CN113754591B - HDAC, JAK and BET three-target inhibitor and preparation method and application thereof - Google Patents

HDAC, JAK and BET three-target inhibitor and preparation method and application thereof Download PDF

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CN113754591B
CN113754591B CN202010503272.9A CN202010503272A CN113754591B CN 113754591 B CN113754591 B CN 113754591B CN 202010503272 A CN202010503272 A CN 202010503272A CN 113754591 B CN113754591 B CN 113754591B
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triethylamine
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CN113754591A (en
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张颖杰
赵春龙
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Shandong University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses an HDAC, JAK and BET three-target inhibitor, a preparation method and application thereof. The HDAC, JAK and BET tri-target inhibitor has a structural general formula shown as (I) or (II). The invention also provides a preparation method of the compound and application of the compound in preparing medicines for preventing or treating diseases related to the activity or abnormal expression of HDAC, JAK and BET.

Description

HDAC, JAK and BET three-target inhibitor and preparation method and application thereof
Technical Field
The invention relates to an HDAC, JAK and BET three-target inhibitor, a preparation method and application thereof, belonging to the technical field of synthesis and medical application of organic compounds.
Background
The combined drug and the multi-target drug can obviously improve the treatment effect on tumors through synergistic effect. Multi-target drugs also have significant advantages over co-administration in improving pharmacokinetic properties, avoiding adverse drug-drug interactions, and improving patient compliance (J Med Chem,62 (2019) 420-444;J Med Chem,62 (2019) 8881-8914).
Histone deacetylases (Histone deacetylase, HDACs), bromodomain and extra terminal domain proteins (Bromodomain and extra-terminal, BET), and JAK kinases (JAKs) have become important biological targets for the treatment of various tumors. Up to now, a total of 5 HDAC inhibitors are approved for the treatment of various hematological neoplasms; a total of 6 JAK inhibitors are approved for the treatment of rheumatoid arthritis and myelofibrosis; although no BET inhibitors are currently approved for sale, there are a number of BET inhibitors that are already in the clinical stage of research in the treatment of various hematological and solid tumors.
Although 5 HDAC inhibitors have been approved for use in the treatment of tumors, HDAC inhibitors have limited therapeutic efficacy against solid tumors, which severely limits the use of HDAC inhibitors in the treatment of tumors. The literature reports that the HDAC inhibitor SAHA enhances histone acetylation on the leukemia inhibitory factor receptor (leukemia inhibitory factor receptor, LIFR) gene promoter in solid tumor cells such as breast Cancer, and the latter "recruits" the epigenetic modification recognition factor BRD4, up-regulates LIFR expression and activates JAK1-STAT3 signaling pathway, and promotes expression of anti-apoptotic genes such as BCL-2, mcl-1, etc., thereby greatly weakening the therapeutic effect of HDAC inhibitors on solid tumors such as breast Cancer (Cancer Cell,30 (2016) 459-473). Thus, blocking the BRD4-JAK1-STAT3-BCL-2/MCL-1 drug resistance signaling pathway in solid tumor cells is expected to enhance the therapeutic effect of HDAC inhibitors on solid tumors. The literature reports that the JAK inhibitors phenanthrene Zhuo Tini (ferratinib) and TG101209 have moderate BRD4 inhibitory activity (Nat Chem Biol,10 (2014) 305-312;ACS Chem Biol,9 (2014) 1160-1171). Therefore, we used JAK inhibitors phenanthrene Zhuo Tini (ferdriinib) and TG101209 as molecular templates, analyzed their binding patterns with JAK and BET, combined with the pharmacophore model of HDAC inhibitors, designed a series of HDAC, JAK and BET tri-target inhibitors.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an HDAC, JAK and BET three-target inhibitor, and a preparation method and application thereof.
The technical scheme of the invention is as follows:
1.HDAC, JAK and BET tri-target inhibitors
HDAC, JAK and BET tri-target inhibitors having the following structural formula (I) or (II), pharmaceutically acceptable salts, solvates or prodrugs thereof:
wherein: x is
Y is
R 1 Hydrogen, various aliphatic hydrocarbon groups, various halogens;
R 2 is a six-membered aryl, para-substituted six-membered aryl, six-membered heteroaryl, para-substituted six-membered heteroaryl;
R 3 is a six-membered aryl, para-substituted six-membered aryl, six-membered heteroaryl, para-substituted six-membered heteroaryl;
preferred according to the invention are those wherein:
x is
Y is
R 1 Methyl, chlorine atom;
R 2 is that
R 3 Is that
Further preferably, the above compound is one of the following:
2. methods of preparing HDAC, JAK and BET tri-target inhibitors
The preparation method of the compound with the structure of the general formula (I) or (II) is shown in one of the following routes:
taking a compound 1 as a starting material, reacting with tert-butylamine to obtain a compound 2, performing a nitroreduction reaction on the compound 2 to obtain an intermediate 3, and performing a nucleophilic substitution reaction on the intermediate 3 and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain key intermediates 4a-4b; nucleophilic substitution reaction is carried out on the compounds 4a-4b and para-aminobenzoic acid or meta-aminobenzoic acid under the catalysis of acid to obtain compounds 5a-5d, then amide condensation is carried out on the intermediates 5a-5d and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine to obtain intermediates 6a-6d, and then THP protecting groups of the compounds 6a-6d are removed under the acidic condition to obtain hydroxamic acid end products 7a-7d; the compounds 5a,5c and o-phenylenediamine are subjected to amide condensation to obtain o-phenylenediamine end products 8a-8b; the compounds 4a-4b respectively react with ethyl p-amino cinnamate through acid-catalyzed nucleophilic substitution reaction to obtain intermediates 9a-9b,9a, reacting with freshly prepared potassium hydroxylamine methanol solution to obtain a final product 10a, performing ester hydrolysis reaction and amide condensation reaction on the intermediate 9b, and finally removing THP protecting groups under acidic conditions to obtain a final product 11a; amide condensation is carried out on the compounds 5a-5d and hydrazine hydrate to obtain intermediates 12a-12d, and then the final products 13a-13d of the hydrazides are obtained through reductive amination;
the first synthesis route is as follows:
reagents and reaction conditions in the above synthetic route: a) Tert-butylamine, tetrahydrofuran, 25 ℃; b) Palladium carbon, 80% hydrazine hydrate, ethanol and refluxing; c) 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine, methanol and water, 45 ℃; d) 3-aminobenzoic acid or 4-amino ethyl cinnamate, concentrated hydrochloric acid, isopropanol, reflux; e) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, triethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, N-dimethylformamide, 25 ℃; f) Ethyl acetate saturated with hydrogen chloride; g) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; h) Potassium hydroxylamine in methanol at 25 ℃; i) Lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; j) 1) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) Ethyl acetate saturated with hydrogen chloride; k) 80% of hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyl urea tetrafluoroborate, triethylamine, dichloromethane and 25 ℃; l) 1) propanal, magnesium sulfate, absolute ethanol, 25 ℃; 2) Sodium cyanoborohydride or sodium borohydride, anhydrous methanol, 25 ℃.
Taking the compound 14 as a raw material, carrying out nucleophilic substitution reaction and nitroreduction reaction on the compound and p-nitrophenol under alkaline conditions to obtain an intermediate 16, and carrying out nucleophilic substitution reaction on the compound 17a-17c and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain key intermediates 18a-18f; the intermediate 18a-8f and the compound 16 undergo nucleophilic substitution through acid catalysis to obtain key intermediates 19a-19f, the intermediates 19a-19d react with freshly prepared potassium hydroxylamine methanol solution to obtain hydroxamic acid end products 20a-20d, and the intermediates 19e-19f undergo condensation reaction with o-phenylenediamine to obtain o-phenylenediamine end products 20e-20f; amide condensation is carried out on the compound 19e and hydrazine hydrate to obtain an intermediate 21, and then reductive amination is carried out to obtain a hydrazide final product 22;
the second synthesis route is as follows:
reagents and reaction conditions in the above synthetic route: a) 4-nitrophenol, cesium carbonate, N, N-dimethylformamide, nitrogen, 100 ℃; b) Palladium on carbon, hydrogen, methanol, 25 ℃; c) 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine, methanol, water, 45 ℃; d) Concentrated hydrochloric acid, isopropanol, 85 ℃ or concentrated hydrochloric acid, isobutanol, 100 ℃; e) Potassium hydroxylamine in methanol; f) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; g) 80% of hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyl urea tetrafluoroborate, triethylamine, dichloromethane and 25 ℃; h) 1) propanal, magnesium sulfate, absolute ethanol, 25 ℃; 2) Sodium borohydride, anhydrous methanol, 25 ℃.
(III) taking the compound 23 as a starting material, carrying out Boc anhydride protection amino, nitro reduction and tertiary butyl sulfinyl chloride condensation reaction on the compound 23 to obtain a compound 26, and carrying out oxidation reaction, boc protection group removal under acidic condition and nucleophilic substitution reaction on the compound 29 to obtain a compound 2, 4-dichloro-5-methylpyrimidine; nucleophilic substitution reaction is carried out on the compound 29 and para aminobenzoic acid under an acidic condition to obtain an intermediate 30, and on one hand, the intermediate 30 and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine undergo amide condensation, and THP protecting groups are removed under the acidic condition to obtain a final product 31; on the other hand, amide condensation is carried out on the o-phenylenediamine to obtain a final product 32; intermediate 29 and ethyl p-amino cinnamate undergo an acid-mediated nucleophilic substitution reaction to obtain intermediate 33, and then undergo an ester hydrolysis reaction, amide condensation and THP protecting group removal under acidic conditions to obtain a final product 35; amide condensation is carried out on the compound 30 and hydrazine hydrate to obtain an intermediate 36, and then a hydrazide final product 37 is obtained through reductive amination;
the synthesis route III is as follows:
reagents and reaction conditions in the above synthetic route: a) Di-tert-butyl dicarbonate, tert-butanol, 60 ℃; b) Ferric trichloride, 80% hydrazine hydrate, active carbon, methanol and refluxing; c) T-butylsulfinyl chloride, pyridine, 0 ℃; d) M-chloroperoxybenzoic acid, dichloromethane, 25 ℃; e) Trifluoroacetic acid, dichloromethane, 25 ℃; f) 2, 4-dichloro-5-methylpyrimidine, methanol and water, 45 ℃; g) 4-aminobenzoic acid, concentrated hydrochloric acid, isobutanol, 100 ℃; h) 1) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) Ethyl acetate saturated with hydrogen chloride; i) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; j) Ethyl 4-amino cinnamate, concentrated hydrochloric acid, isobutanol, 100 ℃; k) Lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; l) 80% hydrazine hydrate, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; m) 1) propanal, magnesium sulfate, absolute ethanol, 25 ℃; 2) Sodium borohydride, anhydrous methanol, 25 ℃.
Starting materials 38a-38b in the fourth step react with N-methylpiperazine under alkaline conditions, intermediate 40a-40b is obtained through nitro reduction, and after nucleophilic substitution reaction of intermediate 40a-40b with compound 18a under acidic conditions, on the one hand, the intermediate reacts with potassium hydroxylamine methanol solution to obtain final products 41a-41b; on the other hand, the intermediate 42 is obtained through ester hydrolysis reaction, and the intermediate 42 is respectively subjected to amide condensation with o-phenylenediamine and n-propyl hydrazine hydrochloride to obtain final products 43 and 44;
the synthesis route four is as follows:
reagents and reaction conditions in the above synthetic route: a) N-methylpiperazine, potassium carbonate, dimethyl sulfoxide, 25 ℃; b) Palladium carbon, 80% hydrazine hydrate, ethanol, 60 ℃; c) 1) 18a, concentrated hydrochloric acid, isobutanol, 100 ℃; 2) Potassium hydroxylamine in methanol at 25 ℃; d) 1) 18a, concentrated hydrochloric acid, isobutanol, 100 ℃; 2) Lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; e) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; f) N-propyl hydrazine hydrochloride, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃.
3. Use of HDAC, JAK and BET tri-target inhibitors
The invention also provides the use of HDAC, JAK and BET tri-target inhibitors in the manufacture of a medicament for the prevention or treatment of diseases associated with HDAC, JAK and BET activities or abnormal expression;
the diseases related to the abnormal activity or expression of HDAC, JAK and BET are various hematological tumors, solid tumors, autoimmune diseases and the like.
The various blood tumors and solid tumors are myelofibrosis, melanoma, multiple myeloma, cutaneous T-cell lymphoma, human erythrocyte leukemia, human chronic myelogenous leukemia, breast cancer, pancreatic cancer, gastric cancer, lung cancer, rectal cancer, colon cancer, prostate cancer and the like, and the autoimmune diseases are rheumatoid arthritis, inflammation and the like.
Furthermore, the present invention also includes pharmaceutical compositions suitable for oral or parenteral administration comprising a compound of the general formula (I) or (II) according to the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
Detailed Description
The invention is further illustrated, but not limited, by the following examples.
The preparation methods of the compounds 7a-7d,8a-8b,10a,11a,13a-3d are respectively exemplified by the compounds 7a,8a,10a,11a,13a, and the specific steps are as follows:
(1) Intermediate 2: preparation of N- (tert-butyl) -3-nitrobenzenesulfonamide
3-Nitrophenesulfonyl chloride (1, 5.0g,22.56 mmol) was added to 50mL tetrahydrofuran at 25deg.C, and tert-butylamine (4.95 g,67.68 mmol) was added. After the addition, stirring was continued for 0.5 hours at 25 ℃, the progress of the reaction was monitored by TLC, after the completion of the reaction, the pH of the solution was adjusted to 2 with 1M hydrochloric acid at 0 ℃, the reaction solution was distilled off under reduced pressure, the obtained solid was slurried with petroleum ether/ethyl acetate, filtered, the cake was washed 3 times with an appropriate amount of water, and the obtained solid was dried in vacuo to give 5.15g of a yellow solid in 88% yield. ESI-MS, m/z=257.10 [ m-H ]] - 。
(2) Intermediate 3: preparation of 3-amino-N- (tert-butyl) benzenesulfonamide
Compound 2 (5.00 g,19.36 mmol) was dissolved in 80mL of ethanol at 25deg.C, and 10% palladium on carbon (0.50 g) and 80% hydrazine hydrate (3.63 g,58.08 mmol) were added. Reflux-reacting for 3 hr under argon protection, and vacuum evaporating to remove solventThe resulting solid was dissolved in dichloromethane, washed 2 times with water, the combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated and dried under vacuum to give 3.35g of a white solid in 76% yield. ESI-MS, m/z=227.13 [ m-H ]] - 。
(3) Intermediate 4a: preparation of N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide
Compound 3 (2.3 g,10.00 mmol) and 2, 4-dichloro-5-methylpyrimidine (1.9 g,11.50 mmol) were added to methanol and water (v: v=1:1.5, 50 mL) at 25℃and reacted for 20 hours at 45℃with gradual solid precipitation during the reaction, after the TLC monitoring was completed, the reaction solution was allowed to stand at room temperature, filtered, and the resultant solid was washed 2 times with methanol and water (v: v=1:1.5) and dried in vacuo to give 2.96g of a white solid in 83% yield. ESI-MS, m/z=353.29 [ m-H ]] - 。
Compound 4b was prepared in a similar manner to compound 4 a.
(4) Intermediate 5a: preparation of 4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzoic acid
Compound 4a (0.35 g,1.00 mmol) and p-aminobenzoic acid (0.21 g,1.50 mmol) were added to 16mL of isopropanol at 25 ℃, 2-3 drops of concentrated hydrochloric acid were added, the reaction was refluxed at 85 ℃ for 3 hours, a solid was gradually precipitated during the reaction, after TLC monitoring the reaction, the reaction solution was allowed to stand to room temperature, filtered, and the obtained solid was washed with isopropanol and ethyl acetate in this order for 1-2 times, and dried under vacuum to obtain 0.37g of a white solid in 81% yield. ESI-MS, m/z=454.27 [ m-H ]] - 。
Compounds 5b-5d were prepared in a similar manner to compound 5 a.
(5) Intermediate 6a: preparation of 4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) -N- ((tetrahydro-2H-pyran-2-yl) oxybenzamide
Compound 5a (0.45 g,1.0 mmol) was dissolved in 30mL of N, N-dimethylformamide at 0deg.C, triethylamine (0.15 g,1.5 mmol) was added sequentially, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.30 g,1.5 mmol), 1-hydroxybenzotriazole (0.20 g,1.5 mmol) was added, and stirring was continued for 30 min at 0deg.CO- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.18 g,1.5 mmol) was then added, the ice bath was removed, the reaction was stirred at 25℃for 12 hours, after which the TLC monitoring was completed, the reaction solution was poured into a large amount of water, extracted 3 times with ethyl acetate, the organic phase was combined and the organic phase was quenched with saturated NaHCO 3 And saturated aqueous NaCl solution for 2 times, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to give 0.30g of a white solid in 55% yield. ESI-MS, m/z=555.13 [ M+H ]] + 。
Compounds 6b-6d were prepared in a similar manner to compound 6 a.
(6) Compound 7a: preparation of 4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) -N-hydroxybenzoamide
Compound 6a (0.18 g,0.32 mmol) was added to 20mL of ethyl acetate at 25deg.C, 0.33mL of hydrogen chloride saturated ethyl acetate was added, stirring was continued for 1 hour, after TLC monitoring the reaction was complete, the reaction solution was filtered, and dried under vacuum to give 0.13g of a white solid in 87% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.11(s,1H),10.70(s,1H),10.04(s,1H),8.02(s,1H),7.93-7.88(m,2H),7.77(d,J＝7.9Hz,1H),7.67-7.60(m,4H),7.45(d,J＝8.4Hz,2H),2.21(s,3H),1.10(s,9H)。 13 C NMR(101MHz,DMSO-d 6 )δ164.14,162.13,151.35,145.40,142.15,140.20,138.15,129.76,129.32,128.82,128.31,128.17,124.36,122.97,120.10,108.49,53.87,30.22,13.88。HRMS(AP-ESI),calcd for C 22 H 26 N 6 O 4 S[M+H] + 471.1814,found 471.1810。
Compounds 7b-7d were prepared in a similar manner to compound 7 a.
(7) Compound 8a: preparation of N- (2-aminophenyl) -4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzamide
Compound 5a (0.23 g,0.50 mmol) was dissolved in 15mL anhydrous N, N-dimethylformamide, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate (0.20 g,0.60 mmol) and triethylamine (0.08 g,0.75 mmol) were added at 0deg.C, and the mixture was stirred and activated for 30 minutes, O-phenylenediamine (0.08 g,0.75 mmol) was added, and the mixture was stirred and activated at 25deg.CAfter the reaction was stirred and TLC monitored, the reaction mixture was poured into a large volume of water, extracted 3 times with ethyl acetate and the organic phase was separated with saturated NaHCO 3 And saturated NaCl solution for 2-3 times, the combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated, purified by column chromatography (dichloromethane/methanol=30:1), dried in vacuo to give 0.10g of a yellow solid in 37% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.44(s,1H),9.35(s,1H),8.68(s,1H),8.19-8.16(m,1H),8.10(d,J＝2.4Hz,1H),8.02(s,1H),7.84(d,J＝8.7Hz,2H),7.80(d,J＝8.8Hz,2H),7.60-7.51(m,3H),7.16(d,J＝7.8Hz,1H),7.02-6.93(m,1H),6.78(d,J＝7.9Hz,1H),6.60(t,J＝7.5Hz,1H),4.85(s,2H),2.17(s,3H),1.13(s,9H)。 13 C NMR(101MHz,DMSO-d 6 )δ165.39,159.55,158.09,156.42,144.99,144.54,143.56,140.77,129.39,128.93,127.05,126.69,126.41,125.71,124.24,120.85,119.70,117.50,116.78,116.64,107.57,53.73,30.26,14.05。HRMS(AP-ESI),calcd for C 28 H 31 N 7 O 3 S[M+H] + 546.2287,found 546.2280.
Compound 8b was prepared in a similar manner to compound 8 a.
(8) Intermediate 9a: (E) Preparation of ethyl 3- (4- ((4- ((3- (N- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylate)
Compound 4a (0.27 g,0.76 mmol) and ethyl p-aminocinnamate (0.13 g,0.69 mmol) were added to 10mL of isobutanol, 53. Mu.L of concentrated hydrochloric acid was added, and after completion of the reaction, the reaction mixture was allowed to stand at room temperature, filtered and dried under vacuum to give 0.25g of a white solid in 71% yield. ESI-MS, m/z=510.40 [ m+h ]] + 。
Intermediate 9b was prepared in a similar manner to compound 9 a.
(9) Compound 10a: (E) Preparation of-3- (4- ((4- ((3- (N- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) -N-hydroxyacrylamide
Compound 9a (0.20 g,0.39 mmol) was added to 8mL of freshly prepared potassium hydroxylamine in methanol at 25℃and reacted for 2 hours with stirring at 25℃after which the reaction mixture was concentrated and taken up in 1The pH of the solution was adjusted to 6 with M hydrochloric acid, the precipitated solid was filtered, and the resulting solid was slurried with ethyl acetate, filtered, and dried in vacuo to give 0.13g of an off-white solid in 68% yield. 1 H NMR(600MHz,DMSO-d 6 )δ10.64(s,1H),9.26(s,1H),8.93(s,1H),8.66(s,1H),8.14-8.12(m,1H),8.10(d,J＝2.0Hz,1H),7.99(s,1H),7.72(d,J＝8.3Hz,2H),7.58(s,1H),7.56-7.51(m,2H),7.42-7.31(m,3H),6.28(d,J＝15.7Hz,1H),2.15(s,3H),1.13(s,9H)。 13 C NMR(101MHz,DMSO-d 6 )δ163.84,159.55,158.14,156.41,144.98,142.86,140.81,138.86,129.36,128.51,127.35,125.73,120.83,119.76,118.63,116.11,107.30,53.73,30.26,14.02。HRMS(AP-ESI),calcd for C 24 H 28 N 6 O 4 S[M+H] + 497.1971,found 497.1973。
(10) Compound 10b: (E) Preparation of-3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-chloropyrimidin-2-yl) amino) phenyl) acrylic acid
Compound 9b (0.20 g,0.38 mmol) was dissolved in 15mL tetrahydrofuran, a mixed solvent of methanol and water (v: v: v=1:1:1), lithium hydroxide (0.16 g,3.77 mmol) was added thereto, and the reaction was heated at 60℃for 1 hour, after the completion of which the reaction was monitored by TLC, the reaction solution was concentrated, the pH of the solution was adjusted to 4-5 with 1M hydrochloric acid, and the obtained solid was filtered and dried in vacuo to give 0.16g of pale yellow solid in 85% yield. ESI-MS, m/z=502.19 [ m+h ]] + 。
Example 2, the preparation of compounds 20a-20d,20e-20f and 22, respectively, was carried out as follows:
(1) Intermediate 15: preparation of 1- (2- (4-nitrophenoxy) ethyl) pyrrolidine
P-nitrophenol (0.70 g,5.0 mmol) was dissolved in 20mL anhydrous N, N-dimethylformamide, and Compound 1 (0.86 g,5.0 mmol) and Cs were added 2 CO 3 (2.4 g,7.5 mmol) was reacted under nitrogen protection at 100deg.C for 4 hours, after TLC monitoring the reaction was completed, the reaction solution was allowed to stand to room temperature, filtered, the filtrate was added to a proper amount of ice water, extracted with ethyl acetate, and the organic phase was extracted with saturated Na 2 CO 3 Washing with NaCl solution, mixing the organic phases, and adding anhydrous magnesium sulfateDrying, filtration and concentration gave 0.40g of a tan oil in 34% yield. ESI-MS, m/z=237.10 [ m+h ]] + 。
(2) Intermediate 16: preparation of 4- (2- (pyrrolidin-1-yl) ethoxy) aniline
Compound 15 (0.75 g,3.17 mmol) was dissolved in 50mL dry methanol and 10% palladium on carbon was added to H 2 After the reaction was completed at room temperature for 12 hours, the palladium on carbon was removed by filtration through celite, the solvent was distilled off, and the reaction mixture was dried to give 0.65g of a yellow oil in 98% yield.
(3) Intermediate 18a: preparation of methyl 4- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzoate
0.55g of an off-white solid, 64% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.11(s,1H),8.15(s,1H),7.96(d,J＝8.5Hz,2H),7.86(d,J＝8.6Hz,2H),3.84(s,3H),2.22(s,3H)。ESI-MS,m/z＝276.19[M-H] - 。
Intermediate 18a-18f was prepared in a similar manner to compound 4 a.
(4) Intermediate 19a: preparation of methyl 4- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzoate hydrochloride
Compound 18a (0.25 g,0.90 mmol) and compound 16 (0.20 g,0.97 mmol) were added to 10mL of isopropanol at 25deg.C, concentrated hydrochloric acid (90 μL,1.08 mmol) was added, and after the addition was completed, the reaction was heated at 85deg.C for 4 hours, after TLC monitoring the reaction was completed, the reaction solution was allowed to stand to room temperature, filtered, and the obtained solid was washed with isopropanol and ethyl acetate, respectively, and dried in vacuo to give 0.26g of an off-white solid in 65% yield. ESI-MS, m/z=448.24 [ m+h ]] + 。
Intermediate 19b-19f is prepared in a similar manner to compound 19a
(5) Compound 20a: preparation of N-hydroxy-4- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzamide
The compound 19a (0.09 g,0.2 mmol) was added to 5mL of freshly prepared potassium hydroxylamine in methanol at 25℃and the reaction was continued for 1.5 hours at 25℃after which the reaction was monitored by TLC and concentrated and adjusted with 1M hydrochloric acidThe pH of the solution was adjusted to 7-8, the solid precipitated, filtered and dried in vacuo to give 15mg of a yellow solid in 17% yield. Mp:144-146 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.85(s,1H),8.36(s,1H),7.89(s,1H),7.82(d,J＝8.5Hz,2H),7.71(d,J＝8.5Hz,2H),7.55(d,J＝8.9Hz,2H),6.81(d,J＝8.9Hz,2H),4.01(t,J＝6.0Hz,2H),2.76(t,J＝6.0Hz,2H),2.12(s,3H),1.72-1.65(m,4H)。 13 C NMR(101MHz,DMSO-d 6 )δ164.42,159.24,158.82,156.58,153.45,134.73,127.54,120.96,120.89,114.67,106.15,67.35,54.95,54.47,23.62,14.07。HRMS(AP-ESI),calcd for C 24 H 28 N 6 O 3 [M+H] + 449.2301,found 449.2299。
Compounds 20b-20d were prepared in a similar manner to compound 20 a.
(6) Compound 20e: preparation of N- (2-aminophenyl) -4- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzamide
0.11g of yellow solid, yield 50%. 1 H NMR(400MHz,DMSO-d 6 )δ9.60(s,1H),8.91(s,1H),8.47(s,1H),7.99-7.91(m,5H),7.57(d,J＝8.5Hz,2H),7.19(d,J＝7.8Hz,1H),6.98(t,J＝7.7Hz,1H),6.85(d,J＝8.6Hz,2H),6.80(d,J＝7.9Hz,1H),6.61(t,J＝7.5Hz,1H),4.91(s,2H),4.05(t,J＝5.8Hz,2H),2.90(t,J＝6.0Hz,2H),2.64(s,4H),2.14(s,3H),1.74-1.67(m,4H)。 13 C NMR(101MHz,DMSO-d 6 )δ165.30,159.20,158.87,156.71,153.44,143.60,143.55,134.75,128.65,128.23,127.05,126.75,124.20,121.10,120.70,116.80,116.69,114.74,106.19,67.09,54.82,54.45,23.57,14.02。HRMS(AP-ESI),calcd for C 30 H 33 N 7 O 2 [M+H] + 524.2774,found 524.2771。
Compounds 20e-20f were prepared in a similar manner to compound 8 a.
(7) Intermediate 21: preparation of 4- ((5-methyl-2- ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzohydrazine
0.37g of off-white solid in 97% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.60(s,1H),9.55(s,1H),9.04(s,1H),8.00-7.82(m,5H),7.50(d,J＝8.6Hz,2H),7.03-6.91(m,2H),4.32(t,J＝5.0Hz,2H),3.57(t,J＝5.1Hz,2H),2.16(s,3H),1.97(s,4H).ESI-MS,m/z＝448.23[M+H] + 。
Intermediate 21 is prepared in a similar manner to compound 12 a.
(8) Compound 22: preparation of 4- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) -N' -propylbenzoyl hydrazine
0.02g of an off-white solid, yield 7%. 1 H NMR(400MHz,DMSO-d 6 )δ9.93(s,1H),8.87(s,1H),8.40(s,1H),7.93-7.83(m,3H),7.79(d,J＝8.6Hz,2H),7.55(d,J＝8.7Hz,2H),6.83(d,J＝8.5Hz,2H),5.06(s,1H),4.03(t,J＝5.8Hz,2H),2.84(brs,2H),2.75(t,J＝7.2Hz,2H),2.59(brs,4H),2.12(s,3H),1.70(brs,4H),1.48(h,J＝7.6Hz,2H),0.92(t,J＝7.4Hz,3H)。HRMS(AP-ESI),calcd for C 27 H 35 N 7 O 2 [M+H] + 490.2930,found 490.2928。
Compound 22 was prepared in a similar manner to compound 13 a.
The preparation method of example 3, compounds 31, 32, 35 and 37 comprises the following specific steps:
(1) Intermediate 24: preparation of (4-chloro-3-nitrophenyl) carbamic acid tert-butyl ester
Compound 23 (1.72 g,10.00 mmol) was added to 15mL of t-butanol at 25℃and (Boc) 2 O (2.40 g,11.00 mmol) was reacted at 60℃for 15 hours after the addition, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=30:1) and dried in vacuo to give 1.76g of a pale yellow solid in 65% yield.
(2) Intermediate 25: preparation of (3-amino-4-chlorophenyl) carbamic acid tert-butyl ester
Compound 24 (1.00 g,3.67 mmol), ferric trichloride (0.10 g,0.37 mmol) and activated carbon (0.5 g) were added to 30mL of methanol at 25 ℃ and after refluxing for 10 minutes, 80% hydrazine hydrate (734 μl,14.68 mmol) was slowly added, and after the addition was completed, the refluxing was continued, after TLC monitoring was completed, the reaction solution was allowed to stand to room temperature, filtered with celite, the filtrate was concentrated, the resulting residue was dissolved in ethyl acetate, washed with water, saturated NaCl solution in this order, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to give 0.73g of a white solid with a yield of 85%.
(3) Intermediate 26: preparation of tert-butyl (3- ((tert-butylsulfinyl) amino) -4-chlorophenyl) carbamate
Tert-butylsulfinyl chloride (0.25 mL,2.00 mmol) and compound 25 (0.49 g,2.00 mmol) were dissolved in 2mL and 3mL of pyridine, respectively, at 25deg.C, a pyridine solution of tert-butylsulfinyl chloride was slowly added dropwise to a pyridine solution of compound 25 at 0deg.C, and after completion of the reaction, which was continued at 0deg.C, ethyl acetate was added to the reaction solution after completion of TLC monitoring, followed by washing with 1M hydrochloric acid and saturated NaCl solution for 2 times, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give 0.42g of pale yellow solid in 61% yield.
(4) Intermediate 27: preparation of tert-butyl (4-chloro-3- (((1, 1-dimethylethyl) sulfonamide) phenyl) carbamate
Compound 26 (0.80 g,2.31 mmol) was dissolved in 15mL of dichloromethane at 25℃and 85% m-CPBA (0.42 g,2.42 mmol) was added, and the reaction was continued with stirring for 4 hours after completion of TLC monitoring the reaction, and saturated Na was used 2 CO 3 The reaction solution was adjusted to pH 8, the organic phase was washed 2 times with saturated NaCl solution, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, concentrated, column chromatographed (dichloromethane/methanol=100:1), dried under vacuum to give 0.60g of a yellow solid in 72% yield.
(5) Intermediate 28: preparation of N- (5-amino-2-chlorophenyl) -2-methylpropane-2-sulfonamide
Compound 27 (0.60 g,1.65 mmol) was dissolved in 4mL of dichloromethane, 4mL of trifluoroacetic acid was added thereto, and the mixture was stirred at 25℃for 1 hour to react with saturated Na 2 CO 3 The pH of the reaction solution was adjusted to be more than 7, 20mL of methylene chloride was added to the reaction solution, and saturated Na was used 2 CO 3 And NaCl solution for 2 times, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to give 0.30g of a brown solid in 70% yield.
(6) Intermediate 29: preparation of N- (2-chloro-5- ((2-chloro-5-methylpyrimidin-4-yl) amino) phenyl) -2-methylpropane-2-sulfonamide
0.32g of a tan solid, 73% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.33(s,1H),9.01(s,1H),8.10(s,1H),7.95(d,J＝2.5Hz,1H),7.59(dd,J＝8.9,2.5Hz,1H),7.46(d,J＝8.8Hz,1H),2.19(s,3H),1.35(s,9H)。
Intermediate 29 is prepared in a similar manner to compound 4 a.
(7) Intermediate 30: preparation of 4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamide) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzoic acid
Compound 29 (0.30 g,0.77 mmol) and para-aminobenzoic acid (0.12 g,0.85 mmol) were added to 15mL of isobutanol at 25deg.C, concentrated hydrochloric acid (96.70 μL,1.16 mmol) was added, and the reaction was completed at 100deg.C for 6 hours, after which the reaction was allowed to stand to room temperature, filtered, and the filter cake was washed 2 times with isobutanol and dried under vacuum to give 0.25g of a white solid in 66% yield.
(8) Compound 31: preparation of 4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamide) phenyl) amino) -5-methylpyrimidin-2-yl) amino) -N-hydroxybenzoamide
Compound 30 (0.25 g,0.51 mmol) was dissolved in 10mL of N, N-dimethylformamide, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate (0.25 g,0.76 mmol) and triethylamine (107.0. Mu.L, 0.76 mmol) were added, the mixture was activated for 20 minutes, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (71.50 mg,0.61 mmol) was added, the reaction was continued to be stirred, 100mL of water was added to the reaction solution after the completion of TLC monitoring, and the organic phase was extracted with saturated Na 2 CO 3 And saturated NaCl for 2 times, and dried over anhydrous magnesium sulfate, filtered, concentrated to give a white solid, dissolved with a small amount of ethyl acetate, added with 5mL of ethyl acetate saturated with hydrogen chloride, reacted at room temperature for 1 hour, filtered, dried under vacuum, and yield 43%. 1 H NMR(400MHz,DMSO-d 6 )δ11.13(s,1H),10.95(s,1H),10.07(s,1H),9.58(s,1H),8.03(s,1H),7.76(d,J＝2.2Hz,1H),7.66(d,J＝8.3Hz,2H),7.57(d,J＝8.5Hz,1H),7.53-7.44(m,3H),2.19(s,3H),1.30(s,9H)。 13 C NMR(101MHz,DMSO-d 6 )δ164.06,162.03,150.93,141.28,140.06,136.81,136.37,129.93,128.43,128.18,125.09,124.28,123.66,120.09,108.54,61.18,24.27,13.98。HRMS(AP-ESI),calcd for C 22 H 25 ClN 6 O 4 S[M+H] + 505.1425,found 505.1410。
(9) Compound 32: preparation of N- (2-aminophenyl) -4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamide) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzamide
0.10g of pale yellow solid, yield 38%. 1 H NMR(400MHz,DMSO-d 6 )δ9.40(d,J＝10.7Hz,2H),9.34(s,1H),8.61(s,1H),8.01(s,1H),7.92(s,1H),7.87(d,J＝8.5Hz,2H),7.84-7.75(m,3H),7.45(d,J＝8.8Hz,1H),7.18(d,J＝7.8Hz,1H),6.98(t,J＝7.6Hz,1H),6.80(d,J＝8.0Hz,1H),6.62(t,J＝7.5Hz,1H),4.89(s,2H),2.16(s,3H),1.34(s,9H)。 13 C NMR(101MHz,DMSO-d 6 )δ165.39,159.47,158.11,156.48,143.59,139.63,135.85,129.47,128.95,127.12,126.73,126.36,124.20,121.56,121.28,121.13,117.43,116.77,116.61,107.44,61.07,24.34,14.06。HRMS(AP-ESI),calcd for C 28 H 30 ClN 7 O 3 S[M+H] + 580.1898,found 580.1878。
Compound 32 was prepared in a similar manner to compound 8 a.
(10) Intermediate 33: (E) Preparation of ethyl-3- (4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamide) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylate
0.23g of pale yellow solid, 66% yield. ESI-MS, m/z=542.31 [ M-H ]] - 。
Intermediate 33 is prepared in a similar manner to compound 30.
(11) Intermediate 34: (E) Preparation of-3- (4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamide) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylic acid
80mg of an off-white solid was obtained in 39% yield. ESI-MS, m/z=516.35 [ m+h ]] + 。
Intermediate 34 is prepared in a similar manner to compound 10 b.
(12) Compound 35: (E) Preparation of-3- (4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamide) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) -N-hydroxyacrylamide
45mg of yellow solid was obtained in 63% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.84(s,1H),10.05(s,1H),9.64(s,1H),8.00(s,1H),7.79(d,J＝2.3Hz,1H),7.66-7.37(m,7H),6.39(d,J＝15.8Hz,1H),2.18(s,3H),1.29(s,9H)。 13 C NMR(101MHz,DMSO-d 6 )δ163.34,162.10,150.91,141.29,138.40,138.16,136.84,136.42,131.05,130.05,128.66,125.13,124.28,123.83,120.99,118.43,108.34,61.20,24.28,13.91。HRMS(AP-ESI),calcd for C 24 H 27 ClN 6 O 4 S[M+H] + 531.1581,found 531.1563。
Compound 35 was prepared in a similar manner to compound 31.
(13) Intermediate 36: preparation of N- (2-chloro-5- ((2- ((4- (hydrazinocarbonyl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) phenyl) -2-methylpropane-2-sulfonamide
0.17g of white solid, 66% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.82(s,1H),9.35(d,J＝18.2Hz,2H),8.64(s,1H),7.98(s,1H),7.86(d,J＝2.5Hz,1H),7.79-7.68(m,5H),7.45-7.42(m,1H),2.14(s,3H),1.33(d,J＝3.8Hz,9H)。
Intermediate 36 was prepared in a similar manner to compound 12 a.
(14) Compound 37: preparation of N- (2-chloro-5- ((5-methyl-2- ((4- (2-propylhydrazine-1-carbonyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-methylpropane-2-sulfonamide
20mg of an off-white solid was obtained in 11% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.76(s,1H),9.35(s,1H),9.27(s,1H),8.60(s,1H),7.98(s,1H),7.86(s,1H),7.79-7.67(m,5H),7.44(d,J＝8.7Hz,1H),5.03(s,1H),2.75(t,J＝7.2Hz,2H),2.14(s,3H),1.48(h,J＝7.5Hz,2H),1.33(s,9H),0.92(t,J＝7.4Hz,3H)。HRMS(AP-ESI),calcd for C 25 H 32 ClN 7 O 3 S[M+H] + 546.2054,found 546.2008.
Compound 37 was prepared in a similar manner to compound 13 a.
The preparation method of example 4, compounds 41a,41b,43 and 44, comprises the following specific steps:
(1) Intermediate 39a: preparation method of 1-methyl-4- (4-nitrophenyl) piperazine
Compound 38a (1.00 g,7.09 mmol) and K 2 CO 3 (1.17 g,8.50 mmol) was added to 15mL of DMSO, stirred at 25℃for 30 min, N-methylpiperazine (865.5. Mu.L, 7.80 mmol) was slowly added dropwise, the reaction was continued with stirring, after TLC monitoring the reaction was completed, the reaction solution was poured into a large amount of ice water, the product was precipitated, filtered, and dried under vacuum to give 1.50g of yellow solid in 95% yield. ESI-MS, m/z=222.20 [ m+h ]] + 。
Intermediate 39b was prepared in a similar manner to compound 39 a.
(2) Intermediate 40a: preparation of 4- (4-methylpiperazin-1-yl) aniline
0.42g of a mauve solid, 61% yield. ESI-MS, m/z=192.20 [ m+h ]] + 。
Intermediate 40a and 40b were prepared in a similar manner to compound 3.
(3) Compound 41a: preparation of N-hydroxy-4- ((5-methyl-2- (((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzamide
Compounds 40a (0.20 g,0.72 mmol) and 18a (0.15 g,0.79 mmol) were added to 10mL of isobutanol, 180. Mu.L of concentrated hydrochloric acid was added, and after the addition, the mixture was heated to react at 100℃for 10 hours, allowed to stand still to room temperature, filtered to give a crude product, 5mL of freshly prepared potassium hydroxylamine methanol solution was added to the crude product, reacted at room temperature for 1 hour, the reaction solution was filtered, concentrated, pH was adjusted to 7 with 1M hydrochloric acid, the product was precipitated, filtered, slurried with ethyl acetate, filtered to give 60mg of a reddish brown solid, yield 19%. 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.96(s,1H),8.79(s,1H),8.37(s,1H),7.89(d,J＝9.9Hz,3H),7.71(d,J＝8.3Hz,2H),7.50(d,J＝8.5Hz,2H),6.84(d,J＝8.5Hz,2H),3.05(t,J＝5.0Hz,4H),2.46(t,J＝4.9Hz,4H),2.23(s,3H),2.12(s,3H)。 13 C NMR(101MHz,DMSO-d 6 )δ164.55,159.15,158.90,156.62,146.25,143.33,133.76,130.17,127.64,126.41,120.74,116.37,105.95,55.21,49.55,46.26,14.00。HRMS(AP-ESI),calcd for C 23 H 28 N 7 O 2 [M+H] + 434.2304,found 434.2285。
Compound 41b was prepared in a similar manner to 41 a.
(4) Intermediate 42: preparation of 4- ((2- ((3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzoic acid
Compounds 40a (0.20 g,0.72 mmol) and 18a (0.15 g,0.79 mmol) were added to 10mL of isobutanol, 149. Mu.L of concentrated hydrochloric acid was added, and after completion of the reaction, the reaction mixture was concentrated, water was added, and saturated NaHCO was used 3 The solution was adjusted to ph=8, extracted with ethyl acetate, the organic phase was washed 2 times with saturated NaCl, dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product was slurried with a mixed solvent of petroleum ether and ethyl acetate to give 0.19g of a white solid, the resulting solid was dissolved in 15mL of a mixed solvent of methanol, water and tetrahydrofuran (v: v=1:1:1), lithium hydroxide (0.19 g,4.44 mmol) was added, and reacted at 60 ℃ for 1 hour, after the reaction was completed, the reaction solution was concentrated, adjusted to ph=7 with 1M hydrochloric acid, the product was precipitated, filtered, and vacuum-dried to give 0.16g of a white solid, yield 52%. ESI-MS, m/z=437.48 [ m+h ]] + 。
(5) Compound 43: preparation of N- (2-aminophenyl) -4- ((2- ((3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzamide
0.10g of an off-white solid, 56% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.57(s,1H),9.09(s,1H),8.51(s,1H),8.02-7.94(m,3H),7.92(d,J＝8.5Hz,2H),7.69(d,J＝15.4Hz,1H),7.30(d,J＝8.8Hz,1H),7.20(d,J＝7.8Hz,1H),6.98(t,J＝7.7Hz,1H),6.91(t,J＝9.4Hz,1H),6.81(d,J＝8.0Hz,1H),6.62(t,J＝7.6Hz,1H),4.89(s,2H),2.93(t,J＝4.8Hz,4H),2.45(t,J＝4.8Hz,4H),2.21(s,3H),2.16(s,3H)。 13 C NMR(101MHz,DMSO-d 6 )δ165.29,159.30,158.41,156.58,156.47(d, 1 J CF ＝241.0Hz),143.55,143.47,137.00(d, 3 J CF ＝11.0Hz),133.70(d, 3 J CF ＝9.0Hz),128.73,128.48,127.04,126.78,124.20,120.99,119.55(d, 4 J CF ＝4.0Hz),116.84,116.73,114.98,107.43(d, 2 J CF ＝26.0Hz,2C),106.85,55.27,50.96,50.93,46.26,14.01。HRMS(AP-ESI),calcd for C 29 H 31 FN 8 O[M+H] + 527.2683,found 527.2665。
Compounds 43 and 44 were prepared in a similar manner to compound 8 a.
Example 5 in vitro HDAC inhibitory Activity evaluation test of target Compounds
We tested the in vitro inhibition activity of the target compounds against HDAC using Class I HDAC1 and Class II HDAC6 as enzyme sources, with the approved marketed non-selective HDAC inhibitor vorinostat (SAHA) as positive control. First, the inhibition rate of the target compound to HDAC1/6 at 0.5 mu M was tested, and based on the preliminary screening result, a compound with better partial activity was selected to further test the IC to HDAC1/6 50 Values.
The experimental results (table 1) show that most of the target compounds of the present invention exhibit better HDAC inhibition. Compound 7a IC for HDAC6 50 A value of 52nM, comparable to the activity of the positive control SAHA; compounds 8a,13a and 13c have good selectivity and inhibition activity on HDAC1, IC 50 Values are 270nM,122nM and 283nM, respectively; whereas compound 31 showed better inhibitory activity against HDAC1/6, IC 50 The values were 402nM and 431nM, respectively.
TABLE 1 evaluation of in vitro HDAC inhibitory Activity
/>
a Inhibition @ 0.5. Mu.M or IC 50 。IC 50 Values are expressed as mean ± SD values of three independent replicates.
Example 6 in vitro JAK1 inhibitory Activity evaluation test of target Compounds
We used a kinase luminescence assay to test the inhibition of JAK1 by a compound of interestSexually, the JAK inhibitor Ruxolitinib (Ruxolitinib), which has been marketed, was used as a positive control. First, the inhibition rate of the target compound to JAK1 at the concentration of 0.5 mu M is tested, then, the inhibition activities of the compound to HDAC and JAK1 are comprehensively considered, 14 target compounds are selected for further testing the IC to JAK1 50 Values.
The experimental results (table 2) show that most of the target compounds show very good inhibitory activity against JAK 1. Compounds 7a,8a,13a,20 c,20e,22 and 31 have better or comparable inhibitory activity against JAK1 than phenanthrene Zhuo Tini (Fedratinib), wherein compound 7a has IC against JAK1 50 A value of 4.5nM is clearly better than phenanthrene Zhuo Tini (Fedratinib).
TABLE 2 evaluation results of in vitro JAK1 inhibitory Activity
/>
a Inhibition @ 0.5. Mu.M or IC 50 。IC 50 Values are expressed as mean ± SD values of three independent replicates.
Example 7 evaluation of BRD4 inhibitory Activity of target Compounds in vitro
We tested the inhibition activity of the target compounds on BRD4 using Homogeneous Time Resolved Fluorescence (HTRF) with phenanthrene Zhuo Tini (Fedratinib) as a positive control. First, the inhibition rate of the target compound to BRD4-BD1 at 10. Mu.M was tested, and the compound with inhibition rate of more than 50% was further tested for IC 50 Values.
The results of the experiment (Table 3) show that most of the target compounds exhibit a certain inhibitory activity against BRD4-BD 1. Compounds 20a,22 and 31 showed better or comparable BRD4-BD1 inhibitory activity than phenanthrene Zhuo Tini (Fedratinib), wherein compound 31 showed the best BRD4-BD1 inhibitory activity, IC 50 The value was 412nM.
TABLE 3 evaluation results of in vitro BRD4 inhibitory Activity
/>
a Inhibition ratio @ 10. Mu.M or IC 50 。IC 50 Values are expressed as mean ± SD values of three independent replicates.
Example 8 in vitro anti-tumor cell proliferation assay
We used the more classical MTT method to test the antiproliferative activity of some target compounds on HEL and MDA-MB-231 cell lines.
The results of the experiment (Table 4) show that most of the compounds selected have better antiproliferative activity on both HEL and MDA-MB-231. The antiproliferative activity of compounds 8a,8b and 32 on HEL was superior to that of the positive controls phenanthrene Zhuo Tini (ferratinib) and Ruxolitinib (Ruxolitinib), while showing comparable antiproliferative activity to that of the positive control vorinostat (SAHA). The antiproliferative activity of compounds 8a,13a,20c and 31 on MDA-MB-231 was significantly better than that of the positive controls vorinostat (SAHA) and Ruxolitinib (Ruxolitinib), comparable to that of the positive control phenanthrene Zhuo Tini (Fedriinib).
TABLE 4 in vitro anti-tumor cell proliferation assay results
a Values are expressed as mean ± SD values of three independent replicates.

Claims (5)

  1. Hdac, JAK and BET tri-target inhibitors, and pharmaceutically acceptable salts thereof, having the structure shown in the following general formula (I) or (II):
    x is
    Y is
    R 1 Methyl, chlorine atom;
    R 2 is that
    R 3 Is that
  2. 2. The HDAC, JAK and BET tri-target inhibitor of claim 1, characterized by one of the following compounds:
  3. 3. the method of preparing the HDAC, JAK and BET tri-target inhibitor of claim 2, as shown in one of the following schemes:
    taking a compound 1 as a starting material, reacting with tert-butylamine to obtain a compound 2, performing a nitroreduction reaction on the compound 2 to obtain an intermediate 3, and performing a nucleophilic substitution reaction on the intermediate 3 and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain key intermediates 4a-4b; nucleophilic substitution reaction is carried out on the compounds 4a-4b and para-aminobenzoic acid or meta-aminobenzoic acid under the catalysis of acid to obtain compounds 5a-5d, then amide condensation is carried out on the intermediates 5a-5d and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine to obtain intermediates 6a-6d, and then THP protecting groups of the compounds 6a-6d are removed under the acidic condition to obtain hydroxamic acid end products 7a-7d; the compounds 5a,5c and o-phenylenediamine are subjected to amide condensation to obtain o-phenylenediamine end products 8a-8b; the compounds 4a-4b respectively react with ethyl p-amino cinnamate through acid-catalyzed nucleophilic substitution reaction to obtain intermediates 9a-9b,9a, reacting with freshly prepared potassium hydroxylamine methanol solution to obtain a final product 10a, performing ester hydrolysis reaction and amide condensation reaction on the intermediate 9b, and finally removing THP protecting groups under acidic conditions to obtain a final product 11a; amide condensation is carried out on the compounds 5a-5d and hydrazine hydrate to obtain intermediates 12a-12d, and then the final products 13a-13d of the hydrazides are obtained through reductive amination;
    the first synthesis route is as follows:
    reagents and reaction conditions in the above synthetic route: a) Tert-butylamine, tetrahydrofuran, 25 ℃; b) Palladium carbon, 80% hydrazine hydrate, ethanol and refluxing; c) 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine, methanol and water, 45 ℃; d) 3-aminobenzoic acid or 4-amino ethyl cinnamate, concentrated hydrochloric acid, isopropanol, reflux; e) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, triethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, N-dimethylformamide, 25 ℃; f) Ethyl acetate saturated with hydrogen chloride; g) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; h) Potassium hydroxylamine in methanol at 25 ℃; i) Lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; j) 1) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) Ethyl acetate saturated with hydrogen chloride; k) 80% of hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyl urea tetrafluoroborate, triethylamine, dichloromethane and 25 ℃; l) 1) propanal, magnesium sulfate, absolute ethanol, 25 ℃; 2) Sodium cyanoborohydride or sodium borohydride, anhydrous methanol, 25 ℃;
    taking the compound 14 as a raw material, carrying out nucleophilic substitution reaction and nitroreduction reaction on the compound and p-nitrophenol under alkaline conditions to obtain an intermediate 16, and carrying out nucleophilic substitution reaction on the compound 17a-17c and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain key intermediates 18a-18f; the intermediate 18a-8f and the compound 16 undergo nucleophilic substitution through acid catalysis to obtain key intermediates 19a-19f, the intermediates 19a-19d react with freshly prepared potassium hydroxylamine methanol solution to obtain hydroxamic acid end products 20a-20d, and the intermediates 19e-19f undergo condensation reaction with o-phenylenediamine to obtain o-phenylenediamine end products 20e-20f; amide condensation is carried out on the compound 19e and hydrazine hydrate to obtain an intermediate 21, and then reductive amination is carried out to obtain a hydrazide final product 22;
    the second synthesis route is as follows:
    reagents and reaction conditions in the above synthetic route: a) 4-nitrophenol, cesium carbonate, N, N-dimethylformamide, nitrogen, 100 ℃; b) Palladium on carbon, hydrogen, methanol, 25 ℃; c) 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine, methanol, water, 45 ℃; d) Concentrated hydrochloric acid, isopropanol, 85 ℃ or concentrated hydrochloric acid, isobutanol, 100 ℃; e) Potassium hydroxylamine in methanol; f) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; g) 80% of hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyl urea tetrafluoroborate, triethylamine, dichloromethane and 25 ℃; h) 1) propanal, magnesium sulfate, absolute ethanol, 25 ℃; 2) Sodium borohydride, anhydrous methanol, 25 ℃;
    (III) taking the compound 23 as a starting material, carrying out Boc anhydride protection amino, nitro reduction and tertiary butyl sulfinyl chloride condensation reaction on the compound 23 to obtain a compound 26, and carrying out oxidation reaction, boc protection group removal under acidic condition and nucleophilic substitution reaction on the compound 29 to obtain a compound 2, 4-dichloro-5-methylpyrimidine; nucleophilic substitution reaction is carried out on the compound 29 and para aminobenzoic acid under an acidic condition to obtain an intermediate 30, and on one hand, the intermediate 30 and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine undergo amide condensation, and THP protecting groups are removed under the acidic condition to obtain a final product 31; on the other hand, amide condensation is carried out on the o-phenylenediamine to obtain a final product 32; intermediate 29 and ethyl p-amino cinnamate undergo an acid-mediated nucleophilic substitution reaction to obtain intermediate 33, and then undergo an ester hydrolysis reaction, amide condensation and THP protecting group removal under acidic conditions to obtain a final product 35; amide condensation is carried out on the compound 30 and hydrazine hydrate to obtain an intermediate 36, and then a hydrazide final product 37 is obtained through reductive amination;
    the synthesis route III is as follows:
    reagents and reaction conditions in the above synthetic route: a) Di-tert-butyl dicarbonate, tert-butanol, 60 ℃; b) Ferric trichloride, 80% hydrazine hydrate, active carbon, methanol and refluxing; c) T-butylsulfinyl chloride, pyridine, 0 ℃; d) M-chloroperoxybenzoic acid, dichloromethane, 25 ℃; e) Trifluoroacetic acid, dichloromethane, 25 ℃; f) 2, 4-dichloro-5-methylpyrimidine, methanol and water, 45 ℃; g) 4-aminobenzoic acid, concentrated hydrochloric acid, isobutanol, 100 ℃; h) 1) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) Ethyl acetate saturated with hydrogen chloride; i) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; j) Ethyl 4-amino cinnamate, concentrated hydrochloric acid, isobutanol, 100 ℃; k) Lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; l) 80% hydrazine hydrate, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; m) 1) propanal, magnesium sulfate, absolute ethanol, 25 ℃; 2) Sodium borohydride, anhydrous methanol, 25 ℃;
    starting materials 38a-38b in the fourth step react with N-methylpiperazine under alkaline conditions, intermediate 40a-40b is obtained through nitro reduction, and after nucleophilic substitution reaction of intermediate 40a-40b with compound 18a under acidic conditions, on the one hand, the intermediate reacts with potassium hydroxylamine methanol solution to obtain final products 41a-41b; on the other hand, the intermediate 42 is obtained through ester hydrolysis reaction, and the intermediate 42 is respectively subjected to amide condensation with o-phenylenediamine and n-propyl hydrazine hydrochloride to obtain final products 43 and 44;
    the synthesis route four is as follows:
    reagents and reaction conditions in the above synthetic route: a) N-methylpiperazine, potassium carbonate, dimethyl sulfoxide, 25 ℃; b) Palladium carbon, 80% hydrazine hydrate, ethanol, 60 ℃; c) 1) 18a, concentrated hydrochloric acid, isobutanol, 100 ℃; 2) Potassium hydroxylamine in methanol at 25 ℃; d) 1) 18a, concentrated hydrochloric acid, isobutanol, 100 ℃; 2) Lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; e) O-phenylenediamine, O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; f) N-propyl hydrazine hydrochloride, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃.
  4. 4. Use of an HDAC, JAK and BET tri-target inhibitor according to any one of claims 1 or 2 in the manufacture of a medicament for the prevention or treatment of human erythroleukemia, breast cancer associated with HDAC, JAK and BET activities or abnormal expression.
  5. 5. A pharmaceutical composition suitable for oral or parenteral administration comprising an HDAC, JAK and BET tri-target inhibitor according to any one of claims 1 or 2 and one or more pharmaceutically acceptable excipients.
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