CN111039875A - HDAC/ALK double-target-point inhibitor and preparation method and application thereof - Google Patents
HDAC/ALK double-target-point inhibitor and preparation method and application thereof Download PDFInfo
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- 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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Abstract
The invention belongs to the field of medicinal chemistry, and particularly relates to an HDAC/ALK double-target inhibitor, a preparation method and an application thereof, wherein the HDAC/ALK double-target inhibitor has a structure shown in a formula I, has good inhibitory activity on HDAC and ALK kinase, has stronger inhibitory activity on HepG2 liver cancer cells than that of the conventional liver cancer resistant medicament Sorafenib at the micromolar level.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an HDAC/ALK double-target inhibitor, and a preparation method and application thereof.
Technical Field
Studies have shown that the development of various tumors is closely related to the abnormal expression and activation of Histone Deacetylases (HDACs). Generally, histone acetylation level and gene transcription activity show positive correlation, and the whole genome protein acetylation level of tumor cells is generally reduced. The histone deacetylase inhibitor can promote the transcription expression of cancer suppressor genes by increasing the acetylation degree of intracellular histone, induce the differentiation or death of tumor cells to achieve the anti-tumor effect, and various histone deacetylase inhibitors are on the market at present.
Anaplastic Lymphoma Kinase (ALK) is a receptor-type protein tyrosine phosphokinase, and is also closely related to the development of various tumors. Among them, the incidence of EML4-ALK fusion (also known as ALK positive mutation) in non-small cell lung cancer (NSCLC) is about 3% to 7%, and the expression rate in adenocarcinoma patients without EGFR mutation or KRas mutation is about 42.8%. Therefore, the mutation and abnormal activity of ALK in various cancers become a drug target for treating ALK positive cancers, and various ALK inhibitors such as crizotinib and ceritinib are currently marketed.
Recently, a plurality of research results show that the combination of HDAC and ALK inhibitor can synergistically enhance the inhibitory activity of ALK inhibitor on tumors such as non-small cell lung cancer, neuroblast cancer and the like, simultaneously improve the sensitivity of ALK inhibitor on drug-resistant cells and reverse the drug resistance of ALK inhibitor. However, potential interactions between different drugs in a combination, as well as differences in pharmacokinetic properties, may reduce efficacy and increase toxicity. The development of multi-target drugs is expected to solve the problems of insensitivity and drug resistance of tumors to single-target drugs and avoid the problems of drug interaction and the like caused by drug combination. At present, no HDAC/ALK double-target inhibitor is reported, so that research and development of a novel HDAC/ALK double-target inhibitor have important application prospects and significance.
Disclosure of Invention
One object of the present invention is to provide a compound capable of simultaneously inhibiting an HDAC target and an ALK target, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the general formula of the compound is shown in formula I:
a second object of the present invention is to provide a process for preparing the compound of formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
The third object of the present invention is to provide a composition comprising the compound of formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier, and a composition comprising the compound of formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another one or more antitumor compositions.
The fourth purpose of the invention is to provide the application of the compound of the general formula I or the pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof in preparing the medicine for preventing and/or treating tumors.
In order to achieve the purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
wherein the content of the first and second substances,
R1selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, and haloalkyl;
R2selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, hydroxy, amino, carboxy, cyano, nitro, cycloalkyl, heterocycloalkyl;
m is selected from 0, 1, 2, 3 and 4;
R3aand R3bIndependently selected from hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, hydroxy, amino, carboxy, cyano, nitro, cycloalkyl, heterocycloalkyl;
R4selected from halogenElements, alkyl, alkoxy, alkoxyalkyl, hydroxy, amino, carboxy, cyano, nitro, cycloalkyl, heterocycloalkyl;
n is selected from 0, 1, 2, 3 and 4;
l is selected from a bond and alkylene;
k is selected from the group consisting of a bond, alkylene, alkenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl, said alkylene, alkenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl groups may be substituted with one or more alkyl, halo, alkoxy, hydroxy, amino, carboxy, cyano and nitro groups, said p being selected from an integer from 1 to 8;
R5and R6Independently selected from hydrogen, hydroxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, which aryl, heteroaryl, cycloalkyl, heterocycloalkyl may be substituted with one or more amino, hydroxyl, carboxyl, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, alkylamino, alkanoylamino, amido, ester, acyl, alkanoyl, alkylaminoacyl, aryl, heteroaryl groups.
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is1Is selected from C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl and halogeno C1-6An alkyl group; further preferably, R1Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, trichloromethyl, trifluoromethyl; even more preferably, R1Is isopropyl.
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is2Selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl, m is selected from 0, 1, 2, 3 and 4; further preferably, R2Selected from halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl, hydroxy, amino, carboxyl, cyano, nitro, m is selected from 0, 1, 2 and 3; even more preferably, R2Is halogen, m is selected from 0 and 1; even more preferably, m is 0.
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is3aAnd R3bIndependently selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8A heterocycloalkyl group; further preferably, R3aAnd R3bIndependently selected from hydrogen, halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8A heterocycloalkyl group; even more preferably, R3aAnd R3bIndependently selected from hydrogen, fluorine, chlorine, bromine and iodine.
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is4Selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl, n is selected from 0 and 1; further preferably, R4Selected from halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl and n is selected from 0 and 1, more preferably n is 0.
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein L is selected from the group consisting of a bond, methylene, ethylene, propylene, isopropylene; further preferably, L is selected from a bond and methylene.
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein K is selected from the group consisting of a bond, methylene, ethylene, propylene, isopropylene, vinylene, propenylene, butenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-phenyl and heteroaryl, said p being selected from the group consisting of integers of 1 to 6, said methylene, ethylene, propylene, isopropylene, vinylene, propenylene, butenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-, phenyl and heteroaryl groups may be substituted by one or more C1-6Alkyl, halogen, C1-6Alkoxy, hydroxy, amino, carboxyl, cyano and nitro substitution; further preferably, K is selected from the group consisting of a bond, methylene, ethylene, ethenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-is selected from the integer of 1-6, the methylene, the ethylene, the ethenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-may be substituted by one or more C1-6Alkyl, halogen, C1-6Alkoxy, hydroxy, amino, carboxyl, cyano and nitro substitution; even more preferably, K is selected from the group consisting of a bond, vinylidene, -NH-C (O) - (CH)2)5-、-NH-C(O)-(CH2)6-、-C(O)-NH-(CH2)5-、-C(O)-NH-(CH2)6-。
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is5And R6Independently selected from hydrogen, hydroxy, benzene, naphthalene, nitrogen heteroaryl, sulfur heteroaryl, oxygen heteroaryl, nitrogen sulfur heteroaryl, oxygen sulfur heteroaryl, nitrogen oxygen heteroaryl, C3-8Cycloalkyl, hetero C3-8Cycloalkyl, said benzene, naphthalene, azaaryl, thiaaryl, oxaaryl, azathiaaryl, oxathiaaryl, C3-8Cycloalkyl, hetero C3-8Cycloalkyl groups may be substituted by one or more amino, hydroxy, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy C1-6Alkyl, halogen, halogeno C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkylamide, amide, ester, acyl, C1-6Alkanoyl radical, C1-6Alkyl amino acyl, aryl, heteroaryl substituted; further preferably, R5Is hydrogen, R6Selected from the group consisting of hydroxy, benzene, naphthalene, azaaryl, thiaaryl, oxaaryl, thiaheteroaryl, oxathiaaryl, and said benzene, naphthalene, azaaryl, oxathiaaryl, and said benzene, naphthalene, thiaaryl, oxathiaaryl, and said benzene, naphthalene, and said1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy C1-6Alkyl, halogen, halogeno C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkylamide, amide, ester, acyl, C1-6Alkanoyl radical, C1-6Alkyl amino acyl, aryl, heteroaryl substituted; even more preferably, R5Is hydrogen, R6Selected from hydroxyl and benzene, said benzene may be substituted by one or more of amino, hydroxyl, carboxyl, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy C1-3Alkyl, halogen, halogeno C1-3Alkyl radical, C1-3Alkylamino radical, C1-3Alkylamide, amide, ester, acyl, C1-3Alkanoyl radical, C1-3Alkyl amino acyl, aryl, heteroaryl substituted.
In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the structure of the compound of formula I is shown in formula Ia:
R1is isopropyl;
R3aselected from fluorine, chlorine, bromine andiodine;
R3bis hydrogen;
l is selected from a bond and methylene;
k is selected from the group consisting of a bond, vinylidene, -NH-C (O) - (CH)2)5-、-NH-C(O)-(CH2)6-、-C(O)-NH-(CH2)5-、-C(O)-NH-(CH2)6-；
R5Is hydrogen;
R6selected from hydroxyl and benzene, said benzene may be substituted by one or more of amino, hydroxyl, carboxyl, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy C1-3Alkyl, halogen, halogeno C1-3Alkyl radical, C1-3Alkylamino radical, C1-3Alkylamide, amide, ester, acyl, C1-3Alkanoyl radical, C1-3Alkyl amino acyl, aryl, heteroaryl substituted.
The present invention provides the following specific compounds:
in a second aspect, the present invention provides a process for the preparation of the compounds of formula I of the present invention. The preparation method of the compound of the general formula I comprises the following steps:
step 1: reacting a compound of formula A with a compound of formula B to produce a compound of formula C;
step 2: reacting the compound of formula C with a substituted hydroxylamine to produce a compound of formula I;
wherein R is1、R2、m、R3a、R3b、R4、n、L、K、R5And R6Has the same meaning as I.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
In some embodiments, the present invention provides pharmaceutical compositions comprising a compound, isomer, solvate, crystal or prodrug of formula I or formula Ia of the present invention, further comprising one or more compounds selected from the group consisting of: IDH1 inhibitors, IDH2 inhibitors, tyrosine protease inhibitors, EGFR inhibitors, VEGFR inhibitors, Bcr-Abl inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies, HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.
The compounds, isomers, solvates, crystals or prodrugs of formula I or formula Ia of the present invention may be formulated in pharmaceutical formulations suitable for oral or parenteral administration in admixture with a pharmaceutically acceptable carrier, diluent or excipient. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides a method for treating and/or preventing tumors by using the compound, isomer, solvate, crystal or prodrug of formula I or formula Ia of the present invention or the pharmaceutical composition of the present invention, and an application in preparing a medicament for treating and/or preventing tumors, comprising administering the compound, isomer, solvate, crystal or prodrug of the present invention or the pharmaceutical composition comprising the compound, isomer, solvate, crystal or prodrug of the present invention to a population prone to tumor or a patient suffering from tumor, so as to effectively reduce the incidence of tumors and prolong the life of the patient suffering from tumor.
In some embodiments, the present invention provides a method of treating a drug resistant tumor by administering to a patient having a drug resistant tumor a therapeutically effective amount of a compound of formula I or formula Ia, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition comprising a compound of formula I or formula Ia, isomer, solvate, crystal or prodrug of the present invention. In other embodiments, the present invention provides the use of a compound of formula I or formula Ia, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention for the preparation of a medicament for the treatment of a drug resistant tumor. The tumors include but are not limited to solid tumors, preferably lung cancer, head and neck tumor, colorectal cancer, bladder cancer, pancreatic cancer, breast cancer, prostate cancer, stomach cancer, oral cancer, liver cancer, ovarian cancer; further preferably, the tumor is ceritinib non-small cell lung cancer.
Description of the terms
The "alkyl group" in the present invention means a straight or branched saturated hydrocarbon group. Suitable alkyl groups are substituted or unsubstituted C1-10Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl and the like.
The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
"alkoxy" in the context of the present invention means-O-alkyl. According to the invention, suitable alkoxy is C1-10Alkoxy radicals, e.g. C1-8Alkoxy radical, C1-7Alkoxy radical, C1-6Alkoxy radical, C1-5Alkoxy radical, C1-4Alkoxy radical, C1-3Alkoxy radicals including methoxy, ethoxy, propoxy, isopropoxy, isobutoxyAnd s-butoxy, and the like.
The "halogen" in the present invention means fluorine, chlorine, bromine and iodine.
"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.
The "aryl" of the present invention refers to an aromatic system which may comprise a single or multiple condensed rings such as bicyclic or tricyclic aromatic rings, wherein at least a portion of the condensed rings form a conjugated aromatic system containing 5 to 50 carbon atoms, preferably about 6 to about 14 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl.
The term "heteroaryl" as used herein refers to an aromatic group having at least one carbon atom of an aromatic monocyclic or polycyclic ring such as bicyclic or tricyclic ring replaced by a heteroatom, said heteroatom being O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridinyl, quinazolinyl, pyrrolyl, imidazolonyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, and the like.
The "alkylene group" of the present invention means a straight or branched divalent group having 1 to 6 carbon atoms.
"alkenylene" in the present invention means a straight or branched divalent group containing 2 to 6 carbon atoms and 1 to 3 double bonds.
"Alkanoylamino" as used herein refers to an alkyl-C (O) -NH-.
The "amido" in the present invention means C (O) H-NH-.
"alkanoyl" in the context of the present invention is intended to mean alkyl-C (O) -.
"Alkylcarbamoyl" according to the present invention means alkyl-NH-C (O) -or alkyl-N (alkyl) -C (O) -.
"solvate" in the present invention refers in the conventional sense to a complex formed by the combination of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water). Solvent means a solvent known or readily determined by one skilled in the art. In the case of water, the solvate is often referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, and the like.
The term "crystalline" as used herein refers to the various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
"isomers" in the present invention refer to stereoisomers produced by spatially different arrangements of atoms in a molecule, including enantiomers and diastereomers.
The "prodrug" of the present invention refers to a compound which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions of an organism, that is, a compound which is converted into a compound of the present invention by oxidation, reduction, hydrolysis or the like by an enzyme and/or a compound which is converted into a compound of the present invention by a hydrolysis reaction of gastric acid or the like.
The "pharmaceutically acceptable salt" of the present invention refers to a pharmaceutically acceptable salt of a compound of the present invention with an acid, including, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, and the like.
The "pharmaceutical composition" of the present invention is intended to include a mixture of any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts, or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers.
By "pharmaceutically acceptable carrier" herein is meant a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes solvents, diluents or other excipients, dispersants, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, and cellulose acetate; malt, gelatin, and the like.
"excipient" in the context of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
Experimental example 1 cell proliferation inhibitory Activity test
The experiment is provided with a solvent control group and a drug experiment group, each group of the drug experiment group is provided with 4 concentrations, and each concentration is provided with 3 parallel holes. Each experiment was repeated three times. In 96-well plates, cells were added at a concentration of 1X 10 per well5Cell suspension 100. mu.L/mL, i.e., 1X 10 cells per well4In addition, care was taken to distribute the cells evenly throughout the wells during seeding. To prevent evaporation of the liquid, one round of wells around the 96-well plate were not seeded with cells and PBS was added for moisturizing. After the cells are attached to the wall, 100. mu.L of the target compound is added to each well of the drug test group at concentrations of 0, 4, 8, 12 and 16. mu.g/mL to give final concentrations of 0, 2,4, 6 and 8. mu.g/mL, respectively. Placing 96-well plate at 37 deg.C and 5% CO2The cultivation is continued in the incubator, and the cultivation is terminated after 72 h. After the cells are treated by the drug for 72 hours, the 96-well plate is taken out, 20 mu L of CCK-8 solution is added into each well, and after the incubation is continued for 0.5 to 4 hours in a cell incubator, the absorbance value (A) of each well is measured at 450nm on an automatic microplate reader. In the preliminary experiment, detection is carried out by a microplate reader after 0.5 hour, 1 hour, 2 hours and 4 hours, and a time point (2 hours) with a more appropriate absorbance range is selected for subsequent experiments.
The growth inhibition of tumor cells by different drug concentrations was calculated as follows:
performing linear regression analysis on the concentration of the drug by using the inhibition rate, and calculating IC by using a linear equation50The value is obtained. The detection result is expressed by mean +/-standard deviation, the experimental result is statistically analyzed by SPSS15.0 software, and P is used<0.05 indicated a significant difference. The results are shown in Table 1
TABLE 1 proliferation inhibitory Activity of test Compounds against human HepG2, A549, NCI-H2228 tumor cells
"-" not tested
The results in Table 1 show that the compounds I-1, I-3 and I-5 have stronger inhibitory activity on human liver cancer HepG2 cells, are equivalent to the conventional anti-liver cancer medicament Sorafenib at the micromolar level. The compounds I-1 and I-3 also have inhibitory activity on EGFR-mutated lung cancer A549 tumor cell strains, and are equivalent to ceritinib. The inhibition activity of the target compound I-3 on the lung cancer cell strain NCI-H2228 with ALK positive mutation is better than that of positive control ceritinib.
EXPERIMENTAL EXAMPLE 2HDAC/ALK enzyme inhibitory Activity assay
Setting positive control holes and negative control holes in a 384-hole reaction plate, adding compounds and enzymes with different concentrations into each other hole, centrifuging, incubating for 15min at room temperature, adding a fluorescent substrate and a stop solution, continuously reading a fluorescent signal by using Synergy, and selecting a linear reaction section by using Synergy to obtain a slope (slope). And further calculating the percentage inhibition rate, wherein the calculation formula is as follows: the enzyme inhibition rate (Mean (max) -sample signal/Mean (max) -blank times 100%, the log value of the compound concentration is taken as the X axis, the corresponding percent inhibition rate is taken as the Y axis, and the analysis software GraphPad Prism 5 is used for fitting a dose-effect curve, so as to obtain the IC of each compound for inhibiting the enzyme activity50The value is obtained. The ALK enzyme inhibitory activity method is similar to the HDAC enzyme inhibitory method. The results are shown in Table 2
TABLE 2 inhibition of HDAC and ALK kinase by test compounds at 10nM and 1000nM concentrations
"-" not tested
The results show that some compounds have strong inhibitory activity on both ALK wild type and mutant kinase and HDAC 1. Among them, the compound I-6 showed a strong double-target inhibitory activity against HDAC1 wild-type kinase at 93 nM and ALK kinase at 10nM, respectively.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
EXAMPLE 1 preparation of N- (2-aminophenyl) -4- [ 5-chloro-4- [2- (propane-2-sulfonyl) -phenylamino ] pyrimidin-2-ylamino ] benzamide (I-1)
Step 1: preparation of methyl 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] benzoate
N- [ (2-isopropylsulfonyl) phenyl ] -2, 5-dichloro-pyrimidin-4-amine (1.0g) and methyl 4-aminobenzoate (0.43g) were weighed into a 50ml eggplant-shaped flask, 10ml of isopropanol and 0.1ml of HCl solution (37%) were added thereto, the reaction was stirred with heating at 90 ℃ and the disappearance of the starting materials was monitored by TLC. The reaction was stopped. After cooling to room temperature, 30ml of cold water was added, extraction was performed with ethyl acetate, and the organic layers were combined, washed with saturated brine 2 times and dried over anhydrous sodium sulfate overnight. Filtering, collecting filtrate, concentrating under reduced pressure to obtain 1.12g crude product, recrystallizing with methanol/water, and precipitating 0.83g white crystal with yield of 72%.
Step 2: preparation of 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] benzoic acid
Methyl 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] benzoate (2.3g) was weighed into a 100ml eggplant-shaped bottle, and 0.6g of an aqueous sodium hydroxide solution (30ml) and 10ml of anhydrous ethanol were added thereto, followed by stirring at 50 ℃ for reaction for 3 hours. TLC monitored the disappearance of starting material. The reaction was stopped. The pH was adjusted to weak acidity with concentrated hydrochloric acid and a white solid precipitated. The solid was filtered by suction and the filter cake was washed with water to give 1.8g of a white powder with a yield of 82%.
And step 3: preparation of N- (2-aminophenyl) -4- [ 5-chloro-4- [2- (propane-2-sulfonyl) -phenylamino ] pyrimidin-2-ylamino ] benzamide (I-1)
Weighing 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl]Amino group]Pyrimidin-2-yl]Amino group]Benzoic acid (0.54g), HOBT (0.18g), EDCI (0.27g), DIEA (0.3g) in 50ml eggplant-shaped flask, 20ml dichloromethane were added, and after stirring reaction at 30 ℃ for 0.5h, o-phenylenediamine (0.13g) was added and the reaction was continued for 18 h.TLC monitored the disappearance of starting material. The reaction was stopped. 40ml of cold water was added, extraction was performed with methylene chloride, and organic layers were combined and washed with saturated brine 2 times and dried over anhydrous sodium sulfate overnight. Filtering, collecting filtrate, concentrating under reduced pressure, and separating by column chromatography (eluent: petroleum ether: ethyl acetate: 1) to obtain 0.4g white powder with yield of 61.2%. m.p.164-166 ℃.1H NMR(600MHz,DMSO)(δ,ppm):δ9.90(s,1H),9.51(d,2H),8.58(s,1H),8.37(s,1H),7.81-7.92(m,4H),7.76(d,2H),7.45(t,1H),7.15(d,1H),6.86-7.02(m,1H),6.79(d,1H),6.61(t,1H),4.88(s,2H),3.48(dt,1H),1.15(d,6H).
EXAMPLE 24 (I-2) preparation of- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] -N-hydroxybenzamide
Step 1: preparation of methyl 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] benzoate
N- [ (2-isopropylsulfonyl) phenyl ] -2, 5-dichloro-pyrimidin-4-amine (1.0g) and methyl 4-aminomethylbenzoate (0.48g) were charged into a 50ml eggplant-shaped flask, followed by addition of 10ml of isopropanol and 0.7g of DIEA, reaction by stirring with heating at 90 ℃ and monitoring by TLC. After the reaction, the temperature was lowered to room temperature, 30ml of cold water was added, extraction was performed with ethyl acetate, and the organic layers were combined, washed with saturated brine 2 times, and dried over anhydrous sodium sulfate overnight. Filtering, collecting filtrate, concentrating under reduced pressure, and performing column chromatography to obtain 0.45g white powder with yield of 34.6%.
Step 2: (I-2) preparation of 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] -N-hydroxybenzamide
Reacting 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl]Amino group]Pyrimidin-2-yl]Amino group]Methyl radical]Methyl benzoate (0.2g) was added to a 25ml eggplant-shaped flask, and 20ml of a freshly prepared hydroxylamine methanol solution was added and reacted with stirring at room temperature for 3 hours. The solution became clear from turbid. TLC monitored the disappearance of starting material. The pH was adjusted to near neutral with saturated ammonium chloride solution and solids precipitated. The solid was filtered off with suction and the filter cake was washed with water to give 0.15g of crude product. Recrystallization from methanol gave 0.11g of pink powder in 55.6% yield. m.p.164-166 ℃.1H NMR(600MHz,DMSO)(δ,ppm):11.16(s,1H),9.38-9.50(m,1H),8.89-9.02(m,1H),7.88-8.23(m,2H),7.32-7.78(m,4H),7.15-7.30(m,3H),4.51(s,2H),3.40-3.50(m,1H),1.24(d,6H).
Example 34- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N-hydroxybenzamide (I-3) preparation
Weighing 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl]Amino group]Pyrimidin-2-yl]Amino group]Methyl benzoate (0.2g) was placed in a 25ml eggplant-shaped flask, 20ml of freshly prepared hydroxylamine methanol solution was added and the reaction was stirred at room temperature for 3 h. TLC monitored the disappearance of starting material. The reaction was stopped. The pH was adjusted to near neutral with saturated ammonium chloride solution and a white solid precipitated. The solid was filtered off with suction and the filter cake was washed with water to give 0.19g of crude product. Recrystallization from methanol gave 0.1g of a white powder with a yield of 50.5%. m.p.174-175 ℃.1H NMR(600MHz,DMSO)(δ,ppm):9.84(s,1H),8.94(s,1H),8.54(s,1H),8.36(s,1H),7.76-8.06(m,2H),7.57-7.77(m,4H),7.45(s,1H),3.40-3.52(m,1H),1.19(d,6H).
EXAMPLE 4 preparation of N- (2-aminophenyl) -4- [ [ 5-chloro-4- [2- (2-isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] benzamide (I-4)
Step 1: preparation of 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] benzoic acid
N- [ (2-isopropylsulfonyl) phenyl ] -2, 5-dichloro-pyrimidin-4-amine (1.0g) and 4-aminomethylbenzoic acid (0.5g) were weighed out in a 50ml eggplant-shaped flask, and 20ml of isopropyl alcohol and DIEA (0.7g) were added thereto, and the reaction was stirred at 90 ℃ and the progress of the reaction was checked by TLC. TLC monitored the disappearance of starting material. The reaction was stopped. After cooling to room temperature, 40ml of cold water was added, extraction was performed with ethyl acetate, and the organic layers were combined, washed with saturated brine 2 times and dried over anhydrous sodium sulfate overnight. Filtering, collecting filtrate, concentrating under reduced pressure to obtain 1.1g crude product, recrystallizing with methanol/water, and precipitating 0.76g white crystal with yield of 51.1%.
Step 2: preparation of N- (2-aminophenyl) -4- [ [ 5-chloro-4- [2- (2-isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] benzamide (I-4)
Weighing 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl]Amino group]Pyrimidin-2-yl]Amino group]Methyl radical]Benzoic acid (0.54g), HOBT (0.15g), EDCI (0.22g), DIEA (0.15g) in 50ml eggplant-shapedIn a flask, 20ml of methylene chloride was added, and after stirring and reacting at 30 ℃ for 0.5h, o-phenylenediamine (0.12g) was further added and the reaction was continued for 18 h. TLC monitored the disappearance of starting material. The reaction was stopped. 40ml of cold water was added, extraction was performed with methylene chloride, and organic layers were combined and washed with saturated brine 2 times and dried over anhydrous sodium sulfate overnight. Filtering, collecting filtrate, concentrating under reduced pressure, and separating by column chromatography to obtain 0.26g white powder with yield of 44.1%. m.p.138-140 ℃.1H NMR(600MHz,DMSO)(δ,ppm):9.60(s,2H),8.15(s,2H),7.91(d,2H),7.70–7.79(m,2H),7.25-7.35(m,3H),7.14(s,1H),6.84-7.04(m,1H),6.77(dd,1H),6.59(d,1H),4.87(s,2H),3.34-3.50(m,1H),1.14(d,6H).
Example 24 preparation of- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] -N-hydroxybenzeneamide (I-5)
Step 1: preparation of tert-butyl 4-bromobenzylcarbamate
Weighing 10g of p-bromobenzylamine, adding into a 250ml single-mouth bottle, adding 50ml of dichloromethane, and sequentially adding Et3N (5.98g) and (Boc)2O (12.9 g). Stirring and reacting for 2h at normal temperature. 200ml of water was added to the reaction system, followed by extraction with methylene chloride (50 ml. times.3), and the methylene chloride layers were combined, washed with water and 100ml of saturated brine in this order, and the methylene chloride layer was dried over anhydrous sodium sulfate. Filtering, concentrating the organic layer to obtain white solid. Drying to obtain a solid 12.56g with a yield of 81.7%.
Step 2: (E) preparation of methyl (E) -3- [4- [ (tert-butoxycarbonylamino) methyl ] phenyl ] acrylate
10g of tert-butyl 4-bromobenzylcarbamate, 9g of methyl acrylate, 9g of DIEA9g, 0.8g of palladium acetate, 2g of tris (2-methylphenyl) phosphine, 60ml of acetonitrile and 30ml are respectively added into a 250ml eggplant-shaped bottle and subjected to reflux reaction at 90 ℃ for 6 hours under the protection of nitrogen. Cooling to room temperature. 200ml of cold water was added to the reaction system, followed by suction filtration. The mother liquor was extracted with ethyl acetate (100 ml. times.2), and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate for 30 minutes. And (5) suction filtration. And (3) adding the mother liquor into a silica gel column for chromatography, merging eluent, and concentrating under reduced pressure to obtain a light yellow solid 3.9g with the yield of 38.3%.
And step 3: (E) preparation of methyl (E) -3- [4- (aminomethyl) phenyl ] acrylate
To a 50ml eggplant type flask were added 2.5g of methyl (E) -3- [4- [ (t-butoxycarbonylamino) methyl ] phenyl ] acrylate, 6ml of trifluoroacetic acid and 20ml of dichloromethane, and the mixture was stirred at ordinary temperature for 2 hours. To the reaction system, 50ml of water was added, the pH was adjusted to weak alkalinity with a saturated sodium carbonate solution, extraction was performed with ethyl acetate (50 ml. times.3), and the organic layers were combined, washed with a saturated saline solution (100ml), and dried over anhydrous sodium sulfate. Suction filtration is carried out, mother liquor is taken and decompressed and concentrated to obtain 1.21g of light yellow oily matter, and the yield is 73.8%.
And 4, step 4: preparation of methyl 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] phenylate
N- [ (2-isopropylsulfonyl) phenyl ] -2, 5-dichloro-pyrimidin-4-amine (0.45g) and (E) -methyl 3- [4- (aminomethyl) phenyl ] acrylate (0.25g) were weighed into a 50ml eggplant-shaped flask, 10ml of isopropanol and 0.34g of DIEA were added thereto, the reaction was stirred with heating at 90 ℃ and was checked by TLC to be complete. After cooling to room temperature, 30ml of cold water was added, extraction was performed with ethyl acetate, and the organic layers were combined, washed with saturated brine 2 times and dried over anhydrous sodium sulfate overnight. Filtering, collecting filtrate, concentrating under reduced pressure, and performing column chromatography to obtain 0.4g white powder with yield of 61.6%.
And 5: preparation of 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] methyl ] -N-hydroxybenzeneamide (I-5)
Weighing 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl]Amino group]Pyrimidin-2-yl]Amino group]Methyl radical]Methyl enoate (0.15g) was placed in a 25ml eggplant-shaped flask, 15ml of freshly prepared hydroxylamine methanol solution was added and the reaction was stirred at ambient temperature for 3 h. The solution became clear from turbid. TLC monitored the disappearance of starting material a. The reaction was stopped. The pH was adjusted to near neutral with saturated ammonium chloride solution and solids precipitated. The solid was filtered off with suction and the filter cake was washed with water to give 0.12g of crude product. Recrystallization from methanol gave 0.08g of pink powder with a yield of 46.7%. m.p.196-198 ℃.1H NMR(600MHz,DMSO)(δ,ppm):10.74(s,1H),9.36-9.50(m,1H),8.89-9.10(m,1H),7.94-8.30(m,2H),7.47-7.93(m,4H),7.41(d,1H),7.30(s,3H),6.40(d,1H),4.45(s,2H),3.35-3.50(m,1H),1.13(d,6H).
Example preparation of 64- [ (5-chloro-4- [ (2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N- [6- (hydroxyamino) -6-oxohexyl ] benzamide (I-6)
Step 1: preparation of 4- [ [ 5-chloro-4- [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] benzoic acid
N- [ (2-isopropylsulfonyl) phenyl ] -2, 5-dichloro-pyrimidin-4-amine (1.02g) and 4-aminobenzoic acid (0.41g) were weighed into a 50ml eggplant-shaped flask, and 20ml of isopropanol and 0.3ml of HCl solution (37%) were added, and the reaction was stirred at 90 ℃ and the progress of the reaction was checked by TLC. TLC monitored the disappearance of starting material a. The reaction was stopped. Cooling to room temperature, adding 30ml cold water to precipitate white solid, filtering, drying to obtain 0.87g white solid with yield of 62.58%.
Step 2: preparation of methyl 6- [4- [ 5-chloro-4- [2- (propane-2-sulfonyl) phenylamino ] -pyrimidin-2-ylamino ] benzoylamino ] hexanoate
In a 50ml eggplant-shaped flask, 4- ((5-chloro-4- (2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (0.80g), HOBT (0.27g), EDCI (0.40g) and DIEA (0.70g) were weighed, 20ml of methylene chloride was added, and after stirring at 30 ℃ for 0.5h, methyl 6-aminocaproate hydrochloride (0.28g) was added and the reaction was continued for 10 h. TLC monitored the disappearance of starting material. The reaction was stopped. 40ml of cold water was added, extraction was performed with methylene chloride, and organic layers were combined and washed with saturated brine 2 times and dried over anhydrous sodium sulfate overnight. Filtration, collection of the filtrate, concentration under reduced pressure, column chromatography (eluent: dichloromethane: methanol: 30: 1) gave 0.60g of a white powder with a yield of 57.19%.
And step 3: preparation of 4- [ (5-chloro-4- [ (2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N- [6- (hydroxyamino) -6-oxohexyl ] benzamide (I-6)
Weighing 6- [4- [ 5-chloro-4- [2- (propane-2-sulfonyl) -phenylamino ] group]-pyrimidin-2-ylamino]-benzoylamino group]Methyl caproate (0.2g) in a 25ml eggplant-shaped flask, 20ml of freshly prepared hydroxylamine methanol solution was added and the reaction was stirred at ambient temperature for 3 h. TLC monitored the disappearance of starting material. The reaction was stopped. The pH was adjusted to near neutral with saturated ammonium chloride solution and a white solid precipitated. The solid was filtered off with suction and the filter cake was washed with water to give 0.21g of crude product. Passing through methanol: pulping with a mixed solvent of water 5:1 to obtain pale white powder 0.17 with a yield of 85%.1H NMR(600MHz,DMSO)δ10.35(s,1H),9.83(s,1H),9.49(s,1H),8.68(s,1H),8.56(s,1H),8.36(s,1H),8.28(t,1H),7.89(d,1H),7.83(t,1H),7.71(dd,4H),7.45(t,1H),3.47(dt,1H),3.23(dd,2H),1.96(t,2H),1.55–1.45(m,4H),1.31–1.24(m,2H),1.17(d,6H).
Example 73 preparation of- [ (5-chloro-4- [ (2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N- [6- (hydroxyamino) -6-oxohexyl ] benzamide (I-7)
The same operation as in example 6 was carried out using 3-aminobenzoic acid as the starting material to obtain a white-like solid with a yield of 78%.1H NMR(600MHz,DMSO)δ10.36(s,1H),9.70(s,1H),9.57(s,1H),8.68(s,2H),8.35(d,2H),8.03(s,1H),7.84(d,1H),7.77(d,1H),7.68(d,1H),7.43(d,1H),7.39–7.24(m,2H),3.46(dt,1H),3.22(d,2H),1.96(dd,2H),1.50(dt,4H),1.28(dd,2H),1.17(d,6H).
Example 84 preparation of- [ (5-chloro-4- [ (2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N- [6- (hydroxyamino) -4-oxobutyl ] benzamide (I-8)
The same operation as in example 6 was carried out using 4-aminobenzoic acid as the starting material to obtain a white-like solid with a yield of 80%.1H NMR(600MHz,DMSO)δ10.42(s,1H),9.83(s,1H),9.26–9.20(m,1H),8.73(s,1H),8.57(s,1H),8.42-8.32(m,2H),7.86(d,2H),7.76–7.62(m,4H),7.45(s,1H),3.47(m,1H),3.35-3.24(m,2H),2.12-2.02(m,2H),1.85–1.75(m,2H),1.17(m,6H).
Example 93- [ (5-chloro-4- [ (2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N- [6- (hydroxyamino) -4-oxobutyl ] benzamide (preparation of I-9)
The same operation as in example 6 was carried out using 3-aminobenzoic acid as the starting material to obtain an off-white solid with a yield of 76%.1H NMR(600MHz,DMSO)δ10.40(s,1H),9.70(s,1H),9.57(s,1H),8.73(d,1H),8.66(s,1H),8.42(t,1H),8.33(s,1H),8.04(s,1H),7.84(dd,1H),7.77(d,1H),7.68(t,1H),7.44(d,1H),7.39–7.30(m,2H),3.46(dt,1H),3.23(dd,2H),2.53–2.48(m,2H),2.01(t,2H),1.78–1.67(m,2H),1.17(d,6H).
Example 103- [ (5-chloro-4- [ (2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N- [6- (hydroxyamino) -7-oxoheptyl ] benzamide (preparation of I-10)
The same operation as in example 6 was carried out using 3-aminobenzoic acid as the starting material to obtain a white-like solid with a yield of 83%.1H NMR(600MHz,DMSO)δ10.35(s,1H),9.70(s,1H),9.57(s,1H),8.68(s,2H),8.34(d,2H),8.03(s,1H),7.84(d,1H),7.77(d,1H),7.68(t,1H),7.43(d,1H),7.39–7.23(m,2H),3.52–3.40(m,1H),3.22(d,2H),1.94(t,2H),1.55-1.40(m,4H),1.38-1.20(m,4H),1.17(d,6H).
Example 114- [ (5-chloro-4- [ (2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] -N- [7- (hydroxyamino) -7-oxoheptyl ] benzamide (preparation of I-11)
The same operation as in example 6 was carried out using 4-aminobenzoic acid as the starting material to obtain a white-like solid with a yield of 83%.1H NMR(600MHz,DMSO)1H NMR(600MHz,DMSO)δ10.38(s,1H),9.84(s,1H),9.49(s,1H),8.69(s,1H),8.58(s,1H),8.36(s,1H),8.31(t,1H),7.88(d,1H),7.83(t,1H),7.71(dd,4H),7.45(t,1H),3.51–3.46(m,1H),3.22(dd,2H),2.02–1.87(m,2H),1.58–1.49(m,4H),1.35–1.25(m,4H),1.13(d,6H).
Example 12N1- [4- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl ] sulfonyl]Amino group]Pyrimidin-2-yl]Amino group]Phenyl radical]-N7-hydroxypimelide (preparation of I-12)
Step 1: n is a radical of2- (4-aminophenyl) -5-chloro-N4Preparation of- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine
N- [ (2-isopropylsulfonyl) phenyl ] -2, 5-dichloro-pyrimidin-4-amine (1.02g) and p-phenylenediamine (0.35g) were weighed into a 50mL eggplant-shaped flask, and 20mL of isopropanol and 0.3mL of HCl solution (37%) were added, and the reaction was stirred with heating at 90 ℃ and the progress of the reaction was checked by TLC. TLC monitored the disappearance of starting material a. The reaction was stopped. Cooling to room temperature, adding 30ml cold water, extracting with ethyl acetate for three times, washing the organic layer with saturated NaCl for three times, drying over night with anhydrous sodium sulfate, filtering, collecting the filtrate, rotary steaming under reduced pressure, and concentrating to obtain 1.06g brown solid with yield of 78.5%.
Step 2: preparation of methyl 7- [ [4- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl ] amino ] pyrimidin-2-yl ] amino ] phenyl ] amino ] -heptanoate
Weighing N2- (4-aminophenyl) -5-chloro-N4- (2- (isopropylsulfonyl)) Phenyl) pyrimidine-2, 4-diamine (0.80g), HOBT (0.28g), EDCI (0.40g), DIEA (0.70g) in a 50ml eggplant-shaped flask, 30ml of dichloromethane were added, and after stirring the reaction at room temperature for 0.5h, methyl 7-aminoheptanoate hydrochloride (0.34g) was added and the reaction was continued for 10 h. TLC monitored the disappearance of starting material. The reaction was stopped. 40ml of cold water was added, extraction was carried out three times with methylene chloride, and the organic layers were combined and washed twice with saturated brine and dried over anhydrous sodium sulfate overnight. Filtration, collection of the filtrate, concentration under reduced pressure, column chromatography (eluent: dichloromethane: methanol: 50: 1) gave 0.62g of white powder in 57.9% yield.
And step 3: n is a radical of1- [4- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl ] sulfonyl]Amino group]Pyrimidin-2-yl]Amino group]Phenyl radical]-N7Preparation of (I-12) hydroxyheptadiamide
Weighing 7- [ [4- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl]Amino group]Pyrimidin-2-yl]Amino group]Phenyl radical]Amino group]Methyl-heptanoate (0.2g) in a 25ml eggplant type flask, 15ml of freshly prepared hydroxylamine methanol solution was added and the reaction was stirred at room temperature for 3 hours. TLC monitored the disappearance of starting material. The reaction was stopped. The pH was adjusted to near neutral with saturated ammonium chloride solution and a white solid precipitated. The solid was filtered off with suction and the filter cake was washed with water to give 0.10g of crude product. Passing through methanol: the mixture of water and 5:1 was slurried to give 0.75g of a pale white powder with a yield of 37.5%.1H NMR(600MHz,DMSO)δ10.35(s,1H),9.77(s,1H),9.48(d,2H),8.68(s,1H),8.60(s,1H),8.27(s,1H),7.86(d,1H),7.74(s,1H),7.48(d,4H),7.40(s,1H),3.45(s,1H),2.27(s,2H),1.95(s,2H),1.55(d,4H),1.27(s,2H),1.17(s,6H).
Example 13N1- [3- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl ] sulfonyl]Amino group]Pyrimidin-2-yl]Amino group]Phenyl radical]-N6Preparation of (I-13) hydroxyadipicolimide
The same operation as in example 12 was carried out using m-phenylenediamine as the starting material to obtain a white-like solid in a yield of 32.2%.1H NMR(600MHz,DMSO)δ10.41(s,1H),9.89(s,1H),9.57(d,2H),8.71(s,2H),8.30(s,1H),7.90–7.80(m,2H),7.69(t,1H),7.36(dd,2H),7.18(dt,2H),3.46(dt,1H),2.29(d,2H),1.98(t,2H),1.54(d,4H),1.19(t,6H).
Example 14N1- [3- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl ] sulfonyl]Amino group]Pyrimidin-2-yl]Amino group]Phenyl radical]-N7Preparation of (I-14) hydroxyheptadiamide
The same operation as in example 12 was carried out using m-phenylenediamine as the starting material to obtain a white-like solid in a yield of 32.2%.1H NMR(600MHz,DMSO)δ10.35(s,1H),9.83(s,1H),9.57(d,2H),8.70(d,2H),8.29(s,1H),7.89–7.80(m,2H),7.70(t,1H),7.35(dd,2H),7.22–7.13(m,2H),3.46(dt,1H),2.28(t,2H),1.95(t,2H),1.61–1.47(m,4H),1.27(dd,2H),1.18(d,6H).
Example 15N1- [3- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl ] sulfonyl]Amino group]Pyrimidin-2-yl]Amino group]Phenyl radical]-N7Preparation of (E) -hydroxyglutaramide (I-15)
The same operation as in example 12 was carried out using p-phenylenediamine as the starting material to obtain a white-like solid with a yield of 42.2%.1H NMR(600MHz,DMSO)δ10.41(s,1H),9.86(s,1H),9.57(d,2H),8.72(s,2H),8.29(d,1H),7.90–7.80(m,2H),7.70(t,1H),7.40–7.30(m,2H),7.18(dt,2H),3.46(dt,1H),2.31(t,2H),2.01(t,2H),1.79(p,2H),1.18(d,6H).
Example 16N1- [4- [ [ 5-chloro-4- [ [2- (isopropylsulfonyl) phenyl ] sulfonyl]Amino group]Pyrimidin-2-yl]Amino group]Phenyl radical]-N7Preparation of (I-16) hydroxyglutaramide
The same operation as in example 12 was carried out using p-phenylenediamine as the starting material to obtain a white-like solid in a yield of 38.2%.1H NMR(600MHz,DMSO)δ10.42(s,1H),9.83(s,1H),9.48(d,2H),8.72(s,1H),8.61(s,1H),8.28(s,1H),7.86(d,1H),7.74(t,1H),7.48(t,4H),7.40(t,1H),3.45(dt,1H),2.40–2.20(m,2H),2.02(t,2H),1.86–1.71(m,2H),1.17(d,6H).
Claims (11)
1. A compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
wherein the content of the first and second substances,
R1selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy, and haloalkyl;
R2selected from halogen, alkyl, alkoxyAlkyl, hydroxy, amino, carboxy, cyano, nitro, cycloalkyl, heterocycloalkyl;
m is selected from 0, 1, 2, 3 and 4;
R3aand R3bIndependently selected from hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, hydroxy, amino, carboxy, cyano, nitro, cycloalkyl, heterocycloalkyl;
R4selected from the group consisting of halogen, alkyl, alkoxy, alkoxyalkyl, hydroxy, amino, carboxy, cyano, nitro, cycloalkyl, heterocycloalkyl;
n is selected from 0, 1, 2, 3 and 4;
l is selected from a bond and alkylene;
k is selected from the group consisting of a bond, alkylene, alkenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl, said alkylene, alkenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-, aryl and heteroaryl groups may be substituted with one or more alkyl, halo, alkoxy, hydroxy, amino, carboxy, cyano and nitro groups, said p being selected from an integer from 1 to 8;
R5and R6Independently selected from hydrogen, hydroxyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, which aryl, heteroaryl, cycloalkyl, heterocycloalkyl may be substituted with one or more amino, hydroxyl, carboxyl, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, alkylamino, alkanoylamino, amido, ester, acyl, alkanoyl, alkylaminoacyl, aryl, heteroaryl groups.
2. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is1Is selected from C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl and halogeno C1-6An alkyl group; further preferably, R1Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, trichloromethyl, trifluoromethyl; even more preferably, R1Is isopropyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is2Selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl, m is selected from 0, 1, 2, 3 and 4; further preferably, R2Selected from halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl, hydroxy, amino, carboxyl, cyano, nitro, m is selected from 0, 1, 2 and 3; even more preferably, R2Is halogen, m is selected from 0 and 1; even more preferably, m is 0.
4. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is3aAnd R3bIndependently selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8A heterocycloalkyl group; further preferably, R3aAnd R3bIndependently selected from hydrogen, halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8A heterocycloalkyl group; even more preferably, R3aAnd R3bIndependently selected from hydrogen, fluorine, chlorine, bromine and iodine.
5. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is4Selected from halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy, amino, carboxyl, cyanoRadical, nitro radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl, n is selected from 0 and 1; further preferably, R4Selected from halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl, hydroxy, amino, carboxyl, cyano, nitro, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl and n is selected from 0 and 1, more preferably n is 0.
6. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein L is selected from the group consisting of a bond, methylene, ethylene, propylene, isopropylene; further preferably, L is selected from a bond and methylene.
7. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein K is selected from the group consisting of a bond, methylene, ethylene, propylene, isopropylene, vinylene, propenylene, butenylene, -NH-c (o) - (CH)2)p-、-C(O)-NH-(CH2) p-phenyl and heteroaryl, said p being selected from the group consisting of integers of 1 to 6, said methylene, ethylene, propylene, isopropylene, vinylene, propenylene, butenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-, phenyl and heteroaryl groups may be substituted by one or more C1-6Alkyl, halogen, C1-6Alkoxy, hydroxy, amino, carboxyl, cyano and nitro substitution; further preferably, K is selected from the group consisting of a bond, methylene, ethylene, ethenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-is selected from the integer of 1-6, the methylene, the ethylene, the ethenylene, -NH-C (O) - (CH)2)p-、-C(O)-NH-(CH2) p-may be substituted by one or more C1-6Alkyl, halogen, C1-6Alkoxy, hydroxy, amino, carboxyl, cyano and nitro substitution; even more preferably, K is selected from the group consisting of a bond, vinylidene, -NH-C (O) - (CH)2)5-、-NH-C(O)-(CH2)6-、-C(O)-NH-(CH2)5-、-C(O)-NH-(CH2)6-。
8. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is5And R6Independently selected from hydrogen, hydroxy, benzene, naphthalene, nitrogen heteroaryl, sulfur heteroaryl, oxygen heteroaryl, nitrogen sulfur heteroaryl, oxygen sulfur heteroaryl, nitrogen oxygen heteroaryl, C3-8Cycloalkyl, hetero C3-8Cycloalkyl, said benzene, naphthalene, azaaryl, thiaaryl, oxaaryl, azathiaaryl, oxathiaaryl, C3-8Cycloalkyl, hetero C3-8Cycloalkyl groups may be substituted by one or more amino, hydroxy, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy C1-6Alkyl, halogen, halogeno C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkylamide, amide, ester, acyl, C1-6Alkanoyl radical, C1-6Alkyl amino acyl, aryl, heteroaryl substituted; further preferably, R5Is hydrogen, R6Selected from the group consisting of hydroxy, benzene, naphthalene, azaaryl, thiaaryl, oxaaryl, thiaheteroaryl, oxathiaaryl, and said benzene, naphthalene, azaaryl, oxathiaaryl, and said benzene, naphthalene, thiaaryl, oxathiaaryl, and said benzene, naphthalene, and said1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy C1-6Alkyl, halogen, halogeno C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkylamide, amide, ester, acyl, C1-6Alkanoyl radical, C1-6Alkyl amino acyl, aryl, heteroaryl substituted; even more preferably, R5Is hydrogen, R6Selected from hydroxyl and benzene, said benzene may be substituted by one or more of amino, hydroxyl, carboxyl, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkoxy C1-3Alkyl, halogen, halogeno C1-3Alkyl radical, C1-3Alkylamino radical, C1-3Alkylamide, amide, ester, acyl, C1-3Alkanoyl radical, C1-3Alkyl amino acyl, aryl, heteroaryl substituted.
9. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein said compound is selected from the group consisting of:
10. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof or a composition according to claim 10 for the manufacture of a medicament for the treatment and/or prophylaxis of tumours.
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| CN113549057B (en) * | 2020-04-24 | 2023-01-31 | 中国药科大学 | Snail inhibitor and derivative thereof, preparation method, pharmaceutical composition and application |
| 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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