CN113754591A - 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 PDFInfo
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- CN113754591A CN113754591A CN202010503272.9A CN202010503272A CN113754591A CN 113754591 A CN113754591 A CN 113754591A CN 202010503272 A CN202010503272 A CN 202010503272A CN 113754591 A CN113754591 A CN 113754591A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- 102000003964 Histone deacetylase Human genes 0.000 title claims abstract description 30
- 108090000353 Histone deacetylase Proteins 0.000 title claims abstract description 30
- 239000003112 inhibitor Substances 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 230000000694 effects Effects 0.000 claims abstract description 10
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 230000001594 aberrant effect Effects 0.000 claims abstract description 4
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 105
- 239000000543 intermediate Substances 0.000 claims description 82
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 75
- 238000006243 chemical reaction Methods 0.000 claims description 73
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 55
- -1 hydrogen chloride saturated ethyl acetate Chemical class 0.000 claims description 53
- 239000007787 solid Substances 0.000 claims description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 46
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 40
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
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- 238000006482 condensation reaction Methods 0.000 claims description 6
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- 238000006268 reductive amination reaction Methods 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
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- DBQDDWSYKOTBGD-UHFFFAOYSA-N tert-butyl n-(3-amino-4-chlorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(Cl)C(N)=C1 DBQDDWSYKOTBGD-UHFFFAOYSA-N 0.000 description 1
- QSPZPPNAGGOCFE-UHFFFAOYSA-N tert-butyl n-(4-chloro-3-nitrophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(Cl)C([N+]([O-])=O)=C1 QSPZPPNAGGOCFE-UHFFFAOYSA-N 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- 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, and a preparation method and application thereof. The HDAC, JAK and BET three-target inhibitor has a structural general formula shown in (I) or (II). The invention also provides a preparation method of the compound and application thereofAnd the use thereof for the preparation of a medicament for the prevention or treatment of a disease associated with aberrant HDAC, JAK and BET activity or expression.
Description
Technical Field
The invention relates to an HDAC, JAK and BET three-target inhibitor, a preparation method and application thereof, and belongs to the technical field of organic compound synthesis and medical application.
Background
The combined medicine and the multi-target medicine can obviously improve the treatment effect on the tumor through the synergistic effect. Compared with combination, the multi-target drug also has obvious advantages in improving pharmacokinetic properties, avoiding poor drug-drug interaction, improving patient compliance, etc. (J Med Chem,62(2019) (420) -.
Histone Deacetylases (HDACs), Bromodomain-containing and extra-terminal domain proteins (BET) and JAK kinases (JAKs) have become important biological targets for the treatment of various tumors. To date, a total of 5 HDAC inhibitors have been approved for the market to treat various hematological neoplasms; a total of 6 JAK inhibitors are approved for marketing to treat rheumatoid arthritis and myelofibrosis; although no BET inhibitors are currently approved for marketing, several BET inhibitors have been in clinical research phase for the treatment of various hematological and solid tumors.
Although 5 HDAC inhibitors have been approved for the treatment of tumors, the therapeutic effect of HDAC inhibitors on solid tumors is very limited, which severely limits the use of HDAC inhibitors for the treatment of tumors. The literature reports that HDAC inhibitor SAHA enhances histone acetylation on a Leukemia Inhibitory Factor Receptor (LIFR) gene promoter in solid tumor cells such as breast Cancer, and the latter 'recruits' epigenetic modification recognition factor BRD4, up-regulates LIFR expression and activates JAK1-STAT3 signal pathway, promotes the expression of anti-apoptosis genes such as BCL-2 and MCL-1, and greatly weakens the treatment effect of HDAC inhibitor on solid tumors such as breast Cancer (Cancer Cell,30 (2016)) 459-473. Therefore, blocking the BRD4-JAK1-STAT3-BCL-2/MCL-1 drug resistance signaling pathway in solid tumor cells is expected to improve the therapeutic effect of HDAC inhibitors on solid tumors. The JAK inhibitors Fedratinib (Fedratinib) and TG101209 were reported to have moderate BRD4 inhibitory activity (Nat Chem Biol,10(2014) 305-1171; ACS Chem Biol,9(2014) 1160-1171). Therefore, a series of HDAC, JAK and BET three-target inhibitors are designed by taking JAK inhibitors, namely Fedratinib and TG101209 as molecular templates, analyzing the binding mode between the JAK inhibitors and BET and combining with a pharmacophore model of the HDAC 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:
HDAC, JAK and BET three-target inhibitors
A three-target inhibitor of HDAC, JAK and BET having the following structural formula (I) or (II), a pharmaceutically acceptable salt, solvate or prodrug thereof:
wherein: x is
Y is
R1Is hydrogen, various aliphatic hydrocarbon groups, various halogens;
R2is a six-membered aryl group, a para-substituted six-membered aryl group, a six-membered heteroaryl group, a para-substituted six-membered heteroaryl group;
R3is a six-membered aryl group, a para-substituted six-membered aryl group, a six-membered heteroaryl group, a para-substituted six-membered heteroaryl group;
preferred according to the invention, wherein:
x is
Y is
R1Is methyl, a chlorine atom;
R2is that
R3Is that
Further preferably, the compound is one of the following:
preparation method of two, HDAC, JAK and BET three-target inhibitor
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 an initial raw material, reacting with tert-butylamine to obtain a compound 2, carrying out nitro reduction reaction on the compound 2 to obtain an intermediate 3, and carrying out nucleophilic substitution reaction on the intermediate 3 and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain key intermediates 4a-4 b; carrying out nucleophilic substitution reaction on the compounds 4a-4b and p-aminobenzoic acid or m-aminobenzoic acid under the catalysis of acid to obtain compounds 5a-5d, then carrying out amide condensation on the intermediates 5a-5d and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine to obtain intermediates 6a-6d, and then removing THP protective groups of the compounds 6a-6d under an acidic condition to obtain hydroxamic acid final products 7a-7 d; carrying out amide condensation on the compounds 5a and 5c and o-phenylenediamine to obtain o-phenylenediamine final products 8a-8 b; respectively carrying out acid-catalyzed nucleophilic substitution reaction on the compounds 4a-4b and ethyl p-aminocinnamate to obtain intermediates 9a-9b, reacting the intermediates 9a with a freshly prepared hydroxylamine potassium methanol solution to obtain a final product 10a, carrying out ester hydrolysis reaction and amide condensation reaction on the intermediate 9b, and finally removing THP protective groups under an acidic condition to obtain a final product 11 a; carrying out amide condensation on the compounds 5a-5d and hydrazine hydrate to obtain intermediates 12a-12d, and then carrying out reductive amination to obtain hydrazide final products 13a-13 d;
the synthesis route one is as follows:
reagents and reaction conditions in the above synthetic route: a) tert-butylamine, tetrahydrofuran, 25 ℃; b) refluxing palladium carbon, 80% hydrazine hydrate and ethanol; c)2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine, methanol and water, 45 ℃; d) refluxing 3-aminobenzoic acid or 4-ethyl amino cinnamate, concentrated hydrochloric acid and isopropanol; e) o- (tetrahydro-2H-pyran-2-yl) hydroxylamine, triethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, N-dimethylformamide, 25 ℃; f) hydrogen chloride saturated ethyl acetate; g) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; h) hydroxylamine potassium in methanol solution, 25 ℃; i) lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; j)1) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) hydrogen chloride saturated ethyl acetate; k) 80% hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; l)1) propionaldehyde, magnesium sulfate, absolute ethanol, 25 ℃; 2) sodium cyanoborohydride or sodium borohydride, anhydrous methanol, 25 ℃.
(II) taking a compound 14 as a raw material, carrying out nucleophilic substitution reaction and nitro reduction reaction on the compound 14 and p-nitrophenol under an alkaline condition to obtain an intermediate 16, and carrying out nucleophilic substitution reaction on a compound 17a-17c and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain a key intermediate 18a-18 f; the intermediates 18a-8f and the compound 16 are subjected to nucleophilic substitution under acid catalysis to obtain key intermediates 19a-19f, the intermediates 19a-19d react with a freshly prepared hydroxylamine potassium methanol solution to obtain hydroxamic acid final products 20a-20d, and the intermediates 19e-19f are subjected to condensation reaction with o-phenylenediamine to obtain o-phenylenediamine final products 20e-20 f; carrying out amide condensation on the compound 19e and hydrazine hydrate to obtain an intermediate 21, and then carrying out reductive amination to obtain a hydrazide final product 22;
the second synthetic 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 and water, 45 ℃; d) concentrated hydrochloric acid, isopropanol, 85 ℃ or concentrated hydrochloric acid, isobutanol, 100 ℃; e) hydroxylamine potassium methanol solution; f) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; g) 80% hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; h)1) propionaldehyde, magnesium sulfate, absolute ethyl alcohol, 25 ℃; 2) sodium borohydride, anhydrous methanol, 25 ℃.
(III) taking a compound 23 as an initial raw material, carrying out Boc anhydride protection amino group, nitro group reduction and tert-butyl sulfinyl chloride condensation reaction on the compound 23 to obtain a compound 26, and carrying out oxidation reaction, Boc protection group removal under an acidic condition and nucleophilic substitution reaction on 2, 4-dichloro-5-methylpyrimidine to obtain a compound 29; the compound 29 and p-aminobenzoic acid are subjected to nucleophilic substitution reaction under an acidic condition to obtain an intermediate 30, the intermediate 30 and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine are subjected to amide condensation on one hand, and a THP protective group is removed under an acidic condition to obtain a final product 31; on the other hand, the product is subjected to amide condensation with o-phenylenediamine to obtain a final product 32; the intermediate 29 and ethyl p-aminocinnamate are subjected to acid-mediated nucleophilic substitution reaction to obtain an intermediate 33, and then a final product 35 is obtained by ester hydrolysis reaction, amide condensation and THP protective group removal under an acidic condition; carrying out amide condensation on the compound 30 and hydrazine hydrate to obtain an intermediate 36, and then carrying out reductive amination to obtain a hydrazide final product 37;
the third synthetic route is as follows:
reagents and reaction conditions in the above synthetic route: a) di-tert-butyl dicarbonate, tert-butanol, 60 ℃; b) refluxing ferric trichloride, 80% hydrazine hydrate, activated carbon and methanol; c) tert-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-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) hydrogen chloride saturated ethyl acetate; i) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; j) ethyl 4-aminocinnamate, concentrated hydrochloric acid, isobutanol, 100 ℃; k) lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; l) 80% hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; m)1) propionaldehyde, magnesium sulfate, absolute ethyl alcohol, 25 ℃; 2) sodium borohydride, anhydrous methanol, 25 ℃.
In the fourth step, the initial raw materials 38a-38b react with N-methyl piperazine under alkaline conditions, intermediates 40a-40b are obtained through nitro reduction, and after nucleophilic substitution reaction of the intermediates 40a-40b with the compound 18a under acidic conditions, on one hand, the intermediates react with hydroxylamine potassium methanol solution to obtain final products 41a-41 b; on the other hand, an ester hydrolysis reaction is carried out to obtain an intermediate 42, and the intermediate 42 and o-phenylenediamine and n-propylhydrazine hydrochloride respectively carry out amide condensation to obtain final products 43 and 44;
the synthesis route 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) hydroxylamine potassium in methanol solution, 25 ℃; d)1)18a, concentrated hydrochloric acid, isobutanol, 100 ℃; 2) lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; e) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; f) n-propyl hydrazine hydrochloride, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃.
Application of three-target inhibitors of HDAC (Histone deacetylase), JAK (JAK) and BET (BET)
The invention also provides the use of a HDAC, JAK and BET three-target inhibitor in the preparation of a medicament for the prevention or treatment of a disease associated with aberrant HDAC, JAK and BET activities or expression;
the diseases related to the abnormal activity or expression of HDAC, JAK and BET are various blood tumors, solid tumors, autoimmune diseases and the like.
The blood tumor and solid tumor include myelofibrosis, melanoma, multiple myeloma, cutaneous T cell lymphoma, human erythroleukemia, human chronic myelogenous leukemia, breast cancer, pancreatic cancer, gastric cancer, lung cancer, rectal cancer, colon cancer, prostate cancer, etc., and the autoimmune disease includes rheumatoid arthritis, inflammation, etc.
In addition, the invention also includes a pharmaceutical composition suitable for oral or parenteral administration, comprising a compound of formula (I) or (II) of the invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
The preparation methods of example 1 and compounds 7a-7d, 8a-8b, 10a, 11a, 13a-3d, taking compounds 7a, 8a, 10a, 11a, 13a as examples respectively, comprise the following steps:
(1) intermediate 2: preparation of N- (tert-butyl) -3-nitrobenzenesulfonamide
3-Nitrobenzenesulfonyl chloride (1, 5.0g, 22.56mmol) was added to 50mL of tetrahydrofuran at 25 deg.C, and tert-butylamine (4.95g, 67.68mmol) was added. After the addition was completed, stirring was continued at 25 ℃ for 0.5 hour, the progress of the reaction was monitored by TLC, after the reaction was completed, 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 filter cake was washed with an appropriate amount of water for 3 times, and the obtained solid was dried under vacuum to give 5.15g of yellow solid with a yield of 88%. ESI-MS, M/z 257.10[ M-H ]]-。
(2) Intermediate 3: preparation of 3-amino-N- (tert-butyl) benzenesulfonamide
Compound 2(5.00g, 19.36mmol) was dissolved in 80mL of ethanol at 25 deg.C, and 10% palladium on carbon (0.50g) and 80% hydrazine hydrate (3.63g, 58.08mmol) were added. The reaction was refluxed for 3 hours under argon atmosphere, after the reaction was completed, the solvent was distilled off under reduced pressure, the obtained solid was dissolved in dichloromethane, washed with water for 2 times, the combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated, and dried under vacuum to obtain 3.35g of a white solid with a yield of 76%. ESI-MS, M/z 227.13[ M-H ]]-。
(3) Intermediate 4 a: preparation of N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide
Compound 3(2.3g, 10.00mmol) and 2, 4-dichloro-5-methylpyrimidine (1.9g, 11.50mmol) were added to methanol and water (v: v ═ 1:1.5,50mL) at 25 ℃ and reacted at 45 ℃ for 20 hours, a solid gradually precipitated during the reaction, after TLC monitoring the reaction was completed, the reaction solution was allowed to stand to room temperature, filtered, and the solid was washed 2 times with methanol and water (v: v ═ 1:1.5) and dried under vacuum to give 2.96g of a white solid in 83% yield. ESI-MS, M/z 353.29[ M-H ]]-。
Compound 4b was prepared in analogy to compound 4 a.
(4) Intermediate 5 a: preparation of 4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzoic acid
Compound 4a (0.35g, 1.00mmol) and p-aminobenzoic acid (0) were added at 25 ℃.21g, 1.50mmol) into 16mL of isopropanol, adding 2-3 drops of concentrated hydrochloric acid, refluxing and reacting at 85 ℃ for 3 hours, gradually precipitating solids in the reaction process, standing the reaction solution to room temperature after the TLC monitoring reaction is finished, filtering, washing the obtained solids with isopropanol and ethyl acetate for 1-2 times in sequence, and drying in vacuum to obtain 0.37g of white solids with the yield of 81%. ESI-MS, M/z 454.27[ M-H ]]-。
Compounds 5b-5d were prepared in analogy to Compound 5 a.
(5) Intermediate 6 a: preparation of 4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) -N- ((tetrahydro-2H-pyran-2-yl) oxybenzamide
Dissolving compound 5a (0.45g, 1.0mmol) in 30mL of N, N-dimethylformamide at 0 deg.C, sequentially adding triethylamine (0.15g, 1.5mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.30g, 1.5mmol), 1-hydroxybenzotriazole (0.20g, 1.5mmol) after addition, stirring at 0 deg.C for 30 min, adding O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.18g, 1.5mmol), removing ice bath, stirring at 25 deg.C for 12 hr, after TLC monitoring reaction, pouring the reaction solution into a large amount of water, extracting with ethyl acetate for 3 times, combining organic phases, sequentially adding saturated NaHCO3And saturated aqueous NaCl solution 2 times, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and dried under vacuum to obtain 0.30g of a white solid with a yield of 55%. ESI-MS, M/z 555.13[ M + H ]]+。
Compounds 6b-6d were prepared in analogy to Compound 6 a.
(6) Compound 7 a: preparation of 4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) -N-hydroxybenzamide
Compound 6a (0.18g, 0.32mmol) was added to 20mL ethyl acetate at 25 deg.C, 0.33mL ethyl acetate saturated with hydrogen chloride was added and stirring was continued for 1 hour, and after TLC monitoring of the reaction was complete, the reaction was filtered and dried under vacuum to give 0.13g white solid in 87% yield.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C22H26N6O4S[M+H]+471.1814,found 471.1810。
Compounds 7b-7d were prepared in analogy to compound 7 a.
(7) Compound 8 a: preparation of N- (2-aminophenyl) -4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzamide
Dissolving a compound 5a (0.23g, 0.50mmol) in 15mL of anhydrous N, N-dimethylformamide, adding O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (0.20g, 0.60mmol) and triethylamine (0.08g, 0.75mmol) at 0 ℃, continuing stirring and activating for 30 minutes after the addition is finished, adding O-phenylenediamine (0.08g, 0.75mmol), stirring and reacting at 25 ℃, pouring a reaction solution into a large amount of water after the TLC monitoring reaction is finished, extracting for 3 times by using ethyl acetate, and respectively using saturated NaHCO for an organic phase3And saturated NaCl solution 2-3 times, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated, purified by column chromatography (dichloromethane/methanol ═ 30:1), and dried in vacuo to give 0.10g of a yellow solid in 37% yield.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C28H31N7O3S[M+H]+546.2287,found 546.2280.
Compound 8b was prepared in analogy to compound 8 a.
(8) Intermediate 9 a: (E) preparation of ethyl (E) -3- (4- ((4- ((3- (N- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylate
Compound 4a (0.27g, 0.76mmol) and ethyl p-aminocinnamate (0.13g, 0.69mmol) were added to 10mL of isobutanol, 53. mu.L of concentrated hydrochloric acid was added, and after the addition was completed, reaction was carried out at 100 ℃ for 4 hours, and after completion of the reaction, the reaction mixture was allowed to stand to room temperature, filtered, and vacuum-dried to obtain 0.25g of a white solid with a yield of 71%. ESI-MS, M/z 510.40[ M + H ]]+。
Intermediate 9b was prepared in analogy to compound 9 a.
(9) Compound 10 a: (E) preparation of (E) -3- (4- ((4- ((3- (N- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) -N-hydroxyacrylamide
Compound 9a (0.20g, 0.39mmol) was added to 8mL of freshly prepared hydroxylamine potassium in methanol at 25 ℃ and the reaction stirred for 2 hours at 25 ℃, after completion of the reaction, the reaction was concentrated, the pH of the solution was adjusted to 6 with 1M hydrochloric acid, the precipitated solid was filtered, the resulting solid was slurried with ethyl acetate, filtered and dried under vacuum to give 0.13g of an off-white solid in 68% yield.1H NMR(600MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C24H28N6O4S[M+H]+497.1971,found 497.1973。
(10) Compound 10 b: (E) preparation of (E) -3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-chloropyrimidin-2-yl) amino) phenyl) acrylic acid
Compound 9b (0.20g, 0.38mmol) was dissolved in a mixed solvent of 15mL tetrahydrofuran, methanol and water (v: v: v ═ 1:1:1) at 25 ℃, lithium hydroxide (0.16g, 3.77mmol) was added, the reaction was heated at 60 ℃ for 1 hour, and the reaction was monitored by TLCAfter completion, the reaction solution was concentrated, the pH of the solution was adjusted to 4 to 5 with 1M hydrochloric acid, and the resulting solid was filtered and dried in vacuo to give 0.16g of a pale yellow solid in 85% yield. ESI-MS, M/z 502.19[ M + H ]]+。
Example 2, preparation of compounds 20a-20d, 20e-20f and 22, exemplified by compounds 20a, 20e and 22, respectively, the specific steps are as follows:
(1) intermediate 15: preparation of 1- (2- (4-nitrophenoxy) ethyl) pyrrolidine
P-nitrophenol (0.70g, 5.0mmol) was dissolved in 20mL of anhydrous N, N-dimethylformamide, and Compound 1(0.86g, 5.0mmol) and Cs were added2CO3(2.4g, 7.5mmol), reacting at 100 deg.C for 4 hours under nitrogen protection, monitoring by TLC, standing the reaction solution to room temperature, filtering, adding the filtrate into appropriate amount of ice water, extracting with ethyl acetate, and collecting the organic phase with saturated Na2CO3And NaCl solution, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 0.40g of a brown yellow 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(0.75g, 3.17mmol) was dissolved in 50mL of anhydrous methanol, 10% palladium on carbon was added, and the reaction solution was stirred in H2Then, the reaction was carried out at room temperature for 12 hours, and after the completion of the TLC monitoring, palladium on carbon was removed by filtration through celite, and the solvent was distilled off and dried to obtain 0.65g of a yellow oily substance with a yield of 98%.
(3) Intermediate 18 a: preparation of methyl 4- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzoate
0.55g of an off-white solid, yield 64%.1H NMR(400MHz,DMSO-d6)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]-。
Intermediates 18a-18f were prepared analogously to compound 4 a.
(4) Intermediate 19 a: preparation of methyl 4- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzoate hydrochloride
Compound 18a (0.25g, 0.90mmol) and compound 16(0.20g, 0.97mmol) were added to 10mL of isopropanol at 25 ℃, concentrated hydrochloric acid (90 μ L,1.08mmol) was added, and after completion of the addition, the reaction was heated at 85 ℃ for 4 hours, and after completion of the TLC monitoring reaction, 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 under vacuum to give 0.26g of an off-white solid in 65% yield. ESI-MS, M/z 448.24[ M + H ]]+。
Intermediates 19b-19f were prepared analogously to compound 19a
(5) Compound 20 a: preparation of N-hydroxy-4- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzamide
Compound 19a (0.09g, 0.2mmol) was added to 5mL of freshly prepared methanolic hydroxylamine potassium solution at 25 ℃ and the reaction was continued for 1.5 hours at 25 ℃ after completion of the addition, and after monitoring by TLC, the reaction was concentrated and the pH of the solution was adjusted to 7-8 with 1M hydrochloric acid to precipitate a solid which was filtered and dried in vacuo to give 15mg of a yellow solid in 17% yield. And Mp: 144 ℃ and 146 ℃.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C24H28N6O3[M+H]+449.2301,found 449.2299。
Compounds 20b-20d were prepared in a similar manner to compound 20 a.
(6) Compound 20 e: 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 a yellow solid, 50% yield.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C30H33N7O2[M+H]+524.2774,found 524.2771。
Compounds 20e-20f were prepared in analogy 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 an off-white solid, yield 97%.1H NMR(400MHz,DMSO-d6)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 was prepared analogously 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%.1H NMR(400MHz,DMSO-d6)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 C27H35N7O2[M+H]+490.2930,found 490.2928。
Compound 22 was prepared similarly to compound 13 a.
The preparation method of the compound 31, 32, 35 and 37 in the embodiment 3 comprises the following steps:
(1) intermediate 24: preparation of tert-butyl (4-chloro-3-nitrophenyl) carbamate
Compound 23(1.72g, 10.00mmol) was added to 15mL t-butanol at 25 deg.C, followed by addition of (Boc)2O (2.40g, 11.00mmol), added, reacted at 60 ℃ for 15 hours, concentrated, and the crude product 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 tert-butyl (3-amino-4-chlorophenyl) carbamate
Compound 24(1.00g, 3.67mmol), ferric trichloride (0.10g, 0.37mmol) and activated carbon (0.5g) were added to 30mL of methanol at 25 ℃, after refluxing for 10 minutes, 80% hydrazine hydrate (734 μ L,14.68mmol) was slowly added, after the completion of the refluxing, the refluxing was continued, after TLC monitoring reaction 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 order, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and dried under vacuum to obtain 0.73g of a white solid at a yield of 85%.
(3) Intermediate 26: preparation of tert-butyl (3- ((tert-butylsulfinyl) amino) -4-chlorophenyl) carbamate
Tert-butylsulfinyl chloride (0.25mL, 2.00mmol) and compound 25(0.49g, 2.00mmol) were dissolved in 2mL and 3mL of pyridine, respectively, at 0 ℃, the pyridine solution of tert-butylsulfinyl chloride was slowly added dropwise to the pyridine solution of compound 25, after the addition was completed, the reaction was continued at 0 ℃, after the TLC monitoring reaction was completed, ethyl acetate was added to the reaction solution, washed with 1M hydrochloric acid and saturated NaCl solution in order for 2 times, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate ═ 5:1) to obtain 0.42g of a pale yellow solid with a yield of 61%.
(4) Intermediate 27: preparation of tert-butyl (4-chloro-3- (((1, 1-dimethylethyl) sulfonamido) phenyl) carbamate
Compound 26(0.80g, 2.31mmol) was dissolved in 15mL of dichloromethane at 25 deg.C, 85% m-CPBA (0.42g, 2.42mmol) was added, the reaction was stirred for 4 hours, and TLC was used to monitor the completion of the reactionWith saturated Na2CO3The 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 yellow solid in 72% yield.
(5) Intermediate 28: preparation of N- (5-amino-2-chlorophenyl) -2-methylpropane-2-sulfonamide
Compound 27(0.60g, 1.65mmol) was dissolved in 4mL of dichloromethane, 4mL of trifluoroacetic acid was added thereto, and after the addition was completed, the reaction was stirred at 25 ℃ for 1 hour, and after the completion of the reaction, saturated Na was added thereto2CO3Adjusting the pH of the reaction solution to be more than 7, adding 20mL of dichloromethane into the reaction solution, and adding saturated Na2CO3And NaCl solution were washed 2 times in sequence, and 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.1H NMR(400MHz,DMSO-d6)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 was prepared analogously to compound 4 a.
(7) Intermediate 30: preparation of 4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamido) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzoic acid
Compound 29(0.30g, 0.77mmol) and p-aminobenzoic acid (0.12g, 0.85mmol) were added to 15mL of isobutanol at 25 ℃, concentrated hydrochloric acid (96.70 μ L, 1.16mmol) was added, the reaction was completed at 100 ℃ for 6 hours, after the reaction was completed, the mixture was allowed to stand to room temperature, filtered, and the filter cake was washed with isobutanol 2 times and dried under vacuum to obtain 0.25g of a white solid with a yield of 66%.
(8) Compound 31: preparation of 4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamido) phenyl) amino) -5-methylpyrimidin-2-yl) amino) -N-hydroxybenzamide
Dissolving compound 30(0.25g, 0.51mmol) in 10mL of N, N-dimethylformamide at 25 ℃, adding O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (0.25g, 0.76mmol) and triethylamine (107.0 muL, 0.76mmol), activating for 20 minutes after the addition is finished, adding O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (71.50mg, 0.61mmol), continuing stirring for reaction, after TLC monitoring reaction is finished, adding 100mL of water into the reaction solution, extracting with ethyl acetate, and using saturated Na for an organic phase2CO3And saturated NaCl for 2 times, and dried with anhydrous magnesium sulfate, filtered, and concentrated to obtain a white solid, which is dissolved with a small amount of ethyl acetate, 5mL of hydrogen chloride-saturated ethyl acetate is added, reacted at room temperature for 1 hour, filtered, and dried under vacuum, with a yield of 43%.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C22H25ClN6O4S[M+H]+505.1425,found 505.1410。
(9) Compound 32: preparation of N- (2-aminophenyl) -4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamido) phenyl) amino) -5-methylpyrimidin-2-yl) amino) benzamide
0.10g of a pale yellow solid, yield 38%.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C28H30ClN7O3S[M+H]+580.1898,found 580.1878。
Compound 32 was prepared analogously to compound 8 a.
(10) Intermediate 33: (E) preparation of ethyl (4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamido) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylate
0.23g of a pale yellow solid, yield 66%. ESI-MS, M/z 542.31[ M-H ]]-。
Intermediate 33 was prepared similarly to compound 30.
(11) Intermediate 34: (E) preparation of (E) -3- (4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamido) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) acrylic acid
80mg of an off-white solid, 39% yield. ESI-MS, M/z 516.35[ M + H ]]+。
Intermediate 34 was prepared similarly to compound 10 b.
(12) Compound 35: (E) preparation of (E) -3- (4- ((4- ((4-chloro-3- ((1, 1-dimethylethyl) sulfonamido) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenyl) -N-hydroxyacrylamide
45mg of a yellow solid, yield 63%.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C24H27ClN6O4S[M+H]+531.1581,found 531.1563。
Compound 35 was prepared analogously 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 a white solid, yield 66%.1H NMR(400MHz,DMSO-d6)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 analogously 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, yield 11%.1H NMR(400MHz,DMSO-d6)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 C25H32ClN7O3S[M+H]+546.2054,found 546.2008.
Compound 37 was prepared in analogy to compound 13 a.
Example 4, preparation of compounds 41a, 41b, 43 and 44, the specific procedure was as follows:
(1) intermediate 39 a: preparation method of 1-methyl-4- (4-nitrophenyl) piperazine
The reaction mixture of compound 38a (1.00g, 7.09mmol) and K2CO3(1.17g, 8.50mmol) was added to 15mL DMSO, stirred at 25 ℃ for 30 minutes, N-methylpiperazine (865.5. mu.L, 7.80mmol) was slowly added dropwise, the reaction was stirred further after the addition was completed, and after the reaction was monitored by TLC, the reaction solution was poured into a large amount of ice water to precipitate the product, which was filtered and dried in vacuo to give 1.50g of a yellow solid with a yield of 95%. ESI-MS, M/z 222.20[ M + H ]]+。
Intermediate 39b was prepared in analogy to compound 39 a.
(2) Intermediate 40 a: preparation of 4- (4-methylpiperazin-1-yl) aniline
0.42g of a purplish red solid, yield 61%. ESI-MS, M/z 192.20[ M + H ]]+。
Intermediates 40a and 40b were prepared in analogy to compound 3.
(3) Compound 41 a: preparation of N-hydroxy-4- ((5-methyl-2- (((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzamide
Adding the compound 40a (0.20g, 0.72mmol) and 18a (0.15g, 0.79mmol) into 10mL of isobutanol, adding 180. mu.L of concentrated hydrochloric acid, heating to react for 10 hours at 100 ℃, standing to room temperature, filtering to obtain a crude product, adding 5mL of freshly prepared hydroxylamine potassium methanol solution into the crude product, reacting for 1 hour at room temperature, filtering the reaction solution, concentrating, adjusting the pH value to 7 with 1M hydrochloric acid, precipitating the product, filtering, pulping with ethyl acetate, and filtering to obtain 60mg of a reddish brown solid with a yield of 19%.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)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 C23H28N7O2[M+H]+434.2304,found 434.2285。
Compound 41b was prepared in analogy 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
Adding compound 40a (0.20g, 0.72mmol) and 18a (0.15g, 0.79mmol) into 10mL of isobutanol, adding 149. mu.L of concentrated hydrochloric acid, heating at 100 ℃ for reaction, concentrating the reaction solution after the reaction is finished, adding water, and reacting with saturated NaHCO3The solution was adjusted to pH 8, extracted with ethyl acetate, the organic phase was washed with saturated NaCl 2 times, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product, which was slurried with a mixed solvent of petroleum ether and ethyl acetate to obtain 0.19g of a white solid, the obtained solid was dissolved in 15mL of a mixed solvent of methanol, water and tetrahydrofuran (v: v: 1:1:1), lithium hydroxide (0.19g, 4.44mmol) was added, the reaction was carried out at 60 ℃ for 1 hour, after the completion of the reaction, the reaction solution was concentrated, adjusted to pH 7 with 1M hydrochloric acid to precipitate the product, and filtered and dried under vacuum to obtain 0.16g of a white solid with a yield of 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, yield 56%.1H NMR(400MHz,DMSO-d6)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)。13C NMR(101MHz,DMSO-d6)δ165.29,159.30,158.41,156.58,156.47(d,1JCF＝241.0Hz),143.55,143.47,137.00(d,3JCF＝11.0Hz),133.70(d,3JCF＝9.0Hz),128.73,128.48,127.04,126.78,124.20,120.99,119.55(d,4JCF＝4.0Hz),116.84,116.73,114.98,107.43(d,2JCF＝26.0Hz,2C),106.85,55.27,50.96,50.93,46.26,14.01。HRMS(AP-ESI),calcd for C29H31FN8O[M+H]+527.2683,found 527.2665。
Compounds 43 and 44 were prepared in analogy to Compound 8 a.
Example 5 evaluation of in vitro HDAC inhibitory Activity of target Compounds
We tested the inhibitory activity of the target compounds on HDACs in vitro using Class I HDAC1 and Class II HDAC6 as enzyme sources, with the approved marketed non-selective HDAC inhibitor vorinostat (SAHA) as a positive control. Firstly, the inhibition rate of the target compound on HDAC1/6 under 0.5 mu M is tested, and partial compounds with better activity are selected according to the primary screening result to further test the IC of the target compound on HDAC1/650The value is obtained.
The experimental results (table 1) show that most of the target compounds of the present invention exhibit better HDAC inhibition. IC of Compound 7a on HDAC650A value of 52nM, comparable to the activity of the positive control SAHA; compounds 8a, 13a and 13c have good selectivity and inhibitory activity, IC, on HDAC150Values were 270nM, 122nM and 283nM, respectively; whileCompound 31 shows better inhibition activity, IC, on HDAC1/650Values were 402nM and 431nM, respectively.
TABLE 1 results of evaluation of HDAC inhibitory Activity in vitro
aInhibition rate @ 0.5. mu.M or IC50。IC50Values are expressed as mean ± SD values of three independent replicates.
Example 6 evaluation of target Compound in vitro JAK1 inhibitory Activity
We used a kinase luminescence assay to test the inhibitory activity of the target compound against JAK1, with the already marketed JAK inhibitor Ruxolitinib (Ruxolitinib) as a positive control. Firstly, the inhibition rate of a target compound on JAK1 at a concentration of 0.5 mu M is tested, then 14 target compounds are selected and further tested on the IC of JAK1 by comprehensively considering the inhibition activity of the compound on HDAC and JAK150The value is obtained.
The results of the experiment (table 2) show that most of the target compounds showed very good inhibitory activity against JAK 1. The inhibitory activity of the compounds 7a, 8a, 13a, 20a, 20c, 20e, 22 and 31 on JAK1 is better than or equal to that of phenanthratinib (Fedratinib), wherein the IC of the compound 7a on JAK150The value of 4.5nM is significantly better than that of Feratinib (Fedratinib).
TABLE 2 evaluation results of in vitro JAK1 inhibitory Activity
aInhibition rate @ 0.5. mu.M or IC50。IC50Values are expressed as mean ± SD values of three independent replicates.
Example 7 evaluation of in vitro BRD4 inhibitory Activity of target Compound
We tested the inhibitory activity of the target compound on BRD4 using homogeneous time-resolved fluorescence technique (HTRF), with phenanthroitinib (Fedratinib) as a positive control. The compounds of interest were first tested for inhibition of BRD4-BD1 at 10. mu.M, compounds with an inhibition of greater than 50% were further tested for IC50The value is obtained.
The experimental results (Table 3) show that most of the target compounds show certain inhibitory activity against BRD4-BD 1. The inhibitory activity of the compounds 20a, 22 and 31 on BRD4-BD1 is better than or equal to that of phenanthratinib (Fedratinib), wherein the compound 31 shows the best BRD4-BD1 inhibitory activity and IC50The value was 412 nM.
TABLE 3 evaluation results of in vitro BRD4 inhibitory Activity
aInhibition rate @ 10. mu.M or IC50。IC50Values are expressed as mean ± SD values of three independent replicates.
Example 8 in vitro antitumor cell proliferation assay
We used the more classical MTT method to test some of the target compounds for their antiproliferative activity against HEL and MDA-MB-231 cell lines.
The results of the experiment (Table 4) show that most of the selected compounds have good antiproliferative activity against both HEL and MDA-MB-231. The antiproliferative activity of compounds 8a, 8b and 32 on HEL was superior to the positive controls phenanthrotinib (Fedratinib) and ruxotinib (Ruxolitinib), while vorinostat (SAHA), a positive control, showed comparable antiproliferative activity. The antiproliferative activity of the compounds 8a, 13a, 20c and 31 on MDA-MB-231 is obviously better than that of positive controls vorinostat (SAHA) and ruxotinib (Ruxolitinib), and is equivalent to that of positive control phenanthratinib (Fedratinib).
TABLE 4 in vitro anti-tumor cell proliferation test results
aValues are expressed as mean ± SD values of three independent replicates.
Claims (8)
1. A three-target inhibitor of HDAC, JAK and BET having the structure shown in formula (I) or (II) below, and pharmaceutically acceptable salts, solvates or prodrugs thereof:
wherein: x is
Y is
R1Is hydrogen, various aliphatic hydrocarbon groups, various halogens;
R2is a six-membered aryl group, a para-substituted six-membered aryl group, a six-membered heteroaryl group, a para-substituted six-membered heteroaryl group;
R3is hexabasic aryl, para-substituted hexabasic aryl, hexabasic heteroaryl and para-substituted hexabasic heteroaryl.
2. The HDAC, JAK and BET triple-target inhibitor of claim 1, wherein:
x is
Y is
R1Is methyl, a chlorine atom;
R2is that
R3Is that
3. The HDAC, JAK and BET triple-target inhibitor according to claim 1 or 2, characterized by being one of the following compounds:
4. a process for the preparation of the HDAC, JAK and BET triple-target inhibitors according to claim 3, as shown in one of the following schemes:
taking a compound 1 as an initial raw material, reacting with tert-butylamine to obtain a compound 2, carrying out nitro reduction reaction on the compound 2 to obtain an intermediate 3, and carrying out nucleophilic substitution reaction on the intermediate 3 and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain key intermediates 4a-4 b; carrying out nucleophilic substitution reaction on the compounds 4a-4b and p-aminobenzoic acid or m-aminobenzoic acid under the catalysis of acid to obtain compounds 5a-5d, then carrying out amide condensation on the intermediates 5a-5d and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine to obtain intermediates 6a-6d, and then removing THP protective groups of the compounds 6a-6d under an acidic condition to obtain hydroxamic acid final products 7a-7 d; carrying out amide condensation on the compounds 5a and 5c and o-phenylenediamine to obtain o-phenylenediamine final products 8a-8 b; respectively carrying out acid-catalyzed nucleophilic substitution reaction on the compounds 4a-4b and ethyl p-aminocinnamate to obtain intermediates 9a-9b, reacting the intermediates 9a with a freshly prepared hydroxylamine potassium methanol solution to obtain a final product 10a, carrying out ester hydrolysis reaction and amide condensation reaction on the intermediate 9b, and finally removing THP protective groups under an acidic condition to obtain a final product 11 a; carrying out amide condensation on the compounds 5a-5d and hydrazine hydrate to obtain intermediates 12a-12d, and then carrying out reductive amination to obtain hydrazide final products 13a-13 d;
the synthesis route one is as follows:
reagents and reaction conditions in the above synthetic route: a) tert-butylamine, tetrahydrofuran, 25 ℃; b) refluxing palladium carbon, 80% hydrazine hydrate and ethanol; c)2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine, methanol and water, 45 ℃; d) refluxing 3-aminobenzoic acid or 4-ethyl amino cinnamate, concentrated hydrochloric acid and isopropanol; e) o- (tetrahydro-2H-pyran-2-yl) hydroxylamine, triethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, N-dimethylformamide, 25 ℃; f) hydrogen chloride saturated ethyl acetate; g) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; h) hydroxylamine potassium in methanol solution, 25 ℃; i) lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; j)1) O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) hydrogen chloride saturated ethyl acetate; k) 80% hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; l)1) propionaldehyde, magnesium sulfate, absolute ethanol, 25 ℃; 2) sodium cyanoborohydride or sodium borohydride, anhydrous methanol, 25 ℃;
(II) taking a compound 14 as a raw material, carrying out nucleophilic substitution reaction and nitro reduction reaction on the compound 14 and p-nitrophenol under an alkaline condition to obtain an intermediate 16, and carrying out nucleophilic substitution reaction on a compound 17a-17c and 2, 4-dichloro-5-methylpyrimidine or 2,4, 5-trichloropyrimidine to obtain a key intermediate 18a-18 f; the intermediates 18a-8f and the compound 16 are subjected to nucleophilic substitution under acid catalysis to obtain key intermediates 19a-19f, the intermediates 19a-19d react with a freshly prepared hydroxylamine potassium methanol solution to obtain hydroxamic acid final products 20a-20d, and the intermediates 19e-19f are subjected to condensation reaction with o-phenylenediamine to obtain o-phenylenediamine final products 20e-20 f; carrying out amide condensation on the compound 19e and hydrazine hydrate to obtain an intermediate 21, and then carrying out reductive amination to obtain a hydrazide final product 22;
the second synthetic 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 and water, 45 ℃; d) concentrated hydrochloric acid, isopropanol, 85 ℃ or concentrated hydrochloric acid, isobutanol, 100 ℃; e) hydroxylamine potassium methanol solution; f) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; g) 80% hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; h)1) propionaldehyde, magnesium sulfate, absolute ethyl alcohol, 25 ℃; 2) sodium borohydride, anhydrous methanol, 25 ℃;
(III) taking a compound 23 as an initial raw material, carrying out Boc anhydride protection amino group, nitro group reduction and tert-butyl sulfinyl chloride condensation reaction on the compound 23 to obtain a compound 26, and carrying out oxidation reaction, Boc protection group removal under an acidic condition and nucleophilic substitution reaction on 2, 4-dichloro-5-methylpyrimidine to obtain a compound 29; the compound 29 and p-aminobenzoic acid are subjected to nucleophilic substitution reaction under an acidic condition to obtain an intermediate 30, the intermediate 30 and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine are subjected to amide condensation on one hand, and a THP protective group is removed under an acidic condition to obtain a final product 31; on the other hand, the product is subjected to amide condensation with o-phenylenediamine to obtain a final product 32; the intermediate 29 and ethyl p-aminocinnamate are subjected to acid-mediated nucleophilic substitution reaction to obtain an intermediate 33, and then a final product 35 is obtained by ester hydrolysis reaction, amide condensation and THP protective group removal under an acidic condition; carrying out amide condensation on the compound 30 and hydrazine hydrate to obtain an intermediate 36, and then carrying out reductive amination to obtain a hydrazide final product 37;
the third synthetic route is as follows:
reagents and reaction conditions in the above synthetic route: a) di-tert-butyl dicarbonate, tert-butanol, 60 ℃; b) refluxing ferric trichloride, 80% hydrazine hydrate, activated carbon and methanol; c) tert-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-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃; 2) hydrogen chloride saturated ethyl acetate; i) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; j) ethyl 4-aminocinnamate, concentrated hydrochloric acid, isobutanol, 100 ℃; k) lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; l) 80% hydrazine hydrate, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, dichloromethane, 25 ℃; m)1) propionaldehyde, magnesium sulfate, absolute ethyl alcohol, 25 ℃; 2) sodium borohydride, anhydrous methanol, 25 ℃;
in the fourth step, the initial raw materials 38a-38b react with N-methyl piperazine under alkaline conditions, intermediates 40a-40b are obtained through nitro reduction, and after nucleophilic substitution reaction of the intermediates 40a-40b with the compound 18a under acidic conditions, on one hand, the intermediates react with hydroxylamine potassium methanol solution to obtain final products 41a-41 b; on the other hand, an ester hydrolysis reaction is carried out to obtain an intermediate 42, and the intermediate 42 and o-phenylenediamine and n-propylhydrazine hydrochloride respectively carry out amide condensation to obtain final products 43 and 44;
the synthesis route 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) hydroxylamine potassium in methanol solution, 25 ℃; d)1)18a, concentrated hydrochloric acid, isobutanol, 100 ℃; 2) lithium hydroxide, tetrahydrofuran, methanol, water, 60 ℃; e) o-phenylenediamine, O-benzotriazole-N, N' -tetramethyluronium tetrafluoroborate, triethylamine, N-dimethylformamide, 25 ℃; f) n-propyl hydrazine hydrochloride, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, triethylamine, N, N-dimethylformamide, 25 ℃.
5. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for the prevention or treatment of a disease associated with aberrant HDAC, JAK and BET activity or expression.
6. The disease associated with aberrant HDAC, JAK and BET activity or expression according to claim 5 is a variety of hematological, solid or autoimmune diseases.
7. The hematological or solid tumor of claim 6, which is myelofibrosis, melanoma, multiple myeloma, cutaneous T cell lymphoma, human erythroleukemia, human chronic myelogenous leukemia, breast cancer, pancreatic cancer, gastric cancer, lung cancer, rectal cancer, colon cancer, or prostate cancer; the autoimmune disease is rheumatoid arthritis or inflammation.
8. A pharmaceutical composition suitable for oral or parenteral administration comprising a triple-target inhibitor of HDAC, JAK and BET as claimed in any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113831338A (en) * | 2021-09-20 | 2021-12-24 | 中国海洋大学 | Histone deacetylase inhibitor and preparation method and application thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626742A (en) * | 2005-11-01 | 2014-03-12 | 塔格根公司 | Bi-aryl meta-pyrimidine inhibitors of kinases |
| CN105017159A (en) * | 2014-04-28 | 2015-11-04 | 四川大学 | 5-fluorine-2,4-bis-substituted aminopyrimidine derivative and preparation method and application thereof |
| WO2016022460A1 (en) * | 2014-08-03 | 2016-02-11 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Potent dual brd4-kinase inhibitors as cancer therapeutics |
| WO2017066428A1 (en) * | 2015-10-13 | 2017-04-20 | H. Lee Moffitt Cancer Center & Research Institute, Inc. | Brd4-kinase inhibitors as cancer therapeutics |
| WO2019242689A1 (en) * | 2018-06-22 | 2019-12-26 | 北京赛特明强医药科技有限公司 | Cyano-substituted pyridine and cyano-substituted pyrimidine compound, and preparation method and application thereof |
-
2020
- 2020-06-05 CN CN202010503272.9A patent/CN113754591B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626742A (en) * | 2005-11-01 | 2014-03-12 | 塔格根公司 | Bi-aryl meta-pyrimidine inhibitors of kinases |
| CN105017159A (en) * | 2014-04-28 | 2015-11-04 | 四川大学 | 5-fluorine-2,4-bis-substituted aminopyrimidine derivative and preparation method and application thereof |
| WO2016022460A1 (en) * | 2014-08-03 | 2016-02-11 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Potent dual brd4-kinase inhibitors as cancer therapeutics |
| WO2017066428A1 (en) * | 2015-10-13 | 2017-04-20 | H. Lee Moffitt Cancer Center & Research Institute, Inc. | Brd4-kinase inhibitors as cancer therapeutics |
| WO2019242689A1 (en) * | 2018-06-22 | 2019-12-26 | 北京赛特明强医药科技有限公司 | Cyano-substituted pyridine and cyano-substituted pyrimidine compound, and preparation method and application thereof |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113831338A (en) * | 2021-09-20 | 2021-12-24 | 中国海洋大学 | Histone deacetylase inhibitor and preparation method and application thereof |
| CN113831338B (en) * | 2021-09-20 | 2022-12-20 | 中国海洋大学 | Histone deacetylase inhibitor and preparation method and application thereof |
| WO2023121251A1 (en) * | 2021-12-21 | 2023-06-29 | 한국원자력의학원 | Egfr and hdac dual inhibitor compounds and medical use thereof |
| CN114031559A (en) * | 2021-12-28 | 2022-02-11 | 南通大学 | Aryl nitrogen-containing heterocycle modified 5-fluoro-pyrimidinediamine benzoate and preparation method and application thereof |
| CN114181160A (en) * | 2021-12-28 | 2022-03-15 | 南通大学 | 2, 4-dianilinopyrimidine-containing hydrazide derivative and preparation method and application thereof |
| CN114181159A (en) * | 2021-12-28 | 2022-03-15 | 南通大学 | Hydrazide derivative containing 2,4, 5-trisubstituted pyrimidine, preparation method and application thereof |
| CN114230524A (en) * | 2021-12-28 | 2022-03-25 | 南通大学 | (5-fluoro-2-anilinopyrimidin-4-yl) amino-N-hydroxybenzamide derivative and preparation method and application thereof |
| CN114181159B (en) * | 2021-12-28 | 2024-02-20 | 南通大学 | 2,4, 5-trisubstituted pyrimidine hydrazide derivative and preparation method and application thereof |
| WO2023166153A1 (en) * | 2022-03-02 | 2023-09-07 | Bash Biotech Inc | New compounds and treatment of renal cell carcinoma |
| WO2023185667A1 (en) * | 2022-03-30 | 2023-10-05 | 山东大学 | Hdac11 subtype selective inhibitor, and preparation method therefor and use thereof |
| CN115286583A (en) * | 2022-08-10 | 2022-11-04 | 山东大学 | Diphenylaminopyrimidine-containing compound, preparation and application thereof as HDACs enzyme inhibitor |
| CN115286583B (en) * | 2022-08-10 | 2024-01-30 | 山东大学 | Diphenylamino pyrimidine-containing compound, preparation and application thereof as HDACs enzyme inhibitor |
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