WO2021078141A1 - 新型嘌呤衍生物及其中间体与制备抗癌症药物的应用 - Google Patents

新型嘌呤衍生物及其中间体与制备抗癌症药物的应用 Download PDF

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WO2021078141A1
WO2021078141A1 PCT/CN2020/122436 CN2020122436W WO2021078141A1 WO 2021078141 A1 WO2021078141 A1 WO 2021078141A1 CN 2020122436 W CN2020122436 W CN 2020122436W WO 2021078141 A1 WO2021078141 A1 WO 2021078141A1
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compound
formula
cancer
represented
general formula
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张飞
冯子侠
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苏州锐明新药研发有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • 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

Definitions

  • the present invention belongs to the field of medicinal chemistry, and particularly relates to a new type of novel purine derivatives and intermediates thereof.
  • the novel purine derivatives have phosphoinositide-3-kinase (PI3K) inhibitory activity and can be used to prepare drugs for the prevention and treatment of tumors. .
  • PI3K phosphoinositide-3-kinase
  • PI3K is an intracellular phosphatidylinositol kinase.
  • the PI3K signaling pathway is usually activated by receptors on the cell surface, such as receptor tyrosine kinases, GPCRs, and some oncogenes, such as RAS.
  • the activated p110 subunit catalyzes the conversion of PIP2 to PIP3 and activates Akt activity. Akt will further transmit the signal to downstream molecules, such as mTORC1, GSK3, and BCL-2 to regulate different cellular physiological processes.
  • mTORC2 activates the Akt molecule through the phosphorylation of Ser 473.
  • PTEN can dephosphorylate PIP3 into PIP2.
  • the downstream signaling pathways of PI3K molecules are more complex, including some feedback loops.
  • Each of the four catalytic isoforms of class I PI3K preferentially regulates specific signal transduction and tumor cell survival, depending on the type of malignant tumor and its genetic or epigenetic changes.
  • p110 ⁇ is essential for the growth of tumor cells driven by PIK3CA mutations or oncogene RAS and receptor tyrosine kinases; p110 ⁇ mediates the occurrence of PTEN-deficient tumors; and p110 ⁇ is highly expressed in leukocytes, thus making It has become an ideal target for the treatment of hematological malignancies.
  • PI3 kinase was discovered to be an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol (D. Whitman et al. (1988) Nature, 332664).
  • PI3K was originally thought to be a single enzyme, but it has been clarified that there are multiple subtypes in PI3K, and PI3K ⁇ is one of them.
  • PI3K ⁇ has high-frequency activating mutations in breast cancer, which is closely related to the development and drug resistance of breast cancer, and has become an important target for the treatment of breast cancer.
  • Copanlisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, which has good inhibitory activity against the PI3K- ⁇ and PI3K- ⁇ subtypes expressed in malignant B cells.
  • PI3K phosphatidylinositol-3-kinase
  • the technical problem to be solved by the present invention is to provide a new type of purine derivative with PI3K inhibitory activity.
  • the present invention also provides an intermediate for preparing the above-mentioned novel purine derivative.
  • the present invention also provides an application of the aforementioned novel purine derivative in the preparation of a medicine for preventing and/or treating diseases mediated by phosphatidylinositol-3-kinase (PI3K).
  • PI3K phosphatidylinositol-3-kinase
  • the present invention adopts the following technical solution:
  • a purine derivative represented by formula (I) or its isomers, pharmaceutically acceptable salts, solvates or crystals (sometimes collectively referred to herein as "compounds of the present invention"):
  • A is -OH, -NH 2 , -SH, B is -C n H 2n -, n is 1, 2, 3 or 4;
  • Z is hydrogen, hydroxyl, C 1-3 alkyl, fluorine, chlorine or bromine, or is selected from fluorine, chlorine and bromine One or more substituted C 1-3 alkyl groups.
  • Z is preferably hydrogen, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, or pentafluoroethyl.
  • Z 1 is hydrogen, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, or pentafluoroethyl.
  • the B may be linear or branched, and there is no particular limitation.
  • the B is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2- , -C(CH 3 ) 2 -or -CH 2 C(CH 3 ) 2 .
  • the B is -CH 2 -.
  • the purine derivative is selected from compounds represented by the following structures:
  • the present invention further provides a pharmaceutical composition comprising one or more of the purine derivatives, isomers thereof, pharmaceutically acceptable salts or solvates thereof provided above.
  • the composition further includes a pharmaceutically acceptable carrier.
  • the present invention provides the purine derivatives described above or their isomers, pharmaceutically acceptable salts, hydrates, solvates, crystals, or pharmaceutical compositions containing the purine derivatives for preparing treatment and/or prevention by phosphatidyl Application of inositol-3-kinase-mediated diseases in medicine.
  • Cancers include but are not limited to kidney cancer, liver cancer, colon cancer, gastrointestinal stromal tumor, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, leukemia and prostate cancer, etc. .
  • the present invention also provides the application of the pharmaceutical composition in the preparation of drugs for treating and/or preventing cancer and a method for treating or preventing cancer by using the pharmaceutical composition.
  • the compound of the present invention is preferably present in a therapeutically effective amount.
  • the pharmaceutically acceptable carrier in the above-mentioned pharmaceutical composition can be, for example, a pharmaceutically acceptable diluent, excipient, filler, binder, disintegrant, absorption enhancer, surfactant, lubricant, flavor Agents, sweeteners, etc.
  • the medicine prepared with the compound of the present invention as an active ingredient can be in various forms such as tablets, powders, capsules, granules, oral liquids, and injection preparations.
  • the dosage form of the pharmaceutical composition is preferably a tablet, capsule or injection.
  • the present invention also provides an intermediate for preparing the purine derivative represented by the above general formula (I) of the present invention, its stereoisomer, pharmaceutically acceptable salt, solvate or crystal, and the intermediate has the formula (II) Show structure:
  • a 1 is tert-butyldimethylsiloxy (TBSO) or A 1 is the same as A in the general formula (I);
  • B and Z are respectively the same as B and Z in the general formula (I), and Y is an amino protecting group.
  • the amino protecting group is tetrahydro-2H-pyran-2-yl (THP).
  • the stereoisomers, pharmaceutically acceptable salts, solvates or crystalline intermediates for the preparation of the novel purine derivatives described above in the present invention include the following compounds:
  • the intermediate represented by formula (II) can be obtained by making the following compound With the compound represented by formula (III) The reaction is obtained; in formula (III), A 1 , B and Z are defined as in formula (II).
  • the reaction in the process of preparing the intermediate represented by formula (II), is carried out under alkaline conditions at a temperature of 30-120°C, and optionally under an inert atmosphere. . More preferably, in the process of preparing the intermediate represented by formula (II), the reaction is carried out at a temperature of 40-110°C, further preferably at a temperature of 50-105°C, and even more preferably at a temperature of 60-110°C. It is carried out at 100°C, and further preferably at a temperature of 70-95°C. According to some specific aspects of the present invention, in the process of preparing the intermediate represented by formula (II), the reaction is carried out at a temperature of 80-90°C.
  • the inert atmosphere is a nitrogen atmosphere.
  • the alkaline condition is formed by adding an alkaline substance, the alkaline substance is selected from potassium acetate, potassium carbonate, potassium phenate, potassium phosphate, potassium tert-butoxide, sodium carbonate, bicarbonate A combination of one or more of sodium, sodium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, tri-n-butylamine, and diisopropylethylamine.
  • the alkaline substance is sodium bicarbonate.
  • the reaction in the process of preparing the intermediate represented by formula (II), the reaction is carried out in 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl and/or It is carried out in the presence of tris(dibenzylideneacetone)dipalladium.
  • the reaction in the process of preparing the intermediate represented by formula (II), the reaction is in the 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl And three (dibenzylideneacetone) two palladium co-existence.
  • the present invention has the following advantages compared with the prior art:
  • the present invention provides a new type of purine derivative, which has excellent PI3K inhibitory activity, and can be applied to treat diseases mediated by phosphoinositide-3-kinase (PI3K), and provide more options for cancer treatment. Excellent choice of drugs.
  • the novel purine derivative of the present invention has a simple structure and a relatively low preparation cost.
  • Figure 1 shows the relationship curve of the inhibitory rate of compound I-1 to compound I-3 and the positive control compound GDC-0941 on PI3K ⁇ .
  • isomers refers to isomers produced by different arrangements of atoms in a molecule in space. Including cis-trans isomers, enantiomers and conformational isomers. All stereoisomers belong to the scope of the present invention.
  • the compounds of the present invention may be individual stereoisomers or a mixture of other isomers such as racemates, or a mixture of all other stereoisomers.
  • salt refers to a pharmaceutically acceptable salt formed by the compound of the present invention and an acid.
  • the acid can be an organic acid or an inorganic acid, and can be specifically selected from: 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, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.
  • solvate refers to the form of the compound of the present invention that forms a solid or liquid complex by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.
  • crystalline refers to various solid forms formed by the compounds of the present invention, including crystal forms and amorphous forms.
  • DBU 1,8-diazabicycloundec-7-ene
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • Pd(dppf)Cl 2 [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride
  • DTT dithiothreitol
  • ATP adenosine triphosphate
  • TK tyrosine kinase
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid.
  • Compound 2 The Chinese name is 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane; the English name is 2-(4-isocyanatophenyl )-4,4,5,5-tetramethyl-1,3,2-dioxaborolane;
  • Compound 3 Chinese name is 1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2- ⁇ )phenyl)urea; the English name is: 1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)urea;
  • Compound 5 The Chinese name is 4-(2-chloro-7H-purin-6-yl)morpholine; the English name is 4-(2-chloro-7H-purin-6-yl)morpholine
  • Compound 7 The Chinese name is 1-(4-(hydroxymethyl)phenyl)-3-(4-(6-morpholine-7-(tetrahydro-2H-pyran-2-yl)-7H-purine -2-yl)phenyl)urea; the English name is: 1-(4-(hydroxymethyl)phenyl)-3-(4-(6-morpholino-7-(tetrahydro-2H-pyran-2-yl)-7H -purin-2-yl)phenyl)urea
  • Compound I-1 The Chinese name is 1-(4-(hydroxymethyl)phenyl)-3-(4-(6-morpholine-7h-purin-2-yl)phenyl)urea; the English name is 1 -(4-(hydroxymethyl)phenyl)-3-(4-(6-morpholino-7H-purin-2-yl)phenyl)urea
  • Compound 9 The Chinese name is (4-nitro-2-(trifluoromethyl)phenyl)methanol; the English name is (4-nitro-2-(trifluoromethyl)phenyl)methanol;
  • Compound 10 Chinese name is tert-butyldimethyl(4-nitro-2-(trifluoromethyl)benzyl)oxy)silane; English name is tert-butyldimethyl((4-nitro-2-(trifluoromethyl) )benzyl)oxy)silane;
  • Compound 11 The Chinese name is 4-((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)aniline; the English name is 4-(((tert-butyldimethylsilyl)oxy)methyl )-3-(trifluoromethyl)aniline;
  • Compound 12 The Chinese name is 1-(4-((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxan-2-yl)phenyl)urea; English name: 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)- 3-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetram ethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea;
  • Compound 13 The Chinese name is 1-(4-((tert-butyldimethylsiloxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(6-morpholine- 7-(Tetrahydro-2H-pyran-2-yl)-7H-purin-2-yl)phenyl)urea; English name: 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)- 3-(trifluoromethyl)phenyl)-3-(4-(6-morpholino-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yl)phenyl)urea
  • Compound I-2 The Chinese name is 1-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-3-(4-(6-morpholin-7H-purin-2-yl) Phenyl)urea; English name: 1-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-3-(4-(6-morpholino-7H-purin-2-yl)pheny l)urea
  • Compound 15 The Chinese name is 4-(2-(benzyloxy)ethyl)morpholine; the English name is 4-(2-(benzyloxy)ethyl)morpholine;
  • Compound 16 Chinese name is 4-(2-((4-nitrobenzyl)oxy)ethyl)morpholine; English name is 4-(2-((4-nitrobenzyl)oxy)ethyl)morpholine;
  • Compound 17 The Chinese name is 4-((2-morpholinoethoxy)methyl)aniline; the English name is 4-((2-morpholinoethoxy)methyl)aniline;
  • Compound 18 The Chinese name is 1-(4-((2-morpholinoxy)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2 -Dioxanol-2-yl)phenyl)urea; English name: 1-(4-((2-morpholinoethoxy)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)urea;
  • Compound 19 The Chinese name is 1-(4-(6-morpholine-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yl)phenyl)-3-(4- ((2-Morpholineoxy)methyl)phenyl)urea; English name is 1-(4-(6-morpholino-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2- yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea
  • Compound I-3 The Chinese name is 1-(4-(6-morpholin-7H-purin-2-yl)phenyl)-3-(4-((2-morpholinoxy)methyl)phenyl ) Urea; the English name is 1-(4-(6-morpholino-7H-purin-2-yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea
  • PI3-Kinase(human)HTRF TM Assay kit detection method is an international method
  • the 3 compounds of Example I-1, I-2, I-3 (below In the experiment, codes RMP-D06, RMP-D07, RMP-D08) were given the half inhibitory concentration of PI3K alpha enzyme (IC 50 determination), and the compound GDC-0941 was used as a positive control.
  • Positive control substance The structural formula of GDC0941 (Pictilisib) is as follows:
  • 4 ⁇ Reaction Buffer was diluted to 1 ⁇ with ddH 2 O, and 1M DTT was added to make the final concentration 5mM. Prepare fresh before each use. For example, to prepare 10mL 1 ⁇ Reaction Buffer, add 2.5mL 4 ⁇ Reaction Buffer, 50 ⁇ L 1M DTT, ddH 2 O 7.45mL. Throughout the experiment, freshly prepared 1 ⁇ Reaction Buffer was used to prepare ATP working solution, substrate and enzyme mixed working solution, etc.
  • test compound was dissolved in DMSO to 1 mM as a storage solution, and then diluted with DMSO by a factor of 4, a total of 10 concentration points. Take 1 ⁇ L each and add 24 ⁇ L 1 ⁇ Reaction Buffer. Take 5 ⁇ L of each diluted solution into a 384-well plate and contain 1% DMSO.
  • 1 ⁇ reaction buffer to prepare 2 ⁇ PIP2 working solution to make the final concentration of 20 ⁇ M and PIP2 reaction final concentration of 10 ⁇ M.
  • 1ml 1 ⁇ reaction buffer/PIP2 working solution take 20 ⁇ L of PIP2 and add to 980 ⁇ L 1 ⁇ reaction buffer.
  • This working fluid should be more than 0.1-0.2ml to meet the control usage and dead volume.
  • the concentration of the kinase working solution is 10ng/well.
  • 10mM ATP is diluted to 40 ⁇ M with 1 ⁇ reaction buffer.
  • the concentration of ATP is 10 ⁇ M.
  • to prepare 2ml ATP working solution take 8 ⁇ L of 10mM ATP and add it to 1992 ⁇ L 1 ⁇ reaction buffer.
  • Stop A and Stop B are mixed in a ratio of 3:1, and can be used after at least 2 hours at room temperature.
  • the stop solution can be stable for 12 hours at room temperature.
  • DM C, DM A and DM B are mixed in a ratio of 18:1:1, and can be used after at least 2 hours at room temperature.
  • the test solution can be stable for 12 hours at room temperature.
  • Emission Ratio(ER) 665nM Emission signal/620nm Emission signal
  • the inhibition rate is calculated with the following formula:
  • Inhibition rate (ER sample- ER 0% )/(ER 100% -ER 0% ) ⁇ 100% [(ER positive-ER sample) / (ER positive-ER negative) * 100%]
  • PI3-Kinase (human) HTRFTM Assay kit to detect the inhibitory rate of PI3K-alpha enzyme at different concentrations of the three compounds, control the DMSO concentration to 1%, each concentration is a duplicate well, and select GDC-0941 as a positive reference substance.
  • the measurement results are shown in Figure 1. According to the test results, the median inhibitory concentration (IC 50 ) of each compound on PI3K-alpha enzyme is summarized in Table 1 below.
  • PI3K ⁇ phosphoinositide-3-kinase
  • the novel purine derivative of the present invention (including its pharmaceutically acceptable salts, etc.) is a new type of PI3K ⁇ Inhibitor. Therefore, it can be applied to treat diseases mediated by phosphoinositide-3-kinase, and treatable malignant tumors include but are not limited to kidney cancer, liver cancer, colon cancer, gastrointestinal stromal tumor, non-small cell lung cancer, breast cancer , Pancreatic cancer, glioma, lymphoma, fibrosarcoma, ovarian cancer, leukemia and prostate cancer.
  • the other compounds of the present invention have basically the same structure as Compound I-1 to Compound I-3, and it can be expected that they have an excellent activity comparable to that of Compound I-1 to Compound I-3.
  • This type of compound is the world’s first new type of compound, which has shown obvious strong activity, and will be used in further new drug research to invent domestically-made innovative drugs, which are urgently needed in the market and have strong effects, small side effects and cheap anti-cancer drugs. .

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Abstract

本发明公开了一种式(I)所示的一类新型嘌呤衍生物或其药学可接受的盐及其中间体和在制备治疗或预防癌症的药物中的应用。该类化合物是新型的PI3K抑制剂，具有优异的抑制活性，有望用于多种恶性肿瘤的治疗。

Description

新型嘌呤衍生物及其中间体与制备抗癌症药物的应用 技术领域
本发明属于医药化学领域，尤其涉及一类新型的新型嘌呤衍生物及其中间体，该新型嘌呤衍生物具有磷酸肌醇-3-激酶(PI3K)抑制活性，可用于制备预防和治疗肿瘤的药物。
背景技术
PI3K是一种胞内磷脂酰肌醇激酶。威尔康乃尔医学院癌症生物医学教授Lewis C.Cantley发现了磷酸肌醇-3-激酶(PI3K)信号通路，同时阐明了其在肿瘤发展过程中所扮演的关键角色。PI3K信号通路通常会被细胞表面的受体所激活，如受体酪氨酸激酶、GPCR以及一些癌基因，如RAS等。活化后的p110亚基催化PIP2向PIP3转化，并激活Akt活性。Akt则会进一步将信号传递至下游分子，如mTORC1、GSK3以及BCL-2等来调节不同的细胞生理学过程。mTORC2则通过473位Ser的磷酸化来活化Akt分子。与此相反，PTEN则能够将PIP3去磷酸化成为PIP2。PI3K分子下游信号通路传递较为复杂，包含了一些反馈循环。I类PI3K的四种催化异构体中的每一种都优先调节特定的信号转导及肿瘤细胞的存活，这取决于恶性肿瘤的类型及其所发生的基因或表观遗传学改变。例如，p110α对于PIK3CA突变或癌基因RAS及受体酪氨酸激酶所驱动的肿瘤细胞的生长至关重要；p110β则会介导PTEN缺失型的肿瘤发生；而p110δ则在白细胞中高表达，从而使其成为治疗血液系统恶性肿瘤的理想靶点。
在二十世纪八十年代后期，发现PI3激酶(PI3K)是将磷脂酰肌醇的肌醇环的3-位磷酸化的酶(D.Whitman等人(1988)Nature，332664)。最初认为PI3K是一种单一酶，但现已澄清，PI3K中存在多个亚型，PI3Kα是其中的一种。PI3Kα在乳腺癌中发生高频激活突变，与乳腺癌发生发展以及耐药密切相关，已成为治疗乳腺癌的重要靶标。
2017年9月14日，美国FDA加速批准拜耳(Bayer Healthcare Pharmaceuticals)的
Figure PCTCN2020122436-appb-000001
(Copanlisib)上市，
Figure PCTCN2020122436-appb-000002
为商品名。用于治疗罹患复发性滤泡性淋巴瘤。
Figure PCTCN2020122436-appb-000003
Copanlisib是磷脂酰肌醇-3-激酶(PI3K)抑制剂，主要针对恶性B细胞中表达的PI3K-α和PI3K-δ两种亚型有很好的抑制活性。
现有PI3Kα抑制剂的种类有限且在临床试验中疗效个体差异大，亟需发现新的PI3Kα抑制剂以及疗效预测生物标志物。
2019年上半年，美国FDA宣布，批准诺华公司(NVS.US)开发的Piqray(alpelisib)上市，与内分泌疗法氟维司群(fulvestrant)联用，治疗携带PIK3CA基因突变的HR+/HER2-晚期或转移性乳腺癌患者。这些患者在接受内分泌疗法之后疾病继续恶化。这是FDA批准的第一款用于治疗乳腺癌的PI3K抑制剂。转移性乳腺癌患者的肿瘤已经扩散到身体的其它部分，最常见的转移器官包括骨骼、肺部、肝脏和大脑。在HR+/HER2-晚期乳腺癌中，PI3K通路的改变是肿瘤恶化，疾病进展和产生治疗耐药性的最常见原因。大约40％的HR+/HER2-晚期乳腺癌患者携带PIK3CA基因突变。Piqray是诺华公司开发的一款口服小分子α特异性PI3K抑制剂，即PI3Kα抑制剂。在携带PIK3CA基因突变的乳腺癌细胞系中，它已显示出抑制PI3K通路的潜力，并具有抑制细胞增殖的作用。本发明也将PI3Kα作为靶点研究新药的起点，尤其是国内还未见有中国发明的PI3Kα抑制剂用于治疗恶性肿瘤。本发明的创新性研究结构将填补国内这一空白。如最终上市将具有重大的社会效益和经济效益。
发明内容
本发明所要解决的技术问题是提供一类具有PI3K抑制活性的新型嘌呤衍生物。
本发明同时还提供了一种制备上述新型嘌呤衍生物的中间体。
本发明同时还提供了一种上述新型嘌呤衍生物在制备预防和/或治疗由磷脂酰肌醇-3-激酶(PI3K)介导的疾病的药物中的应用。
为解决以上技术问题，本发明采取如下一种技术方案：
一种具有式(I)所示的嘌呤衍生物或其异构体、可药用盐、溶剂化物或结晶(在本文中有时统称为“本发明化合物”)：
Figure PCTCN2020122436-appb-000004
式中，A为-OH、-NH 2、-SH、
Figure PCTCN2020122436-appb-000005
B为-C nH 2n-，n为1、2、3或4；Z为氢、羟基、C 1-3烷基、氟、氯或溴，或为被选自氟、氯和溴中的一个或多个所取代的C 1-3烷基。
进一步地，Z优选为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基等。
根据本发明的一些优选且具体的方面，所述嘌呤衍生物的结构如下式(I-a)所示：
Figure PCTCN2020122436-appb-000006
其中，A、B和M的定义分别同前，Z 1的定义同Z。进一步地，Z 1为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基等。
根据本发明的进一步实施方案，所述B可以是直链或支链，没有特别限制。
根据本发明的一些优选方面，所述B为-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH(CH 3)-、-CH(CH 3)CH 2-、-C(CH 3) 2-或-CH 2C(CH 3) 2。尤其优选地，所述B为-CH 2-。
根据本发明的一些优选且具体的方面，所述嘌呤衍生物选自如下结构所示化合物：
Figure PCTCN2020122436-appb-000007
本发明还进一步提供包含一种或多种上述提供的嘌呤衍生物、其异构体、其药物可接受的盐或其溶剂化物的药物组合物。在一些实施实例中，该组合物还包括药物可接受的载体。
本发明提供了上述所述的嘌呤衍生物或其异构体、可药用盐、水合物、溶剂化物、结晶或含有所述嘌呤衍生物的药物组合物在制备治疗和/或预防由磷脂酰肌醇-3-激酶介导的疾病的药物中的应用。
由磷脂酰肌醇-3-激酶介导的疾病通常包括癌症。癌症包括但不限于肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌，纤维肉瘤、卵巢癌、白血病和前列腺癌等。
本发明同时还提供所述药物组合物在制备用于治疗和/或预防癌症药物中的应用以及采用所述药物组合物治疗或预防癌症的方法。
根据本发明的药物组合物，其中本发明化合物优选以治疗有效量存在。
上述药物组合物中药学上可接受的载体，可以是例如药学上可接受的稀释剂、赋型剂、填充剂、粘合剂、崩解剂、吸收促进剂、表面活性剂、润滑剂、香味剂、甜味剂等。
以本发明化合物为活性成分制备的药物可以是片剂、粉剂、胶囊、粒剂、口服液以及注射制剂等多种形式。药物组合物的剂型优选为片剂、胶囊或针剂。
上述各种剂型的药物均可以按药学领域的常规方法制备。
本发明同时还提供制备本发明上述通式(I)所示的嘌呤衍生物，其立体异构体、 可药用盐、溶剂化物或结晶的中间体，该中间体具有如式(II)所示结构：
Figure PCTCN2020122436-appb-000008
式(II)中，A 1为叔丁基二甲基硅氧基(TBSO)或者A 1与所述通式(I)中的A相同；
B、Z分别与所述通式(I)中的B、Z相同，Y为氨基保护基。
根据本发明的一些具体且优选的方面，所述氨基保护基为四氢-2H-吡喃-2-基(THP)。
根据本发明的一些具体且优选的方面，所述制备本发明上述所述的新型嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶的中间体包括如下一些化合物：
Figure PCTCN2020122436-appb-000009
在本发明的一些实施方式中，式(II)所示的中间体可通过使如下化合物
Figure PCTCN2020122436-appb-000010
与式(III)所示化合物
Figure PCTCN2020122436-appb-000011
反应得到；式(III)中，A 1、B和Z的定义同式(II)。
根据本发明的一些优选方面，制备所述的式(II)所示中间体的过程中，所述反 应在碱性条件下、温度30-120℃下进行，还选择性地在惰性气氛下进行。更优选地，制备所述的式(II)所示中间体的过程中，所述反应在温度40-110℃下进行，进一步优选在温度50-105℃下进行，更进一步优选在温度60-100℃下进行，再进一步优选在温度70-95℃下进行。根据本发明的一些具体方面，制备所述的式(II)所示中间体的过程中，所述反应在温度80-90℃下进行。
根据本发明的一些实施方案，所述惰性气氛为氮气气氛。
根据本发明的一些实施方案，所述碱性条件通过添加碱性物质形成，所述碱性物质为选自乙酸钾、碳酸钾、苯酚钾、磷酸钾、叔丁醇钾、碳酸钠、碳酸氢钠、叔丁醇钠、甲醇钠、乙醇钠、三乙基胺、三正丁基胺和二异丙基乙基胺中的一种或多种的组合。根据本发明的一个优选且具体的方面，所述碱性物质为碳酸氢钠。
根据本发明的一些优选方面，制备所述的式(II)所示中间体的过程中，所述反应在2-二环己基磷-2,4,6-三异丙基联苯和/或三(二亚苄基丙酮)二钯存在下进行。根据本发明的一个具体且优选的方面，制备所述的式(II)所示中间体的过程中，所述反应在2-二环己基磷-2,4,6-三异丙基联苯和三(二亚苄基丙酮)二钯共同存在下进行。
由于以上技术方案的实施，本发明与现有技术相比存在如下优势：
本发明提供了新型的嘌呤衍生物，该类新型嘌呤衍生物具有优异的PI3K抑制活性，可以应用于治疗由磷脂肌醇-3-激酶(PI3K)介导的疾病，为癌症治疗提供更多更优的药物选择。此外，相比已有PI3K抑制剂，本发明的新型嘌呤衍生物结构简单，制备成本相对较低。
附图说明
图1显示了化合物I-1至化合物I-3以及阳性对照化合物GDC-0941对PI3Kα的抑制率的关系曲线。
具体实施方式
术语定义
除非另外定义，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围。本发明的化合物可以为单独立体异构体或其它异构体的混合例如外消旋体，或者所有其它立体异构体的混合。
术语“盐”是指本发明所述的化合物与酸形成的药学上可接受的盐，所述的酸可以是有机酸或无机酸，具体可选自：磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂化物的特殊形式，其中与水发生配位。在本发明范围内，溶剂化物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。
以下实施例可以使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。所有化合物的结构均经 1H NMR或MS所确定。
实施例中用到的化合物名称缩写如下：
DBU：1,8-二氮杂二环十一碳-7-烯；DMF：N,N-二甲基甲酰胺；THF:四氢呋喃；Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DTT：二硫苏糖醇；ATP：三磷酸腺苷；TK：酪氨酸激酶；HEPES：4-羟乙基哌嗪乙磺酸。
实施例1 化合物I-1的制备
采取以下路线合成化合物I-1：
Figure PCTCN2020122436-appb-000012
Figure PCTCN2020122436-appb-000013
1.1.化合物2的合成
化合物2：中文名称为2-(4-异氰酸酯苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊烷；英文名称为2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane；
Figure PCTCN2020122436-appb-000014
在300mL的二氯甲烷中分别加入4-氨基苯硼酸频哪醇酯化合物1(10g,45.6mmol)，三乙胺(13.8g，136.8mmol)，冷却到零度，在零度分批缓慢加入三光气(8.1g,27.4mmol)，之后在零度下搅拌50分钟得到化合物2的溶液，直接用于下一步。
1.2.化合物3的合成
化合物3：中文名称为1-(4-(羟甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二恶英-2-基)苯基)脲；英文名称为：1-(4-(hydroxymethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea；
Figure PCTCN2020122436-appb-000015
在零度向上述化合物2的溶液加入对氨基苯甲醇(8.4g，68mmol)，之后在零度下搅拌15分钟，升温至室温，在室温下再搅拌3h。LC-MS检测反应结束后，将反应液浓缩旋干，用二氯甲烷萃取，有机相用碳酸氢钠饱和溶液和氯化钠饱和溶液洗涤，无水硫酸钠干燥，过滤，滤液旋干，经柱层析纯化(二氯甲烷/甲醇＝40:1)，得到黄色固体化合物3(11g,产率＝60％)。测得：ESI-MS m/z＝369[M+1] +. 1H NMR(DMSO-d6,400MHz):δ9.02(s,1H),8.89(s,1H),7.60-7.58(d,J＝8Hz,2H),7.49-7.47(d,J＝8.4Hz,2H),7.42-7.40(d,J＝8Hz,2H),7.24-7.21(d,J＝8.4Hz,2H),5.06(m,1H),4.44-4.42(d,J＝5.6Hz,2H),1.28(s,12H).
1.3.化合物5的合成
化合物5：中文名称为4-(2-氯-7H-嘌呤-6-基)吗啉；英文名称为：4-(2-chloro-7H-purin-6-yl)morpholine
Figure PCTCN2020122436-appb-000016
将2,6-二氯嘌呤(18.9g,0.1mol，化合物4)溶于甲醇(400mL)中，冷却到零度，在0～5度区间内缓慢滴加吗啉(13mL,0.15mol)，之后在零度下搅拌15分钟，升温至室温，在室温下再搅拌3h。LC-MS检测反应结束后，大量黄色固体析出，过滤并且洗涤滤饼，分别使用20mL的甲醇，50mL的水以及50mL的乙醚洗涤得到类白色固体化合物5(21.1g,产率＝88％)。测得：ESI-MS m/z＝240[M+1] +. 1H NMR(DMSO-d6,400MHz):δ11.23(s,1H),8.16(s,1H),4.19(m,4H),3.74-3.71(m,4H).
1.4.化合物6的合成
化合物6：中文名称为4-(2-氯-7-(四氢-2H-吡喃-2-基)-7H-嘌呤-6-基)吗啉；英文名称为：4-(2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-6-yl)morpholine
Figure PCTCN2020122436-appb-000017
将化合物5(16.0g,0.067mol)混悬于乙酸乙酯(480mL)中，室温下加入3,4-二氢-2H-吡喃(8.4g,0.1mol，DHP),一水合4-甲基苯磺酸(1.0g,5.2mmol，TsOH)。反应混合物在75度搅拌过夜，得到黑色溶液。反应液冷却至室温，用饱和的碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥，过滤。滤液减压浓缩至干，残于物加入甲基叔丁基醚(20mL)和石油醚(50mL)，搅拌0.5h,过滤，滤饼真空干燥得到化合物6(20.0g,产率＝92.6％)。测得：ESI-MS m/z＝324[M+1] +. 1H NMR(CDCl 3,400MHz):δ7.91(s,1H),5.72-5.69(m,1H),4.29-3.73(m,10H),2.10–2.02(m,2H),1.91-1.65(m,4H).
1.5.化合物7的合成
化合物7：中文名称为1-(4-(羟甲基)苯基)-3-(4-(6-吗啉-7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基)苯基)尿素；英文名称为：1-(4-(hydroxymethyl)phenyl)-3-(4-(6-morpholino-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yl)phenyl)urea
Figure PCTCN2020122436-appb-000018
将化合物6(2.0g,6.2mmol)溶于1,4-二氧六环(25mL)和水(3mL)中，再加入化合物3(2.3g,6.2mmol),碳酸氢钠(1.7g,20.4mmol)，XPhos(400mg，2-二环己基磷-2,4,6-三异丙基联苯)和Pd2(dba)3(180mg，三(二亚苄基丙酮)二钯)，氮气置换3次。在氮气保护下85度搅拌2天。反应液减压浓缩，加入水(20mL)，用乙酸乙酯(50mL*2)萃取,有机相用无水硫酸钠干燥，过滤，滤液减压浓缩至干，加入甲基叔丁基醚(30mL)，室温下搅拌0.5小时，过滤，滤饼真空干燥得到灰白色固体化合物7(1.3g,产率>39.6％).测得：ESI-MS m/z＝530[M+1] +
1.6.化合物I-1的合成
化合物I-1：中文名称为1-(4-(羟甲基)苯基)-3-(4-(6-吗啉-7h-嘌呤-2-基)苯基) 尿素；英文名称为1-(4-(hydroxymethyl)phenyl)-3-(4-(6-morpholino-7H-purin-2-yl)phenyl)urea
Figure PCTCN2020122436-appb-000019
将化合物7(1.4g,10.6mmol)混悬于1,4-二氧六环(5mL)中，加入氯化氢的二氧六环溶液(4N，15mL)，室温搅拌过夜，LCMS检测反应完全，过滤，滤饼用二氧六环洗涤，真空干燥得到黄色固体化合物I-1(1.0g,产率>21％).测得： 1H NMR(DMSO-d6,400MHz):δ8.36(s,1H),8.24-8.22(m,2H),7.64-7.62(d,J＝8.8Hz,2H),7.50-7.37(m,3H),7.27-7.25(d,J＝8.4Hz,1H),4.72(s,1H),4.45(s,1H),4.28(m,4H),3.82(m,4H).LCMS[mobile phase:from 95％water(0.1％TFA)and 5％CH 3CN to 5％water(0.1％TFA)and 95％CH 3CN in 6.5min,finally under these conditions for 0.5min.]purity is>90％,Rt＝3.699min；MS Calcd.:445；MS Found:446[M+H] +.
实施例2 化合物I-2的制备
采取以下路线合成化合物I-2：
Figure PCTCN2020122436-appb-000020
2.1.化合物9的合成
化合物9：中文名称为(4-硝基-2-(三氟甲基)苯基)甲醇；英文名称为：(4-nitro-2-(trifluoromethyl)phenyl)methanol；
Figure PCTCN2020122436-appb-000021
将化合物8(25.0g,106.4mmol)溶于四氢呋喃(100mL)中，冰浴下缓慢加入硼氢化钠(11.5g,319.1mmol),再缓慢滴加三氟化硼乙醚(20mL)，之后室温搅拌过夜。TLC显示反应结束后，加入100mL的盐水，使用乙酸乙酯(300mL x 3)萃取，有机相用硫酸钠干燥浓缩后，得到化合物9(14.5g,产率＝61％).测得：ESI-MS m/z＝222[M+1] +
2.2.化合物10的合成
化合物10：中文名称为叔丁基二甲基(4-硝基-2-(三氟甲基)苄基)氧基)硅烷；英文名称为tert-butyldimethyl((4-nitro-2-(trifluoromethyl)benzyl)oxy)silane；
Figure PCTCN2020122436-appb-000022
冰浴下在二氯甲烷(120mL)中分别加入化合物9(14.0g，63.64mmol)，叔丁基二甲基氯硅烷(19.2g,127.27mmol)，三乙胺(16.1g,159.1mmol)，对二甲胺基吡啶(0.78g,6.36mmol)，然后反应液在室温搅拌2h。TLC检测反应结束后，加入100mL的盐水,并用二氯甲烷(200mL x 3)萃取，有机相用硫酸钠干燥浓缩后，用柱层析纯化(石油醚/乙酸乙酯＝100:1-50:1)，得到化合物10(15.0g,产率＝70％),直接用于下一步反应。
2.3.化合物11的合成
化合物11：中文名称为4-((叔丁基二甲基硅)氧基)甲基)-3-(三氟甲基)苯胺；英文名称为4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)aniline；
Figure PCTCN2020122436-appb-000023
将化合物10(15.0g,44.78mmol)溶在乙醇/水(200mL/80mL)中，加入氯化铵(15.0g,268.68mmol)，温度升到80度，再次加入铁粉(11.0g,201.49mmol),反应在此温度下反应1h,LCMS检测反应结束后，加入盐水(100mL)过滤，滤液使用乙酸乙酯(200mL x 3)萃取,有机相用硫酸钠干燥后浓缩，得到化合物11(11.0g,产率＝80％)。测得：ESI-MS m/z＝306[M+1] +. 1H NMR(CDCl 3,400MHz):δ7.49(d,J＝8.0Hz,1H),6.90(s,1H),6.83(d,J＝8.0Hz,1H),4.78(s,2H),0.94(s,9H),0.09(s,6H).
2.4.化合物12的合成
化合物12：中文名称为1-(4-((叔丁基二甲基硅基)氧基)甲基)-3-(三氟甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素；英文名称为：1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetram ethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea；
Figure PCTCN2020122436-appb-000024
将化合物11(6.0g,19.68mol)溶于四氢呋喃(90mL)中，加入化合物8(12.0g,49.19 mmol)。室温反应过夜，LCMS检测反应结束后，减压浓缩，用柱层析纯化(石油醚/乙酸乙酯＝10:1-5:1)，得到化合物12(5.5g,产率50％)。测得：ESI-MS m/z＝551.6[M+1] +
2.5.化合物13的合成
化合物13：中文名称为1-(4-((叔丁基二甲基硅氧基)甲基)-3-(三氟甲基)苯基)-3-(4-(6-吗啉-7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基)苯基)尿素；英文名称为：1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(6-morpholino-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yl)phenyl)urea
Figure PCTCN2020122436-appb-000025
将化合物12(5.5g,10.0mmol)溶于1,4-二氧六环(80mL)\水(5mL)中，再加入化合物6(3.6g,11.0mmol),碳酸氢钠(2.6g,30.0mmol)，XPhos(476mg,1.0mmol)和Pd2(dba)3(184mg,0.20mmol)。反应在85度下反应过夜，LCMS检测反应结束后，加入35mL的盐水，并用乙酸乙酯(100mL x 3)萃取，有机相用硫酸钠干燥后浓缩，用柱层析纯化(石油醚/乙酸乙酯＝5:1-1:1)，得到粗产品，再用反向柱纯化得到化合物13(2.0g,产率＝28％)。测得：ESI-MS m/z＝712.9[M+1] +. 1H NMR(CDCl 3,400MHz):δ8.40-8.38(m,2H),7.95(s,1H),7.69-7.67(m,1H),7.60-7.57(m,2H),7.41(d,J＝8.4Hz,2H),7.08(s,1H),7.00(s,1H),5.86-5.82(m,1H),4.83(s,2H),4.35(brs,4H),4.19-4.16(m,1H),3.87-3.78(m,5H),2.16-1.99(m,3H),1.84-1.73(m,3H),0.93(s,9H),0.09(s,6H).
2.6.化合物I-2的合成
化合物I-2：中文名称为1-(4-(羟甲基)-3-(三氟甲基)苯基)-3-(4-(6-吗啉-7H-嘌呤-2-基)苯基)尿素；英文名称为：1-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-3-(4-(6-morpholino-7H-purin-2-yl)pheny l)urea
Figure PCTCN2020122436-appb-000026
将化合物13(2.0g,2.81mmol)溶解在1,4-二氧六环(8mL)里,再加入水(30mL)和1M的盐酸二氧六环(80mL)溶液.室温下搅拌过夜,LCMS检测反应结束后，过滤。得到的不溶物分别使用水，乙腈，和甲基叔丁醚打浆，干燥得到化合物I-2(1.3g,产率92％)。测得： 1H NMR(DMSO-d6,400MHz):δ9.50-9.44(m,2H),8.29-8.27(m,3H),7.97(s,1H),7.68-7.59(m,4H),4.61(s,2H),4.29(brs,4H),3.80-3.78(m,4H). 1H NMR(DMSO-d6+D 2O,400MHz):δ9.36-9.32(m,0.3H),8.29-8.26(m,3H),7.97(s,1H),7.68-7.60(m,4H),4.61(s,2H),4.29(brs,4H),3.80-3.78(m,4H).LCMS[mobile phase:from 95％water(0.02％NH 4Ac)and 5％CH 3CN to 5％water(0.02％NH 4Ac)and 95％CH 3CN in 6.5min,finally under these conditions for 0.5min.]purity is>97％,Rt＝3.485min；MS Calcd.:513；MS Found:514[M+H] +.
实施例3 化合物I-3的制备
采取以下路线合成化合物I-3：
Figure PCTCN2020122436-appb-000027
3.1.化合物15的合成
化合物15：中文名称为4-(2-(苄氧基)乙基)吗啉；英文名称为：4-(2-(benzyloxy)ethyl)morpholine；
Figure PCTCN2020122436-appb-000028
将化合物14(32.8g,0.25mol)溶于DMF(200mL)中，在冰水浴冷却下分次加入NaH(10g，0.25mol)，在室温搅拌1.5小时，滴加溴化苄(39.3g,0.23mol)。反应液在室温搅拌16小时，减压浓缩，加入乙酸乙酯(100mL)，用水洗涤，饱和食盐水洗涤。有机相减压浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)，得到无色的油化合物15(40g,产率78％)。测得：ESI-MS m/z＝222[M+1] +
3.2.化合物16的合成
化合物16：中文名称为4-(2-((4-硝基苄基)氧基)乙基)吗啉；英文名称为：4-(2-((4-nitrobenzyl)oxy)ethyl)morpholine；
Figure PCTCN2020122436-appb-000029
将化合物15(40.0g,0.18mol)溶于乙酸酐(200mL)中，在冰水浴冷却至5度，滴加发烟硝酸(60mL)，在5度搅拌4小时。反应液缓慢倒入碳酸钠水溶液中,使得pH>8，用乙酸乙酯萃取。有机相用水洗涤，饱和食盐水洗涤，减压浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)，得到无色的油化合物16(30.1g,产率62％)。测得：ESI-MS m/z＝267[M+1] +
3.3.化合物17的合成
化合物17：中文名称为4-((2-吗啉氧基)甲基)苯胺；英文名称为：4-((2-morpholinoethoxy)methyl)aniline；
Figure PCTCN2020122436-appb-000030
将化合物16(5.0g,0.018mol)溶于乙酸乙酯(200mL)中，加入10％的钯碳(1.0g)，氢气置换3次，在氢气球下室温搅拌16小时。反应液过滤，滤液减压浓缩至干，得到红色粗品化合物17(4.5g)，直接用于下一步。测得：ESI-MS m/z＝237[M+1] +
3.4.化合物18的合成
化合物18：中文名称为1-(4-((2-吗啉氧基)甲基)苯基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂醇-2-基)苯基)尿素；英文名称为：1-(4-((2-morpholinoethoxy)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea；
Figure PCTCN2020122436-appb-000031
冰浴下向化合物2的二氯甲烷溶液(100mL，来自6.6g的化合物1,30mmol)，滴加化合物17(5.9g,25mmol)的二氯甲烷(30mL)溶液。反应液在室温搅拌过夜，用碳酸氢钠水溶液洗涤，水洗，有机相减压浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)，得到黄色固体化合物18(8.7g,产率72.3％)。测得：ESI-MS m/z＝482[M+1] +
3.5.化合物19的合成
化合物19：中文名称为1-(4-(6-吗啉-7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基)苯基)-3-(4-((2-吗啉氧基)甲基)苯基)尿素；英文名称为1-(4-(6-morpholino-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea
Figure PCTCN2020122436-appb-000032
将化合物18(3.8g,8.28mmol)溶于1,4-二氧六环(80mL)\水(8mL)中，再加入化合物6(3.0g,9.29mmol),碳酸氢钠(2.1g,24.84mmol)，XPhos(395mg)和Pd 2(dba) 3(152mg)。反应在85度下反应过夜，LCMS检测反应结束后，加入20mL的盐水，并用乙酸乙酯萃取，有机相用硫酸钠干燥后浓缩，用硅胶柱层析纯化(二氯甲烷/甲醇＝30：1-10:1),再用反向柱纯化得到化合物19(1.5g,产率＝29％)。测得：ESI-MS m/z＝643.8[M+1] +. 1H NMR(DMSO-d6,400MHz):δ8.89(s,1H),8.72(s,1H),8.35-8.33(m,3H),7.57(d,J＝8.8Hz,2H),7.45(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),5.80-5.75(m,1H),4.39(s,2H),4.30(brs,3H),4.06-4.03(m,1H),3.78-3.71(m,5H),3.56-3.49(m,6H),3.36-3.35(m,1H),2.51-2.47(m,2H),2.39(brs,4H),2.31-2.22(m,1H),1.99-1.97(m,2H),1.79-1.76(m,1H),1.64-1.60(m,2H).
3.6.化合物I-3的合成
化合物I-3：中文名称为1-(4-(6-吗啉-7H-嘌呤-2-基)苯基)-3-(4-((2-吗啉氧基)甲基)苯基)尿素；英文名称为1-(4-(6-morpholino-7H-purin-2-yl)phenyl)-3-(4-((2-morpholinoethoxy)methyl)phenyl)urea
Figure PCTCN2020122436-appb-000033
将化合物19(2.5g,3.89mmol)溶解在0.3M的盐酸1,4-二氧六环(60mL)溶液里,再加入水(5mL).室温下搅拌2h,LCMS检测反应结束后，过滤。得到的不溶物分别使用乙腈，乙酸乙酯和甲基叔丁醚打浆，干燥得到化合物I-3(2.0g,产率91％)。测得： 1H NMR(DMSO-d6,400MHz):δ10.99(s,1H),9.92(s,1H),9.69(s,1H),8.40(s,1H),8.28(d,J＝8.4Hz,2H),7.63(d,J＝9.2Hz,2H),7.49(d,J＝8.4Hz,2H),7.29(d,J＝8.4Hz,2H),4.47(s,2H),4.29(brs,4H),3.96-3.93(m,2H),3.85-3.79(m,8H),3.42-3.34(m,4H),3.16-3.09(m,2H). 1H NMR(DMSO-d6+D 2O,400MHz):δ8.38-8.37(m,1H),8.25(d,J＝8.4Hz,2H),7.63(d,J＝8.4Hz,2H),7.49(d,J＝7.2Hz,2H),7.31(d,J＝8.4Hz,2H),4.49(s,2H),4.29(brs,4H),3.81-3.75(m,10H),3.43-3.35(m,4H),3.17-3.11(m,2H).LCMS[mobile phase:from 95％water(0.02％NH 4Ac)and 5％acetonitrile to 5％water(0.02％NH 4Ac)and 95％acetonitrile in 6.5min,finally under these conditions for 1min.]purity is>97％,Rt＝3.258min；MS Calcd.:558；MS Found:559([M+1] +).
实施例4 实施例化合物的生物活性实验
应用PI3-Kinase(human)HTRF TM Assay kit检测(PI3-Kinase(human)HTRF TM Assay kit检测的方法为国际通用方法)实施例的3个化合物I-1，I-2，I-3(以下实验中分别给予代号RMP-D06，RMP-D07，RMP-D08)对PI3K alpha酶的半数抑制浓度(IC 50测定)，采用化合物GDC-0941作为阳性对照。阳性对照品：GDC0941(Pictilisib)结构式如下：
Figure PCTCN2020122436-appb-000034
7.1材料和仪器
2104
Figure PCTCN2020122436-appb-000035
Multilabel Reader(Cat:2104-0010,PerkinElmer)；
384well opaque balck plate(Cat.6007270,PerkinElmer)；
PI3-Kinase(human)HTRFTM Assay kit(Cat.33-016,Millipore)；
4×Reaction Buffer(Cat.33-002,Millipore)；PIP2 1mM(Cat.33-004,Millipore)；Stop  A(Cat.33-006,Millipore)；Stop B(Cat.33-008,Millipore)；DM A(Cat.33-010,Millipore)；DM B(Cat.33-012,Millipore)；DM C(Cat.33-014,Millipore)；PI3k alpha(Cat.14-602,Millipore)；ATP 10mM(cat PV3227,Invitrogen)；DTT 1M(cat D5545,Sigma)；
待测化化合物I-1，I-2，I-3(以下实验中分别给予代号RMP-D06，RMP-D07，
RMP-D08)，以及GDC-0941。
7.2试剂配制
1×Reaction Buffer
4×Reaction Buffer用ddH 2O稀释至1×，并加入1M DTT使其终浓度为5mM。每次使用前新鲜配制。例如配制10mL 1×Reaction Buffer，加入2.5mL 4×Reaction Buffer,50μL 1M DTT，ddH 2O 7.45mL。整个实验中，用新鲜配制的1×Reaction Buffer配制ATP工作液，底物和酶混合工作液等。
4×化合物工作液
待测化合物用DMSO溶解至1mM作为储存液，然后用DMSO4倍倍比稀释，共10个浓度点。各取1μL加入24μL 1×Reaction Buffer中。每个稀释溶液各取5μL加入384孔板中，并含有1％DMSO。
2×PIP2工作液
用1×reaction buffer配制2×PIP2工作液，使其终浓度为20μM，PIP2的反应终浓度为10μM，例如配制1ml 1x reaction buffer/PIP2工作液，取20μL PIP2加入到980μL 1×reaction buffer中。这个工作液要多配0.1-0.2ml,以满足对照使用和死体积。
2×PIP2/激酶工作液
用2×PIP2工作液稀释激酶，激酶工作液的浓度为10ng/well。
无激酶对照(可视为100％抑制)
即2×PIP2工作液。
4×ATP工作液
10mM的ATP用1×reaction buffer稀释至40μM。在20μL激酶反应体系中，ATP的浓度为10μM。例如配制2ml ATP工作液，取8μL10mM ATP加入到1992μL 1×reaction buffer中。
终止液
Stop A和Stop B按3：1的比例混合，室温放置至少2小时后才可用，终止液可在室温下稳定12个小时。
检测液
DM C，DM A和DM B按照18：1：1的比例混合，室温放置至少2小时后才可用，检测液可在室温下稳定12个小时。
7.3实验流程
Figure PCTCN2020122436-appb-000036
数据分析
计算各孔的Emission Ratio(ER)
Emission Ratio(ER)＝665nM Emission signal/620nm Emission signal
100％抑制对照的平均发射强度比(Emission Ratio)记为：ER 100％
0％抑制对照的平均Emission Ratio记为：ER 0％
计算抑制率
抑制率用以下公式计算：
抑制率＝(ER sample-ER 0％)/(ER 100％-ER 0％)×100％【(ER阳性―ER样品)/(ER阳性―ER阴性)*100％】
7.4实验结果
应用PI3-Kinase(human)HTRFTM Assay kit检测3个化合物不同浓度下对PI3K-alpha酶的抑制率，控制DMSO浓度为1％，每个浓度为复孔，并选取GDC-0941作为阳性参照物进行测定，结果如图1所示。根据检测结果，各化合物对PI3K-alpha酶的半数抑制浓度(IC 50)总结如下表1所示。
表1、待测化合物对PI3K-alpha的半数抑制浓度(IC 50)
化合物名称 IC 50(nM)
RMP-D06 22.6
RMP-D07 214.8
RMP-D08 46.15
GDC0941 31.28
以上实验证明了本发明的新型新型嘌呤衍生物对磷脂肌醇-3-激酶(PI3Kα)的抑制作用，表明本发明的新型新型嘌呤衍生物(包括其可药用盐等)是一种新型PI3Kα抑制剂。因此，可以应用于治疗由磷脂肌醇-3-激酶介导的疾病，可治疗的恶性肿瘤包括但不限于肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌，纤维肉瘤、卵巢癌，白血病和前列腺癌等。
本发明的其他化合物与化合物I-1至化合物I-3具有基本相同的结构，可以预期他们具有与化合物I-1至化合物I-3相当的优异活性。该类化合物是世界上首创的新型化合物，已经显示了明显的强活性,将用于进一步的新药研究，发明出国产的创新药物，用于市场急需的作用强，副作用小而且便宜的抗癌药。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (19)

  1. 通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶，
    Figure PCTCN2020122436-appb-100001
    式中，A为-OH、-NH 2、-SH、
    Figure PCTCN2020122436-appb-100002
    B为-C nH 2n-，n为1、2、3或4；Z为氢、羟基、C 1-3烷基、氟、氯或溴，或为被选自氟、氯和溴中的一个或多个所取代的C 1-3烷基。
  2. 根据权利要求1所述的通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶，其特征在于：Z为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基。
  3. 根据权利要求1所述的通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶，其特征在于：所述嘌呤衍生物的结构如下式(I-a)所示：
    Figure PCTCN2020122436-appb-100003
    其中，A、B的定义分别同前述权利要求1，Z 1为氢、羟基、氟、氯、溴、甲基、乙基、异丙基、三氟甲基或五氟乙基。
  4. 根据权利要求1或3所述的通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶，其特征在于：所述B为-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH(CH 3)-、-CH(CH 3)CH 2-、-C(CH 3) 2-或-CH 2C(CH 3) 2-。
  5. 根据权利要求1或3所述的通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶，其特征在于：所述嘌呤衍生物为选自如下结构所示化合物：
    Figure PCTCN2020122436-appb-100004
  6. 如权利要求1至5中任一项权利要求所述的通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶在制备预防和/或治疗由磷脂酰肌醇-3-激酶(PI3K)介导的疾病的药物中的应用。
  7. 根据权利要求6所述的应用，其特征在于：所述由磷脂酰肌醇-3-激酶(PI3K)介导的疾病包括癌症，所述癌症包括肾癌、肝癌、结肠癌、胃肠道间质瘤、非小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、淋巴癌，纤维肉瘤、卵巢癌、白血病和前列腺癌。
  8. 一种药物组合物，其特征在于：包括一种或多种如权利要求1至5中任一项权利要求所述的通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶，以及药学可接受的载体。
  9. 根据权利要求8所述的药物组合物，其特征在于：所述药物组合物为治疗癌症的组合物。
  10. 一种制备如权利要求1至5中任意一项权利要求所述的通式(I)所示的嘌呤衍生物，其立体异构体、可药用盐、溶剂化物或结晶的中间体，其特征在于：所述中间体具有通式(II)所示结构：
    Figure PCTCN2020122436-appb-100005
    式(II)中，A 1为叔丁基二甲基硅氧基或者A 1与所述通式(I)中的A相同；
    B、Z分别与所述通式(I)中的B、Z相同，Y为氨基保护基。
  11. 根据权利要求10所述的中间体，其特征在于：所述氨基保护基为四氢-2H-吡喃-2-基。
  12. 根据权利要求10或11所述的中间体，其特征在于：所述中间体选自如下结构所示化合物：
    Figure PCTCN2020122436-appb-100006
    THP为四氢-2H-吡喃-2-基。
  13. 根据权利要求11所述的中间体，其特征在于：所述中间体通过使如下化合物
    Figure PCTCN2020122436-appb-100007
    与式(III)所示化合物
    Figure PCTCN2020122436-appb-100008
    反应得到；式(III)中，A 1、B和Z的定义同式(II)。
  14. 根据权利要求13所述的中间体，其特征在于：制备所述的式(II)所示中间体的过程中，所述反应在碱性条件下、温度30-120℃下进行，还选择性地在惰性气氛下进行。
  15. 根据权利要求14所述的中间体，其特征在于：制备所述的式(II)所示中间体的过程中，所述反应在温度40-110℃下进行，进一步优选在温度50-105℃下进行，更进一步优选在温度60-100℃下进行，再进一步优选在温度70-95℃下进行。
  16. 根据权利要求15所述的中间体，其特征在于：制备所述的式(II)所示中间体的过程中，所述反应在温度80-90℃下进行。
  17. 根据权利要求14所述的中间体，其特征在于：所述碱性条件通过添加碱性物质形成，所述碱性物质为选自乙酸钾、碳酸钾、苯酚钾、磷酸钾、叔丁醇钾、碳酸钠、碳酸氢钠、叔丁醇钠、甲醇钠、乙醇钠、三乙基胺、三正丁基胺和二异丙基乙基胺中的一种或多种的组合。
  18. 根据权利要求13或14所述的中间体，其特征在于：制备所述的式(II)所示中间体的过程中，所述反应在2-二环己基磷-2,4,6-三异丙基联苯和/或三(二亚苄基丙酮)二钯存在下进行。
  19. 根据权利要求18所述的中间体，其特征在于：制备所述的式(II)所示中间体的过程中，所述反应在2-二环己基磷-2,4,6-三异丙基联苯和三(二亚苄基丙酮)二钯共同存在下进行。
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