CN113004246B - 1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt and application thereof - Google Patents

1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt and application thereof Download PDF

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CN113004246B
CN113004246B CN202110197192.XA CN202110197192A CN113004246B CN 113004246 B CN113004246 B CN 113004246B CN 202110197192 A CN202110197192 A CN 202110197192A CN 113004246 B CN113004246 B CN 113004246B
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CN113004246A (en
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何林洪
姚华良
黄怀征
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Guangxi Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/70—Other substituted melamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a 1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt thereof, which comprises the following components: the general formula of the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is shown in formula I;

Description

1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt and application thereof
Technical Field
The invention relates to the field of chemical medicine. More particularly, the invention relates to a 1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt and application thereof.
Background
BMX is a member of the TEC family of non-receptor tyrosine kinases, also known as epithelial and endothelial tyrosine kinases (Etk), and is widely expressed in bone marrow, monocytes, granulocytes, epithelial and endothelial cells, as well as brain, prostate, lung and heart, among others. Bmx is capable of mediating the signaling of multiple extracellular stimulus responses, is recruited to the plasma membrane of cells by a variety of lipid or protein molecules (e.g., PIP3, integrin-associated kinases, cytokine receptor-associated kinases, xenotropic Receptor Tyrosine Kinases (RTKs), G protein-coupled receptors (GPCRs) and growth factor receptors (GF), etc.) and activates downstream Src family molecules (SFKs), which in turn phosphorylate Bmx at Tyr 566; the activated Bmx can further phosphorylate STAT3, activate STAT3 to enter a cell nucleus to be specifically combined with a target gene, regulate transcription and exert biological effects, and can activate signal pathways such as Akt/mTOR, MAPKs and NF-kB, participate in physiological activities such as cell proliferation, survival, apoptosis, fibrosis, adhesion, metastasis and angiogenesis, further induce the formation of various epithelial cancers including prostate cancer, lung cancer, cervical cancer, bladder cancer, breast cancer and the like, namely the high expression of BMX can promote the disease process of various cancers. However, it is surprising that BMX homozygote mice show normal phenotype and life span after gene knockout, i.e., BMX is inhibited from silencing and does not have serious toxic or side effects on the living body. Therefore, the development of BMX inhibitors can be safely used for treating various cancers such as prostate cancer, lung cancer and the like.
At present, BMX inhibitors are rarely reported, and are mostly covalent inhibitors, such as
Figure BDA0002947416820000011
These inhibitors exploit the unique cysteine 496(Cys496) of BMX proteins in their catalytically active domain, selectively and rapidly undergoing "michael-addition" reactions with electrophilic fragments of ligands to form strong "C-S" covalent bonds. The covalent interaction force can specifically identify cysteine in the protein active cavity and form a covalent bond with the cysteine, so that the kinase selectivity is improved, and the risk of toxic and side effects is reduced; in addition, the firm covalent acting force can durably precipitate the protein, so that the drug effect is strong and durable, the dosage and the administration frequency are reduced, and the compliance of patients is improved. However, the existing BMX inhibitors have more complex structures and fewer quantities, and therefore, more BMX inhibitors are to be developed for later research selection.
Disclosure of Invention
The invention aims to provide a 1,3, 5-triazine-2-amine-4, 6 substituted derivative or a pharmaceutically acceptable salt, a preparation method and application thereof, and the obtained 1,3, 5-triazine-2-amine-4, 6 substituted derivative has a simple structure and provides a new choice for preparing BMX inhibitors and anticancer drugs.
To achieve these objects and other advantages in accordance with the present invention, there is provided according to one aspect of the present invention a 1,3, 5-triazin-2-amine-4, 6-substituted derivative, or a pharmaceutically acceptable salt thereof, wherein the 1,3, 5-triazin-2-amine-4, 6-substituted derivative has a general formula as shown in formula I;
Figure BDA0002947416820000021
wherein R is1Included
Figure BDA0002947416820000022
R11 is selected from H, C1～C4Alkyl, halogen, C1～C4Halogen-substituted alkyl; r12 is selected from C1～C4Alkyl radical, C1～C4Halogen substituted alkyl, phenyl, substituted phenyl, benzyl, substituted heterocyclic radical;
x comprises
Figure BDA0002947416820000023
Figure BDA0002947416820000024
R2 includes
Figure BDA0002947416820000025
R21 is selected from C2～C4Alkenyl radical, C2～C4Substituted alkenyl, C2～C4Halogen-substituted alkyl, C2～C4Alkynyl, C2～C4Substituted alkynyl.
Further, R1Selected from the following groups:
Figure BDA0002947416820000031
R4and R5Each independently selected from H, CN, halogen and C1～C4An alkyl group.
According to another aspect of the present invention, a process for the preparation of a 1,3, 5-triazin-2-amine-4, 6-substituted derivative, or a pharmaceutically acceptable salt thereof, comprises:
will be provided with
Figure BDA0002947416820000032
Reaction to obtain
Figure BDA0002947416820000033
Will be provided with
Figure BDA0002947416820000034
And NH4OH reaction to give
Figure BDA0002947416820000035
To be provided with
Figure BDA0002947416820000036
For the preparation of reactants
Figure BDA0002947416820000037
According to still another aspect of the invention, the 1,3, 5-triazine-2-amine-4, 6 substituted derivative or the pharmaceutically acceptable salt thereof is used for preparing a medicament for inhibiting non-receptor tyrosine kinase BMX.
Further, the medicament comprises a pharmaceutically acceptable carrier, excipient or diluent.
According to still another aspect of the invention, the 1,3, 5-triazine-2-amine-4, 6 substituted derivative or the pharmaceutically acceptable salt thereof is used for preparing a medicament for treating cancer.
Further, the cancer includes prostate cancer, breast cancer, colon cancer, uterine cancer, EGFR-mutated non-small cell lung cancer.
The invention at least comprises the following beneficial effects:
the 1,3, 5-triazine-2-amine-4, 6 substituted derivative has a simple structure and a good BMX kinase inhibition effect, and provides a new choice for preparing BMX covalent inhibitors and anticancer drugs.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Detailed Description
The present invention is described in further detail below to enable those skilled in the art to practice the invention with reference to the description.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
The embodiment of the application provides a 1,3, 5-triazine-2-amine-4, 6 substituted derivative or a pharmaceutically acceptable salt thereof, wherein the general formula of the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is shown as a formula I;
Figure BDA0002947416820000041
wherein R is1Included
Figure BDA0002947416820000042
R11 is selected from H, C1～C4Alkyl, halogen, C1～C4Halogen-substituted alkyl; r12 is selected from C1～C4Alkyl radical, C1～C4Halogen substituted alkyl, phenyl, substituted phenyl (such as halogen substituted), benzyl, substituted benzyl (such as halogen substituted on benzene), substituted heterocyclic radical (such as containing N five-membered heterocyclic ring and six-membered heterocyclic ring);
x comprises
Figure BDA0002947416820000043
Figure BDA0002947416820000044
R2 includes
Figure BDA0002947416820000045
R21 is selected from C2～C4Alkenyl radical, C2～C4Substituted alkenyl(e.g. halogen substitution), C2～C4Halogen-substituted alkyl, C2～C4Alkynyl, C2～C4Substituted alkynyl (e.g., halo substituted).
In other embodiments, R1Selected from the following groups:
Figure BDA0002947416820000051
R4and R5Each independently selected from H, CN, halogen and C1～C4An alkyl group.
In other embodiments, there are specifically provided 1,3, 5-triazin-2-amine-4, 6 substituted derivatives as shown in Table 1, numbered from II-1 to VIII-5.
TABLE 11, 3, 5-triazin-2-amine-4, 6 substituted derivatives
Figure BDA0002947416820000052
Figure BDA0002947416820000061
Figure BDA0002947416820000071
Figure BDA0002947416820000081
Figure BDA0002947416820000091
Figure BDA0002947416820000101
Figure BDA0002947416820000111
Figure BDA0002947416820000121
Figure BDA0002947416820000131
Figure BDA0002947416820000141
Figure BDA0002947416820000151
Figure BDA0002947416820000161
Figure BDA0002947416820000171
Figure BDA0002947416820000181
Figure BDA0002947416820000191
The examples herein also provide methods for the preparation of 1,3, 5-triazin-2-amine-4, 6 substituted derivatives, and for convenience in the description of the exemplary synthetic routes and methods that follow, the abbreviations for the starting materials or reagents used are now tabulated below.
TABLE 2 reagents and abbreviations
Figure BDA0002947416820000201
The synthetic route for the compound of formula II is as follows:
Figure BDA0002947416820000202
in particular, the amount of the solvent to be used,
Figure BDA0002947416820000203
adding the raw material 1(1.0eq), potassium carbonate (1.3eq) and a proper amount of THF (tetrahydrofuran) into a reaction flask as a solvent, stirring at room temperature, slowly dropping a THF solution of a primary amino derivative (1.0eq) into the reaction flask, and continuously stirring at room temperature for reaction for 2 hours. Stopping the reaction, concentrating under reduced pressure to recover the reaction solvent, EA/H2O extraction of the concentrate, collection of the oil layer, washing of the oil layer with saturated brine, drying over anhydrous sodium sulfate, concentration of the oil layer under reduced pressure, and purification by silica gel column chromatography gave intermediate 2 as a white solid.
Figure BDA0002947416820000211
The raw material 2, an appropriate amount of acetone and 25% ammonia water were added to the reaction flask, and stirred at room temperature for 2 hours, with the formation of a solid gradually. Stopping the reaction, filtering and collecting the solid, washing the filter cake with water for many times, and drying the filter cake to obtain a product 3.
Figure BDA0002947416820000212
The reaction flask was charged with the starting materials 3(1.0eq), (R) -3-Boc-aminopiperidine (1.0eq) and K2CO3(1.5eq), add an appropriate amount of DMF as solvent, heat and stir at 80 ℃ for 2 h. Stopping the reaction, cooling to room temperature, EA/H2O extracting the concentrate, collecting oil layer, washing the oil layer with saturated saline water, drying with anhydrous sodium sulfate, concentrating the oil layer under reduced pressure, and purifying with silica gel column chromatographyIntermediate 4 was obtained as a brown oily liquid.
Figure BDA0002947416820000213
Adding the intermediate 4 and a proper amount of EA into a reaction bottle, dropwise adding a small amount of saturated HCl solution at room temperature, moving to heating reflux for about 1h, monitoring by TLC that the deprotection of the raw material is finished, filtering and collecting solid to obtain an intermediate 5.
Figure BDA0002947416820000214
The intermediate 5(1.0eq) and an appropriate amount of dry DMF were added to a reaction flask, DIEA (3.0eq) and the acid chloride derivative (1.0eq) were added dropwise in this order, and the mixture was allowed to react overnight at room temperature. Extracting the reaction solution with DCM and water, collecting the oil layer, washing the oil layer with saturated brine for 3 times, and removing anhydrous Na2SO4Drying the oil layer, spin-drying the oil layer and purifying with silica gel column to collect target product II.
Similarly, derivatives of Nos. II-1 to VIII-5 can be prepared based on similar preparation methods.
The embodiments of the present application also provide the use of a 1,3, 5-triazin-2-amine-4, 6 substituted derivative, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting the non-receptor tyrosine kinase BMX. The medicament comprises a pharmaceutical composition. Pharmaceutical compositions refer to mixtures of one or more compounds of the invention or their pharmaceutically acceptable salts and prodrugs with other chemical components, including pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. Pharmaceutically acceptable carriers refer to carriers or diluents that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the administered compound. Excipients refer to inert substances added to a pharmaceutical composition to further facilitate administration of the compound. Examples of excipients include, without limitation, calcium carbonate, calcium phosphate, various sugars and types of starch, fiber derivatives, gelatin, vegetable oils, and polyethylene glycols.
Embodiments of the present application also provide the use of a 1,3, 5-triazin-2-amine-4, 6-substituted derivative, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
In other embodiments, the cancer comprises prostate cancer, breast cancer, colon cancer, uterine cancer, EGFR-mutated non-small cell lung cancer.
The following provides pharmacological activity screening experiments, i.e. experiments on the inhibition of BMX kinase activity at the biochemical level in vitro, to verify the above-mentioned use of 1,3, 5-triazin-2-amine-4, 6-substituted derivatives or pharmaceutically acceptable salts thereof.
Materials: BMX kinase (Invitrogen); polypeptide FAM-P22(GL Biochem); ATP, DMSO, and edta (sigma); 96-well plates (Corning), positive control staurosporine (sigma).
The method comprises the following steps:
1.1 Xkinase in alkaline buffer and stop buffer.
1) BMX 1x kinase base buffer contained 50Mm HEPES, Ph 7.5; 0.0015% Brij-35; 10Mm MgCl 2; 2Mm DTT.
2) The stop buffer contained 100Mm HEPES, Ph 7.5; 0.015% Brij-35; 0.2% Coating Reagent # 3; 50Mm EDTA.
2. And (4) preparing the compound.
1) Test compounds were formulated with 100% DMSO at 50-fold the highest concentration tested. Transfer 100 μ l of compound dilution to well plate.
2) Add 100 μ L of 100% DMSO to 2 wells and mark the plate as the original plate. Transfer 10 μ L of compound from the original plate to a new 96-well plate and record as the intermediate plate, add 90 μ L of 1x kinase base buffer to each well of the intermediate plate and place the plate on a shaker to mix the compound solution with the 1x kinase base buffer. Further, 5. mu.L of each mixture was dispensed from the intermediate plate to a 96-well plate to form a duplicate well, and the plate was designated as a detection plate.
3. And (4) carrying out enzyme reaction.
1) Prepare 2.5x enzyme solution and add kinase to 1x kinase base buffer.
2) Prepare 2.5x polypeptide buffer, add FAM-marker polypeptide and ATP to 1x kinase base buffer.
3) Transfer 2.5x enzyme solution to assay plate. Each well of the assay plate was filled with 5. mu.L of compound solution containing 10% DMSO, followed by 10. mu.L of 2.5 Xenzyme solution and incubated at 25 ℃ for 10 min.
4) To each well of the assay plate was added 2.5 Xpolypeptide solution and incubated at 28 ℃ for an appropriate period of time followed by addition of 25. mu.l of stop buffer to stop the enzyme reaction.
4. Reading and recording the raw data of each hole, and performing corresponding conversion on the raw data.
1) Inhibition rate (max-compound conversion)/(max-min) × 100, where the maximum is DMSO control group data and the minimum is blank without enzyme addition.
2) Calculation of median inhibitory concentration IC50Value in log [ administration concentration ]]The abscissa and the ordinate represent the inhibition rate, and a dose-response curve was fitted to Graphpad Prism 5 to determine the drug concentration at 50% inhibition rate, i.e., the IC of the compound at kinase level50The value is obtained.
Table 3 provides the average IC of the derivatives of numbers II-1 to VIII-5 with respect to BTK50Range, wherein "A" represents IC50Values less than 10nM, "B" indicates IC50Values between 10nM and 100nM, "C" denotes IC50Values between 100nM and 1000nM, "D" denotes IC50Values greater than 1000 nM.
TABLE 3 average IC of the respective derivatives50Range
Figure BDA0002947416820000231
Figure BDA0002947416820000241
The number of apparatuses and the scale of the process described herein are intended to simplify the description of the present invention. Applications, modifications and variations of the 1,3, 5-triazin-2-amine-4, 6-substituted derivatives or pharmaceutically acceptable salts and uses of the present invention will be apparent to those skilled in the art.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable to various fields of endeavor for which the invention may be embodied with additional modifications as would be readily apparent to those skilled in the art, and the invention is therefore not limited to the details given herein and to the embodiments shown and described without departing from the generic concept as defined by the claims and their equivalents.

Claims (8)

1,3, 5-triazine-2-amine-4, 6 substituted derivative or pharmaceutically acceptable salt thereof, wherein the general formula of the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is shown as formula I;
Figure FDA0003413436050000011
wherein R is1Is composed of
Figure FDA0003413436050000012
R11 is selected from H, C1～C4Alkyl, halogen, C1～C4Halogen-substituted alkyl; r12 is selected from C1～C4Alkyl radical, C1～C4Halogen substituted alkyl, phenyl, fluorine substituted phenyl, cyano substituted phenyl, methyl substituted phenyl, benzyl, pyridyl;
x is
Figure FDA0003413436050000013
Figure FDA0003413436050000014
R2 is
Figure FDA0003413436050000015
R21 is selected from C2～C4Alkenyl radical, C2～C4Halogen-substituted alkyl, C2～C4Alkynyl.
2. The 1,3, 5-triazin-2-amine-4, 6-substituted derivative of claim 1, wherein when X is
Figure FDA0003413436050000016
R2Is composed of
Figure FDA0003413436050000017
When the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is selected from the following structural formulas:
Figure FDA0003413436050000021
when X is
Figure FDA0003413436050000022
R2Is composed of
Figure FDA0003413436050000023
When the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is selected from the following structural formulas:
Figure FDA0003413436050000024
Figure FDA0003413436050000031
when X is
Figure FDA0003413436050000032
R2Is composed of
Figure FDA0003413436050000033
When the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is selected fromFrom the following structural formula:
Figure FDA0003413436050000034
Figure FDA0003413436050000041
when X is
Figure FDA0003413436050000042
R2Is composed of
Figure FDA0003413436050000043
When the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is selected from the following structural formulas:
Figure FDA0003413436050000044
when X is
Figure FDA0003413436050000051
R2Is composed of
Figure FDA0003413436050000052
When the current is over; the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is selected from the following structural formulas:
Figure FDA0003413436050000053
when X is
Figure FDA0003413436050000061
R2Is composed of
Figure FDA0003413436050000062
When the current is over; the 1,3, 5-triazine-2-amine-4, 6 substituted derivativeSelected from the following structural formulas:
Figure FDA0003413436050000063
3. the 1,3, 5-triazin-2-amine-4, 6-substituted derivative of claim 1, wherein when R1 is
Figure FDA0003413436050000064
When the 1,3, 5-triazine-2-amine-4, 6 substituted derivative is selected from the following structural formulas:
Figure FDA0003413436050000065
Figure FDA0003413436050000071
4. a process for the preparation of a 1,3, 5-triazin-2-amine-4, 6-substituted derivative according to claim 1, or a pharmaceutically acceptable salt thereof, which comprises:
will be provided with
Figure FDA0003413436050000072
And
Figure FDA0003413436050000073
reaction to obtain
Figure FDA0003413436050000074
Will be provided with
Figure FDA0003413436050000075
And NH4OH reaction to give
Figure FDA0003413436050000076
To be provided with
Figure FDA0003413436050000077
For the preparation of reactants
Figure FDA0003413436050000078
5. Use of a 1,3, 5-triazin-2-amine-4, 6-substituted derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a medicament for inhibiting the non-receptor tyrosine kinase BMX.
6. The use of a 1,3, 5-triazin-2-amine-4, 6-substituted derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the medicament comprises a pharmaceutically acceptable carrier, excipient or diluent.
7. Use of a 1,3, 5-triazin-2-amine-4, 6-substituted derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a medicament for the treatment of cancer.
8. The use of a 1,3, 5-triazin-2-amine-4, 6-substituted derivative or a pharmaceutically acceptable salt thereof according to claim 7, wherein the cancer is prostate cancer, breast cancer, colon cancer, uterine cancer or EGFR-mutated non-small cell lung cancer.
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