CN112979659A - Preparation and application of HIF-2 alpha small molecule inhibitor - Google Patents
Preparation and application of HIF-2 alpha small molecule inhibitor Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and relates to an HIF-2 alpha small molecule inhibitor, a preparation method and application thereof. The HIF-2 alpha small molecule inhibitor is shown as the structural general formula I
The invention relates to a compound and a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, wherein molecular simulation drug design software MOE is used for carrying out drug effect group screening and molecular docking, a series of compounds are designed and synthesized according to the dominant structure of final docking and the principle of electronic isostere, and in vitro antitumor activity screening tests show that the compounds have the function of resisting tumorTumor activity. The HIF-2 alpha small molecule inhibitor provided by the invention has better application prospect in the aspect of preventing or treating cancer, especially glioma.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an HIF-2 alpha small molecule inhibitor, a preparation method and application thereof.
Background
Cancer (cancer), a malignant tumor, is a cell differentiation and proliferation disorder of normal cells in the body, and the cells have no control on growth and have infiltration and metastasis. Glioma is a short name for glioma (Gliomas), also called glioma, is the most common primary central nervous system tumor in the cranium, and has high malignancy degree, which accounts for about half of all intracranial primary tumors. Temozolomide (TMZ) is an oral alkylating agent, can pass through the blood-brain barrier and reach the focus, and is one of the first-line chemotherapeutic drugs for clinical treatment of glioma. However, studies have shown that TMZ has an effective rate of about 45% for treating human brain glioma. Among them, the development of resistance of brain glioma to TMZ is the leading cause of chemotherapy failure. Therefore, the search for new chemotherapeutic drugs for treating gliomas is urgent.
Oxygen in the atmosphere is an essential element for the survival of animals, the hypoxic environment is indistinguishable from the occurrence and development of tumors, and both rapid proliferation and reduction/insufficiency of blood supply of the tumors can cause the hypoxic environment. Solid tumors such as glioma exist in a hypoxic microenvironment which can mediate tumor cells to generate chemoradiotherapy resistance through promoting tumor angiogenesis, inducing tumor stem cell-like phenotypic transformation and the like.
The human family of Hypoxia Inducible Factors (HIFs) is a heterodimer consisting of three regulated HIF- α (HIF-1 α, HIF-2 α/EPAS-1, and HIF-3 α) subunits and a constitutive ARNT (also known as HIF- β) subunit. Alpha subunit isomer HIF-1/2 alpha sensitive to hypoxia inducible factor oxygen content at normoxia is degraded through ubiquitination pathway; under hypoxic conditions, stable incorporation of HIF-1/2 α into the nucleus initiates transcriptional expression of downstream target genes, enabling tumor cells to tolerate hypoxic environments.
Research finds that HIF-2 alpha plays an important role in maintaining the growth of tumor cells, so that the development of HIF-2 alpha target inhibition drugs is of great significance. At present, no HIF-2 alpha inhibitor on the market exists, only a small molecule P2977 which can target and inhibit pVHL-deleted renal cancer cells is found, and the HIF-2 alpha inhibitor is currently in the phase II clinical test stage, but the HIF-2 alpha inhibitor which has the effect on glioma and other tumors is not reported. In the previous studies of the subject group, HWM-1, a small molecule, exhibits excellent inhibitory activity against HIF-2. alpha. protein and has excellent inhibitory activity against glioma.
On the basis of the structural skeleton of the small molecule HWM-1 researched in the earlier stage of a subject group, the interaction of hydrogen bond formation and pi-pi conjugation with HIF-2 alpha protein is kept unchanged, molecular simulation drug design software MOE is utilized to carry out drug effect group screening and molecular docking, a series of compounds are designed and synthesized according to the dominant structure of final docking and the principle of electronic isostere, and in vitro antitumor activity screening tests show that the compounds have antitumor activity. Therefore, the development of a novel HIF-2 alpha inhibitor capable of targeting tumor stem cell specific high expression has important clinical significance for inhibiting the occurrence, metastasis and recurrence of tumors.
Disclosure of Invention
In view of the problems in the prior art, the invention aims to provide a HIF-2 alpha small molecule inhibitor, a preparation method and application thereof. The invention utilizes molecular simulation drug design software MOE to carry out drug effect group screening and molecular docking, designs and synthesizes a series of compounds according to the final docked dominant structure and the electronic isostere principle, and in vitro antitumor activity screening tests show that the compounds have antitumor activity. The HIF-2 alpha small molecule inhibitor provided by the invention has better application prospect in the aspect of preventing or treating cancer, especially glioma.
In order to achieve the purpose, the invention adopts the following technical scheme.
An HIF-2 alpha small molecule inhibitor, the HIF-2 alpha small molecule inhibitor is a compound shown as a structural general formula I, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof,
wherein:
m represents 0, 1,2 or 3; n represents 0, 1,2 or 3; x represents 0, 1,2 or 3;
r1 and R2 are the same or different and are respectively and independently selected from hydrogen, trifluoromethyl and alkyl (C1-C4);
r3 is selected from 1-4 same or different hydrogen and halogen;
x is CH or N;
y is a five-membered or six-membered (aromatic) heterocyclic ring, which contains 1-3 heteroatoms selected from N, O, S respectively, and is optionally substituted by 1-3 same or different R4;
r4 is independently selected from 1-4 same or different substituents of hydrogen, halogen, hydroxyl, trifluoromethyl, three-fold methoxyl, amino, azido, nitro, cyano, sulfydryl, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio, allyl, (2-methyl) allyl, (C1-C4) alkoxymethyl, (C1-C4) alkylacyl and (C1-C3) alkylenedioxy.
Further, the HIF-2 alpha small molecule inhibitor is a compound shown as a structural general formula I, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof,
wherein:
m represents 0, 1,2 or 3; n represents 0, 1,2 or 3; x represents 0, 1,2 or 3;
R1、R2the same or different, are respectively and independently selected from hydrogen, trifluoromethyl and methyl;
R31-4 same or different hydrogen, fluorine and bromine are selected;
x is CH or N;
y is
R4Independently selected from 1-4 same or different hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl and three formazanA substituent of oxy, amino, azido, nitro, cyano, mercapto, methyl, ethyl, n-propyl, cyclopropyl, tert-butyl, vinyl, propenyl, 2-methylpropenyl, ethynyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methylthio, ethylthio, allyl, (2-methyl) allyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, formyl, acetyl, propionyl, cyclopropanoyl, butyryl, 2, 3-methylenedioxy, 2, 3-ethylenedioxy.
The compound with the general formula I, the stereoisomer thereof, and the pharmaceutically acceptable salt and/or hydrate thereof have a structure selected from any one of the following:
(1)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N-furan-2-ylmethyl) methylamine;
(2)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (furan-2-ylmethyl) methylamine;
(3)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (furan-2-ylmethyl) methylamine;
(4) n-benzyl-1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
(5) n- (4-fluorobenzyl) -1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
(6) n- (2-bromo-4-fluorobenzyl) -1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
(7)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (isoxazol-5-ylmethyl) methylamine;
(8)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) -N- (isoxazol-5-ylmethyl) methylamine;
(9)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (isoxazol-5-ylmethyl) methylamine;
(10) n-benzyl-1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine;
(11) n- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine;
(12) n- (3-bromobenzene) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine;
(13)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (thiazol-5-ylmethyl) methylamine;
(14)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) -N- (thiazol-5-ylmethyl) methylamine;
(15)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (thiazol-5-ylmethyl) methylamine;
(16) n-benzyl-1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
(17) n- (2-bromo-4-fluorobenzyl) -1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
(18) n- (3-bromobenzene) -1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
(19)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (pyridin-2-ylmethyl) methylamine;
(20)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (pyridin-2-ylmethyl) methylamine;
(21)1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (pyridin-2-ylmethyl) methylamine;
(22) n- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyridin-3-ylmethyl) methylamine;
(23) n- (2-bromo-4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyrimidin-4-ylmethyl) methylamine;
(24) n- (3-bromobenzene) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyrimidin-5-ylmethyl) methylamine;
(25) n- ((1H-pyrazol-3-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzylmethylamine;
(26) n- ((1H-pyrazol-3-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) methylamine;
(27) n- ((1H-pyrazol-5-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) methylamine;
(28) n- ((1H-pyrazolyl-5-yl) methyl) -N-benzyl-1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine;
(29) n- ((1H-pyrazolyl-4-yl) methyl) -N- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine;
(30) n- ((1H-pyrazol-4-yl) methyl) -N- (3-bromophenyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine.
A pharmaceutical composition comprises the HIF-2 alpha small molecule inhibitor and stereoisomer thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, and pharmaceutically acceptable carrier and excipient.
The HIF-2 alpha small molecule inhibitor and the stereoisomer thereof or the pharmaceutically acceptable salt, hydrate, solvate or the pharmaceutical composition of claim 4, can be used for preparing the drugs for preventing or treating tumors.
Further, the tumor is glioma.
Further, the dosage form of the drug is a pharmaceutically therapeutically acceptable dosage form.
Further, the dose of the drug is a pharmaceutically therapeutically acceptable dose.
The following synthetic schemes describe synthetic routes to the compounds of general formula I of this invention, all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final compounds of the present invention are prepared by the methods described in these schematic formulae or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these notations are as defined below or as defined in the claims.
Taking 1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (furan-2-ylmethyl) methylamine (a1) as an example, the synthesis procedure is shown below, all starting materials being commercially available and analytically pure.
The compound can be prepared into a composition by mixing a stereoisomer of the compound shown in the general formula I and pharmaceutically acceptable salts, hydrates or solvates thereof serving as active ingredients with a pharmaceutically acceptable carrier or excipient, and can be prepared into a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, auxiliary agent and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.
The term "alkyl" as used herein, unless otherwise indicated, refers to straight or branched chain alkyl groups; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to an organic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, naphthyl; 5-10 membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5 to 10 atoms, and examples include imidazolyl, pyridyl, pyrimidinyl, (1,2,3) -and (1,2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; 5-10 membered heterocyclic groups include those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, the ring system containing a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double or triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, and gluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, persilicates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with suitable bases include alkali metal, alkaline earth metal, ammonium and N + (Cl-4 alkyl) 4 salts. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, Cl-8 sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. According to one embodiment of the invention, a molecule of the compound of the invention may be associated with a molecule of water, such as a monohydrate; according to one embodiment of the invention, one molecule of the compound of the invention may be associated with more than one molecule of water, such as a dihydrate; according to one embodiment of the invention, one molecule of the compound of the invention may be combined with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The compounds of the present invention or pharmaceutical compositions thereof may be administered in unit dosage forms, and the route of administration may be advocated or extraordinary, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like, preferably as an injection.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, wetting agents, binders, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the adhesive can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, wetting agents, binders, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
The invention also relates to the effect of the compound with the general formula I on inhibiting HIF-2 alpha protein, and also relates to the application of the compound and the pharmaceutically acceptable salt and hydrate thereof in the preparation of medicaments for treating diseases caused by the growth of HIF-2 alpha high-expression CSCs, in particular to the application in the preparation of medicaments for treating glioma.
The "diseases" described in the present invention include, but are not limited to, the following diseases: cancer, including breast cancer, ovarian cancer, bladder cancer, brain cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, adrenal cancer, prostate cancer, stomach cancer, vaginal cancer, cervical cancer, endometrial cancer, thyroid cancer, skin cancer, and the like. Lymphomas of the hemopoietic system, including acute lymphocytic leukemia, B cell lymphoma, Burketts lymphoma, and the like; myeloid hematopoietic tumors, including acute and chronic myelogenous leukemia and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, neuroblastoma, glioma, and the like.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The term "prevention" as used herein refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but does not yet experience or exhibit symptoms of the disease).
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of its clinical symptoms). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
Compared with the prior art, the invention has the following beneficial effects.
(1) The invention provides a micromolecule inhibitor shown in a structural general formula I for the first time through experimental research, and the micromolecule inhibitor can be used as a new anti-tumor medicament for thoroughly eliminating tumors by mainly inhibiting HIF-2 alpha protein and further inhibiting the proliferation of tumor cells.
(2) The red HIF-2 alpha small molecular inhibitor uses triazolopyrazine as a parent nucleus, belongs to aromatic amines, and has lower toxicity compared with aliphatic amines.
(3) The small molecule inhibitor provided by the invention has no obvious inhibition effect on the expression of HIF-1 alpha, is proved to be a specific inhibitor of HIF-2 alpha and has targeting specificity.
(4) The existing HIF-2 alpha inhibitor is mainly used for kidney cancer, and the HIF-2 alpha small molecular inhibitor provided by the invention has a wide anticancer spectrum, has growth inhibition effect on various cancer cells, and especially has good inhibition effect on astrocyte cells.
Drawings
FIG. 1 is a general structural formula of a class of HIF-2 alpha small molecule inhibitors provided by the present invention.
Detailed Description
In order to better explain the invention, the following detailed description of the invention is given in conjunction with specific examples, which are not intended to limit the invention. The examples are intended to illustrate, but not to limit, the scope of the invention. The compound is detected by High Performance Liquid Chromatography (HPLC) and Thin Layer Chromatography (TLC). The structure can then be confirmed using techniques such as infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (1H NMR, 13C NMR), High Resolution Mass Spectroscopy (HRMS), and the like. All reagents used were analytically or chemically pure.
An HIF-2 alpha small molecule inhibitor, the HIF-2 alpha small molecule inhibitor is a compound shown as a structural general formula I, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof,
wherein:
m represents 0, 1,2 or 3; n represents 0, 1,2 or 3; x represents 0, 1,2 or 3;
r1 and R2 are the same or different and are respectively and independently selected from hydrogen, trifluoromethyl and alkyl (C1-C4);
r3 is selected from 1-4 same or different hydrogen and halogen;
x is CH or N;
y is a five-membered or six-membered (aromatic) heterocyclic ring, which contains 1-3 heteroatoms selected from N, O, S respectively, and is optionally substituted by 1-3 same or different R4;
r4 is independently selected from 1-4 same or different substituents of hydrogen, halogen, hydroxyl, trifluoromethyl, three-fold methoxyl, amino, azido, nitro, cyano, sulfydryl, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio, allyl, (2-methyl) allyl, (C1-C4) alkoxymethyl, (C1-C4) alkylacyl and (C1-C3) alkylenedioxy.
Example 11 preparation of- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (furan-2-ylmethyl) methylamine (a 1).
Step 1, 3-bromo-2-chloropyrimidine (10g, 0.052mol) was dissolved in toluene (200mL), cooled to-65 ℃, and DMF (dimethylformamide) (6.2mL, 0.08mol) was added dropwise, after which n-butyllithium (1.57M in n-hexane; 51mL, 0.08mol) was added dropwise. After stirring for 20 minutes, the reaction was terminated with 1N hydrochloric acid, and the reaction solution was extracted with ethyl acetate, washed with water for several layers, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness to obtain the product (intermediate a) which was used in the next step without further purification.
Step 2, to a solution of intermediate a in ethanol (30mL) was slowly added sodium borohydride (2g, 0.052mol) in portions at room temperature, followed by stirring for 30 minutes after the addition. After the reaction was terminated with 36% glacial acetic acid solution, it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated to dryness. The residue was purified by column chromatography to give a yellow powder (intermediate b) (5.6g, 75%).
And 3, dissolving the intermediate b (10g, 0.07mol) prepared in the step 2 in DMF (50mL), cooling to 0 ℃, and dropwise adding thionyl chloride (9.2g, 0.77mol) under stirring. After dropping, the reaction was carried out at room temperature for 1 hour and monitored by TLC. The reaction was diluted with ethyl acetate (40mL) and water was added to quench the reaction, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give intermediate c, which was used in the next step without further purification.
Step 4, add the solution of intermediate c (10g) obtained in step 3 to it in small portions with hydrazine hydrate (10.5g, 0.21mol) and reflux at 85 ℃ and monitor the reaction completion by TLC. After the reaction mixture was cooled, it was stirred in ice water, and the precipitated solid was suction-filtered and the filter cake was dried to give a yellow powder (intermediate d) (9.66g, 87%).
Step 5, intermediate d (5g, 0.063mol) from step 4 was added to triethyl orthoformate (50ml) and reacted at 80 ℃ with TLC monitoring for completion. The reaction solution was cooled and filtered directly, the filter cake was washed with petroleum ether and dried to give a yellow powder (intermediate e) (9.6g, 90%).
And step 6, adding furfural (9.6g,0.1mol) and methanol (90ml) into a 250ml eggplant-shaped bottle, then placing the bottle in an ice bath for stirring, adding sodium borohydride (3.78g,0.1mol) for a few times in the stirring process after the temperature is reduced to 0 ℃, adding benzylamine (10.71g,0.1mol) after no bubbles exist, removing the ice bath, stirring the bottle at room temperature for 6 hours, and evaporating the solvent to dryness to obtain an oily substance (an intermediate f, 17.8g, 95.0%). The product was used in the next step without further purification.
Step 7, adding the intermediate e (2g,0.01mol) prepared in the step 5, potassium carbonate (1.38g, 0.01mol), potassium iodide (0.166g,0.001mol) and N, N-dimethylformamide 90ml into a 250ml eggplant-shaped bottle, stirring for 15min at room temperature, adding the intermediate f (1.87g,0.01mol) prepared in the step 6, placing the mixture into an oil bath, heating to 85 ℃, stirring for 1h, removing the oil bath, cooling to room temperature, adding water for dissolution, extracting a water layer for 2 times by using ethyl acetate, combining organic phases, washing by using saturated salt water, collecting an organic layer, and drying the organic layer by using anhydrous sodium sulfate to obtain milky solid A1(2.65g, 83.0%). ESI-MS m/z: 319.37, respectively;1H-NMR(400MHz，DMSO-d6)δ9.15(s,1H),8.36(d,J＝2.7Hz,1H),7.69(d,J＝2.7Hz,1H),7.36(d,J＝4.2Hz,1H),7.21-7.25(m,5H),6.65(d,J＝1.3Hz,1H),6.32(t,J＝1.3Hz,J＝4.2Hz,1H),4.19(s,1H),3.96(s,1H),3.74(s,2H),3.58(s,2H)。
example 21 preparation of- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (furan-2-ylmethyl) methylamine (a 2).
Preparation methodThe procedure is as in example 1, ESI-MS m/z: 337.36, respectively;1H-NMR(400MHz，DMSO-d6)δ9.13(s,1H),8.36(d,J＝2.7Hz,1H),7.68(d,J＝2.7Hz,1H),7.44(dd,J＝0.32Hz,2H),7.36(d,J＝4.3Hz,1H),7.07(t,2H),6.52(d,J＝0.88Hz,1H),6.30(t,J＝0.88Hz,J＝4.3Hz,1H),3.99(s,2H),3.82(s,2H),3.54(s,2H)。
example 31 preparation of- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (furan-2-ylmethyl) methylamine (a 3).
The preparation method is the same as example 1, ESI-MS m/z: 398.26.
example 4 preparation of N-benzyl-1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine (a 4).
The preparation method is the same as example 1, ESI-MS m/z: 333.4.
example 5 preparation of N- (4-fluorobenzyl) -1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine (a 5).
The preparation method is the same as example 1, ESI-MS m/z: 351.39.
example 6 preparation of N- (2-bromo-4-fluorobenzyl) -1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine (a 6).
The preparation method is the same as example 1, ESI-MS m/z: 430.28.
example 71 preparation of- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (isoxazol-5-ylmethyl) methylamine (A7).
The preparation method is the same as example 1, ESI-MS m/z: 320.36.
example 81 preparation of- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) -N- (isoxazol-5-ylmethyl) methylamine (A8).
The preparation method is the same as example 1, ESI-MS m/z: 417.24.
example 91- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (isoxazol-5-ylmethyl) methylamine (A9) preparation.
The preparation method is the same as example 1, ESI-MS m/z: 399.25.
EXAMPLE 10 preparation of N-benzyl-1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine (A10).
The preparation method is the same as example 1, ESI-MS m/z: 334.38.
EXAMPLE 11 preparation of N- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine (A11).
The preparation method is the same as example 1, ESI-MS m/z: 352.37.
EXAMPLE 12 preparation of N- (3-bromobenzene) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine (A12).
The preparation method is the same as example 1, ESI-MS m/z: 413.28.
example 131- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (thiazol-5-ylmethyl) methylamine (a13) was prepared.
The preparation method is the same as example 1, ESI-MS m/z: 354.41.
example 141- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) -N- (thiazol-5-ylmethyl) methylamine (a14) was prepared.
The preparation method is the same as example 1, ESI-MS m/z: 433.3.
example 151- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (thiazol-5-ylmethyl) methylamine (a15) was prepared.
The preparation method is the same as example 1, ESI-MS m/z: 415.31.
example 16 preparation of N-benzyl-1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine (A16).
The preparation method is the same as example 1, ESI-MS m/z: 350.44.
example 17 preparation of N- (2-bromo-4-fluorobenzyl) -1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine (A17).
The preparation method is the same as example 1, ESI-MS m/z: 447.33.
example 18 preparation of N- (3-bromobenzene) -1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine (A18).
The preparation method is the same as example 1, ESI-MS m/z: 429.34.
example 191- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (pyridin-2-ylmethyl) methylamine (a19) was prepared.
The preparation method is the same as example 1, ESI-MS m/z: 330.4.
example 201 preparation of- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (pyridin-2-ylmethyl) methylamine (a 20).
The preparation method is the same as example 1, ESI-MS m/z: 348.39.
example 211 preparation of- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (pyridin-2-ylmethyl) methylamine (a 21).
The preparation method is the same as example 1, ESI-MS m/z: 409.29.
example 22 preparation of N- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyridin-3-ylmethyl) methylamine (A22).
The preparation method is the same as example 1, ESI-MS m/z: 462.41.
example 23 preparation of N- (2-bromo-4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyrimidin-4-ylmethyl) methylamine (A23).
The preparation method is the same as example 1, ESI-MS m/z: 442.3.
example 24 preparation of N- (3-bromobenzene) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyrimidin-5-ylmethyl) methylamine (A24).
The preparation method is the same as example 1, ESI-MS m/z: 424.31.
example 25 preparation of N- ((1H-pyrazol-3-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzylmethylamine (A25).
The preparation method is the same as example 1, ESI-MS m/z: 319.37.
example 26 preparation of N- ((1H-pyrazol-3-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) methylamine (a 26).
The preparation method is the same as example 1, ESI-MS m/z: 416.26.
example 27 preparation of N- ((1H-pyrazol-5-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) methylamine (A27).
The preparation method is the same as example 1, ESI-MS m/z: 398.27.
example 28 preparation of N- ((1H-pyrazolyl-5-yl) methyl) -N-benzyl-1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine (A28).
The preparation method is the same as example 1, ESI-MS m/z: 333.4.
example 29 preparation of N- ((1H-pyrazolyl-4-yl) methyl) -N- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine (A29).
The preparation method is the same as example 1, ESI-MS m/z: 351.39.
example 30 preparation of N- ((1H-pyrazol-4-yl) methyl) -N- (3-bromophenyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine (A30).
The preparation method is the same as example 1, ESI-MS m/z: 412.3.
the structural formula of the HIF-2 alpha small molecule inhibitor compound prepared in the embodiment 1-30 of the invention is shown in Table 1.
TABLE 1 structural formulas of the HIF-2. alpha. small molecule inhibitors prepared in examples 1-30.
EXAMPLE 31 in vitro studies of the activity of HIF-2 α small molecule inhibitors prepared in examples 1-30 against tumor cells.
The compound of the general structural formula I (HIF-2 alpha small molecule inhibitor prepared in examples 1-30) according to the invention is screened for inhibiting the activity of human brain astrocytomas U118-MG, U-87MG and U251-MG in vitro.
1 test materials.
1.1 cells and reagents.
Human brain astrocytoma cell U118-MG, human brain astrocytoma cell U87-MG and human brain astrocytoma cell U251-MG, DMEM medium, Trypsin-EDTA (0.05%), Fetal Bovine Serum (FBS), dimethyl sulfoxide (DMSO), thiazole blue (MTT).
2 experimental methods.
2.1 cell culture.
Removing U118-MG, U87-MG and U251-MG cells from liquid nitrogen, thawing in 37 deg.C water bath, centrifuging at 1000rpm for 5min, removing supernatant, adding 10% fetal calf serum DMEM medium 1mL respectively, transferring cell suspension into 25cm2In the cell culture flask, 4mL of a medium containing 10% fetal calf serum was added and cultured.
2.2 MTT cell proliferation assay.
Human brain astrocytoma cells (U118-MG, U87-MG and U251-MG) in logarithmic growth phase were digested, and the cell concentration was adjusted to 2X 10 with DMEM medium (purchased from Hyclone, USA) containing 10% fetal bovine serum4Single cell suspension of each/mL, seeded in 96-well plates with 2X 10 cells per well3The cells were allowed to adhere to each other by overnight culture, and then the culture medium was discarded, and 100. mu.L of each well was administered with 3 duplicate wells, and each well was filled with a test sample (0.1. mu.M, 0.3. mu.M, 1. mu.M, 3. mu.M, 10. mu.M, 30. mu.M, 100. mu.M, 300. mu.M, 1000. mu.M, 3000. mu.M) or a positive drug (0.1. mu.M, 0.3. mu.M, 1. mu.M, 3. mu.M, 10. mu.M, 30. mu.M, 100. mu.M, 300. mu.M, 1000. mu.M, 3000. mu.M) at different concentrations. The 96-well plate was placed at 37 ℃ in 5% CO2Culturing for 48h in an incubator; adding 20 mu L of 5mg/mL MTT solution into each well, continuing to culture for 2h, carefully sucking and discarding the solution in each well, adding 100 mu L of DMSO solution into each well, keeping out of the sun, and shaking by a shaking table for 10 min; the absorbance was measured at a wavelength of 570nm (MTT detection) with a microplate reader, and the half-toxic concentration (IC) of the drug was calculated50). The growth inhibition rate was calculated according to the following formula: growth inhibition (%) ([ 1- (dosing well-zero hole)/(control well-zero hole)]100% of the total weight; with SPSS 22.0Software computing IC50The experiment was repeated three times.
Half maximal Inhibitory Concentration (IC) of HIF-2. alpha. Small molecule inhibitors prepared in examples 1-30 against human brain astrocyte cells (U118, U87 and U251)50) The results are shown in Table 2.
TABLE 2 half maximal Inhibitory Concentration (IC) of HIF-2. alpha. Small molecule inhibitors prepared in examples 1-30 on human brain astrocyte cells (U118, U87 and U251)50) And (6) obtaining the result.
The test results clearly show that the compound shown as the structural general formula I has good in-vitro anti-tumor activity, and part of the compound with better activity is equivalent to or superior to a positive control drug TMZ, so that a new way is opened for the deep research and development of new anti-tumor drugs.
While the invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A HIF-2 alpha small molecule inhibitor is characterized in that the HIF-2 alpha small molecule inhibitor is a compound shown as a structural general formula I, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof,
wherein:
m represents 0, 1,2 or 3; n represents 0, 1,2 or 3; x represents 0, 1,2 or 3;
r1 and R2 are the same or different and are respectively and independently selected from hydrogen, trifluoromethyl and alkyl (C1-C4);
r3 is selected from 1-4 same or different hydrogen and halogen;
x is CH or N;
y is a five-membered or six-membered (aromatic) heterocyclic ring, which contains 1-3 heteroatoms selected from N, O, S respectively, and is optionally substituted by 1-3 same or different R4;
r4 is independently selected from 1-4 same or different substituents of hydrogen, halogen, hydroxyl, trifluoromethyl, three-fold methoxyl, amino, azido, nitro, cyano, sulfydryl, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio, allyl, (2-methyl) allyl, (C1-C4) alkoxymethyl, (C1-C4) alkylacyl and (C1-C3) alkylenedioxy.
2. The HIF-2 α small molecule inhibitor of claim 1, wherein the HIF-2 α small molecule inhibitor is a compound of formula I, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof,
wherein:
m represents 0, 1,2 or 3; n represents 0, 1,2 or 3; x represents 0, 1,2 or 3;
R1、R2the same or different, are respectively and independently selected from hydrogen, trifluoromethyl and methyl;
R31-4 same or different hydrogen, fluorine and bromine are selected;
x is CH or N;
y is
R4Independently selected from 1 to 4 substituents which are the same or different from hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, mercapto, methyl, ethyl, n-propyl, cyclopropyl, tert-butyl, vinyl, propenyl, 2-methylpropenyl, ethynyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methylthio, ethylthio, allyl, (2-methyl) allyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, formyl, acetyl, propionyl, cycloproponyl, butyryl, 2, 3-methylenedioxy, 2, 3-ethylenedioxy.
3. The HIF-2 α small molecule inhibitor of claim 1, wherein the structure of the compound of formula I and stereoisomers thereof, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, is selected from any one of the following:
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N-furan-2-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (furan-2-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (furan-2-ylmethyl) methylamine;
n-benzyl-1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
n- (4-fluorobenzyl) -1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
n- (2-bromo-4-fluorobenzyl) -1- (furan-2-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (isoxazol-5-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) -N- (isoxazol-5-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (isoxazol-5-ylmethyl) methylamine;
n-benzyl-1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine;
n- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine;
n- (3-bromobenzene) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (oxazol-5-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (thiazol-5-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) -N- (thiazol-5-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (thiazol-5-ylmethyl) methylamine;
n-benzyl-1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
n- (2-bromo-4-fluorobenzyl) -1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
n- (3-bromobenzene) -1- (isothiazol-5-yl) -N- ((3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzyl-N- (pyridin-2-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (4-fluorobenzyl) -N- (pyridin-2-ylmethyl) methylamine;
1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) -N- (pyridin-2-ylmethyl) methylamine;
n- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyridin-3-ylmethyl) methylamine;
n- (2-bromo-4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyrimidin-4-ylmethyl) methylamine;
n- (3-bromobenzene) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (pyrimidin-5-ylmethyl) methylamine;
n- ((1H-pyrazol-3-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-benzylmethylamine;
n- ((1H-pyrazol-3-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (2-bromo-4-fluorobenzyl) methylamine;
n- ((1H-pyrazol-5-yl) methyl) -1- ([1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N- (3-bromophenyl) methylamine;
n- ((1H-pyrazolyl-5-yl) methyl) -N-benzyl-1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine;
n- ((1H-pyrazolyl-4-yl) methyl) -N- (4-fluorobenzyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine;
n- ((1H-pyrazol-4-yl) methyl) -N- (3-bromophenyl) -1- (3-methyl- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) methylamine.
4. A pharmaceutical composition, comprising the HIF-2 alpha small molecule inhibitor and stereoisomer thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, and pharmaceutically acceptable carrier and excipient.
5. Use of the HIF-2 α small molecule inhibitor of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate thereof, or the pharmaceutical composition of claim 4, for the preparation of a medicament for the prevention or treatment of a tumor.
6. The use of claim 5, wherein the tumor is a glioma.
7. The use according to claim 5, wherein the medicament is in a pharmaceutically and therapeutically acceptable dosage form.
8. The use of claim 5, wherein the dose of the medicament is a pharmaceutically therapeutically acceptable dose.
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| JP2000319277A (en) * | 1999-05-11 | 2000-11-21 | Ono Pharmaceut Co Ltd | Condensed pyrazine compound and medicinal agent having the same as active ingredient |
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| CN1285834A (en) * | 1997-11-11 | 2001-02-28 | 小野药品工业株式会社 | Fused pyrazine compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023134713A1 (en) * | 2022-01-12 | 2023-07-20 | 南方科技大学 | Fused azaheterocyclic derivative, and pharmaceutical composition and use thereof |
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|---|---|
| CN112979659B (en) | 2022-07-08 |
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