CONHOH,-O-(CH 2 ) n2 -Ar-(CH) n3 -CONHOH or-CO-X- (CH) 2 ) n2 -Ar-(CH) n3 -CONHOH；
n l Represents an integer of 0 to 10;
n 2 represents an integer of 0 to 10;
n 3 0 or 2;
x represents a nitrogen atom or an oxygen atom;
ar represents a benzene ring.
2. Carbonyl pyrazole derivative according to claim 1, characterized in that in the general formula I:
R 1 is thiazole;
R 2 is phenyl;
z represents-O- (CH) 2 )n 1 -CONHOH,-CO-X-(CH 2 )n 1 -CONHOH,-O-(CH 2 )n 2 -Ar-(CH)n 3 -CONHOH or-CO-X- (CH) 2 )n 2 -Ar-(CH)n 3 -CONHOH；
n l Represents an integer of 3 to 8;
n 2 1 is shown in the specification;
n 3 0 or 2;
x represents a nitrogen atom.
3. Carbonyl pyrazole derivative according to claim 1, characterized in that it 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
(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
(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
(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
(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) benzamide
N- (4- ((E) -3- (hydroxyamino) -3-oxoprop-1-en-1-yl) benzyl) -4- (2- ((Z) -5-oxo-3-phenyl-4- (2- (thiazol-2-yl) hydrazino) subunit) -4, 5-dihydro-1H-pyrazol-1-yl) thiazol-4-yl) benzamide
(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
(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) pentanoic acid amide
(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
(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
(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
(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
(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.
4. A process for the preparation of a carbonyl pyrazole derivative as claimed in claim 1, comprising the steps of:
synthetic route 1: reacting 2-aminothiazole with sodium nitrite under strong acid condition to generate diazonium salt firstly, then reacting with ethyl benzoylacetate to generate intermediate 2, reacting intermediate 2 with 4- (2-bromoacetyl) benzoic acid under the condition of thiosemicarbazide to generate intermediate 3, and introducing hydroxamic acid group to obtain final compound 4;
synthetic route 2: the method comprises the steps of (1) condensing p-acetyl benzoic acid and various amino acid methyl ester hydrochloride through amide to obtain an intermediate 5-9, brominating to obtain an intermediate 10-14, performing multi-step cyclization to obtain a key intermediate 15-19, and finally introducing hydroxamic acid groups to obtain a final product 20-24;
synthetic route 3: reacting p-hydroxyacetophenone with methyl bromoformate with different structures to obtain an intermediate 25-31, reacting with copper bromide to obtain a brominated product 32-38, performing multi-step cyclization to obtain a key intermediate 39-45, and finally introducing hydroxamic acid groups to obtain a final product 46-52;
the synthetic route is as follows:
scheme 1
Figure FDA0004072558120000031
Reagents and reaction conditions: (a) (i) sodium nitrite, concentrated hydrochloric acid, water, at 0 ℃ for 30min; (ii) sodium acetate, ethyl benzoylacetate, ethanol, 0 ℃,1h; (b) 4- (2-bromoacetyl) benzoic acid, thiosemicarbazide, ethanol, 80 ℃; (c) Isobutyl chloroformate, N-methylmorpholine, tetrahydrofuran, hydroxylamine hydrochloride, potassium hydroxide, methanol, rt,6h;
scheme 2
Figure FDA0004072558120000032
Reagents and reaction conditions: (a) HATU, DIPEA, dichloromethane, room temperature; (b) Copper bromide, ethyl acetate/chloroform with the volume ratio of 1:1, at 80 ℃ for 3 hours; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
scheme 3
Figure FDA0004072558120000033
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 hours; (c) thiosemicarbazide, methanol, 80 ℃; (d) hydroxylamine hydrochloride, potassium hydroxide, methanol, room temperature;
the amino acid methyl ester hydrochloride is 5-aminopentanoic acid methyl ester hydrochloride, 6-aminocaproic acid methyl ester hydrochloride, 7-aminoheptanoic acid methyl ester hydrochloride, 8-aminocaprylic acid methyl ester hydrochloride, 4-aminomethylbenzoic acid methyl ester hydrochloride and 4-aminomethylcinnamic acid methyl ester hydrochloride; the methyl bromoformate is 4-bromobutyrate, 5-bromovalerate, 6-bromohexanoate, 7-bromoheptanoate, 8-bromooctanoate, 4-bromomethylbenzoate and 4-bromomethyl cinnamate.
5. Use of a carbonyl pyrazole derivative according to any one of claims 1 to 3, in the manufacture of a medicament for the prophylaxis or treatment of cancer.
6. A pharmaceutical composition suitable for oral administration to a mammal comprising a carbonyl pyrazole derivative of any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
7. A pharmaceutical composition suitable for parenteral administration to a mammal comprising a carbonyl pyrazole derivative of any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
8. A pharmaceutical composition comprising a carbonyl pyrazole derivative according to any of claims 1 to 3, a pharmaceutically acceptable salt thereof and one or more therapeutically active substances selected from anti-tumour agents.
9. A pharmaceutical composition comprising a carbonyl pyrazole derivative according to any of claims 1 to 3, a pharmaceutically acceptable salt thereof and one or more therapeutically active substances selected from anticancer drugs.
10. A pharmaceutical composition comprising a carbonyl pyrazole derivative according to any of claims 1 to 3, a pharmaceutically acceptable salt thereof and one or more therapeutically active substances selected from chemotherapeutic agents.
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