CN116768857A - EZH2/HDAC double-target inhibitor and preparation method and medical application thereof - Google Patents

EZH2/HDAC double-target inhibitor and preparation method and medical application thereof Download PDF

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CN116768857A
CN116768857A CN202210230503.2A CN202210230503A CN116768857A CN 116768857 A CN116768857 A CN 116768857A CN 202210230503 A CN202210230503 A CN 202210230503A CN 116768857 A CN116768857 A CN 116768857A
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methyl
pyridin
dihydropyridin
oxo
dimethyl
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孔令义
王小兵
陆德华
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China Pharmaceutical University
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention discloses an EZH2/HDAC double-target inhibitor, a preparation method and medical application thereof. Comprises a chemical structure shown in general formulas (I) - (V)A compound or pharmaceutically acceptable salt thereof, wherein R is selected from C 5 ‑C 9 Alkyl, carbonyl alkane chain, benzyl, pyrimidine ring, unsaturated five-membered heterocycle. The invention provides a novel targeted EZH2/HDAC double-target inhibitor, and the compound disclosed by the invention can effectively target EZH2 and HDAC and can be used as an effective therapeutic agent for hematological tumors and other cancers.

Description

EZH2/HDAC double-target inhibitor and preparation method and medical application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to preparation and medical application of an EZH2/HDAC double-target inhibitor.
Background
Currently, most of the batches of drugs based on "single-target single-drug" are increasingly inferior in the treatment of complex, heterogeneous, polygenic cancer diseases. In this case, the combined action of two or more drugs uses different targets in preclinical and clinical settings, however, drug combination therapy is often negated by poor drug-drug interactions, unpredictable Pharmacokinetic (PK) and safety profiles, and poor patient compliance. Recently, dual-target drugs have attracted a great deal of attention from medical researchers. Compared with single-target drugs, double-target drugs can inhibit two pathways involved in disease progression and produce synergistic or additive effects.
Histone Deacetylases (HDACs), also known as lysine deacetylases (KDACs), are of great interest in removing acetyl groups from acetylated lysine residues of different protein substrates, including non-histones and histones. Over-expression of HDACs is associated with a range of human diseases, including some cancers and Central Nervous System (CNS) diseases. Thus, HDACs represent potential targets for cancer treatment. Histone Deacetylase (HDAC) inhibitors are powerful epigenetic modulators, have tremendous therapeutic potential, and are pleiotropic at cellular and systemic levels.
Polycomb inhibition complex 2 (PRC 2) consists of three basic core subunits: enhancers of zeste homologs (EZH 2), embryonal Ectodermal Development (EED), and inhibitors of zeste homologs (SUZ 12). PRC2 was linked from cofactor-transferred methyl S-adenosyl-l-methionine (SAM) to the epsilon-amino group of histone 3 lysine 27 (H3K 27) by each catalytic cycle. EZH2 is an enzymatic subunit of PRC 2. EZH2 has been found in the prostate, breast, kidneyOften over-expressed in lung, myeloma and lymphoma. EZH2 has been identified as a driving factor for lymphoma development as an epigenetic regulator. Tazemetostat is the first selective inhibitor of EZH2-WT and mutants and has been approved by the FDA for the treatment of epithelioid sarcomas. In addition, other molecules also showed good EZH2 inhibitory activity, including GSK126, CPI-1205.EZH2 selective inhibitor C24, which has high potency (IC) for EZH2 50 =12 nM), C24 has a selectivity for EZH2 of 200 times or more (IC) than that of the highly homologous H3K27 methyltransferase EZH1 50 >2.5μM).
Abnormalities in epigenetic modification, coupled with genetic mutations and tumor suppressor gene silencing, are critical to the development and maintenance biology of hematologic malignant cells. HDAC and EZH2 inhibitors have proven to be important epigenetic modulators, and many studies have been conducted on their use in human hematological malignancies. Meanwhile, many researchers have combined HDAC with EZH2 inhibitors to improve the efficacy of treating various hematological cancers. It was shown that simultaneous inhibition of EZH2 and HDAC has a high synergistic effect in human hematological malignancies. Based on this information, rational combination therapy of EZH2 and HDAC inhibitors is a potential therapeutic strategy for the treatment of hematological malignancies. However, combination administration is often accompanied by poor patient compliance, unpredictable Pharmacokinetic (PK) profiles and drug interactions. A strategy to overcome these drawbacks is to develop dual inhibitors of HDAC and EZH 2.
Disclosure of Invention
The invention aims to: a novel EZH2/HDAC dual-target inhibitor was developed for use in the treatment of hematological neoplasms and other diseases associated with EZH2, HDAC.
The technical scheme is as follows: a novel EZH2/HDAC dual-target inhibitor comprising a compound having the structure:
wherein R is selected from- (CH 2) n1 -，-CO(CH 2 ) n2 -benzyl, pyrimidine ring, unsaturated five membered heterocycle; n1=any of 4 to 9An integer, n2=any integer from 3 to 6.
As a preferable mode of the invention, when the structure of the double-target inhibitor is shown as a general formula (I), R is selected from- (CH) 2 ) n1 -，-CO(CH 2 ) n2 -pyrimidine ring, n1=7 or 8, n2=5 or 6; when the structure is shown as a general formula (II), R is selected from-CO (CH) 2 ) n2 -, n2=5 or 6; when the structure is shown as a general formula (III), R is selected from- (CH) 2 ) n1 -n1=5, 6 or 7; when the structure is shown as a general formula (V), R is selected from pyrimidine rings.
The compound of the invention is selected from any one of the following:
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (4- (hydroxyamino) -4-oxobutyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxyamino) -5-oxopentyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (6- (hydroxyamino) -6-oxohexyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (7- (hydroxyamino) -7-oxoheptyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (8- (hydroxyamino) -8-oxooctyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (10- (hydroxyamino) -10-oxodecyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (4- (hydroxycarbamoyl) benzyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- ((5- (hydroxycarbamoyl) furan-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N1- (4- ((4- (5- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) pyridin-2-yl) piperazin-1-yl) methyl) phenyl) -N8-hydroxyoctanediamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxycarbamoyl) pyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxyamino) -5-oxopentanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (6- (hydroxyamino) -6-oxohexanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (7- (hydroxyamino) -7-oxoheptyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (8- (hydroxyamino) -8-oxooctanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide
N1- (4- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) phenyl) -N8-hydroxyoctanediamide
N1- (4- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) phenyl) -N7-hydroxyheptanedioic acid amide
Tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((5- (hydroxyamino) -5-oxopentyl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (6- (hydroxyamino) -6-oxohexyl) amino) -4-methylphenyl) pyridin-3-yl) piperazine-1-carboxylate
Tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((7- (hydroxyamino) -7-oxoheptyl) amino) -4-methylphenyl) pyridin-3-yl) piperazine-1-carboxylate
Tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((8- (hydroxyamino) -8-oxooctyl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (5- (hydroxyamino) -5-oxopentylamino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (6- (hydroxyamino) -6-oxohexanamido) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate
(R) -1- (sec-butyl) -N- (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -3-methyl-1H-indole-4-carboxamide
(R) -1- (sec-butyl) -N- (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxycarbamoyl) pyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -3-methyl-1H-indole-4-carboxamide
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -2-methylbenzamide
2- (4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methylphenyl) pyridin-2-yl) -piperazin-1-yl) -N-hydroxypyrimidine-5-carboxamide as a preferred aspect of the invention, the pharmaceutically acceptable salt of the compound of formula I-V is selected from acid addition salts of compounds of formula I-V with acids selected from: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
A pharmaceutical composition, wherein the compound of the general formula I-V or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier.
Preferably, the pharmaceutical composition is prepared into any one of a tablet, a capsule, a powder, a syrup, a liquid, a suspension, a freeze-dried powder injection or an injection.
The preparation method of the EZH2/HDAC double-target inhibitor comprises the following steps:
route 1: synthesis of target Compounds 10-24 a .
a Reagents and reaction conditions (a) 2-iodopropane, K 2 CO 3 ,CH 3 CN, reflux,12h,75%; (b) Tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 DMF, reflux, N 2 ,4h,80％；(c)NaOH,MeOH/H 2 O, rt,2h,95%; (d) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,84%; (e) CF (compact flash) 3 COOH, DCM, rt,6h,85%; (f) for 10g-20g, various methyl bromoformates Et 3 N, DMF,90 ℃,12h,70-85%; for 21g-24g, various methyl monoformates, HATU, DIPEA, DCM, rt,2h,84-94%; (g) NH (NH) 2 OK,CH 3 OH,rt,3-5h,63-85％；
b For linker R of the designed compound, the left side is attached to the nitrogen atom and the right side is attached to the carbonyl group.
Route 2: synthesis of target Compounds 25, 26 a .
a Reagent and reaction conditions (a) tert-butyl (4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) carbamate, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 ,DMF,reflux,N 2 ,4h,84％；(b)NaOH,MeOH/H 2 O, rt,2h,92%; (c) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,88%; (d) CF (compact flash) 3 COOH, DCM, rt,6h,79%; (e) Various methyl monoformates, HATU, DIPEA, DCM, rt,2h,84-90%; (f) NH (NH) 2 OK,CH 3 OH,rt,3-5h,63-85％
b For linker R of the designed compound, the left side is attached to the nitrogen atom and the right side is attached to the carbonyl group.
Route 3: target compound 27-32 Synthesis a .
a Reagent and reaction conditions (a) tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 ,DMF,reflux,N 2 ,3h,70％；(b)NaOH,MeOH/H 2 O, rt,2h,90%; (c) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,85%; (d) Zinc powder, CH 3 COOH/H 2 O, 0-rt, 12h,65%; (e) for 27-30, various methyl bromoformates, cs 2 CO 3 DMF,90 ℃,1h,50-65%; for 31and 32, various methyl monoformates, et 3 N,DCM,rt,1h,70-81％；(f)NH 2 OK,CH 3 OH,rt,3-5h,60-82％； b For linker R of the designed compound, the left side is attached to the nitrogen atom and the right side is attached to the carbonyl group.
Route 4: synthesis of target Compounds 33, 34 a .
a Reagents and reaction conditions (a) methyl 9-bromononanoate or methyl 2-chloropyrimidine-5-carboxylate, et 3 N,DMF,90℃,12h,70-80％；(b)NH 2 OK,CH 3 OH,rt,3-5h,64-80％；
b For linker R of the designed compound, the left side is attached to the nitrogen atom and the right side is attached to the carbonyl group.
Route 5: synthesis of target Compounds 35, 36 a .
a Reagents and reaction conditions (a) 4- (5- (4, 4),5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 ,DMF,reflux,N 2 ,4h,80％；(b)NaOH,MeOH/H 2 O, rt,2h,92%; (c) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,87%; (d) CF (compact flash) 3 COOH, DCM, rt,6h,88%; (e) Methyl 9-bromononanoate or methyl 2-chloropyrimidine-5-carboxylate, et 3 N,DMF,90℃,12h,70-85％；(f)NH 2 OK,CH 3 OH,rt,3-5h,68-80％。
b For linker R of the designed compound, the left side is attached to the nitrogen atom and the right side is attached to the carbonyl group.
Drawings
FIG. 1 in vivo anti-tumor assay. (a) tumor weight at day 20 post-treatment; (B) Growth curve of transplanted MV4-11 xenograft in nude mice; (C) dissecting a picture of HMV4-11 tumor tissue; (D) weight measurement.
Detailed description of the preferred embodiments
EXAMPLE 1 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (4- (hydroxyamino) -4-oxobutyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (10):
10a (255.1 mg,1.0 mmol) and 2-iodopropane (255.0 mg,1.5 mmol) were dissolved in acetonitrile (10 mL) followed by potassium carbonate (276.4 mg,2 mmol). Reflux reaction at 50 ℃ for 12h, and column separation of 10 b. 10b (148.6 mg,0.5 mmol) and tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate (467.16 mg,0.6 mmol) were then dissolved in DMF (10 mL), [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride and with dichloromethane (27.3 mg,0.05 mmol) and potassium carbonate (138.2 mg,1mmol added) were reacted under reflux at 80℃for 4h under nitrogen protection to give compound 10c at room temperature under CH 3 OH/H 2 O (5:1) for 2h and then neutralized with dilute hydrochloric acid. The amine acid condensation was performed under DIPEA (12.9 mg,0.1 mmol), HATU (570.5 mg,1.5 mmol), DCM (10 mL) and then separated by column to give 10e. Deprotection of 10e (599.7 mg,1 mmol) under TFA/DCM (1:5) gave10f, then 10g was obtained by reacting 10f (499.6 mg,1 mmol) with methyl 4-bromobutyrate (362.1 mg,2 mmol) in the presence of cesium carbonate at 90℃for 12 hours. Then 10g of the solution was dissolved in NH 2 OK/CH 3 OH (10 mL) and stirred at room temperature for 4 hours. When the reaction was complete, the solvent was evaporated under reduced pressure to give a residue, which was dissolved in water (15 mL). The mixture was neutralized by the addition of 1M HCl. The white precipitate was filtered and dried to give compound 10 in 34% yield as a milky white solid. 1 H NMR(600MHz,DMSO-d 6 )δ11.56(s,1H),10.47(s,1H),8.72(s,1H),8.67–8.58(m,2H),8.36(s,1H),8.06(d,J＝9.0Hz,2H),7.85(s,1H),6.95(d,J＝8.9Hz,1H),5.89(s,1H),5.14(p,J＝6.7Hz,1H),4.39(d,J＝4.9Hz,2H),3.56(s,4H),2.49(s,4H),2.38–2.25(m,2H),2.22(s,3H),2.13(s,3H),2.02(t,J＝7.4Hz,2H),1.71(p,J＝7.4Hz,2H),1.49(d,J＝6.6Hz,6H). 13 C NMR(126MHz,DMSO-d 6 )δ169.5,166.3,163.6,158.9,150.2,146.8,143.3,140.2,136.8,135.5,133.2,128.3,125.0,122.1,120.8,119.2,108.9,108.1,107.3,57.7,52.8,49.6,45.1,35.7,30.7,22.7,22.6,19.5,18.7.HRMS:[M+Na] + calcd for C 32 H 40 N 8 NaO 4 ,437.1972,623.3065,found 623.3066.
EXAMPLE 2 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxyamino) -5-oxopentyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (11):
compound 11 was prepared by the same procedure as in example 1 except that methyl 4-bromobutyrate was replaced with methyl 5-bromovalerate. 1 H NMR(600MHz,DMSO-d 6 )δ11.56(s,1H),10.47(s,1H),8.72(s,1H),8.67–8.58(m,2H),8.36(s,1H),8.06(d,J＝9.0Hz,2H),7.85(s,1H),6.95(d,J＝8.9Hz,1H),5.89(s,1H),5.14(p,J＝6.7Hz,1H),4.39(d,J＝4.9Hz,2H),3.56(s,4H),2.49(s,4H),2.38–2.25(m,2H),2.22(s,3H),2.13(s,3H),2.02(t,J＝7.4Hz,2H),1.71(p,J＝7.4Hz,2H),1.49(d,J＝6.6Hz,6H). 13 CNMR(126MHz,DMSO-d 6 )δ169.5,166.3,163.6,158.9,150.2,146.8,143.3,140.2,136.8,135.5,133.2,128.3,125.0,122.1,120.8,119.2,108.9,108.1,107.3,57.7,52.8,49.6,45.1,35.7,30.7,22.7,22.6,19.5,18.7.HRMS:[M+Na] + calcd for C 32 H 42 N 8 NaO 4 ,637.3221,found 637.3224.
Example 3:N preparation of- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (6- (hydroxyamino) -6-oxohexyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (12):
the procedure of example 1 was followed except for substituting methyl 4-bromobutyrate for methyl 6-bromohexanoate to obtain compound 12, 1 H NMR(600MHz,DMSO-d 6 )δ10.41(s,1H),8.65(d,J＝2.5Hz,1H),8.60(t,J＝4.9Hz,1H),8.35(s,1H),8.06(d,J＝5.8Hz,2H),7.84(s,1H),7.79(s,1H),6.95(d,J＝8.9Hz,1H),5.90(s,1H),5.13(p,J＝6.6Hz,1H),4.39(d,J＝4.9Hz,2H),3.55(s,4H),2.47(d,J＝5.1Hz,4H),2.30(t,J＝7.4Hz,2H),2.22(s,3H),2.13(s,3H),1.96(t,J＝7.3Hz,2H),1.53(d,J＝7.5Hz,2H),1.50(d,J＝6.4Hz,6H),1.46(d,J＝7.7Hz,2H),1.28(d,J＝7.5Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.5,166.3,166.0,163.6,158.9,157.5,150.2,146.8,143.3,140.2,136.8,135.5,133.2,128.3,125.0,122.1,120.8,119.2,108.9,108.0,107.3,58.4,53.1,49.6,45.2,35.7,32.7,27.0,26.5,25.6,22.6,19.4,18.7.HRMS:[M+Na] + calcd for C 34 H 44 N 8 NaO 4 ,651.3378,found 651.3379.
EXAMPLE 4 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (7- (hydroxyamino) -7-oxoheptyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (13):
the procedure of example 1 was followed except for substituting methyl 4-bromobutyrate for methyl 7-bromoheptanoate to obtain compound 13, 1 H NMR(600MHz,DMSO-d 6 )δ10.40(s,1H),8.65(d,J＝2.6Hz,1H),8.61(t,J＝5.0Hz,1H),8.36(s,1H),8.09–8.04(m,2H),7.84(d,J＝1.2Hz,1H),6.95(d,J＝8.9Hz,1H),5.89(s,1H),5.14(p,J＝6.6Hz,1H),4.39(d,J＝4.9Hz,2H),3.55(t,J＝5.1Hz,4H),2.46(t,J＝5.0Hz,4H),2.30(t,J＝7.4Hz,2H),2.22(s,3H),2.13(s,3H),1.95(t,J＝7.4Hz,2H),1.51(d,J＝7.1Hz,2H),1.49(d,J＝6.6Hz,6H),1.47–1.44(m,2H),1.30–1.26(m,4H). 13 C NMR(151MHz,DMSO-d 6 )δ169.5,166.3,166.0,163.6,158.9,150.2,146.8,143.3,140.2,136.8,135.5,133.2,128.3,125.0,122.1,120.8,119.2,108.9,108.0,107.3,58.4,53.1,49.6,45.2,35.7,32.7,29.0,27.2,26.7,25.6,22.6,19.4,18.7.HRMS:[M+Na] + calcd for C 35 H 46 N 8 NaO 4 ,665.3534,found 665.3538.
EXAMPLE 5 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (8- (hydroxyamino) -8-oxooctyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (14):
the procedure of example 1 was followed except for substituting methyl 4-bromobutyrate for methyl 8-bromooctanoate to obtain compound 14, 1 H NMR(600MHz,DMSO-d 6 )δ10.41(s,1H),8.66(d,J＝2.5Hz,1H),8.61(s,1H),8.35(s,1H),8.22(s,1H),8.06(d,J＝6.7Hz,2H),7.96(s,1H),7.84(s,1H),6.96(d,J＝8.9Hz,1H),5.89(s,1H),5.14(p,J＝6.6Hz,1H),4.38(d,J＝4.9Hz,2H),3.58(q,J＝6.7,5.4Hz,4H),2.50(s,4H),2.36(q,J＝6.4,5.9Hz,2H),2.21(s,3H),2.13(s,3H),1.95(t,J＝7.4Hz,2H),1.49(d,J＝6.6Hz,6H),1.47(d,J＝7.8Hz,4H),1.32–1.25(m,5H). 13 C NMR(151MHz,DMSO-d 6 )δ169.6,166.3,163.6,162.8,150.2,146.8,143.3,140.2,136.8,135.5,133.2,130.1,128.3,125.1,122.1,120.8,119.2,108.9,108.0,107.3,58.3,52.9,49.6,45.0,36.3,35.7,32.7,31.2,29.0,27.3,25.6,22.6,19.4,18.7.HRMS:[M+Na]+calcd for C 36 H 40 N 8 NaO 4 ,671.3065,found 671.3067.
example 6:N preparation of- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (15):
the procedure of example 1 was followed except for substituting methyl 4-bromobutyrate for methyl 9-bromononanoate to obtain compound 15, 1 H NMR(600MHz,DMSO-d 6 )δ10.39(s,1H),8.65(d,J＝2.5Hz,1H),8.61(t,J＝5.0Hz,1H),8.36(s,1H),8.06(d,J＝9.2Hz,2H),7.84(s,1H),6.96(d,J＝8.9Hz,1H),5.90(s,1H),5.14(q,J＝6.6Hz,1H),4.39(d,J＝4.9Hz,2H),3.55(t,J＝5.1Hz,4H),2.47(t,J＝5.2Hz,4H),2.31(t,J＝7.4Hz,2H),2.22(s,3H),2.13(s,3H),1.94(t,J＝7.4Hz,2H),1.49(d,J＝6.6Hz,6H),1.46(d,J＝8.1Hz,4H),1.28(s,8H). 13 C NMR(151MHz,DMSO-d 6 )δ169.6,166.3,163.6,158.9,150.2,146.8,143.3,140.2,136.8,135.5,133.2,128.3,125.0,122.1,120.8,119.2,108.9,108.0,107.3,58.4,53.0,49.6,45.2,35.7,32.7,29.4,29.2,29.0,27.4,26.7,25.6,22.6,19.4,18.7.HRMS:[M+Na]+calcd for C 37 H 50 N 8 NaO 4 693.3847,found 693.3844.
EXAMPLE 7 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (10- (hydroxyamino) -10-oxodecyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (16):
the procedure of example 1 was followed except for substituting methyl 4-bromobutyrate for methyl 10-bromodecanoate to obtain compound 16, 1 H NMR(600MHz,DMSO-d 6 )δ11.56(s,1H),10.37(s,1H),8.65(d,J＝2.6Hz,1H),8.60(s,1H),8.35(s,1H),8.28(s,2H),8.06(d,J＝8.2Hz,2H),7.84(s,2H),6.95(d,J＝8.9Hz,1H),5.90(s,1H),5.15–5.12(m,1H),4.39(d,J＝4.9Hz,2H),3.55(s,4H),2.46(t,J＝5.1Hz,4H),2.31(t,J＝7.4Hz,2H),2.22(s,3H),2.13(s,3H),1.94(t,J＝7.2Hz,2H),1.49(d,J＝6.5Hz,6H),1.47(t,J＝7.2Hz,4H),1.29–1.27(m,4H),1.26(d,J＝8.0Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ166.4,163.6,158.9,150.3,146.7,143.4,140.2,136.8,135.5,133.2,130.1,128.3,125.0,122.0,120.8,119.2,108.9,108.1,107.3,58.4,53.0,49.6,45.1,35.7,32.7,30.3,29.4,29.2,29.0,27.4,26.6,25.6,22.6,19.4,18.7.[M+Na]+calcd for C 38 H 52 N 8 NaO 4 ,707.4004,found 707.4006.
EXAMPLE 8 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (4- (hydroxycarbamoyl) benzyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (17):
the procedure of example 1 was followed except for substituting methyl 4-bromobutyrate for methyl 4-bromomethylbenzoate to obtain compound 17, 1 H NMR(600MHz,DMSO-d 6 )δ8.65(d,J＝2.5Hz,1H),8.59(t,J＝5.0Hz,1H),8.38(s,2H),8.35(s,1H),8.05(d,J＝7.1Hz,2H),7.83(d,J＝1.3Hz,1H),7.74(d,J＝7.9Hz,2H),7.43(d,J＝7.9Hz,2H),6.95(d,J＝8.9Hz,1H),5.89(s,1H),5.13(p,J＝6.6Hz,1H),4.39(d,J＝4.9Hz,2H),3.58(d,J＝6.8Hz,11H),2.22(s,3H),2.13(s,3H),1.49(d,J＝6.5Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ166.3,165.6,163.6,158.9,150.2,146.8,143.3,141.9,140.2,136.8,135.5,133.2,132.1,129.2,128.3,127.3,125.1,122.1,120.8,119.2,108.9,108.0,107.3,55.4,52.8,49.1,45.2,35.7,22.6,19.4,18.7.[M+Na]+calcd for C 36 H 40 N 8 NaO 4 671.3065,found 671.3067.
EXAMPLE 9 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- ((5- (hydroxycarbamoyl) furan-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (18)
The procedure of example 1 was followed except for substituting methyl 4-bromobutyrate in example 1 with methyl 5- (chloromethyl) 2-furancarboxylate to give compound 18, 1 H NMR(600MHz,DMSO-d 6 )δ8.65(d,J＝2.6Hz,1H),8.60(t,J＝5.0Hz,1H),8.35(s,1H),8.27(s,1H),8.06(d,J＝8.1Hz,2H),7.83(s,1H),7.00(s,1H),6.95(d,J＝8.9Hz,1H),6.46(d,J＝3.3Hz,1H),5.89(s,1H),5.13(p,J＝6.6Hz,1H),4.39(d,J＝4.9Hz,2H),3.57(d,J＝4.7Hz,4H),3.17(s,2H),2.53(s,4H),2.22(s,3H),2.13(s,3H),1.49(d,J＝6.5Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ166.4,163.7,158.8,154.3,150.4,146.7,146.0,143.4,140.1,136.9,135.5,133.2,130.1,128.3,125.1,122.0,120.8,119.2,111.1,109.0,108.2,107.4,54.4,52.5,49.6,49.1,45.1,22.6,21.9,19.4,18.7.[M+Na]+calcd for C 34 H 38 N 8 NaO 5 ,661.2857,found661.2861.
EXAMPLE 10 preparation of N1- (4- ((4- (5- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) pyridin-2-yl) piperazin-1-yl) methyl) phenyl) -N8-hydroxyoctanediamide (19)
Replacement of methyl 4-bromobutyrate in example 1 with 8- ((4- (bromomethyl) phenyl) amino) -8-oxooctanoateMethyl ester, other procedures were followed as in example 1 to give compound 19, 1 H NMR(500MHz,DMSO-d 6 )δ11.58(s,1H),10.20(s,1H),8.72(s,1H),8.70–8.57(m,2H),8.35(s,1H),8.07(s,2H),7.84(s,1H),7.63(d,J＝8.0Hz,2H),7.42–7.23(m,3H),6.97(d,J＝8.9Hz,1H),5.90(s,1H),5.13(p,J＝6.7Hz,1H),4.38(d,J＝4.9Hz,2H),3.59–3.50(m,4H),3.16(d,J＝5.0Hz,4H),2.32(t,J＝7.5Hz,2H),2.21(s,3H),2.13(s,3H),1.95(t,J＝7.3Hz,2H),1.56(t,J＝7.2Hz,2H),1.48(d,J＝6.6Hz,6H),1.29(s,6H),0.84(t,J＝6.8Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ171.8,169.6,166.3,163.6,150.3,147.6,146.7,143.4,140.2,136.9,135.5,133.2,130.1,128.3,124.8,124.7,122.1,120.8,119.4,119.2,109.0,108.1,107.5,49.6,36.8,35.7,32.7,31.7,31.6,30.3,29.5,28.9,25.5,25.5,22.6,19.5,18.7,14.4.[M+Na]+calcd for C 43 H 53 N 9 NaO 5 798.4062,found 798.4064；
EXAMPLE 11 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxycarbamoyl) pyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (20):
the procedure used in example 1 was followed except for substituting methyl 4-bromobutyrate for methyl 2-chloropyrimidine-5-carboxylate to give compound 20, 1 H NMR(500MHz,DMSO-d 6 )δ11.55(s,1H),11.27(s,1H),9.04(s,1H),8.76(s,1H),8.69(d,J＝2.6Hz,1H),8.61(t,J＝5.0Hz,1H),8.35(s,1H),8.11(d,J＝8.7Hz,1H),8.08(s,1H),7.85(s,1H),7.03(d,J＝8.9Hz,1H),5.90(s,1H),5.14(p,J＝6.7Hz,1H),4.39(d,J＝4.8Hz,2H),3.98(dt,J＝19.3,5.2Hz,4H),3.75–3.61(m,4H),2.22(s,3H),2.13(s,3H),1.49(d,J＝6.5Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ166.3,163.6,162.3,161.9,158.6,157.7,150.2,146.8,143.3,140.2,137.0,135.4,133.2,128.3,125.3,122.1,120.8,119.2,115.3,109.0,108.0,107.5,49.6,44.8,43.6,35.7,22.6,19.4,18.7.[M+Na]+calcd for C 33 H 36 N 10 NaO 4 659.2813,found 659.2815.
EXAMPLE 12 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxyamino) -5-oxopentanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (21):
compound 10f (499.6 mg,1 mmol) was coupled with 5-methoxy-5-oxopentanoic acid (175.4 mg,1.2 mmol) in the presence of DIPEA (12.9 mg,0.1 mmol), HATU (570.5 mg,1.5 mmol), DCM (10 mL) for 2h at room temperature, then 21g was isolated by column. 21g is dissolved in NH 2 OK/CH 3 OH (10 mL) and stirred at room temperature for 4 hours. When the reaction was complete, the solvent was evaporated under reduced pressure to give a residue, which was dissolved in water (15 mL). The mixture was neutralized by the addition of 1M hydrochloric acid. The white precipitate was filtered and dried to give compound 21 in 32% yield. 1 H NMR(600MHz,DMSO-d 6 )δ11.57(s,1H),10.48(s,1H),8.68(d,J＝2.6Hz,1H),8.61(t,J＝5.0Hz,1H),8.36(s,1H),8.25(s,1H),8.12–8.07(m,2H),7.85(s,1H),7.00(d,J＝9.0Hz,1H),5.90(s,1H),5.14(p,J＝6.6Hz,1H),4.39(d,J＝4.8Hz,2H),3.63–3.56(m,8H),2.36(t,J＝7.6Hz,2H),2.22(s,3H),2.13(s,3H),2.03(d,J＝7.2Hz,2H),1.75(p,J＝7.5Hz,2H),1.49(d,J＝6.6Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ170.9,166.3,163.6,158.6,150.2,146.7,143.3,140.2,136.9,135.4,133.2,128.3,125.3,122.1,120.8,119.2,109.0,108.1,107.5,49.6,45.3,45.0,44.9,41.1,35.7,32.1,30.2,29.5,22.6,19.4,18.7.[M+Na]+calcd for C 33 H 40 N 8 NaO 5 ,651.3014,found 651.3014.
EXAMPLE 13 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (6- (hydroxyamino) -6-oxohexanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (22):
the procedure of example 12 was followed except for substituting monomethyl adipate for 5-methoxy-5-oxopentanoic acid and preparing compound 22, 1 H NMR(500MHz,DMSO-d 6 )δ10.37(s,1H),8.68(d,J＝2.5Hz,1H),8.61(d,J＝5.1Hz,1H),8.36(s,1H),8.23(s,1H),8.10(d,J＝8.7Hz,1H),8.08(s,1H),7.85(s,1H),6.99(d,J＝8.8Hz,1H),5.90(s,1H),5.19–5.01(m,1H),4.39(d,J＝4.8Hz,2H),3.58(dt,J＝16.2,7.9Hz,8H),2.35(t,J＝7.4Hz,2H),2.22(s,3H),2.13(s,3H),1.96(d,J＝8.3Hz,2H),1.49(d,J＝6.5Hz,6H),1.32–1.25(m,4H). 13 C NMR(126MHz,DMSO-d 6 )δ171.3,166.3,163.6,158.6,150.2,146.8,143.3,140.2,136.9,135.4,133.2,128.3,125.3,122.1,120.9,119.2,109.0,108.0,107.5,49.6,45.3,45.0,41.1,35.7,32.7,29.0,25.1,22.6,19.4,18.7.[M+Na]+calcd for C 34 H 42 N 8 NaO 5 ,655.3170,found 655.3173.
EXAMPLE 14 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (7- (hydroxyamino) -7-oxoheptyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (23):
compound 23 was prepared by substituting 7-methoxy-7-oxoheptanoic acid for 5-methoxy-5-oxopentanoic acid in example 12 and by following the same procedure as in example 12, 1 H NMR(600MHz,DMSO-d 6 )δ10.38(s,1H),8.68(d,J＝2.5Hz,1H),8.61(t,J＝5.0Hz,1H),8.36(s,1H),8.10(dd,J＝8.8,2.6Hz,1H),8.08(s,1H),7.85(s,1H),6.99(d,J＝8.9Hz,1H),5.89(s,1H),5.14(p,J＝6.6Hz,1H),4.39(d,J＝4.9Hz,2H),3.59(td,J＝19.6,18.2,5.6Hz,8H),2.35(t,J＝7.5Hz,2H),2.22(s,3H),2.13(s,3H),1.95(t,J＝7.4Hz,2H),1.56–1.50(m,4H),1.49(d,J＝6.5Hz,6H),1.27(t,J＝7.3Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ171.2,169.5,166.3,164.7,163.6,158.6,157.6,150.2,146.8,143.3,140.2,136.9,135.4,133.2,128.3,125.3,122.1,120.8,119.2,109.0,108.0,107.5,49.6,45.3,45.0,44.9,41.1,35.7,32.7,28.8,25.5,25.0,22.6,19.4,18.7.[M+Na]+calcd for C 35 H 44 N 8 NaO 5 ,679.3327,found 679.3324.
EXAMPLE 15 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (8- (hydroxyamino) -8-oxooctanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide (24):
the procedure of example 12 was followed except for substituting monomethyl suberate with 5-methoxy-5-oxopentanoic acid in example 12 to give compound 24, 1 H NMR(500MHz,DMSO-d 6 )δ10.42(s,1H),8.68(d,J＝2.5Hz,1H),8.61(t,J＝4.9Hz,1H),8.36(s,1H),8.15–8.05(m,2H),7.85(s,1H),7.00(d,J＝8.9Hz,1H),5.90(s,1H),5.14(p,J＝6.7Hz,1H),4.39(d,J＝4.9Hz,2H),3.59(dq,J＝16.1,5.8Hz,8H),2.37(t,J＝6.9Hz,2H),2.22(s,3H),2.13(s,3H),1.98(t,J＝7.0Hz,2H),1.50(t,J＝7.6Hz,9H),1.24(s,4H). 13 CNMR(151MHz,DMSO-d 6 )δ171.3,166.3,163.6,158.6,150.2,146.8,143.3,140.2,136.9,135.4,133.2,128.3,125.3,122.1,120.8,119.2,109.0,108.0,107.5,49.6,45.3,45.1,45.0,41.1,35.7,32.7,29.0,28.9,25.6,25.1,22.6,19.4,18.7.[M+Na]+calcd for C 36 H 46 N 8 NaO 5 ,693.3483,found693.3480.
EXAMPLE 16 preparation of N1- (4- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) phenyl) -N8-hydroxyoctanediamide (25):
the tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate of example 12 was replaced with N-Boc-4-aminophenylboronic acid pinacol ester, 5-methoxy-5-oxopentanoic acid was replaced with monomethyl suberate, the other procedure was the same as in example 12 to give compound 25, 1 H NMR(500MHz,DMSO-d 6 )δ11.53(s,1H),10.39(s,1H),10.09(s,1H),8.68(d,J＝9.1Hz,1H),8.62(t,J＝5.1Hz,1H),8.36(s,1H),8.07(s,1H),7.85(s,1H),7.81(d,J＝8.4Hz,2H),7.75(d,J＝8.4Hz,2H),5.89(s,1H),5.15(p,J＝6.6Hz,1H),4.40(s,2H),2.36(s,2H),2.22(s,3H),2.13(s,3H),1.96(t,J＝7.4Hz,2H),1.60(p,J＝7.3Hz,2H),1.50(d,J＝6.5Hz,6H),1.35–1.25(m,6H). 13 C NMR(126MHz,DMSO-d 6 )δ171.9,169.6,166.4,150.1,140.1,139.6,137.7,134.8,133.2,128.3,128.1,122.1,121.0,119.7,109.7,108.0,49.6,36.9,35.8,32.7,28.9,25.5,25.5,22.6,19.4,18.7.[M+Na]+calcd for C 33 H 40 N 6 NaO 5 ,623.2952,found 623.2957.
EXAMPLE 17 preparation of N1- (4- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) phenyl) -N7-hydroxyheptandiamide (26):
the tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate of example 12 was replaced by N-Boc-4-aminophenylboronic acid pinacol ester, 5-methoxyThe substitution of the base-5-oxopentanoic acid for 7-methoxy-7-oxoheptanoic acid was performed in the same manner as in example 12 to obtain compound 26, 1 H NMR(500MHz,DMSO-d 6 )δ11.55(s,1H),10.49(s,1H),10.32(s,1H),8.69(s,1H),8.64(t,J＝5.1Hz,1H),8.35(s,1H),8.07(s,1H),7.85(s,1H),7.83–7.76(m,4H),5.89(s,1H),5.15(p,J＝6.6Hz,1H),4.39(d,J＝4.9Hz,2H),2.36(t,J＝7.3Hz,2H),2.22(s,3H),2.13(s,3H),1.98(t,J＝7.4Hz,2H),1.60(t,J＝7.5Hz,2H),1.53(d,J＝7.4Hz,2H),1.49(d,J＝6.5Hz,6H),1.30(t,J＝3.6Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ171.3,169.0,165.8,163.0,149.6,142.7,139.5,139.1,137.1,134.1,132.6,127.7,127.5,121.5,120.4,119.1,119.1,109.1,107.5,49.0,36.2,35.1,32.0,28.1,24.8,24.7,22.0,18.9,18.1.[M+Na]+calcd forC 32 H 38 N 6 NaO 5 ,609.2796,found 609.2799.
example 18 preparation of tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((5- (hydroxyamino) -5-oxopentyl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (27):
27a (274.1 mg,1 mmol) and tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate (584.0 mg,1.5 mmol) was dissolved in DMF (10 mL), [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride and with dichloromethane (54.6 mg,0.01 mmol) and potassium carbonate (138.2 addition mg,1 mmol) were reacted under reflux at 80℃for 4h under nitrogen protection to give compound 27b (365.0 mg,0.8 mmol) in CH 3 OH/H 2 Hydrolysis in O (5:1) was left at room temperature for 2h and then neutralized with HCl to afford 27c. After DIPEA (12.9 mg,0.1 mmol), HATU (570.5 mg,1.5 mmol), DCM (10 mL), 27d (576.27 mg,1 mmol) was isolated by a silica gel column. Zinc powder (327.0 mg, 5 mmol), formic acid (1 mL), H 2 27d (576.27 mg,1 mmol) was reduced to 27e (355.3 mg,0.65 mmol) at room temperature under O (5 mL). Coupling of 27e (546.7 mg,1 mmol) with methyl 5-bromopentanoate (195.0 mg,1 mmol) in the presence of cesium carbonate (325.8 mg,1 mmol) gave 27f (396.4 mg,0.6 mmol) which was then dissolved in NH as 27f (396.4 mg; 0.6 mmol) 2 OK/CH 3 OH (10 mL) and stirred at room temperature for 4 hours. When the reaction is completedAt the end of this period, the solvent was evaporated under reduced pressure to give a residue, which was dissolved in water (15 mL). The mixture was neutralized by the addition of 1M HCl. The white precipitate was filtered and dried to give compound 27 (364.0 mg,0.55 mmol) in 33% yield as a light brown solid. 1 H NMR(600MHz,DMSO-d 6 )δ10.40(s,1H),8.32(d,J＝2.5Hz,1H),8.00(s,1H),7.73(dd,J＝8.8,2.6Hz,1H),6.93–6.84(m,2H),6.65(s,1H),6.02(s,1H),4.29(d,J＝5.1Hz,2H),3.91(d,J＝7.2Hz,4H),3.43(s,4H),2.33(s,3H),2.32–2.27(m,2H),2.21(s,3H),2.00(s,3H),1.97(d,J＝12.8Hz,2H),1.57–1.50(m,4H),1.42(s,9H). 13 C NMR(151MHz,DMSO-d 6 )δ170.0,169.4,164.2,162.6,158.4,154.5,148.0,145.4,144.4,139.2,136.0,135.3,126.0,122.1,117.6,113.1,112.2,109.7,107.6,79.5,45.0,44.0,36.2,32.3,28.5,28.0,23.2,20.0,19.2,14.0.[M+Na]+calcd for C 35 H 47 N 7 NaO 6 ,684.3480,found 684.3480.
Example 19 preparation of tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (6- (hydroxyamino) -6-oxohexyl) amino) -4-methylphenyl) pyridin-3-yl) piperazine-1-carboxylate (28):
the procedure used in example 18 was repeated except for substituting methyl 5-bromopentanoate for methyl 6-bromohexylate to give compound 28, 1 H NMR(500MHz,DMSO-d 6 )δ10.53(s,1H),8.31(d,J＝2.5Hz,1H),8.03(d,J＝5.4Hz,1H),7.73(d,J＝2.4Hz,1H),7.57(d,J＝45.4Hz,2H),6.90(d,J＝13.5Hz,2H),6.64(s,1H),6.01(s,1H),5.05(s,1H),4.28(d,J＝5.2Hz,2H),3.88(t,J＝8.0Hz,2H),3.58–3.45(m,6H),3.16(s,1H),2.33(s,3H),2.20(s,3H),1.98(d,J＝6.8Hz,3H),1.96(d,J＝7.4Hz,2H),1.56–1.49(m,4H),1.42(s,9H),1.28(d,J＝7.8Hz,2H). 13 C NMR(126MHz,DMSO-d 6 )δ170.0,169.4,162.6,158.4,154.4,147.8,145.4,144.4,139.2,136.0,126.0,122.2,113.1,109.6,107.6,79.5,49.0,45.0,44.3,36.2,32.6,28.5,28.1,26.5,25.3,20.0,19.2,14.1.[M+Na]+calcd for C36H49N7NaO6,698.3637,found 698.3642.
example 20 preparation of tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((7- (hydroxyamino) -7-oxoheptyl) amino) -4-methylphenyl) pyridin-3-yl) piperazine-1-carboxylate (29):
the procedure used in example 18 was repeated except for substituting methyl 5-bromopentanoate for 7-bromoheptylmethyl ester to give compound 29, 1 H NMR(600MHz,DMSO-d 6 )δ11.48(s,1H),10.36(s,1H),8.66(s,1H),8.39(d,J＝2.6Hz,1H),8.03(t,J＝5.1Hz,1H),7.81(dd,J＝8.8,2.6Hz,1H),6.91(d,J＝8.8Hz,1H),6.68(dd,J＝18.9,1.8Hz,2H),5.86(s,1H),4.92(t,J＝5.6Hz,1H),4.27(d,J＝5.1Hz,2H),3.55–3.49(m,4H),3.44(d,J＝5.3Hz,4H),3.17–3.13(m,2H),2.20(s,3H),2.11(s,3H),2.03(s,3H),1.97–1.91(m,2H),1.59(t,J＝7.3Hz,2H),1.50(q,J＝7.6Hz,2H),1.43(s,9H),1.39–1.34(m,2H),1.32–1.28(m,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.0,169.6,163.5,158.4,154.4,149.9,147.7,145.7,143.2,139.1,136.2,135.6,126.5,122.1,118.2,112.5,107.9,107.6,107.3,79.5,45.0,43.5,35.4,32.7,29.0,28.8,28.5,26.9,25.6,19.4,18.7,14.1.[M+Na]+calcd for C37H51N7NaO6,712.3793,found 712.3793.
example 21 preparation of tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((8- (hydroxyamino) -8-oxooctyl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (30):
compound 30 was prepared by the same procedure as in example 18 except that methyl 5-bromopentanoate used in example 18 was replaced with 8-bromo Xin Jiazhi, 1 H NMR(600MHz,DMSO-d 6 )δ10.33(s,1H),8.32(d,J＝2.5Hz,1H),8.24(s,1H),7.99(t,J＝5.2Hz,1H),7.73(dd,J＝8.8,2.6Hz,1H),6.93–6.83(m,2H),6.65(d,J＝1.9Hz,1H),6.00(s,1H),4.29(d,J＝5.1Hz,2H),3.90(t,J＝7.9Hz,2H),3.51(dd,J＝6.8,3.8Hz,4H),3.45–3.41(m,4H),3.17(s,1H),2.33(s,3H),2.21(s,3H),2.00(s,3H),1.92(t,J＝7.4Hz,2H),1.53(q,J＝7.5Hz,2H),1.50–1.45(m,2H),1.43(s,7H),1.38–1.24(m,6H). 13 C NMR(151MHz,DMSO-d 6 )δ170.0,169.6,162.6,158.4,154.5,148.0,147.7,145.4,144.4,139.2,136.0,135.3,126.0,122.1,117.6,113.1,112.2,109.6,107.6,79.5,49.1,45.0,44.3,36.3,32.7,28.9,28.8,28.5,28.3,26.8,25.5,20.0,19.2,14.0.[M+Na]+calcd for C 38 H 53 N 7 NaO 6 ,726.3950,found 726.3951.
example 22 preparation of tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (5- (hydroxyamino) -5-oxopentylamino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (31):
the procedure of example 18 was followed except for substituting methyl 5-bromopentanoate for methyl 4-chloroformyl butyrate to obtain compound 31, 1 H NMR(600MHz,DMSO-d 6 )δ10.46(s,1H),9.50(s,1H),8.40(d,J＝2.6Hz,1H),8.27(t,J＝5.1Hz,1H),8.24(s,2H),7.83(dd,J＝8.9,2.6Hz,1H),7.61–7.53(m,1H),7.28(d,J＝1.9Hz,1H),6.93(d,J＝8.9Hz,1H),5.88(s,1H),4.30(d,J＝5.0Hz,2H),3.53(dd,J＝6.8,3.9Hz,4H),3.43(t,J＝5.2Hz,4H),2.37(t,J＝7.4Hz,2H),2.21(s,3H),2.15(s,3H),2.12(s,3H),2.05(t,J＝7.6Hz,2H),1.83(p,J＝7.5Hz,2H),1.43(s,9H). 13 C NMR(151MHz,DMSO)δ171.5,169.1,165.6,163.5,154.4,150.2,145.7,143.3,139.3,137.9,136.2,134.9,130.1,128.9,124.9,124.1,122.0,108.1,107.7,79.5,44.9,35.6,35.5,35.4,32.1,29.5,28.5,21.9,19.4,18.7,14.9.[M+Na]+calcd for C 35 H 45 N 7 NaO 7 ,698.3273,found 698.3275.
EXAMPLE 23 preparation of tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (6- (hydroxyamino) -6-oxohexanamido) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate (32):
the procedure used in example 18 was repeated except for substituting methyl 5-bromopentanoate for ethyl 6-chloro-6-oxohexanoate to give compound 32, 1 H NMR(600MHz,DMSO-d 6 )δ9.50(s,1H),8.39(d,J＝2.6Hz,2H),8.27(s,1H),7.82(dd,J＝8.9,2.6Hz,1H),7.60–7.54(m,1H),7.28(d,J＝2.0Hz,1H),6.93(d,J＝8.9Hz,1H),5.87(s,1H),5.33(t,J＝4.9Hz,1H),4.29(d,J＝5.0Hz,2H),3.53(dd,J＝6.7,3.9Hz,8H),2.36(t,J＝6.8Hz,2H),2.21(s,3H),2.15(s,2H),2.12(s,3H),2.01(dd,J＝9.8,5.7Hz,2H),1.57(qd,J＝14.0,12.8,6.4Hz,4H),1.43(s,9H). 13 C NMR(151MHz,DMSO-d 6 )δ171.8,169.1,166.7,163.5,158.5,154.4,150.2,145.7,143.3,139.4,137.9,136.2,135.0,130.1,128.9,124.9,124.0,122.0,108.0,107.7,79.5,44.9,36.0,35.6,35.4,30.3,29.5,28.5,27.0,22.6,19.4,18.7,14.9,14.4.[M+Na]+calcd for C 36 H 47 N 7 NaO 7 712.3429,found 712.3426.
example 24 preparation of (R) -1- (sec-butyl) -N- (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -3-methyl-1H-indole-4-carboxamide (33):
GSK126 (526.7 mg,1 mmol) was coupled with methyl 9-bromononanoate (251.2 mg,1 mmol) in the presence of cesium carbonate (325.8 mg,1 mmol) to give 33a (592.0 mg 0.85 mmol). Then 33a (592.0 mg 0.85 mmol) was dissolved in NH 2 OK/CH 3 OH (10 mL) and stirred at room temperature for 4 hours. When the reaction was complete, the solvent was evaporated under reduced pressure to give a residue, which was dissolved in water (15 mL). The mixture was neutralized by the addition of 1M HCl. The white precipitate was filtered and dried to give compound 33 (384.1 mg,0.55 mmol) in 55% yield as a milky white solid. 1 H NMR(500MHz,DMSO-d 6 )δ11.48(s,1H),10.40(s,1H),8.66(s,1H),8.51(d,J＝2.5Hz,1H),8.14(t,J＝5.1Hz,1H),7.93(d,J＝8.9Hz,1H),7.73(s,1H),7.25(s,1H),7.18(s,1H),6.93(d,J＝8.8Hz,1H),5.87(s,1H),4.60(q,J＝6.9Hz,1H),4.35(d,J＝5.1Hz,2H),3.67–3.48(m,4H),3.02(s,4H),2.24(s,3H),2.16(s,3H),2.12(s,3H),1.95(t,J＝7.4Hz,2H),1.85–1.76(m,2H),1.56–1.45(m,4H),1.41(d,J＝6.7Hz,3H),1.32–1.24(m,10H),0.73(t,J＝7.3Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ169.0,168.6,162.9,149.2,145.3,142.5,137.6,135.8,130.5,129.5,124.3,122.8,121.6,115.9,109.5,107.6,107.3,106.9,51.4,34.9,32.1,29.3,28.9,28.8,28.6,28.5,28.5,28.4,24.9,21.9,20.7,18.8,18.0,13.8,11.5,10.6.[M+Na]+calcd for C 34 H 38 N 8 NaO 5 ,661.2857,found 661.2861.
Example 25 preparation of (R) -1- (sec-butyl) -N- (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxycarbamoyl) pyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -3-methyl-1H-indole-4-carboxamide (34):
will be described in detail below24 is replaced by methyl 2-chloropyrimidine-5-carboxylate, the other operating procedures are the same as in example 24, to obtain compound 34, 1 H NMR(500MHz,DMSO-d 6 )δ11.41(d,J＝102.3Hz,2H),9.07(s,1H),8.77(s,2H),8.54(s,1H),8.19(d,J＝5.3Hz,1H),7.97(dd,J＝9.0,2.6Hz,1H),7.75(s,1H),7.27(s,1H),7.19(s,1H),6.99(d,J＝8.9Hz,1H),5.88(s,1H),4.61(q,J＝7.0Hz,1H),4.35(d,J＝5.1Hz,2H),3.95(d,J＝5.7Hz,4H),3.66(t,J＝5.3Hz,4H),3.38(s,3H),2.24(s,3H),2.16(s,3H),2.12(s,3H),1.86–1.73(m,2H),1.40(d,J＝6.6Hz,3H),0.72(t,J＝7.3Hz,3H). 13 C NMR(126MHz,DMSO-d 6 )δ169.2,163.6,161.9,158.2,157.7,149.9,146.0,143.2,138.2,136.6,131.1,130.1,126.8,124.9,123.4,122.2,116.5,115.3,110.2,108.2,107.9,107.7,52.0,45.0,43.6,35.5,30.0,21.4,19.5,18.7,12.2,11.2.[M+Na]+calcd for C 36 H 41 N 9 NaO 4 ,686.3174,found 686.3176.
EXAMPLE 26 preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -2-methylbenzamide (35):
the procedure of example 1 was otherwise followed except for replacing 10b with 35a, replacing methyl 4-bromobutyrate with methyl 9-bromononanoate to give compound 35, 1 H NMR(600MHz,DMSO-d 6 )δ11.50(s,1H),10.45(s,1H),8.77–8.66(m,1H),8.39(d,J＝2.5Hz,1H),8.18(t,J＝5.0Hz,1H),7.81(dd,J＝8.8,2.6Hz,1H),7.36(d,J＝1.9Hz,1H),7.17(d,J＝1.8Hz,1H),6.90(d,J＝8.9Hz,1H),5.87(s,1H),4.29(d,J＝4.9Hz,2H),3.82(dt,J＝11.7,3.2Hz,2H),3.54(s,4H),3.24(td,J＝11.7,2.0Hz,2H),3.07(q,J＝7.0Hz,2H),3.04–2.97(m,1H),2.65–2.55(m,2H),2.39(p,J＝1.9Hz,2H),2.21(d,J＝8.3Hz,6H),2.11(s,3H),1.94(t,J＝7.4Hz,2H),1.69–1.59(m,2H),1.50(ddq,J＝25.2,14.2,7.2,5.7Hz,6H),1.39–1.12(m,9H),0.82(t,J＝7.0Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ169.6,169.6,163.5,158.6,150.1,149.4,145.8,143.2,140.1,136.2,135.0,132.3,125.2,122.6,122.1,120.4,107.9,107.5,66.8,58.2,52.7,44.9,41.6,35.3,32.7,30.8,29.3,29.2,29.0,27.3,25.6,19.4,18.7,15.0,13.1.[M+Na]+calcd for C 41 H 60 N 7 O 5 ,730.4650,found 730.4650.
EXAMPLE 27 preparation of 2- (4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methylphenyl) pyridin-2-yl) piperazin-1-yl) -N-hydroxypyrimidine-5-carboxamide (36):
the procedure of example 1 was followed except for replacing 10b with 35a, replacing methyl 4-bromobutyrate with methyl 2-chloropyrimidine-5-carboxylate to give compound 36, 1 H NMR(500MHz,DMSO-d 6 )δ11.19(s,1H),8.74(s,2H),8.43(d,J＝2.5Hz,1H),8.17(t,J＝5.1Hz,1H),7.89–7.82(m,1H),7.37(s,1H),7.20(s,1H),6.96(d,J＝8.9Hz,1H),5.87(s,1H),4.30(d,J＝4.9Hz,2H),3.98–3.90(m,4H),3.86–3.79(m,2H),3.66(t,J＝5.2Hz,4H),3.25(s,2H),3.07(t,J＝7.2Hz,2H),3.04–2.98(m,1H),2.22(d,J＝8.6Hz,6H),2.12(s,3H),1.67(d,J＝12.4Hz,2H),1.52(dt,J＝12.0,5.8Hz,2H),0.83(t,J＝7.0Hz,3H). 13 C NMR(126MHz,DMSO-d 6 )δ169.6,163.5,161.9,158.5,157.6,150.0,149.5,145.9,143.3,140.1,136.3,135.0,132.4,125.4,122.6,122.1,120.4,107.9,107.6,66.8,58.3,44.9,43.6,41.7,35.4,30.8,19.4,18.7,15.0,13.2.[M+Na]+calcd for C 37 H 45 N 9 NaO 5 ,718.3436,found 718.3434.
example 28 in vitro detection of inhibitory Activity of HDAC 1and HDAC6
HDAC1 (#. AB 101661) and HDAC6 (#. AB 42632) enzymes were purchased from Abcam. The reaction mixture contained 40. Mu.l of 25mM Tris (pH 8.0), 1mM MgCl2, 0.1mg/mL BSA, 137mM NaCl, 2.7mM KCl, HDACs (HDAC 1, 10ng per well; HDAC6, 20ng per well) in the total volume. Test compounds (3-fold dilutions, 6 concentrations) were diluted in 10% dmso, 5 μl of the dilution was added, the purified recombinant HDAC was pre-incubated for 5 minutes at room temperature, and then the substrate was added. Finally, enzyme substrate was added and the plate incubated at 37℃for 30 minutes with a final volume of 50. Mu.L. The reaction was quenched with 50 μl HDAC Assay Developer for 30 min at room temperature. The assay is performed by quantifying the amount of fluorescent product in the solution after the enzymatic reaction. Then on a multimode enzyme label instrument (Envison 2015)Fluorescence was analyzed with excitation wavelengths of 350-360nm and emission wavelengths of 450-460nm. Calculation of IC using nonlinear regression with normalized dose response fit using Prism GraphPad software 50 Values. All experiments were performed independently at least 3 times.
TABLE 1 HDAC inhibitory Activity of Compounds 10-36 a
a IC 50 Data are expressed as mean ± SD of three independent experiments.
We assessed the HDAC 1and HDAC6 inhibitory activity of the compounds of interest (Table 1). Table 1 shows that the inhibitory activity of HDAC 1and HDAC6 generally increases with increasing linker length, but if the linker length is too long, the inhibitory activity of HDAC 1and HDAC6 decreases, such as compound 15 (HDAC 1 IC) 50 ＝0.70μM，HDAC6 IC 50 =0.39 μm) and 16 (HDAC 1 IC 50 ＝6.02μM，HDAC6 IC 50 =3.32 μm). We also evaluated the inhibitory activity of compounds with unsaturated chains as linkers (17-20), compound 20 showing the best potency, HDAC1 IC 50 =0.12 μm and HDAC6 IC 50 =0.70 μΜ. Replacement of linker linkage positions resulted in compounds 27-32, which exhibited moderate inhibitory activity against HDAC 1and HDAC 6. Kinetics and antiproliferative effects of binding compounds on recombinant PRC2 complexes (tables 2 and 3), we conclude that the linkers of compounds 15 and 20 are more suitable for maintaining the binding to HDAC1And efficacy of HDAC6, we therefore linked linkers to other pharmacophores of EZH2 (33-36), pyrimidine linkers showed better efficacy for HDAC1, alkane linkers showed better efficacy for HDAC 6.
EXAMPLE 29 binding force of representative Compounds to recombinant PRC2 Complex
Binding affinity was assessed at 25 ℃ using a Biacore T200 instrument (GE Healthcare). Briefly, compounds were diluted to indicated concentrations with running buffer (10 mM HEPES supplemented with 5% DMSO). The pH screening for immobilization of the recombinant PRC2 complex (active motif, catalog No. 31387) was performed using 10mM acetate buffers at pH 4.0, 4.5, 5.0 and 5.5. A pH of 5.0 was found to be the most suitable condition for PRC2 immobilization. Recombinant PRC2 of approximately 12,000 Response Units (RU) was immobilized on CM5 sensor chips by standard amine coupling procedures. The compounds were injected into PRC2 immobilization flow cell at concentrations of 0.5, 0.25, 0.125, 0.0625, 0.03125, 0.015625 and 0.0078125 μm at a flow rate of 30 μl/min for 90 seconds and the buffer was allowed to run as dissociation blank for 90 seconds. Calculating steady state K using Biacore T200 evaluation software D Values.
TABLE 2 kinetic results of representative Compounds on recombinant PRC2 complexes a
a The software calculations were evaluated by Biacore T200. k (k) a Is the binding rate constant, k d Is the dissociation rate constant. K (K) D ＝k d /k a
We selected a few representative compounds to assess the binding affinity of PRC2 complexes (table 2). Compound 20 showed the best binding affinity (K D =0.039 μm). After our modification of the pharmacophore of EZH2, compounds 33-36 were obtained, which did not show better binding affinity than 20.
Example 30 antiproliferative Activity of Compounds against different hematological tumor cells and solid tumor cells
MV4-11, HL-60,SU-DHL-10, MDA-MB-231, HCT116 cells were seeded in 96-well plates and then treated with the vector alone or with the test compound for 96 hours. mu.L of CCK8 solution (#C0005, TOPSIENCE) was added and the mixture was incubated at 37℃for 2-5 hours, next, absorbance was measured at 450nm for each well using a plate reader (BioTek), cell viability was calculated As follows: cell viability (%) = [ (As-Ab)/(Ac-Ab)]X 100. (As represents experimental well absorbance, ab represents blank well absorbance, ac represents absorbance control well). In this study, experiments were repeated at least 3 times and IC was plotted by plotting log (inhibitor) v.s 50 Values. Normalized response (variable slope) dose response curves generated using GraphPad Prism 6.
TABLE 3 in vitro anti-proliferation assay a
a IC50, data are presented as mean ± SD of three independent experiments.
b The Combination Index (CI) was calculated according to the Chou-Talalay method. CI (CI)>1 indicates antagonism, ci=1 indicates additive effect, CI<1 represents a synergistic effect.
To further investigate the antiproliferative effect of these dual-target inhibitors, we selected three hematological malignancy cell lines: acute myelogenous leukemia cell HL-60, MV4-11 and diffuse large B cell lymphoma cell SU-DHL-10; two solid tumor cell lines: colon cancer cell HCT-116, triple negative breast cancer cell MDA-MB-231 (Table 3). The combination therapies of SAHA and GSK126, tazemetostat, C24 show synergy in blood cancer cells at a 1:1 ratio, respectively. In contrast, combination therapy treatment of solid tumor cells did not have significant synergy, consistent with our objective of treating hematological malignancies with HDAC inhibitors in combination with EZH2 inhibitors. As shown in Table 3, the joint fingers in MV4-11The number (CI) was the smallest in the three hematological malignancy cell lines, while the combination treatment of SAHA and GSK126 was most effective (ci=0.38). In general, our dual-target compounds have the best inhibitory activity against MV4-11 cells in three hematological cancer cell lines. The most potent compound 20 showed the best inhibitory activity against MV4-11 cells (IC 50 =0.17 μm), superior to the combination therapy of SAHA and GSK126 for MV4-11 (IC 50 ＝0.40μM)。
Example 31 evaluation of antitumor Activity of Compounds in vivo.
Female BALB/c nude mice of the pathogen-free class (6 weeks after birth) were designated to be purchased from Jiangsu Jiugang biotechnology limited. MV4-11 cells (3X 10) 7 Individual cells) were resuspended in PBS and inoculated into the right-hand area for subcutaneous injection. When the average volume of the tumor xenograft was increased to 100mm 3 At this time, the mice were randomly divided into 6 groups (6 mice per group): control group, SAHA (100 mg/kg), GSK126 (100 mg/kg), SAHA+GSK126 (100 mg/kg+100 mg/kg), 20 (50 mg/kg), 20 (100 mg/kg), continuous 20 days intraperitoneal administration. Body weight was monitored every 2 days. Tumors were measured every 2 days with vernier calipers and tumor volumes were calculated according to the following formula: volume (mm 3) =length (mm) ×width (mm) 2 X 0.5. The compound was dissolved in a mixture consisting of 5% dmso, 5% peg400, 5% castor oil, and 85% (20% 2-hydroxypropyl-beta-cyclodextrin in saline). Mice were sacrificed after treatment, tumor tissues were weighed by dissection, and TGI was calculated as follows: tgi= (control mean tumor weight-treatment mean tumor weight)/control mean tumor weight. Multiple comparison tests of one-way anova and Dunnett were used to determine the statistical significance of tumor weight between the treatment and control groups: p ()<0.05, and (x) p<0.01。
A nude mouse MV4-11 xenograft model was established to evaluate the in vivo antitumor efficacy of compound 20. Six groups of mice (six mice per group) were divided according to drug dose and type: control, SAHA (100 mg/kg), GSK126 (100 mg/kg), SAHA+GSK126 (100 mg/kg+100 mg/kg), 20 (50 mg/kg), 20 (100 mg/kg), continuous 20 days intraperitoneal administration. Tumor Growth Inhibition (TGI) was calculated at the end of treatment. The tumor growth of the five treated groups was significantly inhibited by 52.7%, 68.5%, 76.2%, 65.7% and 82.0%, respectively, compared to the control group (tumor growth inhibition). 20 reduced tumor growth in the MV4-11 xenograft model. Although the tumor inhibiting effect in the 50mg/kg group is not better than that of the positive SAHA, the 100mg/kg treatment group is better than that of the positive SAHA and GSK126 and slightly better than that of the SAHA and GSK126 (82.0% vs. 76.2%). The final tumor weight and tumor growth curves are shown in figure 1, A, B, which show increased anti-tumor efficacy in vivo compared to each positive drug alone.

Claims (10)

1. A dual-target inhibitor targeting EZH2/HDAC, characterized by being selected from any one of compounds having the following general structure:
wherein R is selected from- (CH) 2 ) n1 -，-CO(CH 2 ) n2 -benzyl, pyrimidine ring, unsaturated five membered heterocycle; n1=any integer from 4 to 9, and n2=any integer from 3 to 6.
2. The dual-target inhibitor according to claim 1, wherein when the dual-target inhibitor has a structure represented by the general formula (I), R is selected from- (CH) 2 ) n1 -，-CO(CH 2 ) n2 -pyrimidine ring, n1=7 or 8, n2=5 or 6; when the structure is shown as a general formula (II), R is selected from-CO (CH) 2 ) n2 -, n2=5 or 6; when the structure is shown as a general formula (III), R is selected from- (CH) 2 ) n1 -n1=5, 6 or 7; when the structure is shown as a general formula (V), R is selected from pyrimidine rings.
3. Compound according to claim 1, characterized in that the inhibitor is selected from the following compounds:
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (4- (hydroxyamino) -4-oxobutyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxyamino) -5-oxopentyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (6- (hydroxyamino) -6-oxohexyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (7- (hydroxyamino) -7-oxoheptyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (8- (hydroxyamino) -8-oxooctyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (10- (hydroxyamino) -10-oxodecyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (4- (hydroxycarbamoyl) benzyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- ((5- (hydroxycarbamoyl) furan-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n1- (4- ((4- (5- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) pyridin-2-yl) piperazin-1-yl) methyl) phenyl) -N8-hydroxyoctanediamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxycarbamoyl) pyrimidin-2-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxyamino) -5-oxopentanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (6- (hydroxyamino) -6-oxohexanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (7- (hydroxyamino) -7-oxoheptyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (8- (hydroxyamino) -8-oxooctanoyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-1H-indazole-4-carboxamide,
n1- (4- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) phenyl) -N8-hydroxyoctanediamide,
n1- (4- (4- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -1-isopropyl-1H-indazol-6-yl) phenyl) -N7-hydroxyheptandiamide,
tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((5- (hydroxyamino) -5-oxopentyl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate,
tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (6- (hydroxyamino) -6-oxohexyl) amino) -4-methylphenyl) pyridin-3-yl) piperazine-1-carboxylate,
tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((7- (hydroxyamino) -7-oxoheptyl) amino) -4-methylphenyl) pyridin-3-yl) piperazine-1-carboxylate,
tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- ((8- (hydroxyamino) -8-oxooctyl) amino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate,
tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (5- (hydroxyamino) -5-oxopentylamino) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate,
tert-butyl 4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (6- (hydroxyamino) -6-oxohexanamido) -4-methylphenyl) pyridin-2-yl) piperazine-1-carboxylate,
(R) -1- (sec-butyl) -N- (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -3-methyl-1H-indole-4-carboxamide,
(R) -1- (sec-butyl) -N- (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (5- (hydroxycarbamoyl) pyrimidin-2-yl) piperazin-3-yl) -3-methyl-1H-indole-4-carboxamide,
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (6- (4- (9- (hydroxyamino) -9-oxononyl) piperazin-1-yl) pyridin-3-yl) -2-methylbenzamide,
2- (4- (5- (3- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methylphenyl) pyridin-2-yl) piperazin-1-yl) -N-hydroxypyrimidine-5-carboxamide.
4. A EZH2/HDAC dual-target inhibitor according to any of claims 1-3, wherein the pharmaceutically acceptable salt of the compound of formulae (I) - (V) is selected from acid addition salts of the compounds of formulae (I) - (V) with an acid selected from the group consisting of: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
5. The method of preparing an EZH2/HDAC dual target inhibitor according to claim 1, wherein the route of the reaction is as follows:
route 1: synthesis of target Compounds 10-24 a
a Reagents and reaction conditions (a) 2-iodopropane, K 2 CO 3 ,CH 3 CN, reflux,12h,75%; (b) Tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 DMF, reflux, N 2 ,4h,80％；(c)NaOH,MeOH/H 2 O, rt,2h,95%; (d) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,84%; (e) CF (compact flash) 3 COOH, DCM, rt,6h,85%; (f) for 10g-20g, various methyl bromoformates Et 3 N, DMF,90 ℃,12h,70-85%; for 21g-24g, various methyl monoformates, HATU, DIPEA, DCM, rt,2h,84-94%; (g) NH (NH) 2 OK,CH 3 OH,rt,3-5h,63-85％；
b For linker R of the designed compound, the left side is connected with nitrogen atom, and the right side is connected with carbonyl;
route 2: synthesis of target Compounds 25, 26 a
a Reagent and reaction conditions (a) tert-butyl (4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) carbamate, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 ,DMF,reflux,N 2 ,4h,84％；(b)NaOH,MeOH/H 2 O, rt,2h,92%; (c) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,88%; (d) CF (compact flash) 3 COOH, DCM, rt,6h,79%; (e) Various methyl monoformates, HATU, DIPEA, DCM, rt,2h,84-90%; (f) NH (NH) 2 OK,CH 3 OH,rt,3-5h,63-85％
b For linker R of the designed compound, the left side is connected with nitrogen atom, and the right side is connected with carbonyl;
route 3: synthesis of target Compounds 27-32 a
a Reagent and reaction conditions (a) tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 ,DMF,reflux,N 2 ,3h,70％；(b)NaOH,MeOH/H 2 O, rt,2h,90%; (c) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,85%; (d) Zinc powder, CH 3 COOH/H 2 O, 0-rt, 12h,65%; (e) for 27-30, various methyl bromoformates, cs 2 CO 3 DMF,90 ℃,1h,50-65%; for 31and 32, various methyl monoformates, et 3 N,DCM,rt,1h,70-81％；(f)NH 2 OK,CH 3 OH,rt,3-5h,60-82％；
b For linker R of the designed compound, the left side is connected with nitrogen atom, and the right side is connected with carbonyl;
route 4: synthesis of target Compounds 33, 34 a
a Reagents and reaction conditions (a) methyl 9-bromononanoate or methyl 2-chloropyrimidine-5-carboxylate, et 3 N,DMF,90℃,12h,70-80％；(b)NH 2 OK,CH 3 OH,rt,3-5h,64-80％；
b For linker R of the designed compound, the left side is connected with nitrogen atom, and the right side is connected with carbonyl;
route 5: synthesis of target Compounds 35, 36 a
a Reagent and reaction conditions (a) tert-butyl 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate, pdCl 2 (dppf)·CH 2 Cl 2 ,K 2 CO 3 ,DMF,reflux,N 2 ,4h,80％；(b)NaOH,MeOH/H 2 O, rt,2h,92%; (c) 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one, HATU, DIPEA, DCM, rt,2H,87%; (d) CF (compact flash) 3 COOH, DCM, rt,6h,88%; (e) Methyl 9-bromononanoate or methyl 2-chloropyrimidine-5-carboxylate, et 3 N,DMF,90℃,12h,70-85％；(f)NH 2 OK,CH 3 OH,rt,3-5h,68-80％。
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is formulated into any one of a tablet, a capsule, a powder, a syrup, a liquid, a suspension, a lyophilized powder for injection or an injection.
8. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hematological neoplasms or other cancers.
9. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis of EZH2 and HDAC mediated diseases.
10. Use according to claim 9, characterized in that the use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of EZH2 and HDAC mediated hematological neoplasms.
CN202210230503.2A 2022-03-09 2022-03-09 EZH2/HDAC double-target inhibitor and preparation method and medical application thereof Pending CN116768857A (en)

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