Phthalazinone or quinazolinone derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and provides phthalazinone or quinazolinone derivatives as well as a preparation method and application thereof. The phthalazinone or quinazolinone derivative, the stereoisomer thereof, the optical isomer thereof or the pharmaceutically acceptable salt thereof provided by the invention can play an anti-tumor role by inhibiting histone deacetylase, and all have good in-vitro anti-tumor activity; even, the compound has the effect equivalent to or better than that of an anti-cancer drug SAHA (vorinostat) of a positive control group, and targeted tumor resistance can be realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, more particularly, to a phthalazine ketone or quinazolinone derivative and a preparation method and application thereof. BACKGROUND

[0002] The occurrence and development of cancer are related to a variety of endogenous and exogenous factors. Epigenetic modification is another important endogenous factor for the occurrence and development of tumors in addition to genetic factors. Epigenetic modification refers to a reversible or heritable process of regulating gene expression without changing the nucleotide sequence of DNA, which affects the expression of genes and further affects the proliferation, metabolism and apoptosis of cancer cells through DNA demethylation and methylation, histone modification and RNA interference. Histone acetylation / deacetylation mediated by histone deacetylases (HDACs) is a major epigenetic mechanism.

[0003] HDACs are epigenetic enzymes responsible for removing acetyl groups from histone lysine residues to regulate the structure and function of chromatin, and are a common histone modification. According to sequence homology, subcellular localization and catalytic mechanism, HDACs mainly include Zn 2+ dependent type I, II, IV and NAD + dependent type III. Class I has high sequence homology with the transcription factor Rpd3 in yeast, including four subtypes HDAC1, HDAC2, HDAC3 and HDAC8, mainly located in the nucleus, and participates in various biological events through its enzymatic function or the formation of multi-protein auxiliary repressor protein complex. Class II has high sequence homology with the deacetylase Hda1 in yeast, and exists in the nucleus and cytoplasm. According to the difference in catalytic region, it is divided into class IIa and class IIb which can shuttle between cytoplasm and nucleus. The former includes four subtypes HDAC4, HDAC5, HDAC7 and HDAC9, and the latter includes two subtypes HDAC6 and HDAC10. Class IV only contains one subtype HDAC11, mainly located in the nucleus, and is the smallest class of enzymes in the HDACs family, with more than 80% of its sequence being catalytic domain. Class III HDACs are related enzymes with sequence homology to yeast SIRTs, existing in the nucleus, cytoplasm and mitochondria, and having no sequence similarity with other three classes of HDACs. It is a class of HDACs significantly different from other three classes.

[0004] HDACs can affect the growth, proliferation, differentiation, movement, migration, drug resistance and apoptosis of cancer cells through the following mechanisms: (1) under physiological conditions, HDACs and HATs work together to maintain the dynamic balance of histone acetylation; under pathological conditions, external stimuli or gene mutations can lead to overexpression of HDACs, resulting in imbalance of histone acetylation process, making the nucleosome structure more compact, down-regulating tumor suppressor genes, and ultimately leading to the occurrence and development of cancer; (2) affecting the activity of hypoxia inducible factor-1α (HIF-1α) through various pathways to regulate angiogenesis; (3) regulating cell cycle by changing the expression or function of the CIP / KIP family of cyclin-dependent kinases (CDKs); (4) directly regulating apoptosis through endogenous and exogenous apoptosis pathways. In the exogenous apoptosis pathway, HDACs can induce tumor cell apoptosis by up-regulating cell surface death receptors, reducing cellular FADD-like IL-1β converting enzyme inhibitory protein (c-FLIP) and enhancing the formation of death-inducing signaling complex (DISC); (5) promoting cell proliferation by down-regulating CDK inhibitors p27 and p21, and inhibiting or knocking out HDACs will induce apoptosis or cell cycle arrest.

[0005] Therefore, HDACs are closely related to the occurrence, metastasis and drug resistance of cancer, and have become one of the effective targets for targeted cancer therapy. Therefore, it is urgent to develop effective HDACs inhibitors to achieve targeted anti-tumor. SUMMARY

[0006] The present application aims to at least solve one of the technical problems existing in the prior art. To this end, the present application proposes a phthalazine ketone or quinazolinone derivative, a preparation method and application thereof. The phthalazine ketone or quinazolinone derivative, stereoisomer, optical isomer or pharmaceutically acceptable salt thereof provided by the present application has good in vitro anti-tumor activity, can inhibit histone deacetylase to exert its anti-tumor effect, can achieve targeted anti-tumor, and can be used as an HDACs inhibitor.

[0007] A first aspect of the present application provides a phthalazine ketone or quinazolinone derivative represented by formula I, a stereoisomer, an optical isomer or a pharmaceutically acceptable salt thereof.

[0008] In particular, the phthalazinone or quinazolinone derivative represented by formula I, a stereoisomer thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

[0009] The structure of formula I is as follows:

[0010]

[0011] wherein Y is null (when Y is null, it means that the two six-membered rings containing R1and R2are directly connected by a single bond), NH or CONH;

[0012] Z1, Z2, Z3, Z4and Z5are each independently selected from N or CH;

[0013] n is 0, 1 or 2;

[0014] R1and R2are each independently selected from hydrogen or a halogen atom;

[0015] W1is a 4-6-membered cycloalkyl, a 4-10-membered heterocyclic ring, a 6-10-membered aryl or a C1-C6alkyl, which 4-6-membered cycloalkyl, 4-10-membered heterocyclic ring, 6-10-membered aryl is unsubstituted or substituted with 1-3 substituents which are the same or different;

[0016] W2is hydrogen, a 3-6-membered cycloalkyl, a 6-10-membered aryl, a 5-10-membered heterocyclic group, a C1-C3haloalkyl, a C1-C4alkyl or two C1-C4alkyls which are the same or different;

[0017] W3is null, wherein X is O, S or NHCO, and m is a positive integer from 1 to 10, which represents a connection site.

[0018] Preferably, the substituents are C1-C2alkyl, C1-C2acyl, a halogen atom or a trifluoromethyl group.

[0019] Preferably, the 4-10-membered heterocyclic ring and the 5-10-membered heterocyclic group each independently comprise 1-3 heteroatoms which are each independently selected from a nitrogen, a sulfur or an oxygen atom.

[0020] Preferably, the 6-10-membered aryl is unsubstituted or substituted with a C1-C2alkyl, a halogen atom, a trifluoromethyl group, -NH(C1-C3alkyl) or a hydroxyl group.

[0021] Preferably, the 5-10-membered heterocyclic group is unsubstituted or substituted with a C1-C2alkyl, a halogen atom, a trifluoromethyl group, -NH(C1-C3alkyl) or a hydroxyl group.

[0022] Preferably, the halogen atom is a fluorine atom or a chlorine atom.

[0023] Preferably, the alkyl group is a straight-chain or branched-chain alkyl group.

[0024] Preferably, the ring is a monocyclic or fused ring.

[0025] Preferably, m is 5, 6 or 7.

[0026] Preferably, the phthalazinone or quinazolinone derivative has one of the following structures:

[0027]

[0028]

[0029]

[0030]

[0031] Preferably, the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of the compound of Formula I with an acid.

[0032] Preferably, the acid is an organic acid or an inorganic acid.

[0033] Further preferably, the acid is one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid.

[0034] The second aspect of the present application provides a method for preparing a phthalazinone or quinazolinone derivative.

[0035] A method for preparing a phthalazinone or quinazolinone derivative, comprising the following steps:

[0036] An intermediate ester 3 is prepared by a first nucleophilic substitution reaction of a ketone compound (1) which is a bromophthalazinone or quinazolinone with an α-bromo ester (2);

[0037] Then, the intermediate ester 3 is hydrolyzed under basic conditions to obtain an intermediate acid 4, which is condensed with an amine under the action of a polypeptide condensation reagent and an organic base to obtain an intermediate amide 5; the intermediate amide 5 is prepared by a Suzuki coupling reaction to obtain an intermediate 6, and finally, the intermediate 6 is subjected to a first aminolysis reaction with hydroxylamine under basic conditions to obtain the phthalazinone or quinazolinone derivative (when Y is null, this route is adopted, and the final product is 7);

[0038] Alternatively, the intermediate amide 5 is subjected to a Buchwald-Hartwig coupling reaction with an aromatic amine to obtain an intermediate 8, and finally, the intermediate 8 is subjected to a second aminolysis reaction with hydroxylamine under basic conditions to obtain the phthalazinone or quinazolinone derivative (when Y is NH, this route is adopted, and the final product is 9).

[0039] Alternatively, the intermediate amide 5 is converted into the intermediate acid 10 under the action of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and dicyclohexylcarbodiimide (DCC), and the intermediate acid 10 is condensed with an aromatic amine under the action of a condensing agent to obtain the amide 11, and the amide 11 is subjected to a third aminolysis reaction with hydroxylamine to obtain the phthalazinone or quinazolinone derivative (when Y is CONH, this route is adopted, and the final product is 12);

[0040] Alternatively, a nitro-substituted ketone compound (13) and an α-bromo acid ester (2) are subjected to a second nucleophilic substitution reaction to obtain the intermediate 14, the nitro-substituted ketone compound being a nitro-substituted bromophthalazinone or a nitro-substituted quinazolinone; the intermediate 14 is then hydrolyzed to obtain the intermediate acid 15, the intermediate acid 15 and an amine compound are subjected to a condensation reaction to obtain the intermediate 16, the intermediate 16 is subjected to a ferric acid reduction reaction to obtain the intermediate 17, the intermediate 17 and a carboxylic acid compound are subjected to an amide reaction to obtain the intermediate 18, and the intermediate 18 is subjected to a fourth aminolysis reaction with hydroxylamine to obtain the phthalazinone or quinazolinone derivative (when Y is CONH, this route is adopted, and the final product is 19).

[0041] Preferably, the first nucleophilic substitution reaction is carried out under the action of a first catalyst, the first catalyst being at least one of cesium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, and sodium methoxide.

[0042] Preferably, the intermediate ester 3 is subjected to hydrolysis under alkaline conditions, and then subjected to acidification treatment to obtain the intermediate acid 4.

[0043] Preferably, the intermediate amide 5 is converted into the intermediate acid 10 under the action of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dicyclohexylcarbodiimide under the action of a third catalyst, the third catalyst being Pd(OAc)2.

[0044] Preferably, the condensing agent is 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0045] Preferably, the organic base is diisopropylethylamine (DIEA).

[0046] Preferably, the alkaline conditions are the addition of at least one of lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium carbonate.

[0047] Preferably, the amine compound has the following structural formula: wherein W1 is 4-6 membered cycloalkyl, 4-10 membered heterocyclic ring, 6-10 membered aryl or C1-C6 alkyl, the 4-6 membered cycloalkyl, 4-10 membered heterocyclic ring, 6-10 membered aryl being unsubstituted or substituted with 1-3 substituents which are the same or different; and n is 0, 1 or 2.

[0048] Preferably, the carboxylic acid compound has the following structure: wherein Z1, Z2, Z3 are independently selected from N or CH; R2 is selected from hydrogen or halogen atom; W3 is unsubstituted or substituted with 1-3 substituents which are the same or different; wherein X is O, S or NHCO, m is a positive integer from 1 to 10, represents a connecting site.

[0049] A specific preparation route of the phthalazinone or quinazolinone derivative is shown as follows:

[0050]

[0051] or,

[0052]

[0053] or,

[0054]

[0055] or,

[0056]

[0057] A third aspect of the present application provides a use of a phthalazinone or quinazolinone derivative.

[0058] A use of a phthalazinone or quinazolinone derivative, a stereoisomer thereof, an optical isomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a HDACs-mediated disease, inhibiting HDACs, treating or preventing a proliferative disease.

[0059] Preferably, the HDACs-mediated disease is cancer.

[0060] Preferably, the cancer is at least one of leukemia, T-cell lymphoma, non-small cell lung cancer, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer, multiple myeloma.

[0061] A fourth aspect of the present application provides a pharmaceutical composition.

[0062] A pharmaceutical composition comprising the phthalazinone or quinazolinone derivative, a stereoisomer thereof, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0063] Preferably, the pharmaceutical composition further comprises other anti-tumor drugs.

[0064] Preferably, the other anti-tumor drugs are at least one of bortezomib, osimertinib, cisplatin, irinotecan, cetuximab, docetaxel, sapitinib, canertinib.

[0065] The phthalazinone or quinazolinone derivative provided by the present application can be combined with other anti-tumor drugs for treatment, which can be achieved by simultaneous, sequential or separate administration of each therapeutic component.

[0066] Preferably, the pharmaceutical composition further comprises excipients.

[0067] Preferably, the excipients are at least one of pharmaceutically acceptable salts, pharmaceutically acceptable carriers, and pharmaceutically acceptable excipients.

[0068] Compared with the prior art, the present application has the following advantages:

[0069] The phthalazinone or quinazolinone derivative represented by Formula I, its stereoisomer, its optical isomer or its pharmaceutically acceptable salt provided by the present application can exert its anti-tumor effect by inhibiting histone deacetylase, all have good in vitro anti-tumor activity, and even have effects equivalent to or superior to the positive control group of the anti-cancer drug SAHA (vorinostat), and can achieve targeted anti-tumor. DETAILED DESCRIPTION

[0070] In order to make those skilled in the art more clearly understand the technical solutions described in the present application, the following examples are provided for illustration. It should be pointed out that the following examples do not constitute a limitation on the scope of protection required by the present application.

[0071] The raw materials, reagents or devices used in the following examples, unless otherwise specified, can be obtained from conventional commercial channels or can be obtained by existing known methods.

[0072] Nuclear magnetic resonance hydrogen spectrum of the present application 1 H NMR was determined by Bruker ARX-600, and high resolution mass spectrometry HRMS was determined by triple quadrupole liquid chromatography-mass spectrometer; the reagents used were commercially available analytical or chemical pure.

[0073] Example 1 N-hydroxy-7-(4-(1-oxo-2-(2-oxo-1-phenyl-2-(thiazol-2-ylamino)ethyl)-1,2-dihydrophthalazine-6-yl)phenoxy)heptanamide, whose structural formula is as follows:

[0074]

[0075] The preparation method of the above compound comprises the following steps:

[0076] (1) Synthesis of methyl 2-(6-bromo-l-oxophthalazin-2(lH)-yl)-2-phenylacetate (3-1)

[0077] Methyl α-bromophenylacetate (1.02 g, 4.5 mmol) and 6-bromophthalazin-l(2H)-one (1.00 g, 4.4 mmol) were dissolved in 15 mL of acetonitrile, and cesium carbonate (1.8 g, 5.4 mmol) was added, and the reaction was carried out at room temperature for 2 h. The solid was washed with acetonitrile, and the filtrates were combined and concentrated under reduced pressure to obtain 1.6 g of intermediate 3-1.

[0078] The above reaction scheme is as follows:

[0079]

[0080] (2) Synthesis of 2-(6-bromo-l-oxophthalazin-2(lH)-yl)-2-phenylacetic acid (4-1)

[0081] Intermediate 3-1 (1.0 g, 2.7 mmol) was dissolved in 10 mL of methanol and 3 mL of water, and lithium hydroxide (0.26 g, 10.8 mmol) was added, and the reaction was carried out at 50°C for 2 h. The reaction solution was concentrated under reduced pressure to remove methanol, and water was added to dissolve the solution, and dilute hydrochloric acid was added to adjust the pH to 3-4, and the reaction was filtered to obtain 0.7 g of intermediate 4-1.

[0082] The above reaction scheme is as follows:

[0083]

[0084] (3) Synthesis of 2-(6-bromo-l-oxophthalazin-2(lH)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide (5-1)

[0085] Intermediate 4-1 (0.5 g, 1.4 mmol) was dissolved in 5 mL of N,N-dimethylformamide (DMF), and N,N-diisopropylethylamine (DIEA, 0.4 g, 3.1 mmol) and polypeptide condensing reagent 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.0 g, 2.5 mmol) were added, and the reaction was stirred at room temperature for 30 min, and then 2-aminothiazole (0.17 g, 1.7 mmol) was added, and the reaction was carried out at 30°C for 6 h. The reaction solution was poured into a suitable amount of ice water to precipitate a solid, and the solid was filtered, and the crude product was separated and purified by column chromatography to obtain 0.5 g of intermediate 5-1.

[0086] The above reaction scheme is as follows:

[0087]

[0088] (4) Synthesis of methyl 7-(4-(l-oxo-2-(2-oxo-l-phenyl-2-(thiazol-2-ylamino)ethyl)- 1,2-dihydrophthalazine-6-yl)phenoxy)heptanoate (6-1)

[0089] The intermediate 5-1 (0.5 g, 1.1 mmol) was dissolved in 4 mL of 1,4-dioxane, and methyl 7-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)heptanoate (0.62 g, 1.7 mmol) and 1 mL of aqueous sodium carbonate solution (2 mol / L) were added successively, and the mixture was ultrasonicated for 5 min. PdCl2(dppf)2(0.07 mmol) and X-phos (0.1 mmol) were added, and air was replaced with nitrogen for 3 times. The reaction was refluxed under nitrogen protection for 10 h. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and 0.4 g of the intermediate 6-1 was obtained after column chromatography separation and purification.

[0090] The above reaction formula is as follows:

[0091]

[0092] (5) Synthesis of N-hydroxy-7-(4-(l-oxo-2-(2-oxo-l-phenyl-2-(thiazol-2-ylamino)ethyl)- 1,2-dihydrophthalazine-6-yl)phenoxy)heptanamide (compound of Example 1)

[0093] Hydroxylamine hydrochloride and potassium hydroxide were dissolved in an appropriate amount of methanol at a mass ratio of 9:11, and stirred in an ice bath for 30 min. The filtrate was prepared for use. The intermediate 6-1 (0.15 g) was dissolved in an appropriate amount of the above filtrate, and reacted at 30°C for 1 h. The reaction solution was concentrated under reduced pressure until methanol was removed, and then dissolved in water. The pH was adjusted to 6-7 with dilute hydrochloric acid, and the mixture was filtered under suction. The solid was dried, and the target compound was obtained after separation and purification by preparative thin layer chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 12.60 (br, 1H), 10.35 (s, 1H), 8.67 (br, 1H), 8.43 (s, 1H), 8.29 (m, 1H), 8.21 (s, 1H), 8.18 (m, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.45 (m, 1H), 7.42-7.36 (m, 5H), 7.21 (br, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.84 (s, 1H), 4.05 (m, 2H), 1.97 (m, 2H), 1.76-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.35-1.29 (m, 2H); 13C NMR (151 MHz, DMSO-d6) δ 169.57, 168.06, 159.91, 159.13, 145.20, 138.44, 138.07, 135.51, 130.70, 130.52, 130.44 (2C), 130.34, 128.93 (2C), 128.64 (2C), 128.35, 127.09, 125.69, 123.98, 115.64 (2C), 113.80, 113.78, 68.05, 64.92, 32.68, 29.00, 28.81, 25.70, 25.55; HRMS (ESI) m / z 598.2094 [M+H] + , Calcd for 598.2124.

[0094] The above reaction formula is as follows:

[0095]

[0096] Example Two N-hydroxy-7-(4-(4-oxo-3-(2-oxo-l-phenyl-2-(thiazol-2-ylamino)ethyl)- 3,4-dihydroquinazolin-7-yl)phenoxy)heptanamide, whose structural formula is as follows:

[0097]

[0098] With methyl α-bromophenylacetate and 7-bromoquinazolin-4(3H)-one as starting materials, the amount and the rest of the steps are the same as in Example One, and the product is prepared by referring to the synthesis method of Example One. The product 1 H NMR (600 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.67 (s, 1H), 8.23 (m, 1H), 7.90-7.88 (m, 3H), 7.80 (d, J = 8.4 Hz, 2H), 7.52-7.49 (m, 4H), 7.45 (m, 2H), 7.28 (br, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.88 (s, 1H), 4.04 (m, 2H), 1.97 (m, 2H), 1.75-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.34-1.28 (m, 2H); 13C NMR (151 MHz, DMSO-d6) δ 169.57, 167.46, 160.54, 159.83, 158.84, 148.36, 146.46, 146.27, 138.19, 134.05, 130.88, 130.10, 129.96 (2C), 129.83 (2C), 128.95 (2C), 127.50, 125.98, 124.15, 119.71, 115.56 (2C), 114.47, 68.02, 60.58, 32.68, 29.00, 28.80, 25.70, 25.55; HRMS (ESI) m / z: 598.2093 [M+H] + , Calcd for 598.2124. Example Three 7-(4-(2-(l-(4-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0099]

[0100] Example One, using 2-bromo-2-(4-fluorophenyl)acetic acid methyl ester and 6-bromophthalazine-l(2H)-one as starting materials, using the amounts and the remaining steps as in Example One, to give the product 1 H NMR (600 MHz, DMSO-d6) δ 12.61 (br, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.29 (m, 1H), 8.22 (s, 1H), 8.18 (m, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.48-7.45 (m, 3H), 7.24-7.21 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 4.05 (m, 2H), 1.97 (m, 2H), 1.76-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.35-1.29 (m, 2H); 13C NMR (151 MHz, DMSO-d6) δ 169.55, 167.85, 163.27, 161.65, 159.92, 159.09, 145.23, 138.63, 138.10, 132.58, 132.53, 131.63, 130.68, 130.53, 130.39, 128.94 (2C), 127.08, 125.73, 124.04, 115.65 (2C), 115.56, 115.42, 113.94, 68.06, 64.16, 40.51, 40.40, 40.26, 40.12, 39.98, 39.84, 39.70, 39.56, 32.68, 29.00, 28.81, 25.71, 25.55; HRMS (ESI) m / z: 616.2004 [M+H] + , Calcd for 616.2030.

[0101] Example Four 7-(4-(2-(l-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-l-oxo- 1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0102]

[0103] Example One, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromophthalazin-l(2H)-one as starting materials, using the amounts and the remaining steps as in Example One, the product 1 H NMR (600 MHz, DMSO-d6) δ 12.72 (br, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.31 (m, 1H), 8.23 (s, 1H), 8.20 (m, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.49-7.45 (m, 2H), 7.30-7.23 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 4.05 (m, 2H), 1.97 (m, 2H), 1.76-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.35-1.29 (m, 2H); 13C NMR (151 MHz, DMSO-d6) δ 169.58, 167.49, 161.80, 160.17, 159.93, 158.98, 145.32, 138.68, 137.98, 131.35, 131.32, 130.94, 130.90, 130.67, 130.55, 130.47, 128.97 (2C), 127.11, 125.50, 124.83, 124.10, 115.76, 115.66 (2C), 68.07, 59.29, 32.66, 29.00, 28.80, 25.71, 25.56; HRMS (ESI) m / z: 616.2003 [M+H] + , Calcd for 616.2030. Example Five 7-(4-(2-(l-(3-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)- 1-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0104]

[0105] Example One, using 2-bromo-2-(3-fluorophenyl)acetic acid methyl ester and 6-bromophthalazin-l(2H)-one as starting materials, using the amounts and the remaining steps as in Example One, to give the product 1 H NMR (600 MHz, DMSO-d6) δ 12.63 (br, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 8.19 (m, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.47-7.43 (m, 2H), 7.25-7.21 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 6.87 (s, 1H), 4.05 (m, 2H), 1.97 (m, 2H), 1.76-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.35-1.29 (m, 2H); 13C NMR (151 MHz, DMSO-d6) δ 169.57, 167.36, 163.10, 161.48, 159.93, 159.09, 145.27, 138.87, 138.12, 130.67, 130.61, 130.55, 130.43, 128.94 (2C), 127.10, 126.26, 125.77, 124.10, 117.11, 116.97, 115.64 (2C), 115.51, 114.09, 68.05, 64.30, 32.68, 29.00, 28.81, 25.70, 25.55; HRMS (ESI) m / z: 616.2001 [M+H] + , Calcd for 616.2030.

[0106] Example Six N-hydroxy-7-(4-(2-(l-(naphthalen-l-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)heptanamide, having the structural formula:

[0107]

[0108] Example One, using 2-bromo-2-(naphthalen-l-yl)ethyl acetate and 6-bromophthalazine-l(2H)-one as starting materials, using the amounts and the remaining steps as in Example One, the product 1 H NMR (600 MHz, DMSO-d6) δ 12.67 (br, 1H), 10.35 (br, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.31 (m, 1H), 8.22 (s, 1H), 8.19-8.17 (m, 1H), 7.95-7.93 (m, 4H), 7.81 (d, J = 8.4 Hz, 2H), 7.58-7.52 (m, 3H), 7.47 (m, 1H), 7.24 (br, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 4.04 (m, 2H), 1.97 (m, 2H), 1.75-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.35-1.28 (m, 2H); 13CNMR (151 MHz, DMSO-d6) δ 169.56, 167.80, 159.92, 159.18, 158.87, 145.25, 138.62, 138.17, 133.11, 133.06, 132.89, 130.68, 130.55, 130.39, 130.11, 129.49, 128.93 (2C), 128.45, 128.09, 127.97, 127.10, 127.02, 126.80, 125.70, 124.04, 115.63 (2C), 114.12, 68.04, 65.05, 32.68, 29.00, 28.81, 25.71, 25.55; HRMS (ESI) m / z: 648.2252 [M+H] + Calcd for 648.2281.

[0109] Example Seven N-hydroxy-7-(4-(2-(l-(2-methylphenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)- 1-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)heptanamide, having the structural formula:

[0110]

[0111] Example One, using 2-bromo-2-(2-methoxyphenyl)acetic acid methyl ester and 6-bromophthalazin- 1 (2H)-one as starting materials, the product 1 H NMR (600 MHz, DMSO-d6) δ 12.60 (br, 1H), 10.36 (br, 1H), 8.67 (br, 1H), 8.39 (s, 1H), 8.30 (m, 1H), 8.20 (s, 1H), 8.18 (m, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.47 (m, 1H), 7.39 - 7.37 (m, 1H), 7.25 (m, 1H), 7.11 - 7.08 (m, 3H), 7.05 (d, J = 8.4 Hz, 2H), 6.97 - 6.95 (m, 1H), 4.04 (t, J = 6.6 Hz, 1H),, 3.76 (s, 3H), 1.96 (t, J = 6.6 Hz, 1H), 1.76 - 1.71 (m, 2H), 1.55 - 1.50 (m, 2H), 1.45 - 1.40 (m, 2H), 1.35 - 1.29 (m, 2H). HRMS (ESI) m / z: 628.2217 [M+H] +Calcd for 628.2230. Example 8: N-hydroxy-7-(4-(1-oxo-2-(1-oxo-1-(thiazol-2-ylamino)propyl-2-yl)-1,2-dihydrophthalazine-6-yl)phenoxy)heptamide, with the following structural formula:

[0112]

[0113] Using methyl 2-bromopropionate and 6-bromophthalazine-1(2H)-one as starting materials, the amounts and other steps were the same as in Example 1, and the product... 1 H NMR(600MHz,DMSO-d6)δ12.42(br,1H),10.35(br,1H),8.68(br,1H),8.51(s,1H),8.28-8.24(m ,2H),8.17(m,1H),(d,J=8.4Hz,2H),7.47(m,1H),7.21(m,1H),7.11(d,J=8.4Hz,2H),5.70-5.67 (q,J=6.6Hz,1H),4.04(t,J=6.0Hz,1H),1.96(t,J=6.0Hz,1H),1.76-1.71(m,2H),1.67(d,J=6.6 Hz,2H),1.55-1.50(m,2H),1.45-1.41(m,2H),1.34-1.29(m,2H).HRMS(ESI)m / z:536.1959[M+H] + ,Calcd for 536.1968.

[0114] Example 9: 7-(4-(8-fluoro-2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)phenoxy)-N-hydroxyheptamide, the structural formula of which is as follows:

[0115]

[0116] Using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromo-8-fluorophthalazine-1(2H)-one as starting materials, the amounts and remaining steps were the same as in Example 1. The product HRMS (ESI) m / z: 633.1974 [M+H] + ,Calcd for 633.1983.

[0117] Example 10: 7-(4-(5-fluoro-2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)phenoxy)-N-hydroxyheptamide, the structural formula of which is as follows:

[0118]

[0119] Example 1, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromo-5- chlorophthalazine- 1 (2H)-one as starting material, using the same amounts and further steps as in Example 1, the product was 1 H NMR (600 MHz, DMSO-d6) δ 12.60 (br, 1H), 10.33 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 8.19 (m, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.47-7.43 (m, 2H), 7.24-7.21 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.87 (s, 1H), 4.04 (m, 2H), 1.97 (m, 2H), 1.76-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.39 (m, 2H), 1.35-1.29 (m, 2H); HRMS (ESI) m / z: 633.1970 [M+H] + , Calcd for 633.1983.

[0120] Example Eleven 7-(4-(5-chloro-2-(l-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)- 1-oxo- 1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0121]

[0122] Example One, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromo-5- chlorophthalazine- 1 (2H)-one as starting material, using the same amounts and further steps as in Example 1, the product was HRMS (ESI) m / z: 649.1677 [M+H] + , Calcd for 649.1688.

[0123] Example Twelve 7-(2-fluoro-4-(2-(l-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)- 1-oxo- 1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0124]

[0125] Using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine- 1 (2H)-one as starting material, amount and the rest of the steps are the same as Example One, the product HRMS (ESI) m / z: 633.1972 [M+H] + , Calcd for 633.1983.

[0126] Example Thirteen 7-(2-fluoro-4-((2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2- ylamino)ethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)amino)phenoxy)-N- hydroxyheptanamide, whose structural formula is as follows:

[0127]

[0128] The preparation method of the above compound comprises the following steps:

[0129] (1) Synthesis of methyl 7-(2-fluoro-4-((2-(1-(2-fluorophenyl)-2-oxo-2- (thiazol-2-ylamino)ethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)amino)phenoxy)- heptanoate (8-1), whose reaction route is as follows:

[0130]

[0131] Intermediate 5-2 (1.0 g, 2.2 mmol), methyl 7-(4-aminophenoxy)heptanoate (0.7 g, 2.7 mmol) and potassium carbonate (0.9 g, 6.6 mmol) were added to 15 mL 2-butanol, and heated to 100°C. Under nitrogen protection, Pd2(dba)3 (0.22 mmol) and Xphos (3.1 mmol) were added, and the reaction was continued for 9 h. The solvent was evaporated, and the residue was separated and purified by column chromatography to obtain 0.5 g of intermediate 8-1.

[0132] (2) Synthesis of 7-(2-fluoro-4-((2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2- ylamino)ethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)amino)phenoxy)-N- hydroxyheptanamide (compound of Example Thirteen), whose reaction route is as follows:

[0133]

[0134] Dissolve hydroxylamine hydrochloride and potassium hydroxide in methanol at a mass ratio of 9:11, stir in an ice bath for 30 min, and filter. Dissolve intermediate 8-1 (0.2 g) in the above filtrate, and react at 30°C for 1 h. Concentrate the reaction solution under reduced pressure to remove methanol, dissolve in water, adjust the pH to 6-7 with dilute hydrochloric acid, filter, dry the solid, and purify by preparative thin layer chromatography to obtain 79.0 mg of the target compound. HRMS (ESI) m / z: 649.2033 [M+H] + , Calcd for 649.2045.

[0135] Example Fourteen 7-(3-chloro-4-(2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-1- oxo-1, 2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0136]

[0137] Use 2-bromo-2-(2-fluorophenyl)ethyl acetate and 6-bromophthalazine-1 (2H)-one as starting materials, and use the same amount and the remaining steps as in Example One. The product HRMS (ESI) m / z: 650.1629 [M+H] + , Calcd for 650.1640.

[0138] Example Fifteen 7-((5-(2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-1-oxo-1, 2- dihydrophthalazin-6-yl)pyridin-2-yl)oxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0139]

[0140] Use 2-bromo-2-(2-fluorophenyl)ethyl acetate and 6-bromophthalazine-1 (2H)-one as starting materials, and use the same amount and the remaining steps as in Example One. The product HRMS (ESI) m / z: 617.1971 [M+H] + , Calcd for 617.1982.

[0141] Example Sixteen 7-((2-((2-(1-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-1-oxo-1, 2- dihydrophthalazin-6-yl)amino)pyrimidin-5-yl)oxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0142]

[0143] The product was prepared from methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-l(2H)-one using the synthetic procedure of Example Thirteen. HRMS (ESI) m / z: 633.2031 [M+H] + , Calcd for 633.2044.

[0144] Example Seventeen 7-((6-(2-(l-(2-fluorophenyl)-2-oxo-2-(thiazol-2-ylamino)ethyl)- 1 -oxo- 1,2-dihydrophthalazin-6-yl)pyridin-3-yl)oxy)-N-hydroxyheptanamide, having the structural formula:

[0145]

[0146] The product was prepared from methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-l(2H)-one using the synthetic procedure of Example Thirteen. HRMS (ESI) m / z: 633.2031 [M+H] 1 H NMR (600 MHz, DMSO-d6) δ 12.63 (br, 1H), 10.32 (s, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 8.29 (m, 1H), 8.22 (m, 1H), 8.19 (m, 1H), 7.81 (m, 2H), 7.47-7.43 (m, 2H), 7.25-7.21 (m, 4H), 7.11 (m, 1H), 6.87 (s, 1H), 4.05 (m, 2H), 1.97 (m, 2H), 1.76-1.71 (m, 2H), 1.55-1.51 (m, 2H), 1.45-1.40 (m, 2H), 1.35-1.30 (m, 2H); HRMS (ESI) m / z: 617.1976 [M+H] + , Calcd for 617.1982. Example Eighteen 7-((4-(2-(l-(2-fluorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)- 1 -oxo- 1,2-dihydrophthalazin-6-yl)phenyl)thio)-N-hydroxyheptanamide, having the structural formula:

[0147]

[0148] The product was prepared from methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-l(2H)-one using the synthetic procedure of Example Thirteen. HRMS (ESI) m / z: 633.2031 [M+H] 1H NMR (600 MHz, DMSO-d6) δ 10.35 (br, 1H), 9.08 (m, 1H), 8.60 (br, 1H), 8.42 (s, 1H), 8.31 (m, 1H), 8.21 (s, 1H), 8.18-8.16 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.45-7.40 (m, 2H), 7.25-7.21 (m, 2H), 7.11 (d, J = 9.0 Hz, 1H), 6.94 (s, 1H), 4.68-4.59 (m, 1H), 4.01 (m, 2H), 1.97 (m, 2H), 1.75-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.34 1.29 (m, 2H); HRMS (ESI) m / z: 646.1953 [M+H] + , Calcd for 646.1958.

[0149] Example Nineteen 8-(4-(2-(1-(2-fluorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1- oxo-1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyoctanamide, whose structural formula is as follows:

[0150]

[0151] Example One, using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-1(2H)-one as starting materials, using the same amounts and the remaining steps as in Example One, the product 1 H NMR (600 MHz, DMSO-d6) δ 10.35 (br, 1H), 9.08 (m, 1H), 8.60 (br, 1H), 8.42 (s, 1H), 8.31 (m, 1H), 8.21 (s, 1H), 8.18-8.16 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.45-7.40 (m, 2H), 7.25-7.21 (m, 2H), 7.11 (d, J = 9.0 Hz, 1H), 6.94 (s, 1H), 4.68-4.59 (m, 1H), 4.05 (m, 2H), 1.97 (m, 2H), 1.75-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.34-1.29 (m, 2H); 13C NMR (151 MHz, DMSO-d6) δ 169.55, 169.23, 168.09, 160.16, 159.93, 158.98, 145.31, 142.60, 138.92, 131.77, 130.87, 130.68, 130.54, 130.42, 128.94 (2C), 127.18, 125.49, 124.67, 124.08, 123.65, 120.78, 115.65 (2C), 115.57, 68.05, 58.07, 41.28, 32.67, 28.99, 28.80, 25.70, 25.55; HRMS (ESI) m / z: 630.2148 [M+H] + , Calcd for 630.2186.

[0152] Example Twenty Six-(4-(2-(l-(2-fluorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)- 1 -oxo- 1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyhexanamide, whose structural formula is as follows:

[0153]

[0154] Example One, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromophthalazin- 1 (2H)-one as starting materials, using the same amounts and the remaining steps as in Example One, the product 1 H NMR (600 MHz, DMSO-d6) δ 10.39 (br, 1H), 9.18 (m, 1H), 8.68 (br, 1H), 8.43 (s, 1H), 8.31 (m, 1H), 8.22 (s, 1H), 8.18-8.16 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.45-7.41 (m, 2H), 7.25-7.21 (m, 2H), 7.11 (d, J = 9.0 Hz, 1H), 6.93 (s, 1H), 4.68-4.59 (m, 1H), 4.05 (m, 2H), 1.97 (m, 2H), 1.75-1.70 (m, 2H), 1.45-1.40 (m, 2H), 1.33-1.29 (m, 2H); HRMS (ESI) m / z: 616.2026 [M+H] + , Calcd for 616.2030.

[0155] Example Twenty One N 1(4-(2-(1-(2-fluorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1-oxo-1,2- dihydrophthalazin-6-yl)phenyl)-N 8 hydroxyoctanediamide, having the structure:

[0156]

[0157] Using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-1 (2H)-one as starting material, the amount and the rest of the steps are the same as example one, the product HRMS (ESI) m / z: 657.2289 [M+H] + , Calcd for 657.2295.

[0158] Example twenty two 4-(2-(1-(2-fluorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1- oxo-1,2-dihydrophthalazin-6-yl)-N-(7-(hydroxylamino)-7-oxoheptyl)benzamide, having the structure:

[0159]

[0160] Using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-1 (2H)-one as starting material, the amount and the rest of the steps are the same as example one, the product HRMS (ESI) m / z: 657.2288 [M+H] + , Calcd for 657.2295.

[0161] Example twenty three N 1 -(4-(2-(1-(2-fluorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1-oxo-1,2- dihydrophthalazin-6-yl)phenyl)-N 7 hydroxyheptanediamide, having the structure:

[0162]

[0163] Using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-1 (2H)-one as starting material, the amount and the rest of the steps are the same as example one, the product HRMS (ESI) m / z: 643.2136 [M+H] + , Calcd for 643.2136.

[0164] Example Twenty-Four 3-(4-(2-(l-(2-fluorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)- 1 -oxo- 1,2-dihydrophthalazin-6-yl)phenyl)-N-hydroxyacrylamide, having the structural formula:

[0165]

[0166] Example One, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromophthalazin- 1 (2H)-one as starting materials, the product 1 H NMR (600 MHz, DMSO-d6) δ 10.45 (br, 1H), 9.18 (m, 1H), 8.68 (br, 1H), 8.43 (s, 1H), 8.31 (m, 1H), 8.22 (s, 1H), 8.18-8.16 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 3.6 Hz, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.45-7.41 (m, 2H), 7.35 (m, 1H), 7.25-7.21 (m, 2H), 7.11 (d, J = 9.0 Hz, 1H), 6.93 (s, 1H), 6.78 (m, 1H), 4.68-4.59 (m, 1H); HRMS (ESI) m / z: 556.1449 [M+H] + Calcd for 556.1455.

[0167] Example Twenty-Five 7-(4-(2-(l-(2-fluorophenyl)-2-oxo-2-(phenylamino)ethyl)-l-oxo- 1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0168]

[0169] Example One, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromophthalazin- 1 (2H)-one as starting materials, the product 1H NMR(600MHz,DMSO-d6)δ10.52(s,1H),8.42(s,1H),8.31(m,1H),8.21(s,1H),8.18(m,1H) ,7.80(m,2H),7.61(m,2H),7.47-7.43(m,1H),7.35-7.30(m,3H),7.29-7.23(m,2H),7.10 -7.06(m,3H),6.98(s,1H),4.03(t,J=6.6Hz,2H),2.04(t,J=6.6Hz,2H),1.75-1.70(m,2H ),1.51-1.46(m,2H),1.44-1.39(m,2H),1.35-1.29(m,2H).HRMS(ESI)m / z:609.2506[M+H] + ,Calcd for 609.2513.

[0170] Example 26: 7-(4-(2-(1-(2-fluorophenyl)-2-((5-fluorothiazol-2-yl)amino)-2-oxoethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)phenoxy)-N-hydroxyheptamide, the structural formula of which is as follows:

[0171]

[0172] Using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-1(2H)-one as starting materials, with the same amounts and remaining steps as in Example 1, the product HRMS (ESI) m / z: 634.1932 [M+H] + ,Calcd for 634.1936.

[0173] Example 27: 7-(4-(2-(1-((1,3,4-thiadiazol-2-yl)amino)-1-oxopropyl-2-yl)-1-oxo-1,2-dihydrophthalazine-6-yl)phenoxy)-N-hydroxyheptanamide, with the following structural formula:

[0174]

[0175] Using methyl 2-bromopropionate and 6-bromophthalazine-1(2H)-one as starting materials, with the same amounts and remaining steps as in Example 1, the product HRMS (ESI) m / z: 537.1915 [M+H] + ,Calcd for 537.1920.

[0176] Example Twenty-Eight 7-(4-(2-(2-((1 -acetylpiperazin-4-yl)amino)-1 -(2- fluorophenyl)-2-oxoethyl)-1 -oxo-1,2-dihydrophthalazin-6-yl)phenoxy)-N- hydroxyheptanamide, whose structural formula is as follows:

[0177]

[0178] Example One, using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine- 1 (2H)-one as starting materials, the product HRMS (ESI) m / z: 658.3035 [M+H] + , Calcd for 658.3041.

[0179] Example Twenty-Nine 7-(4-(2-(2-(benzo[d]thiazol-5-ylamino)-1 -(2- fluorophenyl)-2-oxoethyl)-1 -oxo-1,2-dihydrophthalazin-6-yl)phenoxy)-N- hydroxyheptanamide, whose structural formula is as follows:

[0180]

[0181] Example One, using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine- 1 (2H)-one as starting materials, the product 1 H NMR (600 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.36 (br, 1H), 9.38 (s, 1H), 8.68 (br, 1H), 8.49 (m, 1H), 8.44 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.20 (m, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.61 (m, 1H), 7.48 - 7.45 (m, 1H), 7.39 (m, 1H), 7.31 - 7.24 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.03 (s, 1H), 4.04 (m, 2H), 1.98 (m, 2H), 1.76 - 1.71 (m, 2H), 1.55 - 1.50 (m, 2H), 1.45 - 1.40 (m, 2H), 1.35 - 1.29 (m, 2H); 13C NMR (151 MHz, DMSO-d6) δ 169.57, 166.56, 161.81, 160.17, 159.94, 159.04, 157.66, 154.03, 145.41, 138.71, 137.83, 131.19, 130.99, 130.68, 130.53, 128.97 (2C), 128.82, 127.11, 125.40, 124.98, 124.14, 123.44, 122.98, 118.52, 115.86, 115.64 (2C), 113.43, 68.05, 59.66, 32.67, 29.00, 28.80, 25.70, 25.55; HRMS (ESI) m / z: 666.2147 [M+H] + Calcd for 666.2186.

[0182] Example Thirty Seven-(4-(2-(2-((4,5-dimethylthiazol-2-yl)amino)-l-(2- fluorophenyl)-2-oxoethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N- hydroxyheptanamide, whose structural formula is as follows:

[0183]

[0184] Example One, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromophthalazin-l(2H)-one as starting materials, using the same amounts and the remaining steps as in Example One, the product 1 H NMR (600 MHz, DMSO-d6) δ 12.44 (br, 1H), 10.35 (br, 1H), 8.67 (br, 1H), 8.43 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.22 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.46 (m, 1H), 7.28 - 7.22 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 4.05 (m, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.97 (m, 2H), 1.75 - 1.71 (m, 2H), 1.55 - 1.50 (m, 2H), 1.45 - 1.40 (m, 2H), 1.35 - 1.30 (m, 2H); 13CNMR (151 MHz, DMSO-d6) δ 169.56, 161.78, 160.15, 159.94, 158.99, 145.37, 138.85, 131.12, 131.09, 131.03, 123.12, 123.03, 130.66, 130.55, 130.50, 128.96 (2C), 127.10, 125.49, 124.89, 124.13, 115.83, 115.68, 115.65 (2C), 68.06, 59.03, 32.67, 29.00, 28.81, 25.71, 25.55, 14.59, 10.86; HRMS (ESI) m / z: 644.2307 [M+H] + , Calcd for 644.2343.

[0185] Example Thirty-one 7-(4-(2-(l-(2-fluorophenyl)-2-oxo-2-((2-(thiazol-2-yl)ethyl)amino)ethyl)- 1 -oxo- 1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0186]

[0187] Example One, using 2-bromo-2-(2-fluorophenyl)acetic acid methyl ester and 6-bromophthalazine- 1 (2H)-one as starting materials, the amount and the rest of the steps are the same as Example One, the product 1 H NMR (600 MHz, DMSO-d6) δ 8.46-8.44 (m, 1H), 8.38 (s, 1H), 8.30 (m, 1H), 8.20 (s, 1H), 8.18-8.16 (m, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 3.0 Hz, 2H), 7.60 (d, J = 3.0 Hz, 2H), 7.42-7.39 (m, 1H), 7.29-7.27 (m, 1H), 7.22-7.17 (m, 2H), 7.11 (d, J = 9.0 Hz, 2H), 6.83 (s, 1H), 4.05-4.02 (t, J = 6.6 Hz, 2H), 3.60-3.55 (m, 1H), 3.50-3.45 (m, 1H), 3.21-3.12 (m, 2H), 1.97-1.95 (t, J = 6.6 Hz, 2H), 1.76-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.35-1.29 (m, 2H). HRMS (ESI) m / z: 644.2338 [M+H] + , Calcd for 644.2343.

[0188] Example Thirty-Two 7-(4-(2-(2-(cyclohexylamino)-l-(2-fluorophenyl)-2- oxoethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0189]

[0190] Example One, using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine- 1 (2H)-one as starting materials. The product was used without further purification. 1 H NMR (600 MHz, DMSO-d6) δ 10.35 (br, 1H), 8.35 (s, 1H), 8.30-8.28 (m, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.43-7.39 (m, 1H), 7.33-7.31 (m, 1H), 7.24-7.19 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 4.04-4.02 (t, J = 6.6 Hz, 2H), 3.65-3.60 (m, 1H), 1.97-1.95 (t, J = 6.6 Hz, 2H), 1.76-1.71 (m, 4H), 1.69-1.64 (m, 2H), 1.55-1.50 (m, 3H), 1.45-1.40 (m, 2H), 1.34-1.30 (m, 2H), 1.27-1.25 (m, 2H), 1.20-1.16 (m, 1H), 1.13-1.09 (m, 2H). HRMS (ESI) m / z: 615.2978 [M + H] + , Calcd for 615.2983.

[0191] Example Thirty-Three 7-(4-(2-(2-(cyclobutylamino)-l-(2-fluorophenyl)-2- oxoethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0192]

[0193] Example One, using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine- 1 (2H)-one as starting materials. The product was used without further purification. 1H NMR (600 MHz, DMSO-d6) δ 10.36 (br, 1H), 8.70 (br, 1H), 8.55 (m, 1H), 8.38 (s, 1H), 8.30-8.28 (m, 1H), 8.19 (s, 1H), 8.17 (m, 1H), 7.80 (d, J = 5.4 Hz, 1H), 7.42-7.40 (m, 1H), 7.31-7.28 (m, 1H), 7.23-7.20 (m, 1H), 7.10 (d, J = 5.4 Hz, 1H), 6.77 (s, 1H), 4.28-4.22 (m, 1H), 4.03 (t, J = 6.0 Hz, 1H), 2.17 (m, 2H), 1.97 (t, J = 6.0 Hz, 1H), 1.94-1.85 (m, 2H), 1.74-1.72 (m, 2H), 1.65-1.59 (m, 2H), 1.55-1.50 (m, 2H), 1.44-1.41 (m, 2H), 1.35-1.30 (m, 2H). HRMS (ESI) m / z: 587.2665 [M+H] + , Calcd for 587.2670.

[0194] Example Thirty-Four N-hydroxy-7-(4-(2-(2-(methylamino)-2-oxo-1- phenylethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)phenoxy)heptanamide, having the structural formula:

[0195]

[0196] Example One, using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazine-1 (2H)-one as starting materials. The product was used without further purification. 1 H NMR (600 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.97 (m, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.39-7.32 (m, 5H), 7.10 (d, J = 8.4 Hz, 2H), 6.62 (s, 1H), 4.04 (t, J = 6.0 Hz, 1H), 2.64 (d, 3H), 2.50, 1.97 (t, J = 6.0 Hz, 1H), 1.75-1.71 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.40 (m, 2H), 1.34-1.30 (m, 2H). HRMS (ESI) m / z: 529.2447 [M+H] +Calcd for 529.2451.

[0197] Example Thirty-Five N-hydroxy-7-(4-(2-(l-(2-hydroxyphenyl)-2-oxo-2-(thiazol-2- ylamino)ethyl)-l-oxo-l,2-dihydrophthalazine-6-yl)phenoxy)heptanamide, having the structural formula:

[0198]

[0199] Example Twenty-Six N-hydroxy-7-(4-(2-(l-(2-hydroxyphenyl)-2-oxo-2-(thiazol-2- ylamino)ethyl)-l-oxo-l,2-dihydrophthalazine-6-yl)phenoxy)heptanamide, having the structural formula: + Calcd for 614.2073.

[0200] Example Thirty-Six 7-(4-(2-(l-(3-chlorophenyl)-2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)- 1-oxo-l,2-dihydrophthalazine-6-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0201]

[0202] Example Twenty-Six N-hydroxy-7-(4-(2-(l-(2-hydroxyphenyl)-2-oxo-2-(thiazol-2- ylamino)ethyl)-l-oxo-l,2-dihydrophthalazine-6-yl)phenoxy)heptanamide, having the structural formula: + Calcd for 646.1891.

[0203] Example Thirty-Seven N-hydroxy-7-(4-(4-oxo-3-(2-oxo-2-((2-(thiazol-2-yl)ethyl)amino)- 1-(3-(trifluoromethyl)phenyl)ethyl)-3,4-dihydroquinazolin-7-yl)phenoxy)heptanamide, having the structural formula:

[0204]

[0205] Example Twenty-Six N-hydroxy-7-(4-(2-(l-(2-hydroxyphenyl)-2-oxo-2-(thiazol-2- ylamino)ethyl)-l-oxo-l,2-dihydrophthalazine-6-yl)phenoxy)heptanamide, having the structural formula: + Calcd for 694.2311.

[0206] Example Thirty-Eight 7-(4-(3-(1-cyclohexyl-2-oxo-2-((2-(thiazol-2-yl)ethyl)amino)ethyl)- 4-oxo-3,4-dihydroquinazolin-7-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0207]

[0208] Example One, using 2-bromo-2-cyclohexylethan-1 -amine and 7-bromoquinazolin-4(3H)- one as starting materials. HRMS (ESI) m / z: 632.2903 [M+H] + , Calcd for 632.2907.

[0209] Example Thirty-Nine 7-(4-(3-(1-(furan-2-yl)-2-oxo-2-((2-(thiazol-2-yl)ethyl)amino)ethyl)- 4-oxo-3,4-dihydroquinazolin-7-yl)phenoxy)-N-hydroxyheptanamide, having the structural formula:

[0210]

[0211] Example One, using 2-bromo-2-cyclohexylethan-1 -amine and 7-bromoquinazolin-4(3H)- one as starting materials. HRMS (ESI) m / z: 632.2903 [M+H] + , Calcd for 616.2230.

[0212] Example Forty N-Hydroxy-7-(4-(4-oxo-3-(4,4,4-trifluoro-1-oxo-1-((2-(thiazol-2- yl)ethyl)amino)butan-2-yl)-3,4-dihydroquinazolin-7-yl)phenoxy)heptanamide, having the structural formula:

[0213]

[0214] Example One, using 2-bromo-2-cyclohexylethan-1 -amine and 7-bromoquinazolin-4(3H)- one as starting materials. HRMS (ESI) m / z: 632.2903 [M+H] + , Calcd for 632.2154.

[0215] Example Forty-One N-Hydroxy-7-(4-(4-oxo-3-(1-oxo-1-((2-(thiazol-2- yl)ethyl)amino)butan-2-yl)-3,4-dihydroquinazolin-7-yl)phenoxy)heptanamide, having the structural formula:

[0216]

[0217] Example 1, product HRMS (ESI) m / z: 578.2425 [M+H] + , Calcd for 578.2437.

[0218] Example Forty-two N-hydroxy-7-(4-(3-(2-methyl-l-oxo-l-((2-(thiazol-2-yl)ethyl)amino)butan-2-yl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenoxy)heptanamide, whose structural formula is as follows:

[0219]

[0220] Example 1, product HRMS (ESI) m / z: 578.2425 [M+H] + , Calcd for 578.2437.

[0221] Example Forty-two N-hydroxy-7-(4-(3-(2-methyl-l-oxo-l-((2-(thiazol-2-yl)ethyl)amino)butan-2-yl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenoxy)heptanamide, whose structural formula is as follows:

[0222]

[0223] Example 1, product HRMS (ESI) m / z: 578.2425 [M+H] 1H NMR(600MHz,DMSO-d6)δ8.46-8.44(m,1H),8.38(s,1H),8.30(m,1H),8.20(s,1H),8.18-8.16(m,1H),7.80(d,J =9.0Hz,2H),7.70(m,1H),7.60(m,1H),7.42-7.39(m,1H),7.29-7.27(m,1H),7.11(d,J=9.0Hz,2H),4.05-4.02( t,J=6.6Hz,2H),3.60-3.55(m,1H),3.50-3.45(m,1H),3.21-3.12(m,2H),1.97-1.95(t,J=6.6Hz,2H),1.76-1. 71(m,2H),1.69(s,6H),1.55-1.50(m,2H),1.45-1.40(m,2H),1.35-1.29(m,2H).HRMS(ESI)m / z:578.2427[M+H] + ,Calcd for 578.2437.

[0224] Example 44: N-hydroxy-7-(4-(3-(1-(3-(methylamino)phenyl)-2-oxo-2-((2-(thiazo-2-yl)ethyl)amino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenoxy)heptamide, the structural formula of which is as follows:

[0225]

[0226] Using methyl 2-bromo-2-(3-(methylamino)phenyl)acetate and 7-bromoquinazolin-4(3H)-one as starting materials, with the same amounts and remaining steps as in Example 1, the product HRMS (ESI) m / z: 655.2760 [M+H] + ,Calcd for 655.2703.

[0227] Example 45 3-(4-(3-(1-(5-fluoro-2-hydroxyphenyl)-2-oxo-2-((2-(thiazol-2-yl)ethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-N-hydroxyacrylamide

[0228]

[0229] Using methyl 2-bromo-2-(5-fluoro-2-methoxyphenyl)acetate and 7-bromoquinazolin-4(3H)-one as starting materials, the amounts and remaining steps were the same as in Example 1. The product HRMS (ESI) m / z: 586.1552 [M+H] +Calcd for 586.1560.

[0230] Example Forty-Six 3-(4-(3-(l-(3,4-dimethylphenyl)-2-oxo-2-((2-(thiazol-2- yl)ethyl)amino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-N- hydroxyacrylamide, having the structural formula:

[0231]

[0232] Example Forty-Six 3-(4-(3-(l-(3,4-dimethylphenyl)-2-oxo-2-((2-(thiazol-2- yl)ethyl)amino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-N- hydroxyacrylamide, having the structural formula: + Calcd for 580.2019.

[0233] Example Forty-Six 3-(4-(3-(l-(3,4-dimethylphenyl)-2-oxo-2-((2-(thiazol-2- yl)ethyl)amino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-N- hydroxyacrylamide, having the structural formula:

[0234]

[0235] Example Forty-Six 3-(4-(3-(l-(3,4-dimethylphenyl)-2-oxo-2-((2-(thiazol-2- yl)ethyl)amino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-N- hydroxyacrylamide, having the structural formula: + Calcd for 553.1658.

[0236] Example Forty-Six 3-(4-(3-(l-(3,4-dimethylphenyl)-2-oxo-2-((2-(thiazol-2- yl)ethyl)amino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-N- hydroxyacrylamide, having the structural formula:

[0237]

[0238] Example Forty-Six 3-(4-(3-(l-(3,4-dimethylphenyl)-2-oxo-2-((2-(thiazol-2- yl)ethyl)amino)ethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenyl)-N- hydroxyacrylamide, having the structural formula: + Calcd for 571.1654.

[0239] Example Forty-Nine 7-(4-(3-(1-(3-fluorophenyl)-2-(hexan-3-ylamino)-2- oxoethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0240]

[0241] Example One, using methyl 2-bromo-2-(3-fluorophenyl)acetate and 7-bromoquinazolin- 4(3H)-one as starting materials, the amounts and the remaining steps are the same as in Example One. The product HRMS (ESI) m / z: 617.3130 [M+H] + , Calcd for 617.3139.

[0242] Example Fifty 7-(4-(3-(2-(butylamino)-1-(3-fluorophenyl)-2-oxoethyl)-4-oxo-3,4- dihydroquinazolin-7-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0243]

[0244] Example One, using methyl 2-bromo-2-(3-fluorophenyl)acetate and 7-bromoquinazolin- 4(3H)-one as starting materials, the amounts and the remaining steps are the same as in Example One. The product HRMS (ESI) m / z: 617.3130 [M+H] + , Calcd for 617.3139.

[0245] Example Fifty 7-(4-(3-(2-(butylamino)-1-(3-fluorophenyl)-2-oxoethyl)-4-oxo-3,4- dihydroquinazolin-7-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0246]

[0247] Example One, using methyl 2-bromo-2-(3-fluorophenyl)acetate and 7-bromoquinazolin- 4(3H)-one as starting materials, the amounts and the remaining steps are the same as in Example One. The product HRMS (ESI) m / z: 617.3130 [M+H] + , Calcd for 617.3139.

[0248] Example Fifty 7-(4-(3-(2-(butylamino)-1-(3-fluorophenyl)-2-oxoethyl)-4-oxo-3,4- dihydroquinazolin-7-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0249]

[0250] Example 1, product HRMS (ESI) m / z: 684.1900 [M+H] + , Calcd for 684.1904.

[0251] Example Fifty-Three 7-(4-(2-(2-((4-acetylthiazol-2-yl)amino)-l-(2- fluorophenyl)-2-oxoethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N- hydroxyheptanamide, whose structural formula is as follows:

[0252]

[0253] Example 1, product HRMS (ESI) m / z: 684.1900 [M+H] + , Calcd for 684.1904.

[0254] Example Fifty-Three 7-(4-(2-(2-((4-acetylthiazol-2-yl)amino)-l-(2- fluorophenyl)-2-oxoethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N- hydroxyheptanamide, whose structural formula is as follows:

[0255]

[0256] Example 1, product HRMS (ESI) m / z: 684.1900 [M+H] + , Calcd for 684.1904.

[0257] Example Fifty-Three 7-(4-(2-(2-((4-acetylthiazol-2-yl)amino)-l-(2- fluorophenyl)-2-oxoethyl)-l-oxo-l,2-dihydrophthalazin-6-yl)phenoxy)-N- hydroxyheptanamide, whose structural formula is as follows:

[0258]

[0259] Example 1, product HRMS (ESI) m / z: 684.1900 [M+H] + , Calcd for 684.1904.

[0260] Example Fifty-Six 7-(4-(2-(1-(2-fluorophenyl)-2-((1-methylpiperidin-4-yl)amino)-2- oxoethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)phenoxy)-N-hydroxyheptanamide, whose structural formula is as follows:

[0261]

[0262] Example One, using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromophthalazin-1 (2H)-one as starting materials, the amount and the rest of the steps are the same. HRMS (ESI) m / z: 630.3081 [M+H] + , Calcd for 630.3092.

[0263] Example Fifty-Seven 2-(1-(2-fluorophenyl)-2-((1-methylpiperazin-4-yl)amino)-2- oxoethyl)-N-(4-((7-(hydroxyamino)-7-oxoheptyl)oxy)phenyl)-1-oxo-1,2- dihydrophthalazin-6-amide, whose structural formula is as follows:

[0264]

[0265] The preparation method of the above compound comprises the following steps:

[0266] (1) Synthesis of 2-(1-(2-fluorophenyl)-2-((1-methylpiperazin-4-yl)amino)-2- oxoethyl)-1-oxo-1,2-dihydrophthalazine-6-carboxylic acid (10-1)

[0267]

[0268] Pd(OAc)2(33.7 mg, 0.15 mmol) and Xantphos (86.8 mg, 0.15 mmol) were added to 10 mL of DMF under nitrogen protection, then formic acid (35.0 mmol), 2-(6-bromo-1-oxophthalazin-2(1H)-yl)-2-(2-fluorophenyl)-N-(1- methylpiperazin-4-yl)acetamide (2.4 g, 5.0 mmol), DCC (2.1 g, 10.0 mmol) and Et3N (1.0 g, 10.0 mmol) were added, and the reaction was carried out at 80°C for 16 h. The reaction solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Column chromatography was used for separation and purification to obtain 1.1 g of intermediate 10-1.

[0269] (2) Synthesis of methyl 7-(4-(2-(l-(2-fluorophenyl)-2-((l-methylpiperazin-4- yl)amino)-2-oxoethyl)-l-oxo-l,2-dihydrophthalazine-6-carboxamido)phenoxy)heptanoate (11-1)

[0270]

[0271] Intermediate 10-1 (0.44 g, 1.0 mmol) was dissolved in 5 mL of DMF, HATU (0.6 g, 1.5 mmol) and DIEA (0.23 g, 1.8 mmol) were added, after stirring at room temperature for 30 min, methyl 7-(4-aminophenoxy)heptanoate (0.33 g, 1.3 mmol) was added, and the reaction was continued at room temperature for 3 h. The reaction solution was poured into a proper amount of ice water, stirred, and suction filtered to obtain 0.3 g of intermediate 11-1.

[0272]

[0273] Hydroxylamine hydrochloride and potassium hydroxide were dissolved in a proper amount of methanol at a mass ratio of 9:11, stirred in an ice bath for 30 min, suction filtered, and the filtrate was used as prepared. Intermediate 11-1 (0.10 g) was dissolved in a proper amount of the above filtrate, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove methanol, dissolved in water, and the pH was adjusted to 6-7 with dilute hydrochloric acid, suction filtered, and the solid was dried in an oven. After separation and purification by preparative thin layer chromatography, the target compound was obtained in an amount of 42.0 mg. HRMS (ESI) m / z: 673.3137 [M+H] + , Calcd for 673.3150.

[0274] Example 58 3-(l-(2-Fluorophenyl)-2-((l-methylpiperazin-4-yl)amino)-2-oxoethyl)-N-(4-(3- (hydroxyamino)-3-oxoprop-l-en-l-yl)phenyl)-4-oxo-3,4-dihydroquinazolin-7-amide, whose structural formula is as follows:

[0275]

[0276] Methyl 2-bromo-2-(2-fluorophenyl)acetate and 7-bromoquinazolin-4(3H)-one were used as starting materials, and the product was prepared according to the synthesis method of Example Fifty-Seven, and the product HRMS (ESI) m / z: 599.2407 [M+H] + , Calcd for 599.2418.

[0277] Example Fifty-Nine 3-(2-(ethylamino)-l-(2-fluorophenyl)-2-oxoethyl)-5-fluoro-N-(4- (hydroxyaminocarbonyl)phenyl)-4-oxo-3,4-dihydroquinazoline-6-amide, having the structural formula:

[0278]

[0279] The product was prepared using methyl 2-bromo-2-(2-fluorophenyl)acetate and 6-bromo-5-fluoroquinazolin-4(3H)-one as starting materials, and following the remainder of the procedure of Example Fifty-Seven. HRMS (ESI) m / z: 522.1577 [M+H] + , Calcd for 522.1589. Example Sixty 4-(3-(hydroxyamino)-3-oxoprop-l-en-l-yl)-N-(4-oxo-3-(l-oxo-l-((thiazol-2- ylmethyl)amino)propan-2-yl)-3,4-dihydroquinazolin-7-yl)benzamide, having the structural formula:

[0280]

[0281] The above compound was prepared by the following method:

[0282] (1) Synthesis of methyl 2-(7-nitro-4-oxoquinazolin-3(4H)-yl)propanoate (14-1)

[0283]

[0284] Methyl 2-bromopropanoate (0.84 g, 5.0 mmol) and 7-nitroquinazolin-4(3H)-one (0.92 g, 4.8 mmol) were dissolved in 10 mL of acetonitrile, and cesium carbonate (2.4 g, 7.5 mmol) was added. The reaction was stirred at room temperature for 2 h. The solid was filtered off, and the filtrate was combined and concentrated under reduced pressure to give 1.2 g of intermediate 14-1.

[0285] (2) Synthesis of 2-(7-nitro-4-oxoquinazolin-3(4H)-yl)propanoic acid (15-1)

[0286]

[0287] Intermediate 14-1 (0.55 g, 2.0 mmol) was dissolved in 5 mL of methanol and 1 mL of water, and lithium hydroxide (0.11 g, 8.0 mmol) was added. The reaction was stirred at 50 °C for 2 h. The reaction was concentrated under reduced pressure to remove methanol, and the residue was dissolved in water. The pH was adjusted to 3-4 with dilute hydrochloric acid, and the resulting solid was filtered off to give 0.3 g of intermediate 15-1.

[0288] (3) Synthesis of 2-(7-nitro-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-ylmethyl)propanamide (16-1)

[0289]

[0290] Intermediate 15-1 (0.3 g, 1.1 mmol) was dissolved in 3 mL of DMF, DIEA (0.2 g, 1.6 mmol) and HATU (0.6 g, 1.5 mmol) were added, after stirring at room temperature for 30 min, thiazol-2-ylmethanamine (0.14 g, 1.2 mmol) was added, and the reaction was continued at 30°C for 6 h. The reaction solution was poured into a proper amount of ice water to precipitate solids, suction filtration was performed, and the crude product was separated and purified by column chromatography to obtain 0.3 g of intermediate 16-1.

[0291] (4) Synthesis of 2-(7-amino-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-ylmethyl)propanamide (17-1)

[0292]

[0293] Intermediate 16-1 (0.3 g, 0.8 mmol) was added to 5 mL of 90% ethanol, and iron powder (0.13 g, 2.4 mmol) and 1 drop of concentrated hydrochloric acid were added, and the reaction was refluxed for 4 h. Hot suction filtration was performed, and the filtrate was evaporated to dryness to obtain 0.2 g of intermediate 17-1.

[0294] (5) Synthesis of methyl 3-(4-((4-oxo-3-(1-oxo-1-((thiazol-2-ylmethyl)amino)propan-2-yl)-3,4-dihydroquinazolin-7-yl)formamido)phenyl)acrylate (18-1)

[0295]

[0296] Intermediate 17-1 (0.2 g, 0.6 mmol) was dissolved in 3 mL of DMF, DIEA (0.1 g, 0.9 mmol) and HATU (0.3 g, 0.8 mmol) were added, after stirring at room temperature for 30 min, 4-(3-methoxy-3-oxoprop-1-en-1-yl)benzoic acid (0.14 g, 0.7 mmol) was added, and the reaction was continued at 30°C for 6 h. The reaction solution was poured into a proper amount of ice water to precipitate solids, suction filtration was performed, and the crude product was separated and purified by column chromatography to obtain 0.2 g of intermediate 18-1.

[0297] (6) Synthesis of 4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)-N-(4-oxo-3-(1-oxo-1-((thiazol-2-ylmethyl)amino)propan-2-yl)-3,4-dihydroquinazolin-7-yl)benzamide (Example Sixty Compound)

[0298]

[0299] Dissolve hydroxylamine hydrochloride and potassium hydroxide in methanol at a mass ratio of 9:11, stir in an ice bath for 30 min, and filter. Dissolve intermediate 18-1 (0.2 g) in the above filtrate, and react at 30°C for 1 h. Concentrate the reaction solution under reduced pressure to remove methanol, dissolve in water, adjust the pH to 6-7 with dilute hydrochloric acid, filter, dry the solid, and purify by preparative thin layer chromatography to obtain 65.0 mg of the target compound. HRMS (ESI) m / z: 519.1439 [M+H] + , Calcd for 519.1451.

[0300] Example sixty-one 3-(1-(2-fluorophenyl)-2-(methylamino)-2-oxoethyl)-N-(6- (hydroxylcarbamoyl)pyridin-3-yl)-4-oxo-3,4-dihydrophthalazine-6-carboxamide, whose structural formula is as follows:

[0301]

[0302] Use methyl 2-bromo-2-(2-fluorophenyl)acetate and 7-bromophthalazine-1 (2H)-one as starting materials, and follow the remaining steps in the synthetic method of Example fifty-seven to obtain the product, which has a product HRMS (ESI) m / z: 491.1468 [M+H] + , Calcd for 491.1479.

[0303] The compound of formula I provided by the present application can be administered alone or in combination with a pharmaceutical carrier. A variety of pharmaceutical dosage forms can be prepared using the compound of formula I, such as tablets, capsules, injections, aerosols, suppositories, films, dripping pills, external liniments, and ointments. The following provides preparation cases:

[0304] Application Example One: Tablets

[0305] Take 10.0 g of the compound of Example Three, add auxiliary materials (4.5 g of starch, 12.5 g of powdered sugar, 1.5 g of sodium carboxymethyl cellulose, and 1.5 g of hydroxypropyl cellulose) 20.0 g, mix uniformly, and press into 100 tablets, each weighing 300 mg.

[0306] Application Example Two: Capsules

[0307] Take 10.0 g of the compound of Example Fifteen, add auxiliary materials (15.0 g of gelatin, 2.0 g of plant cellulose, 2.0 g of plasticizer, and 1.0 g of starch) 20.0 g, mix uniformly, and load into empty capsules, each capsule weighing 300 mg.

[0308] Application Example Three: Injections

[0309] Take the compound 10.0 g of Example XXII, adsorb on activated carbon, filter through a 0.65 μm microporous filter, and fill into a nitrogen tank to make a water injection preparation, 2 mL per bottle, a total of 100 bottles.

[0310] Application Example IV: Drop Pills

[0311] Take the compound 10.0 g of Example XLI, heat and melt it uniformly with gelatin (matrix) 50.0 g, and drop it into low-temperature liquid paraffin to make 1000 drop pills.

[0312] Product Effect Test

[0313] 1. Fluorescence Assay

[0314] Using SAHA as a positive control drug, the fluorescence assay was used to determine the inhibitory activity of the target compounds on HDACs. The reaction system used a detection buffer containing 50 mmol / L Tris-HCl (pH 7.5), 0.01% (v / v) Tween-20 and 50 mmol / L NaCl. The 10 mmol / L stock solution of the test compound was diluted 100 times to the target concentration with DMSO, and then 250 nL was accurately transferred to the detection well plate using the Echo 650 acoustic pipetting system (Labcyte). The diluted compound was pre-incubated with 15 μL of recombinant human HDAC1 enzyme (final concentration 10 nmol / L) in the detection buffer at room temperature (25±2℃) for 15 min. The addition of 10 μL of fluorescent substrate solution [containing peptide Ac-LGK(Ac)-AMC (final concentration 8 μmol / L) and trypsin (final concentration 0.05 μmol / L)] started the enzymatic reaction. The fluorescence signal was continuously monitored for 30 min using a Paradigm multifunctional enzyme marker in kinetic mode (excitation wavelength 355 nm, emission wavelength 460 nm). The test compound was diluted 3 times in gradient in DMSO at 5 concentration points to prepare the working solution, and then the enzyme activity was determined according to the above method. The raw data were normalized with blank control wells containing only 1% DMSO by mass concentration. The concentration response curve was fitted using a four-parameter nonlinear regression model, and the half maximal inhibitory concentration (IC 50 ) was calculated using MS Excel software with XLFit plug-in. The results are as follows.

[0315] 2. MTT Method (MTT Colorimetric Method)

[0316] (1) Human non-small cell lung cancer cells (NCI-H1975), human liver cancer cells (HepG2), and human breast cancer cells (MCF-7) in logarithmic growth phase were selected and prepared into single-cell suspensions after digestion with 0.25% trypsin. Platelet counting was performed using a platelet counter. The cell suspensions were diluted to the desired density with complete culture medium. 96-well plates were set up with blank control wells, cell control wells, and experimental wells. The diluted cell suspension was evenly seeded at 200 μL / well into the cell control wells and experimental wells, with 3 × 10⁶ cells per well. 3 Each sample was then placed in an incubator at 37°C and 5% CO2 for 24 hours.

[0317] (2) The initial drug concentration for both the experimental group and the positive control group (SAHA) was 10.0 μg / mL, and a 3-fold serial dilution was used to set up 5 concentration gradients. After 24 h of culture, the 96-well plates were removed, the cell culture medium was discarded, and different concentration gradients of drug solution were added to the experimental wells at 170 μL / well. The cell control wells were added with complete culture medium without drug. Then, they were incubated in an incubator at 37℃ and 5% CO2 for 72 h.

[0318] (3) Remove the 96-well plate after 72 hours of culture, discard the cell culture medium, add 100 μL of MTT solution (0.5 mg / mL) to each well under dark conditions, and continue incubation in an incubator for 4 hours. Remove the culture medium, add 100 μL of DMSO to each well, shake for 5 minutes, and measure the OD values ​​of each well at both 490 nm and 630 nm using a full-band microplate reader. Take the difference between the two values ​​and calculate the half-maximal inhibitory concentration (IC50) using GraphPadPrism 8.0. 50 value.

[0319] Table 1 Test results of compounds in each example

[0320]

[0321]

[0322] In the table above, "-" indicates that it was not measured.

[0323] As shown in the table above, the compounds of Formula I of the present invention all have good in vitro antitumor activity and HDAC1 inhibitory activity. In particular, the compounds in Examples 4, 8, 10, 19, 21, 26, 29, 31, 33, 40, 41, 47, 53, 56, and 60 have effects comparable to or better than the anticancer drug SAHA (vorinostat) in the positive control group, and can achieve targeted antitumor activity.

Claims

1. A phthalazinone or quinazolinone derivative represented by Formula I, a stereoisomer thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, Formula I is shown as follows: Y is null, NH or CONH; wherein Z1, Z2, Z3, Z4, Z5 are independently selected from N or CH; n is 0, 1 or 2; R1 and R2 are independently selected from hydrogen or halogen atom; W1 is 4-6 membered cycloalkyl, 4-10 membered heterocycle, 6-10 membered aryl or C1-C6 alkyl, the 4-6 membered cycloalkyl, 4-10 membered heterocycle, 6-10 membered aryl is unsubstituted or substituted with 1-3 substituents which are the same or different; W2 is hydrogen, 3-6 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heterocyclyl, C1-C3 haloalkyl, C1-C4 alkyl or two C1-C4 alkyl groups which are the same or different; the 4-10 membered heterocycle, 5-10 membered heterocyclyl independently comprises 1-3 heteroatoms which are independently selected from nitrogen, sulfur or oxygen atom, and / or, the 6-10 membered aryl is unsubstituted or substituted with C1-C2 alkyl, halogen atom, trifluoromethyl, -NH(C1-C3 alkyl) or hydroxyl, and / or, the 5-10 membered heterocyclyl is unsubstituted or substituted with C1-C2 alkyl, halogen atom, trifluoromethyl, -NH(C1-C3 alkyl) or hydroxyl, and / or, the halogen atom is fluorine atom or chlorine atom, and / or, the alkyl is linear or branched alkyl, and / or, the ring is monocyclic or fused ring. W3 is no, wherein X is O, S or NHCO, m is a positive integer from 1 to 10, denotes the point of attachment.

2. The phthalazinone or quinazolinone derivative of Formula I, stereoisomer thereof, optical isomer thereof or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, the phthalazinone or quinazolinone derivative has one of the following structures:

3. The phthalazinone or quinazolinone derivative of Formula I, a stereoisomer thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, a preparation method of the phthalazinone or quinazolinone derivative, comprising the following steps:

4. A process for preparing the phthalazinone or quinazolinone derivative represented by Formula I, a stereoisomer thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized by, a ketone compound is reacted with an α-bromo ester through a first nucleophilic substitution reaction to obtain an intermediate ester 3, the ketone compound is a bromophthalazinone or quinazolinone; then the intermediate ester 3 is hydrolyzed under alkaline conditions to obtain an intermediate acid 4; the intermediate acid 4 is condensed with an amine under the action of a polypeptide condensation reagent and an organic base to obtain an intermediate amide 5; the intermediate amide 5 is subjected to a Suzuki coupling reaction to obtain an intermediate 6; finally, the intermediate 6 is subjected to a first aminolysis reaction with hydroxylamine under alkaline conditions to obtain the phthalazinone or quinazolinone derivative; or, the intermediate amide 5 is subjected to a Buchwald-Hartwig coupling reaction with an aromatic amine to obtain an intermediate 8; finally, the intermediate 8 is subjected to a second aminolysis reaction with hydroxylamine under alkaline conditions to obtain the phthalazinone or quinazolinone derivative; or, the intermediate amide 5 is converted into an intermediate acid 10 under the action of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dicyclohexyl carbodiimide; the intermediate acid 10 is condensed with an aromatic amine under the action of a condensation reagent to obtain an amide 11; the amide 11 is subjected to a third aminolysis reaction with hydroxylamine to obtain the phthalazinone or quinazolinone derivative. ​ Alternatively, the nitro-substituted ketone compound, which is a nitro-substituted bromophthalazine ketone or a nitro-substituted quinazoline ketone, is reacted with an α-bromo acid ester by a second nucleophilic substitution reaction to obtain intermediate 14, which is hydrolyzed to obtain intermediate acid 15, which is condensed with an amine compound to obtain intermediate 16, which is reduced by ferric acid to obtain intermediate 17, which is subjected to an amide reaction with a carboxylic acid compound to obtain intermediate 18, which is subjected to a fourth aminolysis reaction with hydroxylamine to obtain the phthalazine ketone or quinazoline ketone derivative.

5. The preparation method according to claim 4, characterized in that, The condensing agent is 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

6. The preparation method according to claim 4, characterized in that, The organic base is diisopropylethylamine.

7. Use of the phthalazine ketone or quinazoline ketone derivative of formula I, a stereoisomer thereof, an optical isomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the manufacture of a medicament for treating or preventing a HDACs-mediated disease, inhibiting HDACs, treating or preventing a proliferative disease.

8. Use according to claim 7, characterized in that, The HDACs-mediated disease is cancer.

9. Use according to claim 8, characterized in that, The cancer is at least one of leukemia, T-cell lymphoma, non-small cell lung cancer, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cancer, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer, multiple myeloma.

10. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising the phthalazine ketone or quinazoline ketone derivative of formula I, a stereoisomer thereof, an optical isomer thereof, a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3.

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