CN115160222A - Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof - Google Patents

Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof Download PDF

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CN115160222A
CN115160222A CN202210733176.2A CN202210733176A CN115160222A CN 115160222 A CN115160222 A CN 115160222A CN 202210733176 A CN202210733176 A CN 202210733176A CN 115160222 A CN115160222 A CN 115160222A
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phenyl
sulfonamido
hydroxy
acrylamide
quinolin
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CN115160222B (en
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孙伟
贾丽娜
李凯雨
李默涵
黄鑫
李枝猛
田乃鑫
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

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Abstract

The invention relates to a hydroxamic acid compound containing quinoline or isoquinoline, and a preparation method and an application thereof, belonging to the technical field of medicinesThe compound comprises a pharmaceutical composition of the compound, is applied as a histone deacetylase inhibitor and is used for preventing and/or treating diseases related to histone deacetylase, and the structure of the hydroxamic acid compound containing quinoline or isoquinoline is shown in a general formula I:

Description

Hydroxamic acid compound containing quinoline or isoquinoline and preparation and application thereof
the technical field is as follows:
the invention belongs to the technical field of medicines, and particularly relates to a hydroxamic acid compound containing quinoline or isoquinoline, and a preparation method and application thereof, particularly relates to an application of the hydroxamic acid compound as a histone deacetylase inhibitor for preventing and/or treating diseases related to histone deacetylase.
The background art comprises the following steps:
cancer, which has become a leading cause of death worldwide due to its high morbidity and mortality, is one of the most dreaded killers in humans.
In the emerging field of cancer research, epigenetic alterations have an essential function in the development, progression and invasive metastasis of tumors. Histone posttranslational modification is a key process of epigenetic regulation, and a large number of researches show that abnormal reduction of histone acetylation level is closely related to cancers and various immune diseases. Histone deacetylases HDACs are one of the key enzymes regulating the balance of histone acetylation and deacetylation in vivo, and abnormal expression of HDACs is found in many cancers. It follows that HDACs have become an important target for cancer research.
HDACs-mediated deacetylation of histones plays an important role in regulating cell differentiation, proliferation and survival. The hyperacetylation of histones caused by mutations or abnormal expression of HDACs is closely associated with the proliferation, invasion and migration of tumors. Numerous studies have shown that overexpression of HDACs is observed in different types of cancer and is in most cases strongly associated with poor prognosis. Relevant research shows that the HDACs inhibitor can play an anti-tumor role by inducing tumor cell apoptosis, inhibiting tumor tissue micro-angiogenesis and the like, so that the HDACs inhibitor is developed as a novel anti-tumor medicament.
The invention content is as follows:
the invention aims to overcome the defects in the prior art and provides a hydroxamic acid compound containing quinoline or isoquinoline, a preparation method and an application thereof, and an application of the compound as a histone deacetylase inhibitor in preventing and/or treating tumors.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a hydroxamic acid compound containing quinoline or isoquinoline as shown in a general formula I and a pharmaceutically acceptable salt or hydrate thereof.
Figure BDA0003714660120000021
Wherein:
x is N or CH, Y is CH or N; wherein, when X is N, Y is CH; when X is CH, Y is N;
w is carbonyl or (C) 3 -C 5 ) An α, β -unsaturated carbonyl group;
ring A is aryl or heteroaryl, wherein aryl or heteroaryl are each independently optionally substituted with one or more R, R is hydrogen, (C) 1 -C 6 ) Alkyl, cyano, halogen, halo (C) 1 -C 6 ) Alkyl, hydroxy, mercapto or alkoxy;
wherein the aryl group is a 6-10 membered aryl group; the heteroaryl is a five-membered or six-membered heteroaryl, which contains 1-3 heteroatoms of N, O or S, and the rest of ring atoms are C; the aryl group is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl; the six-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) An α, β -unsaturated carbonyl group;
ring a is aryl or heteroaryl;
wherein said aryl group is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; the six-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) An α, β -unsaturated carbonyl group;
ring a is aryl or heteroaryl;
wherein said aryl group is phenyl; the heteroaryl group is pyridyl, pyrazinyl;
further, when ring A is phenyl, phenyl is
Figure BDA0003714660120000022
Further, when ring A is pyridyl, pyridyl is
Figure BDA0003714660120000023
Further, when ring A is pyrazinyl, pyrazinyl is
Figure BDA0003714660120000024
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) An α, β -unsaturated carbonyl group;
ring A is aryl;
wherein said aryl is phenyl;
further, when ring A is phenyl, phenyl is
Figure BDA0003714660120000031
Preferred compounds of the present invention are those of the following structure:
x is N, then Y is CH; or X is CH, then Y is N;
w is-CH = CH-CO-;
ring A is aryl;
wherein said aryl group is phenyl;
further, when ring A is phenyl, phenyl is
Figure BDA0003714660120000032
Specifically, the following compounds are preferred in the present invention:
(E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-1);
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-2);
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (I-3);
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-4);
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-5);
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-6);
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfonamido) phenyl) acrylamide (I-7);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-8);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfonamido) phenyl) acrylamide (I-9);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-10);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-11);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-12);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-13);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-14);
(E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-15);
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-16);
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (I-17);
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-18);
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-19);
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-20);
(E) -N-hydroxy-3- (3- (N- (quinolin-8-yl) sulfonamido) phenyl) acrylamide (I-21);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-22);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfonamido) phenyl) acrylamide (I-23);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-24);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-25);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-26);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-27);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-28);
or salts and hydrates thereof;
the term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; "alkyl" refers to straight or branched chain alkyl.
According to the present invention, the pharmaceutically acceptable salt may be an inorganic acid salt or an organic acid salt; preferably, the inorganic acid salt is selected from salts formed by any one of the following inorganic acids: hydrochloric, hydrobromic, sulfuric, or phosphoric acid; preferably, the organic acid salt is selected from salts formed by any one of the following organic acids: acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, citric acid, salicylic acid, tartaric acid or p-toluenesulfonic acid.
The invention also includes prodrugs of the compounds of the invention. By pharmaceutically acceptable prodrug is meant a prodrug that may itself have weak or even no activity, but which, upon administration, can be converted to-COOH, -NH under physiological conditions (e.g., by metabolism, solvolysis, or another form) 2 -OH, etc., to form a compound of the present invention.
The invention comprises a pharmaceutical composition which contains the hydroxamic acid compound with the quinoline or isoquinoline structure as an active ingredient and pharmaceutically acceptable auxiliary materials. The medicinal auxiliary materials comprise conventional diluents, excipients, fillers, adhesives, wetting agents, disintegrating agents, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
The pharmaceutical composition can be prepared into a plurality of dosage forms, such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The compounds of the invention and pharmaceutical compositions comprising the compounds of the invention may be formulated in a form suitable for intravenous, oral, rectal, parenteral, intranasal or transdermal administration, or in a form suitable for administration by inhalation or by suppository. Oral and intravenous administration are preferred.
The hydroxamic acid compounds containing quinoline or isoquinoline and the pharmaceutical compositions thereof are used as histone deacetylase inhibitors for preventing and/or treating diseases related to abnormal expression of histone deacetylase, such as various cancers, including liver cancer, colon cancer, pancreatic cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer and the like.
The preparation of the hydroxamic acid compound containing quinoline or isoquinoline adopts one of the following two routes:
route one:
Figure BDA0003714660120000051
the substituents are as defined in the summary section, reagents and conditions: HSO 3 Cl,12h；b.RNH 2 ,CH 2 Cl 2 ,pyridine, 1h；c.CH 3 OH,H 2 SO 4 ,4h；d.NH 2 OH,1N NaOH,CH 3 OH,1h.
And a second route:
Figure BDA0003714660120000052
the substituents are as defined in the summary section, reagents and conditions: RNH 2 ,CH 2 Cl 2 ,pyridine,2h；b.methyl acrylate,Pd(OAc) 2 ,POT,Et 3 N,CH 3 CN,60℃,12h；c.NH 2 OH,1N NaOH,CH 3 OH,1h.
The invention has the beneficial effects that:
the hydroxamic acid compounds containing quinoline or isoquinoline have good anti-tumor cell proliferation activity, and the preparation method is simple to operate and mild in condition.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to examples.
Example 1: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-1)
Structural formula of compound (I-1)
Figure BDA0003714660120000053
Step A: (E) Preparation of (E) -3- (4- (chlorosulfonyl) phenyl) acrylic acid
Figure BDA0003714660120000061
Cinnamic acid (1g, 6.76mmol) was slowly added to chlorosulfonic acid (7.84g, 67.6 mmol) in portions with stirring at 0 deg.C, stirring was continued for 30min, then slowly returned to room temperature, and stirring was continued for an additional 12h. After the reaction, the reaction solution was slowly dropped into ice water, and after suction filtration, vacuum drying was carried out to obtain a yellow solid, and the solid was added to 1, 4-dioxane to carry out recrystallization to obtain (E) -3- (4- (chlorosulfonyl) phenyl) acrylic acid as white crystals (0.55 g, yield 33%).
And B: (E) Preparation of (E) -3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylic acid
Figure BDA0003714660120000062
Pyridine (1 ml) and (E) -3- (4- (chlorosulfonyl) phenyl) acrylic acid (1 g, 4.06mmol) were added to a solution of 2-aminoquinoline (0.49g, 3.4 mmol) in dichloromethane (50 ml) at 0 ℃ with stirring. After the addition was complete, the reaction was stirred at 0 ℃ for 1h. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give (E) -3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylic acid as a pale yellow solid (0.6 g, yield 50%).
And C: preparation of methyl (E) -3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylate
Figure BDA0003714660120000063
To a solution of (E) -3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylic acid (0.6 g,1.7 mmol) in methanol (40 ml) was added 1 drop of concentrated H 2 SO 4 . After the addition, the reaction solution was heated under reflux for 4 hours. After completion of the reaction, extraction was performed with ethyl acetate (50 ml. Times.3), and the organic phases were combined, washed 3 times with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentratedAnd (4) shrinking. The crude product was purified by silica gel column chromatography to give methyl (E) -3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylate as a white solid (0.5 g, 80% yield).
Step D: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide
Figure BDA0003714660120000064
To a solution of methyl (E) -3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylate (0.5 g, 1.36 mmol) in methanol (20 ml) was slowly added dropwise a 1mol/L NaOH solution (3 ml) with stirring at 0 ℃ for 10 minutes, and NH was further slowly added dropwise thereto 2 OH solution (3 ml), after the addition was complete, was slowly brought to room temperature and stirring was continued for 1h. After the reaction was completed, the solvent was distilled off under reduced pressure, water (20 ml) was added thereto, the pH was adjusted to neutral with 2mol/L hydrochloric acid, and a solid precipitated, which was filtered off under suction, and dried under vacuum to give (E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-1) as a white solid (0.36 g, yield 73%). Mp is 171.6-173.3 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.09(d,J＝9.0Hz,1H),7.91(d,J ＝8.3Hz,2H),7.74(d,J＝7.8Hz,1H),7.65(d,J＝8.3Hz,2H),7.59(t,J＝7.4Hz,1H),7.52(d,J ＝8.3Hz,1H),7.45(d,J＝15.8Hz,1H),7.29(t,J＝7.4Hz,2H),6.53(d,J＝15.8Hz,1H). ESI-MS m/z:392.08[M+Na] + .
the compounds of examples 2-14 were prepared by the preparation of example 1, selecting the appropriate starting materials.
Example 2: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-2)
Structural formula of compound (I-2)
Figure BDA0003714660120000071
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-2) as a pale yellow solid in 85% yield. Mp is 185.7-187.9 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.82(s,1H),9.10(s,1H),8.55(d,J＝2.5Hz, 1H),7.83(dd,J＝27.4,8.2Hz,6H),7.66(d,J＝8.4Hz,2H),7.55(t,J＝7.2Hz,1H),7.49(t,J＝ 7.4Hz,1H),7.42(d,J＝15.8Hz,1H),6.50(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 3: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (I-3)
Structural formula of compound (I-3)
Figure BDA0003714660120000072
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (I-3) as a white solid in 79% yield. Mp is 228.9-230.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.39(d,J＝8.1Hz,1H),8.18(d,J＝6.3Hz,1H), 7.83(d,J＝8.3Hz,2H),7.65(dd,J＝8.9,1.4Hz,2H),7.61(d,J＝8.2Hz,2H),7.41(ddd,J＝11.8, 8.6,8.1Hz,2H),6.98(d,J＝6.3Hz,1H),6.49(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 4: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-4)
Structural formula of compound (I-4)
Figure BDA0003714660120000081
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-4) as a pale yellow solid in 77% yield. Mp is 199.0-201.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),10.45(s,1H),9.12(s,1H),8.85 (dd,J＝4.1,1.5Hz,1H),8.40(d,J＝8.5Hz,1H),7.85(d,J＝8.5Hz,1H),7.70–7.61(m,5H), 7.47–7.41(m,2H),7.20(d,J＝7.4Hz,1H),6.52(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 5: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-5)
Structural formula of compound (I-5)
Figure BDA0003714660120000082
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-5) as a white solid in 70% yield. Mp is 177.9-179.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.58(s,1H),8.60(d,J＝3.0Hz,1H),8.05(d,J ＝8.2Hz,1H),7.79(d,J＝8.3Hz,2H),7.74(d,J＝8.8Hz,1H),7.60(d,J＝8.2Hz,2H),7.43– 7.36(m,3H),7.32(dd,J＝8.3,4.1Hz,1H),6.48(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 6: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-6)
Structural formula of compound (I-6)
Figure BDA0003714660120000083
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-6) as a white solid in 73% yield. Mp is 182.2-185.3 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.76(dd,J＝4.1,1.4Hz,1H),8.20(d,J＝7.9Hz, 1H),7.83(t,J＝9.8Hz,3H),7.69(d,J＝8.3Hz,2H),7.62(d,J＝0.8Hz,1H),7.41(d,J＝15.8Hz, 1H),7.38(dd,J＝8.8,1.9Hz,1H),7.35(dd,J＝8.2,4.2Hz,1H),6.52(d,J＝15.8Hz,1H). ESI-MS m/z:370.10[M+H] + .
example 7: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfonamido) phenyl) acrylamide (I-7)
Structural formula of compound (I-7)
Figure BDA0003714660120000091
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfonamido) phenyl) acrylamide (I-7) as a pale yellow solid in 85% yield. Mp is 158.2-160.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.20(s,1H),9.36(s,1H),8.81(d,J＝2.3Hz, 1H),8.27(d,J＝8.1Hz,1H),7.89(d,J＝5.1Hz,2H),7.73–7.34(m,8H),6.49(d,J＝15.8Hz, 1H).ESI-MS m/z:370.10[M+H] + .
example 8: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-8)
Structural formula of compound (I-8)
Figure BDA0003714660120000092
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-8) as a pale yellow solid in 70% yield. Mp is 215.5-217.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.38(d,J＝8.2Hz,1H),7.95(d,J＝8.3Hz,2H), 7.72(t,J＝8.5Hz,2H),7.65(d,J＝8.1Hz,2H),7.59(d,J＝6.7Hz,1H),7.56–7.50(m,1H),7.45 (d,J＝15.8Hz,1H),6.97(d,J＝6.0Hz,1H),6.52(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+ H] + .
example 9: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfonamido) phenyl) acrylamide (I-9)
Structural formula of compound (I-9)
Figure BDA0003714660120000093
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfonamido) phenyl) acrylamide (I-9) as a pale yellow solid in 71% yield. Mp is 225.4-228.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.91(s,1H),7.88(t,J＝7.9Hz,3H),7.69(d,J＝ 7.9Hz,1H),7.63(d,J＝8.2Hz,2H),7.55(t,J＝7.5Hz,1H),7.41(d,J＝15.8Hz,1H),7.36– 7.32(m,1H),7.29(s,1H),6.52(d,J＝15.8Hz,1H). ESI-MS m/z:370.14[M+H] + .
example 10: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-10)
Structural formula of compound (I-10)
Figure BDA0003714660120000101
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-10) as a pale yellow solid in 83% yield. Mp is 110.1-112.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.87(s,1H),8.98(s,1H),8.08(d,J＝10.0 Hz,1H),8.03(d,J＝7.9Hz,1H),7.72–7.60(m,7H),7.43(d,J＝15.7Hz,1H),6.53(d,J＝15.8 Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 11: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-11)
Structural formula of compound (I-11)
Figure BDA0003714660120000102
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-11) as a white solid in 80% yield. Mp is 170.7-172.8 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.12(s,1H),8.33(d,J＝5.8Hz, 1H),8.00(d,J＝5.8Hz,1H),7.70(d,J＝8.2Hz,3H),7.58(d,J＝8.2Hz,3H),7.40(dd,J＝15.0, 7.0Hz,2H),7.30(d,J＝7.5Hz,1H),6.48(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 12: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-12)
Structural formula of compound (I-12)
Figure BDA0003714660120000103
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-12) as a pale yellow solid in 77% yield. Mp is 166.0-168.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),9.03(s,1H),8.30(d,J＝5.8 Hz,1H),7.89(d,J＝8.8Hz,1H),7.85(d,J＝8.4Hz,2H),7.66(d,J＝8.3Hz,2H),7.58(d,J＝5.8 Hz,1H),7.46(s,1H),7.41(d,J＝15.8Hz,1H),7.35(dd,J＝8.8,1.8Hz,1H),6.52(d,J＝15.8Hz, 1H).ESI-MS m/z:370.11[M+H] + .
example 13: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-13)
Structural formula of compound (I-13)
Figure BDA0003714660120000111
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-13) as a pale yellow solid in 79% yield. Mp is 171.2-173.2 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.84(s,1H),9.15(s,1H),8.34(d,J＝5.6 Hz,1H),7.82(t,J＝7.6Hz,3H),7.71(s,1H),7.68–7.65(m,3H),7.49(dd,J＝8.8,1.9Hz,1H), 7.41(d,J＝15.8Hz,1H),6.51(d,J＝15.8Hz,1H).ESI-MS m/z:370.12[M+H] + .
example 14: (E) Preparation of (E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-14)
Structural formula of Compound (I-14)
Figure BDA0003714660120000112
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-14) as a pale yellow solid in 75% yield. Mp is 175.2-177.9 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),9.37(s,1H),8.43(d,J＝5.6 Hz,1H),7.77–7.60(m,7H),7.44(d,J＝15.8Hz,1H),7.27(d,J＝7.5Hz,1H),6.52(d,J＝15.9 Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 15: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-15)
Structural formula of compound (I-15)
Figure BDA0003714660120000113
Step A: preparation of 3-bromo-N- (quinolin-2-yl) benzenesulfonamide
Figure BDA0003714660120000114
To a solution of 2-aminoquinoline (0.47g, 3.26mmol) in dichloromethane (50 ml) was added pyridine (1 ml) and 3-bromobenzenesulfonyl chloride (1 g, 3.92mmol) with stirring at 0 ℃. After the addition was complete, the reaction was stirred at 0 ℃ for 2h. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-bromo-N- (quinolin-2-yl) benzenesulfonamide as a pale yellow solid (0.91 g, yield 77%).
And B: preparation of methyl (E) -3- (3- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylate
Figure BDA0003714660120000121
To acetonitrile (50 ml) were added 3-bromo-N- (quinolin-2-yl) benzenesulfonamide (1g, 2.76mmol), methyl acrylate (0.28g, 3.31mmol), palladium acetate (6.20mg, 0.0276 mmol), tris (o-methylphenyl) phosphorus (25.20mg, 0.0828mmol) and triethylamine (6.18mg, 5.52mmol) in this order at room temperature. In N 2 The reaction solution is heated to 60 ℃ for reaction for 12h under protection. After completion of the reaction, ethyl acetate (40 ml. Times.3) was extracted, and the organic phases were combined, washed 3 times with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give methyl (E) -3- (3- (N- (quinolin-2-yl) sulfonamidoyl) phenyl) acrylate as a white solid (0.89 g, 88% yield).
And C: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide
Figure BDA0003714660120000122
To a solution of methyl (E) -3- (3- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylate (0.5 g, 1.36 mmol) in methanol (20 ml) was slowly added dropwise a 1mol/L NaOH solution (3 ml) with stirring at 0 ℃. After stirring for 10 minutesContinuously dropwise adding NH into the solution 2 OH solution (3 ml), after the addition was complete, was slowly returned to room temperature and stirring was continued for 1h. After the reaction was completed, the solvent was distilled off under reduced pressure, water (20 ml) was added thereto, the pH was adjusted to neutral with 2mol/L hydrochloric acid, and a solid precipitated, which was filtered off with suction, and dried under vacuum to give (E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-15) as a white solid (0.42 g, yield 85%). Mp is 197.2-199.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.11(s,1H),8.08(d,J＝6.5Hz, 1H),7.87(d,J＝7.8Hz,1H),7.72(d,J＝7.7Hz,1H),7.66(d,J＝7.3Hz,1H),7.58(t,J＝7.5Hz, 1H),7.50(dd,J＝16.6,9.0Hz,3H),7.33–7.23(m,2H),6.59(d,J＝15.8Hz,1H).ESI-MS m/z: 370.11[M+H] + .
by selecting appropriate starting materials according to the preparation method of example 15, the compounds of example 16 to example 20 and example 22 to example 28 were prepared.
Example 16: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-16)
Structural formula of compound (I-16)
Figure BDA0003714660120000123
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-16) as a white solid in 83% yield. Mp is 182.7-184.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.13(s,1H),8.54(d,J＝2.4Hz, 1H),8.01(s,1H),7.87–7.73(m,4H),7.69(d,J＝7.7Hz,1H),7.55–7.42(m,4H),6.52(d,J＝ 15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 17: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (I-17)
Structural formula of compound (I-17)
Figure BDA0003714660120000131
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (b)I-17) light yellow solid, yield 79%. Mp is 203.1-205.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.39(d,J＝8.1Hz,1H),8.18(d,J＝6.2Hz,1H), 8.00(s,1H),7.79(d,J＝6.3Hz,1H),7.66(d,J＝8.1Hz,1H),7.64–7.59(m,2H),7.49–7.43(m, 2H),7.38(t,J＝7.3Hz,1H),6.96(d,J＝6.1Hz,1H),6.54(d,J＝15.8Hz,1H).ESI-MS m/z: 370.10[M+H] + .
example 18: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-18)
Structural formula of compound (I-18)
Figure BDA0003714660120000132
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-18) as a pale yellow solid in 66% yield. Mp is 222.8-224.6 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.79(s,1H),10.27(s,1H),9.11(s,1H),8.85 (dd,J＝4.0,1.2Hz,1H),8.42(d,J＝8.5Hz,1H),7.84(d,J＝12.6Hz,2H),7.76(d,J＝7.7Hz, 1H),7.62(dd,J＝15.2,7.3Hz,2H),7.52(t,J＝7.8Hz,1H),7.48–7.40(m,2H),7.18(d,J＝7.5 Hz,1H),6.45(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 19: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-19)
Structural formula of compound (I-19)
Figure BDA0003714660120000133
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-19) as a pale yellow solid in 61% yield. Mp is 186.3-189.4 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.80(s,1H),9.13(s,1H),8.76–8.72(m,1H), 8.23(d,J＝8.2Hz,1H),8.01(s,1H),7.88(d,J＝9.0Hz,1H),7.80–7.72(m,2H),7.59(d,J＝1.7 Hz,1H),7.54(t,J＝7.8Hz,1H),7.50(dd,J＝9.1,2.3Hz,1H),7.48–7.40(m,2H),6.51(d,J＝15.8Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 20: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-20)
Structural formula of compound (I-20)
Figure BDA0003714660120000141
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-20) as a pale yellow solid in 90% yield. Mp is 170.5-173.5 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ8.74(dd,J＝4.1,1.5Hz,1H),8.17(d,J＝7.8Hz, 1H),8.02(s,1H),7.79(t,J＝7.4Hz,2H),7.73(d,J＝7.7Hz,1H),7.58(s,1H),7.54(t,J＝7.8Hz, 1H),7.45(d,J＝15.8Hz,1H),7.36(dd,J＝8.8,1.9Hz,1H),7.32(dd,J＝8.1,4.2Hz,1H),6.53(d, J＝15.9Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 22: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-22)
Structural formula of compound (I-22)
Figure BDA0003714660120000142
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-22) as a white solid in 64% yield. Mp is 175.9-177.8 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.86(s,1H),9.10(s,1H),8.38(d,J＝8.3Hz, 1H),8.16(s,1H),7.91(d,J＝7.7Hz,1H),7.75–7.59(m,5H),7.48(d,J＝15.6Hz,3H),6.94(s, 1H),6.56(d,J＝15.8Hz,1H).ESI-MS m/z:370.10[M+H] + .
example 23: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfonamido) phenyl) acrylamide (I-23)
Structural formula of compound (I-23)
Figure BDA0003714660120000143
(E) -N-hydroxy-3- (3- (N- (isoquinoline)-3-yl) sulfonamido) phenyl) acrylamide (I-23) as a pale yellow solid in 89% yield. Mp is 92.3-95.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),8.96(s,1H),8.11(s,1H),7.91 (d,J＝8.1Hz,1H),7.86(d,J＝7.8Hz,1H),7.76(d,J＝8.1Hz,1H),7.70(d,J＝7.7Hz,1H),7.60 (t,J＝7.4Hz,1H),7.52(t,J＝7.8Hz,1H),7.46(d,J＝15.8Hz,1H),7.39(dd,J＝15.9,8.6Hz, 2H),6.56(d,J＝15.8Hz,1H).ESI-MS m/z:370.12[M+H] + .
example 24: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-24)
Structural formula of compound (I-24)
Figure BDA0003714660120000151
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-24) as a pale yellow solid in 82% yield. Mp is 175.4-177.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.81(s,1H),9.11(s,1H),9.07(s,1H), 8.09(s,1H),8.07(d,J＝8.1Hz,1H),8.02(d,J＝8.4Hz,1H),7.84(s,1H),7.74(d,J＝7.6Hz, 1H),7.68(t,J＝7.5Hz,1H),7.66–7.61(m,2H),7.51(t,J＝7.7Hz,1H),7.42(d,J＝15.7Hz,1H), 6.46(d,J＝15.8Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 25: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-25)
Structural formula of compound (I-25)
Figure BDA0003714660120000152
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-25) as a pale yellow solid in 69% yield. Mp is 173.0-176.3 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.77(s,1H),10.26(s,1H),9.20(s,1H), 8.37(d,J＝5.9Hz,1H),7.90(d,J＝5.8Hz,1H),7.84(s,1H),7.79(s,1H),7.70(d,J＝7.5Hz, 1H),7.64(d,J＝7.8Hz,1H),7.49(dt,J＝15.5,7.8Hz,2H),7.42(d,J＝15.8Hz,1H),7.36(d,J＝ 7.5Hz,1H),6.45(d,J＝15.8Hz,1H).ESI-MS m/z:370.09[M+H] + .
example 26: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-26)
Structural formula of compound (I-26)
Figure BDA0003714660120000153
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-26) as a white solid in 78% yield. Mp is 205.3-207.7 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.85(s,1H),9.12(s,1H),8.37(d,J＝5.7Hz, 1H),8.06(s,1H),8.00(d,J＝8.8Hz,1H),7.82(d,J＝7.8Hz,1H),7.77(d,J＝7.7Hz,1H),7.70 (d,J＝5.7Hz,1H),7.60–7.55(m,2H),7.47(d,J＝16.3Hz,1H),7.44(d,J＝8.9Hz,1H),6.54(d, J＝15.9Hz,1H).ESI-MS m/z:370.11[M+H] + .
example 27: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-27)
Structural formula of Compound (I-27)
Figure BDA0003714660120000161
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-27) as a white solid in 65% yield. Mp is 197.2-199.5 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.83(s,1H),9.19(s,1H),8.37(d,J＝5.6Hz, 1H),8.02(s,1H),7.85(d,J＝8.9Hz,1H),7.77(dd,J＝11.6,7.6Hz,3H),7.69(d,J＝5.6Hz,1H), 7.56–7.51(m,2H),7.46(d,J＝15.8Hz,1H),6.52(d,J＝15.9Hz,1H).ESI-MS m/z:370.12[M+ H] + .
example 28: (E) Preparation of (E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-28)
Structural formula of compound (I-28)
Figure BDA0003714660120000162
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-28) as a pale yellow solid in 88% yield. Mp is 142.4-145.1 ℃, 1 H-NMR(600MHz,DMSO-d 6 )δ10.77(s,1H),9.46(s,1H),8.37(d,J＝5.6 Hz,1H),7.89(s,1H),7.67(d,J＝7.9Hz,2H),7.65(d,J＝5.6Hz,1H),7.51(t,J＝7.8Hz,1H), 7.47(t,J＝7.7Hz,2H),7.42(d,J＝15.8Hz,1H),7.18(d,J＝7.5Hz,1H),6.47(d,J＝15.8Hz, 1H).ESI-MS m/z:370.13[M+H] + .
example 29 in vitro antitumor cell proliferation Activity assay of Compounds of interest
MTT method is adopted to test the in vitro anti-proliferation activity of the target compound on A549 and MCF-7 cell strains. Placing the cells in RPMI-1640 medium containing 10% Fetal Bovine Serum (FBS) and making the cells have 5% CO 2 Cultured in an incubator at 37 ℃. Cells in logarithmic growth phase were taken at 3X 10 per well 3 Density of Individual cells it was seeded in 96-well plates, put to contain 5% CO 2 The culture is continued for about 18 to 24 hours in a constant temperature incubator at 37 ℃. According to the experimental design, 100 mu L of compounds with different concentration gradients are added into each well, no compound is added into a blank control group, and Belinostat with the same concentration gradient is added into a positive control group, and the culture is continued in an incubator for 48h. And when the action time of the drug is reached, adding 20 mu L of MTT solution with the concentration of 5mg/ml into each hole in a dark place, incubating in an incubator for 4-6h, then discarding the culture solution, adding 100 mu L of DMSO solution into each hole, and shaking in a dark place for 5min. Placing the 96-well plate in a microplate reader, detecting OD values at a wavelength of 570nm, respectively calculating the inhibition rate of the compound to be detected, wherein the inhibition rate is (%) = (100% absorbance average value-compound absorbance average value)/(100% absorbance average value-blank group absorbance average value) × 100, and calculating IC by SPSS software 50 The value is obtained.
TABLE 1 results of antiproliferative Activity of target Compounds against two types of cancer cell lines
Figure BDA0003714660120000163
Figure BDA0003714660120000171

Claims (10)

1. A hydroxamic acid compound containing quinoline or isoquinoline shown as a general formula I and pharmaceutically acceptable salts or hydrates thereof:
Figure FDA0003714660110000011
wherein the content of the first and second substances,
x is N or CH, Y is CH or N; wherein, when X is N, Y is CH; when X is CH, Y is N;
w is carbonyl or (C) 3 -C 5 ) An α, β -unsaturated carbonyl group;
ring A is aryl or heteroaryl, wherein aryl or heteroaryl are each independently optionally substituted with one or more R, R is hydrogen, (C) 1 -C 6 ) Alkyl, cyano, halogen, halo (C) 1 -C 6 ) Alkyl, hydroxy, mercapto or alkoxy;
wherein the aryl group is a 6-10 membered aryl group; the heteroaryl is a five-membered or six-membered heteroaryl, which contains 1-3 heteroatoms of N, O or S, and the rest ring atoms are C; the aryl group is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl; the six-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.
2. The compound according to claim 1, and pharmaceutically acceptable salts or hydrates thereof, characterized in that:
when X is N, Y is CH; when X is CH, Y is N;
w is carbonyl or (C) 3 -C 5 ) An α, β -unsaturated carbonyl group;
ring A is aryl or heteroaryl; wherein:
the aryl group is phenyl; the five-membered heteroaryl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl; the six-membered heteroaryl group is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
3. The compound according to claim 2, and pharmaceutically acceptable salts or hydrates thereof, characterized in that:
x is N, then Y is CH; or X is CH, then Y is N;
w is carbonyl or (C) 3 -C 5 ) An α, β -unsaturated carbonyl group;
ring A is aryl or heteroaryl;
wherein the aryl group is phenyl; the heteroaryl is pyridyl, pyrazinyl;
when ring A is phenyl, the phenyl group is
Figure FDA0003714660110000012
When ring A is pyridyl, the pyridyl is
Figure FDA0003714660110000013
When ring A is pyrazinyl, the pyrazinyl group is
Figure FDA0003714660110000014
4. A compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts or hydrates thereof, characterized in that:
x is N, then Y is CH; or X is CH, then Y is N;
w is-CH = CH-CO-;
the ring A is aryl, and the aryl is phenyl; phenyl is
Figure FDA0003714660110000021
5. The compound of claim 1, and pharmaceutically acceptable salts or hydrates thereof, wherein the compound is specifically one of the following compounds:
(E) -N-hydroxy-3- (4- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-1);
(E) -N-hydroxy-3- (4- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-2);
(E) -N-hydroxy-3- (4- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (I-3);
(E) -N-hydroxy-3- (4- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-4);
(E) -N-hydroxy-3- (4- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-5);
(E) -N-hydroxy-3- (4- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-6);
(E) -N-hydroxy-3- (4- (N- (quinolin-8-yl) sulfonamido) phenyl) acrylamide (I-7);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-8);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-3-yl) sulfonamido) phenyl) acrylamide (I-9);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-10);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-11);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-12);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-13);
(E) -N-hydroxy-3- (4- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-14);
(E) -N-hydroxy-3- (3- (N- (quinolin-2-yl) sulfonamido) phenyl) acrylamide (I-15);
(E) -N-hydroxy-3- (3- (N- (quinolin-3-yl) sulfonamido) phenyl) acrylamide (I-16);
(E) -N-hydroxy-3- (3- (N- (quinolin-4-yl) sulfonamido) phenyl) acrylamide (I-17);
(E) -N-hydroxy-3- (3- (N- (quinolin-5-yl) sulfonamido) phenyl) acrylamide (I-18);
(E) -N-hydroxy-3- (3- (N- (quinolin-6-yl) sulfonamido) phenyl) acrylamide (I-19);
(E) -N-hydroxy-3- (3- (N- (quinolin-7-yl) sulfonamido) phenyl) acrylamide (I-20);
(E) -N-hydroxy-3- (3- (N- (quinolin-8-yl) sulfonamido) phenyl) acrylamide (I-21);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-1-yl) sulfonamido) phenyl) acrylamide (I-22);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-3-yl) sulfonamido) phenyl) acrylamide (I-23);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-4-yl) sulfonamido) phenyl) acrylamide (I-24);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-5-yl) sulfonamido) phenyl) acrylamide (I-25);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-6-yl) sulfonamido) phenyl) acrylamide (I-26);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-7-yl) sulfonamido) phenyl) acrylamide (I-27);
(E) -N-hydroxy-3- (3- (N- (isoquinolin-8-yl) sulfonamido) phenyl) acrylamide (I-28).
6. The preparation of quinoline-or isoquinoline-containing hydroxamic acid compounds according to claim 1 wherein one of the following two routes is used:
route one:
Figure FDA0003714660110000031
the substituents are as defined in the claims, reagents and conditions: HSO 3 Cl,12h；b.RNH 2 ,CH 2 Cl 2 ,pyridine,1h；c.CH 3 OH,H 2 SO 4 ,4h；d.NH 2 OH,1N NaOH,CH 3 OH,1h；
And a second route:
Figure FDA0003714660110000032
the substituents are as defined in the claims, reagents and conditions: RNH 2 ,CH 2 Cl 2 ,pyridine,2h；b.methyl acrylate,Pd(OAc) 2 ,POT,Et 3 N,CH 3 CN,60℃,12h；c.NH 2 OH,1N NaOH,CH 3 OH,1h。
7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises an acid addition salt of the compound of formula I with an inorganic or organic acid; the inorganic acid salt is selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; the organic acid salt is selected from salts formed by any one of the following organic acids: acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, citric acid, salicylic acid, tartaric acid or p-toluenesulfonic acid.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier therefor.
9. Use of the compound of any one of claims 1 to 5 and a pharmaceutically acceptable salt or hydrate thereof or the pharmaceutical composition of claim 7 for the preparation of a medicament for the prevention and/or treatment of a disease associated with histone deacetylase.
10. Use of a compound according to any one of claims 1 to 5, and a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the prevention and/or treatment of liver, colon, pancreatic, lung, stomach, breast and ovarian cancer.
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